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TRANSFORMAR COMO VOCÊ USA INFORMAÇÕES SOBRE DROGAS

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Apr.27.2022

Nirmatrelvir; Ritonavir

Indications/Dosage

Labeled

    Off-Label

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

    INVESTIGATIONAL USE: 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: Information on 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. Health care providers are advised to consider the benefit-risk for each individual patient.[67203]

    NOTE: Health care providers should choose an authorized therapeutic option with activity against the circulating variants 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 the Omicron SARS-CoV-2 variant (B.1.1.529).[65314] [67203]

    NOTE: Due to the Omicron variant being the dominant variant in many parts of the United States, the National Institutes of Health (NIH) has issued a statement to provide guidance on treating nonhospitalized patients with mild to moderate COVID-19 who are at high risk of progressing to severe disease. The NIH recommends using 1 of the following therapeutics:

    • Preferred therapies (listed in order of preference)
      • nirmatrelvir; ritonavir
      • remdesivir
    • Alternative therapies
      • bebtelovimab OR
      • molnupiravir

    Before prescribing nirmatrelvir; ritonavir, the NIH recommends health care providers carefully 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: There may be logistical or supply constraints that make it impossible to offer the available therapy to all eligible patients, making patient triage necessary. Health care providers should prioritize their use 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]

    NOTE: Nirmatrelvir; ritonavir is NOT authorized for use in patients requiring hospitalization due to severe COVID-19; however, should a patient require hospitalization after starting treatment, the patient may complete the full 5-day treatment course at the discretion of the health care provider.[67203]

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

    Oral dosage

    Adults 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 by mouth 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 days consecutive days is not authorized.[67203]

    Children and Adolescents 12 years and older 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 by mouth 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 days consecutive days is not authorized.[67203]

    Therapeutic Drug Monitoring

    Maximum Dosage Limits

    • Adults

      40 kg or more: 600 mg nirmatrelvir and 200 mg ritonavir per day PO.

      less than 40 kg: Use not authorized.

    • Geriatric

      40 kg or more: 600 mg nirmatrelvir and 200 mg ritonavir per day PO.

      less than 40 kg: Use not authorized.

    • Adolescents

      40 kg or more: 600 mg nirmatrelvir and 200 mg ritonavir per day PO.

      less than 40 kg: Use not authorized.

    • Children

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

      12 years and weighing less than 40 kg: Use not authorized.

      1 to 11 years: Use not authorized.

    • Infants

      Use not authorized.

    • Neonates

      Use not authorized.

    Patients with Hepatic Impairment Dosing

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

    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 authorized.

    † Off-label indication
    Revision Date: 04/27/2022, 11:18:11 AM

    References

    65314 - COVID-19 Treatment Guidelines Panel. Coronavirus Diseases 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Accessed May 31, 2022. Available at on the World Wide Web at: https://covid19treatmentguidelines.nih.gov/.67203 - Food and Drug Administration (FDA). Fact sheet for healthcare providers: emergency use authorization for Paxlovid (nirmatrelvir; ritonavir). Retrieved April 27, 2022. Available on the World Wide Web at https://www.fda.gov/media/155050/download?utm_medium=email&utm_source=govdelivery

    How Supplied

    Nirmatrelvir Oral tablet, Ritonavir Oral tablet

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

    Nirmatrelvir Oral tablet, Ritonavir Oral tablet

    PAXLOVID 150mg-100mg Tablet (00069-1101) (Pfizer Inc.) null

    Nirmatrelvir Oral tablet, Ritonavir Oral tablet

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

    Description/Classification

    Description

    Nirmatrelvir; ritonavir is an investigational oral antiviral medication with activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nirmatrelvir works as a SARS-CoV-2 main protease (Mpro: also referred to as 3CLpro or nsp5 protease) inhibitor and ritonavir (an HIV-1 protease inhibitor and CYP3A inhibitor) is used as a pharmacokinetic enhancer or booster. The combination product is not an FDA-approved medication; however, it has been authorized for emergency use to treat mild to moderate coronavirus disease (COVID-19) in patients (12 years of age and older weighing at least 40 kg) with positive SARS-CoV-2 viral testing who are at high risk for progressing to severe COVID-19, including hospitalization or death. Nirmatrelvir; ritonavir is NOT authorized for use in patients who are hospitalized due to severe COVID-19; however, should a patient require hospitalization after starting treatment, the patient may complete the full 5-day course at the health care providers discretion. The drug is also NOT authorized for use as a pre-exposure or post-exposure prophylaxis to prevent COVID-19. Nirmatrelvir and ritonavir are co-packaged and supplied in 2 different Dose Packs (Paxlovid 300 mg; 100 mg Dose Pack and Paxlovid 150 mg; 100 mg Dose Pack). Each Dose Pack contains a carton holding 5 daily blister cards; DO NOT exceed the authorized treatment duration of 5 consecutive days.[67203]

     

    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. Nirmatrelvir; ritonavir should be started as soon as possible after positive test results for SARS-CoV-2 and within 5 days of symptom onset.[65314]

     

    NOTE: Nirmatrelvir; ritonavir is expected to be active against the Omicron SARS-CoV-2 variant (B.1.1.529).[65314][67203]

    Classifications

    • General Anti-infectives Systemic
      • Antivirals For Systemic Use
        • SARS-CoV-2 Antivirals
          • SARS-CoV-2 Protease Inhibitor Antivirals
    Revision Date: 05/16/2022, 03:44:09 PM

    References

    65314 - COVID-19 Treatment Guidelines Panel. Coronavirus Diseases 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Accessed May 31, 2022. Available at on the World Wide Web at: https://covid19treatmentguidelines.nih.gov/.67203 - Food and Drug Administration (FDA). Fact sheet for healthcare providers: emergency use authorization for Paxlovid (nirmatrelvir; ritonavir). Retrieved April 27, 2022. Available on the World Wide Web at https://www.fda.gov/media/155050/download?utm_medium=email&utm_source=govdelivery

    Administration Information

    General Administration Information

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

     

    NOTE: Nirmatrelvir; ritonavir is not an FDA-approved medication; however, it has been authorized for emergency use as a treatment for mild to moderate COVID-19 in patients with positive SARS-CoV-2 viral testing who are at high risk for progressing to severe COVID-19, including hospitalization or death. Under the Emergency Use Authorization (EUA), health care 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: Nirmatrelvir; ritonavir may ONLY 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 in the antiinfective therapeutic class. 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, health care providers are required to report all medication errors and serious adverse events potentially related to nirmatrelvir; ritonavir therapy within 7 calendar days from the health care 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 in 2 different Dose Packs.
      • Paxlovid 300 mg; 100 mg Dose Pack: Each carton contains 30 tablets divided in 5 daily-dose blister cards. Each daily-dose blister card contains 4 nirmatrelvir (150 mg oval, pink) tablets and 2 ritonavir (100 mg ovaloid, white) tablets.
      • Paxlovid 150 mg; 100 mg Dose Pack: Each carton contains 20 tablets divided in 5 daily-dose blister cards. Each daily-dose blister card contains 2 nirmatrelvir (150 mg oval, pink) tablets and 2 ritonavir (100 mg ovaloid, white) tablets.
    • PHARMACIST INSTRUCTIONS FOR DISPENSING TO PATIENTS WITH MODERATE RENAL IMPAIRMENT (eGFR 30 to 59 mL/minute) WHEN THE PAXLOVID 150 MG; 100 MG DOSE PACK IS UNAVAILABLE:
      • The authorized dose in patients with moderate renal impairment is 150 mg nirmatrelvir and 100 mg ritonavir twice daily. In the event that the Paxlovid 150 mg; 100 mg Dose Pack is unavailable, the Paxlovid 300 mg; 100 mg Dose Pack may be used; however, each daily-dose blister card contains more nirmatrelvir tablets than are needed for dosing patients with moderate renal impairment.
      • Each shipment will include instructions for pharmacists to remove the unneeded, additional nirmatrelvir tablets, and stickers to affix to each daily blister card.
      • Pharmacists must ensure they refer to the instructions entitled "Important Paxlovid EUA Dispensing Information For Patients With Moderate Renal Impairment". Additionally, pharmacists must counsel patients about renal dosing instructions and notify them that their blister cards have been altered at the pharmacy.
      • To dispense 150 mg nirmatrelvir and 100 mg ritonavir for moderate renal impairment, pharmacists must:
        • Remove 1 of the 150 mg nirmatrelvir tablets from the morning dose and 1 of the 150 mg nirmatrelvir tablets from the evening dose of the blister card. The tablets that are removed should be the ones closest to the middle of the blister pack.
        • Affix the blister card with 1 sticker from the provided tear pad to carefully cover the empty blister cavities. The exact placement of this sticker is important to cover the empty blister cavities from the tablets. Ensure the sticker also covers the pre-printed dosing instruction that is on the blister card.
        • Repeat the above 2 steps for every blister card in the carton (each carton contains 5 blister cards for a full 5-day dosing regimen).
        • Affix 1 sticker from the provided tear pad to carefully cover over the pre-printed dosing regimen on the carton.
    • May administer tablets with or without food.
    • Swallow tablets whole with a sufficient amount of fluid. DO NOT chew, break, or crush the tablets.
    • Instruct patients to complete the full 5-day treatment course and continue isolation in accordance with public health recommendations.[67203]

    Clinical Pharmaceutics Information

    From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database
      Revision Date: 05/05/2022, 02:09:15 PM

      References

      67203 - Food and Drug Administration (FDA). Fact sheet for healthcare providers: emergency use authorization for Paxlovid (nirmatrelvir; ritonavir). Retrieved April 27, 2022. 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. June 3, 2022. Retrieved June 8, 2022. Available on the World Wide Web at https://www.fda.gov/media/158165/download

      Adverse Reactions

      Mild

      • diarrhea
      • dysgeusia
      • myalgia
      • pruritus
      • rash
      • urticaria

      Moderate

      • dyspnea
      • hypertension

      Severe

      • angioedema
      • Stevens-Johnson syndrome
      • toxic epidermal necrolysis

      The safety of nirmatrelvir; ritonavir was evaluated in a placebo-controlled trial of non-hospitalized adults with laboratory confirmed SARS-CoV-2 infection and symptomatic COVID-19. A total of 1,109 patients received at least 1 dose of nirmatrelvir; ritonavir and 1,115 received a placebo. Adverse events were reported during treatment and through Day 34 after treatment initiation. Adverse events that occurred in the treatment group at a higher frequency than the placebo group included dysgeusia (6% vs less than 1%, respectively), diarrhea (3% vs 2%), hypertension (1% vs less than 1%), and myalgia (1% vs less than 1%). Overall, 2% of patients in the nirmatrelvir; ritonavir group and 4% in the placebo group discontinued treatment due to an adverse event.[67203]

      Hypersensitivity reactions (i.e., urticaria, angioedema, dyspnea, mild skin rash, pruritus) have been reported with the use of nirmatrelvir; ritonavir, and cases of anaphylaxis, toxic epidermal necrolysis (TEN), and Stevens-Johnson Syndrome (SJS) have been reported with the ritonavir component. 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]

      Revision Date: 04/27/2022, 02:44:55 PM

      References

      67203 - Food and Drug Administration (FDA). Fact sheet for healthcare providers: emergency use authorization for Paxlovid (nirmatrelvir; ritonavir). Retrieved April 27, 2022. Available on the World Wide Web at https://www.fda.gov/media/155050/download?utm_medium=email&utm_source=govdelivery

      Contraindications/Precautions

      Absolute contraindications are italicized.

