ContenidosdeElseviersobremedicamentos
TRANSFORME LA FORMA DE USAR LA INFORMACIÓN SOBRE MEDICAMENTOS
Remdesivir
Indications/Dosage
Labeled
- coronavirus disease 2019 (COVID-19)
- severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection
NOTE: Initiate treatment as soon as possible after the positive test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and within 7 days of symptom onset.[65314][66063][67214]
NOTE: Healthcare 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. Remdesivir has demonstrated activity in vitro and in animal studies against the SARS-CoV-2 Omicron variant and its subvariants.[65314]
NOTE: Logistical or supply constraints may make it impossible to offer the available therapy to all eligible patients, making patient triage necessary. Prioritize use of these therapies for patients at highest risk of clinical progression. Information on which individuals might receive the greatest benefit from anti-SARS-CoV-2 therapeutics for treatment or prevention can be obtained from www.covid19treatmentguidelines.nih.gov/therapies/statement-on-patient-prioritization-for-outpatient-therapies. Healthcare providers are advised to consider the benefit-risk for each individual patient.[65314]
Off-Label
For the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the virus that causes coronavirus disease 2019 (COVID-19)
for the treatment of hospitalized patients with COVID-19
Intravenous dosage (powder for injection)
Adults NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)
200 mg IV once on day 1, followed by 100 mg IV once daily for 4 days. May extend treatment for up to 5 additional days (i.e., 10 days total) if a patient does not demonstrate clinical improvement.[66063] The NIH recommends a treatment duration of 5 days or until hospital discharge. This recommendation is based on study data showing the 5-day course being comparable to 10 days of therapy in hospitalized patients with moderate to severe COVID-19.[65314]
Adults requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)
200 mg IV once on day 1, followed by 100 mg IV once daily for 9 days.[66063] The NIH recommends against starting remdesivir in this population; however, remdesivir may be continued, in combination with dexamethasone, to complete a treatment course in patients who progress to mechanical ventilation or ECMO.[65314]
Children and Adolescents weighing 40 kg or more NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)
200 mg IV once on day 1, followed by 100 mg IV once daily for 4 days. May extend treatment for up to 5 additional days (i.e., 10 days total) if a patient does not demonstrate clinical improvement.[66063]
Children and Adolescents weighing 40 kg or more requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)
200 mg IV once on day 1, followed by 100 mg IV once daily for 9 days.[66063] The NIH recommends against starting remdesivir in this population; however, remdesivir may be continued, in combination with dexamethasone, to complete a treatment course in patients who progress to mechanical ventilation or ECMO.[65314]
Infants, Children, and Adolescents weighing 3 to 39 kg NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)
5 mg/kg/dose IV once on day 1, followed by 2.5 mg/kg/dose IV once daily for 4 days. May extend treatment for up to 5 additional days (i.e., 10 days total) if a patient does not demonstrate clinical improvement.[66063]
Infants, Children, and Adolescents weighing 3 to 39 kg requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)
5 mg/kg/dose IV once on day 1, followed by 2.5 mg/kg/dose IV once daily for 9 days.[66063] The NIH recommends against starting remdesivir in this population; however, remdesivir may be continued, in combination with dexamethasone, to complete a treatment course in patients who progress to mechanical ventilation or ECMO.[65314]
Neonates†
5 mg/kg/dose IV once on day 1, followed by 2.5 mg/kg/dose IV once daily for up to 10 days is being used in an ongoing investigational study (NCT04431453) in neonates 14 to 27 days of age, gestational age more than 37 weeks, and weight 2.5 kg or more.[66492] 2.5 mg/kg/dose IV once on day 1, followed by 1.25 mg/kg/dose IV once daily for 4 days was successfully used in a case report of 2 ex-premature neonates. The first neonate was born at 31 weeks, weighed 2.7 kg, and presented with SARS-CoV-2 infection at 37 weeks of life. The second neonate was born at 33 weeks (birthweight 1.5 kg) and presented with SARS-CoV-2 infection at 35 weeks of life. In both cases, the SARS-CoV-2 RNA PCR became negative only after completion of treatment with remdesivir.[66931] Another case report describes 5 mg/kg/dose IV once on day 1, followed by 1.25 mg/kg/dose IV once daily for 10 days successfully used in an ex-premature neonate (born at 32 weeks) weighing 2.2 kg who presented with SARS-CoV-2 infection at 37 weeks of life.[66493]
Intravenous dosage (solution for injection)
Adults NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)
200 mg IV once on day 1, followed by 100 mg IV once daily for 4 days. May extend treatment for up to 5 additional days (i.e., 10 days total) if a patient does not demonstrate clinical improvement.[66063] The NIH recommends a treatment duration of 5 days or until hospital discharge. This recommendation is based on study data showing the 5-day course being comparable to 10 days of therapy in hospitalized patients with moderate to severe COVID-19.[65314]
Adults requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)
