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Remdesivir

Indications/Dosage

Labeled

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

Off-Label

    † Off-label indication

    For the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the virus that causes coronavirus disease 2019 (COVID-19)

    Intravenous dosage

    Hospitalized Adults NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)

    200 mg IV once on day 1 then 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]

    Hospitalized Adults requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)

    200 mg IV once on day 1 then 100 mg IV once daily for 9 days.[66063]

    Hospitalized Children and Adolescents 12 years and older and weighing 40 kg or more NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)

    200 mg IV once on day 1 then 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]

    Hospitalized Children and Adolescents 12 years and older and weighing 40 kg or more requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)

    200 mg IV once on day 1 then 100 mg IV once daily for 9 days.[66063]

    Hospitalized Children younger than 12 years but weighing 40 kg or more NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)†

    200 mg IV once on day 1 then 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.[65365]

    Hospitalized Children younger than 12 years but weighing 40 kg or more requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)†

    200 mg IV once on day 1 then 100 mg IV once daily for 9 days.[65365]

    Hospitalized Infants, Children, and Adolescents weighing 3.5 to 39 kg NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)†

    5 mg/kg/dose IV once on day 1 then 2.5 mg/kg/dose IV once daily for 4 days is suggested by the FDA in the Emergency Use Authorization (EUA) statement. May extend treatment for up to 5 additional days (i.e., 10 days total) if a patient does not demonstrate clinical improvement. Dosing in pediatric patients is based upon physiologically-based (PBPK) modeling and simulation of pharmacokinetic data from healthy adult subjects.[65365]

    Hospitalized Infants, Children, and Adolescents weighing 3.5 to 39 kg requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)†

    5 mg/kg/dose IV once on day 1 then 2.5 mg/kg/dose IV once daily for 9 days is suggested by the FDA in the Emergency Use Authorization (EUA) statement. Dosing in pediatric patients is based upon physiologically-based (PBPK) modeling and simulation of pharmacokinetic data from healthy adult subjects.[65365]

    Hospitalized Neonates weighing 3.5 kg or more NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)†

    5 mg/kg/dose IV once on day 1 then 2.5 mg/kg/dose IV once daily for 4 days is suggested by the FDA in the Emergency Use Authorization (EUA) statement. May extend treatment for up to 5 additional days (i.e., 10 days total) if a patient does not demonstrate clinical improvement. Dosing in pediatric patients is based upon physiologically-based (PBPK) modeling and simulation of pharmacokinetic data from healthy adult subjects.[65365]

    Hospitalized Neonates weighing 3.5 kg or more requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)†

    5 mg/kg/dose IV once on day 1 then 2.5 mg/kg/dose IV once daily for 9 days is suggested by the FDA in the Emergency Use Authorization (EUA) statement. Dosing in pediatric patients is based upon physiologically-based (PBPK) modeling and simulation of pharmacokinetic data from healthy adult subjects.[65365]

    Therapeutic Drug Monitoring

    Maximum Dosage Limits

    • Adults <p>200 mg IV on day 1, followed by 100 mg IV once daily.</p>
    • Geriatric <p>200 mg IV on day 1, followed by 100 mg IV once daily.</p>
    • Adolescents <p><em>Adolescents weighing 40 kg or more</em>: 200 mg IV on day 1, followed by 100 mg IV once daily.</p> <p><em>Adolescents weighing 39 kg or less</em>: Safety and efficacy have not been established; however, investigational doses of 5 mg/kg/dose IV on day 1, followed by 2.5 mg/kg/dose IV once daily have been used.</p>
    • Children <p><em>Children 12 years and weighing 40 kg or more:</em> 200 mg IV on day 1, followed by 100 mg IV once daily.</p> <p><em>Children 1 to 11 years and weighing 40 kg or more: </em>Safety and efficacy have not been established; however, investigational doses of 200 mg IV on day 1, followed by 100 mg IV once daily have been used.</p> <p><em>Children weighing 39 kg or less</em>: Safety and efficacy have not been established; however, investigational doses of 5 mg/kg/dose IV on day 1, followed by 2.5 mg/kg/dose IV once daily have been used.</p>
    • Infants <p>Safety and efficacy have not been established; however, investigational doses of 5 mg/kg/dose IV on day 1, followed by 2.5 mg/kg/dose IV once daily have been used.</p>
    • Neonates <p><em>Neonates weighing 3.5 kg or more</em>: Safety and efficacy have not been established; however, investigational doses of 5 mg/kg/dose IV on day 1, followed by 2.5 mg/kg/dose IV once daily have been used.</p> <p><em>Neonates weighing less than 3.5 kg:</em> Safety and efficacy have not been established.</p>

    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.

    Patients with Renal Impairment Dosing

    Adult and Pediatric patients

    eGFR 30 mL/minute or more: No dosage adjustment needed.

    eGFR less than 30 mL/minute: Treatment is not recommended.

     

    Term neonates 7 days and older

    Serum creatinine less than 1 mg/dL: No dosage adjustment needed.

    Serum creatinine 1 mg/dL or more: Treatment is not recommended unless the potential benefit outweighs the potential risk.[65365]

     

    Term neonates younger than 7 days

    Recommendations are not available.[65365]

    † Off-label indication
    Revision Date: 10/23/2020, 05:52:50 PM

    References

    65365 - Food and Drug Administration (FDA). Fact sheet for health care providers: emergency use authorization (EUA) of Veklury (remdesivir) for hospitalized pediatric patients weighing 3.5 kg to less than 40 kg or hospitalized pediatric patients less than 12 years of age weighing at least 3.5 kg. Retrieved October 23, 2020. Available on the World Wide Web at https://www.fda.gov/media/137566/download.66063 - Veklury (remdesivir) injection package insert. Foster City, CA: Gilead Sciences, Inc; 2020 Oct.

