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Jul.9.2020

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May.20.2020

Elsevier Drug Monographs

Remdesivir

Indications/Dosage

Labeled

    Off-Label

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

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

    Intravenous dosage

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

    The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend the use of remdesivir in hospitalized patients with severe COVID-19.[65314] 200 mg IV once on day 1 then 100 mg IV once daily for 9 days is suggested by the FDA in the Emergency Use Authorization (EUA) statement.[65364] [65365] This dose is also is being evaluated in multi-center randomized trials.[65130] [65131] [65132] [65133] [65245] [65247] [65248] [65408] [65474]

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

    The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend the use of remdesivir in hospitalized patients with severe COVID-19.[65314] 200 mg IV once on day 1 then 100 mg IV once daily for 4 days in patients with severe disease, defined as a SpO2 of 94% or less on room air or requiring supplemental oxygen, is suggested by the FDA in the Emergency Use Authorization (EUA) statement. May extend treatment for up to 5 additional days if a patient does not demonstrate clinical improvement.[65314] [65364] [65365] This dose is also is being evaluated in multi-center randomized trials.[65130] [65131] [65132] [65133] [65245] [65247] [65248] [65408] [65474]

    Children and Adolescents weighing 40 kg or more requiring invasive mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO)

    The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend the use of remdesivir in hospitalized patients with severe COVID-19.[65314] 200 mg IV once on day 1 then 100 mg IV once daily for 9 days is suggested by the FDA in the Emergency Use Authorization (EUA) statement.[65364] [65365] Dosing in pediatric patients is based upon physiologically-based (PBPK) modeling and simulation of pharmacokinetic data from healthy adult subjects.[65365]

    Children and Adolescents weighing 40 kg or more NOT requiring invasive mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO)

    The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend the use of remdesivir in hospitalized patients with severe COVID-19.[65314] 200 mg IV once on day 1 then 100 mg IV once daily for 4 days in patients with severe disease, defined as a SpO2 of 94% or less on room air or requiring supplemental oxygen, is suggested by the FDA in the Emergency Use Authorization (EUA) statement. May extend treatment for up to 5 additional days if a patient does not demonstrate clinical improvement.[65314] [65364] [65365] Dosing in pediatric patients is based upon physiologically-based (PBPK) modeling and simulation of pharmacokinetic data from healthy adult subjects.[65365]

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

    The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend the use of remdesivir in hospitalized patients with severe COVID-19.[65314] 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.[65364] [65365] Dosing in pediatric patients is based upon physiologically-based (PBPK) modeling and simulation of pharmacokinetic data from healthy adult subjects.[65365]

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

    The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend the use of remdesivir in hospitalized patients with severe COVID-19.[65314] 5 mg/kg/dose IV once on day 1 then 2.5 mg/kg/dose IV once daily for 4 days in patients with severe disease, defined as a SpO2 of 94% or less on room air or requiring supplemental oxygen, is suggested by the FDA in the Emergency Use Authorization (EUA) statement. May extend treatment for up to 5 additional days if a patient does not demonstrate clinical improvement.[65314] [65364] [65365] Dosing in pediatric patients is based upon physiologically-based (PBPK) modeling and simulation of pharmacokinetic data from healthy adult subjects.[65365]

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

    The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend the use of remdesivir in hospitalized patients with severe COVID-19.[65314] 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.[65364] [65365] Dosing in pediatric patients is based upon physiologically-based (PBPK) modeling and simulation of pharmacokinetic data from healthy adult subjects.[65365]

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

    The National Institutes of Health (NIH) COVID-19 treatment recommend the use of remdesivir in hospitalized patients with severe COVID-19.[65314] 5 mg/kg/dose IV once on day 1 then 2.5 mg/kg/dose IV once daily for 4 days in patients with severe disease, defined as a SpO2 of 94% or less on room air or requiring supplemental oxygen, is suggested by the FDA in the Emergency Use Authorization (EUA) statement. May extend treatment for up to 5 additional days if a patient does not demonstrate clinical improvement.[65314] [65364] [65365] 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

      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.

    • Geriatric

      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.

    • Adolescents

      Adolescents weighing 40 kg or more: Safety and efficacy have not been established; investigational doses of 200 mg IV on day 1, followed by 100 mg IV once daily have been used.

      Adolescents weighing 39 kg or less: 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.

    • Children

      Children weighing 40 kg or more: 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.

      Children weighing 39 kg or less: 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.

    • Infants

      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.