200 mg IV once on day 1, followed by 100 mg IV once daily for 9 days.[66063] The NIH recommends against starting remdesivir in this population; however, remdesivir may be continued, in combination with dexamethasone, to complete a treatment course in patients who progress to mechanical ventilation or ECMO.[65314]
Children and Adolescents weighing 40 kg or more NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)
200 mg IV once on day 1, followed by 100 mg IV once daily for 4 days. May extend treatment for up to 5 additional days (i.e., 10 days total) if a patient does not demonstrate clinical improvement.[66063]
Children and Adolescents weighing 40 kg or more requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)
200 mg IV once on day 1, followed by 100 mg IV once daily for 9 days.[66063] The NIH recommends against starting remdesivir in this population; however, remdesivir may be continued, in combination with dexamethasone, to complete a treatment course in patients who progress to mechanical ventilation or ECMO.[65314]
for the treatment of nonhospitalized patients with mild to moderate COVID-19 who are at high risk for progression to severe COVID-19, including hospitalization or death
Intravenous dosage (powder for injection)
Adults
200 mg IV once on day 1, followed by 100 mg IV once daily for 2 days.[66063] [67214] [65314]
Children and Adolescents weighing 40 kg or more
200 mg IV once on day 1, followed by 100 mg IV once daily for 2 days.[66063] [67214]
Infants, Children, and Adolescents weighing 3 to 39 kg
5 mg/kg/dose IV once on day 1, followed by 2.5 mg/kg/dose IV once daily for 2 days.[66063]
Intravenous dosage (solution for injection)
Adults
200 mg IV once on day 1, followed by 100 mg IV once daily for 2 days.[66063] [67214] [65314]
Children and Adolescents weighing 40 kg or more
200 mg IV once on day 1, followed by 100 mg IV once daily for 2 days.[66063] [67214]
Therapeutic Drug Monitoring
Maximum Dosage Limits
- Adults
200 mg IV on day 1, followed by 100 mg IV once daily.
- Geriatric
200 mg IV on day 1, followed by 100 mg IV once daily.
- Adolescents
weight 40 kg or more: 200 mg IV on day 1, followed by 100 mg IV once daily.
weight less than 40 kg: 5 mg/kg/dose IV on day 1, followed by 2.5 mg/kg/dose IV once daily.
- Children
weight 40 kg or more: 200 mg IV on day 1, followed by 100 mg IV once daily.
weight less than 40 kg: 5 mg/kg/dose IV on day 1, followed by 2.5 mg/kg/dose IV once daily.
- Infants
5 mg/kg/dose IV on day 1, followed by 2.5 mg/kg/dose IV once daily.
- Neonates
Safety and efficacy have not been established; however, investigational doses of 2.5 or 5 mg/kg/dose IV on day 1, followed by 1.25 or 2.5 mg/kg/dose IV once daily have been used.
Patients with Hepatic Impairment Dosing
It is unknown if dosage adjustments are needed in patients with hepatic disease. Consider discontinuing treatment if ALT increases to more than 10-times ULN. Discontinue treatment if ALT elevations are accompanied by signs or symptoms of hepatic inflammation.[66063]
Patients with Renal Impairment Dosing
eGFR 30 mL/minute or more: No dosage adjustment needed.
eGFR less than 30 mL/minute: Treatment is not recommended.[66063] However, the National Institutes of Health (NIH) COVID-19 treatment guidelines contain study data (i.e., CATCO study) that suggest remdesivir can be used in patients with an eGFR less than 30 mL/minute if the potential benefits outweigh the risks.[65314]
† Off-label indicationReferences
How Supplied
Remdesivir Powder for solution for injection
Veklury 100mg Powder for Injection (61958-2901) (Gilead Sciences Inc) null
Remdesivir Solution for injection
Veklury 100mg/20mL Solution for Injection (61958-2902) (Gilead Sciences Inc) null
Description/Classification
Description
Remdesivir is an intravenous antiviral medication approved to treat coronavirus disease 2019 (COVID-19) in adults and pediatric patients (28 days and older and weighing at least 3 kg) with positive testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is only indicated for use in patients who are hospitalized with COVID-19 or for patients with mild to moderate COVID-19 who are not hospitalized, but at high risk of progressing to severe COVID-19, including hospitalization or death.[66063]
The National Institutes of Health (NIH) COVID-19 treatment guidelines have recommendations for the use of remdesivir based on disease severity.[65314]
Adult patients
- The NIH guideline recommends remdesivir for use in the following patients with COVID-19:
- Nonhospitalized patients with mild to moderate COVID-19 who are at high risk of progressing to severe COVID-19.
- Hospitalized patients not requiring supplemental oxygen who are at high risk for clinical progression.
- Hospitalized patients who require supplemental oxygen BUT NOT on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO; the NIH recommends remdesivir either alone (patients requiring minimal oxygen) or in combination with dexamethasone.
- Certain hospitalized patients who require high-flow oxygen or noninvasive ventilation, remdesivir may be given in combination with dexamethasone (with or without either baricitinib or tocilizumab). The use of remdesivir monotherapy is not recommended.
- Remdesivir initiation is not recommended in patients on mechanical ventilation or ECMO; however, it may be continued, in combination with dexamethasone, to complete a treatment course in patients who were initiated on therapy prior to progression.
- The NIH recommends against continuing the use of remdesivir in COVID-19 patients discharged from inpatient hospital settings in stable condition, even if receiving supplemental oxygen.