    How Supplied

    Remdesivir Powder for solution for injection

    Veklury 100mg Powder for Injection (61958-2901) (Gilead Sciences Inc) nullVeklury 100mg Powder for Injection package photo

    Remdesivir Solution for injection

    Veklury 100mg/20mL Solution for Injection (61958-2902) (Gilead Sciences Inc) nullVeklury 100mg/20mL Solution for Injection package photo

    Description/Classification

    Description

    Remdesivir is an antiviral medication approved for use in adults and pediatric patients (12 years and older and weighing at least 40 kg) to treat coronavirus disease 2019 (COVID-19) requiring hospitalization.[66063] Although remdesivir is not FDA-approved for use in patients younger than 12 years or weighing less than 40 kg, the FDA has issued an Emergency Use Authorization (EUA) which allows the drug to be used to treat suspected or laboratory-confirmed COVID-19 in hospitalized pediatric patients weighing 3.5 to 39 kg or hospitalized pediatric patients less than 12 years of age weighing at least 3.5 kg.[66064] Remdesivir is also part of an EUA allowing for the combined use of remdesivir and baricitinib to treat suspected or laboratory confirmed COVID-19 in hospitalized patients (2 years and older) who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).[66126]

     

    The National Institutes of Health (NIH) COVID-19 treatment guidelines have released recommendations for the use of remdesivir that are based on disease severity. For patients with mild to moderate COVID-19 (i.e., non-hospitalized patients or hospitalized patients that do not require supplemental oxygen), the NIH state there are insufficient data to recommend for or against the use of remdesivir. For hospitalized patients who require supplemental oxygen BUT NOT on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO, the NIH recommends 5 days of remdesivir either alone or in combination with a corticosteroid. Remdesivir therapy may be stopped early if a patient is discharged from the hospital or may be extended up to 10 days if no improvement is observed at day 5. For hospitalized patients who require oxygen through a high-flow device or noninvasive ventilation, remdesivir may be given in combination with a corticosteroid; however, due to questionable clinical benefit, treatment with remdesivir alone is not recommended. For hospitalized patients who require invasive mechanical ventilation or ECMO and who have recently been intubated, remdesivir may be given in combination with a corticosteroid. For patients who initially started on remdesivir monotherapy and then progressed to requiring high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO, the NIH recommends adding a corticosteroid and continuing remdesivir until the treatment course is completed. The NIH does not make a recommendation regarding the use of remdesivir in combination with baricitinib or other Janus kinase (JAK) inhibitors; however, because of their broad immunosuppressive effect, the NIH recommends against the use of JAK inhibitors outside of clinical trials.[65314]

     

    The World Health Organization (WHO) has issued a conditional recommendation against the use of remdesivir in hospitalized patients, regardless of disease severity. According to the WHO, there is currently no evidence that remdesivir improves survival or other outcomes (e.g., need for mechanical ventilation, time to clinical improvement) in these patients. The WHO does support continued enrollment in clinical trials evaluating the use of remdesivir for COVID-19.[66125]

     

    Data from a randomized, double-blind, placebo-controlled trial [i.e., Adaptive COVID-19 Treatment Trial (ACTT-1)] found remdesivir to be superior to placebo in shortening the time to recover in hospitalized adults with COVID-19 and lung involvement. In this study, the median time to recovery was 10 days in the remdesivir-treated group compared to 15 days in the placebo group (rate ratio for recovery: 1.29; 95% CI: 1.12 to 1.49, p less than 0.001); and the Kaplan-Meier estimates of mortality by day 29 were 11.4% and 15.2% for remdesivir and placebo, respectively (hazard ratio: 0.73; 95% CI: 0.52 to 1.03). Remdesivir was most beneficial when administered early in the course of the disease; however, in most analyses, clinical benefit persisted throughout the duration of symptoms. In patients treated within 10 days of symptom onset, the rate ratio for recovery was 1.37 (95% CI, 1.14 to 1.64); whereas, for those whose treatment was initiated more than 10 days after symptom onset, the rate ratio for recovery was 1.20 (95% CI, 0.94 to 1.52).[65474][66001]

     

    Data from another randomized, double-blind, placebo-controlled, multicenter trial of hospitalized patients with severe COVID-19 found treatment with remdesivir was not associated with statistically significant benefits. Included in this trial were adult patients admitted to the hospital with the following: laboratory-confirmed SARS-CoV-2 infection, symptom onset 12 days or less, SpO2 of 94% or less or a PaO2/FiO2 of 300 mmHg or less, and radiologically confirmed pneumonia. Patients were randomized to receive remdesivir (n = 158) or placebo (n = 79); both treatment groups were allowed concurrent use of corticosteroids, interferons, and lopinavir; ritonavir. The study found no difference in the time to clinical improvement (median, 21 vs. 23 days; hazard ratio: 1.23; 95% CI: 0.87 to 1.75) or in the 28-day mortality rate (14% vs. 13%; 95% CI: 8.1 to 10.3). Additionally, 66% of remdesivir patients and 64% of placebo patients reported adverse events, with 12% of remdesivir recipients and 5% in the placebo group stopping treatment early.[65408]

     

    Preliminary data from an open-label, randomized, multicenter trial conducted by the World Health Organization (WHO), the SOLIDARITY trial, found treatment with remdesivir was not associated with clinical benefit in adults hospitalized with COVID-19. In this trial, a 10 day course of remdesivir (n = 2,743), as compared to a control group (n = 2,708), did not reduce overall in-hospital mortality (10.9% vs. 11.1%; death rate ratio, 0.95; 95% CI, 0.81 to 1.11; p = 0.5), initiation of ventilation in those not already ventilated (295 for remdesivir vs. 284 for the control group), or duration of hospitalization (hospitalized at day 7, 69% for remdesivir and 59% for the control group).[66045]

     

