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    Nirmatrelvir; Ritonavir

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    May.23.2024

    Nirmatrelvir; Ritonavir

    Indications/Dosage

    Labeled

    • coronavirus disease 2019 (COVID-19)
    • severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection

    NOTE: The National Institutes of Health (NIH) has issued a statement to provide guidance on treating nonhospitalized patients with mild to moderate coronavirus disease 2019 (COVID-19) who are at high risk of progressing to severe disease. The NIH recommends using 1 of the following therapeutics:

    • Preferred therapies (Adults and Pediatrics, listed in order of preference)
      • nirmatrelvir; ritonavir
      • remdesivir
    • Alternative therapies (Adults only)
      • molnupiravir

    Before prescribing nirmatrelvir; ritonavir, the NIH recommends a careful review the patient's concomitant medications (including over-the-counter medications and herbal supplements) to evaluate for potential drug interactions. If a significant drug interaction is identified, consider the risks and benefits of treatment. Consider expert consultation, especially for patients receiving highly specialized therapies such as antineoplastics, neuropsychiatric drugs, and certain immunosuppressants.[65314]

    NOTE: Healthcare providers should choose an authorized therapeutic option with activity against the variants circulating in their state, territory, or US jurisdiction. Current variant frequency data are available at: www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-proportions.html. Nirmatrelvir; ritonavir is expected to be active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant and its subvariants, although there is currently a lack of data on the clinical efficacy against these variants.[65314][67203]

    NOTE: Logistical or supply constraints may make it impossible to offer the available therapy to all eligible patients, making patient triage necessary. Prioritize use of these therapies for patients at highest risk of clinical progression. Information on which individuals might receive the greatest benefit from anti-SARS-CoV-2 therapeutics for treatment or prevention can be obtained from www.covid19treatmentguidelines.nih.gov/therapies/statement-on-patient-prioritization-for-outpatient-therapies.[65314]

    Off-Label

      † Off-label indication

      For the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection resulting in mild to moderate coronavirus disease 2019 (COVID-19) in patients who are at high risk for progressing to severe COVID-19, including hospitalization or death

      NOTE: Medical conditions and factors associated with an increased risk for progression to severe COVID-19 can be obtained on the Centers for Disease Control and Prevention (CDC) website at www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html. Healthcare providers are advised to consider the benefit-risk for each individual patient.[67203]

      NOTE: Nirmatrelvir; ritonavir is NOT approved or authorized for use in patients requiring hospitalization due to severe COVID-19; however, should a patient require hospitalization after starting treatment, the full 5-day treatment course may be completed per the healthcare provider's discretion.[67203] [69024] Additionally, the drug may be used in patients who are hospitalized for a diagnosis other than COVID-19, provided they have mild to moderate COVID-19, are at high risk for progression, and are within 5 days of symptom onset.[65314]

      NOTE: Nirmatrelvir; ritonavir is NOT for use as pre-exposure or post-exposure prophylaxis to prevent COVID-19.[67203] [69024]

      Oral dosage

      Adults

      300 mg nirmatrelvir (two 150 mg tablets) and 100 mg ritonavir (one 100 mg tablet) with all 3 tablets taken together PO twice daily for 5 days. Initiate treatment as soon as possible after the positive test for SARS-CoV-2 and within 5 days of symptom onset. Instruct patients to complete the full 5-day treatment course and continue isolation in accordance with public health recommendations; treatment for longer than 5 consecutive days is not approved.[69024] According to the National Institutes of Health (NIH), the optimal management of immunocompromised patients who have prolonged COVID-19 symptoms and evidence of ongoing viral replication despite receiving a course of antiviral therapy is unknown. Some members of the guideline panel suggest using longer or additional courses of nirmatrelvir; ritonavir in these patients; however, there are insufficient data on the efficacy of treatment beyond 5 days or use of a second course.[65314]

      Children and Adolescents 12 to 17 years weighing 40 kg or more†

      300 mg nirmatrelvir (two 150 mg tablets) and 100 mg ritonavir (one 100 mg tablet) with all 3 tablets taken together PO twice daily for 5 days. Initiate treatment as soon as possible after the positive test for SARS-CoV-2 and within 5 days of symptom onset. Instruct patients to complete the full 5-day treatment course and continue isolation in accordance with public health recommendations; treatment for longer than 5 consecutive days is not authorized.[67203]

      Therapeutic Drug Monitoring

      Maximum Dosage Limits

      • Adults

        600 mg nirmatrelvir and 200 mg ritonavir per day PO.

      • Geriatric

        600 mg nirmatrelvir and 200 mg ritonavir per day PO.

      • Adolescents

        weighing 40 kg or more: 600 mg nirmatrelvir and 200 mg ritonavir per day PO per the Emergency Use Authorization.

        weighing less than 40 kg: Safety and efficacy have not been established.

      • Children

        12 years and weighing 40 kg or more: 600 mg nirmatrelvir and 200 mg ritonavir per day PO per the Emergency Use Authorization.

        12 years and weighing less than 40 kg: Safety and efficacy have not been established.

        1 to 11 years: Safety and efficacy have not been established.

      • Infants

        Safety and efficacy have not been established.

      • Neonates

        Safety and efficacy have not been established.

      Patients with Hepatic Impairment Dosing

      No dosage adjustment is needed for mild to moderate hepatic impairment (Child-Pugh A and B). Not recommended for use in patients with severe hepatic impairment (Child-Pugh C), as pharmacokinetic and safety data are unavailable.[69024]

      Patients with Renal Impairment Dosing

      eGFR 60 mL/minute or more: No dosage adjustment is needed.

      eGFR 30 to 59 mL/minute: Reduce dose to 150 mg nirmatrelvir (one 150 mg tablet) and 100 mg ritonavir (one 100 mg tablet) twice daily for 5 days.

      eGFR less than 30 mL/minute: Use not recommended.

      eGFR less than 15 mL/minute on dialysis: Use not recommended.[69024]

      † Off-label indication
      Revision Date: 05/23/2024, 01:37:00 AM

      References

      65314 - COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Accessed March 1, 2024. Available at https://www.covid19treatmentguidelines.nih.gov/67203 - Food and Drug Administration (FDA). Fact sheet for healthcare providers: emergency use authorization for Paxlovid. Retrieved March 13, 2024. Available on the World Wide Web at https://www.fda.gov/media/155050/download?utm_medium=email&utm_source=govdelivery69024 - Paxlovid (nirmatrelvir; ritonavir) package insert. New York, NY: Pfizer Inc; 2023 May.

      How Supplied

      Nirmatrelvir Oral tablet, Ritonavir Oral tablet

      PAXLOVID 150mg-100mg Tablet (Dose Pack) (00069-1101) (Pfizer Inc.) (off market)

      Nirmatrelvir Oral tablet, Ritonavir Oral tablet

      PAXLOVID 150mg-100mg Tablet (Dose Pack) (00069-5317) (Pfizer Inc.) nullPAXLOVID 150mg-100mg Tablet (Dose Pack) package photo

      Nirmatrelvir Oral tablet, Ritonavir Oral tablet

      PAXLOVID 300mg-100mg Tablet (Dose Pack) (00069-1085) (Pfizer Inc.) (off market)

      Nirmatrelvir Oral tablet, Ritonavir Oral tablet

      PAXLOVID 300mg-100mg Tablet (Dose Pack) (00069-0345) (Pfizer Inc.) (off market)

      Nirmatrelvir Oral tablet, Ritonavir Oral tablet

      PAXLOVID 300mg-100mg Tablet (Dose Pack) (00069-1085) (Pfizer Inc.) (off market)

      Nirmatrelvir Oral tablet, Ritonavir Oral tablet

      PAXLOVID 300mg-100mg Tablet (Dose Pack) (00069-5321) (Pfizer Inc.) nullPAXLOVID 300mg-100mg Tablet (Dose Pack) package photo

      Description/Classification

      Description

      Nirmatrelvir; ritonavir is an oral antiviral medication approved by the FDA for the treatment of adults with mild to moderate coronavirus disease 2019 (COVID-19) who are at high risk for progression to severe COVID-19, including hospitalization or death. Nirmatrelvir; ritonavir is not FDA-approved for use in pediatric patients; however, it has been authorized for emergency use to treat pediatric patients (12 to 17 years of age weighing at least 40 kg) with mild to moderate COVID-19 who are at high risk for progression to severe COVID-19, including hospitalization or death. Initiate treatment as soon as possible after diagnosis of COVID-19, and within 5 days of symptom onset. Should a patient require hospitalization for severe COVID-19 after starting treatment, the full 5-day treatment course may be completed per the healthcare provider's discretion. The drug is NOT approved or authorized for use as a pre-exposure or post-exposure prophylaxis to prevent COVID-19. Nirmatrelvir; ritonavir has antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with nirmatrelvir working as a SARS-CoV-2 main protease (Mpro: also referred to as 3CLpro or nsp5 protease) inhibitor and ritonavir acting as a pharmacokinetic enhancer or booster. Nirmatrelvir MUST be given concurrently with ritonavir in order to achieve sufficient plasma concentrations; therefore, the medications are co-packaged and supplied as a Dose Pack (300 mg nirmatrelvir; 100 mg ritonavir Dose Pack or 150 mg nirmatrelvir; 100 mg ritonavir Dose Pack). Each Dose Pack contains 10 single-dose blister cards, enough for a 5-day supply.[67203][69024]

       

      The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend nirmatrelvir; ritonavir as a treatment option for nonhospitalized patients with mild to moderate COVID-19 who are at high risk of progressing to severe disease; however, due to the potential for significant drug interactions with concomitant medications, this regimen may not be a safe choice for all patients. Although the drug is not approved or authorized for use in patients hospitalized due to severe COVID-19, it may be used in patients who are hospitalized for a diagnosis other than COVID-19, provided they have mild to moderate COVID-19, are at high risk for progression, and are within 5 days of symptom onset.[65314]

       

      NOTE: Nirmatrelvir; ritonavir is expected to be active against the Omicron SARS-CoV-2 variant and its subvariants, although there is currently a lack of data on the clinical efficacy against these variants.[65314][67203]

      Classifications

      • General Anti-infectives Systemic
        • Antivirals For Systemic Use
          • SARS-CoV-2 Antivirals
            • SARS-CoV-2 Protease Inhibitor Antivirals
      Revision Date: 05/23/2024, 01:37:00 AM

      References

      65314 - COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Accessed March 1, 2024. Available at https://www.covid19treatmentguidelines.nih.gov/67203 - Food and Drug Administration (FDA). Fact sheet for healthcare providers: emergency use authorization for Paxlovid. Retrieved March 13, 2024. Available on the World Wide Web at https://www.fda.gov/media/155050/download?utm_medium=email&utm_source=govdelivery69024 - Paxlovid (nirmatrelvir; ritonavir) package insert. New York, NY: Pfizer Inc; 2023 May.

      Administration Information

      General Administration Information

      For storage information, see the specific product information within the How Supplied section.

       

      NOTE: Although not FDA-approved for use in pediatric patients, nirmatrelvir; ritonavir has been authorized for emergency use to treat pediatric patients (12 to 17 years of age weighing at least 40 kg) with mild to moderate coronavirus disease (COVID-19) who are at high risk for progression to severe COVID-19, including hospitalization or death. Under the Emergency Use Authorization (EUA), healthcare providers are required to communicate to the patient or caregiver information consistent with the "Fact Sheet for Patients, Parents, and Caregivers" prior to the patient receiving treatment; such information includes the following:

      • The option to accept or refuse nirmatrelvir; ritonavir
      • The significant known and potential risks and benefits of treatment, and the extent to which such potential risks and benefits are unknown
      • Available alternative treatments and the risk and benefits of those alternatives
      • The need to continue to self-isolate and use infection control measures (e.g., wear mask, isolate, social distance, avoid sharing personal items, clean and disinfect, frequent handwashing) according to CDC guidelines

      NOTE: Under the EUA, nirmatrelvir; ritonavir may be prescribed for an individual patient by:

      • Physicians, advanced practice registered nurses, and physician assistants who are licensed or authorized under state law to prescribe drugs.
      • State-licensed pharmacists may prescribe to adults and pediatric patients (12 years and older weighing at least 40 kg) in accordance with the FDA-approved Prescribing information or authorized labeling, as applicable, under the following conditions:
        • Sufficient information is available to assess renal and hepatic function (through access to health records less than 12 months old or via consultation with a healthcare provider in an established provider-patient relationship with the individual patient); AND
        • Sufficient information (i.e., a comprehensive list of prescription and non-prescription medications that the patient is taking) is available to assess for potential drug interactions (obtained though access to health records, patient reporting of medical history, or consultation with a healthcare provider in an established provider-patient relationship with the individual patient).

      If any of the following apply, the state-licensed pharmacist should refer an individual patient for clinical evaluation with a physician, advanced practice registered nurse, or physician assistant licensed or authorized under state law to prescribe drugs:

        • Sufficient information is not available to assess renal and hepatic function.
        • Sufficient information is not available to assess for a potential drug interaction.
        • Modification of other medications is needed due to a potential drug interaction.
        • Nirmatrelvir; ritonavir is not an appropriate therapeutic option based on the EUA or due to potential drug interactions for which recommended monitoring would not be feasible.

      To help identify appropriate candidates for treatment, the FDA has published a "Paxlovid Patient Eligibility Screening Checklist Tool for Prescribers", accessible at www.fda.gov/media/158165/download. This checklist is intended for use as an aid to support clinical decision-making, and is NOT required to prescribe nirmatrelvir; ritonavir under the EUA.[67584]

      NOTE: Under the EUA, healthcare providers are required to report all medication errors and serious adverse events potentially related to nirmatrelvir; ritonavir therapy within 7 calendar days from the healthcare provider's awareness of the event.[67203]

      Route-Specific Administration

      Oral Administration

      • Nirmatrelvir and ritonavir MUST be administered together to achieve sufficient nirmatrelvir plasma concentrations.
      • Nirmatrelvir and ritonavir tablets are co-packaged and supplied as a Dose Pack.
        • 300 mg nirmatrelvir; 100 mg ritonavir Dose Pack: Each carton contains 30 tablets divided in 10 single-dose blister cards (i.e., 5 day supply). Each single-dose blister card contains 2 nirmatrelvir (150 mg oval, pink) tablets and 1 ritonavir (100 mg ovaloid, white) tablet.
        • 150 mg nirmatrelvir; 100 mg ritonavir Dose Pack: Each carton contains 20 tablets divided in 10 single-dose blister cards (i.e., 5 day supply). Each single-dose blister card contains 1 nirmatrelvir (150 mg oval, pink) tablet and 1 ritonavir (100 mg ovaloid, white) tablet.
      • May administer tablets with or without food.
      • Swallow tablets whole with a sufficient amount of fluid. The prescribing information and the EUA recommend against crushing or chewing the tablets. However, the National Institutes of Health (NIH) COVID-19 treatment guidelines suggest the tablets can be split or crushed if necessary.[65314]
      • Instruct patients to complete the full 5-day treatment course and continue isolation in accordance with public health recommendations.[67203][69024]

      Clinical Pharmaceutics Information

      From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database
        Revision Date: 05/23/2024, 01:37:00 AM

        References

        65314 - COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Accessed March 1, 2024. Available at https://www.covid19treatmentguidelines.nih.gov/67203 - Food and Drug Administration (FDA). Fact sheet for healthcare providers: emergency use authorization for Paxlovid. Retrieved March 13, 2024. Available on the World Wide Web at https://www.fda.gov/media/155050/download?utm_medium=email&utm_source=govdelivery67584 - Food and Drug Administration (FDA). Paxlovid patient eligibility screening checklist tool for prescribers. Retrieved February 1, 2023. Available on the World Wide Web at https://www.fda.gov/media/158165/download69024 - Paxlovid (nirmatrelvir; ritonavir) package insert. New York, NY: Pfizer Inc; 2023 May.

        Adverse Reactions

        Mild

        • abdominal pain
        • diarrhea
        • dysgeusia
        • headache
        • malaise
        • nausea
        • vomiting

        Severe

        • anaphylactoid reactions
        • Stevens-Johnson syndrome
        • toxic epidermal necrolysis

        Moderate

        • hypertension

        The safety of nirmatrelvir; ritonavir was evaluated in a placebo-controlled trial of symptomatic adults with laboratory confirmed SARS-CoV-2 infection who were at high risk for progression to severe disease. A total of 1,038 patients received nirmatrelvir; ritonavir and 1,053 received a placebo. Adverse reactions were reported during treatment and through Day 28 after the last dose of treatment. Adverse reactions that occurred in the treatment group at a higher frequency than the placebo group included dysgeusia (5% vs. less than 1%, respectively) and diarrhea (3% vs. 2%).[69024]

        Cases of toxic epidermal necrolysis (TEN), Stevens-Johnson Syndrome (SJS), anaphylaxis or anaphylactoid reactions, and other hypersensitivity reactions have been reported with the use of nirmatrelvir; ritonavir under the Emergency Use Authorization (EUA). If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue use of the drug and initiate appropriate medications and supportive care.[67203] [69024]

        Adverse reactions experienced by recipients of nirmatrelvir; ritonavir under the Emergency Use Authorization (EUA) include abdominal pain, nausea, vomiting, headache, hypertension, and malaise. Due to the voluntary nature of these reports, neither a frequency nor a definitive causal relationship can be established.[67203] [69024]

        Revision Date: 05/23/2024, 01:37:00 AM

        References

        67203 - Food and Drug Administration (FDA). Fact sheet for healthcare providers: emergency use authorization for Paxlovid. Retrieved March 13, 2024. Available on the World Wide Web at https://www.fda.gov/media/155050/download?utm_medium=email&utm_source=govdelivery69024 - Paxlovid (nirmatrelvir; ritonavir) package insert. New York, NY: Pfizer Inc; 2023 May.

        Contraindications/Precautions

        Absolute contraindications are italicized.

        • serious rash
        • antimicrobial resistance
        • breast-feeding
        • dialysis
        • hepatic disease
        • hepatitis
        • human immunodeficiency virus (HIV) infection resistance
        • immunosuppression
        • pregnancy
        • renal disease
        • renal impairment

        Consider the potential for drug interactions (including over-the-counter medications and herbal supplements) prior to and during nirmatrelvir; ritonavir therapy. Nirmatrelvir; ritonavir (a CYP3A inhibitor) is contraindicated for use with medications that are highly dependent on CYP3A for clearance and are associated with serious or life-threatening adverse events. Additionally, the drug is contraindicated for use with strong CYP3A inducers (i.e., apalutamide, carbamazepine, phenobarbital, phenytoin, primidone, rifampin, rifapentine, lumacaftor; ivacaftor, St. John's Wort); concurrent use of strong CYP3A inducers can lead to a marked decrease in plasma concentrations of nirmatrelvir and ritonavir, which may result in loss of therapeutic effect and viral resistance. Due to the delayed offset, nirmatrelvir; ritonavir cannot be started immediately after discontinuing any of the above listed CYP3A inducers.[67203][69024] If a significant drug interaction is identified, consider the risks and benefits of treatment. Consider expert consultation, especially for patients receiving highly specialized therapies such as antineoplastics, neuropsychiatric drugs, and certain immunosuppressants. Potential management strategies to facilitate the use of nirmatrelvir; ritonavir include (depending on the magnitude and significance of the interaction): dose adjustment of the concomitant medication; use of an alternative concomitant medication; increased monitoring for potential adverse reactions; temporarily withholding the concomitant medication. These strategies should be considered during the 5-day treatment and for at least 3 to 5 days after the end of therapy (potentially longer for concomitant medications with long half-lives). In settings where these strategies are not feasible, consider use of an alternative COVID-19 therapeutic. Healthcare providers are advised NOT to adjust the dose of nirmatrelvir; ritonavir to avoid or mitigate a drug interaction.[65314]

        Nirmatrelvir; ritonavir is approved for use as an oral therapy, given over 5 days, to treat mild to moderate COVID-19 in patients at high risk for progression to severe COVID-19, including hospitalization or death. The drug is NOT for use in patients requiring hospitalization due to severe or critical COVID-19; nor is it approved for use as pre-exposure or post-exposure prophylaxis to prevent COVID-19. In order to minimize antimicrobial resistance and transmission of SARS-CoV-2, instruct patients to complete the full 5-day treatment course and continue isolation in accordance with public health recommendations. Should a patient require hospitalization after starting treatment, the full 5-day treatment course should be completed per the healthcare provider's discretion. Use of nirmatrelvir; ritonavir for longer than 5 consecutive days is NOT approved. There are insufficient data on whether treatment beyond 5 days or use of a second course will prevent or treat viral rebound or symptom recurrence.[65314] [67203] [69024]

        There is a potential risk that human immunodeficiency virus (HIV) infection resistance to HIV protease inhibitors may develop if nirmatrelvir; ritonavir therapy is administered to individuals with uncontrolled or undiagnosed HIV infection. However, patients with HIV or HCV infections who are on a ritonavir- or cobicistat-containing regimen should continue their treatment as indicated. No dosage adjustments are required when nirmatrelvir; ritonavir is administered concurrently with other products containing ritonavir or cobicistat.[67203] [69024]

        A dose reduction is required when administering nirmatrelvir; ritonavir to patients with moderate renal impairment (eGFR 30 to 59 mL/minute). The drug is NOT recommended for use in patients with severe renal disease (eGFR less than 30 mL/minute) or patients with end stage renal disease (eGFR less than 15 mL/minute) who are receiving dialysis, as data in this population is limited and the appropriate dosage has not been determined.[67203] [69024] According to the National Institutes of Health (NIH) COVID-19 treatment guidelines, there is no need to check renal function prior to prescribing nirmatrelvir; ritonavir unless the patient is suspected to have moderate or severe renal impairment (i.e., those with an estimated eGFR less than 60 mL/minute). For these patients, healthcare providers may consider checking the renal function. If renal dysfunction is identified, the above dosing recommendations should be followed.[65314]

        Elevated hepatic enzymes, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir; therefore, caution is advised when administering nirmatrelvir; ritonavir to patients with pre-existing hepatic disease, hepatic enzyme abnormalities, or hepatitis. The drug is NOT recommended for use in patients with severe hepatic impairment (Child-Pugh C), as pharmacokinetic and safety data are unavailable in these patients.[67203] [69024]

        The National Institutes of Health (NIH) and the American College of Obstetricians and Gynecologists (ACOG) recommend that nirmatrelvir; ritonavir be offered to pregnant and recently pregnant patients with symptoms of respiratory illness, especially since pregnancy is a risk factor for severe COVID-19. Obstetricians should be aware of potential drug-drug interactions when prescribing this medication; however, nirmatrelvir; ritonavir may be given with oseltamivir in patients with suspected or confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza coinfection. Do not delay antiviral therapy while awaiting respiratory infection test results. Human data regarding the use of nirmatrelvir during pregnancy are too limited to evaluate for a drug-associated risk of major birth defects, miscarriages, or adverse maternal or fetal outcomes; however, information is available from 2 case series describing outcomes among pregnant patients with COVID-19 who received nirmatrelvir; ritonavir. The first case series included 47 patients with COVID-19 and a median gestational age of 28.4 weeks. These patients started nirmatrelvir; ritonavir after a median duration of 1 day of COVID-19 symptoms. No serious adverse events were reported during the study period in either the pregnant patients or the neonates. The other case series included 7 patients with COVID-19 symptoms for approximately 2 days at the start of treatment and a mean gestational age of 26.4 weeks. Six of the 7 patients completed the 5-day treatment course, and all 6 were fully vaccinated (4 had received a booster dose). The 6 patients reported resolution of their COVID-19 symptoms, and no fetal or neonatal adverse effects were observed during the study period. The 1 patient who discontinued treatment, did so because of dysgeusia. In animal embryo-fetal development studies, reduced fetal body weights (9% decrease) were observed in rabbits after maternal administration of nirmatrelvir doses resulting in systemic exposures 11-times higher than clinical exposures at the authorized human dose. No other adverse developmental outcomes were observed in animal reproduction studies with nirmatrelvir at systemic exposures greater than or equal to 3-times higher than clinical exposures at the authorized human dose. Published observational studies on ritonavir use in pregnant patients have not identified an increased risk for major birth defects [i.e., 2.4% (95% CI: 1.9 to 2.9) after first-trimester exposure vs. 2.7% background birth defect rate]; however, published studies with ritonavir are insufficient to identify a drug-associated risk of miscarriages. When evaluating use of nirmatrelvir; ritonavir in pregnant patients, consider that untreated COVID-19 in pregnancy is associated with adverse maternal and fetal outcomes (i.e., preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic disease, fetal death).[65314] [67203] [69024] [70419]

        The National Institutes of Health (NIH) states that nirmatrelvir; ritonavir should be offered to lactating patients who qualify for therapy, and that breast-feeding can continue without interruption.[65314] There are no data available regarding the presence of nirmatrelvir in human milk, the effects on the breast-fed infant, or the effects on milk production. Limited published data show that ritonavir is present in human milk; however, no information is available for the effects of ritonavir on the breast-fed infant or milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, the potential for viral transmission to SARS-CoV-2-negative infants, and the risk of an untreated or inadequately treated condition. Lactating mothers are advised to follow practices according to clinical guidelines to avoid exposing the infant to COVID-19. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.[67203] [69024]

        Nirmatrelvir; ritonavir is contraindicated for use in patients with a history of clinically significant hypersensitivity reactions, such as serious rash [e.g., toxic epidermal necrolysis (TEN) or Stevens-Johnson Syndrome (SJS)], to its active ingredients or any other components of the product. Cases of TEN, SJS, anaphylaxis, and other hypersensitivity reactions have been reported during use of nirmatrelvir; ritonavir. If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue use of the drug and initiate appropriate medications and supportive care.[67203] [69024]

        According to the National Institutes of Health (NIH), the optimal management of patients with immunosuppression who have prolonged COVID-19 symptoms and evidence of ongoing viral replication despite receiving a course of antiviral therapy is unknown. Some members of the guideline panel suggest using longer or additional courses of nirmatrelvir; ritonavir in these patients; however, there are insufficient data on the efficacy of treatment beyond 5 days or use of a second course. If nirmatrelvir; ritonavir is used beyond the FDA approved 5 days treatment course, healthcare providers are advised that the drug-drug interaction potential of ritonavir may change. When ritonavir is used for 10 days or longer, the induction potential may become clinically relevant.[65314]

        Revision Date: 05/23/2024, 01:37:00 AM

        References

        65314 - COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Accessed March 1, 2024. Available at https://www.covid19treatmentguidelines.nih.gov/67203 - Food and Drug Administration (FDA). Fact sheet for healthcare providers: emergency use authorization for Paxlovid. Retrieved March 13, 2024. Available on the World Wide Web at https://www.fda.gov/media/155050/download?utm_medium=email&utm_source=govdelivery69024 - Paxlovid (nirmatrelvir; ritonavir) package insert. New York, NY: Pfizer Inc; 2023 May.70419 - The American College of Obstetricians and Gynecologists. Influenza in pregnancy: prevention and treatment: ACOG Committee Statement No. 7. Obstet Gynecol 2023 Nov;143(2):e1-e7.

        Mechanism of Action

        Nirmatrelvir; ritonavir is an oral antiviral medication with activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Ritonavir is an HIV-1 protease inhibitor and a CYP3A inhibitor. Ritonavir does not have antiviral activity against SARS-CoV-2, but instead is used as a pharmacokinetic enhancer to increase plasma concentrations of nirmatrelvir. Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), also referred to as 3C-like protease (3CLpro) or nsp5 protease. By binding directly to the SARS-CoV-2 Mpro active site, nirmatrelvir renders the virus incapable of processing polyprotein precursors, thereby preventing viral replication.

         

        In a biochemical assay, nirmatrelvir inhibited the activity of recombinant SARS-CoV-2 Mpro with a half-maximal inhibitory concentration (IC50) value of 19.2 nanomolar (nM). The 50% effective concentration (EC50) and 90% effective concentration (EC90) against SARS-CoV-2 in differentiated normal human bronchial epithelial cells after 3 days of drug exposure were 62 nM and 181 nM, respectively. The antiviral activity of nirmatrelvir against the Omicron subvariants BA.2, BA.2.12.1, BA.4, BA.4.6, BA.5, BF.7, BQ.1, BQ.1.11, and XBB.1.5 were assessed in the presence of a P-glycoprotein inhibitor. Nirmatrelvir had a median EC50 value of 83 nM (range: 39 to 146 nM) against the Omicron subvariants, reflecting a fold-change of 1.5 or less compared to the USA-WA1/2022 isolate. Additionally, the antiviral activity of nirmatrelvir against the SARS-CoV-2 Alpha, Beta, Gamma, Delta, Lambda, Mu, and Omicron BA.1 variants were assessed. Nirmatrelvir had a median EC50 value of 25 nM (range: 16 to 141 nM). The Beta (B.1.351) variant was the least susceptible tested with an approximate 3.7-fold reduced susceptibility relative to the USA-WA1/2020 isolate. The other variants had EC50 value fold-changes of 1.1 or less.

         

        SARS-CoV-2 Mpro residues potentially associated with nirmatrelvir resistance have been identified using a variety of methods.

        • SARS-CoV-2 Mpro single amino acid substitutions selected by nirmatrelvir in cell cultures include T21I (1.1- to 4.6-fold EC50 change), L50F (1.5- to 4.2-fold), F140L (4.1-fold), S144A (2.2- to 5.3-fold), E166A (3.3-fold), E166V (25- to 288-fold), A173V (0.9- to 1.7-fold), P252L (5.9-fold), and T304I (1.4- to 5.5-fold).
        • SARS-CoV-2 Mpro multiple amino acid substitutions (i.e. 2 or more) selected by nirmatrelvir in cell cultures include T21I + S144A (9.4-fold EC50 change), T21I + E166V (83-fold), T21I + A173V (3.1-fold), T21I + T304I (3- to 7.9-fold), L50F + E166V (34- to 175-fold), L50F + T304I (5.9-fold), T135I + T304I (3.8-fold), F140L + A173V (10.1-fold), A173V + T304I (20.2-fold), T21I + L50F + A193P + S301P (28.8-fold), T21I + S144A + T304I (27.8-fold), T21I + C160F + A173V + V186A + T304I (28.5-fold), T21I + A173V + T304I (15-fold), and L50F + F140L + L167F + T304I (54.7-fold).

        In the EPIC-HR/SR clinical trials, the following treatment-emergent substitutions in SARS-CoV-2 Mpro were observed in nirmatrelvir; ritonavir-treated subjects: T98I/R/del (n = 4), E166V (n = 3), and W207L/R/del (n = 4). Within the Mpro cleavage sites, the following nirmatrelvir; ritonavir treatment-emergent substitutions were observed: A5328S/V (n = 7) and S6799A/P/Y (n = 4). These cleavage site substitutions were not associated with the concurrence of any specific Mpro substitutions. None of these substitutions in Mpro gene or cleavage regions occurred in nirmatrelvir; ritonavir-treated subjects who also experienced hospitalization; thus, the clinical significance is unknown.

         

        Cross-resistance is not expected between nirmatrelvir and remdesivir, molnupiravir, or anti-SARS-CoV-2 monoclonal antibodies.

         

        Post-treatment increases in SARS-CoV-2 RNA shedding levels (i.e., viral RNA rebound) in nasopharyngeal samples have been observed on Day 10 and Day 14 in a subset of nirmatrelvir; ritonavir-treated patients and placebo recipients, irrespective of COVID-19 symptoms. In the EPIC-HR study, 59 nirmatrelvir; ritonavir recipients with available viral sequence data were identified as having post-treatment viral RNA rebound. Of these 59 subjects, treatment-emergent substitutions in Mpro potentially reducing nirmatrelvir activity were detected in 2 subjects (3%), including E166V and T304I. By Day 14, both subjects had viral RNA shedding less than the lower limit of quantification. Post-treatment viral rebound was not associated with the primary clinical outcome of COVID-19 related hospitalization or death from any cause through Day 28 after the single 5-days course of nirmatrelvir; ritonavir. The clinical relevance of post-treatment increases in viral RNA is unknown.[67203][69024]

        Revision Date: 05/23/2024, 01:37:00 AM

        References

        67203 - Food and Drug Administration (FDA). Fact sheet for healthcare providers: emergency use authorization for Paxlovid. Retrieved March 13, 2024. Available on the World Wide Web at https://www.fda.gov/media/155050/download?utm_medium=email&utm_source=govdelivery69024 - Paxlovid (nirmatrelvir; ritonavir) package insert. New York, NY: Pfizer Inc; 2023 May.

        Pharmacokinetics

        Nirmatrelvir; ritonavir is administered orally. Once in systemic circulation, 69% of nirmatrelvir and approximately 99% of ritonavir is bound to human plasma proteins. The mean apparent volume of distribution during the terminal phase for nirmatrelvir and ritonavir are 104.7 L and 112.4 L, respectively. Nirmatrelvir has a blood-to-plasma ratio of 0.6 and the ratio for ritonavir is 0.14. Nirmatrelvir is a CYP3A4 substrate, but the metabolic clearance is minimal when dosed with ritonavir. Ritonavir is primarily metabolized by CYP3A4, with minor contributions from CYP2D6. Nirmatrelvir is primarily eliminated via the kidneys, with a mean half-life of 6.05 hours. Hepatic metabolism is the major route of elimination for ritonavir, which has a mean half-life of 6.15 hours. The percentage of nirmatrelvir drug-related material excreted in the urine and feces is 49.6% and 35.3%, respectively. The percentage of ritonavir drug-related material excreted in the feces and urine is 86.4% and 11.3%, respectively.[67203][69024]

         

        Affected cytochrome P450 isoenzymes and drug transporters: CYP3A, CYP2D6 P-glycoprotein (P-gp), Organic anion transporting polypeptide (OATP1B1)

        Nirmatrelvir is a substrate for CYP3A4 and the drug transporter P-gp. Nirmatrelvir has the potential to reversibly and time-dependently inhibit CYP3A4, and is also an inhibitor of P-gp and OATP1B1. Nirmatrelvir is also an inducer of CYP2B6, CYP2C8, CYP2C9, and CYP3A4, but there is minimal risk for pharmacokinetic interactions arising from induction of these enzymes at the proposed therapeutic dose. Ritonavir is a substrate for and inhibitor of CYP3A (major) and CYP2D6 (minor). Ritonavir is also a substrate and inhibitor of P-glycoprotein (P-gp).[28380][34557][65314][69024] Additionally, ritonavir appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6.[67203][69024]

        Route-Specific Pharmacokinetics

        Oral Route

        The pharmacokinetics of nirmatrelvir; ritonavir were similar in healthy subjects and in patients with mild to moderate COVID-19. After administration of nirmatrelvir, ritonavir (300 mg/100 mg) twice daily to patients with mild to moderate COVID-19, the predicted Day 5 maximum plasma concentration (Cmax), systemic exposure (AUC), and trough concentration (Cmin) of nirmatrelvir were 3.43 mcg/mL, 30.4 mcg x hour/mL, and 1.57 mcg/mL, respectively. Upon administration of a single nirmatrelvir; ritonavir (300 mg/100 mg) dose to healthy subjects, the time to reach peak concentration (Tmax) was 3 hours for nirmatrelvir and approximately 4 hours for ritonavir. Nirmatrelvir AUC increased in a less than dose proportional manner over a single dose range of 250 to 750 mg and multiple dose range of 75 to 500 mg, when administered with ritonavir. Nirmatrelvir steady state was achieved on Day 2 after administration of the recommended dose and the mean accumulation ratio was approximately 2-fold. No clinically significant differences in the pharmacokinetics of nirmatrelvir were observed after administration with a high fat meal (800 to 1,000 calories; 50% fat) in healthy subjects.[67203][69024]

        Special Populations

        Hepatic Impairment

        A single 100 mg/100 mg dose of nirmatrelvir; ritonavir in patients with moderate hepatic impairment (Child-Pugh B) resulted in nirmatrelvir exposures that were similar to those observed in subjects with normal hepatic function. The pharmacokinetics of nirmatrelvir; ritonavir have not been evaluated in patients with severe hepatic impairment (Child-Pugh C).[67203][69024]

        Renal Impairment

        The pharmacokinetics of nirmatrelvir were compared in healthy subjects and patients with mild, moderate, and severe renal impairment after administration of a single 100 mg/100 mg nirmatrelvir; ritonavir dose. Compared to the healthy controls with no renal impairment, the Cmax and AUC of nirmatrelvir in patients with mild impairment were 30% and 24% higher, in patients with moderate impairment they were 38% and 87% higher, and in patients with severe impairment they were 48% and 204% higher, respectively.[67203][69024]

        Pediatrics

        The pharmacokinetics of nirmatrelvir; ritonavir in patients younger than 18 years have not been evaluated. Using a population PK model, the authorized dosing regimen is expected to result in comparable steady-state plasma exposure of nirmatrelvir in patients 12 years and older who weigh at least 40 kg to those observed in adults after adjusting for body weight.[67203]

        Geriatric

        There were no clinically significant differences in the pharmacokinetics of nirmatrelvir based on age (range: 18 to 86 years).[69024]

        Gender Differences

        There were no clinically significant differences in the pharmacokinetics of nirmatrelvir based on gender.[69024]

        Ethnic Differences

        There were no clinically significant differences in the pharmacokinetics of nirmatrelvir based on ethnicity.[69024]

        Revision Date: 05/23/2024, 01:37:00 AM

        References

        28380 - Phillips E, Rachlis A, Ito S. Digoxin toxicity and ritonavir: a drug interaction mediated through p-glycoprotein? AIDS 2003;17:1577-8.34557 - Lee CG, Gottesman MM, Cardarelli CO. HIV-1 protease inhibitors are substrates for the MDR1 multidrug transporter. Biochemistry 1998;37:3594-601.65314 - COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Accessed March 1, 2024. Available at https://www.covid19treatmentguidelines.nih.gov/67203 - Food and Drug Administration (FDA). Fact sheet for healthcare providers: emergency use authorization for Paxlovid. Retrieved March 13, 2024. Available on the World Wide Web at https://www.fda.gov/media/155050/download?utm_medium=email&utm_source=govdelivery69024 - Paxlovid (nirmatrelvir; ritonavir) package insert. New York, NY: Pfizer Inc; 2023 May.

        Pregnancy/Breast-feeding

        pregnancy

        The National Institutes of Health (NIH) and the American College of Obstetricians and Gynecologists (ACOG) recommend that nirmatrelvir; ritonavir be offered to pregnant and recently pregnant patients with symptoms of respiratory illness, especially since pregnancy is a risk factor for severe COVID-19. Obstetricians should be aware of potential drug-drug interactions when prescribing this medication; however, nirmatrelvir; ritonavir may be given with oseltamivir in patients with suspected or confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza coinfection. Do not delay antiviral therapy while awaiting respiratory infection test results. Human data regarding the use of nirmatrelvir during pregnancy are too limited to evaluate for a drug-associated risk of major birth defects, miscarriages, or adverse maternal or fetal outcomes; however, information is available from 2 case series describing outcomes among pregnant patients with COVID-19 who received nirmatrelvir; ritonavir. The first case series included 47 patients with COVID-19 and a median gestational age of 28.4 weeks. These patients started nirmatrelvir; ritonavir after a median duration of 1 day of COVID-19 symptoms. No serious adverse events were reported during the study period in either the pregnant patients or the neonates. The other case series included 7 patients with COVID-19 symptoms for approximately 2 days at the start of treatment and a mean gestational age of 26.4 weeks. Six of the 7 patients completed the 5-day treatment course, and all 6 were fully vaccinated (4 had received a booster dose). The 6 patients reported resolution of their COVID-19 symptoms, and no fetal or neonatal adverse effects were observed during the study period. The 1 patient who discontinued treatment, did so because of dysgeusia. In animal embryo-fetal development studies, reduced fetal body weights (9% decrease) were observed in rabbits after maternal administration of nirmatrelvir doses resulting in systemic exposures 11-times higher than clinical exposures at the authorized human dose. No other adverse developmental outcomes were observed in animal reproduction studies with nirmatrelvir at systemic exposures greater than or equal to 3-times higher than clinical exposures at the authorized human dose. Published observational studies on ritonavir use in pregnant patients have not identified an increased risk for major birth defects [i.e., 2.4% (95% CI: 1.9 to 2.9) after first-trimester exposure vs. 2.7% background birth defect rate]; however, published studies with ritonavir are insufficient to identify a drug-associated risk of miscarriages. When evaluating use of nirmatrelvir; ritonavir in pregnant patients, consider that untreated COVID-19 in pregnancy is associated with adverse maternal and fetal outcomes (i.e., preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic disease, fetal death).[65314] [67203] [69024] [70419]

        breast-feeding

        The National Institutes of Health (NIH) states that nirmatrelvir; ritonavir should be offered to lactating patients who qualify for therapy, and that breast-feeding can continue without interruption.[65314] There are no data available regarding the presence of nirmatrelvir in human milk, the effects on the breast-fed infant, or the effects on milk production. Limited published data show that ritonavir is present in human milk; however, no information is available for the effects of ritonavir on the breast-fed infant or milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, the potential for viral transmission to SARS-CoV-2-negative infants, and the risk of an untreated or inadequately treated condition. Lactating mothers are advised to follow practices according to clinical guidelines to avoid exposing the infant to COVID-19. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.[67203] [69024]

        Revision Date: 05/23/2024, 01:37:00 AM

        References

        65314 - COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Accessed March 1, 2024. Available at https://www.covid19treatmentguidelines.nih.gov/67203 - Food and Drug Administration (FDA). Fact sheet for healthcare providers: emergency use authorization for Paxlovid. Retrieved March 13, 2024. Available on the World Wide Web at https://www.fda.gov/media/155050/download?utm_medium=email&utm_source=govdelivery69024 - Paxlovid (nirmatrelvir; ritonavir) package insert. New York, NY: Pfizer Inc; 2023 May.70419 - The American College of Obstetricians and Gynecologists. Influenza in pregnancy: prevention and treatment: ACOG Committee Statement No. 7. Obstet Gynecol 2023 Nov;143(2):e1-e7.

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        • Brimonidine; Timolol
        • Brincidofovir
        • Bupivacaine; Lidocaine
        • Bupivacaine; Meloxicam
        • Buprenorphine
        • Buprenorphine; Naloxone
        • Bupropion
        • Bupropion; Naltrexone
        • Calcifediol
        • Capmatinib
        • Carteolol
        • Carvedilol
        • Cenobamate
        • Cetirizine
        • Cetirizine; Pseudoephedrine
        • Chloramphenicol
        • Chlorpheniramine
        • Chlorpheniramine; Dextromethorphan
        • Chlorpheniramine; Dextromethorphan; Phenylephrine
        • Chlorpheniramine; Dextromethorphan; Pseudoephedrine
        • Chlorpheniramine; Ibuprofen; Pseudoephedrine
        • Chlorpheniramine; Phenylephrine
        • Chlorpheniramine; Pseudoephedrine
        • Ciclesonide
        • Cidofovir
        • Cimetidine
        • Cinacalcet
        • Clevidipine
        • Clindamycin
        • Clofarabine
        • Clomipramine
        • Cocaine
        • Conjugated Estrogens
        • Conjugated Estrogens; Bazedoxifene
        • Cyclophosphamide
        • Dapagliflozin
        • Dapagliflozin; Metformin
        • Dapsone
        • Darifenacin
        • Darolutamide
        • Delavirdine
        • Desipramine
        • Dexamethasone
        • Dexlansoprazole
        • Dexmedetomidine
        • Dextroamphetamine
        • Dextromethorphan; Bupropion
        • Dextromethorphan; Diphenhydramine; Phenylephrine
        • Diclofenac
        • Diclofenac; Misoprostol
        • Dienogest; Estradiol valerate
        • Diltiazem
        • Diphenhydramine
        • Diphenhydramine; Ibuprofen
        • Diphenhydramine; Naproxen
        • Diphenhydramine; Phenylephrine
        • Donepezil
        • Donepezil; Memantine
        • Doravirine; Lamivudine; Tenofovir disoproxil fumarate
        • Dorzolamide; Timolol
        • Doxazosin
        • Doxepin
        • Doxercalciferol
        • Drospirenone; Estradiol
        • Dulaglutide
        • Dutasteride
        • Echinacea
        • Edoxaban
        • Efavirenz
        • Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate
        • Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate
        • Eltrombopag
        • Empagliflozin
        • Empagliflozin; Linagliptin
        • Empagliflozin; Linagliptin; Metformin
        • Empagliflozin; Metformin
        • Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate
        • Emtricitabine; Tenofovir Disoproxil Fumarate
        • Enasidenib
        • Enfortumab vedotin
        • Ertugliflozin; Metformin
        • Ertugliflozin; Sitagliptin
        • Esmolol
        • Esomeprazole
        • Esterified Estrogens
        • Esterified Estrogens; Methyltestosterone
        • Estradiol
        • Estradiol; Norethindrone
        • Estradiol; Norgestimate
        • Estradiol; Progesterone
        • Estropipate
        • Ethosuximide
        • Etravirine
        • Exenatide
        • Felodipine
        • Fluconazole
        • Fluoxetine
        • Fluvastatin
        • Fluvoxamine
        • Formoterol; Mometasone
        • Foscarnet
        • Fostamatinib
        • Gefitinib
        • Glimepiride
        • Glipizide
        • Glipizide; Metformin
        • Glyburide
        • Glyburide; Metformin
        • Glycerol Phenylbutyrate
        • grapefruit juice
        • Haloperidol
        • Ifosfamide
        • Imipramine
        • Incretin Mimetics
        • Indacaterol; Glycopyrrolate
        • Insulin Aspart
        • Insulin Aspart; Insulin Aspart Protamine
        • Insulin Degludec
        • Insulin Degludec; Liraglutide
        • Insulin Detemir
        • Insulin Glargine
        • Insulin Glargine; Lixisenatide
        • Insulin Glulisine
        • Insulin Lispro
        • Insulin Lispro; Insulin Lispro Protamine
        • Insulin, Inhaled
        • Insulins
        • Interferon Alfa-2b
        • Interferon Alfa-n3
        • Interferon Beta-1a
        • Interferon Beta-1b
        • Interferon Gamma-1b
        • Interferons
        • Isophane Insulin (NPH)
        • Isradipine
        • Ketamine
        • Labetalol
        • Lacosamide
        • Lamivudine; Tenofovir Disoproxil Fumarate
        • Lansoprazole
        • Ledipasvir; Sofosbuvir
        • Letermovir
        • Leuprolide; Norethindrone
        • Levamlodipine
        • Levocetirizine
        • Levorphanol
        • Lidocaine
        • Lidocaine; Epinephrine
        • Lidocaine; Prilocaine
        • Linagliptin
        • Linagliptin; Metformin
        • Liraglutide
        • Lisdexamfetamine
        • Lixisenatide
        • Loperamide
        • Loperamide; Simethicone
        • Losartan
        • Losartan; Hydrochlorothiazide, HCTZ
        • Maprotiline
        • Meclizine
        • Mefloquine
        • Meloxicam
        • Meropenem
        • Meropenem; Vaborbactam
        • Metformin
        • Metformin; Repaglinide
        • Metformin; Sitagliptin
        • Methadone
        • Methamphetamine
        • Methylprednisolone
        • Metoclopramide
        • Metoprolol
        • Metoprolol; Hydrochlorothiazide, HCTZ
        • Miglitol
        • Mirabegron
        • Mirtazapine
        • Mirvetuximab Soravtansine
        • Mometasone
        • Morphine
        • Morphine; Naltrexone
        • Moxifloxacin
        • Nabilone
        • Nadolol
        • Nanoparticle Albumin-Bound Paclitaxel
        • Naproxen; Esomeprazole
        • Nateglinide
        • Nebivolol
        • Nelfinavir
        • Netupitant, Fosnetupitant; Palonosetron
        • Nevirapine
        • Nicardipine
        • Nimodipine
        • Nintedanib
        • Norethindrone
        • Nortriptyline
        • Odevixibat
        • Olanzapine
        • Olanzapine; Fluoxetine
        • Olanzapine; Samidorphan
        • Oliceridine
        • Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ
        • Olodaterol
        • Olopatadine; Mometasone
        • Olutasidenib
        • Omeprazole
        • Omeprazole; Sodium Bicarbonate
        • Ondansetron
        • Oxcarbazepine
        • Oxybutynin
        • Oxymorphone
        • Paricalcitol
        • Paroxetine
        • Peginterferon Alfa-2a
        • Peginterferon Alfa-2b
        • Peginterferon beta-1a
        • Perampanel
        • Perindopril; Amlodipine
        • Perphenazine; Amitriptyline
        • Phentermine; Topiramate
        • Pindolol
        • Pioglitazone
        • Pioglitazone; Glimepiride
        • Pioglitazone; Metformin
        • Pirfenidone
        • Pitolisant
        • Polatuzumab Vedotin
        • Pomalidomide
        • Posaconazole
        • Pramlintide
        • Praziquantel
        • Prednisolone
        • Prednisone
        • Progesterone
        • Propofol
        • Propranolol
        • Protriptyline
        • Ramelteon
        • Regular Insulin
        • Regular Insulin; Isophane Insulin (NPH)
        • Remifentanil
        • Repaglinide
        • Retapamulin
        • Rifaximin
        • Riluzole
        • Ripretinib
        • Risperidone
        • Rocuronium
        • Romidepsin
        • Ropeginterferon alfa-2b
        • Rosiglitazone
        • Semaglutide
        • Siponimod
        • Sitagliptin
        • Sodium Bicarbonate
        • Sodium Phenylbutyrate; Taurursodiol
        • Sotagliflozin
        • Sotorasib
        • Stiripentol
        • Sufentanil
        • Sulfonylureas
        • Talazoparib
        • Tecovirimat
        • Telmisartan; Amlodipine
        • Telotristat Ethyl
        • Tenofovir Disoproxil Fumarate
        • Terbinafine
        • Theophylline, Aminophylline
        • Thiazolidinediones
        • Thioridazine
        • Tiagabine
        • Timolol
        • Tinidazole
        • Tiotropium; Olodaterol
        • Tirzepatide
        • Tisotumab Vedotin
        • Topiramate
        • Tovorafenib
        • Trandolapril; Verapamil
        • Triamcinolone
        • Tricyclic antidepressants
        • Trimipramine
        • Tucatinib
        • Ulipristal
        • Verapamil
        • Vinorelbine
        • Warfarin
        • Zafirlukast
        • Zaleplon
        • Zolmitriptan
        • Zolpidem