Pediatric patients
- The NIH guideline recommends remdesivir for use in the following pediatric patients with COVID-19:
- Hospitalized pediatric patients of all ages requiring supplemental oxygen. Remdesivir should be used in combination with dexamethasone for those requiring high-flow oxygen or noninvasive ventilation; the addition of dexamethasone may be considered for patients receiving conventional oxygen with increasing oxygen demands, particularly adolescents.
- Remdesivir initiation is not recommended in patients on mechanical ventilation or ECMO; however, it may be continued, in combination with dexamethasone, to complete a treatment course in patients who were initiated on therapy prior to progression.
- Hospitalized patients 12 years and older BUT NOT requiring supplemental oxygen who are at the highest risk for progression to severe disease (i.e., moderate to severely immunocompromised patients regardless of COVID-19 vaccination status and those who are unvaccinated and have additional risk factors for progression). There is insufficient evidence for using remdesivir in younger patients not requiring supplemental oxygen.
- For nonhospitalized patients 12 years and older who are at high risk for progression to severe disease. There is insufficient evidence to recommend either for or against routine use of remdesivir in younger patients or patients with intermediate risk. Consider treatment based on age and other risk factors.
NOTE: Remdesivir has demonstrated activity in vitro and in animal studies against the Omicron SARS-CoV-2 variant and its subvariants.[65314]
Classifications
- General Anti-infectives Systemic
- Antivirals For Systemic Use
- Antiviral RNA-Polymerase Inhibitors
- Antivirals For Systemic Use
References
Administration Information
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
- Administer remdesivir only in a setting with immediate access to medications used for the treatment of severe infusion or hypersensitivity reactions (e.g., anaphylaxis) and with the ability to activate the emergency medical system (EMS), if necessary. Patients should be monitored during the infusion and observed for at least 1 hour after the infusion.
- The product is available in 2 dosage forms, a lyophilized powder for injection and solution for injection. There are differences in the way the 2 formulations are prepared; carefully follow the product-specific instructions. Neither dosage form contains a preservative nor bacteriostatic agent; therefore, aseptic technique must be used during the preparation of the final parenteral solution.
- Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Discard the vial if the lyophilized powder or solution is discolored or contains particulate matter. Prior to dilution, reconstituted remdesivir for injection and remdesivir injection solution should be clear, colorless to yellow, and free of visible particles.[66063]
Intravenous Administration
**For pediatric patients weighing less than 40 kg, use ONLY the lyophilized powder formulation to prepare doses.**[66063]
Remdesivir Lyophilized Powder 100 mg vials
Reconstitution
- Aseptically reconstitute the lyophilized powder by adding 19 mL of Sterile Water for Injection using a suitably sized syringe and needle per vial. Sterile Water for Injection is the preferred diluent for reconstitution of the lyophilized powder. If Sterile Water for Injection is unavailable, 0.9% Sodium Chloride for Injection may be used for reconstitution; however, if 0.9% Sodium Chloride is used for reconstitution, then the subsequent dilution should ONLY be done using the 250 mL 0.9% Sodium Chloride infusion bag.[67310]
- Discard the vial if a vacuum does not pull the diluent into the vial.
- Immediately shake the vial for 30 seconds.
- Allow the contents of the vial to settle for 2 to 3 minutes. A clear solution should result.
- If the contents of the vial are not completely dissolved, shake the vial again for 30 seconds and allow the contents to settle for 2 to 3 minutes. Repeat this process as necessary until the contents of the vial are completely dissolved. Discard the vial if the contents are not completely dissolved.
- After reconstitution, each vial contains 100 mg/20 mL (5 mg/mL) of remdesivir solution.
- Use the reconstituted product immediately to prepare the diluted drug product.[66063]
Dilution
- Adults and Pediatric patients weighing 40 kg or more:
- Withdraw and discard 20 mL (100 mg dose) or 40 mL (200 mg dose) of 0.9% Sodium Chloride from a 100 mL or 250 mL infusion bag using an appropriately sized syringe and needle. NOTE: Use the 250 mL infusion bag if the lyophilized powder was reconstituted using 0.9% Sodium Chloride for Injection.[67310]
- Transfer appropriate dose of reconstituted solution (20 mL or 40 mL) to the infusion bag. Discard any unused reconstituted solution that remains in the vials.
- Gently invert the bag 20 times to mix the solution in the bag. Do not shake
- Storage: The prepared solution is stable for 24 hours at room temperature 20 to 25 degrees C (68 to 77 degrees F) or 48 hours under refrigeration 2 to 8 degrees C (36 to 46 degrees F).[66063]
- Pediatric patients weighing less than 40 kg: The reconstituted solution must be further diluted to a fixed concentration of 1.25 mg/mL using 0.9% Sodium Chloride Injection. Small 0.9% Sodium Chloride infusion bags (e.g., 25 mL, 50 mL, or 100 mL) or an appropriately sized syringe (for volumes less than 50 mL) should be used for pediatric dosing.
- Infusion with an IV bag:
- Prepare an IV bag of 0.9% Sodium Chloride with a volume equal to the total infusion volume minus the volume of reconstituted remdesivir solution that will be diluted to achieve a 1.25 mg/mL solution.