    A manufacturer-sponsored, open-label trial evaluated the use of 5-day (n = 200) and 10-day (n = 197) courses of remdesivir to treat hospitalized patients with severe COVID-19 pneumonia (i.e., lung infiltrates and either receiving supplemental oxygen or a SpO2 of 94% or less on room air); data showed no significant difference in efficacy between the 2 treatment groups. On day 14, clinical improvement of at least 2 points on the 7-point ordinal scale was achieved by 65% in the 5-day group and 54% in the 10-day group. Other data showed numerically more patients discharged from the hospital in the 5-day group than in the 10-day group (60% vs. 52%, respectively), and lower mortality in the 5-day group (8% vs. 11%, respectively). Of note, this study excluded patients who were receiving mechanical ventilation and ECMO at baseline, as well as patients with signs of multiorgan failure. Also, although patients were randomly assigned on a 1:1 basis, those assigned to the 10-day group had significantly worse clinical status at baseline (p = 0.02).[65486]

     

    A multicenter study compared the efficacy of remdesivir vs. standard of care alone in adults with severe COVID-19 using data from an ongoing phase 3 trial (n = 312) and a retrospective cohort of patients (n = 818). Patients had confirmed SARS-CoV-2 infection, were hospitalized, had SpO2 94% or lower on room air or required supplemental oxygen, and had pulmonary infiltrates. On day 14, 74.4% of remdesivir patients had recovered vs. 59% of patients receiving standard of care (aOR, 2.03; 95% CI, 1.34 to 3.09; p less than 0.01). On day 14, an improvement in clinical status of at least 2-points (or being discharged alive) was noted in 71.9% of remdesivir patients compared to 58.8% of patients receiving standard of care (aOR 1.64; 95% CI, 1.10 to 2.43; p = 0.001). On day 14, 7.6% of remdesivir patients had died vs. 12.5% of patients receiving standard of care (aOR, 0.38; 95% CI, 0.22 to 0.68; p = 0.001).[65755]

     

    Efficacy and safety of remdesivir in patients hospitalized with moderate COVID-19 pneumonia (i.e., pulmonary infiltrates and SpO2 greater than 94% on room air) was evaluated in a randomized, open-label, multicenter trial, in which remdesivir 5-day (n = 191) and 10-day (n = 193) therapies were compared against standard care alone (n = 200). In this trial, the 5-day remdesivir group had significantly higher odds of a better clinical status (defined as clinical status at day 11 on a 7-point ordinal scale) as compared to standard care (OR, 1.65; 95% CI, 1.09 to 2.48; p = 0.02); however, the clinical status on day 11 was not significantly different between the 10-day remdesivir group and standard care (p = 0.18). The proportion of patients who developed an adverse event were 51% in the 5-day group, 59% in the 10-day group, and 47% in the standard care group. The difference in safety between the 5-day and standard care groups was not statistically significant (4.8%; 95% CI, -5.2% to 14.7%; p = 0.36), but was significant between the 10-day group and standard care (12%; 95% CI, 1.6% to 21.8%; p = 0.02).[65849]

    Classifications

    • General Anti-infectives Systemic
      • Antivirals For Systemic Use
        • Antiviral RNA-Polymerase Inhibitors
    Revision Date: 11/23/2020, 10:20:39 AM

    References

    65314 - COVID-19 Treatment Guidelines Panel. Coronavirus Diseases 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Accessed December 3, 2020. Available at on the World Wide Web at: https://covid19treatmentguidelines.nih.gov/.65408 - Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomized, double-blind, placebo-controlled, multicentre trial. The Lancet. 2020. Available at: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31022-9/fulltext#seccestitle1065474 - Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19 - preliminary report. N Engl J Med. 2020;DOI:10.1056/NEJMoa2007764.65486 - Goldman JD, Lye D, Hui DS, et al. Remdesivir for 5 or 10 days in patients with severe Covid-19. N Engl J Med 2020 May 27. [Epub Ahead of Print]65755 - Olender SA, Perez KK, Go AS, et al. Remdesivir for severe COVDID-19 versus a cohort receiving standard of care. Clin Infect Dis 2020. [Epub Ahead of Print]65849 - Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: A randomized clinical trial. JAMA 2020. Epub ahead of print, doi: 10.1001/jama.2020.16349.66001 - Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19 - final report. N Engl J Med. 2020;DOI:10.1056/NEJMoa2007764.66045 - WHO Solidarity trial consortium. Repurposed antiviral drugs for COVID-19 – interim WHO SOLIDARITY trial results. medRxiv. 2020. Available on the World Wide Web at: https://doi.org/10.1101/2020.10.15.2020981766063 - Veklury (remdesivir) injection package insert. Foster City, CA: Gilead Sciences, Inc; 2020 Oct.66064 - U.S. Food and Drug Administration. FDA communication on remdesivir Emergency Use Authorization. Updated October 22, 2020. Available at: https://www.fda.gov/media/137564/download. Accessed: October 23, 2020.66125 - World Health Organization. WHO recommends against the use of remdesivir in COVID-19 patients. Updated November 20, 2020. Available at: https://www.who.int/news-room/feature-stories/detail/who-recommends-against-the-use-of-remdesivir-in-covid-19-patients. Accessed: November 20, 2020.66126 - Food and Drug Administration (FDA). Fact sheet for health care providers: emergency use authorization (EUA) of baricitinib. Retrieved November 20, 2020. Available on the World Wide Web at http://pi.lilly.com/eua/baricitinib-eua-factsheet-hcp.pdf.

    Administration Information

    General Administration Information

    For storage information, see the specific product information and study protocols.

     

    NOTE: Prior to administering remdesivir under the Emergency Use Authorization (EUA) to pediatric patients (younger than 12 years or less than 40 kg), the health care provider must communicate to the patient and parent/caregiver information consistent with the "Fact Sheet for Patients and Parents/Caregivers", including:

    • Remdesivir has been authorized for emergency use by the FDA. It is not an FDA approved drug for this population.
    • The patient and parent/caregiver has the option to accept or refuse remdesivir.
    • The significant known and potential risks and benefits of remdesivir, and the extent to which such risks and benefits are unknown.
    • Information on available alternative treatments and the risks and benefits of those alternatives.