      • serious rash
      • antimicrobial resistance
      • breast-feeding
      • hepatic disease
      • hepatitis
      • human immunodeficiency virus (HIV) infection resistance
      • 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, rifampin, 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] 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 facility 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. Health care providers are advised NOT to adjust the dose of nirmatrelvir; ritonavir to avoid or mitigate a drug interaction.[65314]

      Nirmatrelvir; ritonavir is authorized 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 authorized for use in patients requiring hospitalization due to severe or critical COVID-19; nor is it authorized 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 patient may complete the full 5-day treatment course at the discretion of the health care provider. Use of nirmatrelvir; ritonavir for longer than 5 consecutive days is NOT authorized.[67203]

      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]

      A dose reduction is required when administering nirmatrelvir; ritonavir to patients with moderate renal impairment (eGFR 30 to 59 mL/minute). Use of the drug is NOT authorized in patients with severe renal disease (eGFR less than 30 mL/minute), as data in this population is limited and the appropriate dosage has not been determined.[67203]

      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 authorized for use in patients with severe hepatic impairment (Child-Pugh C), as pharmacokinetic and safety data are unavailable in these patients.[67203]

      There are no human data available regarding the use of nirmatrelvir during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriages, or adverse maternal or fetal outcomes. In animal embryo-fetal development studies, reduced fetal body weights (9% decrease) were observed in rabbits following maternal administration of nirmatrelvir doses resulting in systemic exposures 10-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., 2.3% (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).[67203] The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend that nirmatrelvir; ritonavir be offered to pregnant and recently pregnant patients, especially since pregnancy is a risk factor for severe COVID-19. Obstetricians should be aware of potential drug-drug interactions when prescribing this medication.[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, health care providers are encouraged to report the adverse effect to the FDA.[67203]

      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 TENs and SJS have been reported with the ritonavir component, and hypersensitivity reactions (i.e., urticaria, angioedema, dyspnea, mild skin eruptions, pruritus) have been reported with 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]

      Revision Date: 05/16/2022, 12:35:41 PM

      References

      65314 - COVID-19 Treatment Guidelines Panel. Coronavirus Diseases 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Accessed May 31, 2022. Available at on the World Wide Web at: https://covid19treatmentguidelines.nih.gov/.67203 - Food and Drug Administration (FDA). Fact sheet for healthcare providers: emergency use authorization for Paxlovid (nirmatrelvir; ritonavir). Retrieved April 27, 2022. Available on the World Wide Web at https://www.fda.gov/media/155050/download?utm_medium=email&utm_source=govdelivery

      Mechanism of Action

      Nirmatrelvir; ritonavir is an investigational 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. 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 nanomolar and 181 nanomolar, respectively. Nirmatrelvir had similar cell culture antiviral activity against SARS-CoV-2 isolates belonging to the Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Lambda (C.37), Mu (B.1.621), and Omicron (B.1.1.529/BA.1) variants; however, the Beta variant was the least susceptible with an approximate 3-fold reduced susceptibility relative to the USA-WA1/2020 isolate.

       

      Naturally occurring SARS-CoV-2 Mpro amino acid substitutions associated with reduced nirmatrelvir activity in a biochemical assay included G15S (4.4-fold), T135I (3.5-fold), S144A (91.9-fold), H164N (6.4-fold), H172Y (233-fold), Q189K (65.4-fold), and D248E (3.7-fold). Of note, G15S is present in the Lambda variant, which did not have reduced susceptibility to nirmatrelvir in cell culture. Three other Mpro amino acid substitutions with reduced nirmatrelvir activity that have not been naturally observed include Y54A (23.6-fold), F140A (39-fold), and E166A (33.4-fold). The clinical significance of substitutions at these Mpro positions is unknown. In the EPIC-HR clinical trial, treatment-emergent substitutions in SARS-CoV-2 Mpro or Mpro cleavage site that were more common in nirmatrelvir; ritonavir-treated subjects (n = 361) than in placebo (n = 402) included:

      • Mpro substitutions: A7S/T/V (n = 3), L30F (n = 3), M82I/R (n = 3), G109E/R/V (n = 3), P132L/S (n = 4), C145F/R/Y (n = 3), D153H/Y (n = 3), E166V (n = 3), T196A/K/M/R (n = 4), W207L/S/del (n = 5), A260D/T/V (n = 8), D263E (n = 3), A266P/V (n = 3), and V297A/F/del (n = 3)
      • Mpro ORF1ab cleavage site substitutions: Q5324H/R (n = 3), A5328P/S (n = 6), and T6449I/P (n = 3)

      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. In a biochemical assay, the P132H/L/S, A260V, and A266V Mpro substitutions did not reduce nirmatrelvir activity.

       

      Cross-resistance is not expected between nirmatrelvir and remdesivir or anti-SARS-CoV-2 monoclonal antibodies.[67203]

      Revision Date: 04/27/2022, 02:23:21 PM

      References

      67203 - Food and Drug Administration (FDA). Fact sheet for healthcare providers: emergency use authorization for Paxlovid (nirmatrelvir; ritonavir). Retrieved April 27, 2022. Available on the World Wide Web at https://www.fda.gov/media/155050/download?utm_medium=email&utm_source=govdelivery

      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 to form the isopropylthiazole oxidate metabolite M-2. 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]

       

      Affected cytochrome P450 isoenzymes and drug transporters: CYP3A, CYP2D6 P-glycoprotein (P-gp)

      In vitro data indicate that nirmatrelvir is a substrate for CYP3A4 and the drug transporter P-glycoprotein (P-gp). Nirmatrelvir has the potential to reversibly and time-dependently inhibit CYP3A4 and P-gp. 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] Additionally, ritonavir appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6 as well as other enzymes, including glucuronosyl transferase.[67203]

      Route-Specific Pharmacokinetics

      Oral Route

      Following administration of a single 300 mg/100 mg nirmatrelvir; ritonavir dose in health subjects, the maximum plasma concentration (Cmax) of nirmatrelvir was 2.21 mcg/mL and the time to reach peak concentration (Tmax) was 3 hours (range 1.02 to 6 hours). The systemic exposure (AUC) of nirmatrelvir after a single dose was 23.01 mcg x hour/mL. Upon administration of nirmatrelvir; ritonavir, the increase in nirmatrelvir exposure appears to be less than dose proportional up to 750 mg as a single dose and up to 500 mg twice daily as multiple doses. Twice daily dosing over 10 days achieved steady-state on Day 2 with approximately 2-fold accumulation. Dosing with a high-fat meal modestly increased the exposure of nirmatrelvir (approximately 15% increase in mean Cmax and 1.6% in mean AUC) relative to fasting conditions.[67203]

      Special Populations

      Hepatic Impairment

      A single 100 mg/100 mg dose of nirmatrelvir; ritonavir in patients with moderate hepatic impairment 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.[67203]

      Renal Impairment

      The pharmacokinetics of nirmatrelvir were compared in healthy subjects and patients with mild (eGFR 60 to 89 mL/minute), moderate (eGFR 30 to 59 mL/minute), and severe (eGFR less than 30 mL/minute) renal impairment following 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]

      Pediatrics

      The pharmacokinetics of nirmatrelvir; ritonavir in patients less than 18 years of age 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 of age and older who weigh at least 40 kg to those observed in adults after adjusting for body weight.[67203]

      Ethnic Differences

      Systemic exposure to nirmatrelvir in Japanese patients was numerically lower, but not clinically meaningfully different, than those in Western subjects.[67203]

      Revision Date: 05/16/2022, 03:45:28 PM

      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 Diseases 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Accessed May 31, 2022. Available at on the World Wide Web at: https://covid19treatmentguidelines.nih.gov/.67203 - Food and Drug Administration (FDA). Fact sheet for healthcare providers: emergency use authorization for Paxlovid (nirmatrelvir; ritonavir). Retrieved April 27, 2022. Available on the World Wide Web at https://www.fda.gov/media/155050/download?utm_medium=email&utm_source=govdelivery

      Pregnancy/Breast-feeding

      pregnancy

      There are no human data available regarding the use of nirmatrelvir during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriages, or adverse maternal or fetal outcomes. In animal embryo-fetal development studies, reduced fetal body weights (9% decrease) were observed in rabbits following maternal administration of nirmatrelvir doses resulting in systemic exposures 10-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., 2.3% (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).[67203] The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend that nirmatrelvir; ritonavir be offered to pregnant and recently pregnant patients, especially since pregnancy is a risk factor for severe COVID-19. Obstetricians should be aware of potential drug-drug interactions when prescribing this medication.[65314]

      breast-feeding

      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, health care providers are encouraged to report the adverse effect to the FDA.[67203]

      Revision Date: 05/16/2022, 12:35:41 PM

      References

      65314 - COVID-19 Treatment Guidelines Panel. Coronavirus Diseases 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Accessed May 31, 2022. Available at on the World Wide Web at: https://covid19treatmentguidelines.nih.gov/.67203 - Food and Drug Administration (FDA). Fact sheet for healthcare providers: emergency use authorization for Paxlovid (nirmatrelvir; ritonavir). Retrieved April 27, 2022. Available on the World Wide Web at https://www.fda.gov/media/155050/download?utm_medium=email&utm_source=govdelivery

      Interactions

      Level 1 (Severe)

      • Acetaminophen; Propoxyphene
      • Alfuzosin
      • Amiodarone
      • Amobarbital
      • Apalutamide
      • Aspirin, ASA; Butalbital; Caffeine
      • Aspirin, ASA; Butalbital; Caffeine; Codeine
      • Atazanavir; Cobicistat
      • Barbiturates
      • Belladonna Alkaloids; Ergotamine; Phenobarbital
      • Bepridil
      • Butabarbital
      • Butalbital; Acetaminophen
      • Butalbital; Acetaminophen; Caffeine
      • Butalbital; Acetaminophen; Caffeine; Codeine
      • Cabotegravir
      • Cabotegravir; Rilpivirine
      • Carbamazepine
      • Cisapride
      • Clozapine
      • Cobicistat
      • Conivaptan
      • Darunavir; Cobicistat
      • Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide
      • Dextromethorphan; Quinidine
      • Dihydroergotamine
      • Dronedarone
      • Eletriptan
      • Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide
      • Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate
      • Enzalutamide
      • Eplerenone
      • Ergoloid Mesylates
      • Ergonovine
      • Ergot alkaloids
      • Ergotamine
      • Ergotamine; Caffeine
      • Ezetimibe; Simvastatin
      • Finerenone
      • Flecainide
      • Flibanserin
      • Fosphenytoin
      • Idelalisib
      • Isavuconazonium
      • Isoniazid, INH; Pyrazinamide, PZA; Rifampin
      • Isoniazid, INH; Rifampin
      • Ivabradine
      • Lomitapide
      • Lonafarnib
      • Lovastatin
      • Lovastatin; Niacin
      • Lurasidone
      • Mavacamten
      • Meperidine
      • Meperidine; Promethazine
      • Mephobarbital
      • Methohexital
      • Methylergonovine
      • Methysergide
      • Naloxegol
      • Niacin; Simvastatin
      • Pacritinib
      • Pentobarbital
      • Pergolide
      • Phenobarbital
      • Phenobarbital; Hyoscyamine; Atropine; Scopolamine
      • Phenytoin
      • Pimozide
      • Primidone
      • Propafenone
      • Propoxyphene
      • Quinidine
      • Ranolazine
      • Red Yeast Rice
      • Rifampin
      • Rifapentine
      • Secobarbital
      • Silodosin
      • Simvastatin
      • Simvastatin; Sitagliptin
      • St. John's Wort, Hypericum perforatum
      • Terfenadine
      • Thiopental
      • Tolvaptan
      • Triazolam
      • Ubrogepant
      • Voclosporin