- Withdraw the required volume of reconstituted solution containing remdesivir into an appropriately sized syringe.
- Transfer the required volume of reconstituted remdesivir for injection to the 0.9% Sodium Chloride infusion bag.
- Gently invert the bag 20 times to mix the solution in the bag. Do not shake.
- If using an empty infusion bag, transfer the required volume of reconstituted solution to the bag, followed by the volume of 0.9% Sodium Chloride sufficient to achieve a 1.25 mg/mL final volume concentration.
- Storage: The prepared infusion solution is stable for 24 hours at room temperature 20 to 25 degrees C (68 to 77 degrees F) or 48 hours under refrigeration 2 to 8 degrees C (36 to 46 degrees F).[66063]
- Infusion with a syringe:
- Select an appropriately sized syringe equal to or larger than the calculated total volume of 1.25 mg/mL remdesivir solution needed.
- Withdraw the required volume of reconstituted solution containing remdesivir from the vial into the syringe, followed by the required volume of 0.9% Sodium Chloride needed to achieve a 1.25 mg/mL remdesivir solution.
- Mix the syringe by inversion 20 times. Do not shake.
- The prepared diluted solution should be used immediately.[66063]
Remdesivir Solution for Injection 100 mg/20 mL vials
Preparation
- Remove the required number of single-dose vial(s) from storage.
- Equilibrate the vial(s) to room temperature 20 to 25 degrees C (68 to 77 degrees F). Sealed vials can be stored up to 12 hours at room temperature prior to dilution.[66063]
Dilution
- The 100 mg/20 mL remdesivir solution must be further diluted in a 250 mL 0.9% Sodium Chloride infusion bag.
- Withdraw and discard 20 mL (100 mg dose) or 40 mL (200 mg dose) of 0.9% Sodium Chloride from a 250 mL infusion bag using an appropriately sized syringe and needle.
- Inject approximately 10 mL of air into each remdesivir vial above the solution level before withdrawing dose to facilitate withdrawal. Withdraw the appropriate dose of solution (20 mL or 40 mL). The last 5 mL of solution from each vial requires more force to withdraw.
- Transfer the remdesivir solution to the infusion bag.
- Gently invert the bag 20 times to mix the solution in the bag. Do not shake.
- Storage: The prepared solution is stable for 24 hours at room temperature 20 to 25 degrees C (68 to 77 degrees F) or 48 hours under refrigeration 2 to 8 degrees C (36 to 46 degrees F).[66063]
Intermittent IV Infusion
- Infuse over 30 to 120 minutes. Do not administer by any other route.
- Do not mix with or administer simultaneously with other IV medications.
- Monitor patients during the infusion and observe for at least 1 hour after the infusion is complete for signs of hypersensitivity.[66063]
Clinical Pharmaceutics Information
From Trissel's 2‚Ñ¢ Clinical Pharmaceutics DatabaseRemdesivir
References
Adverse Reactions
Moderate
- anemia
- delirium
- dyspnea
- elevated hepatic enzymes
- glycosuria
- hematuria
- hyperbilirubinemia
- hyperglycemia
- hypernatremia
- hypertension
- hypokalemia
- hypotension
- hypoxia
- infusion-related reactions
- leukopenia
- lymphopenia
- phlebitis
- proteinuria
- QT prolongation
- sinus tachycardia
- wheezing
Severe
- acute respiratory distress syndrome (ARDS)
- anaphylactoid reactions
- angioedema
- atrial fibrillation
- bradycardia
- renal failure
- seizures
Mild
- diaphoresis
- diarrhea
- ecchymosis
- fever
- headache
- injection site reaction
- musculoskeletal pain
- nausea
- rash
- shivering
In an open-label compassionate-use study of patients with severe COVID-19 (n = 53), atrial fibrillation (6%) and hypotension (8%) were reported in patients receiving remdesivir.[65245] In a study of patients treated for Ebola virus disease, one patient had a hypotensive episode during the administration of the loading dose of remdesivir, which led to a fatal cardiac arrest; however, the independent pharmacovigilance committee noted that the death could not be readily distinguished from underlying fulminant Ebola virus disease.[65247] Acute respiratory distress syndrome (ARDS) was reported in 4% of patients receiving remdesivir in an open-label compassionate-use study of patients with severe COVID-19 (n = 53).[65245]
Hypersensitivity reactions, including infusion-related reactions and anaphylactoid reactions, have been observed during and after treatment with remdesivir; most occurring within 1 hour. Signs and symptoms may include hypotension, hypertension, sinus tachycardia, bradycardia, hypoxia, fever, dyspnea, wheezing, angioedema, rash, nauseous feeling, diaphoresis, and shivering. Monitor patients during and for at least 1 hour after drug administration. Slowing the infusion rate to a maximum infusion time of up to 120 minutes can be considered to potentially prevent these reactions. If a clinically significant reaction occurs, immediately discontinue the infusion and initiate appropriate treatment. In safety data from clinical trials involving hospitalized adult patients with COVID-19 (n = 1,313), rash was reported in less than 2% of patients treated with remdesivir.[66063] Cases of injection site reaction, including administration site extravasation, phlebitis (n = 8), and ecchymosis (n =5), have also been reported during use of remdesivir.[65247] [66063]
In safety data from clinical trials involving hospitalized adult patients with COVID-19 (n = 1,313), nausea was reported in 3% to 7% of patients receiving remdesivir. Similarly, 6% of nonhospitalized patients (n = 279) who received remdesivir in a Phase 3 trial reported nausea.[66063] In an open-label compassionate-use study of remdesivir in patients with severe COVID-19 (n = 53), diarrhea was reported in 9% of patients.[65245]