    If providing this information will delay treatment to a degree that would endanger the lives of patients, the information must be provided to the patients as soon as practicable after remdesivir is administered.[65365]

    Route-Specific Administration

    Injectable Administration

    • Remdesivir is to be administered in a hospital or in a healthcare setting capable of providing acute care comparable to inpatient hospital care. Prepare and administer remdesivir under the supervision of a healthcare provider
    • The product is available in 2 dosage forms, a lyophilized powder for injection and solution for injection. Neither dosage form contains a preservative or 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

    Remdesivir Lyophilized Powder 100 mg vials:[66063]

    Reconstitution of the Lyophilized Powder 100 mg vial(s):
    Remove the required number of single-dose vial(s) from storage. For each vial:

    • Aseptically reconstitute the lyophilized powder by adding 19 mL of Sterile Water for Injection using a suitably sized syringe and needle per vial. ONLY use Sterile Water for Injection to reconstitute the lyophilized powder.
    • Discard the vial if a vacuum does not pull the Sterile Water for Injection 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.

     

    Dilution of the Reconstituted Lyophilized Powder 100 mg vial(s):

    • The reconstituted solution, containing 100 mg/20 mL remdesivir solution per vial, must be further diluted in either a 100 mL or 250 mL 0.9% Sodium Chloride infusion bag.
    • For a 200 mg loading dose (use 2 vials):
      • Withdraw and discard 40 mL of 0.9% Sodium Chloride from a 100 mL or 250 mL infusion bag using an appropriately sized syringe and needle.
      • Using an appropriately sized syringe and needle, remove 20 mL of the reconstituted solution from 2 remdesivir vials (40 mL total), and transfer to the infusion bag. Discard any unused reconstituted solution that remains in the vials.
    • For a 100 mg maintenance dose (use 1 vial):
      • Withdraw and discard 20 mL of 0.9% Sodium Chloride from a 100 mL or 250 mL infusion bag using an appropriately sized syringe and needle.
      • Using an appropriately sized syringe and needle, remove 20 mL of the reconstituted solution from 1 remdesivir vial and transfer to the infusion bag. Discard any unused reconstituted solution that remains in the vial.
    • 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).

     

    Intermittent IV Infusion:

    • Infuse over 30 to 120 minutes.
    • Do not mix with or administer simultaneously with other IV medications.

     

     

    Remdesivir Solution for Injection 100 mg/20 mL vials:[66063]

    Preparation of the Solution for Injection 100 mg/20 mL vial(s):

    • 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.

     

    Dilution of the Solution for Injection 100 mg/20 mL vial(s):

    • The 100 mg/20 mL remdesivir solution must be further diluted in a 250 mL 0.9% Sodium Chloride infusion bag.
    • For a 200 mg loading dose (use 2 vials):
      • Withdraw and discard 40 mL of 0.9% Sodium Chloride from the 250 mL infusion bag using an appropriately sized syringe and needle.
      • Using 2 remdesivir vials, inject approximately 10 mL of air into each vial above the solution level before withdrawing dose to facilitate withdrawal. Withdraw 20 mL of solution from each vial (40 mL total). The last 5 mL of solution from each vial requires more force to withdraw.
      • Transfer the remdesivir solution to the infusion bag.
    • For a 100 mg maintenance dose (use 1 vial):
      • Withdraw and discard 20 mL of 0.9% Sodium Chloride from the 250 mL infusion bag using an appropriately sized syringe and needle.
      • Using 1 remdesivir vial, inject approximately 10 mL of air into the vial above the solution level before withdrawing dose to facilitate withdrawal. Withdraw 20 mL of solution from the vial. The last 5 mL of solution requires more force to withdraw.
      • Transfer to 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).

     

    Intermittent IV Infusion:

    • Infuse over 30 to 120 minutes.
    • Do not mix with or administer simultaneously with other IV medications.

     

     

    Preparation Instructions per Emergency Use Authorization (EUA)[65365]

    **Remdesivir products are preservative-free; discard any unused portion of single-dose vials. Prepare solutions for infusion on the same day as administration. Maintain records showing the receipt, use, and disposition of remdesivir.

     

    Reconstitution of the Lyophilized Powder 100 mg vial(s):

    **For pediatric patients younger than 12 years or weighing less than 40 kg, use only the lyophilized powder formulation to prepare doses.**

    • For each 100 mg vial, reconstitute with 19 mL of Sterile Water for Injection using a suitably sized syringe and needle per vial. ONLY use Sterile Water for Injection to reconstitute the lyophilized powder.
    • Discard the vial if the vacuum does not pull the Sterile Water for Injection into the vial.
    • Immediately shake 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 for another 30 seconds and then allow to settle for 2 to 3 minutes. Repeat this process as needed until the contents are fully dissolved, resulting in a clear solution. 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.

     

    Dilution for Pediatric Loading Dose using Reconstituted Lyophilized Powder 100 mg vial(s) (patients weighing less than 40 kg):

    • Using only the reconstituted lyophilized powder formulation, calculate the volume of the remdesivir 5 mg/mL solution necessary to make the patient's loading dose of 5 mg/kg.
    • The reconstituted solution must be further diluted to a fixed concentration of 1.25 mg/mL using 0.9% Sodium Chloride Injection. The total volume needed to yield the target remdesivir concentration of 1.25 mg/mL is dependent on the patient's weight.
    • 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).
    • 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.

     

    Dilution for Pediatric Maintenance Doses using Reconstituted Lyophilized Powder 100 mg vial (patients weighing less than 40 kg):

    • Using only the reconstituted lyophilized powder formulation, calculate the volume of remdesivir 5 mg/mL solution necessary to make the patient's maintenance dose of 2.5 mg/kg.
    • The reconstituted solution must be further diluted to a fixed concentration of 1.25 mg/mL using 0.9% Sodium Chloride Injection. The total volume needed to yield the target remdesivir concentration of 1.25 mg/mL is dependent on the patient's weight.
    • 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).
    • 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.