    • Neonates

      Neonates weighing 3.5 kg or more: 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.

      Neonates weighing less than 3.5 kg: Safety and efficacy have not been established.

    Patients with Hepatic Impairment Dosing

    It is unknown if dosage adjustments are needed in patients with hepatic disease; therefore, remdesivir should only be used in patients with hepatic impairment if the potential benefit outweighs the potential risk. Avoid treatment in patients with a baseline ALT greater than or equal to 5-times the upper limit of normal (ULN). Discontinue treatment if ALT increases to 5-times ULN or more or if the increase in ALT is accompanied by signs or symptoms of hepatic inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR.[65365]

    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 unless the potential benefit outweighs the potential risk.[65365]

     

    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: 06/12/2020, 07:49:24 AM

    References

    65130 - Capital Medical University. Mild/moderate 2019-nCoV remdesivir RCT. Retreived March 18, 2020. Available on the World Wide Web at: https://clinicaltrials.gov/ct2/show/NCT04252664?term=remdesivir&draw=2&rank=2.65131 - Gilead Sciences. Study to evaluate the safety and antiviral activity of remdesivir (GS-5734) in participants with moderate coronavirus disease (COVID-19) compared to standard of care treatment. Retreived March 18, 2020. Available on the World Wide Web at: https://clinicaltrials.gov/ct2/show/NCT04292730?term=remdesivir&draw=2&rank=5.65132 - Gilead Sciences. Study to evaluate the safety and antiviral activity of remdesivir (GS-5734) in participants with severe coronavirus disease (COVID-19). Retreived March 18, 2020. Available on the World Wide Web at: https://clinicaltrials.gov/ct2/show/NCT04292899?term=remdesivir&draw=2&rank=4.65133 - 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=3.65245 - 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.65314 - COVID-19 Treatment Guidelines Panel. Coronavirus Diseases 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Accessed June 25, 2020. Available at on the World Wide Web at: https://covid19treatmentguidelines.nih.gov/.65364 - Food and Drug Administration (FDA). Emergency use of remdesivir for the treatment of hospitalized 2019 coronavirus disease (COVID-19) patients: emergency use authorization letter. Retrieved May 1, 2020. Available on the World Wide Web at https://www.fda.gov/media/137564/download.65365 - Food and Drug Administration (FDA). Fact sheet for health care providers: emergency use authorization (EUA) of remdesivir (GS-5734). Retrieved June 15, 2020. Available on the World Wide Web at https://www.fda.gov/media/137566/download.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.

    How Supplied

    Remdesivir Powder for solution for injection

    Remdesivir 100mg Powder for Injection (61958-2901) (Gilead Sciences Inc) null

    Remdesivir Solution for injection

    Remdesivir 100mg/20mL Solution for Injection (61958-2902) (Gilead Sciences Inc) null

    Description/Classification

    Description

    Remdesivir is an investigational antiviral medication with a broad spectrum of in vitro activity against RNA viruses belonging to Filoviridae, Paramyxoviridae, Pneumoviridae, and Orthocoronavirinae families. Although not FDA-approved, the FDA has issued an Emergency Use Authorization (EUA) allowing intravenous remdesivir to be used in hospitalized COVID-19 patients with severe disease, defined as a SpO2 of 94% or less on room air, requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).[65364] [65365] The drug is also available through the Expanded Access or Compassionate Use program for the treatment of COVID-19 infected children and pregnant women and through clinical trials.[65134] [65156] [65161] The National Institutes of Health (NIH) coronavirus disease 2019 (COVID-19) treatment guidelines recommend the use of remdesivir in hospitalized patients with severe COVID-19; however, the guidelines state that there is insufficient evidence to recommend for or against use in patients with mild or moderate COVID-19.[65314]

     

    Preliminary data from a randomized, double-blind, placebo-controlled trial [i.e., Adaptive COVID-19 Treatment Trial (ACTT-1)] found remdesivir was 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 11 days in the remdesivir-treated group compared to 15 days in the placebo group (rate ratio for recovery: 1.32; 95% CI: 1.12 to 1.55, p < 0.001); and the Kaplan-Meier estimates of mortality by 14 days were 7.1% and 11.9% for remdesivir and placebo, respectively (hazard ratio: 0.7; 95% CI: 0.47 to 1.04).[65474] However, 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. They 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]

     

    A manufacturer-sponsored, open-label trial evaluated the use of 5-day (n = 200) and 10-day (n = 197) courses 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]