        Level 4 (Minor)

        • Atazanavir
        • Atovaquone
        • Atovaquone; Proguanil
        • Brentuximab vedotin
        • Bupivacaine
        • Bupivacaine Liposomal
        • Bupivacaine; Epinephrine
        • Doravirine
        • Granisetron
        • Indinavir
        • Lamivudine, 3TC; Zidovudine, ZDV
        • Paclitaxel
        • Rabeprazole
        • Sacubitril; Valsartan
        • Tesamorelin
        • Valsartan
        • Valsartan; Hydrochlorothiazide, HCTZ
        • Zidovudine, ZDV
        Abacavir: (Moderate) Caution is advised when administering abacavir and ritonavir concurrently. Ritonavir appears to induce glucuronosyl transferase, and therefore, has the potential to reduce plasma concentrations of drugs that undergo glucuronidation, such as abacavir. The clinical significance of the potential for this interaction is unknown. [28341] [47165] Abacavir; Dolutegravir; Lamivudine: (Moderate) Caution is advised when administering abacavir and ritonavir concurrently. Ritonavir appears to induce glucuronosyl transferase, and therefore, has the potential to reduce plasma concentrations of drugs that undergo glucuronidation, such as abacavir. The clinical significance of the potential for this interaction is unknown. [28341] [47165] Abacavir; Lamivudine, 3TC: (Moderate) Caution is advised when administering abacavir and ritonavir concurrently. Ritonavir appears to induce glucuronosyl transferase, and therefore, has the potential to reduce plasma concentrations of drugs that undergo glucuronidation, such as abacavir. The clinical significance of the potential for this interaction is unknown. [28341] [47165] Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Caution is advised when administering abacavir and ritonavir concurrently. Ritonavir appears to induce glucuronosyl transferase, and therefore, has the potential to reduce plasma concentrations of drugs that undergo glucuronidation, such as abacavir. The clinical significance of the potential for this interaction is unknown. [28341] [47165] (Minor) Since ritonavir induces glucuronidation, there is the potential for reduction in zidovudine, ZDV plasma concentrations during concurrent therapy with ritonavir. When coadministered with ritonavir, the AUC and Cmax of zidovudine, ZDV are decreased by 12% and 27%. The clinical significance of this interaction is unknown. [28315] [47165] [58664] Abemaciclib: (Major) If coadministration with ritonavir is necessary, reduce the dose of abemaciclib to 100 mg PO twice daily in patients on either of the recommended starting doses of either 200 mg or 150 mg twice daily. In patients who have had already had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the dose of abemaciclib to 50 mg PO twice daily. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. If ritonavir is discontinued, increase the dose of abemaciclib to the original dose after 3 to 5 half-lives of ritonavir. Abemaciclib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 2.5-fold in cancer patients. [47165] [62393] Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and ritonavir; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days. [47165] [62578] [67829] Acarbose: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. [30575] [51227] Acebutolol: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers. [5044] Acetaminophen: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] Acetaminophen; Aspirin: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] (Moderate) Concurrent administration of diphenhydramine with ritonavir may result in elevated plasma concentrations of diphenhydramine. Diphenhydramine is a CYP2D6 substrate, and ritonavir is a CYP2D6 inhibitor. Caution and close monitoring are advised if these drugs are administered together. [34522] [34523] [47165] [58664] Acetaminophen; Caffeine: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with ritonavir may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of ritonavir could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ritonavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Ritonavir is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. [30282] [47165] (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] Acetaminophen; Caffeine; Pyrilamine: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] Acetaminophen; Chlorpheniramine: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] (Moderate) Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together. [34390] [47165] [57935] [58664] Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] (Moderate) Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together. [34390] [47165] [57935] [58664] Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] (Moderate) Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together. [34390] [47165] [57935] [58664] Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] (Moderate) Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together. [34390] [47165] [57935] [58664] Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] (Moderate) Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together. [34390] [47165] [57935] [58664] Acetaminophen; Codeine: (Major) Consider withholding codeine if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. Coadministration may increase codeine exposure, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nirmatrelvir is a CYP3A inhibitor. [33654] [65314] (Moderate) Concomitant use of codeine with ritonavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of ritonavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ritonavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ritonavir is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. [33654] [34883] [47165] (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] Acetaminophen; Dextromethorphan: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] Acetaminophen; Diphenhydramine: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] (Moderate) Concurrent administration of diphenhydramine with ritonavir may result in elevated plasma concentrations of diphenhydramine. Diphenhydramine is a CYP2D6 substrate, and ritonavir is a CYP2D6 inhibitor. Caution and close monitoring are advised if these drugs are administered together. [34522] [34523] [47165] [58664] Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] Acetaminophen; Hydrocodone: (Major) Consider withholding hydrocodone, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the hydrocodone dose. Coadministration may increase hydrocodone exposure, resulting in prolonged opioid effects including fatal respiratory depression. Hydrocodone is metabolized by CYP3A4 and nirmatrelvir is a CYP3A inhibitor. [56303] [65314] [67203] [69024] (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ritonavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ritonavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. [30379] [30391] [47165] [56303] [58531] Acetaminophen; Ibuprofen: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] Acetaminophen; Oxycodone: (Major) Consider withholding oxycodone, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the oxycodone dose. Coadministration may increase oxycodone exposure, resulting in prolonged opioid effects including fatal respiratory depression. Oxycodone is metabolized by CYP3A4 and nirmatrelvir is a CYP3A inhibitor. [60745] [65314] [67203] [69024] (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. If ritonavir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like ritonavir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ritonavir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. [39926] [47165] Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] Acetaminophen; Phenylephrine: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] Acetaminophen; Pseudoephedrine: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] Adagrasib: (Moderate) Monitor for an increase in adagrasib-related adverse effects during concomitant use of ritonavir. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state. [47165] [68325] Adefovir: (Major) Patients who are concurrently taking adefovir with antiretrovirals like the protease inhibitors, are at risk of developing lactic acidosis and severe hepatomegaly with steatosis. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals. A majority of these cases have been in women; obesity and prolonged nucleoside exposure may also be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for hepatic disease; however, cases have also been reported in patients with no known risk factors. Suspend adefovir in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). [28784] Ado-Trastuzumab emtansine: (Major) Avoid coadministration of ritonavir with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until ritonavir has cleared from the circulation (approximately 3 half-lives of ritonavir) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; ritonavir is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted. [28315] [53295] Afatinib: (Moderate) If the concomitant use of ritonavir and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of ritonavir. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and ritonavir is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib. [28315] [55331] Albuterol; Budesonide: (Major) Avoid coadministration of oral budesonide and ritonavir due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. [28315] [31824] [34979] [47165] Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of protease inhibitors is necessary. If the protease inhibitor is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A substrate, and coadministration with CYP3A inhibitors like protease inhibitors can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If the protease inhibitor is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil. [29012] [30072] Alfuzosin: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and alfuzosin is contraindicated. Consider temporary discontinuation of alfuzosin during treatment with ritonavir-boosted nirmatrelvir and for at least 2 to 3 days after treatment completion; if not feasible, consider alternative COVID-19 therapy. Coadministration may increase alfuzosin exposure resulting in increased toxicity. Alfuzosin is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Contraindicated) Concurrent use of alfuzosin and protease inhibitors is contraindicated due to increased alfuzosin exposure. Alfuzosin is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. When coadministered with another strong CYP3A inhibitor, the AUC of alfuzosin was increased by 2.5-fold to 3.2-fold. [28341] [28839] [29012] [32432] [50857] Aliskiren: (Major) Consider temporary discontinuation of aliskiren during treatment with ritonavir-boosted nirmatrelvir and for at least 2 to 3 days after treatment completion; if not feasible, consider alternative COVID-19 therapy. Coadministration may increase aliskiren exposure resulting in increased toxicity. Aliskiren is a substrate of both CYP3A4 and P-glycoprotein (P-gp), and nirmatrelvir is a CYP3A and P-gp inhibitor. [33200] [65314] [69024] (Moderate) The plasma concentrations of aliskiren may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Ritonavir is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of both CYP3A4 and P-gp. [33200] [47165] [56579] Aliskiren; Hydrochlorothiazide, HCTZ: (Major) Consider temporary discontinuation of aliskiren during treatment with ritonavir-boosted nirmatrelvir and for at least 2 to 3 days after treatment completion; if not feasible, consider alternative COVID-19 therapy. Coadministration may increase aliskiren exposure resulting in increased toxicity. Aliskiren is a substrate of both CYP3A4 and P-glycoprotein (P-gp), and nirmatrelvir is a CYP3A and P-gp inhibitor. [33200] [65314] [69024] (Moderate) The plasma concentrations of aliskiren may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Ritonavir is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of both CYP3A4 and P-gp. [33200] [47165] [56579] Almotriptan: (Major) Consider withholding almotriptan, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the almotriptan dose. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Coadministration may increase almotriptan exposure resulting in increased toxicity. Almotriptan is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [31869] [65314] (Moderate) The maximum recommended starting dose of almotriptan is 6.25 mg if coadministration with ritonavir is necessary; do not exceed 12.5 mg within a 24-hour period. Concomitant use of almotriptan and ritonavir should be avoided in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased almotriptan exposure by approximately 60%. [28001] [31869] Alogliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] [51227] Alogliptin; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] [51227] (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30480] [30575] Alogliptin; Pioglitazone: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] [51227] (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8. [28142] [28172] [28380] [30575] [31320] [34557] [47165] [50768] [51227] Alosetron: (Major) Concurrent administration of alosetron with ritonavir may alter alosetron plasma concentrations; however, the precise effect is undefined. Alosetron is metabolized by the hepatic isoenzymes CYP3A4, CYP2C9, and CYP1A2; ritonavir is an inhibitor of CYP3A4 and an inducer of CYP1A2 and possibly CYP2C9. Caution and close monitoring are advised if these drugs are administered together. [28382] [5044] Alpha-glucosidase Inhibitors: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. [30575] [51227] Alprazolam: (Major) Avoid coadministration of alprazolam and ritonavir due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration of alprazolam and ritonavir is necessary, reduce alprazolam to half of the recommended dosage when a patient is started on ritonavir and alprazolam together, or when ritonavir administered to a patient treated with alprazolam. Increase the alprazolam dosage to the target dose after 10 to 14 days of dosing ritonavir and alprazolam together. It is not necessary to reduce alprazolam dose in patients who have been taking ritonavir for more than 10 to 14 days. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with ritonavir, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Short-term low doses of ritonavir (4 doses of 200 mg) increased mean AUC of alprazolam by about 2.5-fold, and did not significantly affect Cmax of alprazolam. The elimination half-life of alprazolam was prolonged (30 hours vs. 13 hours). Upon extended exposure to ritonavir (500 mg, twice daily for 10 days), CYP3A induction offset this inhibition. Alprazolam AUC and Cmax was reduced by 12% and 16%, respectively, in the presence of ritonavir. The elimination half-life of alprazolam was not significantly changed. [28040] [28341] [47165] (Major) Consider withholding alprazolam, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the alprazolam dose. However, do not stop alprazolam abruptly or rapidly reduce the dose as this may precipitate an acute withdrawal reaction, especially in patients who have been receiving high doses over an extended period. Coadministration may increase alprazolam exposure resulting in increased toxicity and excessive sedation. Alprazolam is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [28040] [41538] [65314] Amiodarone: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and amiodarone is contraindicated; consider an alternative COVID-19 therapy. Coadministration may increase amiodarone exposure resulting in increased toxicity. Amiodarone is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Major) Avoid concomitant use of amiodarone and ritonavir due to the risk for increased amiodarone exposure which may increase the risk for adverse effects. Amiodarone is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. [28224] [52887] [56579] Amitriptyline: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with ritonavir is necessary; a dose reduction of the TCA may be necessary. Concurrent use may increase exposure of the TCA. TCAs are CYP2D6 substrates and ritonavir is a CYP2D6 inhibitor. [47165] Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure. [29012] [29090] [47165] Amlodipine; Atorvastatin: (Major) Coadministration of atorvastatin and ritonavir may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher doses of atorvastatin. If concomitant use of these drugs is required, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Atorvastatin is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. [28729] [28774] (Major) Consider temporary discontinuation of atorvastatin during treatment with ritonavir-boosted nirmatrelvir; if this is not feasible, consider an alternative COVID-19 therapy. Atorvastatin does not need to be held prior to or after completing ritonavir-boosted nirmatrelvir. Coadministration may increase atorvastatin exposure resulting in increased toxicity. Atorvastatin is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure. [29012] [29090] [47165] Amlodipine; Benazepril: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure. [29012] [29090] [47165] Amlodipine; Celecoxib: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure. [29012] [29090] [47165] Amlodipine; Olmesartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure. [29012] [29090] [47165] Amlodipine; Valsartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure. [29012] [29090] [47165] (Minor) Valsartan is a substrate of the hepatic efflux transporter MRP2 and ritonavir is an inhibitor of MRP2. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan during coadministration. [28315] [29130] [36646] [39870] [60860] Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure. [29012] [29090] [47165] (Minor) Valsartan is a substrate of the hepatic efflux transporter MRP2 and ritonavir is an inhibitor of MRP2. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan during coadministration. [28315] [29130] [36646] [39870] [60860] Amobarbital: (Contraindicated) Ritonavir-boosted nirmatrelvir is contraindicated for use within 2 weeks of administering barbiturates; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response. The risk for reduced efficacy may persist following barbiturate discontinuation. Nirmatrelvir is a CYP3A substrate and barbiturates are strong CYP3A inducers. [41911] [49229] [49236] [49352] [57048] [57271] [65314] [67203] [69024] (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers. [28315] [46638] Amoxapine: (Major) Ritonavir potently inhibits CYP2D6, and may inhibit the metabolism of amoxapine. Since the magnitude of the interaction with the amoxapine is difficult to predict but may be significant, monitor patients receiving ritonavir and amoxapine concurrently closely. Adjust the dosage of the coadministered drug based on therapeutic response. Amoxapine serum concentration monitoring may be useful to guide adjustments and prevent toxicity. [28558] [46638] [47165] Amoxicillin; Clarithromycin; Omeprazole: (Major) Because the exposure to 14-OH clarithromycin is significantly decreased by ritonavir, consider alternative antibiotic therapy for indications other than Mycobacterium avium. Clarithromycin doses above 1000 mg should not be administered with ritonavir. If coadministration cannot be avoided, clarithromycin dosage reductions are recommended in patients with renal impairment (CrCl 30 to 60 mL/minute, decrease clarithromycin by 50%; CrCl less than 30 mL/minute, decrease clarithromycin by 75%). Concomitant administration of ritonavir and clarithromycin resulted in a 77% increase in clarithromycin exposure and a 100% decrease in 14-OH clarithromycin exposure. The microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria. [28238] [46638] [47165] (Moderate) Increased exposure to omeprazole may occur during concurrent administration of ritonavir. Although dosage adjustment of omeprazole is not normally required, dosage reduction may be considered in patients receiving higher omeprazole doses (e.g., those with Zollinger-Ellison syndrome). Ritonavir is a strong CYP3A4 inhibitor. Omeprazole is a CYP2C19 and CYP3A4 substrate. Coadministration of a dual CYP2C19/strong CYP3A4 inhibitor increased the omeprazole AUC by an average of 4-times. [29564] [47165] Amphetamine: (Moderate) Warn patients that the risk of amphetamine toxicity may be increased during concurrent use of ritonavir, a strong CYP2D6 inhibitor. Amphetamines are partially metabolized by CYP2D6 and have serotonergic properties; inhibition of amphetamine metabolism may increase the risk of serotonin syndrome or other toxicity. If serotonin syndrome occurs, both the amphetamine and CYP2D6 inhibitor should be discontinued and appropriate medical treatment should be implemented. [25887] [29219] [33263] [47165] [57067] Amphetamine; Dextroamphetamine: (Moderate) Warn patients that the risk of amphetamine toxicity may be increased during concurrent use of ritonavir, a strong CYP2D6 inhibitor. Amphetamines are partially metabolized by CYP2D6 and have serotonergic properties; inhibition of amphetamine metabolism may increase the risk of serotonin syndrome or other toxicity. If serotonin syndrome occurs, both the amphetamine and CYP2D6 inhibitor should be discontinued and appropriate medical treatment should be implemented. [25887] [29219] [33263] [47165] [57067] Amphetamines: (Moderate) Warn patients that the risk of amphetamine toxicity may be increased during concurrent use of ritonavir, a strong CYP2D6 inhibitor. Amphetamines are partially metabolized by CYP2D6 and have serotonergic properties; inhibition of amphetamine metabolism may increase the risk of serotonin syndrome or other toxicity. If serotonin syndrome occurs, both the amphetamine and CYP2D6 inhibitor should be discontinued and appropriate medical treatment should be implemented. [25887] [29219] [33263] [47165] [57067] Apalutamide: (Contraindicated) Coadministration of ritonavir with apalutamide is contraindicated as there is a potential for decreased ritonavir concentrations which may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance; exposure to apalutamide may also increase. Ritonavir is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer. [47165] [62874] (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and apalutamide is contraindicated; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response. The risk for reduced efficacy may persist following apalutamide discontinuation. Nirmatrelvir is a CYP3A substrate and apalutamide is a strong CYP3A inducer. [62874] [65314] [67203] [69024] Apixaban: (Major) Reduce the apixaban dose by 50% when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as ritonavir. If patients are already receiving the reduced dose of 2.5 mg twice daily, avoid concomitant administration of apixaban and ritonavir. Concomitant administration of ritonavir and apixaban results in increased exposure to apixaban and an increase in the risk of bleeding. [52739] Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use of ritonavir with aprepitant, fosaprepitant due to substantially increased exposure of aprepitant; after administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. Increased ritonavir exposure may also occur. If coadministration cannot be avoided, use caution and monitor for an increase in ritonavir- and aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. Ritonavir is a strong CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased the AUC of aprepitant by approximately 5-fold, and the mean terminal half-life by approximately 3-fold. Ritonavir is also a is also a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor. When administered as a single oral or single intravenous dose, the inhibitory effect of aprepitant on CYP3A4 is weak and does not result in a clinically significant increase in the AUC of a sensitive substrate. [30676] [40027] [47165] Arformoterol: (Moderate) The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir, include beta-agonists. [28318] [33925] [41231] [47165] Aripiprazole: (Major) Recommendations for managing aripiprazole and ritonavir vary by aripiprazole dosage form. For aripiprazole oral dosage forms, administer a quarter of the usual dose. For monthly extended-release aripiprazole injections (Abilify Maintena), reduce the dosage from 400 mg to 200 mg/month or from 300 mg to 160 mg/month. For extended-release aripiprazole injections given once every 2 months (Abilify Asimtufii), reduce the dosage from 960 mg to 720 mg; avoid use in patients known to be poor metabolizers of CYP2D6. Further dosage reductions may be required in patients who are also receiving a strong CYP2D6 inhibitor; see individual product prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is CYP2D6 and CYP3A substrate; ritonavir is a weak CYP2D6 and strong CYP3A inhibitor. [42845] [47165] [53394] [60196] [63328] [68911] (Major) Recommendations for managing aripiprazole and ritonavir vary by aripiprazole dosage form. For extended-release aripiprazole lauroxil injections (Aristada), reduce the dose to the next lowest strength; no dosage adjustment is required for patients tolerating 441 mg. For extended-release aripiprazole lauroxil injections (Aristada) in patients who are known to be poor metabolizers of CYP2D6, reduce the dose to 441 mg; no dosage adjustment is necessary for patients already tolerating 441 mg. For fixed dose extended-release aripiprazole lauroxil injections (Aristada Initio), avoid concomitant use because the dose cannot be modified. Further dosage reductions may be required in patients who are also receiving a strong CYP2D6 inhibitor; see individual product prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is CYP2D6 and CYP3A substrate; ritonavir is a weak CYP2D6 and strong CYP3A inhibitor. [42845] [47165] [53394] [60196] [63328] [68911] Armodafinil: (Major) Coadministration of ritonavir with armodafinil may result in elevated armodafinil concentrations and decreased ritonavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Armodafinil is a substrate and inducer of CYP3A4, and a P-glycoprotein (P-gp) substrate. Ritonavir is a substrate of CYP3A4 and an inhibitor of P-gp. Ritonavir is also a potent inhibitor of CYP3A4. [33467] [47165] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of armodafinil is necessary. Concomitant use of nirmatrelvir and armodafinil may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and armodafinil is a weak CYP3A inducer. [33467] [67203] Artemether; Lumefantrine: (Major) Ritonavir is a substrate, potent inhibitor, and inducer of the CYP3A4 isoenzyme, depending on the activity of the coadministered drug. Both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased or decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation due to increased drug concentrations, or loss of antimalarial activity depending on the artemether; lumefantrine concentrations. Consider ECG monitoring if ritonavir must be used with or after artemether; lumefantrine treatment. [11416] [35401] [4194] [47165] [5044] [5110] (Major) Ritonavir is a substrate, potent inhibitor, and inducer of the CYP3A4 isoenzyme, depending on the activity of the coadministered drug. Both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased or decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation due to increased drug concentrations, or loss of antimalarial activity depending on the artemether; lumefantrine concentrations. Consider ECG monitoring if ritonavir must be used with or after artemether; lumefantrine treatment. [11416] [35401] [4194] [5044] [5110] [60002] Artesunate: (Moderate) Monitor for a decrease in antimalarial efficacy if artesunate is coadministered with ritonavir. Coadministration of oral artesunate with ritonavir resulted in a decrease in the AUC of the active metabolite of artesunate, dihydroartemisinin, by 38%. [65484] Asciminib: (Moderate) Closely monitor for asciminib-related adverse reactions if concurrent use of asciminib 200 mg twice daily with ritonavir is necessary as asciminib exposure may increase. Asciminib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. [47165] [67087] Aspirin, ASA; Butalbital; Caffeine: (Contraindicated) Ritonavir-boosted nirmatrelvir is contraindicated for use within 2 weeks of administering barbiturates; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response. The risk for reduced efficacy may persist following barbiturate discontinuation. Nirmatrelvir is a CYP3A substrate and barbiturates are strong CYP3A inducers. [41911] [49229] [49236] [49352] [57048] [57271] [65314] [67203] [69024] (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers. [28315] [46638] Aspirin, ASA; Caffeine: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] Aspirin, ASA; Carisoprodol; Codeine: (Major) Consider withholding codeine if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. Coadministration may increase codeine exposure, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nirmatrelvir is a CYP3A inhibitor. [33654] [65314] (Moderate) Concomitant use of codeine with ritonavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of ritonavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ritonavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ritonavir is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. [33654] [34883] [47165] Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Concurrent administration of tipranavir and ritonavir with antacids results in decreased tipranavir concentrations. Administer tipranavir and ritonavir 2 hours before or 1 hour after antacids. [1800] [1802] Aspirin, ASA; Omeprazole: (Moderate) Increased exposure to omeprazole may occur during concurrent administration of ritonavir. Although dosage adjustment of omeprazole is not normally required, dosage reduction may be considered in patients receiving higher omeprazole doses (e.g., those with Zollinger-Ellison syndrome). Ritonavir is a strong CYP3A4 inhibitor. Omeprazole is a CYP2C19 and CYP3A4 substrate. Coadministration of a dual CYP2C19/strong CYP3A4 inhibitor increased the omeprazole AUC by an average of 4-times. [29564] [47165] Aspirin, ASA; Oxycodone: (Major) Consider withholding oxycodone, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the oxycodone dose. Coadministration may increase oxycodone exposure, resulting in prolonged opioid effects including fatal respiratory depression. Oxycodone is metabolized by CYP3A4 and nirmatrelvir is a CYP3A inhibitor. [60745] [65314] [67203] [69024] (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. If ritonavir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like ritonavir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ritonavir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. [39926] [47165] Atazanavir: (Minor) Coadministration of atazanavir with ritonavir results in higher atazanavir concentrations; reduced adult doses of atazanavir 300 mg once daily are recommended when ritonavir (100 mg once daily) is given concomitantly. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including atazanavir) has not been evaluated. Atazanavir is a CYP3A4 substrate; ritonavir is a strong inhibitor of CYP3A4. [28142] [28315] Atazanavir; Cobicistat: (Contraindicated) Use of ritonavir with cobicistat is not recommended, because of similar effects on CYP3A. Both ritonavir and cobicistat are potent inhibitors of CYP3A4. [51664] [58000] [58761] [58763] (Minor) Coadministration of atazanavir with ritonavir results in higher atazanavir concentrations; reduced adult doses of atazanavir 300 mg once daily are recommended when ritonavir (100 mg once daily) is given concomitantly. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including atazanavir) has not been evaluated. Atazanavir is a CYP3A4 substrate; ritonavir is a strong inhibitor of CYP3A4. [28142] [28315] Atenolol: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers. [5044] Atenolol; Chlorthalidone: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers. [5044] Atogepant: (Major) Avoid use of atogepant and ritonavir when atogepant is used for chronic migraine. Limit the dose of atogepant to 10 mg PO once daily for episodic migraine if coadministered with ritonavir. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of CYP3A and ritonavir is a strong CYP3A inhibitor. Coadministration with a strong CYP3A inhibitor resulted in a 5.5-fold increase in atogepant overall exposure and a 2.15-fold increase in atogepant peak concentration. [47165] [67011] Atorvastatin: (Major) Coadministration of atorvastatin and ritonavir may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher doses of atorvastatin. If concomitant use of these drugs is required, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Atorvastatin is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. [28729] [28774] (Major) Consider temporary discontinuation of atorvastatin during treatment with ritonavir-boosted nirmatrelvir; if this is not feasible, consider an alternative COVID-19 therapy. Atorvastatin does not need to be held prior to or after completing ritonavir-boosted nirmatrelvir. Coadministration may increase atorvastatin exposure resulting in increased toxicity. Atorvastatin is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] Atovaquone: (Minor) The concurrent administration of ritonavir with atovaquone may result in decreased plasma levels of atovaquone. The clinical significance and mechanism of this potential interaction are unknown; the manufacturer states that an increase in atovaquone doses may be needed. [28315] [28341] [46638] [58664] Atovaquone; Proguanil: (Minor) The concurrent administration of ritonavir with atovaquone may result in decreased plasma levels of atovaquone. The clinical significance and mechanism of this potential interaction are unknown; the manufacturer states that an increase in atovaquone doses may be needed. [28315] [28341] [46638] [58664] Avacopan: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of ritonavir is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold. [47165] [67036] Avanafil: (Major) Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking strong CYP3A4 inhibitors such as ritonavir, should not take avanafil. For example, ketoconazole increased avanafil AUC and Cmax equal to 13-fold and 3-fold, respectively and prolonged the half-life of avanafil to approximately 9 hours. Likewise, coadministration of ritonavir with avanafil resulted in an approximate 13-fold increase in AUC and 2.4-fold increase in Cmax of avanafil. Therefore, concomitant use with strong CYP3A4 inhibitors is not recommended. [28315] [47165] [49866] (Major) Consider temporary discontinuation of avanafil during treatment with ritonavir-boosted nirmatrelvir and for at least 2 to 3 days after treatment completion; if not feasible, consider alternative COVID-19 therapy. Coadministration may increase avanafil exposure resulting in increased toxicity. Avanafil is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [49866] [65314] [67203] [69024] Avapritinib: (Major) Avoid coadministration of avapritinib with ritonavir due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state. [47165] [64922] Avatrombopag: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with ritonavir. In patients starting ritonavir while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as ritonavir decrease avatrombopag exposure, which may reduce efficacy. [47165] [63175] Axitinib: (Major) Avoid coadministration of axitinib with ritonavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after ritonavir is discontinued. Axitinib is a CYP3A4/5 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers. [47165] [48494] Azelastine; Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and ritonavir is not recommended; use caution with inhaled fluticasone furoate. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving inhaled fluticasone propionate with ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Fluticasone is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with ritonavir increased plasma fluticasone propionate exposure resulting in an 86% decrease in serum cortisol AUC. Another strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. [40360] [40475] [43972] [57805] Barbiturates: (Contraindicated) Ritonavir-boosted nirmatrelvir is contraindicated for use within 2 weeks of administering barbiturates; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response. The risk for reduced efficacy may persist following barbiturate discontinuation. Nirmatrelvir is a CYP3A substrate and barbiturates are strong CYP3A inducers. [41911] [49229] [49236] [49352] [57048] [57271] [65314] [67203] [69024] (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers. [28315] [46638] Bedaquiline: (Major) Concurrent use of bedaquiline and ritonavir should be avoided due to the potential risk of adverse reactions to bedaquiline because of increased systemic exposure. Bedaquiline is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased bedaquiline exposure by 22%. [47165] [52746] Belladonna; Opium: (Moderate) Ritonavir is an inhibitor of the cytochrome P450 3A4 isoenzyme and may decrease the metabolism of opium if the two drugs are coadministered. [4718] Belzutifan: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of belzutifan is necessary. Concomitant use of nirmatrelvir and belzutifan may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and belzutifan is a weak CYP3A inducer. [66875] [67203] (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with belzutifan. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and belzutifan is a weak CYP3A inducer. [66875] [67203] Bendamustine: (Major) Consider the use of an alternative therapy if ritonavir treatment is needed in patients receiving bendamustine. Ritonavir may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and ritonavir is a CYP1A2 inducer. [27493] [47165] [55945] [60454] [64723] Benzhydrocodone; Acetaminophen: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] (Moderate) Concurrent use of benzhydrocodone with ritonavir may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of ritonavir in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If ritonavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Ritonavir is a strong inhibitor of CYP3A4 and a weak in vitro inhibitor of CYP2D6. [47165] [62889] Benzphetamine: (Moderate) Warn patients that the risk of amphetamine toxicity may be increased during concurrent use of ritonavir, a strong CYP2D6 inhibitor. Amphetamines are partially metabolized by CYP2D6 and have serotonergic properties; inhibition of amphetamine metabolism may increase the risk of serotonin syndrome or other toxicity. If serotonin syndrome occurs, both the amphetamine and CYP2D6 inhibitor should be discontinued and appropriate medical treatment should be implemented. [25887] [29219] [33263] [47165] [57067] Betamethasone: (Moderate) Consider an alternative corticosteroid that is less affected by CYP3A4 (i.e., beclomethasone or prednisolone), particularly for long-term use, in patients receiving ritonavir. Coadministration may significantly increase betamethasone exposure increasing the risk for Cushing's syndrome and adrenal suppression. Ritonavir is a strong CYP3A4 inhibitor and betamethasone is a CYP3A4 substrate. Another strong CYP3A4 inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%. [28341] [47165] [63066] Betaxolol: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers. [5044] Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving ritonavir. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving ritonavir. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; ritonavir inhibits P-gp. [28380] [56579] [62037] Bexagliflozin: (Moderate) Monitor for a decrease in bexagliflozin efficacy during concomitant use of bexagliflozin and ritonavir and adjust therapy as appropriate. Concomitant use may decrease bexagliflozin exposure. Bexagliflozin is a UGT substrate and ritonavir is a UGT inducer. [47165] [68485] Bexarotene: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of bexarotene is necessary. Concomitant use of nirmatrelvir and bexarotene may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and bexarotene is a moderate CYP3A inducer. [59747] [67203] (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with bexarotene. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and bexarotene is a moderate CYP3A inducer. [59747] [67203] Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Ritonavir oral solution and capsules contain ethanol. Administration of ritonavir oral solution or capsules to patients receiving or who have recently received disulfiram or metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations of ritonavir (e.g., tablets, oral powder). [28315] [28581] [47165] Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Ritonavir oral solution and capsules contain ethanol. Administration of ritonavir oral solution or capsules to patients receiving or who have recently received disulfiram or metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations of ritonavir (e.g., tablets, oral powder). [28315] [28581] [47165] Bisoprolol: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers. [5044] Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers. [5044] Bortezomib: (Moderate) In vitro studies with human liver microsomes indicate that bortezomib is a significant substrate for CYP3A4. Agents that inhibit CYP3A4, such ritonavir, may increase the exposure to bortezomib and increase the risk for toxicity. The manufacturer warns that patients who are receiving bortezomib concurrently with potent CYP3A4 inhibitors should be closely monitored for potential toxicity. Additionally, ritonavir can cause peripheral neuropathy. It may be prudent to monitor patients for signs and symptoms of neuropathy. [28383] Bosentan: (Major) Avoid concomitant use of ritonavir-boosted nirmatrelvir and bosentan and consider an alternative COVID-19 therapy. If ritonavir-boosted nirmatrelvir must be used, discontinue use of bosentan at least 36 hours before starting ritonavir-boosted nirmatrelvir. Coadministration may increase bosentan exposure resulting in increased toxicity and/or decrease nirmatrelvir exposure and reduce its efficacy. Bosentan is a CYP3A substrate and moderate CYP3A inducer; nirmatrelvir is a CYP3A substrate and CYP3A inhibitor. [28496] [65314] [67203] [69024] (Major) Do not administer bosentan with anti-retroviral protease inhibitors that are not boosted with ritonavir as decreased protease inhibitor concentrations are expected. In addition, administration of anti-retroviral protease inhibitors with bosentan may increase bosentan serum concentrations due to the inhibition of the CYP3A4 isoenzyme. In patients who have been receiving protease inhibitor therapy for at least 10 days, initiate bosentan at the recommended initial dose once daily or every other day based on tolerability. For patients on bosentan who need protease inhibitor therapy, discontinue use of bosentan at least 36 hours prior to starting protease inhibitor therapy. After 10 days of the protease inhibitor therapy, bosentan may be restarted at the recommended initial dose once daily or every other day based on tolerability. Bosentan is a substrate for organic anion transport protein (OATP), CYP3A, and CYP2C9. In healthy subjects, initial and steady state trough plasma concentrations of bosentan were approximately 48-fold and 5-fold higher, respectively, after coadministration of bosentan 125 mg twice daily PO and lopinavir; ritonavir 400/100 mg twice daily PO compared to those measured after bosentan alone. This is most likely explained by inhibition by lopinavir of OATP-mediated uptake into hepatocytes; toxicity of bosentan is possible. Monitor for potential adverse effects of bosentan during coadministration with CYP2C9 or CYP3A4 inhibitors; excessive bosentan dosage may result in hypotension or elevated hepatic enzyme. Additionally, bosentan is a significant inducer of CYP3A4 and CYP2C9 hepatic enzymes. Theoretically, bosentan may increase the clearance of the protease inhibitors and potentially lead to a reduction of anti-retroviral efficacy. However, this interaction has not been studied. [28142] [28315] [28341] [28496] [28731] [28839] [28995] [29012] [31320] [32432] [46638] [56579] [61510] [61511] [61512] [61513] Bosutinib: (Major) Avoid concomitant use of bosutinib and ritonavir or lopinavir; ritonavir as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor. [28315] [51739] Brentuximab vedotin: (Minor) Concomitant administration of brentuximab vedotin and ritonavir may increase the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. The manufacturer suggests that potent CYP3A4 inhibitors, such as ritonavir, may alter MMAE exposure as MMAE is a CYP3A4 substrate. Monitor patients for adverse reactions. [11416] [45378] [5044] [5110] Brexpiprazole: (Major) Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the brexpiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 inhibitor in combination with a moderate to strong inhibitor of CYP2D6. Ritonavir (including lopinavir; ritonavir) is a strong inhibitor of CYP3A4 and a moderate inhibitor of CYP2D6. If these agents are used in combination, the patient should be carefully monitored for brexpiprazole-related adverse reactions. If the co-administered CYP inhibitor is discontinued, adjust the brexpiprazole dose to its original level. [59949] Brigatinib: (Major) Avoid coadministration of brigatinib with ritonavir if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of ritonavir, resume the brigatinib dose that was tolerated prior to initiation of ritonavir. Brigatinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively. [28315] [61909] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of brigatinib is necessary. Concomitant use of nirmatrelvir and brigatinib may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and brigatinib is a weak CYP3A inducer. [61909] [67203] Brimonidine; Timolol: (Moderate) Timolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as ritonavir, may impair timolol metabolism; the clinical significance of such interactions is unknown. [5044] [5270] Brincidofovir: (Moderate) Postpone the administration of ritonavir-boosted nirmatrelvir for at least three hours after brincidofovir administration and increase monitoring for brincidofovir-related adverse reactions (i.e., elevated hepatic enzymes and bilirubin, diarrhea, other gastrointestinal adverse events) if concomitant use of brincidofovir and ritonavir-boosted nirmatrelvir is necessary. [65314] [66710] Bromocriptine: (Major) When bromocriptine is used for diabetes, avoid coadministration with ritonavir ensuring adequate washout before initiating bromocriptine. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may significantly increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; ritonavir is a strong inhibitor of CYP3A4. [28337] [35591] [47165] Budesonide: (Major) Avoid coadministration of oral budesonide and ritonavir due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. [28315] [31824] [34979] [47165] Budesonide; Formoterol: (Major) Avoid coadministration of oral budesonide and ritonavir due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. [28315] [31824] [34979] [47165] Budesonide; Glycopyrrolate; Formoterol: (Major) Avoid coadministration of oral budesonide and ritonavir due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. [28315] [31824] [34979] [47165] Bupivacaine Liposomal: (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed. [4718] Bupivacaine: (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed. [4718] Bupivacaine; Epinephrine: (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed. [4718] Bupivacaine; Lidocaine: (Moderate) Anti-retroviral protease inhibitors can inhibit hepatic cytochrome P450 3A4, an isoenzyme that is partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and anti-retroviral protease inhibitors should be carefully monitored due to the potential for serious toxicity. [4718] [5172] (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed. [4718] Bupivacaine; Meloxicam: (Moderate) Concurrent administration of meloxicam with ritonavir may result in elevated meloxicam plasma concentrations. Meloxicam is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [47165] [58664] [6352] (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed. [4718] Buprenorphine: (Moderate) Concomitant use of buprenorphine and ritonavir can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when ritonavir is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping ritonavir, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If ritonavir is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and ritonavir is a strong CYP3A4 inhibitor. [41235] [41666] [47165] Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine and ritonavir can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when ritonavir is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping ritonavir, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If ritonavir is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and ritonavir is a strong CYP3A4 inhibitor. [41235] [41666] [47165] Bupropion: (Moderate) Concurrent administration of bupropion with ritonavir results in decreased concentrations of bupropion and its active metabolite. According to the manufacturers of bupropion, increased doses of bupropion may be necessary during concurrent therapy; however, the maximum recommended dose of bupropion should not be exceeded. Closely monitor bupropion efficacy if these drugs are given together. Ritonavir induces CYP2B6, which is responsible for bupropion's metabolism. In one study, ritonavir 100 mg twice daily reduced the AUC and Cmax of bupropion by 22% and 21%, respectively. In addition, exposure to the active metabolite of bupropion (hydroxybupropion) was decreased by 23%. When given with ritonavir 600 mg twice daily, the AUC and Cmax of bupropion decreased by 66% and 63% respectively and exposure to hydroxybupropion decreased by 78%. [28058] [28315] [34743] [34744] [34745] [34746] [44095] Bupropion; Naltrexone: (Moderate) Concurrent administration of bupropion with ritonavir results in decreased concentrations of bupropion and its active metabolite. According to the manufacturers of bupropion, increased doses of bupropion may be necessary during concurrent therapy; however, the maximum recommended dose of bupropion should not be exceeded. Closely monitor bupropion efficacy if these drugs are given together. Ritonavir induces CYP2B6, which is responsible for bupropion's metabolism. In one study, ritonavir 100 mg twice daily reduced the AUC and Cmax of bupropion by 22% and 21%, respectively. In addition, exposure to the active metabolite of bupropion (hydroxybupropion) was decreased by 23%. When given with ritonavir 600 mg twice daily, the AUC and Cmax of bupropion decreased by 66% and 63% respectively and exposure to hydroxybupropion decreased by 78%. [28058] [28315] [34743] [34744] [34745] [34746] [44095] Buspirone: (Major) When buspirone is administered with a potent inhibitor of CYP3A4 like ritonavir, a low dose of buspirone used cautiously is recommended. Some patients receiving drugs that are potent inhibitors of CYP3A4 with buspirone have reported lightheadedness, asthenia, dizziness, and drowsiness. If the two drugs are to be used in combination, a low dose of buspirone (e.g., 2.5 mg PO twice daily) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment. Several other anti-retroviral protease inhibitors also inhibit CYP3A4, and these may interact with buspirone in a similar manner. [28001] [28501] Butalbital; Acetaminophen: (Contraindicated) Ritonavir-boosted nirmatrelvir is contraindicated for use within 2 weeks of administering barbiturates; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response. The risk for reduced efficacy may persist following barbiturate discontinuation. Nirmatrelvir is a CYP3A substrate and barbiturates are strong CYP3A inducers. [41911] [49229] [49236] [49352] [57048] [57271] [65314] [67203] [69024] (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers. [28315] [46638] (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] Butalbital; Acetaminophen; Caffeine: (Contraindicated) Ritonavir-boosted nirmatrelvir is contraindicated for use within 2 weeks of administering barbiturates; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response. The risk for reduced efficacy may persist following barbiturate discontinuation. Nirmatrelvir is a CYP3A substrate and barbiturates are strong CYP3A inducers. [41911] [49229] [49236] [49352] [57048] [57271] [65314] [67203] [69024] (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers. [28315] [46638] (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] Butalbital; Acetaminophen; Caffeine; Codeine: (Contraindicated) Ritonavir-boosted nirmatrelvir is contraindicated for use within 2 weeks of administering barbiturates; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response. The risk for reduced efficacy may persist following barbiturate discontinuation. Nirmatrelvir is a CYP3A substrate and barbiturates are strong CYP3A inducers. [41911] [49229] [49236] [49352] [57048] [57271] [65314] [67203] [69024] (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers. [28315] [46638] (Major) Consider withholding codeine if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. Coadministration may increase codeine exposure, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nirmatrelvir is a CYP3A inhibitor. [33654] [65314] (Moderate) Concomitant use of codeine with ritonavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of ritonavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ritonavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ritonavir is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. [33654] [34883] [47165] (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] Butalbital; Aspirin; Caffeine; Codeine: (Contraindicated) Ritonavir-boosted nirmatrelvir is contraindicated for use within 2 weeks of administering barbiturates; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response. The risk for reduced efficacy may persist following barbiturate discontinuation. Nirmatrelvir is a CYP3A substrate and barbiturates are strong CYP3A inducers. [41911] [49229] [49236] [49352] [57048] [57271] [65314] [67203] [69024] (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers. [28315] [46638] (Major) Consider withholding codeine if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. Coadministration may increase codeine exposure, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nirmatrelvir is a CYP3A inhibitor. [33654] [65314] (Moderate) Concomitant use of codeine with ritonavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of ritonavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ritonavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ritonavir is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. [33654] [34883] [47165] Cabazitaxel: (Major) Avoid coadministration of cabazitaxel with ritonavir if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and ritonavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%. [40981] [47165] Cabotegravir: (Contraindicated) Coadministration of cabotegravir and ritonavir is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; ritonavir is an inducer of UGT. Coadministration with another UGT inducer decreased cabotegravir exposure by 59%. [47165] [66315] Cabotegravir; Rilpivirine: (Contraindicated) Coadministration of cabotegravir and ritonavir is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; ritonavir is an inducer of UGT. Coadministration with another UGT inducer decreased cabotegravir exposure by 59%. [47165] [66315] Cabozantinib: (Major) Avoid concomitant use of cabozantinib and ritonavir due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with ritonavir 2 to 3 days after discontinuation of ritonavir. Cabozantinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%. [34557] [52506] [60738] Calcifediol: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with ritonavir. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with ritonavir. Ritonavir, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol. [60895] Calcium, Magnesium, Potassium, Sodium Oxybates: (Major) One case report describes a possible interaction between sodium oxybate and ritonavir and saquinavir, leading to repetitive, clonic contractions. The patient also experienced shallow respirations, a heart rate of 40 beats per min, and was responsive only to painful stimuli. The exact contribution of ritonavir and saquinavir to this reaction cannot be determined since several other compounds were detected through a urinary toxin screen. [2546] Canagliflozin: (Major) Increase the canagliflozin dose to 200 mg/day in persons who are tolerating canagliflozin 100 mg/day and receiving concomitant ritonavir. The canagliflozin dose may be further increased to 300 mg/day for persons with an eGFR of 60 mL/minute/1.73 m2 or more who require additional glycemic control; consider adding another antihyperglycemic agent for persons with an eGFR less than 60 mL/minute/1.73 m2 who require additional glycemic control. Canagliflozin is an UGT1A9 and UGT2B4 substrate, and ritonavir is an UGT inducer. Coadministration with a nonselective inducer of several UGT enzymes decreased canagliflozin exposure by 51%. This decrease in exposure may decrease canagliflozin efficacy. [30575] [53972] Canagliflozin; Metformin: (Major) Increase the canagliflozin dose to 200 mg/day in persons who are tolerating canagliflozin 100 mg/day and receiving concomitant ritonavir. The canagliflozin dose may be further increased to 300 mg/day for persons with an eGFR of 60 mL/minute/1.73 m2 or more who require additional glycemic control; consider adding another antihyperglycemic agent for persons with an eGFR less than 60 mL/minute/1.73 m2 who require additional glycemic control. Canagliflozin is an UGT1A9 and UGT2B4 substrate, and ritonavir is an UGT inducer. Coadministration with a nonselective inducer of several UGT enzymes decreased canagliflozin exposure by 51%. This decrease in exposure may decrease canagliflozin efficacy. [30575] [53972] (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30480] [30575] Capivasertib: (Major) Avoid coadministration of capivasertib with ritonavir due to increased capivasertib exposure which may increase the risk for capivasertib-related adverse effects. If coadministration is necessary, reduce the dose of capivasertib to 320 mg PO twice daily for 4 days followed by 3 days off; monitor for adverse reactions. Capivasertib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor is predicted to increase the overall exposure of capivasertib by up to 1.7-fold. [56579] [69896] Capmatinib: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with ritonavir is necessary. Capmatinib is a CYP3A substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%. [47165] [56579] [65377] Carbamazepine: (Contraindicated) Ritonavir-boosted nirmatrelvir is contraindicated for use within 2 weeks of administering carbamazepine; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response. The risk for reduced efficacy may persist following carbamazepine discontinuation. Nirmatrelvir is a CYP3A substrate and carbamazepine is a strong CYP3A inducer. [41237] [65314] [67203] [69024] (Major) Avoid concomitant use of ritonavir and carbamazepine. Concomitant use may increase carbamazepine exposure, resulting in toxicity and/or decrease ritonavir exposure, resulting in reduced efficacy. If concomitant use is necessary, monitor for reduced virologic response and for carbamazepine toxicity; a carbamazepine dose reduction may be needed. Ritonavir is a CYP3A and P-gp substrate and CYP3A inducer; carbamazepine is a CYP3A and P-gp inducer. [28315] [46638] Cariprazine: (Major) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. When a strong CYP3A4 inhibitor, such as ritonavir, is initiated in a patient who is on a stable dose of cariprazine, reduce the cariprazine dosage by half. For adult patients taking cariprazine 4.5 mg daily, the dosage should be reduced to 1.5 mg or 3 mg daily. For patients taking cariprazine 1.5 mg daily, the dosing frequency should be adjusted to every other day. When the CYP3A4 inhibitor is withdrawn, the cariprazine dosage may need to be increased. When initiating cariprazine in a patient who is stable on a strong CYP3A4 inhibitor, the patient should be administered 1.5 mg of cariprazine on Day 1 and on Day 3 with no dose administered on Day 2. From Day 4 onward, the dose should be administered at 1.5 mg daily, then increased to a maximum dose of 3 mg daily. When the CYP3A4 inhibitor is withdrawn, the cariprazine dosage may need to be increased. [28341] [60164] Carteolol: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers. [5044] Carvedilol: (Moderate) Inhibitors of the hepatic CYP450 isozyme CYP2D6, such as ritonavir, may inhibit the hepatic oxidative metabolism of carvedilol. In addition, both drugs are inhibitors and subtrates for P-glycoprotein (P-gp). Close monitoring of serum drug concentrations and/or therapeutic and adverse effects is required when carvedilol is coadministered with ritonavir. [4718] [5044] [5267] Celecoxib; Tramadol: (Major) Tramadol is primarily metabolized by CYP2D6 and CYP3A4; drugs that inhibit these enzymes, such as ritonavir, may decrease the metabolism of tramadol. This may result in a decreased concentration of the active metabolite (O-desmethyltramadol) leading to decreased analgesic effects and possibly increased side effects (seizures and serotonin syndrome) due to higher tramadol concentrations. [40255] [5043] [9316] (Moderate) Monitor for decreased analgesic effects and possibly increased side effects (seizures and serotonin syndrome) when administering tramadol concurrently with ritonavir-boosted nirmatrelvir. Tramadol is primarily metabolized by CYP2D6 and CYP3A4; drugs that inhibit these enzymes, such as ritonavir-boosted nirmatrelvir, may decrease the metabolism of tramadol. This may result in a decreased concentration of the active metabolite (O-desmethyltramadol) and increased concentrations of tramadol. [32475] [65314] Cenobamate: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of cenobamate is necessary. Concomitant use of nirmatrelvir and cenobamate may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. [64768] [67203] (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with cenobamate. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. [64768] [67203] Ceritinib: (Major) Avoid concomitant use of ceritinib with ritonavir due to increased ceritinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is necessary, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg and monitor for ceritinib-related adverse reactions. After ritonavir is discontinued, resume the dose of ceritinib taken prior to initiating ritonavir. Ceritinib is a CYP3A substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A inhibitor increased ceritinib exposure by 2.9-fold. [47165] [57094] Cetirizine: (Moderate) Coadministration of cetirizine and ritonavir resulted in a 42% increase in the AUC, 53% increase in half-life, and 29% decrease in clearance of cetirizine. Cetirizine did not alter ritonavir disposition. [28874] [33350] Cetirizine; Pseudoephedrine: (Moderate) Coadministration of cetirizine and ritonavir resulted in a 42% increase in the AUC, 53% increase in half-life, and 29% decrease in clearance of cetirizine. Cetirizine did not alter ritonavir disposition. [28874] [33350] Chloramphenicol: (Moderate) Concurrent administration of chloramphenicol with ritonavir may result in elevated plasma concentrations of ritonavir, and subsequent adverse events. Chloramphenicol is an inhibitor of the hepatic isoenzyme CYP3A4; ritonavir is a substrate of this enzyme. Monitor patient for ritonavir-related adverse events. [29624] [58664] Chlordiazepoxide: (Major) Consider withholding chlordiazepoxide, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the chlordiazepoxide dose. However, do not stop chlordiazepoxide abruptly or rapidly reduce the dose as this may precipitate an acute withdrawal reaction, especially in patients who have been receiving high doses over an extended period. Coadministration may increase chlordiazepoxide exposure resulting in increased toxicity and excessive sedation. Chlordiazepoxide is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed. [32432] [5286] Chlordiazepoxide; Amitriptyline: (Major) Consider withholding chlordiazepoxide, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the chlordiazepoxide dose. However, do not stop chlordiazepoxide abruptly or rapidly reduce the dose as this may precipitate an acute withdrawal reaction, especially in patients who have been receiving high doses over an extended period. Coadministration may increase chlordiazepoxide exposure resulting in increased toxicity and excessive sedation. Chlordiazepoxide is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed. [32432] [5286] (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with ritonavir is necessary; a dose reduction of the TCA may be necessary. Concurrent use may increase exposure of the TCA. TCAs are CYP2D6 substrates and ritonavir is a CYP2D6 inhibitor. [47165] Chlordiazepoxide; Clidinium: (Major) Consider withholding chlordiazepoxide, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the chlordiazepoxide dose. However, do not stop chlordiazepoxide abruptly or rapidly reduce the dose as this may precipitate an acute withdrawal reaction, especially in patients who have been receiving high doses over an extended period. Coadministration may increase chlordiazepoxide exposure resulting in increased toxicity and excessive sedation. Chlordiazepoxide is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed. [32432] [5286] Chlorpheniramine: (Moderate) Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together. [34390] [47165] [57935] [58664] Chlorpheniramine; Codeine: (Major) Consider withholding codeine if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. Coadministration may increase codeine exposure, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nirmatrelvir is a CYP3A inhibitor. [33654] [65314] (Moderate) Concomitant use of codeine with ritonavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of ritonavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ritonavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ritonavir is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. [33654] [34883] [47165] (Moderate) Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together. [34390] [47165] [57935] [58664] Chlorpheniramine; Dextromethorphan: (Moderate) Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together. [34390] [47165] [57935] [58664] Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together. [34390] [47165] [57935] [58664] Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together. [34390] [47165] [57935] [58664] Chlorpheniramine; Hydrocodone: (Major) Consider withholding hydrocodone, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the hydrocodone dose. Coadministration may increase hydrocodone exposure, resulting in prolonged opioid effects including fatal respiratory depression. Hydrocodone is metabolized by CYP3A4 and nirmatrelvir is a CYP3A inhibitor. [56303] [65314] [67203] [69024] (Moderate) Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together. [34390] [47165] [57935] [58664] (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ritonavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ritonavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. [30379] [30391] [47165] [56303] [58531] Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together. [34390] [47165] [57935] [58664] Chlorpheniramine; Phenylephrine: (Moderate) Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together. [34390] [47165] [57935] [58664] Chlorpheniramine; Pseudoephedrine: (Moderate) Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together. [34390] [47165] [57935] [58664] Ciclesonide: (Moderate) Coadministration of ciclesonide with ritonavir may cause elevated ciclesonide serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Ciclesonide is a CYP3A4 substrate; ritonavir is a strong inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use. [28341] [47165] Cidofovir: (Moderate) Additive adverse effects may be seen when cidofovir is given with other agents that cause neutropenia. Patients receiving anti-retroviral protease inhibitors in combination with cidofovir may have an increased risk of iritis or uveitis. [24859] Cilostazol: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with protease inhibitors and monitor for an increase in cilostazol-related adverse reactions. Concurrent use may increase cilostazol exposure. Cilostazol is a CYP3A substrate; protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a strong CYP3A inhibitor increased the cilostazol AUC by 117%. Coadministration with a moderate CYP3A inhibitor increased the AUC of cilostazol (single dose) by 73%; the AUC of 4-trans-hydroxycilostazol increased by 141%. [29012] [47165] [48620] Cimetidine: (Moderate) Concurrent administration of cimetidine with ritonavir may result in elevated plasma concentrations of ritonavir. Cimetidine is an inhibitor of the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is partially metabolized by both of these enzymes. Monitor for adverse events if these drugs are administered together. [34364] [56579] [57012] [58664] Cinacalcet: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of ritonavir and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%. [28126] [47165] [58664] Cisapride: (Contraindicated) Concomitant use of protease inhibitors and cisapride is contraindicated; use increases cisapride exposure and the risk for cisapride-related adverse effects such as QT/QTc prolongation and torsade de pointes (TdP). Cisapride is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Concomitant use of cisapride with CYP3A inhibitors also is disallowed under the Propulsid Limited Access Program. [46638] [69152] (Major) Avoid concomitant use of ritonavir-boosted nirmatrelvir and cisapride and consider an alternative COVID-19 therapy. Coadministration may increase cisapride exposure resulting in increased toxicity. Cisapride is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] Clarithromycin: (Major) Because the exposure to 14-OH clarithromycin is significantly decreased by ritonavir, consider alternative antibiotic therapy for indications other than Mycobacterium avium. Clarithromycin doses above 1000 mg should not be administered with ritonavir. If coadministration cannot be avoided, clarithromycin dosage reductions are recommended in patients with renal impairment (CrCl 30 to 60 mL/minute, decrease clarithromycin by 50%; CrCl less than 30 mL/minute, decrease clarithromycin by 75%). Concomitant administration of ritonavir and clarithromycin resulted in a 77% increase in clarithromycin exposure and a 100% decrease in 14-OH clarithromycin exposure. The microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria. [28238] [46638] [47165] Clevidipine: (Moderate) Ritonavir is expected to decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. [5044] Clindamycin: (Moderate) Monitor for an increase in clindamycin-related adverse reactions with coadministration of ritonavir as concurrent use may increase clindamycin exposure. Clindamycin is a CYP3A4 substrate; ritonavir is a strong inhibitor of CYP3A4. [44982] [47165] Clobazam: (Major) Consider withholding clobazam, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the clobazam dose. However, do not stop clobazam abruptly or rapidly reduce the dose as this may precipitate an acute withdrawal reaction, especially in patients who have been receiving high doses over an extended period. Coadministration may increase clobazam exposure resulting in increased toxicity and excessive sedation. Clonazepam is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. Also, concurrent use may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and clobazam is a weak CYP3A inducer. [46370] [67203] (Moderate) Monitor for reduced response to ritonavir and increased adverse effects from both clobazam and ritonavir during concurrent use. Coadministration may result in elevated plasma concentrations of clobazam and altered concentrations of ritonavir. Clobazam is a substrate of CYP3A4, weak inducer of CYP3A4, and an inhibitor of CYP2D6. Ritonavir is a substrate of CYP3A4 and CYP2D6. Ritonavir is also a strong inhibitor of CYP3A4. [46370] [47165] Clofarabine: (Moderate) Concomitant use of clofarabine, a substrate of OCT1, and ritonavir, an inhibitor of OCT1, may result in increased clofarabine levels. Therefore, monitor for signs of clofarabine toxicity such as gastrointestinal toxicity (e.g., nausea, vomiting, diarrhea, mucosal inflammation), hematologic toxicity, and skin toxicity (e.g., hand and foot syndrome, rash, pruritus) in patients also receiving OCT1 inhibitors. [51834] [54578] Clomipramine: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with ritonavir is necessary; a dose reduction of the TCA may be necessary. Concurrent use may increase exposure of the TCA. TCAs are CYP2D6 substrates and ritonavir is a CYP2D6 inhibitor. [47165] Clonazepam: (Major) Consider withholding clonazepam, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the clonazepam dose. However, do not stop clonazepam abruptly or rapidly reduce the dose as this may precipitate an acute withdrawal reaction, especially in patients who have been receiving high doses over an extended period. Coadministration may increase clonazepam exposure resulting in increased toxicity and excessive sedation. Clonazepam is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [41554] [65314] [67203] [69024] (Moderate) Monitor for increased sedation and respiratory depression if clonazepam is coadministered with protease inhibitors; adjust the dose of clonazepam if necessary. The systemic exposure of clonazepam may be increased resulting in an increase in treatment-related adverse reactions. Clonazepam is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. [28315] [29012] [32432] [41554] Clopidogrel: (Major) Avoid concomitant use of clopidogrel and ritonavir due to the risk for decreased clopidogrel efficacy. Consider the use of an alternative antiplatelet agent such as prasugrel. Ritonavir has been observed to decrease the concentration of clopidogrel's active metabolite by 69% and significantly reduce clopidogrel's antiplatelet activity as measured by the VerifyNow P2Y12 assay. Clopidogrel may be converted to its active metabolite partially via CYP3A; ritonavir is a strong CYP3A inhibitor. [46638] [65314] [67902] (Major) Avoid concomitant use of ritonavir-boosted nirmatrelvir and clopidogrel and consider an alternative COVID-19 therapy. Coadministration may reduce clopidogrel exposure and increase the risk of developing a clot. It may be acceptable to continue clopidogrel if the benefit of ritonavir-boosted nirmatrelvir treatment outweighs the risk of reduced clopidogrel effectiveness. For patients at very high risk of thrombosis (e.g., those who received a coronary stent within the past 6 weeks), consider prescribing an alternative antiplatelet agent or an alternative COVID-19 therapy. [65314] [69024] Clorazepate: (Major) Consider withholding clorazepate, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the clorazepate dose. However, do not stop clorazepate abruptly or rapidly reduce the dose as this may precipitate an acute withdrawal reaction, especially in patients who have been receiving high doses over an extended period. Coadministration may increase clorazepate exposure resulting in increased toxicity and excessive sedation. Clorazepate is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of N-desmethyldiazepam, the active metabolite of clorazepate, and increase the potential for benzodiazepine toxicity. Monitor patients closely who receive concurrent therapy. [46638] [4718] [5074] Clozapine: (Major) Avoid concurrent use of ritonavir-boosted nirmatrelvir and clozapine; consider an alternative COVID-19 therapy. If concurrent use is necessary, consider reducing the clozapine dose and monitoring for adverse reactions. Coadministration may increase clozapine exposure resulting in increased toxicity. Clozapine is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Major) Consider a clozapine dose adjustment if coadministered with ritonavir and monitor for efficacy and adverse reactions. If ritonavir is discontinued, monitor for lack of clozapine effect and adverse effects and adjust dose if necessary. A clinically relevant increase or decrease in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4, CYP2D6, and CYP1A2. Ritonavir is a strong CYP3A4 and weak CYP2D6 inhibitor and a moderate inducer of CYP1A2. [28262] [47165] [56579] Cobicistat: (Contraindicated) Use of ritonavir with cobicistat is not recommended, because of similar effects on CYP3A. Both ritonavir and cobicistat are potent inhibitors of CYP3A4. [51664] [58000] [58761] [58763] Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with ritonavir due to the risk of cobimetinib toxicity. Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; ritonavir is a P-gp inhibitor as well as a strong CYP3A inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). [28380] [34557] [47165] [60281] Cocaine: (Moderate) Concurrent use of cocaine with ritonavir may result in elevated plasma concentrations of cocaine and ritonavir. Cocaine is a substrate/inhibitor of CYP3A4 and an inhibitor of CYP2D6; ritonavir is a substrate/inhibitor of both these enzymes. While single uses of topical cocaine for local anethesia would not be expected to have clinically significant interactions, users of systemic cocaine could experience adverse events. [57067] [58664] Codeine: (Major) Consider withholding codeine if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. Coadministration may increase codeine exposure, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nirmatrelvir is a CYP3A inhibitor. [33654] [65314] (Moderate) Concomitant use of codeine with ritonavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of ritonavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ritonavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ritonavir is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. [33654] [34883] [47165] Codeine; Guaifenesin: (Major) Consider withholding codeine if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. Coadministration may increase codeine exposure, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nirmatrelvir is a CYP3A inhibitor. [33654] [65314] (Moderate) Concomitant use of codeine with ritonavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of ritonavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ritonavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ritonavir is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. [33654] [34883] [47165] Codeine; Guaifenesin; Pseudoephedrine: (Major) Consider withholding codeine if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. Coadministration may increase codeine exposure, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nirmatrelvir is a CYP3A inhibitor. [33654] [65314] (Moderate) Concomitant use of codeine with ritonavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of ritonavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ritonavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ritonavir is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. [33654] [34883] [47165] Codeine; Phenylephrine; Promethazine: (Major) Consider withholding codeine if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. Coadministration may increase codeine exposure, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nirmatrelvir is a CYP3A inhibitor. [33654] [65314] (Moderate) Concomitant use of codeine with ritonavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of ritonavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ritonavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ritonavir is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. [33654] [34883] [47165] Codeine; Promethazine: (Major) Consider withholding codeine if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. Coadministration may increase codeine exposure, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nirmatrelvir is a CYP3A inhibitor. [33654] [65314] (Moderate) Concomitant use of codeine with ritonavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of ritonavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ritonavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ritonavir is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. [33654] [34883] [47165] Colchicine: (Major) Avoid concomitant use of colchicine and ritonavir due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a CYP3A and P-gp substrate and ritonavir is a dual strong CYP3A and P-gp inhibitor. Concomitant use has been observed to increase colchicine overall exposure by 4-fold. [28380] [34557] [36114] [47165] [58111] [63965] [69117] (Major) Concomitant use of ritonavir-boosted nirmatrelvir and colchicine is contraindicated in patients with renal and/or hepatic impairment. Consider temporary discontinuation of colchicine during treatment with ritonavir-boosted nirmatrelvir and for at least 2 to 3 days after treatment completion; if not feasible, consider alternative COVID-19 therapy. Coadministration may increase colchicine exposure resulting in increased toxicity. Colchicine is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] Conivaptan: (Contraindicated) Coadministration of conivaptan and ritonavir is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a CYP3A substrate; ritonavir is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold. [31764] [47165] Conjugated Estrogens: (Moderate) In vitro and in vivo studies have shown that estrogens are metabolized partially by CYP3A4. Inhibitors of CYP3A4, such as ritonavir, may increase the exposure of conjugated estrogens resulting in an increased risk of estrogen-related side effects or endometrial hyperplasia. Therefore, when chronically coadministering ritonavir (more than 30 days) with conjugated estrogens, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. Patients should report any breakthrough bleeding or adverse events to their prescribers. [28315] [56074] Conjugated Estrogens; Bazedoxifene: (Moderate) In vitro and in vivo studies have shown that estrogens are metabolized partially by CYP3A4. Inhibitors of CYP3A4, such as ritonavir, may increase the exposure of conjugated estrogens resulting in an increased risk of estrogen-related side effects or endometrial hyperplasia. Therefore, when chronically coadministering ritonavir (more than 30 days) with conjugated estrogens, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. Patients should report any breakthrough bleeding or adverse events to their prescribers. [28315] [56074] Conjugated Estrogens; Medroxyprogesterone: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with ritonavir, a strong CYP3A inhibitor should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is metabolized primarily by hydroxylation via the CYP3A4 in vitro. [28380] [34557] [47165] [57648] (Moderate) In vitro and in vivo studies have shown that estrogens are metabolized partially by CYP3A4. Inhibitors of CYP3A4, such as ritonavir, may increase the exposure of conjugated estrogens resulting in an increased risk of estrogen-related side effects or endometrial hyperplasia. Therefore, when chronically coadministering ritonavir (more than 30 days) with conjugated estrogens, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. Patients should report any breakthrough bleeding or adverse events to their prescribers. [28315] [56074] Copanlisib: (Major) Avoid the concomitant use of copanlisib and ritonavir if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; ritonavir is a strong CYP3A inhibitor. [47165] [62347] Crizotinib: (Major) Avoid concomitant use of crizotinib and ritonavir due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%. [45458] [47165] [56579] Cyclophosphamide: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. [65780] [65781] [65782] Cyclosporine: (Major) Before prescribing ritonavir-boosted nirmatrelvir for a patient receiving cyclosporine, the patient's specialist provider(s) should be consulted, given the significant drug-drug interaction potential and because close monitoring may not be feasible. If this is not feasible, consider an alternative COVID-19 therapy. Coadministration may increase cyclosporine exposure resulting in increased toxicity. Cyclosporine is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [28404] [65314] [67203] [69024] (Moderate) An interaction is anticipated to occur with protease inhibitors and cyclosporine, as CYP3A4 is inhibited by protease inhibitors and cyclosporine is a CYP3A4 substrate. Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with an anti-retroviral protease inhibitor is necessary. In a study of 18 HIV-infected patients who underwent renal or hepatic transplant and received concomitant therapy with protease inhibitors and cyclosporine, there was a 3-fold increase in cyclosporine AUC resulting in an 85% reduction in cyclosporine dose over a 2-year period. In another study, HIV-infected, liver and kidney transplant patients required 4- to 5-fold reductions in cyclosporine dose and approximate 50% increases in dosing interval when cyclosporine was coadministered with protease inhibitors. Consider a reduction in cyclosporine dose to 25 mg every 1 to 2 days when coadministered with a boosted protease inhibitor. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased from 150 to 200 mcg/mL up to 580 mcg/mL. Dosages of both agents were decreased by 50% leading to resolution of symptoms. [28142] [28341] [28404] [28839] [28995] [29198] [32432] [65478] [65479] [65481] [65482] [65483] Dabigatran: (Major) Depending on the patients renal function and dabigatran indication, concomitant use with ritonavir-boosted nirmatrelvir should either be avoided, or the dose of dabigatran should be reduced. Coadministration increases dabigatran exposure and maximum plasma concentration resulting in increased bleeding risk. Dabigatran is a P-glycoprotein (P-gp) substrate and nirmatrelvir is a P-gp inhibitor. [67203] (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with ritonavir is necessary in patients with creatinine clearance (CrCl) greater than 50 mL/minute. Avoid coadministration in patients with CrCl less than 50 mL/minute when dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery. Avoid coadministration in patients with CrCl less than 30 mL/minute in patients with non-valvular atrial fibrillation. Serum concentrations of dabigatran are expected to be higher in patients with renal impairment compared to patients with normal renal function. Dabigatran is a P-gp substrate and ritonavir is a P-gp inhibitor. [28380] [34557] [42121] Dabrafenib: (Major) The concomitant use of dabrafenib, a CYP3A4 substrate and a moderate CYP3A4 inducer, and ritonavir, a strong CYP3A4 inhibitor and a CYP3A4 substrate and inducer, may result in altered levels of either agent; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib or ritonavir adverse effects and/or reduced efficacy. [28315] [54802] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of dabrafenib is necessary. Concomitant use of nirmatrelvir and dabrafenib may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and dabrafenib is a moderate CYP3A inducer. [54802] [67203] Dapagliflozin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] [51227] Dapagliflozin; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] [51227] (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30480] [30575] Dapagliflozin; Saxagliptin: (Major) The metabolism of saxagliptin is primarily mediated by CYP3A4/5. The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP3A4/5 inhibitor such as ritonavir. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have also been reported with use of anti-retroviral protease inhibitors, such as ritonavir. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] [36111] [51227] (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] [51227] Dapsone: (Moderate) Concurrent administration of dapsone with ritonavir may result in elevated dapsone plasma concentrations. Dapsone is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [11191] [47165] [58664] Daridorexant: (Major) Avoid concomitant use of daridorexant and ritonavir. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%. [47165] [67248] Darifenacin: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with ritonavir due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. [30711] [47165] Darolutamide: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with ritonavir is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Ritonavir is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively. [28380] [34557] [47165] [64525] Darunavir; Cobicistat: (Contraindicated) Use of ritonavir with cobicistat is not recommended, because of similar effects on CYP3A. Both ritonavir and cobicistat are potent inhibitors of CYP3A4. [51664] [58000] [58761] [58763] Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Contraindicated) Use of ritonavir with cobicistat is not recommended, because of similar effects on CYP3A. Both ritonavir and cobicistat are potent inhibitors of CYP3A4. [51664] [58000] [58761] [58763] Dasatinib: (Major) Avoid coadministration of dasatinib and ritonavir due to the potential for increased dasatinib exposure and subsequent toxicity including QT prolongation and torsade de pointes (TdP). An alternative to ritonavir with no or minimal enzyme inhibition potential is recommended if possible. If coadministration cannot be avoided, consider a dasatinib dose reduction to 40 mg PO daily if original dose was 140 mg daily, 20 mg PO daily if original dose was 100 mg daily, or 20 mg PO daily if original dose was 70 mg daily. Concomitant use of ritonavir is not recommended in patients receiving dasatinib 60 mg or 40 mg daily. If dasatinib is not tolerated after dose reduction, consider alternative therapies. If ritonavir is stopped, allow a washout of approximately 1 week before increasing the dasatinib dose. Dasatinib is a CYP3A4 substrate that has the potential to prolong the QT interval; ritonavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of dasatinib by 4-fold and 5-fold, respectively. [47165] [60087] Deferasirox: (Major) Deferasirox undergoes UGT metabolism, and ritonavir is a potent inducer of this enzyme system. The concomitant administration of deferasirox (single dose of 30 mg/kg) and the potent UGT inducer rifampin (i.e., rifampicin 600 mg/day for 9 days) resulted in a decrease in deferasirox AUC by 44%. Although specific drug interaction studies of deferasirox and ritonavir are not available, a similar interaction may occur. Avoid the concomitant use of ritonavir and deferasirox if possible. If ritonavir and deferasirox coadministration is necessary, consider increasing the initial dose of deferasirox. Monitor serum ferritin concentrations and clinical response for further modifications. [31807] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of deferasirox is necessary. Concomitant use of nirmatrelvir and deferasirox may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and deferasirox is a weak CYP3A inducer. [31807] [67203] Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with ritonavir. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; ritonavir is a strong inhibitor of CYP3A4. Administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold. [47165] [61750] Delavirdine: (Moderate) Monitor for increased toxicity of ritonavir during coadministration of delavirdine. Appropriate doses of ritonavir in combination with delavirdine with respect to safety and efficacy have not been established. The exposure to ritonavir has been increased by 70% during concurrent administration of delavirdine. [28476] [46638] [47165] Desipramine: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with ritonavir is necessary; a dose reduction of the TCA may be necessary. Concurrent use may increase exposure of the TCA. TCAs are CYP2D6 substrates and ritonavir is a CYP2D6 inhibitor. [47165] Desogestrel; Ethinyl Estradiol: (Major) Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. [46638] [5044] (Major) The FDA recommends consideration of an additional, non-hormonal method of contraception during the 5 days of treatment with ritonavir-boosted nirmatrelvir and until one menstrual cycle after stopping ritonavir-boosted nirmatrelvir. However, the NIH COVID-19 guidelines suggest the potential decrease in ethinyl estradiol exposure is not expected to be clinically significant during the 5 days of therapy. [65314] [67203] [69024] Dexamethasone: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of dexamethasone is necessary. Concomitant use of nirmatrelvir and dexamethasone may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and dexamethasone is a CYP3A inducer. [67203] [69153] (Moderate) Monitor for steroid-related adverse reactions and a decrease in ritonavir efficacy if concomitant use of dexamethasone and ritonavir is necessary. If long term coadministration is required, consider using an alternative corticosteroid, such as prednisone or prednisolone. Concomitant use may increase dexamethasone concentrations and decrease ritonavir exposure. Dexamethasone is a CYP3A substrate and CYP3A inducer; ritonavir is a CYP3A substrate and strong CYP3A inhibitor. Another strong CYP3A inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects. [46638] [47165] [69153] Dexlansoprazole: (Moderate) Concurrent administration of dexlansoprazole with ritonavir may result in elevated dexlansoprazole plasma concentrations. Dexlansoprazole is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and monitoring for adverse effects are advised if these drugs are administered together. [40029] [47165] [58664] Dexmedetomidine: (Moderate) Use caution if ritonavir is coadministered with dexmedetomidine due to the potential for decreased dexmedetomidine exposure which may decrease its efficacy. Limited data suggests that dexmedetomidine is metabolized by several enzymes, including CYP2C19. Ritonavir is an inducer of CYP2C19. [47165] [65210] [65222] Dextroamphetamine: (Moderate) Warn patients that the risk of amphetamine toxicity may be increased during concurrent use of ritonavir, a strong CYP2D6 inhibitor. Amphetamines are partially metabolized by CYP2D6 and have serotonergic properties; inhibition of amphetamine metabolism may increase the risk of serotonin syndrome or other toxicity. If serotonin syndrome occurs, both the amphetamine and CYP2D6 inhibitor should be discontinued and appropriate medical treatment should be implemented. [25887] [29219] [33263] [47165] [57067] Dextromethorphan; Bupropion: (Moderate) Concurrent administration of bupropion with ritonavir results in decreased concentrations of bupropion and its active metabolite. According to the manufacturers of bupropion, increased doses of bupropion may be necessary during concurrent therapy; however, the maximum recommended dose of bupropion should not be exceeded. Closely monitor bupropion efficacy if these drugs are given together. Ritonavir induces CYP2B6, which is responsible for bupropion's metabolism. In one study, ritonavir 100 mg twice daily reduced the AUC and Cmax of bupropion by 22% and 21%, respectively. In addition, exposure to the active metabolite of bupropion (hydroxybupropion) was decreased by 23%. When given with ritonavir 600 mg twice daily, the AUC and Cmax of bupropion decreased by 66% and 63% respectively and exposure to hydroxybupropion decreased by 78%. [28058] [28315] [34743] [34744] [34745] [34746] [44095] Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Concurrent administration of diphenhydramine with ritonavir may result in elevated plasma concentrations of diphenhydramine. Diphenhydramine is a CYP2D6 substrate, and ritonavir is a CYP2D6 inhibitor. Caution and close monitoring are advised if these drugs are administered together. [34522] [34523] [47165] [58664] Dextromethorphan; Quinidine: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and quinidine is contraindicated; consider an alternative COVID-19 therapy. Coadministration may increase quinidine exposure resulting in increased toxicity. Quinidine is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Major) Coadministration of HIV treatment doses of ritonavir and quinidine is contraindicated due to the potential for serious or life-threatening reactions, such as cardiac arrhythmias. Cautious consideration may be given to administering quinidine with boosting doses of ritonavir. Ritonavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, such as quinidine, should be expected with concurrent use. [28315] [42280] [46638] [47165] [47357] Diazepam: (Major) Consider withholding diazepam, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the diazepam dose. However, do not stop diazepam abruptly or rapidly reduce the dose as this may precipitate an acute withdrawal reaction, especially in patients have been receiving high doses over an extended period. Coadministration may increase diazepam exposure resulting in increased toxicity and excessive sedation. Diazepam is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [64930] [65314] [67203] [69024] (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with protease inhibitors is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and protease inhibitors are moderate to strong CYP3A4 inhibitors. [28142] [28839] [29012] [47165] [64930] Diclofenac: (Moderate) Concurrent administration of diclofenac with ritonavir may result in elevated diclofenac plasma concentrations. Diclofenac is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring for adverse effects are advised if these drugs are administered together. [11181] [47165] [58664] Diclofenac; Misoprostol: (Moderate) Concurrent administration of diclofenac with ritonavir may result in elevated diclofenac plasma concentrations. Diclofenac is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring for adverse effects are advised if these drugs are administered together. [11181] [47165] [58664] Dienogest; Estradiol valerate: (Moderate) Ritonavir has been shown to increase the metabolism of ethinyl estradiol. Ritonavir is a substrate and inhibitor of CYP3A4. It is not known if the effects of protease inhibitors are similar on estradiol; however, estradiol is metabolized by CYP3A4, similar to ethinyl estradiol. [28315] Digoxin: (Major) In a pharmacokinetic study of 11 healthy men, increases in digoxin AUC (86%), volume of distribution, and half-life were seen, while renal and non-renal clearance decreased, when coadministered with ritonavir. It appears that this interaction is mediated by ritonavir's inhibition or P-glycoprotein-mediated renal tubular secretion of digoxin. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including digoxin) has not been evaluated. Measure serum digoxin concentrations before initiating ritonavir or lopinavir; ritonavir. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30 to 50% or by modifying the dosing frequency and continue monitoring. [28272] [28380] [30195] Dihydroergotamine: (Contraindicated) Concomitant use of ergotamine with ritonavir is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. [28852] [56579] [66964] (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and ergot alkaloids is contraindicated; consider an alternative COVID-19 therapy. Coadministration may increase ergot alkaloids' exposure resulting in increased toxicity. Ergot alkaloids are CYP3A substrates and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] Diltiazem: (Moderate) Ritonavir is expected to decrease the hepatic CYP metabolism of diltiazem, resulting in increased diltiazem concentrations. If coadministration of these drugs is warranted, do so with caution and careful monitoring. A decreased diltiazem dose may be warranted. In addition, ritonavir and diltiazem both prolong the PR interval and caution for increased risk is recommended with coadministration. [47165] Diphenhydramine: (Moderate) Concurrent administration of diphenhydramine with ritonavir may result in elevated plasma concentrations of diphenhydramine. Diphenhydramine is a CYP2D6 substrate, and ritonavir is a CYP2D6 inhibitor. Caution and close monitoring are advised if these drugs are administered together. [34522] [34523] [47165] [58664] Diphenhydramine; Ibuprofen: (Moderate) Concurrent administration of diphenhydramine with ritonavir may result in elevated plasma concentrations of diphenhydramine. Diphenhydramine is a CYP2D6 substrate, and ritonavir is a CYP2D6 inhibitor. Caution and close monitoring are advised if these drugs are administered together. [34522] [34523] [47165] [58664] Diphenhydramine; Naproxen: (Moderate) Concurrent administration of diphenhydramine with ritonavir may result in elevated plasma concentrations of diphenhydramine. Diphenhydramine is a CYP2D6 substrate, and ritonavir is a CYP2D6 inhibitor. Caution and close monitoring are advised if these drugs are administered together. [34522] [34523] [47165] [58664] Diphenhydramine; Phenylephrine: (Moderate) Concurrent administration of diphenhydramine with ritonavir may result in elevated plasma concentrations of diphenhydramine. Diphenhydramine is a CYP2D6 substrate, and ritonavir is a CYP2D6 inhibitor. Caution and close monitoring are advised if these drugs are administered together. [34522] [34523] [47165] [58664] Disopyramide: (Major) Avoid concomitant use of ritonavir-boosted nirmatrelvir and disopyramide and consider an alternative COVID-19 therapy. Coadministration may increase disopyramide exposure resulting in increased toxicity. Disopyramide is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Major) Caution is warranted when ritonavir is coadministered with antiarrhythmics, including disopyramide. Ritonavir is an inhibitor of CYP3A4, and increased concentrations of disopyramide may be expected during coadministration. Therapeutic antiarrhythmic concentration monitoring is suggested when available. Monitor therapeutic response closely; dosage reduction may be needed. In some cases, the drug interaction may require more than 50% dosage reduction due to potent inhibitory effects and drug accumulation. Cardiac and neurologic events have been reported when ritonavir was concurrently administered with disopyramide. [28001] [28228] [28315] Disulfiram: (Major) Oral solutions of ritonavir contain ethanol. Administration of ritonavir oral solution to patients receiving or who have recently received disulfiram may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations. [28315] [48545] Docetaxel: (Major) Avoid coadministration of docetaxel with ritonavir if possible due to increased plasma concentrations of docetaxel. If concomitant use is unavoidable, closely monitor for docetaxel-related adverse reactions and consider a 50% dose reduction of docetaxel. Docetaxel is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased docetaxel exposure by 2.2-fold. [47165] [60484] Dofetilide: (Major) Avoid concomitant use of ritonavir-boosted nirmatrelvir and dofetilide and consider an alternative COVID-19 therapy. Coadministration may increase dofetilide exposure resulting in increased toxicity. Dofetilide is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] (Moderate) Concomitant use of dofetilide and ritonavir may increase the risk of QT prolongation and torsade de pointes (TdP) due to increased dofetilide exposure. Dofetilide is metabolized to a small degree by CYP3A4; ritonavir is a potent inhibitor of CYP3A4. [28221] [47165] Donepezil: (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Ritonavir is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate. [29640] [47165] Donepezil; Memantine: (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Ritonavir is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate. [29640] [47165] Doravirine: (Minor) Coadministration of doravirine and ritonavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; ritonavir is a strong inhibitor. In a drug interaction study, concurrent use of ritonavir increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant. [63484] Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, concurrently with inhibitors of P-gp and BCRP, such as ritonavir. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. [28193] [58664] (Minor) Coadministration of doravirine and ritonavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; ritonavir is a strong inhibitor. In a drug interaction study, concurrent use of ritonavir increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant. [63484] Dorzolamide; Timolol: (Moderate) Timolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as ritonavir, may impair timolol metabolism; the clinical significance of such interactions is unknown. [5044] [5270] Doxazosin: (Moderate) Monitor blood pressure and for signs of hypotension during coadministration. The plasma concentrations of doxazosin may be elevated when administered concurrently with ritonavir. Ritonavir is a strong CYP3A4 inhibitor; doxazosin is a CYP3A4 substrate. Coadministration of doxazosin with a moderate CYP3A4 inhibitor resulted in a 10% increase in mean AUC and an insignificant increase in mean Cmax and mean half-life of doxazosin. Although not studied in combination with doxazosin, strong CYP3A4 inhibitors may have a larger impact on doxazosin concentrations and therefore should be used with caution. [29824] [47165] [56579] Doxepin: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with ritonavir is necessary; a dose reduction of the TCA may be necessary. Concurrent use may increase exposure of the TCA. TCAs are CYP2D6 substrates and ritonavir is a CYP2D6 inhibitor. [47165] Doxercalciferol: (Moderate) Protease inhibitors may decrease efficacy of doxercalciferol. Doxercalciferol is converted in the liver to 1,25-dihydroxyergocalciferol, the major active metabolite, and 1-alpha, 24-dihydroxyvitamin D2, a minor metabolite. Although not specifically studied, cytochrome P450 enzyme inhibitors, including protease inhibitors, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if these drugs are administered together. [30802] [49493] Doxorubicin Liposomal: (Major) Avoid coadministration of ritonavir with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Ritonavir is a strong CYP3A4 inhibitor and a P-gp inhibitor; doxorubicin is a CYP3A4 and P-gp substrate. Concurrent use of CYP3A4 and/or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions. [47165] [56361] Doxorubicin: (Major) Avoid coadministration of ritonavir with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Ritonavir is a strong CYP3A4 inhibitor and a P-gp inhibitor; doxorubicin is a CYP3A4 and P-gp substrate. Concurrent use of CYP3A4 and/or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions. [47165] [56361] Dronabinol: (Major) Use caution if coadministration of dronabinol with ritonavir is necessary, and closely monitor for an increase in dronabinol-related adverse reactions (e.g., cognitive impairment, psychosis, seizures, and hemodynamic instability, as well as feeling high, dizziness, confusion, somnolence). Ritonavir is a strong inhibitor of CYP3A4 and a moderate CYP2C9 inducer; it is contraindicated with sensitive drugs that are highly dependent on CYP3A4/5 for clearance. Dronabinol is a CYP2C9 and 3A4 substrate; concomitant use may result in elevated plasma concentrations of dronabinol. [30431] [47165] [60951] Dronedarone: (Contraindicated) Coadministration of dronedarone with ritonavir is contraindicated due to the potential for increased dronedarone exposure and QT prolongation. Dronedarone is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. [36101] [47165] (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and dronedarone is contraindicated; consider an alternative COVID-19 therapy. Coadministration may increase dronedarone exposure resulting in increased toxicity. Dronedarone is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] Drospirenone; Estradiol: (Moderate) Ritonavir has been shown to increase the metabolism of ethinyl estradiol. Ritonavir is a substrate and inhibitor of CYP3A4. It is not known if the effects of protease inhibitors are similar on estradiol; however, estradiol is metabolized by CYP3A4, similar to ethinyl estradiol. [28315] Drospirenone; Ethinyl Estradiol: (Major) Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. [46638] [5044] (Major) The FDA recommends consideration of an additional, non-hormonal method of contraception during the 5 days of treatment with ritonavir-boosted nirmatrelvir and until one menstrual cycle after stopping ritonavir-boosted nirmatrelvir. However, the NIH COVID-19 guidelines suggest the potential decrease in ethinyl estradiol exposure is not expected to be clinically significant during the 5 days of therapy. [65314] [67203] [69024] Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. [46638] [5044] (Major) The FDA recommends consideration of an additional, non-hormonal method of contraception during the 5 days of treatment with ritonavir-boosted nirmatrelvir and until one menstrual cycle after stopping ritonavir-boosted nirmatrelvir. However, the NIH COVID-19 guidelines suggest the potential decrease in ethinyl estradiol exposure is not expected to be clinically significant during the 5 days of therapy. [65314] [67203] [69024] Dulaglutide: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] [50113] [50814] Dutasteride: (Moderate) Concurrent administration of dutasteride with protease inhibitors may result in elevated dutasteride plasma concentrations. Dutasteride is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitors of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [28001] [28875] Dutasteride; Tamsulosin: (Major) Consider withholding tamsulosin, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the tamsulosin dose for patients receiving a dose of 0.8 mg daily. Coadministration may increase tamsulosin exposure resulting in increased hypotension or orthostasis. Tamsulosin is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [29677] [65314] [67203] [69024] (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of anti-retroviral protease inhibitors. Tamsulosin is extensively metabolized by CYP3A4 and CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension. Therefore, concomitant use of tamsulosin with a strong CYP3A4 inhibitor, or an agent with both CYP3A4 and CYP2D6 inhibitor activity, should be avoided. [29677] [4194] [8102] (Moderate) Concurrent administration of dutasteride with protease inhibitors may result in elevated dutasteride plasma concentrations. Dutasteride is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitors of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [28001] [28875] Duvelisib: (Major) Reduce duvelisib dose to 15 mg PO twice daily and monitor for increased toxicity when coadministered with ritonavir. Coadministration may increase the exposure of duvelisib. Duvelisib is a CYP3A substrate; ritonavir is a strong CYP3A inhibitor. The increase in exposure to duvelisib is estimated to be approximately 2-fold when used concomitantly with strong CYP3A inhibitors such as ritonavir. [47165] [63571] Echinacea: (Moderate) Use Echinacea sp. with caution in patients taking medications for human immunodeficiency virus (HIV) infection. Some experts have suggested that Echinacea's effects on the immune system might cause problems for patients with HIV infection, particularly with long-term use. There may be less risk with short-term use (less than 2 weeks). A few pharmacokinetic studies have shown reductions in blood levels of some antiretroviral medications when Echinacea was given, presumably due to CYP induction. However, more study is needed for various HIV treatment regimens. Of the agents studied, the interactions do not appear to be significant or to require dose adjustments at the time of use. Although no dose adjustments are required, monitoring drug concentrations may give reassurance during co-administration. Monitor viral load and other parameters carefully during therapy. [25398] [30456] [61924] [61926] [61927] Edoxaban: (Moderate) Coadministration of edoxaban and ritonavir may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and ritonavir is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of ritonavir; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism. [28315] [58685] Efavirenz: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of efavirenz is necessary. Concomitant use of nirmatrelvir and efavirenz may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. [28442] [67203] [69024] (Moderate) Monitor for elevation of liver enzymes and for adverse clinical experiences (e.g., dizziness, nausea, paresthesia) when efavirenz is coadministered with ritonavir. Concurrent use is is expected to result in increased concentrations of both drugs. [28442] [47165] Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, concurrently with inhibitors of P-gp and BCRP, such as ritonavir. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. [28193] [58664] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of efavirenz is necessary. Concomitant use of nirmatrelvir and efavirenz may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. [28442] [67203] [69024] (Moderate) Monitor for elevation of liver enzymes and for adverse clinical experiences (e.g., dizziness, nausea, paresthesia) when efavirenz is coadministered with ritonavir. Concurrent use is is expected to result in increased concentrations of both drugs. [28442] [47165] Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, concurrently with inhibitors of P-gp and BCRP, such as ritonavir. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. [28193] [58664] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of efavirenz is necessary. Concomitant use of nirmatrelvir and efavirenz may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. [28442] [67203] [69024] (Moderate) Monitor for elevation of liver enzymes and for adverse clinical experiences (e.g., dizziness, nausea, paresthesia) when efavirenz is coadministered with ritonavir. Concurrent use is is expected to result in increased concentrations of both drugs. [28442] [47165] Elacestrant: (Major) Avoid concomitant use of elacestrant and ritonavir due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. Elacestrant is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased elacestrant overall exposure by 5.3-fold. [47165] [68530] Elagolix: (Major) Concomitant use of elagolix 200 mg twice daily and ritonavir for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and ritonavir to 6 months. Monitor for elagolix-related side effects and reduced response to ritonavir. Elagolix is a CYP3A substrate and a weak to moderate CYP3A4 inducer; ritonavir is a strong inhibitor of CYP3A and a CYP3A4 substrate. Coadministration may increase elagolix plasma concentrations and decrease ritonavir concentrations. In drug interaction studies, coadministration of elagolix with another strong CYP3A inhibitor increased the Cmax and AUC of elagolix by 77% and 120%, respectively. [28341] [63387] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of elagolix is necessary. Concomitant use of nirmatrelvir and elagolix may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and elagolix is a moderate CYP3A inducer. [63387] [67203] Elagolix; Estradiol; Norethindrone acetate: (Major) Concomitant use of elagolix 200 mg twice daily and ritonavir for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and ritonavir to 6 months. Monitor for elagolix-related side effects and reduced response to ritonavir. Elagolix is a CYP3A substrate and a weak to moderate CYP3A4 inducer; ritonavir is a strong inhibitor of CYP3A and a CYP3A4 substrate. Coadministration may increase elagolix plasma concentrations and decrease ritonavir concentrations. In drug interaction studies, coadministration of elagolix with another strong CYP3A inhibitor increased the Cmax and AUC of elagolix by 77% and 120%, respectively. [28341] [63387] (Moderate) Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. For example, ritonavir (also found in combinations like lopinavir; ritonavir, and used as a booster in many HIV treatment regimens) may decrease the metabolism of norethindrone, raising norethindrone concentrations. Women receiving norethindrone for hormone replacement or contraception should report potential hormonal adverse effects (e.g., bleeding pattern changes, acne, emotional lability) or any changes in efficacy (e.g., noted changes in bleeding patterns) to their prescribers. Because norethindrone-containing contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive norethindrone contraception concurrently with ritonavir should use an additional barrier method of contraception such as condoms. [58679] [7731] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of elagolix is necessary. Concomitant use of nirmatrelvir and elagolix may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and elagolix is a moderate CYP3A inducer. [63387] [67203] (Moderate) Ritonavir has been shown to increase the metabolism of ethinyl estradiol. Ritonavir is a substrate and inhibitor of CYP3A4. It is not known if the effects of protease inhibitors are similar on estradiol; however, estradiol is metabolized by CYP3A4, similar to ethinyl estradiol. [28315] Elbasvir; Grazoprevir: (Major) Concurrent administration of elbasvir with ritonavir should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ritonavir is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. [47165] [60523] (Major) Concurrent administration of grazoprevir with ritonavir should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ritonavir is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A. In addition, concentrations of ritonavir (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor). [47165] [60523] Eletriptan: (Contraindicated) Due to the potential for serious adverse reactions including cardiovascular and cerebrovascular events, use of eletriptan within 72 hours of ritonavir-boosted nirmatrelvir is contraindicated. Coadministration may increase eletriptan exposure resulting in increased toxicity. Eletriptan is metabolized via CYP3A4 and nirmatrelvir is a CYP3A inhibitor. [67203] [69024] (Contraindicated) Eletriptan is contraindicated for use within 72 hours of using any drug that is a potent CYP3A4 inhibitor as described in the prescribing information of the interacting drug including protease inhibitors. Eletriptan is metabolized via CYP3A4, and coadministration with protease inhibitors may cause increased eletriptan concentrations and thus toxicity. [28341] [47165] Elexacaftor; tezacaftor; ivacaftor: (Major) If ritonavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. [47165] [48524] (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor to twice a week in the morning, approximately 3 to 4 days apart (i.e., Day 1 and Day 4) when coadministered with ritonavir; omit the evening dose of ivacaftor. Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; ritonavir is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased elexacaftor exposure by 2.8- fold, tezacaftor exposure by 4.5-fold, and ivacaftor exposure by 15.6-fold. [47165] [64697] (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with ritonavir; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); ritonavir is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively. [47165] [62870] Eliglustat: (Major) Coadministration of eliglustat and ritonavir is contraindicated in intermediate or poor CYP2D6 metabolizers (IMs or PMs). In extensive CYP2D6 metabolizers (EMs), coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. The coadministration of eliglustat with ritonavir and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients. Eliglustat is a CYP3A and CYP2D6 substrate. Coadministration of eliglustat with CYP3A inhibitors, such as ritonavir, increases eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); this risk is the highest in CYP2D6 IMs and PMs because a larger portion of the eliglustat dose is metabolized via CYP3A. [28341] [47165] [57803] Eltrombopag: (Moderate) Eltrombopag is metabolized by CYP1A2. The significance of administering inducers of CYP1A2, such as ritonavir, on the systemic exposure of eltrombopag has not been established. Monitor patients for a decrease in the efficacy of eltrombopag if these drugs are coadministered. [27493] [28315] [40392] Eluxadoline: (Major) When administered concurrently with ritonavir, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); ritonavir is an OATP1B1 inhibitor. [59741] Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Contraindicated) Use of ritonavir with cobicistat is not recommended, because of similar effects on CYP3A. Both ritonavir and cobicistat are potent inhibitors of CYP3A4. [51664] [58000] [58761] [58763] (Moderate) Concurrent administration of elvitegravir with ritonavir may result in elevated elvitegravir plasma concentrations. Elvitegravir is a substrate of the hepatic isoenzyme CYP3A4. Ritonavir inhibits the CYP3A4 enzyme. Caution and close monitoring are advised if these drugs are administered together. [51664] [58001] [58664] Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Contraindicated) Use of ritonavir with cobicistat is not recommended, because of similar effects on CYP3A. Both ritonavir and cobicistat are potent inhibitors of CYP3A4. [51664] [58000] [58761] [58763] (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, concurrently with inhibitors of P-gp and BCRP, such as ritonavir. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. [28193] [58664] (Moderate) Concurrent administration of elvitegravir with ritonavir may result in elevated elvitegravir plasma concentrations. Elvitegravir is a substrate of the hepatic isoenzyme CYP3A4. Ritonavir inhibits the CYP3A4 enzyme. Caution and close monitoring are advised if these drugs are administered together. [51664] [58001] [58664] Empagliflozin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] [51227] Empagliflozin; Linagliptin: (Moderate) Monitor for changes in glycemic control, specifically hyperglycemia, if ritonavir is administered concurrently with linagliptin. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. [28315] [30575] [31240] [34557] (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] [51227] Empagliflozin; Linagliptin; Metformin: (Moderate) Monitor for changes in glycemic control, specifically hyperglycemia, if ritonavir is administered concurrently with linagliptin. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. [28315] [30575] [31240] [34557] (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] [51227] (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30480] [30575] Empagliflozin; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] [51227] (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30480] [30575] Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, concurrently with inhibitors of P-gp and BCRP, such as ritonavir. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. [28193] [58664] Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, concurrently with inhibitors of P-gp and BCRP, such as ritonavir. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. [28193] [58664] Enasidenib: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of enasidenib is necessary. Concomitant use of nirmatrelvir and enasidenib may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and enasidenib is a CYP3A inducer. [62181] [67203] (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with enasidenib. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and enasidenib is a weak CYP3A inducer. [62181] [67203] Encorafenib: (Contraindicated) Concurrent use of ritonavir and encorafenib is contraindicated due to the risk of decreased ritonavir exposure which may result in loss of virologic control and drug resistance. Concomitant use may also increase encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Ritonavir is a CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold. [47165] [63317] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of encorafenib is necessary. Concomitant use of nirmatrelvir and encorafenib may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and encorafenib is a CYP3A inducer. [63317] [67203] Enfortumab vedotin: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with ritonavir is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; ritonavir is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%. [28380] [34557] [64845] Entrectinib: (Major) Avoid coadministration of entrectinib with ritonavir due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold. [56579] [64567] Enzalutamide: (Contraindicated) Coadministration of ritonavir with enzalutamide is contraindicated as there is a potential for decreased ritonavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is metabolized by CYP3A4; enzalutamide is a strong CYP3A4 inducer. [47165] [51727] (Major) Avoid concomitant use of ritonavir-boosted nirmatrelvir and enzalutamide and consider an alternative COVID-19 therapy. Concomitant use of nirmatrelvir and enzalutamide may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and enzalutamide is a strong CYP3A inducer. [51727] [65314] [67203] Eplerenone: (Contraindicated) Coadministration of ritonavir and eplerenone is contraindicated. Ritonavir potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension. [27990] (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and eplerenone is contraindicated due to the potential for hyperkalemia; consider an alternative COVID-19 therapy. Coadministration may increase eplerenone exposure resulting in increased toxicity. Eplerenone is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] Erdafitinib: (Major) Avoid coadministration of erdafitinib and ritonavir due to the risk for increased plasma concentrations of erdafitinib. If concomitant use is necessary, closely monitor for erdafitinib-related adverse reactions and consider dose modifications as clinically appropriate. Erdafitinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased erdafitinib overall exposure by 134%. [56579] [64064] Ergoloid Mesylates: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and ergot alkaloids is contraindicated; consider an alternative COVID-19 therapy. Coadministration may increase ergot alkaloids' exposure resulting in increased toxicity. Ergot alkaloids are CYP3A substrates and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] Ergot alkaloids: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and ergot alkaloids is contraindicated; consider an alternative COVID-19 therapy. Coadministration may increase ergot alkaloids' exposure resulting in increased toxicity. Ergot alkaloids are CYP3A substrates and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] Ergotamine: (Contraindicated) Concomitant use of ergotamine with ritonavir is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. [28852] [56579] [66964] (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and ergot alkaloids is contraindicated; consider an alternative COVID-19 therapy. Coadministration may increase ergot alkaloids' exposure resulting in increased toxicity. Ergot alkaloids are CYP3A substrates and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] Ergotamine; Caffeine: (Contraindicated) Concomitant use of ergotamine with ritonavir is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. [28852] [56579] [66964] (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and ergot alkaloids is contraindicated; consider an alternative COVID-19 therapy. Coadministration may increase ergot alkaloids' exposure resulting in increased toxicity. Ergot alkaloids are CYP3A substrates and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] Erlotinib: (Major) Avoid coadministration of erlotinib with ritonavir if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%. [30555] [47165] Ertugliflozin; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30480] [30575] Ertugliflozin; Sitagliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] Erythromycin: (Major) Consider temporary discontinuation of erythromycin during treatment with ritonavir-boosted nirmatrelvir and for at least 2 to 3 days after treatment completion; if not feasible, consider alternative COVID-19 therapy. Coadministration may increase nirmatrelvir exposure resulting in increased toxicity. Erythromycin inhibits CYP3A4 and P-glycoprotein (P-gp), while nirmatrelvir is a substrate for CYP3A4 and P-gp. [53544] [65314] [69024] (Moderate) Caution is warranted with the use of erythromycin and ritonavir as erythromycin may increase ritonavir serum concentrations resulting in increased treatment-related adverse effects. Erythromycin inhibits CYP3A4 and P-glycoprotein (P-gp), while ritonavir is a substrate of both CYP3A4 and P-gp. [47165] [53544] Eslicarbazepine: (Major) Concurrent administration of eslicarbazepine with ritonavir may result in decreased plasma concentrations of ritonavir. Eslicarbazepine is an inducer of the hepatic isoenzyme CYP3A4; ritonavir is metabolized by this enzyme. Caution and close monitoring for decreased antiviral efficacy are advised if these drugs are administered together. [56436] [58664] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of eslicarbazepine is necessary. Concomitant use of nirmatrelvir and eslicarbazepine may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and eslicarbazepine is a moderate CYP3A inducer. [56436] [67203] Esmolol: (Moderate) Ritonavir is expected to decrease the hepatic CYP metabolism of beta-blockers, resulting in increased beta-blocker concentrations. Cardiac and neurologic events have been reported when ritonavir is concurrently administered with beta-blockers. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including beta-blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased beta-blocker doses may be warranted. [5044] Esomeprazole: (Moderate) Concurrent administration of esomeprazole with ritonavir may result in elevated esomeprazole plasma concentrations. Esomeprazole is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Monitor patients for increased side effects if these drugs are administered together. [58664] [6265] Estazolam: (Major) Consider withholding estazolam, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the estazolam dose. However, do not stop estazolam abruptly or rapidly reduce the dose as this may precipitate an acute withdrawal reaction, especially in patients who have been receiving high doses over an extended period. Coadministration may increase estazolam exposure resulting in increased toxicity and excessive sedation. Estazolam is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Moderate) In vitro studies with human liver microsomes indicate that the biotransformation of estazolam to the major circulating metabolite 4-hydroxy-estazolam is mediated by CYP3A. In theory, CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of estazolam and increase the potential for benzodiazepine toxicity (i.e., prolonged sedation and respiratory depression). [30413] [32432] [46638] Esterified Estrogens: (Moderate) Ritonavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers. [28315] [28341] Esterified Estrogens; Methyltestosterone: (Moderate) Ritonavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers. [28315] [28341] Estradiol: (Moderate) Ritonavir has been shown to increase the metabolism of ethinyl estradiol. Ritonavir is a substrate and inhibitor of CYP3A4. It is not known if the effects of protease inhibitors are similar on estradiol; however, estradiol is metabolized by CYP3A4, similar to ethinyl estradiol. [28315] Estradiol; Levonorgestrel: (Major) Data on the effects that protease inhibitors have on the serum concentrations of estrogens and progestins are complex. Some protease inhibitors increase (i.e., ritonavir, lopinavir; ritonavir, nelfinavir, tipranavir) and others decrease (i.e., atazanavir, indinavir) the metabolism of hormonal contraceptives. The safety and efficacy of hormonal contraceptives may be affected if coadministered with protease inhibitors. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors concurrently should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with protease inhibitors to use an additional method of contraception to protect against unwanted pregnancy, unless other drug-specific recommendations are made by the manufacturer of the protease inhibitor. Furthermore, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with protease inhibitors should use an additional barrier method of contraception such as condoms. [46638] [5044] (Moderate) Ritonavir has been shown to increase the metabolism of ethinyl estradiol. Ritonavir is a substrate and inhibitor of CYP3A4. It is not known if the effects of protease inhibitors are similar on estradiol; however, estradiol is metabolized by CYP3A4, similar to ethinyl estradiol. [28315] Estradiol; Norethindrone: (Moderate) Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. For example, ritonavir (also found in combinations like lopinavir; ritonavir, and used as a booster in many HIV treatment regimens) may decrease the metabolism of norethindrone, raising norethindrone concentrations. Women receiving norethindrone for hormone replacement or contraception should report potential hormonal adverse effects (e.g., bleeding pattern changes, acne, emotional lability) or any changes in efficacy (e.g., noted changes in bleeding patterns) to their prescribers. Because norethindrone-containing contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive norethindrone contraception concurrently with ritonavir should use an additional barrier method of contraception such as condoms. [58679] [7731] (Moderate) Ritonavir has been shown to increase the metabolism of ethinyl estradiol. Ritonavir is a substrate and inhibitor of CYP3A4. It is not known if the effects of protease inhibitors are similar on estradiol; however, estradiol is metabolized by CYP3A4, similar to ethinyl estradiol. [28315] Estradiol; Norgestimate: (Moderate) Ritonavir has been shown to increase the metabolism of ethinyl estradiol. Ritonavir is a substrate and inhibitor of CYP3A4. It is not known if the effects of protease inhibitors are similar on estradiol; however, estradiol is metabolized by CYP3A4, similar to ethinyl estradiol. [28315] Estradiol; Progesterone: (Moderate) Ritonavir has been shown to increase the metabolism of ethinyl estradiol. Ritonavir is a substrate and inhibitor of CYP3A4. It is not known if the effects of protease inhibitors are similar on estradiol; however, estradiol is metabolized by CYP3A4, similar to ethinyl estradiol. [28315] (Moderate) Use caution if coadministration of ritonavir with progesterone is necessary, as the systemic exposure of progesterone may be increased resulting in an increase in treatment-related adverse reactions. Ritonavir is a strong CYP3A4 inhibitor. Progesterone is metabolized primarily by hydroxylation via a CYP3A4. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). [47165] [63694] Estropipate: (Moderate) Ritonavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers. [5044] [5070] Eszopiclone: (Major) The adult dose of eszopiclone should not exceed 2 mg/day during co-administration of potent CYP3A4 inhibitors, such as anti-retroviral protease inhibitors. CYP3A4 is a primary metabolic pathway for eszopiclone, and increased systemic exposure to eszopiclone increases the risk of next-day psychomotor or memory impairment, which may decrease the ability to perform tasks requiring full mental alertness such as driving. [30571] [31320] Ethanol: (Major) Concurrent administration of alcohol with ritonavir may result in decreased plasma concentrations of ritonavir, which may affect antiviral efficacy. Alcohol is an inducer of the hepatic isoenzyme CYP3A4; ritonavir is a substrate of this enzyme. Caution and close monitoring are advised if alcohol and ritonavir are administered together. [34760] [34761] [34762] [58664] Ethinyl Estradiol; Norelgestromin: (Major) Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. [46638] [5044] (Major) The FDA recommends consideration of an additional, non-hormonal method of contraception during the 5 days of treatment with ritonavir-boosted nirmatrelvir and until one menstrual cycle after stopping ritonavir-boosted nirmatrelvir. However, the NIH COVID-19 guidelines suggest the potential decrease in ethinyl estradiol exposure is not expected to be clinically significant during the 5 days of therapy. [65314] [67203] [69024] Ethinyl Estradiol; Norethindrone Acetate: (Major) Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. [46638] [5044] (Major) The FDA recommends consideration of an additional, non-hormonal method of contraception during the 5 days of treatment with ritonavir-boosted nirmatrelvir and until one menstrual cycle after stopping ritonavir-boosted nirmatrelvir. However, the NIH COVID-19 guidelines suggest the potential decrease in ethinyl estradiol exposure is not expected to be clinically significant during the 5 days of therapy. [65314] [67203] [69024] (Moderate) Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. For example, ritonavir (also found in combinations like lopinavir; ritonavir, and used as a booster in many HIV treatment regimens) may decrease the metabolism of norethindrone, raising norethindrone concentrations. Women receiving norethindrone for hormone replacement or contraception should report potential hormonal adverse effects (e.g., bleeding pattern changes, acne, emotional lability) or any changes in efficacy (e.g., noted changes in bleeding patterns) to their prescribers. Because norethindrone-containing contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive norethindrone contraception concurrently with ritonavir should use an additional barrier method of contraception such as condoms. [58679] [7731] Ethinyl Estradiol; Norgestrel: (Major) Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. [46638] [5044] (Major) The FDA recommends consideration of an additional, non-hormonal method of contraception during the 5 days of treatment with ritonavir-boosted nirmatrelvir and until one menstrual cycle after stopping ritonavir-boosted nirmatrelvir. However, the NIH COVID-19 guidelines suggest the potential decrease in ethinyl estradiol exposure is not expected to be clinically significant during the 5 days of therapy. [65314] [67203] [69024] Ethosuximide: (Moderate) Ritonavir decreases the hepatic CYP metabolism of ethosuximide, resulting in increased ethosuximide concentrations. If coadministration is warranted, do so with caution and careful monitoring of ethosuximide concentrations. A 50% dose reduction of ethosuximide may be needed. [27896] [28001] [28315] [46638] Ethotoin: (Major) Avoid concomitant use of ritonavir and hydantoins. Concomitant use may decrease the exposure of ritonavir and hydantoins, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the hydantoin. A dose increase of the hydantoin may be necessary. Ritonavir is a CYP3A substrate and inducer and hydantoins are CYP3A inducers. [28315] [46638] Ethynodiol Diacetate; Ethinyl Estradiol: (Major) Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. [46638] [5044] (Major) The FDA recommends consideration of an additional, non-hormonal method of contraception during the 5 days of treatment with ritonavir-boosted nirmatrelvir and until one menstrual cycle after stopping ritonavir-boosted nirmatrelvir. However, the NIH COVID-19 guidelines suggest the potential decrease in ethinyl estradiol exposure is not expected to be clinically significant during the 5 days of therapy. [65314] [67203] [69024] Etonogestrel: (Major) Coadministration may result in an increased or decreased effect of etonogestrel. Contraceptive efficacy may be reduced. Etonogestrel is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor and CYP3A4 inducer. [41597] [46375] [47165] Etonogestrel; Ethinyl Estradiol: (Major) Coadministration may result in an increased or decreased effect of etonogestrel. Contraceptive efficacy may be reduced. Etonogestrel is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor and CYP3A4 inducer. [41597] [46375] [47165] (Major) Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. [46638] [5044] (Major) The FDA recommends consideration of an additional, non-hormonal method of contraception during the 5 days of treatment with ritonavir-boosted nirmatrelvir and until one menstrual cycle after stopping ritonavir-boosted nirmatrelvir. However, the NIH COVID-19 guidelines suggest the potential decrease in ethinyl estradiol exposure is not expected to be clinically significant during the 5 days of therapy. [65314] [67203] [69024] Etrasimod: (Major) Avoid concomitant use of etrasimod and ritonavir in CYP2C9 poor metabolizers due to the risk for increased etrasimod exposure which may increase the risk for adverse effects. Etrasimod is a CYP2C9 and CYP3A substrate and ritonavir is a strong CYP3A inhibitor. [56579] [69114] Etravirine: (Moderate) Concomitant use of etravirine with full-dose ritonavir (i.e., 600 mg twice daily) may cause a significant decrease in etravirine plasma concentration and, thus, a loss of therapeutic effect. Etravirine and full-dose ritonavir should not be coadministered. [33718] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of etravirine is necessary. Concomitant use of nirmatrelvir and etravirine may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and etravirine is a moderate CYP3A inducer. [33718] [67203] Everolimus: (Major) Avoid coadministration of everolimus with ritonavir due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Ritonavir is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold. [28380] [34557] [47165] [49823] [49903] (Major) Before prescribing ritonavir-boosted nirmatrelvir for a patient receiving everolimus, the patient's specialist provider(s) should be consulted, given the significant drug-drug interaction potential and because close monitoring may not be feasible. If this is not feasible, consider an alternative COVID-19 therapy. Coadministration may increase everolimus exposure resulting in increased toxicity. Everolimus is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [49823] [65314] [67203] [69024] Exenatide: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] [50113] [50814] Ezetimibe; Simvastatin: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and simvastatin is contraindicated. Discontinue use of simvastatin at least 12 hours before, during, and 5 days after treatment with ritonavir-boosted nirmatrelvir. Coadministration may increase simvastatin exposure resulting in increased toxicity. Simvastatin is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors. [28605] [39682] [46638] [61510] [61511] [61512] [61513] Fedratinib: (Major) Avoid coadministration of fedratinib with ritonavir as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If ritonavir is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold. [28315] [64568] (Major) Consider withholding fedratinib, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the fedratinib dose. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. When ritonavir-boosted nirmatrelvir is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Coadministration may increase fedratinib exposure resulting in increased toxicity. Fedratinib is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [64568] [65314] Felodipine: (Moderate) Concurrent use of felodipine and protease inhibitors should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Concurrent use of a strong CYP3A inhibitor increased felodipine AUC and half-life by approximately 8-fold and 2-fold, respectively. Concurrent use of a moderate CYP3A inhibitor increased felodipine AUC and half-life by approximately 2.5-fold and 2-fold, respectively. [28541] [29012] [32432] [47165] Fentanyl: (Major) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. If ritonavir is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ritonavir can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If ritonavir is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. Clinical investigations have suggested that ritonavir may decrease the clearance of fentanyl by 67%, increase the elimination half-life from 9.4 to 20.1 hours, and increase the systemic exposure of fentanyl by 174% (range: 52 to 420%). [26403] [29623] [29763] [32731] [40943] [47165] (Major) Consider withholding fentanyl, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the fentanyl dose. Coadministration may increase fentanyl exposure resulting in adverse events, including potentially fatal respiratory depression. Fentanyl is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [29623] [65314] [67203] [69024] Fesoterodine: (Major) Limit the dose of fesoterodine to 4 mg once daily in adults and pediatric patients weighing more than 35 kg if coadministered with anti-retroviral protease inhibitors. Avoid use of fesoterodine and protease inhibitors in pediatric patients weighing 25 to 35 kg. Concurrent use may increase fesoterodine exposure. Fesoterodine is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor led to approximately a doubling of the overall exposure of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine. [28142] [32432] [34539] [47165] Fexinidazole: (Major) Avoid concomitant use of fexinidazole and ritonavir and monitor for decreased fexinidazole efficacy if coadministration is necessary. Concomitant use may limit conversion of fexinidazole to its active metabolites. Fexinidazole is converted to its active metabolites via CYP3A and ritonavir is a strong CYP3A inhibitor. [47165] [66812] Finasteride; Tadalafil: (Major) Avoid concomitant use of ritonavir-boosted nirmatrelvir and tadalafil, when used for pulmonary hypertension, and consider an alternative COVID-19 therapy. Consider withholding tadalafil, when used for erectile dysfunction, during concomitant receipt of ritonavir-boosted nirmatrelvir. Coadministration may increase tadalafil exposure resulting in increased toxicity. Tadalafil is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ritonavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of ritonavir therapy. Stop tadalafil at least 24 hours prior to starting ritonavir. After at least 1 week of ritonavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Coadministration of ritonavir with tadalafil results in a 124% increase in tadalafil AUC. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4. [28220] [28315] [40259] Finerenone: (Contraindicated) Concomitant use of finerenone and ritonavir is contraindicated. Concomitant use may increase finerenone exposure and the risk for finerenone-related adverse reactions. Finerenone is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased overall exposure to finerenone by more than 400%. [47165] [66793] (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and finerenone is contraindicated due to the potential for serious adverse reactions including hyperkalemia, hypotension, and hyponatremia; consider an alternative COVID-19 therapy. Coadministration may increase finerenone exposure resulting in increased toxicity. Finerenone is a CYP3A4 substrate and nirmatrelvir is a CYP3A inhibitor. [66793] [67203] [69024] Flecainide: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and flecainide is contraindicated; consider an alternative COVID-19 therapy. Coadministration may increase flecainide exposure resulting in increased toxicity. Flecainide is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Major) Concurrent use of HIV treatment doses of ritonavir with flecainide is contraindicated. Cautious consideration may be given to administering flecainide with boosting doses of ritonavir. The potential increase in plasma concentrations of flecainide could result in significant adverse effects. [47165] Flibanserin: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and flibanserin is contraindicated due to the potential for hypotension, syncope, and CNS depression. Consider temporary discontinuation of flibanserin during treatment with ritonavir-boosted nirmatrelvir and for at least 2 to 3 days after treatment completion; if not feasible, consider alternative COVID-19 therapy. Coadministration may increase flibanserin exposure resulting in increased toxicity. Flibanserin is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Contraindicated) The concomitant use of flibanserin and strong CYP3A4 inhibitors, such as ritonavir, is contraindicated. Strong CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a strong CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a strong CYP3A4 inhibitor following flibanserin use, start the strong CYP3A4 inhibitor at least 2 days after the last dose of flibanserin. [60099] Fluconazole: (Moderate) Caution is warranted with the use of fluconazole and ritonavir as ritonavir serum concentrations may be increased resulting in increased treatment-related adverse effects. Fluconazole is a moderate CYP3A4 inhibitor, while ritonavir is a substrate of CYP3A4. [28315] [28674] Fluoxetine: (Moderate) Monitor for increased fluoxetine-related adverse effects if coadministered with ritonavir. Concurrent use may result in increased fluoxetine exposure. Fluoxetine is a CYP2D6 substrate and ritonavir is a weak CYP2D6 inhibitor. [44058] [47165] Flurazepam: (Major) Consider withholding flurazepam, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the flurazepam dose. However, do not stop flurazepam abruptly or rapidly reduce the dose as this may precipitate an acute withdrawal reaction, especially in patients who have been receiving high doses over an extended period. Coadministration may increase flurazepam exposure resulting in increased toxicity and excessive sedation. Flurazepam is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Moderate) Monitor for an increase in flurazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with protease inhibitors is necessary. Concurrent use may increase flurazepam exposure. Flurazepam is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. [28556] [29012] [32432] [47165] [62105] Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and ritonavir is not recommended; use caution with inhaled fluticasone furoate. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving inhaled fluticasone propionate with ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Fluticasone is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with ritonavir increased plasma fluticasone propionate exposure resulting in an 86% decrease in serum cortisol AUC. Another strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. [40360] [40475] [43972] [57805] Fluticasone; Salmeterol: (Major) Avoid concomitant use of salmeterol with ritonavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose. [28467] [44026] [47165] (Major) Coadministration of inhaled fluticasone propionate and ritonavir is not recommended; use caution with inhaled fluticasone furoate. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving inhaled fluticasone propionate with ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Fluticasone is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with ritonavir increased plasma fluticasone propionate exposure resulting in an 86% decrease in serum cortisol AUC. Another strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. [40360] [40475] [43972] [57805] (Major) Consider temporary discontinuation of salmeterol during treatment with ritonavir-boosted nirmatrelvir and for at least 2 to 3 days after treatment completion; if not feasible, consider alternative COVID-19 therapy. Coadministration may increase salmeterol exposure resulting in increased toxicity, including QT prolongation, palpitations, and sinus tachycardia. Salmeterol is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [28467] [65314] [67203] [69024] Fluticasone; Umeclidinium; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and ritonavir is not recommended; use caution with inhaled fluticasone furoate. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving inhaled fluticasone propionate with ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Fluticasone is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with ritonavir increased plasma fluticasone propionate exposure resulting in an 86% decrease in serum cortisol AUC. Another strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. [40360] [40475] [43972] [57805] Fluticasone; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and ritonavir is not recommended; use caution with inhaled fluticasone furoate. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving inhaled fluticasone propionate with ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Fluticasone is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with ritonavir increased plasma fluticasone propionate exposure resulting in an 86% decrease in serum cortisol AUC. Another strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. [40360] [40475] [43972] [57805] Fluvastatin: (Moderate) Ritonavir is an inhibitor of CYP3A4 and may increase exposure to drugs metabolized by this enzyme, such as fluvastatin. Because fluvastatin does not rely exclusively on CYP3A4 for its metabolism (approximately 20%), ritonavir may not interact to the same extent as expected with other HMG-CoA reductase inhibitors. Elevated serum concentrations of fluvastatin may increase the risk for adverse reactions, such as myopathy. [28774] [45527] [58664] Fluvoxamine: (Moderate) Concurrent administration of fluvoxamine with ritonavir may result in increased plasma concentrations of one or both drugs. Fluvoxamine is partially metabolized by CYP2D6 and ritonavir is a weak CYP2D6 inhibitor. In addition, ritonavir is metabolized by CYP3A4, and fluvoxamine is a moderate CYP3A4 inhibitor. Caution and close monitoring are advised if these drugs are administered together. [47165] [50507] Food: (Major) Advise patients to avoid cannabis use during protease inhibitor treatment. Concomitant use may alter the exposure of some cannabinoids and increase the risk for adverse reactions. The cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP3A substrates and protease inhibitors are strong CYP3A inhibitors. Concomitant use of a cannabinoid product containing THC and CBD at an approximate 1:1 ratio with another strong CYP3A inhibitor increased THC, 11-OH-THC, and CBD peak exposures by 1.3-, 3-, and 1.9-fold respectively. [31320] [32432] [47165] [67470] [67473] [67474] Formoterol; Mometasone: (Moderate) Coadministration of mometasone with ritonavir (a strong CYP3A4 inhibitor) may cause mometasone serum concentrations to increase, potentially resulting in Cushing's syndrome and adrenal suppression. Consider use of an alternative corticosteroid whose concentrations are less affected by strong CYP3A4 inhibitors, such as beclomethasone and prednisolone, especially during long-term treatment. [28341] [47165] [58620] Foscarnet: (Moderate) Abnormal renal function has been observed in clinical practice during the use of foscarnet in combination with ritonavir. If these drugs are administered together, monitor kidney function. [28377] [47165] Fosphenytoin: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and fosphenytoin is contraindicated; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response. The risk for reduced efficacy may persist following fosphenytoin discontinuation. Nirmatrelvir is a CYP3A substrate and fosphenytoin is a strong CYP3A inducer. [56579] [65314] [67203] (Major) Avoid concomitant use of ritonavir and hydantoins. Concomitant use may decrease the exposure of ritonavir and hydantoins, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the hydantoin. A dose increase of the hydantoin may be necessary. Ritonavir is a CYP3A substrate and inducer and hydantoins are CYP3A inducers. [28315] [46638] Fostamatinib: (Moderate) Monitor for fostamatinib toxicities that may require fostamatinib dose reduction (i.e., elevated hepatic enzymes, neutropenia, high blood pressure, severe diarrhea) if given concurrently with a strong CYP3A4 inhibitor. Concomitant use of fostamatinib with a strong CYP3A4 inhibitor increases exposure to the major active metabolite, R406, which may increase the risk of adverse reactions. R406 is extensively metabolized by CYP3A4; ritonavir is a strong CYP3A4 inhibitor. Coadministration of fostamatinib with another strong CYP3A4 inhibitor increased R406 AUC by 102% and Cmax by 37%. [47165] [63084] Futibatinib: (Major) Avoid concurrent use of futibatinib and ritonavir. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; ritonavir is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%. [47165] [68013] Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with ritonavir is necessary. Gefitinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%. [28341] [45935] [47165] [56579] Gilteritinib: (Major) Consider an alternative to ritonavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. [47165] [63787] Glasdegib: (Major) Consider an alternative to ritonavir during treatment with glasdegib. Concurrent use may increase glasdegib exposure resulting in treatment-related adverse events including QT prolongation. If coadministration cannot be avoided, monitor for increased adverse events; more frequent ECG monitoring is recommended. Glasdegib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study. [47165] [63777] Glecaprevir; Pibrentasvir: (Major) Avoid concomitant use of ritonavir-boosted nirmatrelvir and glecaprevir; pibrentasvir and consider an alternative COVID-19 therapy. Coadministration may increase glecaprevir; pibrentasvir exposure resulting in increased toxicity. Glecaprevir is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Major) Coadministration of glecaprevir with ritonavir is not recommended as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of CYP3A4 and P-glycoprotein (P-gp); ritonavir is an inhibitor of CYP3A4 and P-gp. Additionally, ritonavir is a P-gp substrate and glecaprevir is a P-gp inhibitor; concentrations of ritonavir may also be increased. [28380] [34557] [62201] (Major) Coadministration of pibrentasvir with ritonavir is not recommended as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of the drug transporter P-glycoprotein (P-gp); ritonavir is an inhibitor of P-gp. Additionally, ritonavir is a P-gp substrate and pibrentasvir is a P-gp inhibitor; concentrations of ritonavir may also be increased. [28380] [34557] [62201] Glimepiride: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [28380] [29012] [30575] [31320] [34471] [34472] [34489] [34490] [34491] [34557] [47165] [51227] [58000] [58763] Glipizide: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [28380] [29012] [30575] [31320] [34471] [34472] [34489] [34490] [34491] [34557] [47165] [51227] [58000] [58763] Glipizide; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [28380] [29012] [30575] [31320] [34471] [34472] [34489] [34490] [34491] [34557] [47165] [51227] [58000] [58763] (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30480] [30575] Glyburide: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [28380] [29012] [30575] [31320] [34471] [34472] [34489] [34490] [34491] [34557] [47165] [51227] [58000] [58763] Glyburide; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [28380] [29012] [30575] [31320] [34471] [34472] [34489] [34490] [34491] [34557] [47165] [51227] [58000] [58763] (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30480] [30575] Glycerol Phenylbutyrate: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of glycerol phenylbutyrate is necessary. Concomitant use of nirmatrelvir and glycerol phenylbutyrate may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and glycerol phenylbutyrate is a CYP3A inducer. [53022] [67203] (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with glycerol phenylbutyrate. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer. [53022] [67203] Granisetron: (Minor) Plasma concentrations of granisetron may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as gastrointestinal or CNS effects, is recommended during coadministration. Ritonavir is a CYP3A4 inhibitor; granisetron is a CYP3A4 substrate. [28315] [31723] [47165] Grapefruit juice: (Moderate) Concurrent administration of ritonavir with grapefruit juice may result in elevated ritonavir concentrations. Grapefruit juice is an inhibitor of the hepatic isoenzymes CYP3A4 and CYP2D6, and an inhibitor of the drug transporter P-glycoprotein (P-gp). Ritonavir is metabolized by both enzymes and is a substrate for P-gp. Caution and close monitoring are advised if these drugs are administered together. [58664] Griseofulvin: (Major) Ritonavir oral solution and capsules contain ethanol. Administration of ritonavir oral solution and capsules to patients receiving or who have recently received griseofulvin may result in disulfiram-like reactions (e.g., abdominal cramps, nausea/vomiting, headaches, and flushing). A disulfiram reaction would not be expected to occur with non-ethanol containing formulations of ritonavir (e.g., tablets or oral powder). [28315] [29964] [65243] Guanfacine: (Major) Ritonavir may significantly alter guanfacine plasma concentrations. Guanfacine is primarily metabolized by CYP3A4. Ritonavir is a potent CYP3A4 inhibitor; moderate CYP3A4 induction has been reported with concomitant use of voriconazole. The net effect of this potential interaction is unclear, but guanfacine dosage adjustments, most likely a dose decrease, may be required. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if used with a moderate to strong CYP3A4 inhibitor, the guanfacine dosage should be decreased to half of the recommended dose and the patient should be closely monitored for alpha-adrenergic effects (e.g., hypotension, drowsiness, bradycardia). However, if used with a moderate to strong CYP3A4 inducer, labeling recommends to consider doubling the recommended dose of guanfacine ER; if the inducer is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If the inducer or inhibitor is discontinued, guanfacine ER should return to its recommended dose (with downward titration occurring over 1 to 2 weeks). Specific recommendations for immediate-release (IR) guanfacine are not available. [27493] [43566] [47165] Haloperidol: (Moderate) Mild to moderate increases in haloperidol plasma concentrations have been reported during concurrent use of haloperidol and inhibitors of CYP3A4 or CYP2D6, such as ritonavir. Elevated haloperidol concentrations may increase the risk of adverse effects. Closely monitor for adverse events when these medications are coadministered. [28307] [47165] Homatropine; Hydrocodone: (Major) Consider withholding hydrocodone, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the hydrocodone dose. Coadministration may increase hydrocodone exposure, resulting in prolonged opioid effects including fatal respiratory depression. Hydrocodone is metabolized by CYP3A4 and nirmatrelvir is a CYP3A inhibitor. [56303] [65314] [67203] [69024] (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ritonavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ritonavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. [30379] [30391] [47165] [56303] [58531] Hydantoins: (Major) Avoid concomitant use of ritonavir and hydantoins. Concomitant use may decrease the exposure of ritonavir and hydantoins, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the hydantoin. A dose increase of the hydantoin may be necessary. Ritonavir is a CYP3A substrate and inducer and hydantoins are CYP3A inducers. [28315] [46638] Hydrocodone: (Major) Consider withholding hydrocodone, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the hydrocodone dose. Coadministration may increase hydrocodone exposure, resulting in prolonged opioid effects including fatal respiratory depression. Hydrocodone is metabolized by CYP3A4 and nirmatrelvir is a CYP3A inhibitor. [56303] [65314] [67203] [69024] (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ritonavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ritonavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. [30379] [30391] [47165] [56303] [58531] Hydrocodone; Ibuprofen: (Major) Consider withholding hydrocodone, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the hydrocodone dose. Coadministration may increase hydrocodone exposure, resulting in prolonged opioid effects including fatal respiratory depression. Hydrocodone is metabolized by CYP3A4 and nirmatrelvir is a CYP3A inhibitor. [56303] [65314] [67203] [69024] (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ritonavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ritonavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. [30379] [30391] [47165] [56303] [58531] Ibrexafungerp: (Major) Decrease the ibrexafungerp dose to 150 mg PO every 12 hours for 1 day if administered concurrently with ritonavir. Coadministration may result in increased ibrexafungerp exposure and toxicity. Ibrexafungerp is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of ibrexafungerp by 5.8-fold and 2.5-fold, respectively. [47165] [66705] Ibrutinib: (Major) Avoid concomitant use of ibrutinib and ritonavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold. [47165] [56410] Ibuprofen; Oxycodone: (Major) Consider withholding oxycodone, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the oxycodone dose. Coadministration may increase oxycodone exposure, resulting in prolonged opioid effects including fatal respiratory depression. Oxycodone is metabolized by CYP3A4 and nirmatrelvir is a CYP3A inhibitor. [60745] [65314] [67203] [69024] (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. If ritonavir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like ritonavir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ritonavir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. [39926] [47165] Idelalisib: (Contraindicated) Concomitant use of idelalisib, a CYP3A4 substrate, and ritonavir, a strong CYP3A4 inhibitor, may increase the exposure of idelalisib. Additionally, idelalisib is a strong CYP3A inhibitor while ritonavir is a CYP3A substrate. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib. Avoid concomitant use of idelalisib and ritonavir. [5070] [57675] Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with ritonavir is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Ritonavir is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment. [47165] [51027] Iloperidone: (Major) Reduce the iloperidone dose by one-half if coadministered with ritonavir. If ritonavir is discontinued, increase the iloperidone dose to the previous level. Increased iloperidone exposure may occur with concurrent use. Iloperidone is a CYP3A4 substrate. Ritonavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of iloperidone and its metabolites P88 and P95 by 57%, 55% and 35%, respectively. [36146] [47165] Imatinib: (Major) Protease Inhibitors inhibit cytochrome P450 CYP3A4 and may decrease the metabolism of imatinib and increase imatinib concentrations leading to an increased incidence of adverse reactions. In addition, because imatinib inhibits CYP2C9, CYP2D6, and CYP3A4/5, the metabolism of protease inhibitors may be decreased by imatinib. Close monitoring of the antiviral and antineoplastic responses is recommended. [28240] [28341] Imipramine: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with ritonavir is necessary; a dose reduction of the TCA may be necessary. Concurrent use may increase exposure of the TCA. TCAs are CYP2D6 substrates and ritonavir is a CYP2D6 inhibitor. [47165] Incretin Mimetics: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] [50113] [50814] Indacaterol; Glycopyrrolate: (Moderate) Although no dosage adjustment of the 75 mcg indacaterol daily dose is needed, use caution if indacaterol and ritonavir are used concurrently. Monitor the patient clinically for beta-agonist side effects like tremor, nervousness, or fast, irregular heart rate. In addition, both ritonavir and long-acting beta agonists (LABAs) are associated with QT prolongation; concomitant use may increase the risk of QT prolongation. By inhibiting CYP3A4, CYP2D6, and P-glycoprotein, ritonavir reduces indacaterol metabolism. In drug interaction studies, coadministration of indacaterol 300 mcg (single dose) with ritonavir (300 mg twice daily for 7.5 days) resulted in a 1.7-fold increase in indacaterol exposure (AUC) whereas indacaterol maximal concentration (Cmax) was unaffected. [44979] [47165] [51080] [59321] [60263] Indinavir: (Minor) Ritonavir inhibits the clearance of indinavir, and increased indinavir serum concentrations are seen with concurrent administration. In a pharmacokinetic study in healthy volunteers, the AUC of single indinavir dose increased 185 to 475% during concurrent ritonavir dosing; the mean indinavir half-life increased from 1.2 to 2.7 hours. In an observational study of HIV-infected patients, the combination of indinavir 1200 mg and ritonavir 100 mg, both twice daily, led to high systemic exposure to indinavir and was not well tolerated. The combination of indinavir 800 mg and ritonavir 100 mg twice daily resulted in therapeutic indinavir serum concentrations with improved tolerability and similar maximum serum concentrations as the approved indinavir dosage of 800 mg three times a day. Patients should be closely monitored for possible indinavir toxicity during concurrent administration; indinavir dosage reductions may be necessary. The recommended dosing regimen for this combination is indinavir 800 mg twice daily plus ritonavir 100 or 200 mg twice daily. [26120] [26121] [46638] Infigratinib: (Major) Avoid concomitant use of infigratinib and ritonavir. Coadministration may increase infigratinib exposure, increasing the risk for adverse effects. Infigratinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC of infigratinib by 622%. [47165] [66702] Insulin Aspart: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. [30575] [60172] Insulin Aspart; Insulin Aspart Protamine: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. [30575] [60172] Insulin Degludec: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. [30575] [60172] Insulin Degludec; Liraglutide: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. [30575] [60172] (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] [50113] [50814] Insulin Detemir: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. [30575] [60172] Insulin Glargine: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. [30575] [60172] Insulin Glargine; Lixisenatide: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. [30575] [60172] (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] [50113] [50814] Insulin Glulisine: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. [30575] [60172] Insulin Lispro: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. [30575] [60172] Insulin Lispro; Insulin Lispro Protamine: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. [30575] [60172] Insulin, Inhaled: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. [30575] [60172] Insulins: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. [30575] [60172] Interferon Alfa-2b: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. [31649] [34878] Interferon Alfa-n3: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. [31649] [34878] Interferon Beta-1a: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. [31649] [34878] Interferon Beta-1b: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. [31649] [34878] Interferon Gamma-1b: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. [31649] [34878] Interferons: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. [31649] [34878] Irinotecan Liposomal: (Major) Avoid administration of ritonavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Ritonavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38. [30469] [47165] Irinotecan: (Major) Avoid administration of ritonavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Ritonavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38. [30469] [47165] Isavuconazonium: (Contraindicated) Concomitant use of isavuconazonium with high-dose ritonavir (i.e., 400 mg every 12 hours) is contraindicated due to the risk for increased isavuconazole serum concentrations and serious adverse reactions, such as hepatic toxicity. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of hepatic isoenzyme CYP3A4; ritonavir is a strong inhibitor of this enzyme. According to the manufacturer, coadministration of isavuconazole with strong CYP3A4 inhibitors is contraindicated. Isavuconazole serum concentrations were increased 5-fold when coadministered with ketoconazole, another strong CYP3A4 inhibitor. Elevated ritonavir concentrations may also be seen with coadministration, as ritonavir is a substrate and isavuconazole is an inhibitor of CYP3A4 and the drug transporter P-glycoprotein (P-gp). [47165] [59042] Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Contraindicated) Coadministration of rifampin and ritonavir results in markedly decreased ritonavir concentrations; HIV treatment failure and virologic resistance would be expected. Rifampin (300 or 600 mg daily for 10 days) decreases the AUC and Cmax of ritonavir (500 mg every 12 hours for 20 days) by 35% and 25%, respectively. Coadministration may lead to loss of virologic response if ritonavir is the sole protease inhibitor and increase the risk of hepatotoxicity. The DHHS/NIH HIV Treatment Guidelines recommend ritonavir and rifampin should not be coadministered and suggest the consideration of alternative antimycobacterial agents, such as rifabutin. However, CDC guidelines suggest no change in ritonavir or rifampin dose when the drugs are coadministered, but this appears to only be in the setting of low-dose ritonavir (i.e., 100 mg or 200 mg twice daily) used to 'boost' concentrations of other protease inhibitors. In this setting it would be less likely to produce adverse events than higher ritonavir doses; however, a net CYP3A4 induction still results when used with rifampin. [1299] [30314] [46638] (Contraindicated) Ritonavir-boosted nirmatrelvir is contraindicated for use within 2 weeks of administering rifampin; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response. The risk for reduced efficacy may persist following rifampin discontinuation. Nirmatrelvir is a CYP3A substrate and rifampin is a strong CYP3A inducer. [56579] [65314] [67203] [69024] Isoniazid, INH; Rifampin: (Contraindicated) Coadministration of rifampin and ritonavir results in markedly decreased ritonavir concentrations; HIV treatment failure and virologic resistance would be expected. Rifampin (300 or 600 mg daily for 10 days) decreases the AUC and Cmax of ritonavir (500 mg every 12 hours for 20 days) by 35% and 25%, respectively. Coadministration may lead to loss of virologic response if ritonavir is the sole protease inhibitor and increase the risk of hepatotoxicity. The DHHS/NIH HIV Treatment Guidelines recommend ritonavir and rifampin should not be coadministered and suggest the consideration of alternative antimycobacterial agents, such as rifabutin. However, CDC guidelines suggest no change in ritonavir or rifampin dose when the drugs are coadministered, but this appears to only be in the setting of low-dose ritonavir (i.e., 100 mg or 200 mg twice daily) used to 'boost' concentrations of other protease inhibitors. In this setting it would be less likely to produce adverse events than higher ritonavir doses; however, a net CYP3A4 induction still results when used with rifampin. [1299] [30314] [46638] (Contraindicated) Ritonavir-boosted nirmatrelvir is contraindicated for use within 2 weeks of administering rifampin; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response. The risk for reduced efficacy may persist following rifampin discontinuation. Nirmatrelvir is a CYP3A substrate and rifampin is a strong CYP3A inducer. [56579] [65314] [67203] [69024] Isophane Insulin (NPH): (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. [30575] [60172] Isradipine: (Moderate) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with protease inhibitors is necessary. Concomitant use may increase isradipine exposure. Isradipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. [29012] [32432] [47165] [62065] Istradefylline: (Major) Do not exceed 20 mg once daily of istradefylline if administered with ritonavir as istradefylline exposure and adverse effects may increase. Ritonavir is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study. [47165] [64590] Itraconazole: (Major) When administering itraconazole with ritonavir or ritonavir-containing drugs, do not exceed the maximum recommended itraconazole dose of 200 mg per day. Concurrent administration may result in increased exposure to both drugs. Monitor patients for itraconazole and ritonavir-associated adverse effects. Both itraconazole and ritonavir are strong CYP3A4 inhibitors and substrates. [27983] [47165] Ivabradine: (Contraindicated) Coadministration of ivabradine and ritonavir is contraindicated. Ivabradine is primarily metabolized by CYP3A4; ritonavir is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances. [59430] (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and ivabradine is contraindicated due to the potential for bradycardia or conduction disturbances; consider an alternative COVID-19 therapy. Coadministration may increase ivabradine exposure resulting in increased toxicity. Ivabradine is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [67203] [69024] Ivacaftor: (Major) If ritonavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. [47165] [48524] Ivosidenib: (Major) Avoid coadministration of ivosidenib with ritonavir due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If ritonavir is discontinued, wait at least 5 half-lives of ritonavir before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax. [47165] [63368] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of ivosidenib is necessary. Concomitant use of nirmatrelvir and ivosidenib may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and ivosidenib is a weak CYP3A inducer. [63368] [67203] [69024] Ixabepilone: (Major) Avoid concurrent use of ixabepilone and ritonavir due to increased ixabepilone exposure, which may increase the risk of adverse reactions. If concomitant use is unavoidable, reduce the dose of ixabepilone to 20 mg/m2. Ixabepilone is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ixabepilone exposure by 79%. [33563] [47165] Ketamine: (Moderate) Use caution if ritonavir is coadministered with ketamine due to the potential for increased ketamine exposure which may increase the risk of toxicity. Ketamine is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. [37294] [47165] [65210] Ketoconazole: (Major) Avoid ritonavir for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of ketoconazole and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for ketoconazole-related adverse reactions; a ketoconazole dose reduction may be necessary. Ketoconazole is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. [27982] [47165] [67231] Labetalol: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers. [5044] Lacosamide: (Moderate) Use caution during concurrent use of lacosamide and ritonavir, particularly in patients with renal or hepatic impairment. Lacosamide is a CYP3A4 substrate; ritonavir is a potent inhibitor of CYP3A4. Patients with renal or hepatic impairment may have significantly increased exposure to lacosamide if coadministered with a strong CYP3A4 inhibitor. Dosage reduction of lacosamide may be necessary in this population. [28315] [34626] Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Since ritonavir induces glucuronidation, there is the potential for reduction in zidovudine, ZDV plasma concentrations during concurrent therapy with ritonavir. When coadministered with ritonavir, the AUC and Cmax of zidovudine, ZDV are decreased by 12% and 27%. The clinical significance of this interaction is unknown. [28315] [47165] [58664] Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, concurrently with inhibitors of P-gp and BCRP, such as ritonavir. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. [28193] [58664] Lamotrigine: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant lopinavir; ritonavir use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and lopinavir; ritonavir induces glucuronidation. During concurrent use of lamotrigine with lopinavir; ritonavir in 18 healthy subjects, induction of glucuronidation by lopinavir (400 mg twice daily); ritonavir (100 mg twice daily) decreased lamotrigine AUC, Cmax, and half-life by approximately 50% to 55.4%. [28451] Lansoprazole: (Moderate) Increased exposure to lansoprazole may occur during concurrent administration of ritonavir. Although dosage adjustment of lansoprazole is not normally required, dosage reduction may be considered in patients receiving higher lansoprazole doses (e.g., those with Zollinger-Ellison syndrome). Ritonavir is a strong CYP3A4 inhibitor. Lansoprazole is a CYP2C19 and CYP3A4 substrate. Coadministration of a dual CYP2C19/strong CYP3A4 inhibitor increased the lansoprazole AUC by an average of 4-times. [40596] [47165] Lansoprazole; Amoxicillin; Clarithromycin: (Major) Because the exposure to 14-OH clarithromycin is significantly decreased by ritonavir, consider alternative antibiotic therapy for indications other than Mycobacterium avium. Clarithromycin doses above 1000 mg should not be administered with ritonavir. If coadministration cannot be avoided, clarithromycin dosage reductions are recommended in patients with renal impairment (CrCl 30 to 60 mL/minute, decrease clarithromycin by 50%; CrCl less than 30 mL/minute, decrease clarithromycin by 75%). Concomitant administration of ritonavir and clarithromycin resulted in a 77% increase in clarithromycin exposure and a 100% decrease in 14-OH clarithromycin exposure. The microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria. [28238] [46638] [47165] (Moderate) Increased exposure to lansoprazole may occur during concurrent administration of ritonavir. Although dosage adjustment of lansoprazole is not normally required, dosage reduction may be considered in patients receiving higher lansoprazole doses (e.g., those with Zollinger-Ellison syndrome). Ritonavir is a strong CYP3A4 inhibitor. Lansoprazole is a CYP2C19 and CYP3A4 substrate. Coadministration of a dual CYP2C19/strong CYP3A4 inhibitor increased the lansoprazole AUC by an average of 4-times. [40596] [47165] Lapatinib: (Major) Avoid coadministration of lapatinib with ritonavir due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If ritonavir is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased lapatinib exposure by 3.6-fold and increased the half-life of lapatinib by 1.7-fold. [33192] [47165] Larotrectinib: (Major) Avoid coadministration of larotrectinib with ritonavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If ritonavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of ritonavir. Larotrectinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study. [47165] [63780] Ledipasvir; Sofosbuvir: (Moderate) Caution is warranted when ritonavir is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Ritonavir is an inhibitor of the transporter P-glycoprotein (P-gp). Both ledipasvir and sofosbuvir are substrates of P-gp. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects. [28380] [47165] [58167] Lefamulin: (Major) Avoid coadministration of ritonavir with oral lefamulin due to increased lefamulin exposure; ritonavir may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and ritonavir is a P-gp and strong CYP3A4 inhibitor. Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively. [47165] [64576] Lemborexant: (Major) Avoid coadministration of lemborexant and ritonavir as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse CNS effects. Lemborexant is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of lemborexant with another strong CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold. [47165] [64870] Leniolisib: (Major) Avoid concomitant use of leniolisib and ritonavir due to the risk for increased leniolisib exposure which may increase the risk for adverse effects. Leniolisib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased leniolisib overall exposure by 2-fold. [47165] [68778] Letermovir: (Moderate) A clinically relevant increase in the plasma concentration of ritonavir may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Ritonavir is primarily metabolized by CYP3A. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. [47165] [62611] Leuprolide; Norethindrone: (Moderate) Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. For example, ritonavir (also found in combinations like lopinavir; ritonavir, and used as a booster in many HIV treatment regimens) may decrease the metabolism of norethindrone, raising norethindrone concentrations. Women receiving norethindrone for hormone replacement or contraception should report potential hormonal adverse effects (e.g., bleeding pattern changes, acne, emotional lability) or any changes in efficacy (e.g., noted changes in bleeding patterns) to their prescribers. Because norethindrone-containing contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive norethindrone contraception concurrently with ritonavir should use an additional barrier method of contraception such as condoms. [58679] [7731] Levamlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure. [29012] [29090] [47165] Levocetirizine: (Moderate) Coadministration of cetirizine and ritonavir resulted in a 42% increase in the AUC, 53% increase in half-life, and 29% decrease in clearance of cetirizine. Cetirizine did not alter ritonavir disposition. [28874] [33350] Levoketoconazole: (Major) Avoid ritonavir for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of ketoconazole and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for ketoconazole-related adverse reactions; a ketoconazole dose reduction may be necessary. Ketoconazole is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. [27982] [47165] [67231] Levomilnacipran: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors such as ritonavir. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention. Additionally, ritonavir could further increase levomilnacipran concentrations by inhibiting its P-glycoprotein (P-gp) metabolism. [55469] Levonorgestrel: (Major) Data on the effects that protease inhibitors have on the serum concentrations of estrogens and progestins are complex. Some protease inhibitors increase (i.e., ritonavir, lopinavir; ritonavir, nelfinavir, tipranavir) and others decrease (i.e., atazanavir, indinavir) the metabolism of hormonal contraceptives. The safety and efficacy of hormonal contraceptives may be affected if coadministered with protease inhibitors. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors concurrently should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with protease inhibitors to use an additional method of contraception to protect against unwanted pregnancy, unless other drug-specific recommendations are made by the manufacturer of the protease inhibitor. Furthermore, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with protease inhibitors should use an additional barrier method of contraception such as condoms. [46638] [5044] Levonorgestrel; Ethinyl Estradiol: (Major) Data on the effects that protease inhibitors have on the serum concentrations of estrogens and progestins are complex. Some protease inhibitors increase (i.e., ritonavir, lopinavir; ritonavir, nelfinavir, tipranavir) and others decrease (i.e., atazanavir, indinavir) the metabolism of hormonal contraceptives. The safety and efficacy of hormonal contraceptives may be affected if coadministered with protease inhibitors. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors concurrently should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with protease inhibitors to use an additional method of contraception to protect against unwanted pregnancy, unless other drug-specific recommendations are made by the manufacturer of the protease inhibitor. Furthermore, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with protease inhibitors should use an additional barrier method of contraception such as condoms. [46638] [5044] (Major) Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. [46638] [5044] (Major) The FDA recommends consideration of an additional, non-hormonal method of contraception during the 5 days of treatment with ritonavir-boosted nirmatrelvir and until one menstrual cycle after stopping ritonavir-boosted nirmatrelvir. However, the NIH COVID-19 guidelines suggest the potential decrease in ethinyl estradiol exposure is not expected to be clinically significant during the 5 days of therapy. [65314] [67203] [69024] Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Data on the effects that protease inhibitors have on the serum concentrations of estrogens and progestins are complex. Some protease inhibitors increase (i.e., ritonavir, lopinavir; ritonavir, nelfinavir, tipranavir) and others decrease (i.e., atazanavir, indinavir) the metabolism of hormonal contraceptives. The safety and efficacy of hormonal contraceptives may be affected if coadministered with protease inhibitors. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors concurrently should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with protease inhibitors to use an additional method of contraception to protect against unwanted pregnancy, unless other drug-specific recommendations are made by the manufacturer of the protease inhibitor. Furthermore, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with protease inhibitors should use an additional barrier method of contraception such as condoms. [46638] [5044] (Major) Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. [46638] [5044] (Major) The FDA recommends consideration of an additional, non-hormonal method of contraception during the 5 days of treatment with ritonavir-boosted nirmatrelvir and until one menstrual cycle after stopping ritonavir-boosted nirmatrelvir. However, the NIH COVID-19 guidelines suggest the potential decrease in ethinyl estradiol exposure is not expected to be clinically significant during the 5 days of therapy. [65314] [67203] [69024] Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) Data on the effects that protease inhibitors have on the serum concentrations of estrogens and progestins are complex. Some protease inhibitors increase (i.e., ritonavir, lopinavir; ritonavir, nelfinavir, tipranavir) and others decrease (i.e., atazanavir, indinavir) the metabolism of hormonal contraceptives. The safety and efficacy of hormonal contraceptives may be affected if coadministered with protease inhibitors. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors concurrently should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with protease inhibitors to use an additional method of contraception to protect against unwanted pregnancy, unless other drug-specific recommendations are made by the manufacturer of the protease inhibitor. Furthermore, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with protease inhibitors should use an additional barrier method of contraception such as condoms. [46638] [5044] (Major) Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. [46638] [5044] (Major) The FDA recommends consideration of an additional, non-hormonal method of contraception during the 5 days of treatment with ritonavir-boosted nirmatrelvir and until one menstrual cycle after stopping ritonavir-boosted nirmatrelvir. However, the NIH COVID-19 guidelines suggest the potential decrease in ethinyl estradiol exposure is not expected to be clinically significant during the 5 days of therapy. [65314] [67203] [69024] Levorphanol: (Moderate) Ritonavir is an inhibitor of the cytochrome P450 3A4 isoenzyme and may decrease the metabolism of levorphanol if the two drugs are coadministered. [4718] Lidocaine: (Moderate) Anti-retroviral protease inhibitors can inhibit hepatic cytochrome P450 3A4, an isoenzyme that is partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and anti-retroviral protease inhibitors should be carefully monitored due to the potential for serious toxicity. [4718] [5172] Lidocaine; Epinephrine: (Moderate) Anti-retroviral protease inhibitors can inhibit hepatic cytochrome P450 3A4, an isoenzyme that is partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and anti-retroviral protease inhibitors should be carefully monitored due to the potential for serious toxicity. [4718] [5172] Lidocaine; Prilocaine: (Moderate) Anti-retroviral protease inhibitors can inhibit hepatic cytochrome P450 3A4, an isoenzyme that is partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and anti-retroviral protease inhibitors should be carefully monitored due to the potential for serious toxicity. [4718] [5172] Linagliptin: (Moderate) Monitor for changes in glycemic control, specifically hyperglycemia, if ritonavir is administered concurrently with linagliptin. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. [28315] [30575] [31240] [34557] Linagliptin; Metformin: (Moderate) Monitor for changes in glycemic control, specifically hyperglycemia, if ritonavir is administered concurrently with linagliptin. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. [28315] [30575] [31240] [34557] (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30480] [30575] Liraglutide: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] [50113] [50814] Lisdexamfetamine: (Moderate) Warn patients that the risk of amphetamine toxicity may be increased during concurrent use of ritonavir, a strong CYP2D6 inhibitor. Amphetamines are partially metabolized by CYP2D6 and have serotonergic properties; inhibition of amphetamine metabolism may increase the risk of serotonin syndrome or other toxicity. If serotonin syndrome occurs, both the amphetamine and CYP2D6 inhibitor should be discontinued and appropriate medical treatment should be implemented. [25887] [29219] [33263] [47165] [57067] Lixisenatide: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] [50113] [50814] Lomitapide: (Contraindicated) Concomitant use of ritonavir and lomitapide is contraindicated. If treatment with ritonavir is unavoidable, lomitapide should be stopped during the course of treatment. Ritonavir is a strong CYP3A4 inhibitor. The exposure to lomitapide was increased 27-fold in the presence of ketoconazole, a strong CYP3A4 inhibitor. [52698] (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and lomitapide is contraindicated due to the potential for hepatotoxicity and gastrointestinal adverse reactions. Consider temporary discontinuation of lomitapide during treatment with ritonavir-boosted nirmatrelvir and for at least 2 to 3 days after treatment completion; if not feasible, consider alternative COVID-19 therapy. Coadministration may increase lomitapide exposure resulting in increased toxicity. Lomitapide is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [52698] [65314] [67203] [69024] Lonafarnib: (Contraindicated) Coadministration of lonafarnib and ritonavir is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; ritonavir is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%. [47165] [66129] Loperamide: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with ritonavir. Concurrent use may increase loperamide exposure. Loperamide is a CYP3A4 and P-gp substrate and ritonavir is a strong CYP3A4 and P-gp inhibitor. Coadministration with ritonavir increased loperamide plasma concentrations by 2- to 3-fold. [33607] [47165] Loperamide; Simethicone: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with ritonavir. Concurrent use may increase loperamide exposure. Loperamide is a CYP3A4 and P-gp substrate and ritonavir is a strong CYP3A4 and P-gp inhibitor. Coadministration with ritonavir increased loperamide plasma concentrations by 2- to 3-fold. [33607] [47165] Lorlatinib: (Major) Avoid coadministration of lorlatinib with ritonavir due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. Ritonavir plasma concentrations may also decrease, leading to reduced efficacy and increasing the potential for viral resistance. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If ritonavir is discontinued, resume the original dose of lorlatinib after 3 half-lives of ritonavir. Lorlatinib is a CYP3A substrate and moderate inducer. Ritonavir is a CYP3A4 substrate and strong inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%. [47165] [63732] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of lorlatinib is necessary. Concomitant use of nirmatrelvir and lorlatinib may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and lorlatinib is a moderate CYP3A inducer. [63732] [67203] Losartan: (Moderate) Concurrent administration of losartan with ritonavir may result in elevated losartan plasma concentrations. Losartan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [47165] [5339] [58664] Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Concurrent administration of losartan with ritonavir may result in elevated losartan plasma concentrations. Losartan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [47165] [5339] [58664] Lovastatin: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and lovastatin is contraindicated. Discontinue use of lovastatin at least 12 hours before, during, and 5 days after treatment with ritonavir-boosted nirmatrelvir. Coadministration may increase lovastatin exposure resulting in increased toxicity. Lovastatin is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Contraindicated) Concurrent use of lovastatin and anti-retroviral protease inhibitors is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is substantially increased if lovastatin is administered concomitantly with anti-retroviral protease inhibitors. Lovastatin is a substrate of CYP3A4 and anti-retroviral protease inhibitors are strong inhibitors of CYP3A4; therefore, coadministration may result in substantial increases in plasma concentrations of lovastatin. [28604] Lumacaftor; Ivacaftor: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and lumacaftor; ivacaftor is contraindicated; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response and possible resistance. The risk for reduced efficacy may persist following lumacaftor; ivacaftor discontinuation. Nirmatrelvir is a CYP3A substrate and lumacaftor; ivacaftor is a strong CYP3A inducer. [59891] [67203] [69024] (Major) If ritonavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. [47165] [48524] (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of ritonavir; avoid concurrent use if possible. If concomitant use of ritonavir is necessary, monitor antiretroviral efficacy and adjust therapy as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when ritonavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking ritonavir, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking ritonavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Ritonavir is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of ritonavir and decrease its therapeutic efficacy. Although ritonavir is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold. Lastly, ritonavir is also a substrate of the drug transporter P-glycoprotein (P-gp), and lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect on P-gp substrates is not clear, but their exposure may be affected. [28142] [59891] Lumacaftor; Ivacaftor: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and lumacaftor; ivacaftor is contraindicated; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response and possible resistance. The risk for reduced efficacy may persist following lumacaftor; ivacaftor discontinuation. Nirmatrelvir is a CYP3A substrate and lumacaftor; ivacaftor is a strong CYP3A inducer. [59891] [67203] [69024] (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of ritonavir; avoid concurrent use if possible. If concomitant use of ritonavir is necessary, monitor antiretroviral efficacy and adjust therapy as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when ritonavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking ritonavir, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking ritonavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Ritonavir is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of ritonavir and decrease its therapeutic efficacy. Although ritonavir is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold. Lastly, ritonavir is also a substrate of the drug transporter P-glycoprotein (P-gp), and lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect on P-gp substrates is not clear, but their exposure may be affected. [28142] [59891] Lumateperone: (Major) Consider withholding lumateperone, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the lumateperone dose. Reduce the dose of lumateperone to 10.5 mg once daily if concomitant use of ritonavir-boosted nirmatrelvir is necessary. Coadministration may increase lumateperone exposure resulting in increased toxicity. Lumateperone is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Major) Reduce the dose of lumateperone to 10.5 mg once daily if concomitant use of ritonavir is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor increased lumateperone exposure by approximately 4-fold. [47165] [56579] [64885] Lurasidone: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and lurasidone is contraindicated; consider an alternative COVID-19 therapy. Coadministration may increase lurasidone exposure resulting in increased toxicity. Lurasidone is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Contraindicated) Concurrent use of lurasidone with strong CYP3A4 inhibitors, such as ritonavir, is contraindicated. Lurasidone is primarily metabolized by CYP3A4. Increased lurasidone plasma concentrations are expected when the drug is co-administered with inhibitors of CYP3A4. [28315] [42227] [47165] Lurbinectedin: (Major) Avoid concomitant use of lurbinectedin and ritonavir due to the risk of increased lurbinectedin exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of lurbinectedin by 50%. Lurbinectedin is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of lurbinectedin by 2.7-fold. [47165] [65593] Macitentan: (Major) Avoid concurrent use of macitentan and ritonavir. Ritonavir is a strong inhibitor of CYP3A4. Coadministration of macitentan with another strong CYP3A4 inhibitor approximately doubled macitentan exposure. Consider alternative treatment options for pulmonary hypertension if treatment with ritonavir is necessary. [56260] Macitentan; Tadalafil: (Major) Avoid concomitant use of ritonavir-boosted nirmatrelvir and tadalafil, when used for pulmonary hypertension, and consider an alternative COVID-19 therapy. Consider withholding tadalafil, when used for erectile dysfunction, during concomitant receipt of ritonavir-boosted nirmatrelvir. Coadministration may increase tadalafil exposure resulting in increased toxicity. Tadalafil is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Major) Avoid concurrent use of macitentan and ritonavir. Ritonavir is a strong inhibitor of CYP3A4. Coadministration of macitentan with another strong CYP3A4 inhibitor approximately doubled macitentan exposure. Consider alternative treatment options for pulmonary hypertension if treatment with ritonavir is necessary. [56260] (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ritonavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of ritonavir therapy. Stop tadalafil at least 24 hours prior to starting ritonavir. After at least 1 week of ritonavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Coadministration of ritonavir with tadalafil results in a 124% increase in tadalafil AUC. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4. [28220] [28315] [40259] Maprotiline: (Moderate) Ritonavir potently inhibits the CYP2D6 and CYP3A4 isozymes, and thus may inhibit the metabolism of maprotiline. Since the magnitude of the interaction with the maprotiline is difficult to predict but may be significant, monitor patients receiving ritonavir and maprotiline concurrently closely. Adjust the dosage of maprotiline based on therapeutic response. Maprotiline serum concentration monitoring may be useful to guide adjustments and prevent toxicity. [28759] [46638] [47165] [5542] Maraviroc: (Major) Coadministration of maraviroc (a substrate of CYP3A, P-gp, MRP2) with ritonavir (a strong CYP3A4 inhibitor and P-gp/MRP2 inhibitor) has been reported to significantly increase maraviroc concentrations. Reduce the dose of maraviroc when coadministered with strong CYP3A inhibitors; coadministration of maraviroc with strong CYP3A inhibitors is contraindicated in patients with CrCl less than 30 mL/min. Adjust the maraviroc dosage as follows when administered with ritonavir (with or without a concomitant CYP3A inducer): adults and children weighing 40 kg or more: 150 mg PO twice daily; children weighing 30 to 39 kg: 100 mg PO twice daily; children weighing 20 to 29 kg: 75 mg PO twice daily (or 80 mg PO twice daily for solution); children weighing 10 to 19 kg: 50 mg PO twice daily; children weighing 2 to 9 kg: use not recommended. [28380] [33473] [46638] [60845] Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with ritonavir due to risk of heart failure due to systolic dysfunction. Concomitant use increases mavacamten exposure and may decrease plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mavacamten is a substrate and moderate inducer of CYP3A and ritonavir is a substrate and strong inhibitor of CYP3A. Concomitant use with a strong CYP3A inhibitor is predicted to increase mavacamten overall exposure up to 130%. [47165] [67543] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of mavacamten is necessary. Concomitant use of nirmatrelvir and mavacamten may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and mavacamten is a CYP3A inducer. [67203] [67543] Mavorixafor: (Major) Decrease the mavorixafor dose to 200 mg PO once daily and monitor for adverse effects if concomitant use with ritonavir is necessary. Concomitant use may increase mavorixafor exposure and the risk for mavorixafor-related adverse effects. Mavorixafor is a CYP3A and P-gp substrate and ritonavir is a strong CYP3A and P-gp inhibitor. Concomitant use with another strong CYP3A and P-gp inhibitor increased mavorixafor overall exposure by 2-fold. [28380] [34557] [47165] [70577] Meclizine: (Moderate) Concurrent administration of meclizine with ritonavir may result in elevated meclizine plasma concentrations. Meclizine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [43856] [47165] [58664] Medroxyprogesterone: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with ritonavir, a strong CYP3A inhibitor should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is metabolized primarily by hydroxylation via the CYP3A4 in vitro. [28380] [34557] [47165] [57648] Mefloquine: (Moderate) The plasma concentrations of mefloquine may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as GI or neuropsychiatric effects, is recommended during coadministration. Ritonavir is a strong inhibitor of CYP3A4 and P-glycoprotein (P-gp) inhibitor, while mefloquine is a CYP3A4 and P-gp substrate. [28301] [47165] Meloxicam: (Moderate) Concurrent administration of meloxicam with ritonavir may result in elevated meloxicam plasma concentrations. Meloxicam is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [47165] [58664] [6352] Meperidine: (Contraindicated) Concomitant use of high-dose, long-term meperidine therapy with ritonavir is not recommended due the increased concentration of the neurotoxic metabolite of meperidine, normeperidine. Ritonavir is associated with a 62% decrease in meperidine AUC thought to be due to increased meperidine metabolism. The AUC and Cmax of normeperidine, the toxic metabolite of meperidine, increased 47% and 87%, respectively, with concurrent administration of ritonavir. [28315] [46638] [47165] [58664] (Major) Consider withholding meperidine, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the meperidine dose. Coadministration may increase meperidine exposure resulting in increased toxicity, including potentially fatal respiratory depression. Meperidine is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] Meropenem: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of meropenem is necessary. Concomitant use of nirmatrelvir and meropenem may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and meropenem is a CYP3A inducer. [62277] [67203] (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with meropenem. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and meropenem is a weak CYP3A inducer. [62277] [67203] Meropenem; Vaborbactam: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of meropenem is necessary. Concomitant use of nirmatrelvir and meropenem may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and meropenem is a CYP3A inducer. [62277] [67203] (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with meropenem. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and meropenem is a weak CYP3A inducer. [62277] [67203] Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30480] [30575] Metformin; Repaglinide: (Moderate) Coadministration of repaglinide and protease inhibitors may increase or decrease glucose concentrations and increase repaglinide AUC; if coadministration is necessary, repaglinide dosage adjustment may be necessary and increased frequency of glucose monitoring is recommended. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. In addition, repaglinide is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are potent CYP3A4 inhibitors and inhibitors of OATP. [29751] [31281] [36049] [61511] [61513] (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30480] [30575] Metformin; Saxagliptin: (Major) The metabolism of saxagliptin is primarily mediated by CYP3A4/5. The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP3A4/5 inhibitor such as ritonavir. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have also been reported with use of anti-retroviral protease inhibitors, such as ritonavir. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] [36111] [51227] (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30480] [30575] Metformin; Sitagliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30480] [30575] Methadone: (Moderate) Coadministration of ritonavir with methadone has resulted in decreased methadone plasma concentrations. However, because methadone is metabolized by multiple CYP450 enzymes, including CYP3A4, CYP2C19, CYP2C9, and CYP2D6, and ritonavir is known to inhibit CYP3A4 and CYP2D6 and induce CYP2C19 and CYP2C9, the potential for increased methadone exposure should also be considered with concomitant administration. Therefore, concurrent use may increase or prolong opioid effects, resulting in fatal overdose or may decrease methadone efficacy or produce onset of withdrawal symptoms in patients physically dependent on methadone. Monitor for respiratory depression, sedation, and signs of opioid withdrawal. Consider adjusting the methadone dose until stable drug effects are achieved. If ritonavir is discontinued, and its CYP450 effects decline, methadone plasma concentrations may increase or decrease. Closely monitor for increased opioid adverse effects and for evidence of withdrawal and adjust the methadone dose as necessary when ritonavir is discontinued. [33136] [47165] Methamphetamine: (Moderate) Warn patients that the risk of amphetamine toxicity may be increased during concurrent use of ritonavir, a strong CYP2D6 inhibitor. Amphetamines are partially metabolized by CYP2D6 and have serotonergic properties; inhibition of amphetamine metabolism may increase the risk of serotonin syndrome or other toxicity. If serotonin syndrome occurs, both the amphetamine and CYP2D6 inhibitor should be discontinued and appropriate medical treatment should be implemented. [25887] [29219] [33263] [47165] [57067] Methohexital: (Contraindicated) Ritonavir-boosted nirmatrelvir is contraindicated for use within 2 weeks of administering barbiturates; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response. The risk for reduced efficacy may persist following barbiturate discontinuation. Nirmatrelvir is a CYP3A substrate and barbiturates are strong CYP3A inducers. [41911] [49229] [49236] [49352] [57048] [57271] [65314] [67203] [69024] (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers. [28315] [46638] Methylergonovine: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and ergot alkaloids is contraindicated; consider an alternative COVID-19 therapy. Coadministration may increase ergot alkaloids' exposure resulting in increased toxicity. Ergot alkaloids are CYP3A substrates and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Major) Avoid concomitant use of methylergonovine with ritonavir. Concomitant use may increase methylergonovine exposure and the risk for vasospasm which may lead to cerebral or peripheral ischemia. Methylergonovine is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. [48893] [56579] Methylprednisolone: (Moderate) Monitor for corticosteroid-related adverse events if methylprednisolone is used with ritonavir. Concurrent use may increase the exposure of methylprednisolone. Methylprednisolone is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Other strong CYP3A4 inhibitors have been reported to decrease the metabolism of certain corticosteroids by up to 60%. [30015] [47165] [58664] Metoclopramide: (Moderate) Concurrent administration of metoclopramide with ritonavir may result in elevated plasma concentrations of metoclopramide. Metoclopromide is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [34515] [47165] [58664] Metoprolol: (Moderate) Metoprolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as ritonavir, may impair metoprolol metabolism. Clinicians should be alert to exaggerated beta-blocker effects if metoprolol is given with these drugs. [5044] [5269] Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Metoprolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as ritonavir, may impair metoprolol metabolism. Clinicians should be alert to exaggerated beta-blocker effects if metoprolol is given with these drugs. [5044] [5269] Metronidazole: (Major) Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Ritonavir oral solution and capsules contain ethanol. Administration of ritonavir oral solution or capsules to patients receiving or who have recently received disulfiram or metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations of ritonavir (e.g., tablets, oral powder). [28315] [28581] [47165] Mexiletine: (Major) Avoid concomitant use of ritonavir-boosted nirmatrelvir and mexiletine and consider an alternative COVID-19 therapy. Coadministration may increase mexiletine exposure resulting in increased toxicity. Mexiletine is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] (Major) Ritonavir is an inhibitor of CYP3A4 and CYP2D6 (in vitro), and may increase exposure to drugs metabolized by these enzymes, such as mexiletine. Increased mexiletine serum concentrations may increase the risk for adverse reactions. [47165] [60002] Midazolam: (Major) Concomitant use of ritonavir-boosted nirmatrelvir and oral midazolam is contraindicated; consider an alternative COVID-19 therapy. Coadministration may increase midazolam exposure resulting in increased toxicity. The significance of an interaction with IV midazolam is uncertain, but may be less significant due to absence of an effect on pre-systemic midazolam clearance. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with ritonavir-boosted nirmatrelvir, as these benzodiazepines are not oxidatively metabolized. Midazolam is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Major) Protease inhibitors may increase midazolam concentrations; the risk for midazolam-related adverse effects varies by midazolam dosage form and route of administration. Oral midazolam use is contraindicated. Intranasal midazolam should be avoided when possible. Additional monitoring and a dosage reduction may be necessary with parenteral midazolam. Midazolam is a CYP3A substrate and protease inhibitors are CYP3A inhibitors. Protease inhibitors have been shown to increase oral midazolam AUCs by up to 3-fold, resulting in clinically significant potentiation of sedation. [28995] [32432] [44717] [44859] [47165] [64166] Midostaurin: (Major) Avoid the concomitant use of midostaurin and ritonavir due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone. [47165] [61906] Mifepristone: (Major) Caution is advised when administering ritonavir with mifepristone because increased serum concentrations of either drug may occur. When mifepristone is used in the treatment of Cushing's syndrome, coadministration with ritonavir should be done only when necessary, and in such cases the dose of mifepristone should be limited to a maximum dose of 900 mg per day. In a patient already receiving ritonavir, initiate mifepristone at a dose of 300 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with ritonavir is initiated in a patient already receiving mifepristone 300 mg, dosage adjustments are not required. If therapy with ritonavir is initiated in a patient already receiving mifepristone 600 mg, reduce dose of mifepristone to 300 mg and titrate to a maximum of 600 mg if clinically indicated. If therapy with ritonavir is initiated in a patient already receiving 900 mg, reduce dose of mifepristone to 600 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with ritonavir is initiated in a patient already receiving 1,200 mg, reduce the mifepristone dose to 900 mg. Both mifepristone and ritonavir are substrates and strong inhibitors of CYP3A4. [28003] [47165] [48697] Miglitol: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. [30575] [51227] Mirabegron: (Moderate) Concurrent administration of mirabegron with ritonavir may result in elevated plasma concentrations of ritonavir. Mirabegron is a moderate inhibitor of CYP2D6. Ritonavir is a CYP2D6 substrate. Caution and close monitoring are advised if these drugs are administered together. [28380] [47165] [51111] Mirtazapine: (Moderate) The plasma concentrations of mirtazapine may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as CNS or GI effects, is recommended during coadministration. Ritonavir is a strong CYP3A4 inhibitor, while mirtazapine is a CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased mirtazapine exposure by approximately 50%. [40942] [47165] Mirvetuximab Soravtansine: (Moderate) Closely monitor for mirvetuximab soravtansine-related adverse reactions if concomitant use of ritonavir is necessary. DM4, the cytotoxic component of mirvetuximab soravtansine, is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use may increase unconjugated DM4 exposure. [47165] [68173] Mitapivat: (Major) Avoid coadministration of mitapivat with ritonavir due to increased risk of adverse reactions from mitapivat. Coadministration increases mitapivat concentrations and may decrease ritonavir concentrations leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mitapivat is a CYP3A substrate and weak inducer and ritonavir is a CYP3A substrate and strong inhibitor. Concomitant use with other strong CYP3A inhibitors increased mitapivat overall exposure by 3.6 to 4.9-fold. [47165] [67203] [67403] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of mitapivat is necessary. Concomitant use of nirmatrelvir and mitapivat may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and mitapivat is a weak CYP3A inducer. [67203] [67403] Mitotane: (Major) Avoid the concomitant use of mitotane with ritonavir due to the potential for reduced antiretroviral efficacy and the potential development of viral resistance. If coadministration cannot be avoided, monitor for decreased efficacy of ritonavir. Mitotane is a strong CYP3A4 inducer and ritonavir is a CYP3A4 substrates; coadministration may result in decreased plasma concentrations of ritonavir. Another strong CYP3A inducer, rifampin (300 or 600 mg daily for 10 days), decreased the AUC and Cmax of ritonavir (500 mg every 12 hours for 20 days) by 35% and 25%, respectively. [41934] [46638] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of mitotane is necessary. Concomitant use of nirmatrelvir and mitotane may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and mitotane is a strong CYP3A inducer. [41934] [67203] Mobocertinib: (Major) Avoid concomitant use of mobocertinib and ritonavir. Concomitant use may increase mobocertinib exposure and the risk for adverse reactions such as QT prolongation. Mobocertinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Use of a strong CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 374% to 419%. [47165] [66990] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of mobocertinib is necessary. Concomitant use of nirmatrelvir and mobocertinib may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and mobocertinib is a weak CYP3A inducer. [66990] [67203] Modafinil: (Major) Concurrent administration of modafinil with ritonavir may result in elevated plasma concentrations of modafinil and decreased concentrations of ritonavir. Modafinil is a substrate and inducer of the hepatic isoenzyme CYP3A4; ritonavir is a CYP3A4 substrate. In addition, ritonavir is a potent CYP3A4 inhibitor. Because the resultant effect of coadministration of a CYP3A4 inducer (modafinil) and inhibitor (ritonavir) on the plasma concentrations of these drugs is not defined, caution and close monitoring are advised if these drugs are administered together. [41243] [58664] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of modafinil is necessary. Concomitant use of nirmatrelvir and modafinil may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and modafinil is a weak CYP3A inducer. [41243] [67203] Mometasone: (Moderate) Coadministration of mometasone with ritonavir (a strong CYP3A4 inhibitor) may cause mometasone serum concentrations to increase, potentially resulting in Cushing's syndrome and adrenal suppression. Consider use of an alternative corticosteroid whose concentrations are less affected by strong CYP3A4 inhibitors, such as beclomethasone and prednisolone, especially during long-term treatment. [28341] [47165] [58620] Morphine: (Moderate) Close clinical monitoring is advised when administering morphine with ritonavir due to an increased potential for morphine-related adverse events, including hypotension, respiratory depression, profound sedation, coma, and death. Dosage reductions of morphine and/or ritonavir may be required. Morphine is a substrate of the drug efflux transporter P-glycoprotein (P-gp); ritonavir is an inhibitor of this efflux protein. Coadministration may cause an approximate 2-fold increase in morphine exposure. [28380] [34557] [40951] Morphine; Naltrexone: (Moderate) Close clinical monitoring is advised when administering morphine with ritonavir due to an increased potential for morphine-related adverse events, including hypotension, respiratory depression, profound sedation, coma, and death. Dosage reductions of morphine and/or ritonavir may be required. Morphine is a substrate of the drug efflux transporter P-glycoprotein (P-gp); ritonavir is an inhibitor of this efflux protein. Coadministration may cause an approximate 2-fold increase in morphine exposure. [28380] [34557] [40951] Moxifloxacin: (Moderate) Concomitant use of ritonavir with moxifloxacin may increase ritonavir adverse effects. After 3 days of ritonavir 400 mg twice daily plus moxifloxacin (400 mg once daily), ritonavir exposure was approximately 1.5 times higher than exposure that has been observed with ritonavir 600 mg twice-daily alone. Caution and close monitoring is advised if these drugs are administered together. [47165] [60002] Nabilone: (Moderate) Coadministration of ritonavir and oral THC results in increased THC concentrations. A decreased dose of nabilone may be needed if these drugs are coadministered with ritonavir. [5044] Nadolol: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers. [5044] Nafcillin: (Major) Concurrent administration of nafcillin with ritonavir may result in decreased plasma concentrations of ritonavir, which may affect antiviral efficacy. Nafcillin is an inducer of the hepatic isoenzyme CYP3A4; ritonavir is a CYP3A4 substrate. Caution and close monitoring are advised if these drugs are administered together. [11312] [11313] [58664] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of nafcillin is necessary. Concomitant use of nirmatrelvir and nafcillin may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and nafcillin is a moderate CYP3A inducer. [34456] [67203] Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with ritonavir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; ritonavir is a moderate P-gp inhibitor and a strong CYP3A4 inhibitor. [28380] [34557] [47165] [61831] Naloxegol: (Contraindicated) Concomitant use of naloxegol with ritonavir is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as ritonavir, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. [47165] [57937] (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and naloxegol is contraindicated due to the potential for opioid withdrawal symptoms; consider an alternative COVID-19 therapy. Coadministration can significantly increase naloxegol exposure which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate and nirmatrelvir is a CYP3A inhibitor. [57937] [67203] [69024] Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with ritonavir is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors. [30742] [47165] Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and protease inhibitors; a sirolimus dosage reduction may be considered if concomitant use is necessary. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. [28610] [46638] [67136] (Major) Before prescribing ritonavir-boosted nirmatrelvir for a patient receiving sirolimus, the patient's specialist provider(s) should be consulted, given the significant drug-drug interaction potential and because close monitoring may not be feasible. If this is not feasible, consider an alternative COVID-19 therapy. Coadministration may increase sirolimus exposure resulting in increased toxicity. Sirolimus is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [28610] [65314] [67203] [69024] Naproxen; Esomeprazole: (Moderate) Concurrent administration of esomeprazole with ritonavir may result in elevated esomeprazole plasma concentrations. Esomeprazole is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Monitor patients for increased side effects if these drugs are administered together. [58664] [6265] Nateglinide: (Moderate) Concurrent administration of nateglinide with some protease inhibitors may result in elevated nateglinide plasma concentrations via inhibition of CYP2C9. Ritonavir may induce CYP2C9 leading to a reduction of nateglinide concentrations. Monitor blood glucose concentrations during coadministration as hypoglycemia or hyperglycemia could occur. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Monitor blood glucose concentrations during coadministration. Caution and close monitoring are advised if these drugs are administered together. [30585] [45644] [47165] Nebivolol: (Moderate) Ritonavir is expected to decrease the hepatic CYP metabolism of beta-blockers like nebivolol, resulting in increased beta-blocker concentrations. Cardiac and neurologic events have been reported when ritonavir is concurrently administered with beta-blockers. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including beta-blockers) has not been evaluated. If coadministration of nebivolol and ritonavir is warranted, do so with caution and careful monitoring. Decreased beta-blocker doses may be warranted. [28315] [60860] Nefazodone: (Major) Elevated plasma concentrations of nefazodone and ritonavir may occur. Both ritonavir and nefazodone are CYP3A4 substrates/potent inhibitors. Cardiac and neurologic events have been reported when ritonavir was concurrently administered with nefazodone. If coadministration of these drugs is warranted, do so with caution and careful monitoring. A 50% reduction in the nefazodone dose may be warranted. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs with potential bradycardic effects has not been evaluated. [28315] [47165] [4718] [5044] [5414] [54634] [5772] Nelfinavir: (Moderate) Concurrent administration of ritonavir and nelfinavir results in a 1.5-fold increase of nelfinavir AUC. Dosage recommendations for coadministration from HIV treatment guidelines are ritonavir 400 mg twice daily plus nelfinavir 500 to 750 mg twice daily. Both ritonavir and nelfinavir are potent inhibitors and substrates of CYP3A4 and P-glycoprotein (P-gp). [11417] [11418] [28839] [46638] Neratinib: (Major) Avoid concomitant use of ritonavir with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations. [47165] [62127] Netupitant, Fosnetupitant; Palonosetron: (Moderate) Coadministration may result in increased netupitant and ritonavir exposure. Netupitant is a CYP3A4 substrate and moderate inhibitor of CYP3A4; the inhibitory effect on CYP3A4 can last for multiple days. Ritonavir is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased netupitant exposure by 140%. No dosage adjustment is necessary. [47165] [58171] Nevirapine: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of nevirapine is necessary. Concomitant use of nirmatrelvir and nevirapine may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and nevirapine is a CYP3A inducer. [42456] [67203] [69024] (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with nevirapine. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Additionally, monitor for an increase in nevirapine-related adverse reactions if coadministration with ritonavir is necessary. Ritonavir is a CYP3A substrate and strong CYP3A inhibitor; nevirapine is a CYP3A substrate and weak CYP3A inducer. Coadministration with a moderate CYP3A4 inhibitor increased nevirapine exposure by 100%; concomitant use with a strong CYP3A4 inhibitor may also increase nevirapine exposure. [42456] [58664] NiCARdipine: (Moderate) Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. [11537] [28315] [47165] [50341] [56565] NIFEdipine: (Major) According to the manufacturer of nifedipine, coadministration with ritonavir may result in increased exposure to nifedipine, and initiation of nifedipine should begin with the lowest available dose. Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. [28315] [29068] [31749] Nilotinib: (Major) Avoid the concomitant use of nilotinib and ritonavir. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If ritonavir is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate and moderate inhibitor of CYP3A4 and ritonavir is a substrate and a strong inhibitor of CYP3A4. [28315] [47165] [58766] Nimodipine: (Moderate) Anti-retroviral protease inhibitors are CYP3A4 inhibitors and may decrease the hepatic metabolism of nimodipine, leading to increased plasma concentrations of nimodipine. In addition, ritonavir and calcium channel blockers both prolong the PR interval and the manufacturer for ritonavir recommends caution during coadministration. Monitor therapeutic response and for adverse effects, such as hypotension. Decreased calcium-channel blocker doses may be warranted. [28315] [29082] [32432] [47165] Nintedanib: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as ritonavir, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%. [28341] [47165] [58203] Nirogacestat: (Major) Avoid concomitant use of nirogacestat and ritonavir due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold. [56579] [69917] Nisoldipine: (Major) Avoid coadministration of nisoldipine with protease inhibitors due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with another CYP3A inhibitor increased the AUC of nisoldipine by 30% to 45%. [28315] [29012] [32432] [47165] Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. [46638] [5044] (Major) The FDA recommends consideration of an additional, non-hormonal method of contraception during the 5 days of treatment with ritonavir-boosted nirmatrelvir and until one menstrual cycle after stopping ritonavir-boosted nirmatrelvir. However, the NIH COVID-19 guidelines suggest the potential decrease in ethinyl estradiol exposure is not expected to be clinically significant during the 5 days of therapy. [65314] [67203] [69024] (Moderate) Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. For example, ritonavir (also found in combinations like lopinavir; ritonavir, and used as a booster in many HIV treatment regimens) may decrease the metabolism of norethindrone, raising norethindrone concentrations. Women receiving norethindrone for hormone replacement or contraception should report potential hormonal adverse effects (e.g., bleeding pattern changes, acne, emotional lability) or any changes in efficacy (e.g., noted changes in bleeding patterns) to their prescribers. Because norethindrone-containing contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive norethindrone contraception concurrently with ritonavir should use an additional barrier method of contraception such as condoms. [58679] [7731] Norethindrone: (Moderate) Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. For example, ritonavir (also found in combinations like lopinavir; ritonavir, and used as a booster in many HIV treatment regimens) may decrease the metabolism of norethindrone, raising norethindrone concentrations. Women receiving norethindrone for hormone replacement or contraception should report potential hormonal adverse effects (e.g., bleeding pattern changes, acne, emotional lability) or any changes in efficacy (e.g., noted changes in bleeding patterns) to their prescribers. Because norethindrone-containing contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive norethindrone contraception concurrently with ritonavir should use an additional barrier method of contraception such as condoms. [58679] [7731] Norethindrone; Ethinyl Estradiol: (Major) Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. [46638] [5044] (Major) The FDA recommends consideration of an additional, non-hormonal method of contraception during the 5 days of treatment with ritonavir-boosted nirmatrelvir and until one menstrual cycle after stopping ritonavir-boosted nirmatrelvir. However, the NIH COVID-19 guidelines suggest the potential decrease in ethinyl estradiol exposure is not expected to be clinically significant during the 5 days of therapy. [65314] [67203] [69024] (Moderate) Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. For example, ritonavir (also found in combinations like lopinavir; ritonavir, and used as a booster in many HIV treatment regimens) may decrease the metabolism of norethindrone, raising norethindrone concentrations. Women receiving norethindrone for hormone replacement or contraception should report potential hormonal adverse effects (e.g., bleeding pattern changes, acne, emotional lability) or any changes in efficacy (e.g., noted changes in bleeding patterns) to their prescribers. Because norethindrone-containing contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive norethindrone contraception concurrently with ritonavir should use an additional barrier method of contraception such as condoms. [58679] [7731] Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. [46638] [5044] (Major) The FDA recommends consideration of an additional, non-hormonal method of contraception during the 5 days of treatment with ritonavir-boosted nirmatrelvir and until one menstrual cycle after stopping ritonavir-boosted nirmatrelvir. However, the NIH COVID-19 guidelines suggest the potential decrease in ethinyl estradiol exposure is not expected to be clinically significant during the 5 days of therapy. [65314] [67203] [69024] (Moderate) Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. For example, ritonavir (also found in combinations like lopinavir; ritonavir, and used as a booster in many HIV treatment regimens) may decrease the metabolism of norethindrone, raising norethindrone concentrations. Women receiving norethindrone for hormone replacement or contraception should report potential hormonal adverse effects (e.g., bleeding pattern changes, acne, emotional lability) or any changes in efficacy (e.g., noted changes in bleeding patterns) to their prescribers. Because norethindrone-containing contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive norethindrone contraception concurrently with ritonavir should use an additional barrier method of contraception such as condoms. [58679] [7731] Norgestimate; Ethinyl Estradiol: (Major) Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. [46638] [5044] (Major) The FDA recommends consideration of an additional, non-hormonal method of contraception during the 5 days of treatment with ritonavir-boosted nirmatrelvir and until one menstrual cycle after stopping ritonavir-boosted nirmatrelvir. However, the NIH COVID-19 guidelines suggest the potential decrease in ethinyl estradiol exposure is not expected to be clinically significant during the 5 days of therapy. [65314] [67203] [69024] Nortriptyline: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with ritonavir is necessary; a dose reduction of the TCA may be necessary. Concurrent use may increase exposure of the TCA. TCAs are CYP2D6 substrates and ritonavir is a CYP2D6 inhibitor. [47165] Odevixibat: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of odevixibat is necessary. Concomitant use of nirmatrelvir and odevixibat may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and odevixibat is a weak CYP3A inducer. [66816] [67203] (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with odevixibat. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and odevixibat is a weak CYP3A inducer. [66816] [67203] Olanzapine: (Moderate) Ritonavir may reduce olanzapine serum concentrations by approximately 50%; how this affects olanzapine efficacy, however, is not known. Ritonavir appears to induce olanzapine's metabolism by either CYP1A2 or glucuronide conjugation. If ritonavir and olanzapine are used concurrently, monitor for reduced olanzapine effect and adjust olanzapine dose as needed. [27275] Olanzapine; Fluoxetine: (Moderate) Monitor for increased fluoxetine-related adverse effects if coadministered with ritonavir. Concurrent use may result in increased fluoxetine exposure. Fluoxetine is a CYP2D6 substrate and ritonavir is a weak CYP2D6 inhibitor. [44058] [47165] (Moderate) Ritonavir may reduce olanzapine serum concentrations by approximately 50%; how this affects olanzapine efficacy, however, is not known. Ritonavir appears to induce olanzapine's metabolism by either CYP1A2 or glucuronide conjugation. If ritonavir and olanzapine are used concurrently, monitor for reduced olanzapine effect and adjust olanzapine dose as needed. [27275] Olanzapine; Samidorphan: (Moderate) Ritonavir may reduce olanzapine serum concentrations by approximately 50%; how this affects olanzapine efficacy, however, is not known. Ritonavir appears to induce olanzapine's metabolism by either CYP1A2 or glucuronide conjugation. If ritonavir and olanzapine are used concurrently, monitor for reduced olanzapine effect and adjust olanzapine dose as needed. [27275] Olaparib: (Major) Avoid coadministration of olaparib with ritonavir due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 100 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after ritonavir is discontinued. Olaparib is a CYP3A substrate and ritonavir is a strong CYP3A4 inhibitor; concomitant use may increase olaparib exposure. Coadministration with another strong CYP3A inhibitor increased the olaparib Cmax by 42% and the AUC by 170%. [28380] [34557] [47165] [58662] Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and ritonavir is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and ritonavir may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If ritonavir is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. [47165] [65809] Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure. [29012] [29090] [47165] Olodaterol: (Moderate) Beta-agonists, such as olodaterol, may be associated with adverse cardiovascular effects including QT interval prolongation. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with olodaterol include ritonavir. [47165] [57710] Olopatadine; Mometasone: (Moderate) Coadministration of mometasone with ritonavir (a strong CYP3A4 inhibitor) may cause mometasone serum concentrations to increase, potentially resulting in Cushing's syndrome and adrenal suppression. Consider use of an alternative corticosteroid whose concentrations are less affected by strong CYP3A4 inhibitors, such as beclomethasone and prednisolone, especially during long-term treatment. [28341] [47165] [58620] Olutasidenib: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of olutasidenib is necessary. Concomitant use of nirmatrelvir and olutasidenib may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and olutasidenib is a CYP3A inducer. [67203] [68242] (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with olutasidenib. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and olutasidenib is a weak CYP3A inducer. [67203] [68242] Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and ritonavir. If concomitant use is necessary, decrease omaveloxolone dose to 50 mg once daily. Concomitant use may increase omaveloxolone exposure and the risk for omaveloxolone-related adverse effects. Additionally, monitor for decreased efficacy of ritonavir as concomitant use may decrease ritonavir exposure. Omaveloxolone is a CYP3A substrate and weak CYP3A inducer and ritonavir is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased omaveloxolone overall exposure by 4-fold. [47165] [67203] [68644] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of omaveloxolone is necessary. Concomitant use may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and omaveloxolone is a CYP3A inducer. [67203] [68644] Omeprazole: (Moderate) Increased exposure to omeprazole may occur during concurrent administration of ritonavir. Although dosage adjustment of omeprazole is not normally required, dosage reduction may be considered in patients receiving higher omeprazole doses (e.g., those with Zollinger-Ellison syndrome). Ritonavir is a strong CYP3A4 inhibitor. Omeprazole is a CYP2C19 and CYP3A4 substrate. Coadministration of a dual CYP2C19/strong CYP3A4 inhibitor increased the omeprazole AUC by an average of 4-times. [29564] [47165] Omeprazole; Amoxicillin; Rifabutin: (Major) Reduce the rifabutin dose to 150 mg PO once daily and monitor for adverse effects, such as uveitis and neutropenia, if concomitant use with ritonavir is necessary. Although the FDA-approved labeling recommends reducing the rifabutin dose by at least 75% (to a maximum 150 mg every other day or 3 times per week), lower rifabutin exposure has been reported in persons living with HIV than in healthy subjects and acquired rifamycin resistance has been reported in these persons receiving 3 times weekly regimens. Monitor response and consider therapeutic drug monitoring (TDM) when rifabutin is used with a ritonavir-boosted protease inhibitor and adjust dose accordingly. Rifabutin is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with ritonavir (alone) increased the AUC of rifabutin by 300%. [29210] [34362] [46638] (Moderate) Increased exposure to omeprazole may occur during concurrent administration of ritonavir. Although dosage adjustment of omeprazole is not normally required, dosage reduction may be considered in patients receiving higher omeprazole doses (e.g., those with Zollinger-Ellison syndrome). Ritonavir is a strong CYP3A4 inhibitor. Omeprazole is a CYP2C19 and CYP3A4 substrate. Coadministration of a dual CYP2C19/strong CYP3A4 inhibitor increased the omeprazole AUC by an average of 4-times. [29564] [47165] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of rifabutin is necessary. Concomitant use of nirmatrelvir and rifabutin may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. [29210] [29812] [34549] [34550] [67203] [69024] Omeprazole; Sodium Bicarbonate: (Moderate) Concurrent administration of tipranavir and ritonavir with antacids results in decreased tipranavir concentrations. Administer tipranavir and ritonavir 2 hours before or 1 hour after antacids. [1800] [1802] (Moderate) Increased exposure to omeprazole may occur during concurrent administration of ritonavir. Although dosage adjustment of omeprazole is not normally required, dosage reduction may be considered in patients receiving higher omeprazole doses (e.g., those with Zollinger-Ellison syndrome). Ritonavir is a strong CYP3A4 inhibitor. Omeprazole is a CYP2C19 and CYP3A4 substrate. Coadministration of a dual CYP2C19/strong CYP3A4 inhibitor increased the omeprazole AUC by an average of 4-times. [29564] [47165] Ondansetron: (Moderate) Caution and close monitoring are advised if these drugs are administered together. Ondansetron exposure may be altered resulting in increased adverse effects or decreased efficacy. Ondansetron is metabolized by the hepatic isoenzymes CYP3A4, CYP2D6, and CYP1A2; ritonavir inhibits CYP3A4 and CYP2D6 and induces CYP1A2. [31266] [47165] Oritavancin: (Major) Ritonavir is metabolized by CYP3A4 and CYP2D6 (minor); oritavancin is a weak CYP3A4 and CYP2D6 inducer. Plasma concentrations and efficacy of ritonavir may be reduced if these drugs are administered concurrently. [27493] [27494] [34557] [57741] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of oritavancin is necessary. Concomitant use of nirmatrelvir and oritavancin may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and oritavancin is a weak CYP3A inducer. [57741] [67203] Orlistat: (Major) According to the manufacturer of orlistat, HIV RNA levels should be frequently monitored in patients receiving orlistat while being treated for HIV infection with anti-retroviral protease inhibitors. Loss of virological control has been reported in HIV-infected patients taking orlistat with atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, lopinavir; ritonavir, and emtricitabine; efavirenz; tenofovir disoproxil fumarate. The exact mechanism for this interaction is not known, but may involve inhibition of systemic absorption of the anti-retroviral agent. If an increased HIV viral load is confirmed, orlistat should be discontinued. [27971] Osilodrostat: (Major) Reduce the dose of osilodrostat by one-half during coadministration of ritonavir; concurrent use may increase osilodrostat exposure and the risk of osilodrostat-related adverse reactions. Osilodrostat is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. [47165] [65098] Ospemifene: (Major) Use caution when administering ospemifene to a patient taking ritonavir, as concurrent use may increase ospemifene systemic exposure and increase the risk of ospemifene-related adverse reactions. Consider if alternative therapy is appropriate. Ritonavir is a strong CYP3A4 inhibitor and a CYP2C9 inhibitor, and ospemifene is a CYP3A4 and CYP2C9 substrate. Co-administration of ospemifene with a drug known to inhibit CYP3A4 and CYP2C9 isoenzymes increased the ospemifene exposure 2.7-fold. [47165] [53344] Oxcarbazepine: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of oxcarbazepine is necessary. Concomitant use of nirmatrelvir and oxcarbazepine may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and oxcarbazepine is a weak CYP3A inducer. [29014] [67203] (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with oxcarbazepine. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and oxcarbazepine is a weak CYP3A inducer. [29014] [67203] Oxybutynin: (Moderate) Monitor for an increase in oxybutynin-related adverse reactions if coadministration with protease inhibitors is necessary. Oxybutynin is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with another strong CYP3A inhibitor increased mean oxybutynin plasma concentrations by approximately 2-fold. Concomitant use with moderate CYP3A inhibitors may alter the mean pharmacokinetic parameters of oxybutynin, although the clinical relevance of these potential interactions is unknown. [29796] [47165] [58664] Oxycodone: (Major) Consider withholding oxycodone, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the oxycodone dose. Coadministration may increase oxycodone exposure, resulting in prolonged opioid effects including fatal respiratory depression. Oxycodone is metabolized by CYP3A4 and nirmatrelvir is a CYP3A inhibitor. [60745] [65314] [67203] [69024] (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. If ritonavir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like ritonavir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ritonavir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. [39926] [47165] Oxymorphone: (Moderate) Ritonavir is an inhibitor of the cytochrome P450 3A4 isoenzyme and may decrease the metabolism of oxymorphone if the two drugs are coadministered. [4718] Paclitaxel: (Minor) Due to ritonavir's potential inhibitory effects on various hepatic isoenzymes, numerous drug interactions may occur with ritonavir. Close monitoring of serum drug concentrations and/or therapeutic and adverse effects is required when paclitaxel (a CYP2C8 and CYP3A4 substrate) is coadministered with ritonavir (a CYP3A4 inhibitor). In addition, paclitaxel is a substrate of the drug transporter P-glycoprotein (P-gp), and ritonavir also inhibits P-gp. [28001] [28341] [28380] [28498] [49806] [56579] [58664] Pacritinib: (Contraindicated) Concurrent use of pacritinib with ritonavir is contraindicated due to increased pacritinib exposure which increases the risk of adverse reactions. Pacritinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. [47165] [67427] Palbociclib: (Major) Avoid coadministration of ritonavir with palbociclib; significantly increased plasma exposure of palbociclib may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If ritonavir is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of ritonavir) to the dose used before initiation of ritonavir. Palbociclib is primarily metabolized by CYP3A4 and ritonavir is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively. [47165] [58768] [64721] Palovarotene: (Major) Avoid concomitant use of palovarotene and ritonavir due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. Palovarotene is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased palovarotene overall exposure by 3-fold. [56579] [69324] Panobinostat: (Major) Reduce the starting dose of panobinostat to10 mg when coadministered with ritonavir. Concurrent use may increase systemic exposure of panobinostat. Panobinostat is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of panobinostat by 73%. [47165] [58821] Paricalcitol: (Moderate) Paricalcitol is partially metabolized by CYP3A4. Care should be taken when dosing paricalcitol with strong CYP3A4 inhibitors, such as protease inhibitors. Dose adjustments of paricalcitol may be required. Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with this combination. [42290] Paroxetine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with ritonavir is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and ritonavir is a weak CYP2D6 inhibitor. [28260] [60002] Pazopanib: (Major) Avoid coadministration of pazopanib and ritonavir due to the potential for increased pazopanib exposure. If concurrent use is unavoidable, reduce the pazopanib dose to 400 mg PO once daily; further dose adjustments may be necessary if adverse effects occur. Pazopanib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased the Cmax and AUC of pazopanib by 1.5-fold and 1.7-fold, respectively. [37098] [47165] Peginterferon Alfa-2a: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. [31649] [34878] Peginterferon Alfa-2b: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. [31649] [34878] Peginterferon beta-1a: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. [31649] [34878] Pemigatinib: (Major) Avoid coadministration of pemigatinib and ritonavir due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If ritonavir is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of ritonavir. Pemigatinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased pemigatinib exposure by 88%. [47165] [65307] Pentobarbital: (Contraindicated) Ritonavir-boosted nirmatrelvir is contraindicated for use within 2 weeks of administering barbiturates; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response. The risk for reduced efficacy may persist following barbiturate discontinuation. Nirmatrelvir is a CYP3A substrate and barbiturates are strong CYP3A inducers. [41911] [49229] [49236] [49352] [57048] [57271] [65314] [67203] [69024] (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers. [28315] [46638] Perampanel: (Moderate) Concurrent use of perampanel with ritonavir may decrease ritonavir concentrations and increase perampanel concentrations. Both drugs are metabolized by CYP3A4. Ritonavir is also a CYP3A4 inhibitor, while perampanel is a weak inducer of CYP3A4. Monitor patients for increases in adverse effects such as anger, anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required. [51834] [52140] Perindopril; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure. [29012] [29090] [47165] Perphenazine; Amitriptyline: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with ritonavir is necessary; a dose reduction of the TCA may be necessary. Concurrent use may increase exposure of the TCA. TCAs are CYP2D6 substrates and ritonavir is a CYP2D6 inhibitor. [47165] Pexidartinib: (Major) Avoid concomitant use of pexidartinib and ritonavir due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects; concomitant use may also decrease ritonavir plasma concentrations and reduce its efficacy. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If ritonavir is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of ritonavir. Pexidartinib is a CYP3A and substrate and moderate CYP3A inducer; ritonavir is a CYP3A substrate and strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased pexidartinib exposure by 70%. [47165] [64535] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of pexidartinib is necessary. Concomitant use of nirmatrelvir and pexidartinib may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and pexidartinib is a moderate CYP3A inducer. [64535] [67203] Phenobarbital: (Contraindicated) Ritonavir-boosted nirmatrelvir is contraindicated for use within 2 weeks of administering barbiturates; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response. The risk for reduced efficacy may persist following barbiturate discontinuation. Nirmatrelvir is a CYP3A substrate and barbiturates are strong CYP3A inducers. [41911] [49229] [49236] [49352] [57048] [57271] [65314] [67203] [69024] (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers. [28315] [46638] Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Contraindicated) Ritonavir-boosted nirmatrelvir is contraindicated for use within 2 weeks of administering barbiturates; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response. The risk for reduced efficacy may persist following barbiturate discontinuation. Nirmatrelvir is a CYP3A substrate and barbiturates are strong CYP3A inducers. [41911] [49229] [49236] [49352] [57048] [57271] [65314] [67203] [69024] (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers. [28315] [46638] Phentermine; Topiramate: (Moderate) Concurrent administration of topiramate with ritonavir may result in decreased concentrations of ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir is metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together. [28378] [57036] [58664] Phenytoin: (Contraindicated) Ritonavir-boosted nirmatrelvir is contraindicated for use within 2 weeks of administering phenytoin; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response. The risk for reduced efficacy may persist following phenytoin discontinuation. Nirmatrelvir is a CYP3A substrate and phenytoin is a strong CYP3A inducer. [56579] [65314] [67203] [69024] (Major) Avoid concomitant use of ritonavir and hydantoins. Concomitant use may decrease the exposure of ritonavir and hydantoins, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the hydantoin. A dose increase of the hydantoin may be necessary. Ritonavir is a CYP3A substrate and inducer and hydantoins are CYP3A inducers. [28315] [46638] Pimavanserin: (Major) Reduce the dose of pimavanserin to 10 mg PO once daily and monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation if coadministration with ritonavir is necessary. Concurrent use may increase pimavanserin exposure. Pimavanserin is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with a strong CYP3A4 inhibitor increased exposure to pimavanserin by 3-fold. [47165] [60748] Pimozide: (Contraindicated) Coadministration of pimozide with protease inhibitors is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Pimozide is thought to be metabolized through CYP3A4, and to a lesser extent CYP1A2 and CYP2D6. Elevated pimozide plasma levels are probable when coadministered with CYP450 inhibitors, such as the protease inhibitors. Increased plasma concentrations of pimozide have been associated with QT prolongation and serious cardiovascular adverse events including death due to TdP. [43463] (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and pimozide is contraindicated; consider an alternative COVID-19 therapy. Coadministration may increase pimozide exposure resulting in increased toxicity. Pimozide is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] Pindolol: (Moderate) Ritonavir is expected to decrease the hepatic CYP metabolism of pindolol, resulting in increased beta-blocker concentrations. Cardiac and neurologic events have been reported when ritonavir is concurrently administered with beta-blockers. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including beta-blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased beta-blocker doses may be warranted. [28315] Pioglitazone: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8. [28142] [28172] [28380] [30575] [31320] [34557] [47165] [50768] [51227] Pioglitazone; Glimepiride: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [28380] [29012] [30575] [31320] [34471] [34472] [34489] [34490] [34491] [34557] [47165] [51227] [58000] [58763] (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8. [28142] [28172] [28380] [30575] [31320] [34557] [47165] [50768] [51227] Pioglitazone; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30480] [30575] (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8. [28142] [28172] [28380] [30575] [31320] [34557] [47165] [50768] [51227] Pirfenidone: (Moderate) Concurrent administration of pirfenidone with ritonavir may result in elevated plasma concentrations of ritonavir. Pirfenidone is a mild inhibitor of CYP3A4 and the drug transporter P-glycoprotein (P-gp); ritonavir is a substrate of both CYP3A4 and P-gp. Monitor for antiviral adverse effects if these drugs are administered together. [58189] [58664] Piroxicam: (Major) Avoid concomitant use of ritonavir-boosted nirmatrelvir and piroxicam and consider an alternative COVID-19 therapy. Coadministration may increase piroxicam exposure resulting in increased toxicity. Piroxicam is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] Pirtobrutinib: (Major) Avoid concomitant use of pirtobrutinib and ritonavir due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of ritonavir use. Resume the previous dose of pirtobrutinib after ritonavir is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%. [47165] [68520] Pitolisant: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of pitolisant is necessary. Concomitant use of nirmatrelvir and pitolisant may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and pitolisant is a weak CYP3A inducer. [64562] [67203] (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with pitolisant. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and pitolisant is a weak CYP3A inducer. [64562] [67203] Polatuzumab Vedotin: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of ritonavir due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; ritonavir is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%. [47165] [64290] Pomalidomide: (Moderate) Use pomalidomide and ritonavir together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and ritonavir is a CYP1A2 inducer. [28315] [59487] Ponatinib: (Major) Avoid coadministration of ponatinib and ritonavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of ritonavir and consider alternative therapy. After ritonavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting ritonavir. Ponatinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%. [47165] [52603] Ponesimod: (Major) Avoid concurrent use of ponesimod and ritonavir and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is an UGT1A1 substrate and ritonavir is an UGT1A1 inducer that may decrease ponesimod exposure. [47165] [66527] Posaconazole: (Moderate) Perform frequent monitoring of adverse effects and toxicity of ritonavir during coadministration with posaconazole. These drugs used in combination may result in elevated ritonavir plasma concentrations, causing an increased risk for ritonavir-related adverse events. Data from one study found the Cmax and AUC of ritonavir increased by 49% and 80%, respectively, when administered with posaconazole. [32723] Pralsetinib: (Major) Avoid concomitant use of ritonavir and pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of pralsetinib to 200 mg once daily for patients taking a daily dose of 400 mg or 300 mg, and to 100 mg once daily for patients taking a daily dose of 200 mg. Pralsetinib is a CYP3A and P-gp substrate and ritonavir is a combined strong CYP3A and P-gp inhibitor. Coadministration with a combined strong CYP3A and P-gp inhibitor is predicted to increase the overall exposure of pralsetinib by 251%. [28380] [34557] [47165] [65884] Pramlintide: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. [30575] [51227] Praziquantel: (Moderate) Monitor for increased side effects of praziquantel if administered with ritonavir. Concurrent administration may result in elevated praziquantel plasma concentrations. Praziquantel is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. [27480] [34457] [34458] [34459] [47165] [58664] Prednisolone: (Moderate) Ritonavir inhibits CYP3A4, and prednisolone is a CYP3A4 substrate. Monitor patients for corticosteroid-related side effects if prednisone or prednisolone and ritonavir are taken. [4194] [58664] Prednisone: (Moderate) Coadministration of prednisone with ritonavir (a strong CYP3A4 inhibitor) may cause prednisone serum concentrations to increase, potentially resulting in Cushing's syndrome and adrenal suppression. Consider use of an alternative corticosteroid whose concentrations are less affected by strong CYP3A4 inhibitors, such as beclomethasone and prednisolone, especially during long-term treatment. [47165] [58664] Primidone: (Contraindicated) Ritonavir-boosted nirmatrelvir is contraindicated for use within 2 weeks of administering barbiturates; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response. The risk for reduced efficacy may persist following barbiturate discontinuation. Nirmatrelvir is a CYP3A substrate and barbiturates are strong CYP3A inducers. [41911] [49229] [49236] [49352] [57048] [57271] [65314] [67203] [69024] (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers. [28315] [46638] Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and ritonavir due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a CYP3A and P-gp substrate and ritonavir is a dual strong CYP3A and P-gp inhibitor. Concomitant use has been observed to increase colchicine overall exposure by 4-fold. [28380] [34557] [36114] [47165] [58111] [63965] [69117] (Major) Concomitant use of ritonavir-boosted nirmatrelvir and colchicine is contraindicated in patients with renal and/or hepatic impairment. Consider temporary discontinuation of colchicine during treatment with ritonavir-boosted nirmatrelvir and for at least 2 to 3 days after treatment completion; if not feasible, consider alternative COVID-19 therapy. Coadministration may increase colchicine exposure resulting in increased toxicity. Colchicine is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] Progesterone: (Moderate) Use caution if coadministration of ritonavir with progesterone is necessary, as the systemic exposure of progesterone may be increased resulting in an increase in treatment-related adverse reactions. Ritonavir is a strong CYP3A4 inhibitor. Progesterone is metabolized primarily by hydroxylation via a CYP3A4. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). [47165] [63694] Propafenone: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and propafenone is contraindicated; consider an alternative COVID-19 therapy. Coadministration may increase propafenone exposure resulting in increased toxicity. Propafenone is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Major) Avoid use of propafenone and ritonavir; concurrent use may increase propafenone exposure and therefore increase the risk for arrhythmias. This combination is listed as a contraindication in the ritonavir FDA-approved labeling. Propafenone is a CYP3A and CYP2D6 substrate; ritonavir is CYP2D6 and strong CYP3A inhibitor. [28287] [28315] [46638] Propofol: (Moderate) Use caution if ritonavir is coadministered with propofol due to the potential for decreased propofol exposure which may decrease its efficacy. Propofol is a CYP2B6 substrate and ritonavir is a CYP2B6 inducer. [47165] [65210] [65225] Propranolol: (Moderate) Concurrent administration of propranolol with ritonavir may result in elevated propranolol plasma concentrations. Cardiac and neurologic events have been reported when ritonavir is concurrently administered with beta-blockers. Propranolol is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Decreased beta-blocker dosage may be needed. [28315] [47165] [4998] [58664] Protriptyline: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with ritonavir is necessary; a dose reduction of the TCA may be necessary. Concurrent use may increase exposure of the TCA. TCAs are CYP2D6 substrates and ritonavir is a CYP2D6 inhibitor. [47165] Quazepam: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of quazepam and increase the potential for benzodiazepine toxicity. A decrease in the quazepam dose may be needed. [28001] [28345] [32432] Quetiapine: (Major) The manufacturer of quetiapine recommends a quetiapine dose reduction to one-sixth the original dose during concurrent administration of strong CYP3A4 inhibitors, such as ritonavir. When ritonavir is discontinued, the dose should be increased by 6-fold. The plasma concentrations of quetiapine may be elevated when administered concurrently with ritonavir. [29118] [47165] Quinidine: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and quinidine is contraindicated; consider an alternative COVID-19 therapy. Coadministration may increase quinidine exposure resulting in increased toxicity. Quinidine is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Major) Coadministration of HIV treatment doses of ritonavir and quinidine is contraindicated due to the potential for serious or life-threatening reactions, such as cardiac arrhythmias. Cautious consideration may be given to administering quinidine with boosting doses of ritonavir. Ritonavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, such as quinidine, should be expected with concurrent use. [28315] [42280] [46638] [47165] [47357] Quinine: (Major) Concomitant use of quinine and ritonavir should be avoided due to increased quinine concentrations. In a study of healthy patients who received a single oral 600 mg dose of quinine with the 15th dose of ritonavir (200 mg PO Q12h for 9 days), there was a 4-fold increase in the mean quinine AUC and Cmax and an increase in the mean quinine elimination half-life (13.4 h vs. 11.2 h) when compared to quinine administered alone. There were no significant changes in the ritonavir pharmacokinetics. Ritonavir is a potent CYP3A4 inhibitor and quinine is a CYP3A4 substrate. [11191] [31403] [47165] Quizartinib: (Major) Avoid concomitant use of ritonavir with quizartinib due to the risk of increased quizartinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of quizartinib to 26.5 mg for patients taking a daily dose of 53 mg, and to 17.7 mg for patients taking a daily dose of 35.4 mg or 26.5 mg; interrupt quizartinib therapy for the duration of the strong CYP3A inhibitor use for patients already taking a daily dose of 17.7 mg. Quizartinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of quizartinib by 94%. [56579] [69220] Rabeprazole: (Minor) Concurrent administration of rabeprazole with ritonavir may result in increased rabeprazole plasma concentrations; however, the clinical significance of this interaction is unclear. Rabeprazole is metabolized by the hepatic isoenzymes CYP2C19 and CYP3A4; ritonavir is a potent inhibitor of CYP3A4. Monitor for rabeprazole-associated adverse events if these drugs are administered together. [40337] [41276] [58664] Ramelteon: (Moderate) The serum concentrations of ramelteon may increase when ramelteon is administered with strong CYP3A4 inhibitors like the anti-retroviral protease inhibitors. Because there is the potential for multiple CYPP450 enzyme inhibition interactions between protease inhibitors and ramelteon, caution should be used if these 2 drugs are coadministered. The patient should be monitored closely for toxicity even though ramelteon has a wide therapeutic index. [31359] [31360] [4718] [5074] [8143] [8145] Ranolazine: (Contraindicated) Concomitant use of ranolazine with ritonavir is contraindicated due to the potential for increased ranolazine plasma concentrations and therefore increased risk of QTc prolongation and possibly torsade de pointes. Ranolazine is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) substrate; ritonavir is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-gp. Coadministration of another strong CYP3A4 inhibitor increased plasma concentrations of ranolazine by 220%. [31938] [47165] (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and ranolazine is contraindicated. Consider temporary discontinuation of ranolazine during treatment with ritonavir-boosted nirmatrelvir and for at least 2 to 3 days after treatment completion; if not feasible, consider alternative COVID-19 therapy. Coadministration may increase ranolazine exposure resulting in increased toxicity. Ranolazine is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] Red Yeast Rice: (Contraindicated) The risk of myopathy, including rhabdomyolysis, may be increased when anti-retroviral protease inhibitors are given in combination with most HMG-CoA reductase inhibitors. Since compounds in red yeast rice claim to have HMG-CoA reductase inhibitor activity, coadministration of red yeast rice with anti-retroviral protease inhibitors is not recommended. [5335] [5911] Regorafenib: (Major) Avoid coadministration of regorafenib with ritonavir due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each. [47165] [51883] Regular Insulin: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. [30575] [60172] Regular Insulin; Isophane Insulin (NPH): (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. [30575] [60172] Relugolix: (Major) Avoid concomitant use of relugolix and oral ritonavir. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects; QT prolongation may also occur. If concomitant use is unavoidable, administer ritonavir at least six hours after relugolix and monitor for adverse reactions. Obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Relugolix is a P-glycoprotein (P-gp) substrate that may prolong the QT/QTc interval. Ritonavir is a P-gp inhibitor that is also associated with QT prolongation. [28380] [34557] [66183] Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral ritonavir. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects; QT prolongation may also occur. If concomitant use is unavoidable, administer ritonavir at least six hours after relugolix and monitor for adverse reactions. Obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Relugolix is a P-glycoprotein (P-gp) substrate that may prolong the QT/QTc interval. Ritonavir is a P-gp inhibitor that is also associated with QT prolongation. [28380] [34557] [66183] (Moderate) Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. For example, ritonavir (also found in combinations like lopinavir; ritonavir, and used as a booster in many HIV treatment regimens) may decrease the metabolism of norethindrone, raising norethindrone concentrations. Women receiving norethindrone for hormone replacement or contraception should report potential hormonal adverse effects (e.g., bleeding pattern changes, acne, emotional lability) or any changes in efficacy (e.g., noted changes in bleeding patterns) to their prescribers. Because norethindrone-containing contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive norethindrone contraception concurrently with ritonavir should use an additional barrier method of contraception such as condoms. [58679] [7731] (Moderate) Ritonavir has been shown to increase the metabolism of ethinyl estradiol. Ritonavir is a substrate and inhibitor of CYP3A4. It is not known if the effects of protease inhibitors are similar on estradiol; however, estradiol is metabolized by CYP3A4, similar to ethinyl estradiol. [28315] Remifentanil: (Moderate) Ritonavir is an inhibitor of the cytochrome P450 3A4 isoenzyme and may decrease the metabolism of remifentanil if the two drugs are coadministered. [4718] Repaglinide: (Moderate) Coadministration of repaglinide and protease inhibitors may increase or decrease glucose concentrations and increase repaglinide AUC; if coadministration is necessary, repaglinide dosage adjustment may be necessary and increased frequency of glucose monitoring is recommended. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. In addition, repaglinide is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are potent CYP3A4 inhibitors and inhibitors of OATP. [29751] [31281] [36049] [61511] [61513] Repotrectinib: (Major) Avoid coadministration of repotrectinib with ritonavir due to increased repotrectinib exposure which may increase the risk for repotrectinib-related adverse effects. Concomitant use may also decrease ritonavir exposure and efficacy which may increase the risk for viral resistance. Repotrectinib is a CYP3A and P-gp substrate and and moderate CYP3A inducer; ritonavir is a CYP3A inducer and strong CYP3A and P-gp inhibitor. Coadministration with another strong CYP3A and P-gp inhibitor increased repotrectinib exposure by 5.9-fold. [28380] [34557] [47165] [69884] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of repotrectinib is necessary. Concomitant use of nirmatrelvir and repotrectinib may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and repotrectinib is a CYP3A inducer. [67203] [69884] Retapamulin: (Moderate) Coadministration of retapamulin with strong CYP3A4 inhibitors, such as ritonavir, in patients younger than 24 months is not recommended. Systemic exposure of topically administered retapamulin may be higher in patients younger than 24 months than in patients 2 years and older. Retapamulin is a CYP3A4 substrate. [33239] [47165] Ribavirin: (Major) The concomitant use of ribavirin and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. [34878] Ribociclib: (Major) Avoid coadministration of ribociclib with ritonavir due to the potential for significantly increased exposure to ribociclib. If coadministration cannot be avoided, reduce the dose of ribociclib to 400 mg once daily. If ritonavir is discontinued, resume the previous ribociclib dose after at least 5 half-lives of ritonavir. Ribociclib is a CYP3A4 substrate. Ritonavir is a strong CYP3A4 inhibitor. Coadministration with a strong inhibitor increased the ribociclib AUC and Cmax by 3.2-fold and 1.7-fold, respectively, in healthy volunteers. [61816] Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with ritonavir due to the potential for significantly increased exposure to ribociclib. If coadministration cannot be avoided, reduce the dose of ribociclib to 400 mg once daily. If ritonavir is discontinued, resume the previous ribociclib dose after at least 5 half-lives of ritonavir. Ribociclib is a CYP3A4 substrate. Ritonavir is a strong CYP3A4 inhibitor. Coadministration with a strong inhibitor increased the ribociclib AUC and Cmax by 3.2-fold and 1.7-fold, respectively, in healthy volunteers. [61816] Rifabutin: (Major) Reduce the rifabutin dose to 150 mg PO once daily and monitor for adverse effects, such as uveitis and neutropenia, if concomitant use with ritonavir is necessary. Although the FDA-approved labeling recommends reducing the rifabutin dose by at least 75% (to a maximum 150 mg every other day or 3 times per week), lower rifabutin exposure has been reported in persons living with HIV than in healthy subjects and acquired rifamycin resistance has been reported in these persons receiving 3 times weekly regimens. Monitor response and consider therapeutic drug monitoring (TDM) when rifabutin is used with a ritonavir-boosted protease inhibitor and adjust dose accordingly. Rifabutin is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with ritonavir (alone) increased the AUC of rifabutin by 300%. [29210] [34362] [46638] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of rifabutin is necessary. Concomitant use of nirmatrelvir and rifabutin may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. [29210] [29812] [34549] [34550] [67203] [69024] Rifampin: (Contraindicated) Coadministration of rifampin and ritonavir results in markedly decreased ritonavir concentrations; HIV treatment failure and virologic resistance would be expected. Rifampin (300 or 600 mg daily for 10 days) decreases the AUC and Cmax of ritonavir (500 mg every 12 hours for 20 days) by 35% and 25%, respectively. Coadministration may lead to loss of virologic response if ritonavir is the sole protease inhibitor and increase the risk of hepatotoxicity. The DHHS/NIH HIV Treatment Guidelines recommend ritonavir and rifampin should not be coadministered and suggest the consideration of alternative antimycobacterial agents, such as rifabutin. However, CDC guidelines suggest no change in ritonavir or rifampin dose when the drugs are coadministered, but this appears to only be in the setting of low-dose ritonavir (i.e., 100 mg or 200 mg twice daily) used to 'boost' concentrations of other protease inhibitors. In this setting it would be less likely to produce adverse events than higher ritonavir doses; however, a net CYP3A4 induction still results when used with rifampin. [1299] [30314] [46638] (Contraindicated) Ritonavir-boosted nirmatrelvir is contraindicated for use within 2 weeks of administering rifampin; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response. The risk for reduced efficacy may persist following rifampin discontinuation. Nirmatrelvir is a CYP3A substrate and rifampin is a strong CYP3A inducer. [56579] [65314] [67203] [69024] Rifapentine: (Contraindicated) Ritonavir-boosted nirmatrelvir is contraindicated for use within 2 weeks of administering rifapentine; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response. The risk for reduced efficacy may persist following rifapentine discontinuation. Nirmatrelvir is a CYP3A substrate and rifapentine is a strong CYP3A inducer. [28483] [65314] [67203] [69024] (Major) Avoid coadministration of protease inhibitors and rifapentine as concurrent use may result in significant decreases in the plasma concentrations of the antiretroviral agents, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Protease inhibitors are CYP3A4 substrates and rifapentine is a strong CYP3A4 inducer. Additionally, HIV patients treated with rifapentine have a higher rate of TB relapse than those treated with other rifamycin-based regimens; an alternative agent is recommended. [32432] [46638] [65685] Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with ritonavir is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and ritonavir is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold. [28380] [29289] [34557] Riluzole: (Moderate) Coadministration of riluzole with ritonavir may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and ritonavir is a CYP1A2 inducer. [29747] [47165] Rimegepant: (Major) Avoid coadministration of rimegepant with ritonavir; concurrent use may significantly increase rimegepant exposure. Rimegepant is a CYP3A4 and P-gp substrate; ritonavir is a strong CYP3A4 inhibitor and P-gp inhibitor. Coadministration of rimegepant with another strong CYP3A4 inhibitor increased rimegepant exposure by 4-fold. [28380] [34557] [47165] [65052] Riociguat: (Major) Concomitant use of riociguat with strong cytochrome CYP inhibitors and P-glycoprotein (P-gp)/breast cancer resistance protein (BCRP) inhibitors, such as ritonavir, increases riociguat exposure and may result in hypotension. Consider a starting adult dose of 0.5 mg PO three times a day when initiating riociguat in patients receiving strong CYP and P-gp/BCRP inhibitors. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effect of riociguat. [56096] Ripretinib: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with ritonavir. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%. [47165] [65431] Risperidone: (Moderate) Ritonavir may increase risperidone exposure; use together with caution and monitor for adverse effects of risperidone, including QT prolongation or other risperidone side effects. A decreased dosage of risperidone may be required. Risperidone is primarily metabolized by CYP2D6 and is also partially metabolized by CYP3A4; ritonavir inhibits both CYP2D6 and CYP3A4. [22256] [28414] [47165] [59321] [63411] Rivaroxaban: (Major) Avoid concomitant administration of rivaroxaban and ritonavir; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Concurrent use of a single dose of rivaroxaban and ritonavir, a combined P-gp and strong CYP3A4 inhibitor, led to an increase in the rivaroxaban AUC by 150% and Cmax by 60%. Similar increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed. [28315] [44854] [47165] (Major) Consider temporary discontinuation of rivaroxaban during treatment with ritonavir-boosted nirmatrelvir and for at least 2 to 3 days after treatment completion. For patients at high risk of arterial or venous thrombosis, consult the primary or specialty provider and consider using an alternative anticoagulant or COVID-19 therapy. Coadministration may increase rivaroxaban exposure resulting in increased risk of bleeding. Rivaroxaban is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [69024] Rocuronium: (Moderate) Monitor clinical effect and decrease the rocuronium dosage, if needed, if rocuronium is used concomitantly with ritonavir. Ritonavir may potentially decrease biliary excretion of rocuronium. [47165] [65210] Roflumilast: (Major) Patients receiving roflumilast may have altered serum concentrations if coadministered with ritonavir. Ritonavir is a potent inhibitor and an inducer of CYP3A4, and roflumilast is a CYP3A4 substrate. Specific pharmacokinetic study of this potential interaction has not been conducted. [11416] [43551] [5044] [5110] Romidepsin: (Moderate) Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity during initial administration of romidepsin with ritonavir. Romidepsin is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In a pharmacokinetic drug interaction trial a strong CYP3A4 inhibitor increased romidepsin AUC by approximately 25%. [37292] [47165] Ropeginterferon alfa-2b: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. [31649] [34878] Rosiglitazone: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8. [28142] [28172] [28380] [30575] [31320] [34557] [47165] [50768] [51227] Rosuvastatin: (Major) Consider temporary discontinuation of rosuvastatin during treatment with ritonavir-boosted nirmatrelvir; if this is not feasible, consider an alternative COVID-19 therapy. Rosuvastatin does not need to be held prior to or after completing ritonavir-boosted nirmatrelvir. Coadministration may increase rosuvastatin exposure resulting in increased toxicity. Rosuvastatin is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] Rosuvastatin; Ezetimibe: (Major) Consider temporary discontinuation of rosuvastatin during treatment with ritonavir-boosted nirmatrelvir; if this is not feasible, consider an alternative COVID-19 therapy. Rosuvastatin does not need to be held prior to or after completing ritonavir-boosted nirmatrelvir. Coadministration may increase rosuvastatin exposure resulting in increased toxicity. Rosuvastatin is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] Ruxolitinib: (Major) Consider withholding ruxolitinib, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the ruxolitinib dose. Reduce the ruxolitinib dosage when coadministered with ritonavir-boosted nirmatrelvir in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur. No dose adjustments are necessary for patients with graft-versus-host disease; however, monitor blood counts more frequently for toxicity and adjust ruxolitinib dosage for adverse reactions. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Avoid the use of ritonavir-boosted nirmatrelvir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. Ruxolitinib is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [46782] [65314] (Major) Reduce the ruxolitinib dosage when coadministered with ritonavir in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur. No dose adjustments are necessary for patients with graft-versus-host disease; however, monitor blood counts more frequently for toxicity and adjust ruxolitinib dosage for adverse reactions. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Avoid the use of ritonavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. Ruxolitinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. [46782] [47165] Sacituzumab Govitecan: (Major) Avoid coadministration of sacituzumab govitecan and ritonavir due to the risk of decreased sacituzumab govitecan exposure which may reduce its efficacy. The cytotoxic component of sacituzumab govitecan, SN-38, is metabolized by UGT1A1 and ritonavir is a UGT1A1 inducer. Formal drug interaction studies with sacituzumab govitecan have not been conducted but the concomitant use of UGT1A1 inducers is expected to decrease SN-38 exposure. [47165] [65328] Sacubitril; Valsartan: (Minor) Valsartan is a substrate of the hepatic efflux transporter MRP2 and ritonavir is an inhibitor of MRP2. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan during coadministration. [28315] [29130] [36646] [39870] [60860] Salmeterol: (Major) Avoid concomitant use of salmeterol with ritonavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose. [28467] [44026] [47165] (Major) Consider temporary discontinuation of salmeterol during treatment with ritonavir-boosted nirmatrelvir and for at least 2 to 3 days after treatment completion; if not feasible, consider alternative COVID-19 therapy. Coadministration may increase salmeterol exposure resulting in increased toxicity, including QT prolongation, palpitations, and sinus tachycardia. Salmeterol is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [28467] [65314] [67203] [69024] Saxagliptin: (Major) The metabolism of saxagliptin is primarily mediated by CYP3A4/5. The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP3A4/5 inhibitor such as ritonavir. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have also been reported with use of anti-retroviral protease inhibitors, such as ritonavir. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] [36111] [51227] Secobarbital: (Contraindicated) Ritonavir-boosted nirmatrelvir is contraindicated for use within 2 weeks of administering barbiturates; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response. The risk for reduced efficacy may persist following barbiturate discontinuation. Nirmatrelvir is a CYP3A substrate and barbiturates are strong CYP3A inducers. [41911] [49229] [49236] [49352] [57048] [57271] [65314] [67203] [69024] (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers. [28315] [46638] Segesterone Acetate; Ethinyl Estradiol: (Major) Coadministration may result in an increased or decreased effect of segesterone. Contraceptive efficacy may be reduced. Segesterone is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor and CYP3A4 inducer. [47165] [63429] (Major) Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. [46638] [5044] (Major) The FDA recommends consideration of an additional, non-hormonal method of contraception during the 5 days of treatment with ritonavir-boosted nirmatrelvir and until one menstrual cycle after stopping ritonavir-boosted nirmatrelvir. However, the NIH COVID-19 guidelines suggest the potential decrease in ethinyl estradiol exposure is not expected to be clinically significant during the 5 days of therapy. [65314] [67203] [69024] Selpercatinib: (Major) Avoid coadministration of selpercatinib and ritonavir due to the risk of increased selpercatinib exposure which may increase the risk of adverse reactions, including QT prolongation. If coadministration is unavoidable, reduce the dose of selpercatinib to 40 mg PO twice daily if original dose was 120 mg twice daily, and to 80 mg PO twice daily if original dose was 160 mg twice daily. Monitor ECGs for QT prolongation more frequently. If ritonavir is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of ritonavir. Selpercatinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selpercatinib exposure by 133%. [47165] [65387] Selumetinib: (Major) Avoid coadministration of selumetinib and ritonavir due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If ritonavir is discontinued, resume the original selumetinib dose after 3 elimination half-lives of ritonavir. Selumetinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%. [47165] [65246] Semaglutide: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] [50113] [50814] Sildenafil: (Major) Coadministration of ritonavir is contraindicated in patients receiving sildenafil for pulmonary arterial hypertension (PAH). If used for erectile dysfunction, the dose of sildenafil should not exceed 25 mg in 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use substantially increases the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Ritonavir, a strong CYP3A4 inhibitor, increased the AUC of sildenafil, a sensitive CYP3A4 substrate, by 11-fold in a drug interaction study. [2548] [28315] [46638] (Major) Concomitant use of ritonavir-boosted nirmatrelvir and sildenafil, when used for pulmonary arterial hypertension (PAH), is contraindicated; consider an alternative COVID-19 therapy. Consider withholding sildenafil, when used for erectile dysfunction, during concomitant receipt of ritonavir-boosted nirmatrelvir. Coadministration may increase sildenafil exposure resulting in increased toxicity. Sildenafil is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] Silodosin: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and silodosin is contraindicated due to the potential for postural hypotension. Consider temporary discontinuation of silodosin during treatment with ritonavir-boosted nirmatrelvir and for at least 2 to 3 days after treatment completion; if not feasible, consider alternative COVID-19 therapy. Coadministration may increase silodosin exposure resulting in increased toxicity. Silodosin is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [34483] [65314] [67203] [69024] (Contraindicated) Concurrent use of silodosin and ritonavir is contraindicated. Silodosin is extensively metabolized by CYP3A4; ritonavir is a potent inhibitor of this enzyme. Also of note, silodosin is a P-glycoprotein (P-gp) substrate and ritonavir is a P-gp inhibitor. Coadministration may cause significant increases in silodosin plasma concentrations, potentially resulting in adverse events. [34483] Simvastatin: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and simvastatin is contraindicated. Discontinue use of simvastatin at least 12 hours before, during, and 5 days after treatment with ritonavir-boosted nirmatrelvir. Coadministration may increase simvastatin exposure resulting in increased toxicity. Simvastatin is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors. [28605] [39682] [46638] [61510] [61511] [61512] [61513] Siponimod: (Moderate) Concomitant use of siponimod and ritonavir may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod. [47165] [64031] Sirolimus: (Major) Avoid concomitant use of sirolimus and protease inhibitors; a sirolimus dosage reduction may be considered if concomitant use is necessary. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. [28610] [46638] [67136] (Major) Before prescribing ritonavir-boosted nirmatrelvir for a patient receiving sirolimus, the patient's specialist provider(s) should be consulted, given the significant drug-drug interaction potential and because close monitoring may not be feasible. If this is not feasible, consider an alternative COVID-19 therapy. Coadministration may increase sirolimus exposure resulting in increased toxicity. Sirolimus is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [28610] [65314] [67203] [69024] Sitagliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] Sodium Bicarbonate: (Moderate) Concurrent administration of tipranavir and ritonavir with antacids results in decreased tipranavir concentrations. Administer tipranavir and ritonavir 2 hours before or 1 hour after antacids. [1800] [1802] Sodium Oxybate: (Major) One case report describes a possible interaction between sodium oxybate and ritonavir and saquinavir, leading to repetitive, clonic contractions. The patient also experienced shallow respirations, a heart rate of 40 beats per min, and was responsive only to painful stimuli. The exact contribution of ritonavir and saquinavir to this reaction cannot be determined since several other compounds were detected through a urinary toxin screen. [2546] Sodium Phenylbutyrate; Taurursodiol: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of taurursodiol is necessary. Concomitant use of nirmatrelvir and taurursodiol may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and taurursodiol is a CYP3A inducer. [67203] [68007] (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with taurursodiol. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and taurursodiol is a weak CYP3A inducer. [67203] [68007] Solifenacin: (Major) Consider withholding solifenacin, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the solifenacin dose. If these drugs must be administered together, do not exceed solifenacin 5 mg per day in adults; do not exceed the initial solifenacin starting dose in pediatric patients. Coadministration may increase solifenacin exposure resulting in increased toxicity. Solifenacin is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] (Major) Use of ritonavir with solifenacin may increase exposure to solifenacin and risk for solifenacin-related side effects. If these drugs must be administered together, do not exceed solifenacin 5 mg per day in adults; do not exceed the initial solifenacin starting dose in pediatric patients. Ritonavir is a potent CYP3A4 inhibitor and solifenacin is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased solifenacin exposure by 2.7-fold. [47165] [54021] [65485] Sonidegib: (Major) Avoid coadministration of sonidegib with ritonavir due to increased plasma concentrations of sonidegib which may increase the risk of treatment-related adverse reactions. Sonidegib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased sonidegib exposure by 2.2-fold. [47165] [58864] [60000] [60002] Sotagliflozin: (Moderate) Monitor for a decrease in sotagliflozin efficacy during concomitant use of sotagliflozin and ritonavir and adjust therapy as appropriate. Concomitant use may decrease sotagliflozin exposure. Sotagliflozin is a UGT substrate and ritonavir is a UGT inducer. Concomitant use with another UGT inducer reduced sotagliflozin overall exposure by 45%. [47165] [69050] Sotalol: (Major) The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include sotalol. [28234] [47165] Sotorasib: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of sotorasib is necessary. Concomitant use of nirmatrelvir and sotorasib may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. [66700] [67203] (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with sotorasib. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and sotorasib is a moderate CYP3A4 inducer. [47165] [66700] Sparsentan: (Major) Avoid concomitant use of sparsentan and ritonavir. Concomitant use may increase sparsentan exposure and the risk for sparsentan-related adverse effects. Sparsentan is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased sparsentan overall exposure by 174%. [47165] [68641] St. John's Wort, Hypericum perforatum: (Contraindicated) Coadministration of protease inhibitors and St. John's wort is contraindicated due to the risk of decreased plasma concentrations of the antiviral agents, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Protease inhibitors are CYP3A4 substrates and St. John's wort is a strong CYP3A4 inducer. [28315] [46638] [57202] [57852] (Contraindicated) Ritonavir-boosted nirmatrelvir is contraindicated for use within 2 weeks of administering St. John's Wort; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response. The risk for reduced efficacy may persist following St. John's Wort discontinuation. Nirmatrelvir is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. [57202] [57852] [65314] [67203] [69024] Stiripentol: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of stiripentol is necessary. Concomitant use of nirmatrelvir and stiripentol may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and stiripentol is a CYP3A inducer and inhibitor; the net effect of stiripentol on CYP3A is unknown. [63456] [67203] (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with stiripentol. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and stiripentol is a CYP3A inducer and inhibitor; the net effect of stiripentol on CYP3A is unknown. [63456] [67203] Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if protease inhibitors must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of protease inhibitors is necessary. If protease inhibitors is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A substrate, and coadministration with a CYP3A inhibitor like protease inhibitors can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If protease inhibitors is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil. [30966] [47165] [63731] Sulfonylureas: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [28380] [29012] [30575] [31320] [34471] [34472] [34489] [34490] [34491] [34557] [47165] [51227] [58000] [58763] Sunitinib: (Major) Avoid coadministration of ritonavir with sunitinib if possible due to increased sunitinib exposure, which may increase the risk of QT prolongation. If concomitant use is unavoidable, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Consider reducing the daily dose of sunitinib to a minimum of 37.5 mg for patients with GIST or RCC, and to a minimum of 25 mg for patients with pNET. Sunitinib is a CYP3A4 substrate that can cause QT prolongation. Ritonavir is a strong CYP3A4 inhibitor that also causes QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased exposure to sunitinib and its primary active metabolite by 51%. [31970] [47165] Suvorexant: (Major) Coadministration of suvorexant and ritonavir is not recommended due to the potential for significantly increased suvorexant exposure. Suvorexant is a CYP3A4 substrate. Ritonavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the suvorexant AUC by 2.8-fold. [57780] (Major) Consider temporary discontinuation of suvorexant during treatment with ritonavir-boosted nirmatrelvir and for at least 2 to 3 days after treatment completion; if not feasible, consider alternative COVID-19 therapy. Coadministration may increase suvorexant exposure resulting in increased toxicity. Suvorexant is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [57780] [65314] [67203] [69024] Tacrolimus: (Major) Before prescribing ritonavir-boosted nirmatrelvir for a patient receiving tacrolimus, the patient's specialist provider(s) should be consulted, given the significant drug-drug interaction potential and because close monitoring may not be feasible. If this is not feasible, consider an alternative COVID-19 therapy. Coadministration may increase tacrolimus exposure resulting in increased toxicity. Tacrolimus is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [28611] [65314] [67203] [69024] (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentrations if coadministration with ritonavir is necessary; a dose reduction to 0.5 mg to 1 mg once per week may be necessary. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; ritonavir is a strong CYP3A4 inhibitor. In 1 study, the tacrolimus half-life increased to 10.6 days in 1 patient and 20.6 days in another following coadministration with lopinavir; ritonavir. Up to 80% reductions in tacrolimus dosages and 7-fold increase in dosage intervals were needed when tacrolimus was coadministered with protease inhibitors in studies. [28611] [47165] [55401] [65478] [65480] [65483] Tadalafil: (Major) Avoid concomitant use of ritonavir-boosted nirmatrelvir and tadalafil, when used for pulmonary hypertension, and consider an alternative COVID-19 therapy. Consider withholding tadalafil, when used for erectile dysfunction, during concomitant receipt of ritonavir-boosted nirmatrelvir. Coadministration may increase tadalafil exposure resulting in increased toxicity. Tadalafil is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ritonavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of ritonavir therapy. Stop tadalafil at least 24 hours prior to starting ritonavir. After at least 1 week of ritonavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Coadministration of ritonavir with tadalafil results in a 124% increase in tadalafil AUC. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4. [28220] [28315] [40259] Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with ritonavir is necessary. Talazoparib is a P-gp substrate and ritonavir is a P-gp inhibitor. [28380] [63651] Tamsulosin: (Major) Consider withholding tamsulosin, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the tamsulosin dose for patients receiving a dose of 0.8 mg daily. Coadministration may increase tamsulosin exposure resulting in increased hypotension or orthostasis. Tamsulosin is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [29677] [65314] [67203] [69024] (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of anti-retroviral protease inhibitors. Tamsulosin is extensively metabolized by CYP3A4 and CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension. Therefore, concomitant use of tamsulosin with a strong CYP3A4 inhibitor, or an agent with both CYP3A4 and CYP2D6 inhibitor activity, should be avoided. [29677] [4194] [8102] Tasimelteon: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as ritonavir, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%. [56665] Tazemetostat: (Major) Avoid coadministration of tazemetostat with ritonavir as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. Tazemetostat is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold. [47165] [64952] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of tazemostat is necessary. Concomitant use of nirmatrelvir and tazemostat may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and tazemostat is a weak CYP3A inducer. [64952] [67203] Tecovirimat: (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with tecovirimat. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and tecovirimat is a weak CYP3A inducer. [63353] [67203] Telmisartan; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure. [29012] [29090] [47165] Telotristat Ethyl: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of telotristat is necessary. Concomitant use of nirmatrelvir and telotristat may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and telotristat is a weak CYP3A inducer. [61795] [67203] (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with telotristat. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and telotristat is a weak CYP3A inducer. [61795] [67203] Temsirolimus: (Major) Avoid coadministration of ritonavir with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus); exposure to ritonavir may also increase. If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of ritonavir before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. Ritonavir is also a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of ritonavir. [34557] [47165] [50586] Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, concurrently with inhibitors of P-gp and BCRP, such as ritonavir. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. [28193] [58664] Terbinafine: (Moderate) Caution is advised when administering terbinafine with ritonavir. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may alter the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP1A2, CYP2C9, and CYP3A4; ritonavir is an inducer of CYP1A2 and CYP2C9, and an inhibitor/inducer of CYP3A4. Monitor patients for adverse reactions and breakthrough fungal infections if these drugs are coadministered. [37590] [43880] [43881] [47165] [56538] Tesamorelin: (Minor) Use caution when coadministering tesamorelin with ritonavir as their concurrent use may alter ritonavir plasma concentrations. In a pharmacokinetic study, multiple 2 mg doses of tesamorelin administered with ritonavir resulted in a 9% decrease in ritonavir AUC and an 11% decrease in ritonavir Cmax. The clinical impact of these pharmacokinetic changes is unknown; however, patients should be monitored for decreased ritonavir efficacy. [42405] Tezacaftor; Ivacaftor: (Major) If ritonavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. [47165] [48524] (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with ritonavir; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); ritonavir is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively. [47165] [62870] Theophylline, Aminophylline: (Moderate) Ritonavir decreased theophylline AUC and Cmax by 43% and 52%, respectively, when the two drugs were coadministered. Higher dosages of aminophylline might be required. [1800] [5044] (Moderate) Ritonavir decreased theophylline AUC and Cmax by 43% and 52%, respectively, when the two drugs were coadministered. If these drugs are used together, therapeutic drug monitoring should be considered. Higher dosages of theophylline might be required. [47165] Thiazolidinediones: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8. [28142] [28172] [28380] [30575] [31320] [34557] [47165] [50768] [51227] Thioridazine: (Moderate) Close clinical monitoring is recommended during coadministration; thioridazine dose reductions may be required. The plasma concentrations of thioridazine may be elevated when administered concurrently with ritonavir. Elevated levels of thioridazine may result in prolongation of the QTc interval and may increase the risk of serious, potentially fatal, cardiac arrhythmias, such as torsades de pointes. [43069] [47165] Thiotepa: (Major) Avoid the concomitant use of thiotepa and ritonavir if possible; reduced metabolism to the active thiotepa metabolite may result in decreased thiotepa efficacy. Consider an alternative agent with no or minimal potential to inhibit CYP3A4. If coadministration is necessary, monitor patients for signs of reduced thiotepa efficacy. In vitro, thiotepa is metabolized via CYP3A4 to the active metabolite, TEPA; ritonavir is a strong CYP3A4 inhibitor. [47165] [61718] Tiagabine: (Moderate) Concurrent administration of tiagabine with ritonavir may result in elevated tiagabine plasma concentrations. Tiagabine is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [58664] [7573] Ticagrelor: (Major) Avoid the concomitant use of ticagrelor and ritonavir. Ticagrelor is a substrate of CYP3A4/5 and P-glycoprotein (P-gp), and ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor. Concomitant use with ritonavir substantially increases ticagrelor exposure which may increase the bleeding risk. In addition, ticagrelor is also a mild CYP3A4 inhibitor and P-gp inhibitor. Ritonavir is a substrate of both CYP3A4 and P-gp. [44951] (Major) Consider temporary discontinuation of ticagrelor during treatment with ritonavir-boosted nirmatrelvir and for at least 2 to 3 days after treatment completion. For patients at very high risk of thrombosis, consider prescribing an alternative antiplatelet or COVID-19 therapy. Coadministration may increase ticagrelor exposure resulting in increased toxicity. Ticagrelor is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [69024] Timolol: (Moderate) Timolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as ritonavir, may impair timolol metabolism; the clinical significance of such interactions is unknown. [5044] [5270] Tinidazole: (Moderate) Coadministration of tinidazole with ritonavir may accelerate the elimination of tinidazole, decreasing the plasma concentration of tinidazole, or may prolong the half-life of tinidazole, increasing the plasma concentration of tinidazole. Tinidazole is a CYP3A4 substrate, and ritonavir is a CYP3A4 inhibitor and strong CYP3A4 inducer. Additionally, ritonavir oral solution and capsules contain ethanol. Medications with significant alcohol content should not be ingested during therapy with tinidazole and should be avoided for 3 days after therapy is discontinued. Administration of ritonavir oral solution and capsules to patients receiving or who have recently received tinidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations of ritonavir (e.g., tablets or oral powder). [28315] [29931] [47165] Tiotropium; Olodaterol: (Moderate) Beta-agonists, such as olodaterol, may be associated with adverse cardiovascular effects including QT interval prolongation. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with olodaterol include ritonavir. [47165] [57710] Tirzepatide: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] [50113] [50814] Tisotumab Vedotin: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with ritonavir is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%. [47165] [66996] Tofacitinib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ritonavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with ritonavir. Ritonavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [28315] [52315] [56579] (Major) Consider withholding tofacitinib, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the tofacitinib dose. In patients receiving tofacitinib 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Coadministration may increase tofacitinib exposure resulting in increased toxicity. Tofacitinib is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] Tolterodine: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with ritonavir. Concurrent use may increase tolterodine exposure. Ritonavir is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A inhibitors. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers. [31112] [43295] [47165] Tolvaptan: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and tolvaptan is contraindicated due to the potential for dehydration, hypovolemia, and hyperkalemia; consider an alternative COVID-19 therapy. Coadministration may increase tolvaptan exposure resulting in increased toxicity. Tolvaptan is a sensitive CYP3A4 substrate and nirmatrelvir is a CYP3A inhibitor. [35780] [63106] [67203] [69024] (Contraindicated) The concomitant use of tolvaptan and ritonavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; ritonavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors. [35780] [47165] [63106] Topiramate: (Moderate) Concurrent administration of topiramate with ritonavir may result in decreased concentrations of ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir is metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together. [28378] [57036] [58664] Topotecan: (Major) Avoid coadministration of ritonavir with oral topotecan due to increased topotecan exposure; ritonavir may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and ritonavir is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone. [28380] [33536] [33578] [46322] Toremifene: (Major) Avoid coadministration of ritonavir with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%. [28822] [47165] Tovorafenib: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of tovorafenib is necessary. Concomitant use of nirmatrelvir and tovorafenib may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and tovorafenib is a CYP3A inducer. [67203] [70542] (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with tovorafenib. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and tovorafenib is a weak CYP3A inducer. [67203] [70542] Trabectedin: (Major) Avoid the concomitant use of trabectedin with ritonavir due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone. [47165] [60248] traMADol: (Major) Tramadol is primarily metabolized by CYP2D6 and CYP3A4; drugs that inhibit these enzymes, such as ritonavir, may decrease the metabolism of tramadol. This may result in a decreased concentration of the active metabolite (O-desmethyltramadol) leading to decreased analgesic effects and possibly increased side effects (seizures and serotonin syndrome) due to higher tramadol concentrations. [40255] [5043] [9316] (Moderate) Monitor for decreased analgesic effects and possibly increased side effects (seizures and serotonin syndrome) when administering tramadol concurrently with ritonavir-boosted nirmatrelvir. Tramadol is primarily metabolized by CYP2D6 and CYP3A4; drugs that inhibit these enzymes, such as ritonavir-boosted nirmatrelvir, may decrease the metabolism of tramadol. This may result in a decreased concentration of the active metabolite (O-desmethyltramadol) and increased concentrations of tramadol. [32475] [65314] Tramadol; Acetaminophen: (Major) Tramadol is primarily metabolized by CYP2D6 and CYP3A4; drugs that inhibit these enzymes, such as ritonavir, may decrease the metabolism of tramadol. This may result in a decreased concentration of the active metabolite (O-desmethyltramadol) leading to decreased analgesic effects and possibly increased side effects (seizures and serotonin syndrome) due to higher tramadol concentrations. [40255] [5043] [9316] (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [25460] [28100] [58664] (Moderate) Monitor for decreased analgesic effects and possibly increased side effects (seizures and serotonin syndrome) when administering tramadol concurrently with ritonavir-boosted nirmatrelvir. Tramadol is primarily metabolized by CYP2D6 and CYP3A4; drugs that inhibit these enzymes, such as ritonavir-boosted nirmatrelvir, may decrease the metabolism of tramadol. This may result in a decreased concentration of the active metabolite (O-desmethyltramadol) and increased concentrations of tramadol. [32475] [65314] Trandolapril; Verapamil: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil and ritonavir. Coadministration may increase the exposure of verapamil. Verapamil is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. [29702] [40025] [47165] Trazodone: (Major) Avoid coadministration of trazodone with ritonavir due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone. [28315] [38831] [46638] [47165] Triamcinolone: (Moderate) Ritonavir may inhibit the CYP3A4 metabolism of triamcinolone, resulting in increased plasma triamcinolone concentrations and reduced serum cortisol concentrations. There have been reports of clinically significant drug interactions in patients receiving ritonavir (a strong CYP3A4 inhibitor) along with corticosteroids resulting in systemic corticosteroid effects including, but not limited to, Cushing syndrome and adrenal suppression. Consider the benefit-risk of concomitant use and monitor for systemic corticosteroid side effects. Consider using an alternative treatment to triamcinolone, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone or prednisolone). In some patients, a corticosteroid dose adjustment may be needed. If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal. [28341] [47165] [56202] Triazolam: (Contraindicated) Coadministration of triazolam, a primary CYP3A4 substrate, with strong CYP3A4 inhibitors, such as protease inhibitors, is contraindicated by the manufacturer of triazolam due to the risk for increased and prolonged sedation and respiratory depression. Concurrent use is expected to produce large increases in systemic exposure to triazolam, with the potential for serious adverse effects. [28142] [28341] [28731] [28839] [28995] [29012] [31320] [32432] [41543] [46638] [47165] (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and triazolam is contraindicated. Consider temporary discontinuation of triazolam during treatment with ritonavir-boosted nirmatrelvir and for at least 2 to 3 days after treatment completion; if not feasible, consider alternative COVID-19 therapy. Coadministration may increase triazolam exposure resulting in increased toxicity. Triazolam is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] Tricyclic antidepressants: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with ritonavir is necessary; a dose reduction of the TCA may be necessary. Concurrent use may increase exposure of the TCA. TCAs are CYP2D6 substrates and ritonavir is a CYP2D6 inhibitor. [47165] Trimipramine: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with ritonavir is necessary; a dose reduction of the TCA may be necessary. Concurrent use may increase exposure of the TCA. TCAs are CYP2D6 substrates and ritonavir is a CYP2D6 inhibitor. [47165] Tucatinib: (Moderate) Monitor for increased toxicity of ritonavir if coadministered with tucatinib. Concurrent use may increase the plasma concentrations of ritonavir. Ritonavir is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. [47165] [65295] Ubrogepant: (Contraindicated) Coadministration of ubrogepant and ritonavir is contraindicated as concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor resulted in a 9.7-fold increase in the exposure of ubrogepant. [47165] [64874] (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and ubrogepant is contraindicated due to the potential for serious adverse reactions; consider an alternative COVID-19 therapy. Coadministration may increase ubrogepant exposure resulting in increased toxicity. Ubrogepant is a CYP3A4 substrate and nirmatrelvir is a CYP3A inhibitor. [64874] [67203] [69024] Ulipristal: (Moderate) Use of ulipristal and ritonavir may increase the plasma concentration of ulipristal but is not likely to be significant for emergency contraceptive use. Avoid ritonavir if ulipristal is given chronically for hormonal conditions. Ulipristal is a substrate of CYP3A4 and ritonavir is a potent CYP3A4 inhibitor and in chronic use, may induce CYP3A4. Use together is likely to increase ulipristal concentrations overall, which may increase the risk for ulipristal-related adverse reactions. [41569] [50623] Upadacitinib: (Major) Consider withholding upadacitinib, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the upadacitinib dose. Do not exceed an upadacitinib induction dose of 30 mg PO once daily for 8 weeks and a maintenance dose of 15 mg once daily if coadministered with ritonavir-boosted nirmatrelvir in patients with ulcerative colitis. Do not exceed an upadacitinib dose of 15 mg PO once daily if coadministered with ritonavir-boosted nirmatrelvir in patients with arthritis or dermatitis. Monitor closely for adverse reactions. Concurrent use may increase upadacitinib exposure resulting in increased toxicity. Upadacitinib is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Major) During concomitant use of upadacitinib and ritonavir reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold. [47165] [56579] [64572] Valbenazine: (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as ritonavir. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant. [61873] Valproic Acid, Divalproex Sodium: (Major) In a single case report, possible ritonavir-mediated induction of valproic acid glucuronidation resulted in a decrease in valproic acid concentrations and efficacy. A man with bipolar disorder and HIV was stabilized on valproic acid 250 mg PO three times daily. Treatment was started with lopinavir; ritonavir and lamivudine, 3TC; zidovudine, ZDV in addition to the valproic acid. Three weeks after starting the antiretroviral medication, his manic symptoms worsened. Upon hospital admission due to the mania, his valproic acid concentration had decreased 48% (from 495 to 238 micromol/l). His valproic acid dose was increased to 1500 mg and olanzapine was introduced. The valproic acid concentration following this dose escalation was 392 micromol/l, and the patient improved clinically. Of note, the patient had also received paroxetine for treatment of comorbid depression when the antiretrovirals were initiated, but the SSRI was discontinued by the patient after 5 days. The SSRI may have contributed to the initial hypomanic episode. Clinicians should be aware of this potential interaction and closely monitor valproic acid concentrations and efficacy. A valproic acid dose increase may be needed. In addition, valproic acid is an inducer of P-glycoprotein (P-gp) and an inhibitor/inducer of CYP3A4; ritonavir is a substrate of both CYP3A4 and P-gp. [57048] [57080] [8650] Valsartan: (Minor) Valsartan is a substrate of the hepatic efflux transporter MRP2 and ritonavir is an inhibitor of MRP2. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan during coadministration. [28315] [29130] [36646] [39870] [60860] Valsartan; Hydrochlorothiazide, HCTZ: (Minor) Valsartan is a substrate of the hepatic efflux transporter MRP2 and ritonavir is an inhibitor of MRP2. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan during coadministration. [28315] [29130] [36646] [39870] [60860] Vamorolone: (Major) Decrease the vamorolone dose to 4 mg/kg once daily (max: 200 mg) and monitor for adverse effects if concomitant use with ritonavir is necessary. Concomitant use may increase vamorolone exposure and the risk for vamorolone-related adverse effects. Vamorolone is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased vamorolone overall exposure by 44%. [56579] [69702] Vardenafil: (Major) Consider withholding vardenafil during receipt of ritonavir-boosted nirmatrelvir. Coadministration may increase vardenafil exposure resulting in increased toxicity. Vardenafil is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] [69024] (Major) Do not use vardenafil orally disintegrating tablets with ritonavir due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 72-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; ritonavir is a strong CYP3A4 inhibitor. Coadministration of ritonavir with vardenafil resulted in a 49-fold increase in vardenafil AUC and a 13-fold increase in vardenafil Cmax. Concomitant use may increase the risk of vardenafil-related adverse effects, such as prolonged erection or QT prolongation. [28216] [41124] [46638] [47165] Vemurafenib: (Major) Avoid the concomitant use of vemurafenib and ritonavir; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with ritonavir cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%. [45335] [47165] Venetoclax: (Major) Coadministration of ritonavir with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of ritonavir. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Coadministration of ritonavir, a strong CYP3A, P-gp, and OATP1B1/B3 inhibitor increased the venetoclax AUC by 690% in a drug interaction study. [47165] [60706] Verapamil: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil and ritonavir. Coadministration may increase the exposure of verapamil. Verapamil is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. [29702] [40025] [47165] Vilazodone: (Major) Because CYP3A4 is the primary isoenzyme involved in the metabolism of vilazodone, the manufacturer of vilazodone recommends that the daily dose not exceed 20 mg/day during concurrent use of a strong CYP3A4 inhibitor, such as ritonavir. The original vilazodone dose can be resumed when the CYP3A4 inhibitor is discontinued. [28315] [43177] vinBLAStine: (Major) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with ritonavir is necessary. Vinblastine is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. [28341] [28380] [34653] [34655] [47165] [56579] [57949] [59581] Vincristine Liposomal: (Major) The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a CYP3A4 and P-gp inhibitor. [28155] [28498] [28731] [29472] [31320] [32432] [34654] [34655] [34656] [47165] [49123] [50768] [50769] [51080] [51432] [57949] Vincristine: (Major) The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a CYP3A4 and P-gp inhibitor. [28155] [28498] [28731] [29472] [31320] [32432] [34654] [34655] [34656] [47165] [49123] [50768] [50769] [51080] [51432] [57949] Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with ritonavir is necessary. Vinorelbine is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. [47165] [56871] Voclosporin: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and voclosporin is contraindicated due to the potential for acute or chronic nephrotoxicity; consider an alternative COVID-19 therapy. Coadministration may increase voclosporin exposure resulting in increased toxicity. Voclosporin is a sensitive CYP3A4 substrate and nirmatrelvir is a CYP3A inhibitor. [66336] [67203] [69024] (Contraindicated) Concomitant use of voclosporin and ritonavir is contraindicated; concomitant use may increase the exposure of voclosporin and the risk of voclosporin-related adverse effects such as nephrotoxicity, hypertension, and QT prolongation. Voclosporin is a sensitive CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased voclosporin exposure by approximately 19-fold. [47165] [66336] Vonoprazan; Amoxicillin; Clarithromycin: (Major) Because the exposure to 14-OH clarithromycin is significantly decreased by ritonavir, consider alternative antibiotic therapy for indications other than Mycobacterium avium. Clarithromycin doses above 1000 mg should not be administered with ritonavir. If coadministration cannot be avoided, clarithromycin dosage reductions are recommended in patients with renal impairment (CrCl 30 to 60 mL/minute, decrease clarithromycin by 50%; CrCl less than 30 mL/minute, decrease clarithromycin by 75%). Concomitant administration of ritonavir and clarithromycin resulted in a 77% increase in clarithromycin exposure and a 100% decrease in 14-OH clarithromycin exposure. The microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria. [28238] [46638] [47165] Vorapaxar: (Major) Avoid coadministration of vorapaxar and ritonavir. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with ritonavir, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications. [57151] (Major) Consider temporary discontinuation of vorapaxar during treatment with ritonavir-boosted nirmatrelvir and for at least 2 to 3 days after treatment completion; if not feasible, consider alternative COVID-19 therapy. Coadministration may increase vorapaxar exposure resulting in increased toxicity. Vorapaxar is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [69024] Voriconazole: (Major) Coadministration of voriconazole and ritonavir at doses of 400 mg every 12 hours is contraindicated, and coadministration of voriconazole with ritonavir at doses of 100 mg or less should be avoided unless an assessment of the benefit to risk ratio justifies concurrent use. In 1 study, coadministration of ritonavir 400 mg every 12 hours for 9 days resulted in an 82% decrease in voriconazole AUC. Low dose ritonavir (100 mg every 12 hours) decreased voriconazole AUC concentrations by 39%. [28158] [28315] [46638] [47165] Vorinostat: (Major) The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include vorinostat. [32789] [47165] Warfarin: (Moderate) Closely monitor INR and adjust the warfarin dosage as appropriate based on response if warfarin and ritonavir coadministration is necessary. Ritonavir has a complex effect on warfarin concentrations which may result in increased bleeding risk or reduced warfarin efficacy. Warfarin is a mixture of S- and R-enantiomers: the S-enantiomer exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer has a slower clearance. Ritonavir has been observed to increase overall exposure to the S-enantiomer of warfarin by 9% and decrease overall exposure to the R-enantiomer of warfarin by 33%. [28549] [46638] [47165] [56579] Zafirlukast: (Moderate) Concurrent administration of zafirlukast with ritonavir may result in elevated plasma concentrations of ritonavir. In vitro, zafirlukast is an inhibitor of the hepatic isoenzyme CYP3A4. Ritonavir is a substrate for CYP3A4. Caution and close monitoring are advised if these drugs are administered together. [2129] [28222] [58664] [7806] [9700] Zaleplon: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as ritonavir, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability. [29887] Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO once daily if coadministered with ritonavir. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Interrupt zanubrutinib therapy as recommended for adverse reactions. After discontinuation of ritonavir, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. The AUC of zanubrutinib was increased by 278% when coadministered with another strong CYP3A4 inhibitor. [47165] [64748] (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of zanubrutinib is necessary. Concomitant use of nirmatrelvir and zanubrutinib may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and zanubrutinib is a weak CYP3A inducer. [64748] [67203] Zidovudine, ZDV: (Minor) Since ritonavir induces glucuronidation, there is the potential for reduction in zidovudine, ZDV plasma concentrations during concurrent therapy with ritonavir. When coadministered with ritonavir, the AUC and Cmax of zidovudine, ZDV are decreased by 12% and 27%. The clinical significance of this interaction is unknown. [28315] [47165] [58664] Ziprasidone: (Major) Concomitant use of ziprasidone and ritonavir should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. The use of ritonavir could result in QT prolongation. In addition, the plasma concentrations of ziprasidone may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as extrapyramidal symptoms and CNS effects, is recommended during coadministration. Ritonavir is a strong CYP3A4 inhibitor and ziprasidone is a partial CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the AUC and Cmax of ziprasidone by about 35 to 40%. [28233] [47165] Zolmitriptan: (Moderate) Concurrent administration of zolmitriptan with ritonavir may result in elevated zolmitriptan plasma concentrations. Zolmitriptan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [57037] [58664] Zolpidem: (Moderate) Consider decreasing the dose of zolpidem if coadministration with protease inhibitors is necessary. Zolpidem is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%. [28001] [28315] [32432] [57789] Zuranolone: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with ritonavir is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold. [56579] [69264]
        Revision Date: 05/23/2024, 01:37:00 AM