     

    Dilution for 200 mg Pediatric Loading Dose using 2 Reconstituted Lyophilized Powder 100 mg vials (patients younger than 12 years but weighing 40 kg or more):

    • The reconstituted lyophilized powder must be further diluted in either 100 mL or 250 mL of 0.9% Sodium Chloride Injection.
    • Withdraw and discard 40 mL from an infusion bag containing either 100 mL or 250 mL 0.9% Sodium Chloride Injection.
    • Using 2 remdesivir vials, withdraw 20 mL of reconstituted solution from each vial (40 mL total).
    • Transfer a total of 40 mL of reconstituted remdesivir 5 mg/mL solution from the 2 vials into the 0.9% Sodium Chloride Injection bag.
    • Gently invert bag 20 times to mix the solution. 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).

     

    Dilution for 100 mg Maintenance Doses using a single Reconstituted Lyophilized Powder 100 mg vial (patients younger than 12 years but weighing 40 kg or more):

    • The reconstituted lyophilized powder must be further diluted in either 100 mL or 250 mL of 0.9% Sodium Chloride Injection.
    • Withdraw and discard 20 mL from an infusion bag containing either 100 mL or 250 mL of 0.9% Sodium Chloride injection.
    • Using 1 remdesivir vial, withdraw 20 mL of reconstituted solution from the vial.
    • Transfer 20 mL of reconstituted remdesivir 5 mg/mL solution from the vial into the 0.9% Sodium Chloride Injection bag.
    • Gently invert bag 20 times to mix the solution. 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).

     

    Intermittent IV Infusion:

    • Infuse over 30 to 120 minutes.
    • Do not mix with or administer simultaneously with other IV medications.

    Clinical Pharmaceutics Information

    From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database

    Remdesivir

      Revision Date: 10/23/2020, 06:46:57 PMCopyright 2004-2020 by Lawrence A. Trissel. All Rights Reserved.

      References

      65365 - Food and Drug Administration (FDA). Fact sheet for health care providers: emergency use authorization (EUA) of Veklury (remdesivir) for hospitalized pediatric patients weighing 3.5 kg to less than 40 kg or hospitalized pediatric patients less than 12 years of age weighing at least 3.5 kg. Retrieved October 23, 2020. Available on the World Wide Web at https://www.fda.gov/media/137566/download.66063 - Veklury (remdesivir) injection package insert. Foster City, CA: Gilead Sciences, Inc; 2020 Oct.

      Adverse Reactions

      Moderate

      • anemia
      • constipation
      • delirium
      • dyspnea
      • elevated hepatic enzymes
      • hematuria
      • hyperbilirubinemia
      • hyperglycemia
      • hypernatremia
      • hypertension
      • hypokalemia
      • hypotension
      • hypoxia
      • infusion-related reactions
      • phlebitis
      • sinus tachycardia
      • wheezing

      Severe

      • anaphylactoid reactions
      • angioedema
      • atrial fibrillation
      • bradycardia
      • respiratory arrest
      • seizures

      Mild

      • diaphoresis
      • diarrhea
      • ecchymosis
      • fever
      • headache
      • nausea
      • rash
      • shivering

      In an open-label compassionate-use study of remdesivir used in patients with severe COVID-19 (n = 53), hypotension was reported in 8% of patients.[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 lead 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]

      In an open-label compassionate-use study of remdesivir used in patients with severe COVID-19 (n = 53), atrial fibrillation was reported in 6% of patients.[65245]

      During clinical trials, less than 2% of patients treated with remdesivir developed a rash. In an open-label compassionate-use study of remdesivir used in patients with severe COVID-19 (n = 53), rash was reported in 8% of patients.[65245] [66063]

      Hypersensitivity reactions including infusion-related reactions and anaphylactoid reactions have occurred during and after treatment with remdesivir. Signs and symptoms may include hypotension, hypertension, sinus tachycardia, bradycardia, hypoxia, pyrexia, dyspnea, wheezing, angioedema, rash, nauseous feeling, diaphoresis, and shivering. Monitor patients during and 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.[65365] [66063]

      Safety data from clinical trials involving hospitalized patients with COVID-19 found 3% to 7% of patients who received remdesivir experienced nausea, 5% to 6% experienced diarrhea, and 7% developed constipation.[65365] [66063] In an open-label compassionate-use study of remdesivir used in patients with severe COVID-19 (n = 53), diarrhea was reported in 9% of patients.[65245]

      Safety data from the Adaptive COVID-19 Treatment Trial (ACTT-1) found 3% to 6% of remdesivir recipients and 6% to 8% of those receiving placebo developed elevated hepatic enzymes; while hyperbilirubinemia and increased prothrombin time were observed in 2% and 9% of remdesivir and 5% and 4% of placebo patients, respectively. Data from other clinical trials involving hospitalized patients with COVID-19 found up to 8% of patients treated with remdesivir developed increased hepatic enzymes, and 2% or less developed Grade 3 hyperbilirubinemia.[65365] [66063] In the compassionate-use program of patients with severe COVID-19, elevated hepatic enzymes were reported in 12% (n = 19/163) of remdesivir recipients. The time to onset from the first dose ranged from 1 to 16 days. Treatment was discontinued in 4 patients as per protocol. Serious hepatic-related laboratory abnormalities were identified in 7 patients, and 1 serious adverse event (SAE) of increased blood bilirubin was reported in a critically ill patient with septic shock and multiorgan failure. None of the other cases had reported adverse events suggestive of hyperbilirubinemia or symptoms of hepatitis. 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] [65365] Transient treatment-emergent elevations in AST and ALT were observed during studies in healthy volunteers. None of these elevations were graded in single-ascending dose studies, and all were Grade 1 or 2 in multiple-dose studies. Some ALT and AST elevations were associated with graded prothrombin time (PT) elevations; however, there were no graded changes in INR.[65247] Hepatotoxicity is an identified risk.[65248]