      Level 2 (Major)

      • Abemaciclib
      • Acalabrutinib
      • Acetaminophen; Codeine
      • Acetaminophen; Hydrocodone
      • Acetaminophen; Oxycodone
      • Adefovir
      • Ado-Trastuzumab emtansine
      • Aliskiren
      • Aliskiren; Amlodipine
      • Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ
      • Aliskiren; Hydrochlorothiazide, HCTZ
      • Aliskiren; Valsartan
      • Almotriptan
      • Alosetron
      • Alprazolam
      • Amlodipine; Atorvastatin
      • Amoxapine
      • Amoxicillin; Clarithromycin; Omeprazole
      • Apixaban
      • Aprepitant, Fosaprepitant
      • Aripiprazole
      • Armodafinil
      • Artemether; Lumefantrine
      • Aspirin, ASA; Carisoprodol; Codeine
      • Aspirin, ASA; Oxycodone
      • Atogepant
      • Atorvastatin
      • Atorvastatin; Ezetimibe
      • Avacopan
      • Avanafil
      • Avapritinib
      • Avatrombopag
      • Axitinib
      • Azelastine; Fluticasone
      • Bedaquiline
      • Bendamustine
      • Berotralstat
      • Betrixaban
      • Bismuth Subcitrate Potassium; Metronidazole; Tetracycline
      • Bismuth Subsalicylate; Metronidazole; Tetracycline
      • Boceprevir
      • Bosentan
      • Bosutinib
      • Brexpiprazole
      • Brigatinib
      • Bromocriptine
      • Brompheniramine; Guaifenesin; Hydrocodone
      • Brompheniramine; Hydrocodone; Pseudoephedrine
      • Budesonide
      • Budesonide; Formoterol
      • Budesonide; Glycopyrrolate; Formoterol
      • Buspirone
      • Cabazitaxel
      • Cabozantinib
      • Calcium, Magnesium, Potassium, Sodium Oxybates
      • Carbinoxamine; Hydrocodone; Phenylephrine
      • Carbinoxamine; Hydrocodone; Pseudoephedrine
      • Cariprazine
      • Celecoxib; Tramadol
      • Ceritinib
      • Chlordiazepoxide
      • Chlordiazepoxide; Amitriptyline
      • Chlordiazepoxide; Clidinium
      • Chlorpheniramine; Codeine
      • Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine
      • Chlorpheniramine; Hydrocodone
      • Chlorpheniramine; Hydrocodone; Phenylephrine
      • Chlorpheniramine; Hydrocodone; Pseudoephedrine
      • Cilostazol
      • Clarithromycin
      • Clonazepam
      • Clopidogrel
      • Clorazepate
      • Cobimetinib
      • Codeine
      • Codeine; Guaifenesin
      • Codeine; Guaifenesin; Pseudoephedrine
      • Codeine; Phenylephrine; Promethazine
      • Codeine; Promethazine
      • Colchicine
      • Conjugated Estrogens; Medroxyprogesterone
      • Copanlisib
      • Crizotinib
      • Cyclosporine
      • Dabigatran
      • Dabrafenib
      • Daclatasvir
      • Dapagliflozin; Saxagliptin
      • Daridorexant
      • Dasatinib
      • Deferasirox
      • Deflazacort
      • Desogestrel; Ethinyl Estradiol
      • Diazepam
      • Digoxin
      • Diltiazem
      • Diphenhydramine; Hydrocodone; Phenylephrine
      • Disopyramide
      • Disulfiram
      • Docetaxel
      • Dofetilide
      • Doxorubicin
      • Doxorubicin Liposomal
      • Dronabinol
      • Drospirenone; Ethinyl Estradiol
      • Drospirenone; Ethinyl Estradiol; Levomefolate
      • Dutasteride; Tamsulosin
      • Duvelisib
      • Elagolix
      • Elagolix; Estradiol; Norethindrone acetate
      • Elbasvir; Grazoprevir
      • Elexacaftor; tezacaftor; ivacaftor
      • Eliglustat
      • Eluxadoline
      • Encainide
      • Encorafenib
      • Entrectinib
      • Erdafitinib
      • Erlotinib
      • Erythromycin
      • Erythromycin; Sulfisoxazole
      • Eslicarbazepine
      • Estazolam
      • Estradiol Cypionate; Medroxyprogesterone
      • Estradiol; Levonorgestrel
      • Eszopiclone
      • Ethanol
      • Ethinyl Estradiol
      • Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate
      • Ethinyl Estradiol; Norelgestromin
      • Ethinyl Estradiol; Norethindrone Acetate
      • Ethinyl Estradiol; Norgestrel
      • Ethotoin
      • Ethynodiol Diacetate; Ethinyl Estradiol
      • Etonogestrel
      • Etonogestrel; Ethinyl Estradiol
      • Everolimus
      • Fedratinib
      • Felbamate
      • Fentanyl
      • Fesoterodine
      • Flurazepam
      • Fluticasone
      • Fluticasone; Salmeterol
      • Fluticasone; Umeclidinium; Vilanterol
      • Fluticasone; Vilanterol
      • food
      • Gilteritinib
      • Glasdegib
      • Glecaprevir; Pibrentasvir
      • Griseofulvin
      • Guaifenesin; Hydrocodone
      • Guaifenesin; Hydrocodone; Pseudoephedrine
      • Guanfacine
      • Homatropine; Hydrocodone
      • Hydantoins
      • Hydrocodone
      • Hydrocodone; Ibuprofen
      • Hydrocodone; Phenylephrine
      • Hydrocodone; Potassium Guaiacolsulfonate
      • Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine
      • Hydrocodone; Pseudoephedrine
      • Ibrexafungerp
      • Ibrutinib
      • Ibuprofen; Oxycodone
      • Iloperidone
      • Imatinib
      • Infigratinib
      • Interferon Alfa-2b; Ribavirin
      • Irinotecan
      • Irinotecan Liposomal
      • Istradefylline
      • Itraconazole
      • Ivacaftor
      • Ivosidenib
      • Ixabepilone
      • Ketoconazole
      • Lamotrigine
      • Lansoprazole; Amoxicillin; Clarithromycin
      • Lanthanum Carbonate
      • Lapatinib
      • Larotrectinib
      • Lefamulin
      • Lemborexant
      • Levoketoconazole
      • Levomethadyl
      • Levomilnacipran
      • Levonorgestrel
      • Levonorgestrel; Ethinyl Estradiol
      • Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate
      • Lorlatinib
      • Lumacaftor; Ivacaftor
      • Lumacaftor; Ivacaftor
      • Lumateperone
      • Lurbinectedin
      • Macitentan
      • Maraviroc
      • Medroxyprogesterone
      • Mestranol; Norethindrone
      • Metformin; Saxagliptin
      • Metronidazole
      • Mexiletine
      • Midazolam
      • Midostaurin
      • Mifepristone
      • Mitapivat
      • Mitotane
      • Mobocertinib
      • Modafinil
      • Nafcillin
      • Naldemedine
      • Nanoparticle Albumin-Bound Sirolimus
      • Nefazodone
      • Neratinib
      • Nifedipine
      • Nilotinib
      • Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate
      • Norethindrone; Ethinyl Estradiol
      • Norethindrone; Ethinyl Estradiol; Ferrous fumarate
      • Norgestimate; Ethinyl Estradiol
      • Olaparib
      • Omeprazole; Amoxicillin; Rifabutin
      • Oritavancin
      • Orlistat
      • Osilodrostat
      • Ospemifene
      • Oxcarbazepine
      • Oxycodone
      • Palbociclib
      • Panobinostat
      • Pazopanib
      • Pemigatinib
      • Pexidartinib
      • Pimavanserin
      • Piroxicam
      • Ponatinib
      • Ponesimod
      • Pralsetinib
      • Probenecid; Colchicine
      • Quazepam
      • Quetiapine
      • Quinine
      • Regorafenib
      • Relugolix
      • Relugolix; Estradiol; Norethindrone acetate
      • Ribavirin
      • Ribociclib
      • Ribociclib; Letrozole
      • Rifabutin
      • Rimegepant
      • Riociguat
      • Rivaroxaban
      • Roflumilast
      • Rosuvastatin
      • Rosuvastatin; Ezetimibe
      • Ruxolitinib
      • Sacituzumab Govitecan
      • Salmeterol
      • Saxagliptin
      • Segesterone Acetate; Ethinyl Estradiol
      • Selpercatinib
      • Selumetinib
      • Sildenafil
      • Simeprevir
      • Sirolimus
      • Sodium Oxybate
      • Solifenacin
      • Sonidegib
      • Sotalol
      • Sunitinib
      • Suvorexant
      • Tacrolimus
      • Tadalafil
      • Tamsulosin
      • Tasimelteon
      • Tazemetostat
      • Telithromycin
      • Temsirolimus
      • Tepotinib
      • Tezacaftor; Ivacaftor
      • Thiotepa
      • Ticagrelor
      • Tofacitinib
      • Tolterodine
      • Topotecan
      • Toremifene
      • Trabectedin
      • Tramadol
      • Tramadol; Acetaminophen
      • Trazodone
      • Upadacitinib
      • Valbenazine
      • Valproic Acid, Divalproex Sodium
      • Vardenafil
      • Vemurafenib
      • Venetoclax
      • Vilazodone
      • Vinblastine
      • Vincristine
      • Vincristine Liposomal
      • Vonoprazan; Amoxicillin; Clarithromycin
      • Vorapaxar
      • Voriconazole
      • Vorinostat
      • Voxelotor
      • Zalcitabine, ddC
      • Zanubrutinib
      • Ziprasidone

      Level 3 (Moderate)