In safety data from clinical trials involving hospitalized adult patients with COVID-19 (n = 1,313), elevated hepatic enzymes were reported in 2% to 8% of patients receiving remdesivir. Hyperbilirubinemia, including Grade 3 or 4, has been reported in 2% or less of patients receiving remdesivir in clinical trials. In safety data from a clinical trial involving hospitalized pediatric patients with COVID-19 (n = 53), the most common hepatic adverse reaction (all grades) was increased ALT (6%). Other hepatic laboratory abnormalities (Grades 3 to 4) occurring in patients receiving remdesivir and who had at least 1 post-baseline value for the specified test were increased direct bilirubin (9%, n = 2/23) and increased ALT (4%, n = 2/51). Two patients permanently discontinued remdesivir due to increased ALT (n = 1) and increased AST and hyperbilirubinemia (n = 1).[66063] In patients with severe COVID-19, it may be difficult to attribute hepatotoxicity to remdesivir rather than the underlying disease; however, mild to moderate (Grade 1 and 2) elevated hepatic enzymes have also been associated with the use of remdesivir in healthy volunteers and patients infected with the Ebola virus.[65245] [66063] Hepatotoxicity is an identified risk with remdesivir.[65248]
In safety data from clinical trials involving hospitalized adult patients with COVID-19 (n = 1,313), the most frequently reported hematologic adverse event was decreased hemoglobin or anemia which was reported in 1% to 15% of patients receiving remdesivir. In safety data from the Adaptive COVID-19 Treatment Trial (ACTT-1), decreased lymphocytes or lymphopenia (11%) and increased prothrombin time (9%) were reported in patients receiving remdesivir (n = 532). In a Phase 3 trial involving nonhospitalized patients (n = 279), decreased lymphocytes and increased prothrombin time were reported in 2% and 1% of remdesivir recipients, respectively. In safety data from a clinical trial involving hospitalized pediatric patients with COVID-19 (n = 53), hematologic laboratory abnormalities (Grades 3 to 4) occurring in patients receiving remdesivir and who had at least 1 post-baseline value for the specified test were decreased hemoglobin or anemia (18%, n = 9/51), increased prothrombin time (7%, n = 3/46), increased aPTT (7%, n = 3/45), decreased lymphocytes or lymphopenia (6%, n = 2/33), and decreased WBC or leukopenia (4%, n = 2/51).[66063]
In safety data from clinical trials involving hospitalized adult patients with COVID-19 (n = 1,313), the most frequently reported metabolic adverse event for remdesivir was increased blood glucose or hyperglycemia occurring in 3% to 12% of patients. Similarly, 6% of nonhospitalized patients (n = 279) who received remdesivir in a Phase 3 trial reported increased blood glucose. In safety data from a clinical trial involving hospitalized pediatric patients with COVID-19 (n = 53), metabolic laboratory abnormalities (Grades 3 to 4) occurring in patients receiving remdesivir and who had at least 1 post-baseline value for the specified test were increased blood glucose or hyperglycemia (4%, n = 2/52) and decreased potassium or hypokalemia (4%, n = 2/52).[66063] In an open-label compassionate-use study of remdesivir in patients with severe COVID-19 (n = 53), 6% of patients developed hypernatremia.[65245]
In safety data from clinical trials involving hospitalized adult patients with COVID-19 (n = 1,313), the most frequently reported renal adverse events for remdesivir were decreased creatinine clearance and/or glomerular filtration rate (2% to 19%) and increased creatinine (5% to 15%). Acute kidney injury (renal failure) was reported in 3 patients who received remdesivir. Similarly, in a Phase 3 trial of nonhospitalized patients (n = 279) who received remdesivir, decreased creatinine clearance and increased creatinine were reported in 6% and 3% of patients, respectively. In safety data from a clinical trial involving hospitalized pediatric patients with COVID-19 (n = 53), renal laboratory abnormalities (Grades 3 to 4) occurring in patients receiving remdesivir and who had at least 1 post-baseline value for the specified test were decreased eGFR (18%, n = 7/40), increased creatinine (10%, n = 5/52), proteinuria (6%, n = 2/36), and glycosuria (4%, n = 2/46).[66063] In an open-label compassionate-use study of remdesivir in patients with severe COVID-19 (n = 53), renal adverse events reported included acute kidney injury (6%), renal impairment (8%), and hematuria (4%).[65245]
In safety data from clinical trials involving hospitalized adult patients with COVID-19 (n = 1,313), generalized seizures were reported by less than 2% of patients treated with remdesivir.[66063] In pooled data from Gilead-sponsored studies (n = 138), headache was reported in 6 patients and extremity pain (musculoskeletal pain) was reported in 5 patients.[65247] Delirium was reported in 4% of patients treated with remdesivir in a small open-label compassionate use study (n = 53).[65245]
QT prolongation has been reported with remdesivir; however, confounding factors (e.g., age, comorbid conditions, concomitant medications) make it difficult to assess the contribution of remdesivir on QT prolongation. There is no compelling evidence for risk of torsades de pointes (TdP) with use of remdesivir.[68632] [68633] [68634] [68635]
References
Contraindications/Precautions
Absolute contraindications are italicized.