      Safety data from the Adaptive COVID-19 Treatment Trial (ACTT-1) identified adverse events (Grade 3 or higher) in 8% of patients treated with remdesivir (n = 532) and 9% of patients who received a placebo (n = 516). The most frequently reported adverse events for remdesivir and placebo were decreased hemoglobin or anemia (15% vs. 22%, respectively), acute renal injury (7% vs. 7%), decreased creatinine clearance (18% vs. 20%), respiratory arrest or failure (5% vs. 8%), fever (5% vs. 3%), increased blood glucose or hyperglycemia (12% vs. 13%), and decreased lymphocytes (11% vs. 18%). Data from other clinical trials found 6% to 11% of remdesivir recipients developed acute respiratory failure, 1% to 6% had decreased hemoglobin, 2% to 10% had decreased creatinine clearance, and 3% to 11% had increased blood glucose.[65365] [66063]

      Nonclinical toxicology studies have shown renal abnormalities with remdesivir; however, clear evidence of nephrotoxicity has not been reported. In an open-label compassionate-use study of remdesivir used in patients with severe COVID-19 (n = 53), renal adverse events reported included acute renal injury (6%), renal impairment (8%), and hematuria (4%).[65245]

      Safety data from a clinical trial involving hospitalized patients with COVID-19 found 5% to 7% of patients who received remdesivir developed hypokalemia.[65365] In an open-label compassionate-use study of remdesivir used in patients with severe COVID-19 (n = 53), 6% of patients had hypernatremia.[65245]

      In pooled data from Gilead-sponsored studies (n = 138), ecchymosis was reported in 5 patients.[65247]

      Cases of administration site extravasation have been reported during use of remdesivir under the Emergency Use Authorization.[66063] In pooled data from Gilead-sponsored studies (n = 138), phlebitis was reported in 8 patients.[65247]

      In an open-label compassionate-use study of remdesivir used in patients with severe COVID-19 (n = 53), 4% of patients had delirium.[65245]

      Safety data from a clinical trial involving hospitalized patients with COVID-19 found 5% of patients who received remdesivir developed a headache.[65365] In pooled data from Gilead-sponsored studies (n = 138), a headache was reported in 6 patients, and extremity pain was reported in 5 patients.[65247]

      Generalized seizures were reported by less than 2% of patients treated with remdesivir during clinical trials.[66063]

      Revision Date: 10/23/2020, 04:44:00 PM

      References

      65245 - Grein J, Ohmagari N, Shin D, et al. Compassionate use of remdesivir for patients with severe Covid-19. New Engl J Med 2020. [Epub ahead of print]65247 - European Medicines Agency. Summary on compassionate use: Remdesivir Gilead. April 3, 2020. Retrieved April 13, 2020. Available on the World Wide Web at: https://www.ema.europa.eu/documents/other/summary-compassionate-use-remdesivir-gilead_en.pdf.65248 - European Medicines Agency. Conditions of use, conditions for distribution and patients targeted and conditions for safety monitoring adressed to member states for compassionate use: Remdesivir Gilead. April 3, 2020. Retrieved April 13, 2020. Available on the World Wide Web at: https://www.ema.europa.eu/documents/other/conditions-use-conditions-distribution-patients-targeted-conditions-safety-monitoring-adressed_en-2.pdf.65365 - Food and Drug Administration (FDA). Fact sheet for health care providers: emergency use authorization (EUA) of Veklury (remdesivir) for hospitalized pediatric patients weighing 3.5 kg to less than 40 kg or hospitalized pediatric patients less than 12 years of age weighing at least 3.5 kg. Retrieved October 23, 2020. Available on the World Wide Web at https://www.fda.gov/media/137566/download.66063 - Veklury (remdesivir) injection package insert. Foster City, CA: Gilead Sciences, Inc; 2020 Oct.

      Contraindications/Precautions

      Absolute contraindications are italicized.

      • dialysis
      • renal failure
      • breast-feeding
      • children
      • hepatic disease
      • infants
      • infusion-related reactions
      • neonates
      • pregnancy
      • renal impairment

      Remdesivir is contraindicated in patients with hypersensitivity to remdesivir.[65247][65248][65365] [66063]

      Hypersensitivity reactions including infusion-related reactions and anaphylaxis have occurred during and after treatment with remdesivir. Monitor patients during and 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.[65365] [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 adult and pediatric patients with an estimated glomerular filtration rate (eGFR) less than 30 mL/minute or in term neonates 7 days and older with serum creatinine greater than or equal to 1 mg/dL. Recommendations are not available for term neonates younger than 7 days.[65365] 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. Intravenous formulations of remdesivir contain sulfobutyl ether beta-cyclodextrin sodium (SBECD) as a solubility enhancer. SBECD is renally cleared and accumulates in patients with decreased renal function.[65247] [65248] [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]

      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; however, an observational study described the compassionate use of remdesivir in 67 pregnant and 19 immediately postpartum (median postpartum day = 1; range 0 to 3 days) women with severe COVID-19. 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.[66019] In animal studies involving rats and rabbits, no adverse effects on embryo-fetal development were observed following exposure to the predominant circulating metabolite (GS-441524) that were 4-times the exposure at the recommended human dose. The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend that remdesivir not be withheld from pregnant women if its use is otherwise indicated.[65314] The manufacturer recommends administering remdesivir during pregnancy only if the potential benefit to the mother justifies the potential risks to the fetus.[65365] [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. 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] [65365] [66063]

      Safety and efficacy of remdesivir have not been established in neonates, infants, or children younger than 12 years of age or weighing less than 40 kg. Although remdesivir is not FDA-approved for use in this patient population, the FDA has issued an Emergency Use Authorization (EUA) which allows the drug to be used to treat suspected or laboratory-confirmed COVID-19 in hospitalized pediatric patients weighing 3.5 to 39 kg or hospitalized pediatric patients less than 12 years of age weighing at least 3.5 kg. Health care providers administering remdesivir under the EUA must report all medication errors and serious adverse events to the FDA within 7 calendar days of occurrence.[65365] [66064]