      • Abacavir
      • Abacavir; Dolutegravir; Lamivudine
      • Abacavir; Lamivudine, 3TC
      • Abacavir; Lamivudine, 3TC; Zidovudine, ZDV
      • Acarbose
      • Acebutolol
      • Acetaminophen
      • Acetaminophen; Aspirin
      • Acetaminophen; Aspirin, ASA; Caffeine
      • Acetaminophen; Aspirin; Diphenhydramine
      • Acetaminophen; Caffeine
      • Acetaminophen; Caffeine; Dihydrocodeine
      • Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine
      • Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide
      • Acetaminophen; Caffeine; Pyrilamine
      • Acetaminophen; Chlorpheniramine
      • Acetaminophen; Chlorpheniramine; Dextromethorphan
      • Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine
      • Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine
      • Acetaminophen; Chlorpheniramine; Phenylephrine
      • Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine
      • Acetaminophen; Dextromethorphan
      • Acetaminophen; Dextromethorphan; Doxylamine
      • Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine
      • Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine
      • Acetaminophen; Dextromethorphan; Phenylephrine
      • Acetaminophen; Dextromethorphan; Pseudoephedrine
      • Acetaminophen; Dichloralphenazone; Isometheptene
      • Acetaminophen; Diphenhydramine
      • Acetaminophen; Guaifenesin; Phenylephrine
      • Acetaminophen; Pamabrom; Pyrilamine
      • Acetaminophen; Pentazocine
      • Acetaminophen; Pseudoephedrine
      • Afatinib
      • Aldesleukin, IL-2
      • Alfentanil
      • Alogliptin
      • Alogliptin; Metformin
      • Alogliptin; Pioglitazone
      • Alpha-glucosidase Inhibitors
      • Amitriptyline
      • Amlodipine
      • Amlodipine; Benazepril
      • Amlodipine; Celecoxib
      • Amlodipine; Olmesartan
      • Amlodipine; Valsartan
      • Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ
      • Amphetamine
      • Amphetamine; Dextroamphetamine
      • Amphetamines
      • Arformoterol
      • Artesunate
      • Asciminib
      • Aspirin, ASA; Caffeine; Dihydrocodeine
      • Aspirin, ASA; Citric Acid; Sodium Bicarbonate
      • Aspirin, ASA; Omeprazole
      • Atenolol
      • Atenolol; Chlorthalidone
      • Belladonna; Opium
      • Belzutifan
      • Bendroflumethiazide; Nadolol
      • Benzhydrocodone; Acetaminophen
      • Benzphetamine
      • Betamethasone
      • Betaxolol
      • Bexarotene
      • Bisoprolol
      • Bisoprolol; Hydrochlorothiazide, HCTZ
      • Bortezomib
      • Brimonidine; Timolol
      • Bupivacaine; Lidocaine
      • Bupivacaine; Meloxicam
      • Buprenorphine
      • Buprenorphine; Naloxone
      • Bupropion
      • Bupropion; Naltrexone
      • Calcifediol
      • Canagliflozin
      • Canagliflozin; Metformin
      • Capmatinib
      • Carbetapentane; Chlorpheniramine
      • Carbetapentane; Chlorpheniramine; Phenylephrine
      • Carbetapentane; Diphenhydramine; Phenylephrine
      • Carteolol
      • Carvedilol
      • Cenobamate
      • Cetirizine
      • Cetirizine; Pseudoephedrine
      • Chloramphenicol
      • Chlorpheniramine
      • Chlorpheniramine; Dextromethorphan
      • Chlorpheniramine; Dextromethorphan; Phenylephrine
      • Chlorpheniramine; Dextromethorphan; Pseudoephedrine
      • Chlorpheniramine; Dihydrocodeine; Phenylephrine
      • Chlorpheniramine; Dihydrocodeine; Pseudoephedrine
      • Chlorpheniramine; Ibuprofen; Pseudoephedrine
      • Chlorpheniramine; Phenylephrine
      • Chlorpheniramine; Pseudoephedrine
      • Ciclesonide
      • Cidofovir
      • Cimetidine
      • Cinacalcet
      • Clevidipine
      • Clindamycin
      • Clobazam
      • Clofarabine
      • Clomipramine
      • Cocaine
      • Conjugated Estrogens
      • Conjugated Estrogens; Bazedoxifene
      • Cyclophosphamide
      • Dapagliflozin
      • Dapagliflozin; Metformin
      • Dapsone
      • Darifenacin
      • Darolutamide
      • Delavirdine
      • Desipramine
      • Dexamethasone
      • Dexlansoprazole
      • Dexmedetomidine
      • Dextroamphetamine
      • Dextromethorphan; Diphenhydramine; Phenylephrine
      • Diclofenac
      • Diclofenac; Misoprostol
      • Dienogest; Estradiol valerate
      • Dihydrocodeine; Guaifenesin; Pseudoephedrine
      • Diphenhydramine
      • Diphenhydramine; Ibuprofen
      • Diphenhydramine; Naproxen
      • Diphenhydramine; Phenylephrine
      • Donepezil
      • Donepezil; Memantine
      • Doravirine; Lamivudine; Tenofovir disoproxil fumarate
      • Dorzolamide; Timolol
      • Doxazosin
      • Doxepin
      • Doxercalciferol
      • Drospirenone; Estradiol
      • Dutasteride
      • Echinacea
      • Edoxaban
      • Efavirenz
      • Efavirenz; Emtricitabine; Tenofovir
      • Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate
      • Eltrombopag
      • Elvitegravir
      • Empagliflozin
      • Empagliflozin; Linagliptin
      • Empagliflozin; Linagliptin; Metformin
      • Empagliflozin; Metformin
      • Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate
      • Emtricitabine; Tenofovir disoproxil fumarate
      • Enalapril; Felodipine
      • Enfortumab vedotin
      • Ertugliflozin; Metformin
      • Ertugliflozin; Sitagliptin
      • Esmolol
      • Esomeprazole
      • Esterified Estrogens
      • Esterified Estrogens; Methyltestosterone
      • Estradiol
      • Estradiol; Norethindrone
      • Estradiol; Norgestimate
      • Estradiol; Progesterone
      • Estropipate
      • Ethosuximide
      • Etravirine
      • Felodipine
      • Fluconazole
      • Fluoxetine
      • Fluvastatin
      • Fluvoxamine
      • Formoterol; Mometasone
      • Fosamprenavir
      • Foscarnet
      • Fostamatinib
      • Gefitinib
      • Glipizide; Metformin
      • Glyburide; Metformin
      • grapefruit juice
      • Halofantrine
      • Haloperidol
      • Ifosfamide
      • Imipramine
      • Incretin Mimetics
      • Indacaterol
      • Indacaterol; Glycopyrrolate
      • Insulins
      • Interferons
      • Isradipine
      • Ketamine
      • Labetalol
      • Lacosamide
      • Lamivudine; Tenofovir Disoproxil Fumarate
      • Lansoprazole
      • Lansoprazole; Naproxen
      • Ledipasvir; Sofosbuvir
      • Lesinurad
      • Lesinurad; Allopurinol
      • Letermovir
      • Leuprolide; Norethindrone
      • Levamlodipine
      • Levocetirizine
      • Levorphanol
      • Lidocaine
      • Lidocaine; Epinephrine
      • Lidocaine; Prilocaine
      • Linagliptin
      • Linagliptin; Metformin
      • Lisdexamfetamine
      • Loperamide
      • Loperamide; Simethicone
      • Losartan
      • Losartan; Hydrochlorothiazide, HCTZ
      • Maprotiline
      • Meclizine
      • Mefloquine
      • Meloxicam
      • Metformin
      • Metformin; Repaglinide
      • Metformin; Rosiglitazone
      • Metformin; Sitagliptin
      • Methadone
      • Methamphetamine
      • Methylprednisolone
      • Metoclopramide
      • Metoprolol
      • Metoprolol; Hydrochlorothiazide, HCTZ
      • Miglitol
      • Mirabegron
      • Mirtazapine
      • Mometasone
      • Morphine
      • Morphine; Naltrexone
      • Moxifloxacin
      • Nabilone
      • Nadolol
      • Nanoparticle Albumin-Bound Paclitaxel
      • Naproxen; Esomeprazole
      • Nateglinide
      • Nebivolol
      • Nebivolol; Valsartan
      • Nelfinavir
      • Netupitant, Fosnetupitant; Palonosetron
      • Nevirapine
      • Nicardipine
      • Nimodipine
      • Nintedanib
      • Nisoldipine
      • Norethindrone
      • Nortriptyline
      • Odevixibat
      • Olanzapine
      • Olanzapine; Fluoxetine
      • Olanzapine; Samidorphan
      • Oliceridine
      • Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ
      • Olodaterol
      • Omeprazole
      • Omeprazole; Sodium Bicarbonate
      • Ondansetron
      • Oxybutynin
      • Oxymorphone
      • Paricalcitol
      • Paroxetine
      • Penbutolol
      • Perampanel
      • Perindopril; Amlodipine
      • Perphenazine; Amitriptyline
      • Phentermine; Topiramate
      • Pindolol
      • Pioglitazone; Metformin
      • Pirfenidone
      • Pitolisant
      • Polatuzumab Vedotin
      • Pomalidomide
      • Posaconazole
      • Pramlintide
      • Praziquantel
      • Prednisolone
      • Prednisone
      • Progesterone
      • Propofol
      • Propranolol
      • Propranolol; Hydrochlorothiazide, HCTZ
      • Protriptyline
      • Ramelteon
      • Remifentanil
      • Repaglinide
      • Retapamulin
      • Rifaximin
      • Riluzole
      • Ripretinib
      • Risperidone
      • Rocuronium
      • Romidepsin
      • Sibutramine
      • Siponimod
      • Sitagliptin
      • Sodium Bicarbonate
      • Sotorasib
      • Sufentanil
      • Sulfonylureas
      • Talazoparib
      • Tecovirimat
      • Telmisartan; Amlodipine
      • Telotristat Ethyl
      • Teniposide
      • Tenofovir, PMPA
      • Terbinafine
      • Theophylline, Aminophylline
      • Thiazolidinediones
      • Thioridazine
      • Tiagabine
      • Timolol
      • Tinidazole
      • Tiotropium; Olodaterol
      • Tisotumab Vedotin
      • Topiramate
      • Trandolapril; Verapamil
      • Triamcinolone
      • Tricyclic antidepressants
      • Trimetrexate
      • Trimipramine
      • Tucatinib
      • Ulipristal
      • Verapamil
      • Vinorelbine
      • Warfarin
      • Yohimbine
      • Zafirlukast
      • Zaleplon
      • Zileuton
      • Zolmitriptan
      • Zolpidem
      • Zonisamide

      Level 4 (Minor)