- dialysis
- renal failure
- breast-feeding
- hepatic disease
- infusion-related reactions
- pregnancy
- renal impairment
Remdesivir is contraindicated in patients with hypersensitivity to remdesivir or any components of the product.[66063]
Hypersensitivity reactions, including infusion-related reactions and anaphylaxis, have been observed during and after treatment with remdesivir; most occurring within 1 hour. Monitor patients during and for at least 1 hour after administration for the following adverse reactions: hypotension, hypertension, tachycardia, bradycardia, hypoxia, fever, dyspnea, wheezing, angioedema, rash, nausea, diaphoresis, and shivering. Slowing the infusion rate to a maximum infusion time of up to 120 minutes can be considered to potentially prevent these reactions. If a clinically significant reaction occurs, immediately discontinue the infusion and initiate appropriate treatment.[66063]
All potential recipients of remdesivir must have their renal function monitored prior to and during treatment, as clinically appropriate. Treatment with remdesivir is not recommended in patients with an estimated glomerular filtration rate (eGFR) less than 30 mL/minute, as most study protocols contraindicate the use of remdesivir in patients with severe renal impairment (eGFR less than 30 mL/minute), renal failure, and in patients receiving dialysis or continuous renal replacement therapy.[66063] However, the National Institutes of Health (NIH) COVID-19 treatment guidelines contain study data (i.e., CATCO study) that suggest remdesivir can be used in patients with an eGFR less than 30 mL/minute if the potential benefits outweigh the risks.[65314] Intravenous formulations of remdesivir contain sulfobutyl ether beta-cyclodextrin sodium (SBECD) as a solubility enhancer, which is renally cleared and accumulates in patients with decreased renal function. If available, consider preferential use of the lyophilized powder formulation in patients with renal impairment, as it contains less SBECD (3 grams per 100 mg vial) as compared to the solution formulation (6 grams per 100 mg/20 mL vial).[65247] [65248] [65314] [66063]
Caution is advised when administering remdesivir to patients with hepatic disease, as treatment has been associated with an increase in hepatic enzymes. Conduct liver function testing (LFT) in all patients before and during treatment, as clinically appropriate. For elevated hepatic enzymes developing during therapy, consider treatment discontinuation if the increase in ALT is greater than 10-times the upper limit of normal. If the ALT increase is accompanied by signs or symptoms of hepatic inflammation, discontinue remdesivir.[66063]
The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend that remdesivir be offered to pregnant patients if indicated. When evaluating the risk and benefits of remdesivir, consider that COVID-19 in pregnancy is associated with adverse maternal and fetal outcomes, including preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic disease, and fetal death. Data regarding the use of remdesivir during pregnancy are insufficient to determine the drug-associated risk for major birth defects, miscarriages, or adverse maternal or fetal outcomes. No adequate and well-controlled studies have been conducted. A systemic review of 13 observational studies that included 113 pregnant patients found few adverse effects from the use of remdesivir during pregnancy. The most common adverse event was mild elevations in transaminase concentrations. Among 95 pregnant patients with moderate, severe, or critical COVID-19 who were included in a secondary analysis of data from a COVID-19 pregnancy registry in Texas, the composite maternal and neonatal outcomes were similar between those who received remdesivir (n = 39) and those who did not. Remdesivir was discontinued in 16.7% of patients due to elevated transaminase concentrations; however, it was not possible to determine if the elevated concentrations were due to the drug, COVID-19, or pregnancy-related conditions. In another report, remdesivir was well tolerated among 67 pregnant and 19 postpartum patients (median postpartum day = 1; range 0 to 3 days) who were hospitalized with severe COVID-19 and received remdesivir through a compassionate use program. In this study, 45 deliveries were observed. No neonatal deaths occurred during the 28-day observation period; however, 1 spontaneous miscarriage occurred at 17 weeks gestation in a mother with concurrent S. aureus bacteremia, endocarditis, and septic arthritis.[65314] [66019] In animal studies involving rats and rabbits, no adverse effects on embryo-fetal development were observed after exposure to the predominant circulating metabolite (GS-441524) that were 4-times the exposure at the recommended human dose. There is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to remdesivir during pregnancy. Pregnant and recently pregnant patients can enroll at covid-pr.pregistry.com or call 1-800-616-3791 to obtain more information.[66063]
There are no data regarding the presence of remdesivir in human milk, the effects on the breast-fed infant, or the effects on milk production. The National Institutes of Health (NIH) states that concentrations of remdesivir that would reach a breast-fed infant are estimated to be low; thus, if indicated, treatment should be offered to a lactating patient and breast-feeding can continue without interruption.[65314] 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. 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.[65248] [66063]
References
Mechanism of Action
Remdesivir is a monophosphoramidate prodrug of remdesivir triphosphate (RDV-TP), an adenosine analog that acts as an inhibitor of RNA-dependent RNA polymerases (RdRps). Remdesivir triphosphate competes with adenosine-triphosphate for incorporation into nascent viral RNA chains. Once incorporated into the viral RNA at position i, RDV-TP terminates RNA synthesis at position i+3. Because RDV-TP does not cause immediate chain termination (i.e., 3 additional nucleotides are incorporated after RDV-TP), the drug appears to evade proofreading by viral exoribonuclease (an enzyme thought to excise nucleotide analog inhibitors). Remdesivir causes delayed RNA chain termination during the process of viral replication.