      Revision Date: 11/24/2020, 08:19:19 AM

      References

      65247 - European Medicines Agency. Summary on compassionate use: Remdesivir Gilead. April 3, 2020. Retrieved April 13, 2020. Available on the World Wide Web at: https://www.ema.europa.eu/documents/other/summary-compassionate-use-remdesivir-gilead_en.pdf.65248 - European Medicines Agency. Conditions of use, conditions for distribution and patients targeted and conditions for safety monitoring adressed to member states for compassionate use: Remdesivir Gilead. April 3, 2020. Retrieved April 13, 2020. Available on the World Wide Web at: https://www.ema.europa.eu/documents/other/conditions-use-conditions-distribution-patients-targeted-conditions-safety-monitoring-adressed_en-2.pdf.65314 - COVID-19 Treatment Guidelines Panel. Coronavirus Diseases 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Accessed December 3, 2020. Available at on the World Wide Web at: https://covid19treatmentguidelines.nih.gov/.65365 - Food and Drug Administration (FDA). Fact sheet for health care providers: emergency use authorization (EUA) of Veklury (remdesivir) for hospitalized pediatric patients weighing 3.5 kg to less than 40 kg or hospitalized pediatric patients less than 12 years of age weighing at least 3.5 kg. Retrieved October 23, 2020. Available on the World Wide Web at https://www.fda.gov/media/137566/download.66019 - Burwick RM, Yawetz S, Stephenson KE, et al. Compassionate use of remdesivir in pregnant women with severe Covid-19. Clin Infect Dis. Retrieved October 13, 2020. Available on the World Wide Web at: https://doi.org/10.1093/cid/ciaa146666063 - Veklury (remdesivir) injection package insert. Foster City, CA: Gilead Sciences, Inc; 2020 Oct.66064 - U.S. Food and Drug Administration. FDA communication on remdesivir Emergency Use Authorization. Updated October 22, 2020. Available at: https://www.fda.gov/media/137564/download. Accessed: October 23, 2020.

      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-TP 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 Vero cells at 24 hours and 48 hours post-treatment are 137 nM and 750 nM, respectively. No clinical data are available regarding the development of SARS-CoV-2 resistance to remdesivir.[65120][65133][65134][65135][65136][65137][65156][65161][65247][65248][65365][66063]

      Revision Date: 10/23/2020, 04:16:08 PM

      References

      65120 - Wang M, Cao R, Zhang L, et al. Remdesivir and Chloroquine Effectively Inhibit the Recently Emerged Novel Coronavirus (2019-nCoV) in Vitro. Cell Res 2020;30(3):269-271.65133 - U.S. Army Medical Research and Development Command. Expanded access remdesivir (RDV; GS-5734). Retreived March 18, 2020. Available on the World Wide Web at: https://clinicaltrials.gov/ct2/show/NCT04302766?term=remdesivir&draw=2&rank=3.65134 - Brown AJ, Won JJ, Graham RL, et al. Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase. Antiviral Research 2019;169:1-10.65135 - Agostini ML, Andres EL, Sims AC, et al. Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. mBIO 2018;9:e00221-18.65136 - de Wit, Feldmann F, Cronin J, et al. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci U S A. 2020;117(12):6771-6776. [Epub ahead of print]65137 - Ko W, Rolain J, Lee N, et al. Arguments in favor of remdesivir for treating SARS-CoV-2 infections. Int J Antimicrob Agents 2020.[Epub ahead of print]65156 - Gordon CJ, Tchesnokov EP, Feng JY, et al. The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus. J Biol Chem 2020;295(15):4773-4779. [Epub ahead of print]65161 - Warren TK, Jordan R, Lo MK, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 2016;531(7594):381-385.65247 - European Medicines Agency. Summary on compassionate use: Remdesivir Gilead. April 3, 2020. Retrieved April 13, 2020. Available on the World Wide Web at: https://www.ema.europa.eu/documents/other/summary-compassionate-use-remdesivir-gilead_en.pdf.65248 - European Medicines Agency. Conditions of use, conditions for distribution and patients targeted and conditions for safety monitoring adressed to member states for compassionate use: Remdesivir Gilead. April 3, 2020. Retrieved April 13, 2020. Available on the World Wide Web at: https://www.ema.europa.eu/documents/other/conditions-use-conditions-distribution-patients-targeted-conditions-safety-monitoring-adressed_en-2.pdf.65365 - Food and Drug Administration (FDA). Fact sheet for health care providers: emergency use authorization (EUA) of Veklury (remdesivir) for hospitalized pediatric patients weighing 3.5 kg to less than 40 kg or hospitalized pediatric patients less than 12 years of age weighing at least 3.5 kg. Retrieved October 23, 2020. Available on the World Wide Web at https://www.fda.gov/media/137566/download.66063 - Veklury (remdesivir) injection package insert. Foster City, CA: Gilead Sciences, Inc; 2020 Oct.

      Pharmacokinetics

      Remdesivir is administered via intravenous infusion.