      • Atazanavir
      • Atovaquone
      • Atovaquone; Proguanil
      • Brentuximab vedotin
      • Bupivacaine
      • Bupivacaine Liposomal
      • Bupivacaine; Epinephrine
      • Doravirine
      • Granisetron
      • Indinavir
      • Lamivudine, 3TC; Zidovudine, ZDV
      • Levobupivacaine
      • 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] 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. [7238] [7335] 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; Magnesium Salicylate; Phenyltoloxamine: (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; Phenyltoloxamine; Salicylamide: (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; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (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; Dichloralphenazone; Isometheptene: (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 an alternative COVID-19 therapy. 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] (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; Oxycodone: (Major) Consider withholding oxycodone if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. 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] (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; Pentazocine: (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; Propoxyphene: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and propoxyphene is contraindicated; consider an alternative COVID-19 therapy. Coadministration may increase propoxyphene exposure resulting in increased toxicity. Propoxyphene is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] (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) Due to effects on microsomal isoenzymes responsible for hepatic metabolism, ritonavir may alter the response and/or increase the AUC of opiate analgesics. Concurrent use of ritonavir and propoxyphene is not recommended, due the increased formation of the neurotoxic metabolites of propoxyphene. Also, propoxyphene is a substrate/inhibitor of CYP3A4. Increased serum concentrations of propoxyphene can occur from concurrent use of ritonavir, a CYP3A4 inhibitor. A reduced dosage of propoxyphene may be needed. Monitor for CNS and respiratory depression. [11379] [36008] [4718] [5044] 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] 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] Aldesleukin, IL-2: (Moderate) Concurrent administration of aldesleukin, IL-2 with ritonavir may result in increased plasma concentrations of ritonavir. Aldesleukin, IL-2 increases IL-6 concentrations, and IL-6 is an inhibitor of the hepatic isoenzyme CYP3A4; ritonavir is a substrate of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [2356] [34540] [58664] Alfentanil: (Moderate) Alfentanil is metabolized by the hepatic isoenzyme CYP3A4. Drugs that inhibit this enzyme, such as protease inhibitors, may alter responses to alfentanil. A dose reduction of one or both drugs may be warranted. Monitor closely for oversedation and respiratory depression. [28001] [28995] [47165] Alfuzosin: (Contraindicated) Coadministration of alfuzosin with protease inhibitors is contraindicated as potentially increased alfuzosin concentrations can result in hypotension, and potentially life-threatening cardiac arrhythmia. Alfuzosin is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. [28341] [28731] [28839] [28995] [29012] [31320] [32432] [50857] (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] 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] (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; Amlodipine: (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] (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. 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. [29090] [47165] [58664] (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; Amlodipine; 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] (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. 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. [29090] [47165] [58664] (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] (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; Valsartan: (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] (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] (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] Almotriptan: (Major) Ritonavir may increase the systemic exposure of almotriptan. 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. Almotriptan is a CYP3A4 substrate and ritonavir is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure. [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. [7238] [7335] 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. [7238] [7335] (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. [7238] [7335] 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. [7238] [7335] 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 an alternative COVID-19 therapy. Coadministration may increase alprazolam exposure resulting in increased toxicity. 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] (Major) Coadministration of HIV treatment doses of ritonavir and amiodarone is contraindicated due to the potential for serious or life-threatening reactions, such as cardiac arrhythmias. Cautious consideration may be given to administering amiodarone with boosting doses of ritonavir. Ritonavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, such as amiodarone, should be expected with concurrent use. [47165] Amitriptyline: (Moderate) A dose reduction of the tricyclic antidepressant (TCA) may be necessary when coadministered with ritonavir. Concurrent use may result in elevated TCA plasma concentrations. [47165] Amlodipine: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. 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. [29090] [47165] [58664] Amlodipine; Atorvastatin: (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] (Major) Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with ritonavir. The risk of developing myopathy/rhabdomyolysis increases when atorvastatin is used concomitantly with ritonavir. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and lopinavir; ritonavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. [43900] (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. 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. [29090] [47165] [58664] Amlodipine; Benazepril: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. 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. [29090] [47165] [58664] Amlodipine; Celecoxib: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. 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. [29090] [47165] [58664] Amlodipine; Olmesartan: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. 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. [29090] [47165] [58664] Amlodipine; Valsartan: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. 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. [29090] [47165] [58664] (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) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. 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. [29090] [47165] [58664] (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] (Major) Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. [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] 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) Because aripiprazole is metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the oral aripiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving inhibitors of both CYP3A4 and CYP2D6 such as ritonavir. Patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor, such as ritonavir, should have a dose reduction to 200 mg/month IM. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified. [28341] [42845] [47165] [53394] [60196] [63328] 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] (Major) Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. [46638] Aspirin, ASA; Butalbital; 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] (Major) Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. [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] Aspirin, ASA; 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] 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 an alternative COVID-19 therapy. 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] (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) Limit the dose of atogepant to 10 mg PO once daily 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 exposure and a 2.15-fold increase in atogepant peak concentration. [47165] [67011] Atorvastatin: (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] (Major) Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with ritonavir. The risk of developing myopathy/rhabdomyolysis increases when atorvastatin is used concomitantly with ritonavir. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and lopinavir; ritonavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. [43900] Atorvastatin; Ezetimibe: (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] (Major) Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with ritonavir. The risk of developing myopathy/rhabdomyolysis increases when atorvastatin is used concomitantly with ritonavir. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and lopinavir; ritonavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. [43900] 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] 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] (Major) Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. [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 Alkaloids; Ergotamine; Phenobarbital: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred. [28142] [28341] [28731] [28839] [28995] [32432] [46638] [5018] [5044] [5623] [5747] [8102] (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] (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] (Major) Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. [46638] 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] Bendroflumethiazide; Nadolol: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers. [5044] 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] Bepridil: (Contraindicated) Ritonavir can produce large increases in plasma concentrations of certain drugs metabolized by cytochrome P450 3A4. The concurrent use of ritonavir is contraindicated with bepridil. [46638] [5044] Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking ritonavir. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Additionally, monitor for ritonavir-related adverse effects as concurrent use may increase the exposure of ritonavir. Berotralstat is a P-gp substrate and moderate CYP3A4 inhibitor; ritonavir is a CYP3A4 substrate and P-gp inhibitor. Coadministration with another P-gp inhibitor increased berotralstat exposure by 69%. [28380] [34557] [66159] 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] 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] Boceprevir: (Major) Concurrent administration of ritonavir with boceprevir is not recommended due to the potential for HIV and hepatitis C treatment failures. This combination has resulted in decreased serum concentrations of both medications. Ritonavir is an inhibitor, inducer, and substrate of the hepatic isoenzyme CYP3A4; boceprevir is an inhibitor and substrate of this isoenzyme. Additionally, both drugs are substrates and inhibitors of the drug efflux transporter P-glycoprotein (PGP). If these drugs are coadministered, health care providers are advised to closely monitor for decreased treatment response and virologic rebound. Health care providers are also encouraged to report any drug-related adverse reactions to the FDA MedWatch Program. [28315] [44314] [48674] 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. 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] (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] 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] Brompheniramine; Guaifenesin; Hydrocodone: (Major) Consider withholding hydrocodone if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. 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] (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] Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Consider withholding hydrocodone if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. 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] (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] 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 will 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. 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 will 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. 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] Butabarbital: (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] (Major) Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. [46638] 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] (Major) Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. [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] (Major) Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. [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] (Major) Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. [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] 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: (Moderate) Monitor for decreased efficacy of canagliflozin if coadministration with ritonavir is necessary. In patients taking ritonavir who have an eGFR of 60 mL/min/1.73 m2 or greater and are currently tolerating a canagliflozin dose of 100 mg once daily, increase the dose of canagliflozin to 200 mg (taken as two 100 mg tablets) once daily. In patients who are tolerating canagliflozin to 200 mg and who require additional glycemic control, the dose may be increased to 300 mg once daily. In patients taking ritonavir who have an eGFR less than 60 mL/min/1.73 m2, and are currently tolerating a canagliflozin dose of 100 mg once daily, increase the dose of canagliflozin to 200 mg (taken as two 100 mg tablets) once daily. Consider other antihyperglycemic therapy in patients who require additional glycemic control. Canagliflozin is a UGT1A9 and 2B4 substrate and ritonavir is a UGT inducer. Coadministration with a nonselective inducer of several UGT enzymes decreased canagliflozin exposure by 51%. In addition, new onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of antiretroviral 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] [47165] [53972] Canagliflozin; Metformin: (Moderate) Monitor for decreased efficacy of canagliflozin if coadministration with ritonavir is necessary. In patients taking ritonavir who have an eGFR of 60 mL/min/1.73 m2 or greater and are currently tolerating a canagliflozin dose of 100 mg once daily, increase the dose of canagliflozin to 200 mg (taken as two 100 mg tablets) once daily. In patients who are tolerating canagliflozin to 200 mg and who require additional glycemic control, the dose may be increased to 300 mg once daily. In patients taking ritonavir who have an eGFR less than 60 mL/min/1.73 m2, and are currently tolerating a canagliflozin dose of 100 mg once daily, increase the dose of canagliflozin to 200 mg (taken as two 100 mg tablets) once daily. Consider other antihyperglycemic therapy in patients who require additional glycemic control. Canagliflozin is a UGT1A9 and 2B4 substrate and ritonavir is a UGT inducer. Coadministration with a nonselective inducer of several UGT enzymes decreased canagliflozin exposure by 51%. In addition, new onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of antiretroviral 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] [47165] [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] 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] (Major) Ritonavir decreases the hepatic CYP metabolism of carbamazepine, resulting in increased carbamazepine concentrations. In addition, carbamazepine increases the metabolism of the protease inhibitors and may lead to decreased efficacy of these medications. Carbamazepine is a potent inducer and substrate of the hepatic isoenzyme CYP3A4; ritonavir is a substrate and inhibitor of this isoenzyme. In addition, carbamazepine induces P-glycoprotein (P-gp), a drug efflux transporter for which ritonavir is a substrate. Treatment failures have been reported with protease inhibitors when carbamazepine is used concomitantly. The appropriate drug-dose adjustments necessary to ensure optimum levels of both antiretroviral drugs and carbamazepine are unknown. If used concomitantly, the patient should be observed for changes in the clinical efficacy of the antiretroviral regimen or for carbamazepine toxicity. [28315] [46638] Carbetapentane; 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] Carbetapentane; 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] Carbetapentane; 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] Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Consider withholding hydrocodone if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. 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] (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] Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Consider withholding hydrocodone if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. 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] (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] 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) Consider withholding tramadol if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. Coadministration may increase tramadol exposure resulting in increased toxicity. Tramadol is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [32475] [65314] (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] 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) 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) 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) A dose reduction of the tricyclic antidepressant (TCA) may be necessary when coadministered with ritonavir. Concurrent use may result in elevated TCA plasma concentrations. [47165] Chlordiazepoxide; Clidinium: (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; Dihydrocodeine; Phenylephrine: (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 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; Dihydrocodeine; Pseudoephedrine: (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 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; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Consider withholding hydrocodone if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. 