Remdesivir has a broad spectrum of in vitro antiviral activity against RNA viruses, including viruses belonging to Filoviridae, Paramyxoviridae, Pneumoviridae, and Orthocoronavirinae families. The 50% effective concentration (EC50) against a clinical isolate of SARS-CoV-2 in primary human airway epithelial (HAE) cells is 9.9 nM after 48 hours of treatment. The EC50 against SARS-CoV-2 in the continuous human lung epithelial cell lines Calu-3 and A549-hACE2 is 280 nM after 72 hours of treatment and 115 nM after 48 hours of treatment. Against clinical isolates of the following SARS-CoV-2 variants [Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Epsilon (B.1.429), Kappa (B.1.617.1), Lambda (C.37), Iota (B.1.526), Zeta (P.2), and Delta (B.1.617.2)], remdesivir retains antiviral activity that is similar (i.e., less than 2.5-fold change in EC50 value) to an earlier lineage SARS-CoV-2 isolate (lineage A). Remdesivir also maintains activity (1.1-fold or less change in EC50 value) against clinical isolates of Omicron variants (B.1.1.529/BA.1, BA.2, BA.2.12.1, BA.2.75, BA.4, BA.4.6, BA.5, BF.5, BQ.1.1, and XBB).
SARS-CoV-2 isolates with the following amino acid substitutions in viral RNA-dependent RNA polymerase (nsp12) have been selected in cell culture: V166A, N198S, S759A, V792I, C799F, and C799R. When these substitutions were individually introduced into a wild-type recombinant virus, the susceptibility to remdesivir decreased by 1.7- to 3.5-fold. In a cell culture resistance selection experiment, the nsp12 amino acid substitution E802D emerged and resulted in a 2.5-fold reduction in susceptibility to remdesivir. This nsp12 E802D substitution has emerged in 1 remdesivir treated patient, and resulted in a 2.5-fold increase in the remdesivir EC50 value. In another section study using a SARS-CoV-2 isolate containing the P323L substitution in viral polymerase, a single amino acid substitution at V166L emerged. In recombinant SARS-CoV-2 with substitutions at P323L alone and P323L + V166L in combination, the reductions in remdesivir susceptibility were 1.3- and 1.5-fold, respectively. In clinical trials, the rate of emerging nsp12 substitutions in patients treated with remdesivir was similar to those who received placebo. Specific substitutions that emerged in remdesivir treated subjects included nsp12 V792I, C799F, and A376V. These substitutions were associated with a 2.2-, 2.5-, and 12.6-fold decrease in remdesivir susceptibility, respectively.
Note: SARS-CoV-2 RNA shedding results from clinical trials indicate that remdesivir does not significantly reduce the amount of detectable SARS-CoV-2 RNA in oropharyngeal or nasopharyngeal swabs or in plasma samples as compared to placebo.[65120][65133][65134][65135][65136][65137][65156][65161][65247][65248][65365][66063]
Revision Date: 05/02/2023, 12:43:35 PMReferences
Pharmacokinetics
Remdesivir is administered via intravenous infusion. It is extensively metabolized. The rapid decline in remdesivir plasma concentrations is accompanied by the sequential appearance of the intermediate metabolite GS-704277 and the nucleoside metabolite GS-441524. Within cells, the GS-441524 monophosphate undergoes rapid conversion to the pharmacologically active analog of adenosine triphosphate, GS-443902. The pharmacokinetic parameters of remdesivir and its metabolites (GS-441524 and GS-704277) were evaluated in a multiple dose study involving healthy adults. In this study, the percent bound to human plasma proteins and the blood-to-plasma ratio were 88% to 93.6% and 0.68 to 1 for remdesivir, 2% and 1.19 for GS-441524, and 1% and 0.56 for GS-704277, respectively. Remdesivir is predominately metabolized by carboxylesterase 1 (CES1, 80%), with minor contributions from cathepsin A (CatA, 10%) and CYP3A (10%). The metabolite GS-704277 is further metabolized by histidine triad nucleotide-binding protein 1 (HINT1), while GS-441524 is not significantly metabolized. The elimination half-lives for remdesivir, GS-441524, and GS-704277 are 1 hour, 27 hours, and 1.3 hours, respectively. The major route of elimination for remdesivir and GS-704277 is via metabolism, with only 10% of remdesivir and 2.9% of GS-704277 being excreted in the urine. GS-441524 is primarily eliminated via glomerular filtration and active tubular secretion (49% in urine and 0.5% in feces).[66063]
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CES1, CatA, OATP1B1, OATP1B3, MATE1, P-gp, UGT1A1
In vitro, remdesivir is a substrate for the enzymes CYP3A4, CES1, and CatA and the drug transporters organic anion transporting polypeptide 1B1 (OATP1B1) and P-glycoprotein (P-gp); the metabolite GS-704277 is a substrate for OATP1B1 and OATP1B3. Remdesivir is an in vitro inhibitor of CYP3A4, UDP glucuronosyltransferase 1A1 (UGT1A1), OATP1B1, OATP1B3, and the multidrug and toxin extrusion protein 1 (MATE1). No inhibitory effects have been identified for GS-704277 or GS-441524. Based on a drug interaction study, no clinically significant drug interactions are expected with inducers of CYP3A4 or inhibitors of OATP1B1/1B3 and P-gp.[66063]