        References

        1299 - Centers for Disease Control and Prevention (CDC). Notice to Readers: Updated guidelines for the use of rifamycins for the treatment of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR 2004;53:37. Available on the World Wide Web at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5302a6.htm.1800 - US Department of Health and Human Services (DHHS) and National Institutes of Health (NIH). The Living Document: Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Retrieved March 18, 2008. Available on the World Wide Web at www.aidsinfo.nih.gov.1802 - Baselga J, Albanell J, Molina MA, et al. Mechanism of action of trastuzumab and scientific update. Semin Oncol 2001;28(5 Suppl 16):4-11.2129 - Katial RK, Stelzle RC, Bonner MW, et al. A drug interaction between zafirlukast and theophylline. Arch Intern Med 1998;158:1713-5.2546 - Harrington RD, Woodward JA, Hooton TM, et al. Life-threatening interactions between HIV-1 protease inhibitors and the illicit drugs MDMA and gamma-hydroxybutyrate. Arch Intern Med 1999;159:2221-4.2548 - Hall MCS, Ahmad S. Interaction between sildenafil and HIV-1 combination therapy. Lancet 1999;353;2071-2.4194 - Piscitelli SC, Gallicano KD. Interactions among drugs for HIV and opportunistic infections. N Engl J Med 2001;344:984-96.4718 - Hansten PD, Horn JR. Cytochrome P450 Enzymes and Drug Interactions, Table of Cytochrome P450 Substrates, Inhibitors, Inducers and P-glycoprotein, with Footnotes. In: The Top 100 Drug Interactions - A guide to Patient Management. 2008 Edition. Freeland, WA: H&H Publications; 2008:142-157.4998 - Propranolol tablet package insert. Parsippany, NJ: Actavis Pharma, Inc.; 2015 Aug.5043 - Tramadol hydrochloride tablets package insert. Parsippany, NJ: Teva Pharmaceuticals; 2023 Dec.5044 - Norvir (ritonavir capsules) package insert. North Chicago, IL: AbbVie Inc; 2020 Oct.5070 - Kaletra (lopinavir; ritonavir) tablet and solution package insert. North Chicago, IL: AbbVie Inc; 2020 Oct.5074 - Agenerase® (amprenavir) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2005 Nov.5110 - Phillips E, Rachlis A, Ito S. Digoxin toxicity and ritonavir: a drug interaction mediated through p-glycoprotein? AIDS 2003;17:1577-8.5172 - Sustiva (efavirenz) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2023 Nov.5267 - Coreg (carvedilol) package insert. Wixom, MI: Woodward Pharma Services LLC; 2023 Jul.5269 - Toprol-XL (metoprolol succinate) tablet package insert. Lincolnshire, IL: Melinta Therapeutics; 2023 Mar.5270 - Timolol tablets package insert. Morgantown, WV: Mylan Pharmaceuticals Inc.; 2020 July.5286 - Tanaka E. Clinically significant pharmacokinetic drug interactions with benzodiazepines. J Clin Pharm Ther 1999;24:347-55.5335 - Mevacor (lovastatin) package insert. Whitehouse Station, NJ: Merck & Co., Inc.; 2012 Oct.5339 - Cozaar (losartan potassium) package insert. Jersey City, NJ: Organon & Co., Inc.; 2021 Oct.5414 - Nefazodone tablet package insert. North Wales, PA: Teva Pharmaceuticals USA, Inc.; 2015 Sept.5542 - Brachtendorf L, Jetter A, Beckurts KT, et al. Cytochrome P450 enzymes contributing to demethylation of maprotiline in man. Pharmacol Toxicol 2002;90:144-9.5772 - Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet 2000;38:41-57.5911 - Wang JJ, Lee CL, Pan TM. Improvement of monacolin K, gama-aminobutyric acid and citrinin production ratio as a function of environmental conditions of Monascus purpureus NTU 601. J Ind Microbiol Biotechnol 2003;30:669-76.6265 - Nexium (esomeprazole) capsules, granules package insert. Wilmington, DE: AstraZeneca; 2023 July.6352 - Mobic (meloxicam) package insert. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2021 Apr.7573 - Gabitril (tiagabine) package insert. North Wales, PA: Teva Pharmaceuticals USA, Inc.; 2016 Aug.7731 - Nor-QD tablets (norethindrone) package insert. Parsippany, NJ: Watson Pharma, Inc.; 2011 Jul.7806 - Walsky RL, Gaman EA, Obach RS. Examination of 209 drugs for inhibition of cytochrome P450 2C8. J Clin Pharmacol 2005;45:68-78.8102 - Aptivus (tipranavir) package insert. Ridgefield, CT: Boehringer Ingelheim; 2024 Apr.8143 - Rozerem (ramelteon) tablet package insert. Lexington, MA: Takeda Pharmaceuticals America, Inc.; 2021 Nov.8145 - Cajochen C. TAK-375 Takeda. Curr Opin Investig Drugs 2005;6:114-21.8650 - Sheehan NL, Brouillette MJ, Delisle MS, et al. Possible interaction between lopinavir/ritonavir and valproic acid exacerbates bipolar disorder. Ann Pharmacother. 2006;40:147-50.9316 - Tramadol hydrochloride extended-release tablets package insert. Baltimore, MD: Lupin Pharmaceuticals, Inc.; 2023 Sep.9700 - Jaakkola T, Backman JT, Neuvonen M, et al. Montelukast and zafirlukast do not affect the pharmacokinetics of the CYP2C8 substrate pioglitazone. Eur J Clin Pharmacol 2006;62:503-9.11181 - Tang W, Stearns RA, Wang RW, et al. Roles of human hepatic cytochrome P450s 2C9 and 3A4 in the metabolic activation of diclofenac. Chem Res Toxicol 1999;12:192-9.11191 - Giao PT, de Vries PJ. Pharmacokinetic interactions of antimalarial agents. Clin Pharmacokinet 2001;40:343-73.11312 - Yasuda K, Ranade A, Venkataramanan R, et al. A comprehensive in vitro and in silico analysis of antibiotics that activate pregnane X receptor and induce CYP3A4 in liver and intestine. Drug Metab Dispos 2008;36:1689-97.11313 - Lang CC, Jamal SK, Mohamed Z, et al. Evidence of an interaction between nifedipine and nafcillin in humans. Br J Clin Pharmacol 2003;55:588-90.11416 - Lee CG, Gottesman MM, Cardarelli CO. HIV-1 protease inhibitors are substrates for the MDR1 multidrug transporter. Biochemistry 1998;37:3594-601.11417 - Storch CH, Theile D, Lindenmaier H, et al. Comparison of inhibitory activity of anti-HIV drugs on P-glycoprotein. Biochem Pharmacol 2007;73:1573-81.11418 - Choo EF, Leake B, Wandel C, et al. Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. Drug Metab Dispos 2000;28:655-60.11537 - Katoh M, Nakajima M, Yamazaki H, et al. Inhibitory potencies of 1,4-dihydropyridine calcium antagonists to P-glycoprotein-mediated transport: comparison with the effects of CYP3A4. Pharm Res 2000;17:1189-97.22256 - Risperdal Consta (risperidone long-acting injection) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2021 Feb.24859 - Davis JL, et al. Iritis and hypotony after treatment with intravenous cidofovir for cytomegalovirus retinitis. Arch Ophthal 1997;115:733-7.25398 - Melchart D, Linde K, Worku F, et al. Results of five randomized studies on the immunomodulatory activity of preparations of Echinacea. J Altern Complement Med 1995;1:145-60.25460 - Tolman KG. Hepatotoxicity of non-narcotic analgesics. Am J Med 1998;105:13S-19S.25887 - Harrington RD, Woodward JA, Hooton TM, et al. Life-threatening interactions between HIV-1 protease inhibitors and the illicit drugs MDMA and gamma-hydroxybutyrate. Arch Intern Med 1999;159:2221-4.26120 - Hsu A, Granneman GR, Cao G, et al. Pharmacokinetic interaction between ritonavir and indinavir in healthy volunteers. Antimicrob Agents Chemother 1998;42:2784-91.26121 - van Heeswijk RP, Veldkamp AI, Hoetelmans RM, et al. The steady-state plasma pharmacokinetics of indinavir alone and in combination with a low dose of ritonavir in twice daily dosing regimens in HIV-1 infected individuals. AIDS. 1999; 13:F95-9.26403 - Olkkola KT, Palkama VJ, Neuvonen PJ. Ritonavir's role in reducing fentanyl clearance and prolonging its half-life. Anesthesiology 1999;91:681-5.27275 - Penzak SR, Hon YY, Lawhorn WD, et al. Influence of ritonavir on olanzapine pharmacokinetics in healthy volunteers. J Clin Psychopharmacol 2002;22:366-70.27480 - Ridtitid W, Wongnawa M, Mahatthanatrakul W, et al. Rifampin markedly decreases plasma concentrations of praziquantel in healthy volunteers. Clin Pharmacol Ther 2002;72:505-13.27493 - Piscitelli SC, Gallicano KD. Interactions among drugs for HIV and opportunistic infections. N Engl J Med 2001;344:984-96.27494 - Hsu A, Granneman GR, Bertz RJ. Ritonavir: clinical pharmacokinetics and interactions with other anti-HIV agents. Clin Pharmacokinet 1998;35:275-91.27896 - Bachmann K, He Y, Sarver JG, et al. Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of ethosuximide by human hepatic microsomal enzymes. Xenobiotica 2003;33:265-76.27971 - Xenical (orlistat) package insert. Montgomery, AL: H2-Pharma, LLC; 2022 Nov.27982 - Ketoconazole tablets package insert. Morgantown, WV: Mylan Pharmaceuticals, Inc.; 2017 Sept.27983 - Sporanox (itraconazole) capsules package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2024 Feb.27990 - Inspra (eplerenone) package insert. New York, NY: Pfizer Inc; 2020 Aug.28001 - Hansten PD, Horn JR. Cytochrome P450 Enzymes and Drug Interactions, Table of Cytochrome P450 Substrates, Inhibitors, Inducers and P-glycoprotein, with Footnotes. In: The Top 100 Drug Interactions - A guide to Patient Management. 2008 Edition. Freeland, WA: H&H Publications; 2008:142-157.28003 - Mifeprex (Mifepristone, RU-486) package insert. New York, NY: Danco Laboratories, LLC.; 2023 Mar.28040 - Xanax (alprazolam tablet) package insert. New York, NY: Pharmacia & Upjohn Company; 2023 Jan.28058 - Wellbutrin XL (bupropion) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2019 Nov.28100 - Manyike PT, Kharasch ED, Kalhorn TF, et al. Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation. Clin Pharmacol Ther 2000;67:275-282.28126 - Sensipar (cinacalcet) package insert. Thousand Oaks, CA: Amgen Inc.; 2019 Dec.28142 - Reyataz (atazanavir) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2023 Nov.28155 - Chan JD. Pharmacokinetic drug interactions of vinca alkaloids: summary of case reports. Pharmacotherapy 1998;18:1304-7.28158 - VFEND (voriconazole) tablets, suspension, and injection package insert. New York, NY: Pfizer Inc; 2022 Oct.28172 - Avandia (rosiglitazone) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2019 Feb.28193 - Viread (tenofovir disoproxil fumarate) package insert. Foster City, CA: Gilead Sciences, Inc; 2019 Apr.28216 - Levitra (vardenafil) package insert. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc.; 2023 Mar.28220 - Cialis (tadalafil) package insert. Indianapolis, IN: Lilly ICOS, LLC; 2018 Feb.28221 - Tikosyn (dofetilide) package insert. New York, NY: Pfizer Labs; 2019 Aug.28222 - Accolate (zafirlukast) package insert. Wilmington, DE: AstraZeneca; 2015 Dec.28224 - Pacerone (amiodarone) tablets package insert. Maple Grove, MN: Upsher-Smith Laboratories, LLC.; 2018 Nov.28228 - Norpace and Norpace CR (disopyramide) package insert. Chicago, IL: G.D. Searle LLC division of Pfizer Inc; 2016 Aug.28233 - Geodon (ziprasidone) package insert. New York, NY: Pfizer: 2021 May.28234 - Betapace (sotalol) package insert. Wayne, NJ: Berlex Laboratories; 2011 Aug.28238 - Biaxin (clarithromycin) package insert. North Chicago, IL: AbbVie, Inc.; 2019 Sep.28240 - Gleevec (imatinib mesylate) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2014 May.28260 - Paxil (paroxetine) tablet package insert. Weston, FL: Apotex Corp.; 2023 Aug.28262 - Clozaril (clozapine) tablets package insert. Rosemont, PA: HLS Therapeutics (USA), Inc.; 2023 May.28272 - Lanoxin (digoxin) tablets package insert. St. Michael, Barbados: Concordia Pharmaceuticals Inc.; 2020 Apr..28287 - Rythmol SR (propafenone hydrochloride) capsule extended release package insert. Research Triangle Park, NC: GlaxoSmithKline; 2018 Nov.28301 - Mefloquine hydrochloride package insert. North Wales PA: Teva Pharmaceuticals USA Inc.; 2019 Mar.28307 - Haldol (haloperidol) injection for immediate release package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2020 Feb.28315 - Norvir (ritonavir capsules) package insert. North Chicago, IL: AbbVie Inc; 2020 Oct.28318 - Xopenex (levalbuterol) package insert. Marlborough, MA: Sepracor Inc.; 2009 Feb.28337 - Parlodel (bromocriptine) tablets and capsules package insert. Parsippany, NJ: Validus Pharmaceuticals LLC; 2021 Jul.28341 - Kaletra (lopinavir; ritonavir) tablet and solution package insert. North Chicago, IL: AbbVie Inc; 2020 Oct.28345 - Agenerase® (amprenavir) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2005 Nov.28377 - Foscavir (foscarnet) package insert. Lake Forest, IL: Hospira, Inc.; 2020 Oct.28378 - Topamax (topiramate) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2023 May.28380 - Phillips E, Rachlis A, Ito S. Digoxin toxicity and ritonavir: a drug interaction mediated through p-glycoprotein? AIDS 2003;17:1577-8.28382 - Lotronex (alosetron) package insert. San Diego, CA: Promethus Laboratories, Inc.; 2019 April.28383 - Velcade (bortezomib) injection package insert. Lexington, MA: Takeda Pharmaceuticals America, Inc..; 2022 Aug.28404 - Neoral (cyclosporine) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2023 Sept.28414 - Risperdal (risperidone tablets, oral solution, and orally disintegrating tablets) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2022 Aug.28442 - Sustiva (efavirenz) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2023 Nov.28451 - Lamictal (lamotrigine) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2021 Mar.28467 - Serevent Diskus (salmeterol xinafoate inhalation powder) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2019 July.28476 - Rescriptor (delavirdine) package insert. Research Triangle Park, NC: ViiV Healthcare; 2019 Aug.28483 - Priftin (rifapentine) package insert. Bridgewater, NJ: Sanofi-Aventis Pharmaceuticals Inc.; 2020 Jun.28496 - Tracleer (bosentan) package insert. Titusville, NJ: Actelion Pharmaceuticals US, Inc.; 2024 Feb.28498 - Lum BL, Gosland MP, Kaubish S, et al. Molecular targets in oncology; implications of the multidrug resistance gene. Pharmacotherapy 1993;13:88-109.28501 - Buspirone tablets package insert. Parsippany, NJ: Teva Pharmaceuticals; 2023 Mar.28541 - Felodipine package insert. East Windsor, NJ: Aurobindo Pharma USA, Inc.; 2020 Jan.28549 - Coumadin (warfarin tablets) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2017 Aug.28556 - Tanaka E. Clinically significant pharmacokinetic drug interactions with benzodiazepines. J Clin Pharm Ther 1999;24:347-55.28558 - Amoxapine package insert. Parsippany, NJ: Actavis Pharma, Inc.; 2015 Feb.28581 - Flagyl (metronidazole tablets) package insert. New York, NY: Pfizer, Inc.; 2023 Oct.28604 - Mevacor (lovastatin) package insert. Whitehouse Station, NJ: Merck & Co., Inc.; 2012 Oct.28605 - Zocor (simvastatin) package insert. Jersey City, NJ: Organon & Co.; 2023 Aug.28610 - Rapamune (sirolimus) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2022 Aug.28611 - Prograf (tacrolimus) capsules, injection, and granules for oral suspension package insert. Northbrook, IL: Astellas Pharma US, Inc.; 2023 Aug.28674 - Diflucan oral tablet and suspension (fluconazole) package insert. New York, NY: Pfizer; 2024 Feb.28729 - Lipitor (atorvastatin calcium) package insert. Morgantown, WV: Viatris Specialty LLC; 2024 Apr.28731 - Crixivan (indinavir) package insert. Whitehouse Station, NJ: Merck & Co., Inc.; 2016 Sept.28759 - Maprotiline HCl tablet package insert. Morgantown WV: Mylan Pharmaceuticals Inc; 2014 Dec.28774 - Williams D, Feely J. Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clin Pharmacokinet 2002;41:343-370.28784 - Hepsera (adefovir dipivoxil) package insert. Foster City, CA: Gilead Sciences, Inc.; 2018 Dec.28822 - Fareston (toremifene citrate) tablets package insert. Bedminster, NJ: Kyowa Kirin Inc.; 2017 May.28839 - Viracept (nelfinavir mesylate) package insert. Research Triangle Park, NC: ViiV Healthcare Company; 2021 Mar.28852 - Cafergot (caffeine; ergotamine) tablets package insert. Princeton, NJ: Sandoz, Inc.; 2018 May.28874 - Zyrtec (Cetirizine HCl tablets, chewable tablets, and 1 mg/mL oral solution) Rx only package insert. Pfizer Labs: 2006 May. (prescription label prior to product nonprescription switch in U.S.)28875 - Avodart (dutasteride soft gelatin capsules) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2020 Jan.28995 - Invirase (saquinavir) package insert. South San Francisco, CA: Genentech Inc.; 2020 Sept.29012 - Lexiva (fosamprenavir calcium) package insert. Research Triangle Park, NC: ViiV Healthcare; 2019 Mar29014 - Trileptal (oxcarbazepine) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2019 Jan.29068 - Procardia (nifedipine) package insert. New York, NY: Pfizer Labs, Inc.; 2016 Jul.29082 - Nimodipine capsule package insert. Livonia, MI: Major Pharmaceuticals; 2015 Dec.29090 - Norvasc (amlodipine) package insert. New York, NY: Pfizer Labs; 2019 Jan.29118 - Seroquel (quetiapine fumarate) package insert. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2022 Jan.29130 - Diovan (valsartan) tablets package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2021 Apr.29198 - Sandimmune (cyclosporine) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2023 Sept.29210 - Mycobutin (rifabutin) package insert. New York, NY: Pharmacia and Upjohn, Co.; 2021 Sep.29219 - Ramamoorthy Y, Yu AM, Suh N, et al. Reduced (+/-)-3,4-methylenedioxymethamphetamine ("Ecstasy") metabolism with cytochrome P450 2D6 inhibitors and pharmacogenetic variants in vitro. Biochem Pharmacol. 2002;63:2111-9.29289 - Xifaxan (rifaximin) package insert. Bridgewater, NJ: Salix Pharmaceuticals, Inc.; 2023 Oct.29472 - Vincristine sulfate injection package insert. Lake Forest, IL: Hospira, Inc.; 2023 Jan.29564 - Prilosec (omeprazole) package insert. Wilmington, DE: AstraZeneca; 2023 July.29623 - Fentanyl transdermal system package insert. Webster Groves, MO: SpecGx LLC; 2024 Jan.29624 - Park JY, Kim KA, Kim SL. Chloramphenicol is a potent inhibitor of cytochrome P450 isoforms CYP2C19 and CYP3A4 in human liver microsomes. Antimicrob Agents Chemother 2003;47:3464-9.29640 - Aricept (donepezil hydrochloride) package insert. Woodcliff Lake, NJ: Eisai Co., Ltd.; 2017 March.29677 - Flomax (tamsulosin) package insert. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2014 Oct.29702 - Covera-HS (verapamil hydrochloride tablets) package insert. New York, NY: Pfizer Inc.; 2011 Oct.29747 - Riluzole tablet package insert. Cranbury, NJ: Sun Pharmaceutical Industries Inc.; 2017 Jan.29751 - Niemi M, Kajosaari LI, Neuvonen M, et al. The CYP2C8 inhibitor trimethoprim increases the plasma concentrations of repaglinide in healthy subjects. Br J Clin Pharmacol 2004;57:441-7.29763 - Actiq (oral transmucosal fentanyl citrate) package insert. Parsippany, NJ: Teva Pharmaceuticals USA, Inc.; 2023 Dec.29796 - Ditropan XL (oxybutynin chloride) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2021 Mar.29812 - Burman WJ, Gallicano K, Peloquin C. Comparative pharmacokinetics and pharmacodynamics of the rifamycin antibacterials. Clin Pharmacokinet. 2001;40:327-41.29824 - Cardura (doxazosin) package insert. New York, NY:Pfizer;2021 Jun.29887 - Sonata (zaleplon) package insert. Bristol, TN: King Pharmaceuticals; 2019 Aug.29931 - Tindamax (tinidazole) package insert. San Antonio, TX: Mission Pharmacal; 2021 Dec.29964 - Gris-Peg (griseofulvin ultramicrosize) package insert. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; 2016 Apr..30015 - Medrol (methylprednisolone) tablet package insert. New York, NY: Pfizer; Pharmacia and Upjohn Company LLC; 2023 Dec.30072 - Alfentanil hydrochloride injection package insert. Lake Forest, IL: Akorn, Inc.; 2023 Dec.30195 - Ding R, Tayrouz Y, Riedel KD, et al. Substantial pharmacokinetic interaction between digoxin and ritonavir in healthy volunteers. Clin Pharmacol Ther 2004;76:73-84.30282 - Synalgos-DC (aspirin; caffeine; dihydrocodeine) capsules package insert. Atlanta, GA: Mikart, Inc.; 2019 Oct.30314 - Rifadin capsules and injection (rifampin) package insert. Bridgewater, NJ: Sanofi-Aventis, LLC; 2023 Dec.30379 - Hycodan (hydrocodone bitartrate; homatropine methylbromide) package insert. Malvern, PA: Endo Pharmaceuticals Inc.; 2023 Dec.30391 - Hutchinson MR, Menelaou A, Foster DJ, et al. CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes. Br J Clin Pharmacol 2004;57:287-97.30413 - Prosom (estazolam) tablets package insert. North Chicago, IL: Abbott Laboratories; 2004 Jan.30431 - Marinol (dronabinol, THC) package insert. Marietta, GA: Unimed Pharmaceuticals, Inc.; 2023 Jan.30456 - German Commission E. Echinacea Purpurea herb, Echinaceae purpureae herrba, monograph Published March 2, 1989. In: Blumenthal, M et al ., eds. The complete German Commission E Monographs -Therapeutic Guide to Alternative Medicines. Boston MA: Integrative Medicine Communications for the American Botanical Council; 1998:122-3.30469 - Camptosar (irinotecan) package insert. Kalamazoo, MI: Pharmacia and Upjohn Company; 2022 Jan.30480 - Apidra (Insulin glulisine) package insert. Kansas City, MO: Aventis Pharmaceuticals, Inc.; 2004 Apr.30555 - Tarceva (erlotinib) package insert. Northbrook, IL: OSI Pharmaceuticals, LLC; 2016 Sept.30571 - Lunesta (eszopiclone) tablets package insert. Marlborough, MA: Sunovion Pharmaceuticals Inc; 2019 Aug.30575 - Luna B, Feinglos MN. Drug-induced hyperglycemia. JAMA 2001;286:1945-8.30585 - Pandit MK, Burke J, Gustafson AB, et al. Drug-induced disorders of glucose tolerance. Ann Intern Med 1993;118:529-39.30676 - Emend (aprepitant oral products) package insert. Whitehouse Station, NJ: Merck & Co.,Inc.; 2019 Nov.30711 - Enablex (darifenacin extended-release tablets) package insert. Madison, NJ: Allergan USA, Inc.; 2021 Jul.30742 - Abraxane (paclitaxel protein-bound particles) injection package insert. Summit, NJ: Celgene Corporation; 2020 Aug.30802 - Hansten PD, Horn JR. Top 100 Drug Interactions Monographs. In: The Top 100 Drug Interactions - A guide to Patient Management. 2007 Edition. Freeland, WA: H&H Publications; 2007:4-141.30966 - Sufentanil citrate injection package insert. Lake Forest, IL: Hospira, Inc.; 2023 Dec31112 - Detrol (tolterodine tartrate) package insert. New York, NY: Pharmacia and Upjohn Co., division of Pfizer; 2016 Nov.31240 - Tradjenta (linagliptin) package insert. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc.; 2023 June.31266 - Zofran (ondansetron) injection package insert. Research Triangle Park, NC: GlaxoSmithKline; 2021 Oct.31281 - Bidstrup TB, Bjornsdottir I, Sidelmann UG, et al. CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitro biotransformation of the insulin secretagogue repaglinide. Br J Clin Pharmacol 2003;56:305-14.31320 - Aptivus (tipranavir) package insert. Ridgefield, CT: Boehringer Ingelheim; 2024 Apr.31359 - Rozerem (ramelteon) tablet package insert. Lexington, MA: Takeda Pharmaceuticals America, Inc.; 2021 Nov.31360 - Cajochen C. TAK-375 Takeda. Curr Opin Investig Drugs 2005;6:114-21.31403 - Qualaquin (quinine sulfate) capsules package insert. Cranbury, NJ: Sun Pharmaceutical Industries, Inc.; 2019 Jun.31649 - Mauss S, Valenti WA, DePamphilis JB, et al. Risk factors for hepatic decompensation in patients with HIV/HCV coinfection and liver cirrhosis during interferon-based therapy. AIDS 18;13:21-25.31723 - Kytril injection (granisetron) package insert. Nutley, NJ: Roche Pharmaceuticals; 2011 Nov.31749 - Adalat CC (nifedipine extended-release tablets) package insert. Cookeville, TN: Aphena Pharma Solutions; 2014 May.31764 - Vaprisol (conivaptan hydrochloride injection) package insert. Deerfield, IL: Baxter Healthcare Corporation; 2016 Oct.31807 - Exjade (deferasirox) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2020 Jul.31824 - Rhinocort Aqua (budesonide) nasal spray package insert. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017 Jan.31869 - Axert (almotriptan) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2017 May.31938 - Ranexa (ranolazine extended-release tablets) package insert. Foster City, CA: Gilead Sciences, Inc. 2019 Oct.31970 - Sunitinib (Sutent) package insert. New York, NY: Pfizer Labs; 2020 Aug.32432 - Prezista (darunavir) package insert. Horsham, PA: Janssen Products, LP; 2023 Mar.32475 - Tramadol hydrochloride extended-release tablets package insert. Baltimore, MD: Lupin Pharmaceuticals, Inc.; 2023 Sep.32723 - Noxafil (posaconazole) package insert. Whitehouse Station, NJ: Merck & Co. Inc.: 2022 Jan.32731 - Fentora (fentanyl buccal tablet) package insert. Parsippany, NJ: Teva Pharmaceuticals USA, Inc.; 2023 Dec.32789 - Zolinza (vorinostat) capsules package insert. Whitehouse Station, NJ: Merck & Co., Inc.; 2018 Dec.33136 - Methadone hydrochloride tablets package insert. Webster Groves, MO: SpecGx LLC; 2024 Jan.33192 - Tykerb (lapatinib) tablet package insert. Research Triangle Park, NC: GlaxoSmithKline; 2022 March.33200 - Tekturna (aliskiren) package insert. Orlando, FL: Noden Pharma USA Inc; 2020 Jun.33239 - Altabax (retapamulin) package insert. Exton PA: Almirall, LLC; 2019 Sep.33263 - Vyvanse (lisdexamfetamine) capsules and chewable tablets package insert. Lexington, MA: Takeda Pharmaceuticals America, Inc.; 2023 Oct.33350 - Xyzal (levocetirizine) package insert. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2019 April.33467 - Nuvigil (armodafinil) package insert. Frazer, PA: Cephalon Inc; 2017 Feb.33473 - Selzentry (maraviroc) package insert. Research Triangle Park, NC: ViiV Healthcare; 2020 Oct.33536 - Hycamtin (topotecan) capsules package insert. Research Triangle Park, NC: GlaxoSmithKline; 2018 Sept.33563 - Ixempra (ixabepilone) for injection package insert. Princeton, NJ: R-Pharm US LLC; 2023 Jan.33578 - Kruijtzer CMF, Beijnen JH, Rosing H, et al. Increased oral bioavailability of topotecanin combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918. J Clin Oncol 2002;20:2943-50.33607 - Loperamide hydrochloride capsules (Rx-only) package insert. Morgantown, WV: Mylan Pharmaceuticals Inc; 2022 Sept.33654 - Codeine sulfate tablets package insert. Berkeley Heights, NJ: Hikma Pharmaceuticals USA, Inc.; 2023 Dec.33718 - Intelence (etravirine) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2019 July.33925 - Ventolin HFA (albuterol sulfate) Inhalation Aerosol package insert. Research Triangle Park, NC: GlaxoSmithKline; 2008 Mar.34362 - Panel on Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: recommendations from the National Institutes of Health, the Centers for Disease Control and Prevention, the HIV Medicine Association, and the Infectious Diseases Society of America. Accessed Oct 10, 2023. Available at https://clinicalinfo.hiv.gov/en/guidelines/34364 - Humphries TJ, Merritt GJ. Review article: drug interactions with agents used to treat acid-related diseases. Aliment Pharmacol Ther 1999;13:18-26.34390 - Hamelin BA, Bouayad A, Drolet B, Gravel A, Turgeon J. In vitro characterization of cytochrome P450 2D6 inhibition by classic histamine H1 receptor antagonists. Drug Metab Dispos 1998; 26(6): 536-9.34456 - Lang CC, Jamal SK, Mohamed Z, et al. Evidence of an interaction between nifedipine and nafcillin in humans. Br J Clin Pharmacol 2003;55:588-90.34457 - Masimirembwa CM, Hasler JA. Characterisation of praziquantel metabolism by rat liver microsomes using cytochrome P450 inhibitors. Biochem Pharmacol 1994;48:1779-83.34458 - Godawska-Matysik A, Kiec-Kononowicz K. Biotransformation of praziquantel by human cytochrome p450 3A4 (CYP 3A4). Acta Pol Pharm 2006;63:381-5.34459 - Ridtitid W, Ratsamemonthon K, Mahatthanatrakul W, et al. Pharmacokinetic interaction between ketoconazole and praziquantel in healthy volunteers. J Clin Pharm Ther 2007;32:585-93.34471 - Goldstein PE, Boom A, van Geffel J, et al. P-glycoprotein inhibition by glibenclamide and related compounds. Pflugers Arch 1999;437:652-60.34472 - Kirchheiner J, Roots I, Goldammer M, et al. Effect of genetic polymorphisms in cytochrome p450 (CYP) 2C9 and CYP2C8 on the pharmacokinetics of oral antidiabetic drugs: clinical relevance. Clin Pharmacokinet 2005;44:1209-25.34483 - Rapaflo (silodosin) package insert. Madison, NJ: Allergan USA, Inc.; 2020 Dec.34489 - Wire MB, Shelton MJ, Studenberg S. Fosamprenavir clinical pharmacokinetics and drug interactions of the amprenavir prodrug. Clin Pharmacokinet 2006;45:137-68.34490 - Polli JW, Jarrett JL, Studenberg SD, et al. Role of P-glycoprotein on the CNS disposition of amprenavir (141W94), an HIV protease inhibitor. Pharm Res 1999;16:1206-12.34491 - Fung HB, Kirschenbaum HL, Hameed R. Amprenavir: a new human immunodeficiency virus type 1 protease inhibitor. Clin Ther 2000;22:549-72.34515 - Desta Z, Wu GM, Morocho AM, et al. The gastoprokinetic and antiemetic drug metoclopramide is a substrate and inhibitor of cytochrome P450 2D6. Drug Metab Dispos 2002;30:336-343.34522 - Akutsu T, Kobayashi K, Sakurada K, et al. Identification of human cytochrome p450 isozymes involved in diphenhydramine N-demethylation. Drug Metab Dispos 2007;35:72-8.34523 - Hamelin BA, Bouayad A, Methot J, et al. Significant interaction between the nonprescription antihistamine diphenhydramine and the CYP2D6 substrate metoprolol in healthy men with high or low CYP2D6 activity. Clin Pharmacol Ther 2000;67:466-477.34539 - Toviaz (fesoterodine fumarate) ER tablets package insert. New York, NY: Pfizer, Inc.; 2024 Feb.34549 - Reinach B, de Sousa G, Dostert P, et al. Comparative effects of rifabutin and rifampicin on cytochromes P450 and UDP-glucuronosyl-transferases expression in fresh and cryopreserved human hepatocytes. Chem Biol Interact 1999;121:37-48.34550 - Kuper JI, DAprile M. Drug-Drug interactions of clinical significance in the treatment of patients with Mycobacterium avium complex disease. Clin Pharmacokinet 2000;39:203-14.34557 - Lee CG, Gottesman MM, Cardarelli CO. HIV-1 protease inhibitors are substrates for the MDR1 multidrug transporter. Biochemistry 1998;37:3594-601.34626 - Vimpat (lacosamide) package insert. Smyrna, GA: UCB, Inc.; 2023 Oct.34653 - Schinkel AH, Wagenaar E, Mol C, et al. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest 1996;97:2517-2524.34654 - Schinkel AH, Smit J, van Tellingen O, et al. Disruption of mouse mdr1a p-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 1994;491-502.34655 - Vinblastine package insert. Bedford, NH: Bedford Laboratories; 2001 Dec.34656 - Huang R, Murry D, Foster D, et al. Role of xenobiotic efflux transporters in resistance to vincristine. Biomed Pharmacother 2008;62:59-64.34743 - Hesse LM, von Moltke LL, Shader RI, et al. Ritonavir, efavirenz, and nelfinavir inhibit CYP2B6 activity in vitro: potential drug interactions with bupropion. Drug Metab Dispos 2001;29:100-2.34744 - Hogeland GW, Swindells S, McNabb JC, et al. Lopinavir/ritonavir reduces bupropion plasma concentrations in healthy subjects. Clin Pharmacol Ther 2007;81:69-75.34745 - Kharasch ED, Mitchell D, Coles R, et al. Rapid clinical induction of hepatic cytochrome P4502B6 activity by ritonavir. Antimicrob Agents Chemother 2008;52:1663-9.34746 - Foisy MM, Yakiwchuk EM, Hughes CA. Induction effects of ritonavir: implications for drug interactions. Ann Pharmacother 2008l;42:1048-59.34760 - Liangpunsakul S, Kolwankar D, Pinto A, et al. Activity of CYP2E1 and CYP3A enzymes in adults with moderate alcohol consumption: a comparison with nonalcoholics. Hepatology 2005;41:1144-50.34761 - Lieber CS. Microsomal ethanol-oxidizing system (MEOS): the first 30 years (1968-1998) - a review. Alcohol Clin Exp Res 1999;23:991-1007.34762 - Oneta CM, Lieber CS, Li J, et al. Dynamics of cytochrome P4502E1 activity in man: induction by ethanol and disappearance during withdrawal phase. J Hepatol 2002;36:47 -52.34878 - Soriano V, Puoti M, Sulkowski M, et al. Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV-HIV International Panel. AIDS 2007;21:1073-89.34883 - Promethazine and codeine oral solution package insert. Baudette, MN: ANI Pharmaceuticals, Inc.; 2018 Jun.34979 - Entocort EC (budesonide) capsules package insert. Wilmington, DE: AstraZeneca LP; 2020 July35401 - Coartem (artemether; lumefantrine) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2019 Aug.35591 - Cycloset (bromocriptine mesylate) package insert. Tiverton, RI: VeroScience LLC; 2020 Aug.35780 - Samsca (tolvaptan) package insert. Rockville, MD: Otsuka America Pharmaceutical, Inc.; 2021 Apr.36049 - Prandin (repaglinide) tablets package insert. Plainsboro, NJ: Novo Nordisk Inc.; 2019 Jan.36101 - Multaq (dronedarone) package insert. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2023 Oct.36111 - Onglyza (saxagliptin) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2019 Jun.36114 - Colcrys (colchicine) package insert. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 2020 May.36146 - Fanapt (iloperidone) package insert. Washington, DC: Vanda Pharmaceuticals, Inc.; 2024 Apr.36646 - Valturna (aliskiren; valsartan) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012 Jan.37098 - Votrient (pazopanib) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2011 Oct.37292 - Istodax (romidepsin) injection package insert. Summit, NJ: Celgene Corporation; 2021 July.37294 - Hijazi Y, Boulieu R. Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes. Drug Metab Dispos 2002;30(7):853-858.37590 - Elewski B, Tavakkol A. Safety and tolerability of oral antifungal agents in the treatment of fungal nail disease: a proven reality. Ther Clin Risk Manag. 2005;1(4):299-306.38831 - Oleptro (trazodone hydrochloride) extended-release tablets package insert. Dublin, Ireland: Labopharm Europe Limited; 2014 Jul.39682 - Food and Drug Administration MedWatch. Ongoing safety review of high-dose Zocor (simvastatin) and increased risk of muscle injury. Retrieved March 19, 2010. Available on the World Wide Web at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm205404.htm.39870 - Niemi M. Role of OATP transporters in the disposition of drugs. Pharmacogenomics 2007;8:787-802.39926 - OxyContin (oxycodone hydrochloride) extended-release tablets package insert. Stamford, CT: Purdue Pharma L.P.; 2023 Dec.40025 - Verelan PM (verapamil hydrochloride extended-release capsules) package insert. Gainesville GA: Recro Technology LLC;2019 Oct.40027 - Emend (fosaprepitant dimeglumine injection) package insert. Whitehouse Station, NJ: Merck & Co.,Inc.; 2022 May.40029 - Dexilant (dexlansoprazole) package insert. Lexington, MA: Takeda Pharmaceuticals America, Inc.; 2023 July.40255 - Rybix ODT (tramadol) package insert. San Diego, CA: Victory Pharma, Inc.; 2009 Dec.40259 - Adcirca (tadalafil) package insert. Indianapolis, IN: Eli Lilly and Company; 2020 Sept.40337 - Aciphex (rabeprazole) delayed-release tablets package insert. Woodcliff Lake, NJ: Eisai Inc.; 2023 July.40360 - Flovent Diskus (fluticasone) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2017 July.40392 - Promacta (eltrombopag) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2023 Mar.40475 - Flovent Diskus (fluticasone) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2019 Jan.40596 - Prevacid Solutab (lansoprazole) delayed-release capsules and disintegrating tablets package insert. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 2023 Aug40942 - Remeron and Remeron SolTabs (mirtazapine tablets and ODT tablets) package insert. Whitehouse Station, NJ: Merck Sharp & Dohme Corp.; 2021 Nov.40943 - Onsolis (fentanyl buccal soluble film) package insert. Raleigh, NC: BioDelivery Sciences, International, Inc.; 2021 Mar.40951 - MS Contin (morphine sulfate extended-release tablets) package insert. Stamford, CT: Purdue Pharma L.P.; 2023 Dec.40981 - Jevtana (cabazitaxel) package insert. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2023 July.41124 - Staxyn (vardenafil orally disintegrating tablets) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2023 Apr.41231 - Foradil inhalation powder (formoterol fumarate) package insert. Kenilworth, NJ: Schering Corporation; 2012 Nov.41235 - Butrans (buprenorphine transdermal system) package insert. Stamford, CT: Purdue Pharma L.P.; 2023 Dec.41237 - Tegretol (carbamazepine) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2023 Sep.41243 - Provigil (modafinil) package insert. Frazer, PA: Cephalon; 2015 Jan.41276 - Blume H, Donath F, Warnke A, et al. Pharmacokinetic drug interaction profiles of proton pump inhibitors. Drug Saf 2006;29:769-84.41538 - Xanax XR (alprazolam extended-release tablet) package insert. New York, NY: Pharmacia & Upjohn Company; 2023 Jan.41543 - Halcion (triazolam) package insert. New York, NY: Pharmacia and Upjohn Company; 2023 Jan.41554 - Klonopin (clonazepam) tablets package insert. Montgomery, AL: H2-Pharma, LLC; 2023 Jan.41569 - Ella (ulipristal 30 mg tablets) package insert. Paris, France: Laboratoire HRA Pharma; 2021 Jun.41597 - Implanon (etonogestrel) package insert. Whitehouse Station, NJ: Merck & Co., Inc.; 2017 March.41666 - Suboxone (buprenorphine; naloxone) sublingual film package insert. North Chesterfield, VA: Indivior Inc; 2023 Dec.41911 - Brevital (methohexital) package insert. Chestnut Ridge, NY: Par Pharmaceutical; 2020 Oct.41934 - Lysodren (mitotane) package insert. Sermoneta, Italy: Corden Pharma Latina S.p.A.; 2024 Jan.42121 - Pradaxa (dabigatran) oral capsules package insert. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2023 Nov.42227 - Latuda (lurasidone) package insert. Marlborough, MA: Sunovion Pharmaceuticals, Inc.; 2019 Dec.42280 - Nuedexta (dextromethorphan hydrobromide; quinidine sulfate capsule) package insert. Aliso Viejo, CA: Avanir Pharmaceuticals, Inc.; 2019 Jun.42290 - Zemplar (paricalcitol) capsule package insert. North Chicago, IL: AbbVie Inc.; 2021 Apr.42405 - Egrifta (tesamorelin) package insert. Montreal, Quebec: Theratechnologies, Inc.; 2019 Jul.42456 - Viramune (nevirapine) tablets and oral suspension package insert. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2022 Jun.42845 - Abilify (aripiprazole) tablets, discmelt orally-disintegrating tablets, oral solution, and intramuscular injection package insert. Rockville, MD: Otsuka America Pharmaceutical, Inc.; 2022 Nov.43069 - Thioridazine package insert. Philadelphia, PA:Mutual Pharmaceutical Company, Inc;2010 Sept.43177 - Viibryd (vilazodone) tablets package insert. Madison, NJ; Allergan USA, Inc.: 2024 Apr.43295 - Detrol LA (tolterodine extended-release capsules) package insert. New York, NY: Pharmacia and Upjohn Co., division of Pfizer; 2018 July.43463 - Pimozide tablets package insert. Chestnut Ridge, NY: Par Pharmaceuticals; 2017 March.43551 - Daliresp (roflumilast) package insert. Wilmington, DE: AstraZeneca Pharmaceuticals, LP; 2018 Jan.43566 - Intuniv (guanfacine extended-release tablets) package insert. Lexington, MA: Shire US Inc.; 2020 Aug.43856 - Antivert (meclizine) package insert. East Brunswick, NJ: Casper Pharma LLC; 2019 Jun.43880 - Lamisil (terbinafine oral granules) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2019 Mar.43881 - Terbinafine tablets package insert. Princeton, NJ: Bionpharma Inc.; 2021 Nov.43972 - Flovent HFA (fluticasone) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2021 Aug.44026 - Advair HFA (fluticasone propionate; salmeterol inhalation aerosol) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2021 Aug.44058 - Prozac Weekly (fluoxetine hydrochloride delayed-release capsules) package insert. Indianapolis, IN: Lilly USA, LLC; 2017 Mar.44095 - Aplenzin (bupropion hydrobromide) extended-release tablet package insert. Bridgewater, NJ: Bausch Health US, LLC.; 2024 Mar.44717 - Midazolam oral syrup package insert. Miami, FL: Atlantic Biologicals Corporation; 2021 Feb.44854 - Xarelto (rivaroxaban) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2023 Feb.44859 - Midazolam injection package insert. Lake Forest, IL: Hospira, Inc.; 2020 Jan.44951 - Brilinta (ticagrelor) package insert. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2024 Mar.44979 - Arcapta Neohaler (indacaterol inhalation powder) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2021 July.44982 - Cleocin (clindamycin capsules) package insert. New York, NY: Pharmacia and Upjohn Co; 2022 May.45335 - Zelboraf (vemurafenib) tablet package insert. South San Francisco, CA: Genentech USA, Inc.; 2020 May.45378 - Adcetris (brentuximab vedotin) injection package insert. Bothell, WA: Seagen Inc; 2023 June.45458 - Xalkori (crizotinib) capsules and pellets package insert. New York, NY: Pfizer Labs; 2023 Sept.45527 - Lescol/Lescol XL (fluvastatin capsules/ fluvastatin sodium extended-release tablets) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2017 Aug.45644 - Starlix (nateglinide) tablets package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation.; 2021 Oct.45935 - Gefitinib (Iressa) package insert. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2021 May.46322 - Hycamtin (topotecan hydrochloride) for Injection package insert. Research Triangle Park, NC: GlaxoSmithKline; 2018 Sept.46370 - Onfi (clobazam) package insert. Deerfield, IL: Lundbeck Inc.; 2024 Mar.46375 - Nexplanon (etonogestrel) package insert. Jersey City, NJ: Organon & Co.; 2023 Sept.46638 - Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. Available at https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-arv/whats-new-guidelines. Accessed Mar 11, 2024.46782 - Jakafi (ruxolitinib) tablets package insert. Wilmington, DE: Incyte Corporation; 2022 Dec.47165 - Norvir (ritonavir tablets, solution, and powder) package insert. North Chicago, IL: AbbVie Inc; 2022 Dec.47357 - Quinidine gluconate extended-release tablet package insert. Princeton, NJ: Eywa Pharma Inc.; 2021 Dec.48494 - Inlyta (axitinib) package insert. New York, NY: Pfizer Inc; 2022 Sept.48524 - Kalydeco (ivacaftor) package insert. Boston, MA: Vertex Pharmaceuticals Incorporated; 2023 August.48545 - Antabuse (disulfiram) tablet package insert. Pomona, NY: Duramed Pharmaceuticals, Inc.; 2010 Feb.48620 - Pletal (cilostazol) package insert. Rockville, MD: Otsuka America Pharmaceutical, Inc.; 2017 May.48697 - Korlym (mifepristone) tablet package insert. Menlo Park, CA: Corcept Therapeutics; 2019 Nov.48893 - Methergine (methylergonovine maleate) tablets package insert. East Hanover, NJ: Lupin Pharmaceuticals Inc.; 2016 Jan.49123 - Vincasar PFS (vincristine) package insert. Irvine, CA: Teva Parenteral Medicines, Inc.; 2014 Aug.49229 - Amytal (amobarbital sodium) package insert. Bridgewater, NJ: Bausch Health US, LLC; 2020 Jul.49236 - Butisol (butabarbital sodium) tablet and solution package insert. Somerset, NJ; Meda Pharmaceuticals, Inc.; 2018 Dec.49352 - Seconal (secobarbital sodium) capsules package insert. Jacksonville, Fl: Ranbaxy Pharmaceuticals, Inc.; 2008 Sept.49493 - Hectorol (doxercalciferol) injection package insert. Cambridge, MA: Genzyme Corporation; 2016 Jun.49806 - Taxol (paclitaxel) prescribing information. Bristol Myers Squibb: Princeton, NJ; 2011 Apr.49823 - Afinitor (everolimus) tablets package insert. East Hanover, NJ:Novartis Pharmaceuticals Corporation; 2022 Feb.49866 - Stendra (avanafil) package insert. Freehold, NJ: Metuchen Pharmaceuticals, LLC.; 2022 Oct.49903 - Zortress (everolimus) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2024 Feb.50113 - Lee EC, Walmsley S, Fantus IG. New-onset diabetes mellitus associated with protease inhibitor therapy in an HIV-positive patient: case report and review. CMAJ. 1999;161(2):161-164.50341 - Cardene SR (nicardipine) package insert. Bedminster, NJ: EKR Therapeutics, Inc.; 2016 Aug.50507 - Luvox CR (fluvoxamine maleate extended-release capsules) package insert. Palo Alto, CA: Jazz Pharmaceuticals, Inc.; 2017 Jan.50586 - Torisel (temsirolimus) injection package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc; 2018 March.50623 - Ulipristal (Esmya 5 mg tablets) European package insert. London UK; Gedeon Richter (UK) Ltd: 2017 Aug.50768 - Lexiva (fosamprenavir calcium) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2008 Mar.50769 - Invirase (saquinavir) package insert. South San Francisco, CA: Genentech Inc.; 2016 Sept.50814 - Carr A, Miller J, Samaras K, Burton S. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS. 1998;12(7):F51-F58.50857 - Uroxatral (alfuzosin extended-release tablets) package insert. St. Michael, Barbados: Concordia Pharmaceuticals, INC.; 2015 May.51027 - Ifex (ifosfamide) package insert. Deerfield, IL: Baxter Healthcare Corp; 2018 Jul51080 - Kaletra (lopinavir; ritonavir) capsule package insert. North Chicago, IL: AbbVie Inc; 2020 Oct.51111 - Myrbetriq (mirabegron extended-release tablets and oral suspension) package insert. Northbrook, Illinois: Astellas Pharma US, Inc.; 2021 March.51227 - Apidra (insulin glulisine [rDNA origin]) injection package insert. Bridgewater, NJ: Sanofi-Aventis US LLC; 2022 Nov.51432 - Marqibo (vincristine sulfate liposome) injection package insert. East Windsor, NJ: Acrotech Biopharma LLC; 2022 Mar.51664 - Stribild (elvitegravir; cobicistat; emtricitabine; tenofovir disoproxil fumarate) package insert. Foster City, CA: Gilead Sciences, Inc; 2021 Sept.51727 - Xtandi (enzalutamide) capsule and tablet package insert. Northbrook, IL:Astellas Pharma US, Inc.; 2023 Nov.51739 - Bosulif (bosutinib) tablet and capsule package insert. Pfizer Labs:New York, NY; 2023 Sept.51834 - Food and Drug Administration (FDA): Drug development and drug interactions. Retrieved Sep 19, 2012. Available on the World Wide Web http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm#transporter.51883 - Stivarga (regorafenib) tablet package insert. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2020 July.52140 - Perampanel (Fycompa) tablets and oral suspension package insert. Woodcliff Lake, NJ: Eisai Inc.; 2019 May.52315 - Xeljanz and Xeljanz XR (tofacitinib) package insert. New York, NY: Pfizer, Inc.; 2024 May.52506 - Cometriq (Cabozantinib) capsules package insert. South San Francisco, CA:Exelixis, Inc.; 2023 Aug52603 - Iclusig (ponatinib) tablet package insert. Cambridge, MA: Takeda Pharmaceuticals Company Limited; 2024 Mar.52698 - Juxtapid (lomitapide) package insert. Cambridge, MA: Aegerion Pharmaceuticals, Inc.; 2019 Dec.52739 - Eliquis (apixaban) package insert. Bristol-Myers Squibb Company; Princeton, NJ. 2021 Apr.52746 - Sirturo (bedaquiline) tablets package insert. Horsham, PA: Janssen Products, LP; 2023 Oct.52887 - Nexterone (amiodarone) injection package insert. Deerfield, IL: Baxter Healthcare Corporation; 2021 Sept.53022 - Ravicti (Glycerol phenylbutyrate) package insert. Lake Forest, IL: Horizon Pharma USA, Inc.; 2021 Sept.53295 - Ado-trastuzumab emtansine (Kadcyla) Package Insert. San Francisco, CA: Genentech, Inc; 2022 Feb.53344 - Osphena (ospemifene) tablets package insert. Florham Park, N.J: Shionogi, Inc.; 2019 Jan.53394 - Abilify Maintena (aripiprazole) extended-release intramuscular injection package insert. Rockville, MD:Otsuka America Pharmaceutical, Inc.; 2020 June.53544 - Erythromycin delayed-release capsule package insert; Greenville, NC: Mayne Pharma; 2018 Apr53972 - Invokana (canagliflozin) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2023 June.54021 - Vesicare (solifenacin) package insert. Norman, OK: Astellas Pharma Technologies, Inc.; 2020 May.54578 - Clolar (clofarabine) injection package insert. Cambridge, MA: Genzyme Corporation; 2022 July.54634 - Owen JR, Nemeroff CB. New antidepressants and the cytochrome P450 system: focus on venlafaxine, nefazodone, and mirtazapine. Depress Anxiety 1998;7:24-32.54802 - Tafinlar (dabrafenib) capsules package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2024 Mar.55331 - Gilotrif (afatinib) tablets package insert. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2022 April.55401 - Astagraf XL (tacrolimus extended-release capsules) package insert. Northbrook, IL: Astellas Pharma US, Inc.; 2023 Aug.55469 - Fetzima (levomilnacipran) extended-release capsules package insert. North Chicago, IL: AbbVie, Inc.; 2024 Apr.55945 - Treanda (bendamustine) injection package insert. North Wales, PA: Teva Pharmaceuticals USA, Inc.; 2022 Oct.56074 - Duavee (conjugated estrogens and bazedoxifene) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2024 March.56096 - Adempas (riociguat) package insert. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2021 Sep.56202 - Kenalog-10 (triamcinolone acetonide) injection package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2018 Jun.56260 - Opsumit (macitentan) package insert. Titusville, NJ: Actelion Pharmaceuticals US, Inc.; 2024 Mar.56303 - Hydrocodone bitartrate extended-release capsules package insert. Morristown, NJ: Alvogen, Inc.; 2023 Dec.56361 - Doxorubicin hydrochloride injection package insert. New York, NY: Pfizer Labs; 2019 Dec.56410 - Imbruvica (ibrutinib) capsules, tablets, and oral suspension package insert. Sunnyvale, CA: Pharmacyclics, Inc.; 2024 May.56436 - Aptiom (eslicarbazepine acetate) package insert. Marlborough, MA: Sunovion Pharmaceuticals Inc.; 2019 Mar.56538 - Vickers AE, Sinclair JR, Zollinger M. Multiple cytochrome P-450s involved in the metabolism of terbinafine suggest a limited potential for drug-drug interactions. Drug Metab Dispos. 1999;27(9):1029-1038.56565 - Wessler JD, Grip LT, Mendell J, et al. The P-glycoprotein transport system and cardiovascular drugs. J Am Coll Cardiol 2013;61:2495-502.56579 - Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Updated Mar 10, 2020. Retrieved from the World Wide Web at www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm56665 - Hetlioz (tasimelteon) package insert. Washington, D.C.: Vanda Pharmaceuticals, Inc.; 2020 Dec.56871 - Navelbine (vinorelbine) injection package insert. Parsippany, NJ: Pierre Fabre Pharmaceuticals Inc; 2020 Jan.57012 - Welage LS, Berardi RR. Drug interactions with anti-ulcer agents: considerations in the treatment of acid-peptic disease. J Pharm Pract. 1994;7:177-195.57036 - Brodie MJ, Mintzer S, Pack AM, et al. Enzyme induction with antiepileptic drugs: cause for concern? Epilepsia 2013;54:11-27.57037 - Lionetto L, Casolla B, Mastropietri F, et al. Pharmacokinetic evaluation of zolmitriptan for the treatment of migraines. Expert Opin Drug Metab Toxicol 2012;8:1043-50.57048 - Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Retrieved from the World Wide Web December 27, 2013. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm#major57067 - Lindsey WT, Stewart D, Childress D. Drug interactions between common illicit drugs and prescription therapies. Am J Drug Alcohol Abuse 2012;38:334-43.57080 - de Leon J, Santoro V, D'Arrigo C, et al. Interactions between antiepileptics and second generation antipsychotics. Expert Opin Drug Metab Toxicol 2012;8:311-34.57094 - Zykadia (ceritinib) package insert. Indianapolis, IN: Novartis; 2021 Oct.57151 - Zontivity (vorapaxar) package insert. Parsippany, NJ: Aralez Pharmaceuticals US Inc.; 2019 Nov.57202 - Zhou S, Chan E, Pan S, et al. Pharmacokinetic interactions of drugs with St John's wort. J Psychopharmacol 2004;18:262-76.57271 - Phenobarbital tablets package insert. Eatontown, NJ: West-ward Pharmaceuticals Corp.; 2012 Mar.57648 - Depo-Provera (medroxyprogesterone acetate 400 mg/ml) injection suspension package insert. New York, NY: Pharmacia & Upjohn Company; 2017 Apr.57675 - Zydelig (idelalisib) tablet package insert. Foster City, CA:Gilead Sciences, Inc.; 2022 Feb.57710 - Striverdi Respimat (olodaterol) package insert. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2019 May.57741 - Orbactiv (oritavancin) package insert. Lincolnshire, IL: Melinta Therapeutics, LLC; 2022 Jan.57780 - Belsomra (suvorexant) tablets package insert. Whitehouse Station, NJ: Merck Sharp & Dohme Corp.; 2021 Mar.57789 - Ambien (zolpidem immediate-release tablets) package insert. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2022 Feb.57803 - Cerdelga (eliglustat) capsules. Waterford, Ireland: Genzyme Ireland, Ltd.;2018 Sept.57805 - Arnuity Ellipta (fluticasone) package insert. Research Triangle Park, NC: GlaxoSmithkline; Oct 2023.57852 - Dostalek M, Pistovcakova J, Jurica J, et al. The effect of St John's wort (hypericum perforatum) on cytochrome p450 1a2 activity in perfused rat liver. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2011;155:253-7.57935 - Guidelines for prevention of opportunistic infections among hematopoietic stem cell transplant recipients: recommendations of CDC, the infectious disease society of america, and the american society of blood and marrow transplantation. Biol Blood Marrow Transpl. 2000;6:659-713.57937 - Movantik (naloxegol) package insert. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2020 April.57949 - Wils P, Phung-Ba V, Warnery A, et al. Polarized transport of docetaxel and vinblastine mediated by P-glycoprotein in human intestinal epithelial cell monolayers. Biochemical Pharmacology. 1994;48(7):1528-1530.58000 - Tybost (cobicistat) package insert. Foster City, CA: Gilead Sciences, Inc; 2021 Sept.58001 - Vitekta (elvitegravir) package insert. Foster City, CA: Gilead Sciences, Inc; 2015 Jul.58111 - Mitigare (colchicine capsules) package insert. Columbus, OH: Hikma Specialty USA Inc.; 2024 May.58167 - Harvoni (ledipasvir; sofosbuvir) tablet and oral pellets package insert. Foster City, CA: Gilead Sciences, Inc; 2020 Mar.58171 - Akynzeo (fosnetupitant; palonosetron injection and netupitant; palonosetron capsules) package insert. Lugano, Switzerland: Helsinn Healthcare; 2023 February.58189 - Esbriet (pirfenidone) capsules and film-coated tablets package insert. South San Fransisco, CA: Genentech USA, Inc.; 2023 Feb.58203 - Ofev (nintedanib) capsule package insert. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2022 Jan.58531 - Hysingla ER (hydrocodone) extended release tablets package insert. Stamford, CT: Purdue Pharma L.P.; 2023 Dec.58620 - Asmanex HFA (mometasone furoate inhalation aerosol) package insert. Whitehouse Station, NJ: Merck & Co., Inc.: 2019 Aug.58662 - Lynparza (olaparib) tablets package insert. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2023 Nov.58664 - Viekira Pak (ombitasvir; paritaprevir; ritonavir; dasabuvir) tablet package insert. North Chicago, IL: AbbVie, Inc; 2019 Dec.58679 - Atrio J, Stanczyk FZ, Neely M, et al. Effect of protease inhibitors on steady-state pharmacokinetics of oral norethindrone contraception in HIV-infected women. J Acquir Immune Defic Syndr. 2014;65:72-77.58685 - Savaysa (edoxaban) package insert. Basking Ridge, NJ: Daiichi Sankyo, Inc.; 2023 Oct.58761 - Evotaz (atazanavir and cobicistat) tablet package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2023 May.58763 - Prezcobix (darunavir and cobicistat) tablets package insert. Horsham, PA: Janssen Products, LP; 2023 Mar.58766 - Tasigna (nilotinib) capsules package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2024 Feb.58768 - Ibrance (palbociclib) capsules package insert. New York, NY: Pfizer Inc; 2023 Sept.58821 - Farydak (panobinostat) capsules package insert. Las Vegas, NV: Secura Bio, Inc.; 2021 Sept.58864 - Catley L, Weisberg E, Kiziltepe T, et al. Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood 2006;108(10):3441-3449.59042 - Cresemba (isavuconazonium) package insert. Northbrook, IL: Astellas Pharma US, Inc; 2023 Dec.59321 - CredibleMeds. QT drug lists. Available on the World Wide Web at http://www.crediblemeds.org.59430 - Corlanor (ivabradine) package insert. Thousand Oaks, CA: Amgen Inc.; 2021 Aug.59487 - Pomalyst (pomalidomide) capsules package insert. Summit, NJ: Celgene Corporation; 2021 Oct.59581 - Vinorelbine package insert. Lake Forest, IL: Hospira, Inc; 2015 Jan.59741 - Viberzi (eluxadoline) package insert. Parsippany, NJ: Actavis Pharma, Inc.; 2020 June.59747 - Targretin (bexarotene) capsules package insert. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; 2013 May.59891 - Orkambi (lumacaftor; ivacaftor) tablet package insert. Boston, MA: Vertex Pharmaceuticals, Inc. 2023 August59949 - Rexulti (brexpiprazole) tablets package insert. Rockville, MD: Otsuka America Pharmaceutical Inc; 2024 May.60000 - Odomzo (sonidegib) capsules package insert. Cranbury, NJ: Sun Pharmaceutical Industries, Inc.; 2023 Aug.60002 - Technivie (ombitasvir; paritaprevir; ritonavir) tablet package insert. North Chicago, IL: AbbVie, Inc; 2019 Dec.60087 - Sprycel (dasatinib) tablet package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2023 Feb.60099 - Addyi (flibanserin tablets) package insert. Raleigh, NC: Sprout Pharmaceuticals, Inc.; 2021 Sept.60164 - Vraylar (cariprazine capsules) package insert. Madison, NJ:Allergan USA, Inc.; 2022 Dec.60172 - Tresiba (insulin degludec) injection package insert. Plainsboro, NJ: Novo Nordisk Inc.; 2022 July.60196 - Aristada (aripiprazole lauroxil) extended-release intramuscular suspension package insert. Waltham, MA: Alkermes, Inc.; 2020 Feb.60248 - Yondelis (trabectedin) injection package insert. Horsham, PA: Janssen Products, LP; 2018 July.60263 - Utibron Neohaler (indacaterol; glycopyrrolate) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2021 July.60281 - Cotellic (cobimetinib) tablets package insert. San Francisco, CA: Genentech USA, Inc; 2023 May.60454 - Bendeka (bendamustine hydrochloride) injection package insert. North Wales, PA: Teva Pharmaceuticals USA, Inc.; 2024 Jan.60484 - Taxotere (docetaxel) injection package insert. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2023 Feb.60523 - Zepatier (elbasvir; grazoprevir) tablet package insert. Whitehouse Station, NJ: Merck, Inc; 2021 Dec.60706 - Venclexa (venetoclax) tabs package insert. South San Francisco, CA: Genentech, Inc.; 2020 Nov.60738 - Cabometyx (Cabozantinib) tablets package insert. Alameda, CA: Exelixis, Inc.; 2023 Sept.60745 - Xtampza ER (oxycodone hydrochloride) extended-release capsule package insert. Cincinnati OH: Patheon Pharmaceuticals; 2023 Dec.60748 - Nuplazid (pimavanserin) package insert. San Diego, CA: Acadia; 2023 Sept.60845 - Gutmann H, Fricker G, Drewe J, et al. Interactions of HIV protease inhibitors with ATP-dependent drug export proteins. Mol Pharmacol. 1999;56:383-389.60860 - Byvalson (nebivolol and valsartan) tablets package insert. Irvine, CA: Allergan USA, Inc.; 2023 Jun.60895 - Calcifediol (Rayaldee) extended-release capsules package insert. Miami, FL: Opko Pharmaceuticals, LLC; 2019 Dec.60951 - Syndros (dronabinol) oral solution package insert. Chandler, AZ; Insys Therapeutics, Inc. 2024 May.61510 - Kiser JJ, Gerber JG, Predhomme JA, et al. Drug/Drug interaction between lopinavir/ritonavir and rosuvastatin in healthy volunteers. J Acquir Immune Defic Syndr. 2008;47:570-57861511 - Karlgren M, Ahlin G, Bergstrom CA, et al. In Vitro and In Silico strategies to identify OATP1B1 inhibitors and predict clinical drug-drug interactions. Pharm Res. 2012;29:411-42661512 - Busti AJ, Bain AM, Hall RG, et al. Effects of atazanavir/ritonavir or fosamprenavir/ritonavir on the pharmacokinetics of rosuvastin. J Cardiovasc Pharmacol. 2008;51:605-61061513 - Annaert P, Ye ZW, Stieger B, et al. Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1. Xenobiotica. 2010;40(3):163-17661718 - Tepadina (thiotepa) injection package insert. Bridgewater, NJ: Amneal Biosciences LLC; 2017 May.61750 - Emflaza (deflazacort) tablets and oral suspension. South Plainfield, NJ: PTC Therapeutics; 2021 Jul.61795 - Xermelo (telotristat ethyl) package insert. The Woodlands, TX: Lexicon Pharmaceuticals, Inc; 2020 Oct.61816 - Kisqali (ribociclib) tablets package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2023 Aug.61831 - Symproic (naldemedine) package insert. Florham Park, NJ: Shionogi, Inc.; 2018 Jan.61873 - Ingrezza and Ingrezza Sprinkle (valbenazine) capsules package insert. San Diego, CA: Neurocrine Biosciences, Inc.; 2024 Apr.61906 - Rydapt (midostaurin) capsule package insert. East Hanover,NJ: Novartis Pharmaceuticals Corporation; 2023 May.61909 - Alunbrig (brigatinib) tablet package insert. Cambridge, MA: Ariad Pharmaceuticals Inc.; 2022 March.61924 - Gorski JC, Huang SM, Pinto AP, et al. The effect of echinacea (Echinacea purpurea root) on cytochrome P450 activity in vivo. Clin Pharmacol Ther. 2004;75:89-100.61926 - Penzak SR, Robertson SM, Hunt JD, et al. Echinacea purpurea significantly induces cytochrome P450 3A activity but does not alter lopinavir-ritonavir exposure in healthy subjects. Pharmacotherapy. 2010;30:797-805.61927 - Molto J, Valle M, Miranda C, et al. Herb-drug interaction between Echinacea purpurea and darunavir-ritonavir in HIV-infected patients. Antimicrob Agents Chemother. 2011;55:326-330. Epub 2010 Nov 15.62037 - Bevyxxa (betrixaban) capsules package insert. South San Francisco, Ca: Portola Pharmaceuticals, Inc.; 2020 Aug.62065 - Isradipine package insert. Parsippany, NJ: Watson Pharma, Inc.; 2014 June.62105 - Altamura AC, Moliterno D, Paletta S, et al. Understanding the pharmacokinetics of anxiolytic drugs. Expert Opin Drug Metab Toxicol 2013;9:423-40.62127 - Nerlynx (neratinib) package insert. Los Angeles, CA: Puma Biotechnology, Inc; 2021 June.62181 - Idhifa (enasidenib) tablet package insert. Summit, NJ: Celgene Corporation; 2023 Dec.62201 - Mavyret (glecaprevir; pibrentasvir) tablets package insert. North Chicago, IL: AbbVie Inc.; 2023 Oct.62277 - Vabomere (meropenem; vaborbactam) package insert. Parsippany, NJ: The Medicines Company; 2018 Jul.62347 - Aliqopa (copanlisib) injection package insert. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2023 Sept.62393 - Verzenio (abemaciclib) tablets package insert. Indianapolis, IN: Lilly USA, LLC; 2023 March.62578 - Calquence (acalabrutinib) capsules package insert. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2022 Mar62611 - Prevymis (letermovir) package insert. Rahway, NJ: Merck Sharp and Dohme, LLC.; 2023 Aug.62870 - Symdeko (tezacaftor; ivacaftor and ivacaftor tablets) package insert. Boston, MA; Vertex Pharmaceuticals Incorporated: 2023 August.62874 - Erleada (apalutamide) tablets package insert. Horsham, PA: Janssen Products, LP; 2023 Dec.62889 - Apadaz (benzhydrocodone; acetaminophen) tablets package insert. Celebration, FL: Zevra Therapeutics, Inc.; 2023 Dec.63066 - Celestone Soluspan (Betamethasone sodium phosphate and betamethasone acetate injection package insert). Whitehouse Station, NJ: Merck & Co., Inc.; 2022 Sept.63084 - Tavalisse (fostamatinib disodium hexahydrate) tablets package insert. South San Francisco, CA: Rigel Pharmaceuticals, Inc.; 2018 Apr.63106 - Jynarque (tolvaptan) tablets package insert. Rockville, MD: Otsuka America Pharmaceutical, Inc.; 2020 Oct.63175 - Doptelet (avatrombopag) tablets package insert. Durham, NC: AkaRx, Inc.; 2021 Oct.63317 - Braftovi (encorafenib) capsules package insert. Boulder, CO: Array BioPharma Inc.; 2023 Oct.63328 - Aristada Initio (aripiprazole lauroxil extended-release injectable suspension) package insert. Altham, MA:Alkermes, Inc.; 2020 Feb.63353 - TPOXX (tecovirimat) package insert. Corvallis, OR: SIGA Technologies, Inc; 2022 May.63368 - Tibsovo (ivosidenib) tablet package insert. Cambridge, MA: Agios Pharmaceuticals; 2023 Oct.63387 - Orilissa (elagolix) tablets package insert. North Chicago, IL: AbbVie Inc.; 2023 Jun.63411 - Perseris (risperidone extended-release subcutaneous injectable suspension) package insert. North Chesterfield, VA: Indivior, Inc.; 2022 Dec.63429 - Annovera (segesterone acetate and ethinyl estradiol vaginal ring) package insert. New York, NY: Population Council; 2022 April.63456 - Diacomit (stiripentol) package insert. Beauvais, France: Biocodex; 2022 Jul.63484 - Pifeltro (doravirine) package insert. Whitehouse Station, NJ: Merck & Co., Inc.; 2022 Jan.63571 - Copiktra (duvelisib) capsules package insert. Las Vegas, NV: Secura Bio, Inc.; 2021 Dec.63651 - Talzenna (talazoparib) capsules package insert. New York, NY: Pfizer Labs; 2024 March.63694 - Bijuva (estradiol; progesterone) capsules package insert. Boca Raton, FL: TherapeuticsMD, Inc.; 2024 Feb.63731 - Dsuvia (sufentanil) sublingual tablets package insert. Hayward, CA: AcelRx Pharmaceuticals, Inc.; 2023 Dec.63732 - Lorbrena (lorlatinib) tablets package insert. New York, NY: Pfizer Labs; 2021 March.63777 - Daurismo (glasdegib) tablets package insert. New York, NY: Pfizer Labs; 2023 Mar.63780 - Vitrakvi (larotrectinib) capsules and oral solution package insert. Stamford, CT: Loxo Oncology, Inc.; 2023 Nov.63787 - Xospata (gilteritinib) tablets package insert. Northbrook, IL: Astellas Pharma US, Inc.; 2022 Jan.63965 - Gloperba (colchicine) oral solution package insert. Ferndale, MI: Ferndale Laboratories, Inc.; 2019 Jan.64031 - Mayzent (siponimod) tablets package insert. East Hanover, NJ: Novartis Pharmaceutical Corporation; 2023 Aug.64064 - Balversa (erdafitinib) tablets package insert. Horsham, PA: Janssen Products, LP; 2024 Jan.64166 - Nayzilam (midazolam) nasal spray package insert. Smyrna, GA: UCG, Inc.; 2023 Jan.64290 - Polivy (polatuzumab vedotin-piiq) injection package insert. South San Francisco, CA: Genentech, Inc.; 2023 Apr.64525 - Nubeqa (darolutamide) tablets package insert. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; 2023 Oct.64535 - Turalio (pexidartinib) capsules package insert. Basking Ridge, NJ: Daiichi Sankyo, Inc.; 2023 Nov.64562 - Wakix (pitolisant) tablets package insert. Plymouth Meeting, PA: Harmony Biosciences, LLC; 2022 Dec.64567 - Rozlytrek (entrectinib) package insert. South San Francisco, CA: Genentech Inc.; 2024 Jan.64568 - Inrebic (fedratinib) capsules package insert. Summit, NJ: Celgene Corporation; 2021 Dec.64572 - Rinvoq (upadacitinib) package insert. North Chicago, IL: Abbvie Inc.; 2024 April.64576 - Xenleta (lefamulin) package insert. Dublin, Ireland: Nabriva Therapeutics US, Inc.; 2021 Mar.64590 - Nourianz (istradefylline) tablets package insert. Bedminster, NJ: Kyowa Kirin, Inc.; 2019 Aug.64697 - Trikafta (elexacaftor; tezacaftor; ivacaftor and ivacaftor tablets) package insert. Boston, MA; Vertex Pharmaceuticals Incorporated: 2023 August.64721 - Ibrance (palbociclib) tablets package insert. New York, NY: Pfizer Inc; 2023 Sept.64723 - Belrapzo (bendamustine) injection package insert. Woodcliff Lake, NJ: Eagle Pharmaceuticals, Inc.; 2024 Jan.64748 - Brukinsa (zanubrutinib) capsules package insert. San Mateo, CA: BeiGene USA, Inc; 2024 Mar.64768 - Xcorpi (cenobamate) tablets package insert. Paramus, NJ: SK Life Science, Inc.; 2024 Apr.64845 - Padcev (enfortumab vedotin-ejfv) injection package insert. Northbrook, Illinois: Astellas Pharma US, Inc; 2023 Dec.64870 - Dayvigo (lemborexant) tablets package insert. Nutley, NJ: Eisai Inc.; 2023 Apr.64874 - Ubrelvy (ubrogepant) tablets package insert. Madison, NJ: Allergan USA, Inc.; 2023 Feb.64885 - Caplyta (lumateperone) capsules package insert. New York, NY; Intra-Cellular Therapies, Inc.; 2023 Jun.64922 - Ayvakit (avapritinib) tablets package insert. Cambridge, MA: Blueprint Medicines Corporation; 2023 May64930 - Valtoco (diazepam) nasal spray package insert. San Diego, CA: Neurelis, Inc.; 2023 Jan.64952 - Tazverik (tazemetostat) tablet package insert. Cambridge, MA: Epizyme, Inc.; 2023 Nov.65052 - Nurtec ODT (rimegepant) orally disintegrating tablet package insert. New Haven, CT: Biohaven Pharmaceuticals, Inc.; 2022 Apr.65098 - Isturisa (osilodrostat) tablet package insert. Lebanon, NJ: Recordati Rare Disease, Inc.; 2020 Mar.65210 - University of Liverpool. COVID-19 Drug Interactions. Retrived April 6, 2020. Available on the World Wide Web at https://www.covid19-druginteractions.org/.65222 - Karol MD, Maze M. Pharmacokinetics and interaction pharmacodynamics of dexmedetomidine in humans. Bailliere’s Clinical Anaesthesiol 2000;14:261-269.65225 - Oda Y, Hamaoka N, Hiroi T, et al. Involvement of human liver cytochrome P4502B6 in the metabolism of propofol. Br J Clin Pharmacol 2001;51:281-285.65243 - Fett DL, Vukov LF. An unusual case of severe griseofulvin-alcohol interaction. Ann Emerg Med 1994;24:95-97.65246 - Koselugo (selumetinib) capsules package insert. Wilmington, DE: AstraZeneca Pharmaceuticals, LP; 2024 Jan.65295 - Tukysa (tucatinib) tablets package insert. Bothell, WA: Seattle Genetics, Inc.; 2023 Jan65307 - Pemazyre (pemigatinib) tablets package insert. Wilmington, DE: Incyte Corporation: 2021 Feb.65314 - COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Accessed March 1, 2024. Available at https://www.covid19treatmentguidelines.nih.gov/65328 - Trodelvy (sacituzumab govitecan-hziy) for injection package insert. Morris Plains, NJ: Immunomedics, Inc.; 2023 Feb.65377 - Tabrecta (capmatinib) tablets package insert. Novartis Pharmaceuticals Corporation;East Hanover, NJ:2023 March.65387 - Retevmo (selpercatinib) capsules package insert. Indianapolis, IN: Eli Lilly and Company; 2022 Sept.65431 - Qinlock (ripretinib) tablets package insert. Waltham, MA: Deciphera Pharmaceuticals, LLC; 2023 Oct.65478 - Elens L, Langman LJ, Hesselink DA, et al. Pharmacologic treatment of transplant recipients infected with SARS-CoV-2: considerations regarding therapeutic monitoring and drug-drug interactions. Ther Drug Monit 2020;42:360-368.65479 - Frassetto L, Baluom M, Jacobsen W, et al. Cyclosporine pharmacokinetics and dosing modifications in human immunodeficiency virus-infected liver and kidney transplant recipients. Transplantation 2005;80:13-17.65480 - Jain AB, Venkataramanan R, Eghtesad B, et al. Effect of coadministered lopinavir and ritonavir (Kaletra) on tacrolimus blood concentration in liver transplantation patients. Liver Transpl 2003;9:954-960.65481 - Frassetto LA, Browne M, Cheng A, et al. Immunosuppressant pharmacokinetics and dosing modifications in HIV-1 infected liver and kidney transplant recipients. Am J Transplant 2007;7:2816-2820.65482 - Vogel M, Voigt E, Michaelis HC, et al. Management of drug-to-drug interactions between cyclosporine A and the protease inhibitor lopinavir/ritonavir in liver-transplanted HIV-infected patients. Liver Transpl 2004;10:939-944.65483 - Marfo K, Greenstein S. Antiretroviral and immunosuppressive drug-drug interactions in human immunodeficiency virus-infected liver and kidney transplant recipients. Transplant Proc 2009;41:3796-3799.65484 - Artesunate for injection package insert. Wilmington, DE: Amivas Inc; 2023 Jul.65485 - Vesicare LS (solifenacin) oral suspension package insert. Northbrook, IL: Astella Pharma US, Inc.; 2022 Oct.65593 - Zepzelca (lurbinectedin) injection package insert. Palo Alto, CA: Jazz Pharmaceuticals, Inc.; 2023 July.65685 - Dooley KE, Bliven-Sizemore EE, Weiner M, et al. Safety and pharmacokinetics of escalating daily doses of the antituberculosis drug rifapentine in healthy volunteers. Clin Pharmacol Ther 2012; 91:565780 - Cyclophosphamide for injection package insert. Orlando, FL: Ingenus Pharmaceuticals, LLC; 2023 Jan.65781 - Cyclophosphamide capsules package insert. Eatontown, NJ: West-Ward Pharmaceuticals Corp; 2019 Sept.65782 - Cyclophosphamide powder for solution package insert. Bridgewater, NJ: Amneal Pharmaceuticals LLC; 2023 Aug.65809 - Olinvyk (oliceridine) injection package insert. Chesterbrook, PA: Trevana, Inc. 2023 Dec.65884 - Gavreto (pralsetinib) capsules package insert. San Francisco, CA: Genentech, Inc.; 2024 March.66129 - Zokinvy (lonafarnib) capsules package insert. Palo Alto, CA: Eiger BioPharmaceuticals, Inc.; 2020 Nov.66183 - Orgovyx (relugolix) tablets package insert. Brisbane, CA: Myovant Sciences, Inc.; 2023 Mar.66315 - Vocabria (cabotegravir) package insert. Durham, NC: ViiV Healthcare; 2023 Dec.66336 - Lupkynis (voclosporin) capsules package insert. Rockville, MD: Aurinia Pharma U.S., Inc.; 2024 Apr.66527 - Ponvory (ponesimod) tablet package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2023 Aug.66700 - Lumakras (sotorasib) tablet package insert. Thousand Oaks, CA: Amgen, Inc.; 2023 Apr.66702 - Truseltiq (Infigratinib) capsules package insert. Brisbane, CA: QED Therapeutics, Inc.; 2021 May.66705 - Brexafemme (ibrexafungerp) package insert. Jersey City, NJ: Scynexis, Inc; 2022 Nov.66710 - Tembexa (brincidofovir) package insert. Whippany, NJ: Cambrex Whippany, Inc; 2021 Aug.66793 - Kerendia (finerenone) tablets package insert. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2022 Sept.66812 - Fexinidazole package insert. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2021 Dec.66816 - Bylvay (odevixibat) capsules package insert. Boston, MA; Albireo Pharma, Inc.: 2023 Jun.66875 - Welireg (belzutifan) tablets package insert. Whitehouse Station, NJ: Merck Sharp and Dohme Corp.; 2023 Dec.66964 - Trudhesa (dihydroergotamine mesylate) nasal spray package insert. Seattle, WA: Impel NeuroPharma, Inc.; 2021 Sep.66990 - Exkivity (mobocertinib) capsules package insert. Lexington, MA: Takeda Pharmaceuticals America, Inc.; 2023 Sept.66996 - Tivdak (tisotumab vedotin-tftv) injection package insert. Seagen Inc.; Bothell, WA: 2024 April.67011 - Qulipta (atogepant) tablet package insert. Dublin, Ireland: Forest Laboratories Ireland Ltd.; 2023 Apr.67036 - Tavneos (avacopan) capsules package insert. Cincinnati, OH; ChemoCentryx, Inc.: 2021 Oct.67087 - Scemblix (asciminib) tablets package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation: 2023 Nov.67136 - Fyarro (sirolimus protein-bound particles) injectable suspension package insert. Pacific Palisades, CA: Aadi Bioscience, Inc.; 2021 Nov.67203 - Food and Drug Administration (FDA). Fact sheet for healthcare providers: emergency use authorization for Paxlovid. Retrieved March 13, 2024. Available on the World Wide Web at https://www.fda.gov/media/155050/download?utm_medium=email&utm_source=govdelivery67231 - Recorlev (levoketoconazole) package insert. Chicago, IL: Xeris Pharmaceuticals, Inc.; 2021 Dec.67248 - Quviviq (daridorexant) tablet package insert. Radnor, PA: Idorsia Pharmaceuticals US Inc; 2023 Oct.67403 - Pyrukynd (mitapivat) tablets package insert.Cambridge, MA: Agios Pharmaceuticals, Inc.; 2022 Feb.67427 - Vonjo (pacritinib) capsules package insert. Seattle, WA: CTI BioPharma Corp; 2023 Aug.67470 - Scott C, White L, Wright S, et al. A Phase I, open-label, randomized, crossover study in three parallel groups to evaluate the effect of Rifampicin, Ketoconazole, and Omeprazole on the pharmacokinetics of THC/CBD oromucosal spray in healthy volunteers. SpringerPlus 2013;2:236.67473 - Arellano AL, Papaseit E, Romaguera A, et al. Neuropsychiatric and general interactions of natural and synthetic cannabinoids with drugs of abuse and medicines. CNS Neurol Disord - Drug Targets 2017;16:554-566.67474 - Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev 2014;46:86-95.67543 - Camzyos (mavacamten) package insert. Princeton, NJ: Bristol-Myers Squibb; 2024 Apr.67829 - Calquence (acalabrutinib) tablets package insert. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2022 Aug.67902 - Marsousi N, Daali Y, Fontana P, Reny JL, Ancrenaz-Sirot V, Calmy A, Rudaz S, Desmeules JA, Samer CF. Impact of Boosted Antiretroviral Therapy on the Pharmacokinetics and Efficacy of Clopidogrel and Prasugrel Active Metabolites. Clin Pharmacokinet. 2018 Oct;57(10):1347-1354.68007 - Relyvrio (sodium phenylbutyrate and taurursodiol) oral suspension package insert. Cambridge, MA: Amylyx Pharmaceuticals, Inc., 2022 Sep.68013 - Lytgobi (futibatinib) tablets package insert. Princeton, NJ: Taiho Oncology, Inc.; 2024 April.68173 - Elahere (mirvetuximab soravtansine) inj package insert. Waltham, MA: Immunogen, Inc.: 2024 March.68242 - Rezlidhia (olutasidenib) capsules package insert. Greenville, NC; Metrics Contract Services; 2022 Dec.68325 - Krazati (adagrasib) tablets package insert. San Diego, CA: Mirati Therapeutics, Inc.; 2022 Dec.68485 - Brenzavvy (Bexagliflozin) tablets package insert. Marlborough, MA: TheracosBio, LLC.; 2023 Sept.68520 - Jaypirca (pirtobrutinib) tablets package insert. Indianapolis, IN: Lilly USA, LLC; 2023 Dec.68530 - Orserdu (elacestrant) tablets package insert. New York, NY; Stemline Therapeutics, Inc: 2023 Jan.68641 - Sparsentan (Filspari) package insert. San Diego, CA: Travere Therapeutics, Inc.; 2023 Feb.68644 - Skyclarys (omaveloxolone) capsules package insert. Cambridge, MA: Reata Pharmaceuticals, Inc.; 2024 Jan.68778 - Joenja (leniolisib) package insert. Saint Quentin Fallavier, France; Skyepharma Production SAS. 2023 Mar.68911 - Abilify Asimtufii (aripiprazole) extended-release injectable suspension package insert. Rockville, MD: Otsuka America Pharmaceutical, Inc.; 2023 Apr.69024 - Paxlovid (nirmatrelvir; ritonavir) package insert. New York, NY: Pfizer Inc; 2023 May.69050 - Inpefa (sotagliflozin) package insert. The Woodlands, TX: Lexicon Pharmaceuticals, Inc.; 2023 May.69114 - Velsipity (etrasimod) package insert. New York, NY: Pfizer, Inc.; 2023 June69117 - Lodoco (colchicine) tablet package insert. Parsippany, NJ: AGEPHA Pharma USA, LLC; 2023 Jun.69152 - Propulsid (cisapride) Limited Access Program Disallowed Medications and Foods List by Generic Name. Janssen Pharmaceuticals, Inc. Available at: www.propulsid-lap.com. Accessed Jul 6, 2023.69153 - Jacobs TG, Marzolini C, Back DJ, Burger DM. Dexamethasone is a dose-dependent perpetrator of drug-drug interactions: implications for use in people living with HIV. J Antimicrob Chemother. 2022 Feb 23;77(3):568-573.69220 - Vanflyta (quizartinib) tablets package insert. Basking Ridge, NJ: Daiichi Sankyo, Inc.; 2023 July.69264 - Zurzuvae (zuranolone) capsules package insert. Cambridge, MA: Biogen Inc; 2023 Aug.69324 - Sohonos (palovarotene) capsules package insert. Cambridge, MA: Ipsen Biopharmaceuticals, Inc.; 2023 Aug.69702 - Agamree (vamorolone) package insert. Burlington, MA: Santhera Pharmaceuticals; 2023 Oct.69884 - Augtyro (repotrectinib) capsules package insert. Princeton, NJ: Bristol-Meyers Squibb Company; 2023 Nov.69896 - Truqap (capivasertib) tablets package insert. Wilmington, DE; AstraZeneca Pharmaceuticals LP: 2023 Nov.69917 - Ogsiveo (nirogacestat) tablets package insert. Stamford, CT: SpringWorks Therapeutics, Inc.; 2023 Nov.70542 - Ojemda (tovorafenib) tablets and oral suspension package insert. Brisbane CA: Day One Biopharmaceuticals, Inc.;2024 Apr.70577 - Xolremdi (mavorixafor) capsules package insert. Boston, MA: X4 Pharmaceuticals, Inc.; 2024 Apr.

        Monitoring Parameters

        • LFTs
        • serum creatinine

        US Drug Names

        • PAXLOVID
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