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] (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; Hydrocodone: (Major) Consider withholding hydrocodone if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. 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] (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; Hydrocodone; Phenylephrine: (Major) Consider withholding hydrocodone if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. 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] (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; Hydrocodone; Pseudoephedrine: (Major) Consider withholding hydrocodone if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. 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] (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) Concurrent administration of cilostazol with protease inhibitors can result in elevated cilostazol plasma concentrations; the manufacturer recommends prescribers consider up to a 50% reduction in cilostazol dosage during concurrent administration. Cilostazol is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together. [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) Concurrent administration of cinacalcet with ritonavir may result in elevated plasma concentrations of cinacalcet. Cinacalcet is a substrate of CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. [47165] [58664] Cisapride: (Contraindicated) Concurrent use of cisapride with anti-retroviral protease inhibitors (PI) is contraindicated due to the risk of life threatening cardiac arrhythmias such as torsade de pointes (TdP). Cisapride is metabolized by CYP3A4, and all PIs inhibit this enzyme; thus, coadministration may increases cisapride plasma concentrations and increase the risk of adverse events. Cases of QT prolongation and ventricular arrhythmias, including TdP and death, have been observed during post-marketing surveillance when cisapride is administered with potent CYP3A4 inhibitors. [28978] [28995] [46638] [47221] (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: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of clobazam is necessary. Concomitant use of nirmatrelvir and clobazam 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) A dose reduction of the tricyclic antidepressant (TCA) may be necessary when coadministered with ritonavir. Concurrent use may result in elevated TCA plasma concentrations. [47165] Clonazepam: (Major) Consider temporary discontinuation of clonazepam 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 clonazepam exposure resulting in increased toxicity. Clonazepam is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [41554] [65314] (Moderate) Use protease inhibitors cautiously and carefully monitor patients receiving concurrent clonazepam due to impaired metabolism of clonazepam leading to exaggerated concentrations and adverse effects, such as CNS and/or respiratory depression. Clonazepam is a CYP3A4 substrate. Protease inhibitors are CYP3A4 inhibitors. [28315] [28444] [32432] Clopidogrel: (Major) Avoid coadministration of clopidogrel with ritonavir due to the potential for decreased clopidogrel efficacy. Prasugrel is preferred to clopidogrel if coadministration with ritonavir is necessary. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that inhibition of CYP3A4 also reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Ritonavir is a strong CYP3A4 inhibitor. [28315] [65211] [65250] (Major) Avoid concomitant use of ritonavir-boosted nirmatrelvir and clopidogrel and consider an alternative COVID-19 therapy. Coadministration may increase clopidogrel exposure resulting in increased toxicity. Clopidogrel is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] Clorazepate: (Major) Consider temporary discontinuation of clorazepate 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 clorazepate exposure resulting in increased toxicity. Clorazepate is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] (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: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and clozapine is contraindicated; consider an alternative COVID-19 therapy. Coadministration may increase clozapine exposure resulting in increased toxicity. Clozapine is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] (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) 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] (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and ritonavir in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Ritonavir can inhibit colchicine's metabolism via P-glycoprotein (P-gp) and CYP3A4, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken ritonavir in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day. [27493] [28380] [34557] [34558] [36114] [61147] 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 ritonavir and crizotinib due to increased plasma concentrations of crizotinib, which may increase the incidence and severity of adverse reactions. If concomitant use is necessary for patients with non-small cell lung cancer, reduce the dose of crizotinib to 250 mg PO once daily. If concomitant use is necessary for patients with anaplastic large cell lymphoma, reduce the dose of crizotinib to 250 mg PO twice daily for BSA of 1.7 m2 or more; 200 mg PO twice daily for BSA of 1.17 to 1.69 m2; and 250 mg PO once daily for BSA of 0.81 to 1.16 m2; do not use this combination in patients with a BSA of 0.6 to 0.8 m2. Resume the original crizotinib dose after discontinuation of ritonavir. Crizotinib is a CYP3A substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC of single-dose crizotinib by 216%. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC of crizotinib by 57% compared to crizotinib alone. [45458] [47165] 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) 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. [2357] [28142] [28341] [28839] [28995] [32432] [4718] [5936] [65478] [65479] [65481] [65482] [65483] (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] 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) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with ritonavir, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. 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 with P-gp inhibitors like ritonavir in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with ritonavir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran. [27493] [28380] [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] Daclatasvir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as ritonavir. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects. In addition, the therapeutic effects of ritonavir, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor. [28380] [34557] [47165] [60001] 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. [7238] [7335] 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. [7238] [7335] (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. [36111] [7238] [7335] (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. [7238] [7335] 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) A dose reduction of the tricyclic antidepressant (TCA) may be necessary when coadministered with ritonavir. Concurrent use may result in elevated TCA plasma concentrations. [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] Dexamethasone: (Moderate) Close monitoring of therapeutic and adverse effects is required when dexamethasone is coadministered with ritonavir. Ritonavir inhibits CYP3A4 and dexamethasone is a CYP3A4 substrate. [4718] [5070] [5206] (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 moderate CYP3A inducer. [54286] [67203] 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; 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] (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 temporary discontinuation of diazepam 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 diazepam exposure resulting in increased toxicity. Diazepam is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [64930] [65314] (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of diazepam and increase the potential for benzodiazepine toxicity. Prolonged sedation and respiratory depression can occur. A decrease in the diazepam dose may be needed [28001] [28345] [28556] [47165] [55901] 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] Dihydrocodeine; Guaifenesin; Pseudoephedrine: (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] Dihydroergotamine: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred. [28142] [28341] [28731] [28839] [28995] [32432] [46638] [5018] [5044] [5623] [5747] [8102] (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] Diltiazem: (Major) Ritonavir is expected to decreases 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. Decreased diltiazem may be warranted. In addition, ritonavir and diltiazem both prolong the PR interval and caution for increased risk is recommended with coadministration. [4718] [5044] 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; Hydrocodone; Phenylephrine: (Major) Consider withholding hydrocodone if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. 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] (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] (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] 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] (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) A dose reduction of the tricyclic antidepressant (TCA) may be necessary when coadministered with ritonavir. Concurrent use may result in elevated TCA plasma concentrations. [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) 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] (Contraindicated) The concomitant use of dronedarone and ritonavir is contraindicated. Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ritonavir is a strong inhibitor of CYP3A4, is an inducer of CYP3A, and is a substrate of CYP3A and P-gp. Repeated doses of ketoconazole, also a strong CYP3A4 inhibitor, increased dronedarone exposure 17-fold and increased dronedarone Cmax 9-fold. Furthermore, coadministration of dronedarone and ritonavir may, theoretically, result in decreased concentrations of dronedarone due to CYP3A induction by ritonavir; the net effect on dronedarone plasma concentrations is not known. However, no data exist regarding the safe administration of dronedarone with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated. Also, the effects of dronedarone on the pharmacokinetics of ritonavir have not been described, although an increase in ritonavir serum concentrations is possible. [36101] 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] 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] 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 an alternative COVID-19 therapy. Coadministration may increase tamsulosin exposure resulting in increased toxicity. Tamsulosin is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [29677] [65314] (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] (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: (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] (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] (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] 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) 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. Ivacaftor is a CYP3A substrate and ritonavir is a CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. [48524] (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor when coadministered with ritonavir; coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 2 elexacaftor/tezacaftor/ivacaftor combination tablets 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. Elexacaftor, tezacaftor, and ivacaftor are CYP3A4 substrates (ivacaftor is a sensitive substrate); ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 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: (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 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. [7238] [7335] 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. [7238] [7335] 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. [7238] [7335] (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. [7238] [7335] (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] Enalapril; Felodipine: (Moderate) Concurrent administration of felodipine with protease inhibitors may result in elevated felodipine plasma concentrations. This increase in felodipine concentration may lead to increased therapeutic and adverse effects, such as lower blood pressure, dizziness, and headache. Felodipine is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitors of this enzyme. In addition, ritonavir 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. [32432] [47165] Encainide: (Major) Concurrent administration of encainide with ritonavir may result in elevated encainide plasma concentrations. Encainide is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme and may increase serum encainide concentrations by as much as 2-fold. Because encainide has a narrow therapeutic index and adverse events may be severe, close monitoring and dose adjustment are advised if these drugs are administered together. [28315] [47165] [57084] [58664] Encorafenib: (Major) Avoid coadministration of encorafenib and ritonavir due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of ritonavir. If ritonavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of ritonavir. Encorafenib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively. [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 and inhibitor; the net effect of encorafenib on CYP3A is unknown. [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 resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If ritonavir is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of ritonavir. Entrectinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study. [47165] [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] (Major) Avoid concomitant use of ritonavir-boosted nirmatrelvir and eplerenone and 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] Erdafitinib: (Major) Avoid coadministration of erdafitinib and ritonavir due to the risk of increased plasma concentrations of erdafitinib. If concomitant use is unavoidable, closely monitor for erdafitinib-related adverse reactions and consider dose modifications as clinically appropriate. If ritonavir is discontinued, the dose of erdafitinib may be increased in the absence of drug-related toxicity. Erdafitinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. The mean ratios for the Cmax and AUC of erdafitinib were 105% and 134%, respectively, when coadministered with another strong CYP3A4 inhibitor. [47165] [64064] Ergoloid Mesylates: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred. [28142] [28341] [28731] [28839] [28995] [32432] [46638] [5018] [5044] [5623] [5747] [8102] (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] Ergonovine: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred. [28142] [28341] [28731] [28839] [28995] [32432] [46638] [5018] [5044] [5623] [5747] [8102] (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] Ergot alkaloids: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred. [28142] [28341] [28731] [28839] [28995] [32432] [46638] [5018] [5044] [5623] [5747] [8102] (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] Ergotamine: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred. [28142] [28341] [28731] [28839] [28995] [32432] [46638] [5018] [5044] [5623] [5747] [8102] (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] Ergotamine; Caffeine: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred. [28142] [28341] [28731] [28839] [28995] [32432] [46638] [5018] [5044] [5623] [5747] [8102] (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] 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] (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] Erythromycin; Sulfisoxazole: (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] (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 temporary discontinuation of estazolam 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 estazolam exposure resulting in increased toxicity. Estazolam is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] (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 Cypionate; 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) 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: (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: (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] Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (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] 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] 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] (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] 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) Concurrent use of ritonavir with ethotoin, phenytoin, or fosphenytoin should be avoided when possible. Increased doses of anticonvulsants may be required due to metabolism induction by ritonavir. Additionally, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. [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] 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] 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] 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] (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] Felbamate: (Major) Concurrent administration of felbamate with ritonavir may result in decreased plasma concentrations of ritonavir. Felbamate is a mild inducer of the hepatic isoenzyme CYP3A4; ritonavir is metabolized by this enzyme. Monitor for antiviral efficacy if these drugs are administered together. [4190] [58664] Felodipine: (Moderate) Concurrent administration of felodipine with protease inhibitors may result in elevated felodipine plasma concentrations. This increase in felodipine concentration may lead to increased therapeutic and adverse effects, such as lower blood pressure, dizziness, and headache. Felodipine is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitors of this enzyme. In addition, ritonavir 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. [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 an alternative COVID-19 therapy. 