Route-Specific Pharmacokinetics
Oral Route
Remdesivir is not suitable for oral delivery due to significant first-pass clearance.[65247]
Intravenous Route
After multiple remdesivir doses to healthy adults, the maximum plasma concentrations (Cmax) and systemic exposures (AUC) were 2,700 ng/mL and 1,710 ng x hour/mL for remdesivir, 143 ng/mL and 2,410 ng x hour/mL for GS-441524, and 198 ng/mL and 392 ng x hour/mL for GS-704277, respectively. The times to reach peak concentration were 0.67 to 0.68 hours for remdesivir, 1.51 to 2 hours for GS-441524, and 0.75 hours for GS-704277.[66063]
Special Populations
Hepatic Impairment
There are no data available on the pharmacokinetics of remdesivir in patients with hepatic impairment.[66063]
Renal Impairment
There are no data available on the pharmacokinetics of remdesivir in patients with renal impairment.[66063] Both IV formulations of remdesivir contain sulfobutyl ether beta-cyclodextrin sodium (SBEDC) as a solubility enhancer. SBEDC is renally cleared and accumulates in patients with decreased renal function. The main metabolite for remdesivir, GS-441524, may theoretically increase in patients with impaired renal function.[65247]
Pediatrics
Based on population pharmacokinetic models, geometric mean estimated exposures (AUCtau, Cmax, and Ctau) in pediatric patients 28 days to 17 years and weighing at least 3 kg were higher for remdesivir (33% to 129%), GS-441524 (0% to 60%), and GS-704277 (37% to 124%) as compared to those in adult patients with COVID-19; however, the increases were not considered clinically significant.[66063]
References
Pregnancy/Breast-feeding
pregnancy
The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend that remdesivir be offered to pregnant patients if indicated. When evaluating the risk and benefits of remdesivir, consider that COVID-19 in pregnancy is associated with adverse maternal and fetal outcomes, including preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic disease, and fetal death. Data regarding the use of remdesivir during pregnancy are insufficient to determine the drug-associated risk for major birth defects, miscarriages, or adverse maternal or fetal outcomes. No adequate and well-controlled studies have been conducted. A systemic review of 13 observational studies that included 113 pregnant patients found few adverse effects from the use of remdesivir during pregnancy. The most common adverse event was mild elevations in transaminase concentrations. Among 95 pregnant patients with moderate, severe, or critical COVID-19 who were included in a secondary analysis of data from a COVID-19 pregnancy registry in Texas, the composite maternal and neonatal outcomes were similar between those who received remdesivir (n = 39) and those who did not. Remdesivir was discontinued in 16.7% of patients due to elevated transaminase concentrations; however, it was not possible to determine if the elevated concentrations were due to the drug, COVID-19, or pregnancy-related conditions. In another report, remdesivir was well tolerated among 67 pregnant and 19 postpartum patients (median postpartum day = 1; range 0 to 3 days) who were hospitalized with severe COVID-19 and received remdesivir through a compassionate use program. In this study, 45 deliveries were observed. No neonatal deaths occurred during the 28-day observation period; however, 1 spontaneous miscarriage occurred at 17 weeks gestation in a mother with concurrent S. aureus bacteremia, endocarditis, and septic arthritis.[65314] [66019] In animal studies involving rats and rabbits, no adverse effects on embryo-fetal development were observed after exposure to the predominant circulating metabolite (GS-441524) that were 4-times the exposure at the recommended human dose. There is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to remdesivir during pregnancy. Pregnant and recently pregnant patients can enroll at covid-pr.pregistry.com or call 1-800-616-3791 to obtain more information.[66063]
breast-feeding
There are no data regarding the presence of remdesivir in human milk, the effects on the breast-fed infant, or the effects on milk production. The National Institutes of Health (NIH) states that concentrations of remdesivir that would reach a breast-fed infant are estimated to be low; thus, if indicated, treatment should be offered to a lactating patient and breast-feeding can continue without interruption.[65314] 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. 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.[65248] [66063]
References
Interactions
Level 2 (Major)
- Chloroquine
- Hydroxychloroquine
References
Monitoring Parameters
- CBC with differential
- LFTs
- prothrombin time (PT)
- serum creatinine/BUN
- serum electrolytes
US Drug Names
- Veklury