       

      Preliminary data show that remdesivir 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.[65365] 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 (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, OATP1B1, OATP1B3, MATE1, P-gp

      In vitro, remdesivir is a substrate for CYP3A4 and the drug transporters organic anion transporting polypeptide 1B1 (OATP1B1) and p-glycoprotein (P-gp). Remdesivir is an in vitro inhibitor of CYP3A4, OATP1B1, OATP1B3, and the multidrug and toxin extrusion protein 1 (MATE1). The metabolite GS-704277 is a substrate of OATP1B1 and OATP1B3. The clinical relevance has not been established.[66063]

      Route-Specific Pharmacokinetics

      Oral Route

      Remdesivir is not suitable for oral delivery due to significant first-pass clearance.[65247]

      Intravenous Route

      Remdesivir and its major metabolite, GS-441524, exhibit a linear pharmacokinetic profile. Both the lyophilized powder formulation and the solution for injection formulation provided comparable remdesivir pharmacokinetic parameters.[65365] After multiple remdesivir doses to healthy adults, the maximum plasma concentrations (Cmax) and systemic exposures (AUC) were 2,229 ng/mL and 1,585 ng x hour/mL for remdesivir, 145 ng/mL and 2,229 ng x hour/mL for GS-441524, and 246 ng/mL and 462 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.[65247][65365][66063]

      Renal Impairment

      There are no data available on the pharmacokinetics of remdesivir in patients with renal impairment.[65365][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

      For pediatric patients weighing 40 kg or more, administration of the recommended adult dosing regimen is expected to produce exposures of both remdesivir and the major metabolite, GS-441524, that are within the expected adult steady-state exposure range.[66063] In pediatric patients weighing 3.5 to 39 kg, the recommended weight-based dosing regimen is expected to produce remdesivir exposures that are comparable to those observed in adults while limiting the exposure of GS-441524 in very young children.[65365]

      Revision Date: 10/23/2020, 05:26:26 PM

      References

      65247 - European Medicines Agency. Summary on compassionate use: Remdesivir Gilead. April 3, 2020. Retrieved April 13, 2020. Available on the World Wide Web at: https://www.ema.europa.eu/documents/other/summary-compassionate-use-remdesivir-gilead_en.pdf.65365 - Food and Drug Administration (FDA). Fact sheet for health care providers: emergency use authorization (EUA) of Veklury (remdesivir) for hospitalized pediatric patients weighing 3.5 kg to less than 40 kg or hospitalized pediatric patients less than 12 years of age weighing at least 3.5 kg. Retrieved October 23, 2020. Available on the World Wide Web at https://www.fda.gov/media/137566/download.66063 - Veklury (remdesivir) injection package insert. Foster City, CA: Gilead Sciences, Inc; 2020 Oct.

      Pregnancy/Breast-feeding

      pregnancy

      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; however, an observational study described the compassionate use of remdesivir in 67 pregnant and 19 immediately postpartum (median postpartum day = 1; range 0 to 3 days) women with severe COVID-19. 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.[66019] In animal studies involving rats and rabbits, no adverse effects on embryo-fetal development were observed following exposure to the predominant circulating metabolite (GS-441524) that were 4-times the exposure at the recommended human dose. The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend that remdesivir not be withheld from pregnant women if its use is otherwise indicated.[65314] The manufacturer recommends administering remdesivir during pregnancy only if the potential benefit to the mother justifies the potential risks to the fetus.[65365] [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. 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] [65365] [66063]

      Revision Date: 11/05/2020, 01:58:46 PM

      References

      65247 - European Medicines Agency. Summary on compassionate use: Remdesivir Gilead. April 3, 2020. Retrieved April 13, 2020. Available on the World Wide Web at: https://www.ema.europa.eu/documents/other/summary-compassionate-use-remdesivir-gilead_en.pdf.65248 - European Medicines Agency. Conditions of use, conditions for distribution and patients targeted and conditions for safety monitoring adressed to member states for compassionate use: Remdesivir Gilead. April 3, 2020. Retrieved April 13, 2020. Available on the World Wide Web at: https://www.ema.europa.eu/documents/other/conditions-use-conditions-distribution-patients-targeted-conditions-safety-monitoring-adressed_en-2.pdf.65314 - COVID-19 Treatment Guidelines Panel. Coronavirus Diseases 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Accessed December 3, 2020. Available at on the World Wide Web at: https://covid19treatmentguidelines.nih.gov/.65365 - Food and Drug Administration (FDA). Fact sheet for health care providers: emergency use authorization (EUA) of Veklury (remdesivir) for hospitalized pediatric patients weighing 3.5 kg to less than 40 kg or hospitalized pediatric patients less than 12 years of age weighing at least 3.5 kg. Retrieved October 23, 2020. Available on the World Wide Web at https://www.fda.gov/media/137566/download.66019 - Burwick RM, Yawetz S, Stephenson KE, et al. Compassionate use of remdesivir in pregnant women with severe Covid-19. Clin Infect Dis. Retrieved October 13, 2020. Available on the World Wide Web at: https://doi.org/10.1093/cid/ciaa146666063 - Veklury (remdesivir) injection package insert. Foster City, CA: Gilead Sciences, Inc; 2020 Oct.

      Interactions

      Level 2 (Major)

      • Chloroquine
      • Hydroxychloroquine
      Chloroquine: (Major) Coadministration of remdesivir and chloroquine is not recommended. The antiviral activity of remdesivir was antagonized by chloroquine phosphate in a dose-dependent manner when the 2 drugs were co-incubated at clinically relevant concentrations in an in vitro study. [65365] [66063] Hydroxychloroquine: (Major) Coadministration of remdesivir and hydroxychloroquine is not recommended. The antiviral activity of remdesivir was antagonized by chloroquine phosphate in a dose-dependent manner when the 2 drugs were co-incubated at clinically relevant concentrations in an in vitro study. [65365] [66063]
      Revision Date: 11/13/2020, 02:28:00 AM

      References

      65365 - Food and Drug Administration (FDA). Fact sheet for health care providers: emergency use authorization (EUA) of Veklury (remdesivir) for hospitalized pediatric patients weighing 3.5 kg to less than 40 kg or hospitalized pediatric patients less than 12 years of age weighing at least 3.5 kg. Retrieved October 23, 2020. Available on the World Wide Web at https://www.fda.gov/media/137566/download.66063 - Veklury (remdesivir) injection package insert. Foster City, CA: Gilead Sciences, Inc; 2020 Oct.

      Monitoring Parameters

      • CBC with differential
      • LFTs
      • prothrombin time (PT)
      • serum creatinine/BUN
      • serum electrolytes

      US Drug Names

      • Veklury

      Global Drug names

      United Kingdom

      • Veklury - (Gilead)