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] 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] 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] 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] (Major) Concurrent use of HIV treatment doses of ritonavir with flecainide is contraindicated. Cautious consideration may be given to administering amiodarone with boosting doses of ritonavir. The potential increase in plasma concentrations of flecainide could result in significant adverse effects. [47165] Flibanserin: (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] (Major) 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] 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) A dose reduction of fluoxetine may ne necessary if coadministered with ritonavir. Increased fluoxetine exposure may occur. Cardiac and neurologic events have been reported when ritonavir has been administered with fluoxetine. [47165] Flurazepam: (Major) Consider temporary discontinuation of flurazepam 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 flurazepam exposure resulting in increased toxicity. Flurazepam is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of flurazepam and increase the potential for benzodiazepine toxicity. A decrease in the flurazepam dose may be needed. [28001] [28345] [32432] 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] 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 marijuana 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] Fosamprenavir: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of fosamprenavir is necessary. Concomitant use of nirmatrelvir and fosamprenavir may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and fosamprenavir is a CYP3A inducer and inhibitor; the net effect of fosamprenavir on CYP3A is unknown. [29012] [34489] [34491] [67203] 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) Concurrent use of ritonavir with ethotoin, phenytoin, or fosphenytoin should be avoided when possible. Increased doses of anticonvulsants may be required due to metabolism induction by ritonavir. Additionally, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. [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] 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] (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] 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. 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; 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] 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] Guaifenesin; Hydrocodone: (Major) Consider withholding hydrocodone if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. 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] (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] Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Consider withholding hydrocodone if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. 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] (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] 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] Halofantrine: (Moderate) Protease Inhibitors significantly inhibit cytochrome CYP3A4,and may lead to an inhibition of halofantrine metabolism, placing the patient at risk for halofantrine cardiac toxicity. [4718] [4968] 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 an alternative COVID-19 therapy. 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] (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) Concurrent use of ritonavir with ethotoin, phenytoin, or fosphenytoin should be avoided when possible. Increased doses of anticonvulsants may be required due to metabolism induction by ritonavir. Additionally, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. [28315] [46638] Hydrocodone: (Major) Consider withholding hydrocodone if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. 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] (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 an alternative COVID-19 therapy. 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] (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; Phenylephrine: (Major) Consider withholding hydrocodone if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. 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] (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; Potassium Guaiacolsulfonate: (Major) Consider withholding hydrocodone if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. 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] (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; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Consider withholding hydrocodone if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. 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] (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; Pseudoephedrine: (Major) Consider withholding hydrocodone if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. 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] (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 an alternative COVID-19 therapy. 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] (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) A dose reduction of the tricyclic antidepressant (TCA) may be necessary when coadministered with ritonavir. Concurrent use may result in elevated TCA plasma concentrations. [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: (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] 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] 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; 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] 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] 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] Isradipine: (Moderate) Concurrent administration of isradipine with protease inhibitors may result in elevated isradipine plasma concentrations and increased hypotensive effects. Isradipine is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitors of this enzyme. In addition, ritonavir 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. [29128] [32432] [47165] 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] Ivacaftor: (Major) If ritonavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and ritonavir is a CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. [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] 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] Lansoprazole; Naproxen: (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] Lanthanum Carbonate: (Major) Oral compounds known to interact with antacids, like protease inhibitors, should not be taken within 2 hours of dosing with lanthanum carbonate. If these agents are used concomitantly, space the dosing intervals appropriately. Monitor serum concentrations and clinical condition. [9126] 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] Lesinurad: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of lesinurad is necessary. Concomitant use of nirmatrelvir and lesinurad may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and lesinurad is a weak CYP3A inducer. [60473] [67203] (Moderate) Ritonavir may decrease the systemic exposure and therapeutic effect of lesinurad; monitor for potential reduction in efficacy. Ritonavir is a CYP2C9 inducer, and lesinurad is a CYP2C9 substrate. [26120] [28315] [60473] Lesinurad; Allopurinol: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of lesinurad is necessary. Concomitant use of nirmatrelvir and lesinurad may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and lesinurad is a weak CYP3A inducer. [60473] [67203] (Moderate) Ritonavir may decrease the systemic exposure and therapeutic effect of lesinurad; monitor for potential reduction in efficacy. Ritonavir is a CYP2C9 inducer, and lesinurad is a CYP2C9 substrate. [26120] [28315] [60473] 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) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. 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. [29090] [47165] [58664] Levobupivacaine: (Minor) Levobupivacaine is metabolized by CYP3A4 and CYP1A2. Known inhibitors of CYP3A4, such as ritonavir, may result in increased systemic levels of levobupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of levobupivacaine may be needed. [5637] 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] Levomethadyl: (Major) Agents that inhibit hepatic cytochrome P450 CYP 3A4, including ritonavir, may decrease the metabolism of levomethadyl, increase levomethadyl levels, and may precipitate severe arrhythmias including torsade de pointes. [4718] 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] 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] 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] 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] 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] (Major) 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] 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] (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] Lovastatin; Niacin: (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] (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: (Major) If ritonavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and ritonavir is a CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. [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: (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) Avoid concomitant use of ritonavir-boosted nirmatrelvir and lumateperone and consider an alternative COVID-19 therapy. Coadministration may increase lumateperone exposure resulting in increased toxicity. Lumateperone is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] (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] (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 coadministration of lurbinectedin and ritonavir due to the risk of increased lurbinectedin exposure which may increase the incidence of lurbinectedin-related adverse reactions. Lurbinectedin is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. [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] 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] 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] (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and meperidine is contraindicated; consider an alternative COVID-19 therapy. Coadministration may increase meperidine exposure resulting in increased toxicity. Meperidine is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] Meperidine; Promethazine: (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] (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and meperidine is contraindicated; consider an alternative COVID-19 therapy. Coadministration may increase meperidine exposure resulting in increased toxicity. Meperidine is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] Mephobarbital: (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] (Major) Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. [46638] Mestranol; Norethindrone: (Major) Ritonavir increases the metabolism of mestranol. Women receiving hormonal contraceptives and 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 ritonavir 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 ritonavir should use an additional barrier method of contraception such as condoms. [5044] [7731] (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] 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; 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. 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. [36111] [7238] [7335] (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] (Major) Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. [46638] Methylergonovine: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred. [28142] [28341] [28731] [28839] [28995] [32432] [46638] [5018] [5044] [5623] [5747] [8102] (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] 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] Methysergide: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred. [28142] [28341] [28731] [28839] [28995] [32432] [46638] [5018] [5044] [5623] [5747] [8102] (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] 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] (Major) The use of oral midazolam and anti-retroviral protease inhibitors is contraindicated due to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression. Parenteral midazolam can be used with protease inhibitors in a setting that allows for close clinical monitoring with the ability to manage respiratory depression or sedation should they occur; a reduction in the dose of parenteral midazolam may be warranted. Lorazepam, oxazepam, or temazepam may be safer alternatives, as these benzodiazepines are not oxidatively metabolized. Midazolam is metabolized by hepatic isozyme CYP3A4. Protease inhibitors have been shown to increase oral midazolam AUCs by up to 3-fold, resulting in clinically significant potentiation of sedation. [28142] [28341] [28731] [28839] [28995] [29012] [31320] [32432] [44859] [47165] 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. [7238] [7335] 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] 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] 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 the use of sirolimus with potent CYP3A4 inhibitors, such as protease inhibitors. Protease inhibitors may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4. [28610] [28995] [47165] (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] 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] Nebivolol; Valsartan: (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] (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] 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) Concurrent administration of nevirapine with ritonavir may result in elevated nevirapine plasma concentrations and decreased concentrations of ritonavir. Nevirapine is a substrate and inducer of the hepatic isoenzyme CYP3A4; ritonavir is a substrate and potent inhibitor of this enzyme. Caution and close monitoring for antiviral efficacy and adverse effects are advised if these drugs are administered together. [5222] [58664] (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 moderate CYP3A inducer. [42456] [67203] Niacin; 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] (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] 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] [38968] [47165] [58203] Nisoldipine: (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. In addition, 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] [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] (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] (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] (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] Nortriptyline: (Moderate) A dose reduction of the tricyclic antidepressant (TCA) may be necessary when coadministered with ritonavir. Concurrent use may result in elevated TCA plasma concentrations. [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) A dose reduction of fluoxetine may ne necessary if coadministered with ritonavir. Increased fluoxetine exposure may occur. Cardiac and neurologic events have been reported when ritonavir has been administered with fluoxetine. [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) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. 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. [29090] [47165] [58664] 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] 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) Coadministration of ritonavir and rifabutin results in clinically significant alterations of rifabutin pharmacokinetic parameters, with the rifabutin AUC being increased by 430%. In patients receiving any dosage of ritonavir, the dose of rifabutin should always be decreased to 150 mg every day or 300 mg three times per week. [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] 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: (Major) Concurrent administration of oxcarbazepine with ritonavir should be undertaken with caution and careful monitoring of antiviral efficacy. Oxcarbazepine is a moderate inducer of the hepatic isoenzyme CYP3A4, and ritonavir is a CYP3A4 substrate. [29014] [58664] (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] Oxybutynin: (Moderate) Oxybutynin is metabolized by CYP3A4. Caution should be used when oxybutynin is given in combination with inhibitors of CYP3A4, such as protease inhibitors. Monitor for adverse effects if these drugs are administered together. [29796] [47165] [58664] Oxycodone: (Major) Consider withholding oxycodone if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. 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] (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] 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] 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] Penbutolol: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers. [5044] 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] (Major) Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. [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] Pergolide: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred. [28142] [28341] [28731] [28839] [28995] [32432] [46638] [5018] [5044] [5623] [5747] [8102] (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] Perindopril; Amlodipine: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. 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. [29090] [47165] [58664] Perphenazine; Amitriptyline: (Moderate) A dose reduction of the tricyclic antidepressant (TCA) may be necessary when coadministered with ritonavir. Concurrent use may result in elevated TCA plasma concentrations. [47165] Pexidartinib: (Major) Avoid coadministration of pexidartinib with ritonavir as concurrent use may increase exposure to pexidartinib and decrease exposure to ritonavir. If concurrent use cannot be avoided, reduce the dose of pexidartinib and monitor patients for a loss of ritonavir efficacy. If ritonavir is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of ritonavir. Dose adjustments are as follows: 800 mg/day or 600 mg/day of pexidartinib, reduce to 200 mg twice daily; 400 mg/day of pexidartinib, reduce to 200 mg once daily. Both drugs are CYP3A4 substrates. Additionally, pexidartinib is a moderate CYP3A4 inducer and ritonavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased pexidartinib exposure by 70%. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. [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] (Major) Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. [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] (Major) Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. [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] (Major) Concurrent use of ritonavir with ethotoin, phenytoin, or fosphenytoin should be avoided when possible. Increased doses of anticonvulsants may be required due to metabolism induction by ritonavir. Additionally, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. [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] 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; 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] 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] 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 coadministration of ritonavir with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is unavoidable, 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. After ritonavir has been discontinued for 3 to 5 elimination half-lives, resume the pralsetinib dose taken prior to initiating ritonavir. Pralsetinib is a CYP3A and P-glycoprotein (P-gp) substrate and ritonavir is a combined P-gp and strong CYP3A inhibitor. Coadministration with another combined P-gp and strong CYP3A inhibitor increased the AUC 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] (Major) Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. [46638] Probenecid; Colchicine: (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] (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and ritonavir in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Ritonavir can inhibit colchicine's metabolism via P-glycoprotein (P-gp) and CYP3A4, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken ritonavir in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day. [27493] [28380] [34557] [34558] [36114] [61147] 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] (Major) Coadministration of HIV treatment doses of ritonavir and propafenone is contraindicated due to the potential for serious or life-threatening reactions, such as cardiac arrhythmias. However, propafenone and ritonavir may be coadministered with caution to patients receiving ritonavir as a boosting agent. Ritonavir inhibits both CYP3A4 and CYP2D6. Drugs that inhibit both pathways are expected to increase propafenone serum concentrations. [28287] [28315] [46638] [58664] 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] Propoxyphene: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and propoxyphene is contraindicated; consider an alternative COVID-19 therapy. Coadministration may increase propoxyphene exposure resulting in increased toxicity. Propoxyphene is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] (Moderate) Due to effects on microsomal isoenzymes responsible for hepatic metabolism, ritonavir may alter the response and/or increase the AUC of opiate analgesics. Concurrent use of ritonavir and propoxyphene is not recommended, due the increased formation of the neurotoxic metabolites of propoxyphene. Also, propoxyphene is a substrate/inhibitor of CYP3A4. Increased serum concentrations of propoxyphene can occur from concurrent use of ritonavir, a CYP3A4 inhibitor. A reduced dosage of propoxyphene may be needed. Monitor for CNS and respiratory depression. [11379] [36008] [4718] [5044] 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] Propranolol; Hydrochlorothiazide, HCTZ: (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) A dose reduction of the tricyclic antidepressant (TCA) may be necessary when coadministered with ritonavir. Concurrent use may result in elevated TCA plasma concentrations. [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] (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] [28315] [31403] [38968] 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] 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] 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] 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) Coadministration of ritonavir and rifabutin results in clinically significant alterations of rifabutin pharmacokinetic parameters, with the rifabutin AUC being increased by 430%. In patients receiving any dosage of ritonavir, the dose of rifabutin should always be decreased to 150 mg every day or 300 mg three times per week. [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] 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] 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] (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 toxicity. Rivaroxaban is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] 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] 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] 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] Ruxolitinib: (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] 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. [36111] [7238] [7335] 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] (Major) Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. [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] 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] Sibutramine: (Moderate) Due to ritonavir's potential inhibitory effects on various hepatic isoenzymes, close monitoring of serum drug concentrations and/or therapeutic and adverse effects is required when sibutramine is coadministered with ritonavir; dosage reduction may be needed. [4718] 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] Silodosin: (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] (Major) 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] Simeprevir: (Major) Avoid concurrent use of simeprevir and ritonavir. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by ritonavir causes significantly increased plasma concentrations of simeprevir, potentially resulting in adverse effects. [28380] [47165] [56471] [56579] 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] (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] Simvastatin; Sitagliptin: (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] (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] (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] 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 the use of sirolimus with potent CYP3A4 inhibitors, such as protease inhibitors. Protease inhibitors may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4. [28610] [28995] [47165] (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] 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] Solifenacin: (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 the concomitant use of sonidegib and ritonavir as sonidegib levels may be significantly increased resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively [28315] [58864] [60000] [60002] 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] St. John's Wort, Hypericum perforatum: (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] (Contraindicated) Use of St. John's wort with protease inhibitors is contraindicated. St. John's wort is an inducer of CYP3A and is expected to significantly decrease the plasma concentrations of all currently marketed protease inhibitors. Reductions in plasma concentrations of these drugs could lead to HIV treatment failures or the development of viral-resistance. St. John's wort in all forms, including teas, should be avoided in HIV patients treated with these agents. [2718] [28315] [28731] [28995] [46638] [4718] [4865] [4935] [8102] Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if a protease inhibitor must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of a protease inhibitor is necessary. If a protease inhibitor is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a strong CYP3A4 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 a protease inhibitor 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] 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] (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentrations if coadministration with ritonavir is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Consider a tacrolimus dose reduction to 0.5 mg to 1 mg once per week when coadministered with a protease inhibitor. In one study, the tacrolimus half-life increased to 10.6 days in one patient and 20.6 days in another following coadministration of tacrolimus and 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. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; ritonavir is a strong CYP3A4 inhibitor. [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] (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-glycoprotein (P-gp) substrate and ritonavir is a P-gp inhibitor. Coadministration with other P-gp inhibitors increased talazoparib exposure by 8% to 45%. [28380] [34557] [63651] Tamsulosin: (Major) Consider withholding tamsulosin if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. Coadministration may increase tamsulosin exposure resulting in increased toxicity. Tamsulosin is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [29677] [65314] (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 a diminished response to nirmatrelvir if concomitant use of tecovirimat is necessary. Concomitant use of nirmatrelvir and tecovirimat may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and tecovirimat is a weak CYP3A inducer. [63353] [67203] (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] Telithromycin: (Major) Avoid coadministration of telithromycin and ritonavir due to increased telithromycin exposure which may increase the risk of QT prolongation; ritonavir exposure may also increase. Both drugs are substrates and strong inhibitors of CYP3A4. [28156] [47165] Telmisartan; Amlodipine: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. 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. [29090] [47165] [58664] 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] Teniposide: (Moderate) Concurrent administration of teniposide with ritonavir may result in elevated teniposide plasma concentrations. Teniposide is a substrate for CYP3A4 and P-glycoprotein (P-gp); ritonavir inhibits both CYP3A44 and P-gp. Caution and close monitoring are advised if these drugs are administered together. [28498] [34660] [47165] [48961] [58664] Tenofovir, PMPA: (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] Tepotinib: (Major) Avoid concomitant use of tepotinib and ritonavir due to increased plasma concentrations of tepotinib, which may increase the incidence and severity of adverse reactions. Tepotinib is a CYP3A and P-gp substrate; ritonavir is a dual strong CYP3A and P-gp inhibitor. [28380] [34557] [47165] [66372] 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] Terfenadine: (Contraindicated) Caution should be used in patients receiving protease inhibitors concurrently with drugs metabolized via CYP3A4 and known to cause QT prolongation. Protease inhibitors inhibit the CYP3A4 isoenzyme at clinically relevant concentrations, which may lead to increased serum concentrations of terfenadine and an increased potential for QT prolongation or other adverse effects. Serious and/or life-threatening drug interactions could potentially occur between protease inhibitors and terfenadine. [141] [1800] [4865] [5044] 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. Ivacaftor is a CYP3A substrate and ritonavir is a CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. [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] Thiopental: (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] (Major) Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. [46638] 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] 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] 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] 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 CYP3A4 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 CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers. [31112] [43295] [47165] Tolvaptan: (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] 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) Consider withholding tramadol if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. Coadministration may increase tramadol exposure resulting in increased toxicity. Tramadol is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [32475] [65314] (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] Tramadol; Acetaminophen: (Major) Consider withholding tramadol if clinically appropriate during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider an alternative COVID-19 therapy. Coadministration may increase tramadol exposure resulting in increased toxicity. Tramadol is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [32475] [65314] (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] Trandolapril; Verapamil: (Moderate) Concurrent administration of verapamil with ritonavir may result in elevated plasma concentrations of both drugs. Both verapamil and ritonavir are substrates and inhibitors of CYP3A4. Verapamil also inhibits the drug transporter P-glycoprotein (P-gp); ritonavir is a substrate of P-gp. 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. [11554] [40025] [5044] [56565] [6446] 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] Tricyclic antidepressants: (Moderate) A dose reduction of the tricyclic antidepressant (TCA) may be necessary when coadministered with ritonavir. Concurrent use may result in elevated TCA plasma concentrations. [47165] Trimetrexate: (Moderate) Protease inhibitors inhibit the cytochrome P450 3A4 isoenzyme. Concurrent administration of trimetrexate with protease inhibitors may result in increased trimetrexate levels. Monitor patients closely. [4718] [5172] [5206] [5224] Trimipramine: (Moderate) A dose reduction of the tricyclic antidepressant (TCA) may be necessary when coadministered with ritonavir. Concurrent use may result in elevated TCA plasma concentrations. [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] 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) 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 in patients with Ulcerative Colitis. Do not exceed an upadacitinib dose of 15 mg PO once daily if coadministered with ritonavir in patients with arthritis or dermatitis. Monitor closely for adverse reactions. Concurrent use may increase upadacitinib exposure. Upadacitinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concurrent use of a strong inhibitor increased upadacitinib exposure by 75%. [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] 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] (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) Concurrent administration of verapamil with ritonavir may result in elevated plasma concentrations of both drugs. Both verapamil and ritonavir are substrates and inhibitors of CYP3A4. Verapamil also inhibits the drug transporter P-glycoprotein (P-gp); ritonavir is a substrate of P-gp. 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. [11554] [40025] [5044] [56565] [6446] 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 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] 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 should be avoided unless an assessment of the benefit to risk ratio justifies concurrent use. In one study, concurrent administration of voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) and ritonavir (400 mg every 12 hours for 9 days) resulted in a 66% and 82% decrease in voriconazole Cmax and AUC, respectively. Low dose ritonavir (100 mg every 12 hours) decreased voriconazole Cmax and AUC concentrations by 24% and 39%, respectively. [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] Voxelotor: (Major) Avoid coadministration of voxelotor and ritonavir as concurrent use may increase voxelotor exposure and lead to increased toxicity. If coadministration is unavoidable, reduce voxelotor dosage to 1,000 mg PO once daily. Voxelotor is a substrate of CYP3A4; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase voxelotor exposure by 42% to 83%. [47165] [64778] Warfarin: (Moderate) Monitor the INR and adjust the dose as necessary if warfarin is coadministered with ritonavir: concurrent use may increase the risk of bleeding or reduce efficacy. Ritonavir is a CYP 3A4 inhibitor as well as a CYP1A4, CYP2C9, and CYP3A4 inducer. Warfarin is a substrate of CYP3A4, CYP2C9, and CYP1A2. [28549] [47165] Yohimbine: (Moderate) Concurrent administration of yohimbine with ritonavir may result in elevated yohimbine plasma concentrations. Yohimbine is metabolized by the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is an inhibitor of these enzymes. Caution and close monitoring are advised if these drugs are administered together. [42997] [57066] [58664] 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] Zalcitabine, ddC: (Major) Zalcitabine may cause peripheral neuropathy and coadministration with other drugs associated with peripheral neuropathy, such as ritonavir, should be avoided when possible. [1800] [6580] 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] Zileuton: (Moderate) Concurrent administration of zileuton with protease inhibitors may result in elevated zileuton plasma concentrations. Zileuton is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together [34597] [34598] [51119] 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] Zonisamide: (Moderate) Concurrent administration of zonisamide with ritonavir may result in elevated plasma concentrations of both zonisamide and ritonavir. Zonisamide is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Additionally, zonisamide is a weak inhibitor of P-gp, and ritonavir is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates. Caution and close monitoring are advised if these drugs are administered together. [28843] [58664]
      Revision Date: 06/21/2022, 02:27:00 AM

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      Monitoring Parameters

      • LFTs
      • serum creatinine

      US Drug Names

      • PAXLOVID
      ;