    Classifications

    • General Anti-infectives Systemic
      • Antivirals For Systemic Use
        • Other Systemic Antivirals
    Revision Date: 06/12/2020, 08:47:15 AM

    References

    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;169:1-10.65156 - 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):381-385.65314 - COVID-19 Treatment Guidelines Panel. Coronavirus Diseases 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Accessed June 25, 2020. Available at on the World Wide Web at: https://covid19treatmentguidelines.nih.gov/.65364 - Food and Drug Administration (FDA). Emergency use of remdesivir for the treatment of hospitalized 2019 coronavirus disease (COVID-19) patients: emergency use authorization letter. Retrieved May 1, 2020. Available on the World Wide Web at https://www.fda.gov/media/137564/download.65365 - Food and Drug Administration (FDA). Fact sheet for health care providers: emergency use authorization (EUA) of remdesivir (GS-5734). Retrieved June 15, 2020. Available on the World Wide Web at https://www.fda.gov/media/137566/download.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; DOI:10.1056/NEJMoa2015301.

    Administration Information

    General Administration Information

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

     

    NOTE: Prior to administering remdesivir under the Emergency Use Authorization (EUA), the health care provider must communicate to the patient or 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.
    • The patient or 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

    • Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    If the patient is enrolled in a clinical trial, follow the specific instructions provided by the study protocol.

     

    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 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 to give a concentration of 5 mg/mL.
    • 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.
    • Further dilution is required prior to administration.
    • Storage: Store remdesivir lyophilized powder vials below 30 degrees C (below 86 degrees F) until required for use.
      • Total storage time from reconstitution to administration should not exceed 4 hours at room temperature (20 to 25 degrees C; 68 to 77 degrees F) or 24 hours under refrigeration (2 to 8 degrees C; 36 to 46 degrees F).

     

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

    **Do not use to prepare doses for pediatric patients weighing less than 40 kg.

    • Remove remdesivir solution for injection vial(s) from the refrigerator and allow to come to room temperature (20 to 25 degrees C; 68 to 77 degrees F) before diluting.
    • Inspect the vial to ensure container closure is free from defects, and the solution is free of particulate matter before use.
    • Storage: Store remdesivir solution for injection under refrigeration (2 to 8 degrees C; 36 to 46 degrees F) until required for use. Sealed vials can be stored up to 12 hours at room temperature before dilution.

     

    Dilution:

    Dilution of the 200 mg Loading Dose using 2 Reconstituted Lyophilized Powder 100 mg vials (patients weighing 40 kg or more):

    • The reconstituted lyophilized powder must be further diluted in either 100 mL or 250 mL of 0.9% NaCl Injection.
    • Withdraw and discard 40 mL from an infusion bag containing either 100 mL or 250 mL 0.9% NaCl 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% NaCl Injection bag.
    • Gently invert bag 20 times to mix the solution. Do not shake.
    • Storage: The prepared solution is stable for 4 hours at room temperature (20 to 25 degrees C; 68 to 77 degrees F) or 24 hours under refrigeration (2 to 8 degrees C; 36 to 46 degrees F).
      • For solutions prepared using the reconstituted lyophilized powder, total storage time from reconstitution to administration should not exceed 4 hours at room temperature or 24 hours under refrigeration.

     

    Dilution of the 100 mg Maintenance Doses using a single Reconstituted Lyophilized Powder 100 mg vial (patients weighing 40 kg or more):

    • The reconstituted lyophilized powder must be further diluted in either 100 mL or 250 mL of 0.9% NaCl Injection.
    • Withdraw and discard 20 mL from an infusion bag containing either 100 mL or 250 mL of 0.9% NaCl 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% NaCl Injection bag.
    • Gently invert bag 20 times to mix the solution. Do not shake.
    • Storage: The prepared solution is stable for 4 hours at room temperature (20 to 25 degrees C; 68 to 77 degrees F) or 24 hours under refrigeration (2 to 8 degrees C; 36 to 46 degrees F).
      • For solutions prepared using the reconstituted lyophilized powder, total storage time from reconstitution to administration should not exceed 4 hours at room temperature or 24 hours under refrigeration.

     

    Dilution of the 200 mg Loading Dose using 2 Solution for Injection 100 mg/20 mL vials (patients weighing 40 kg or more):

    • The injection solution must be further diluted in 250 mL of 0.9% NaCl Injection.
    • From a 250 mL infusion bag of 0.9% NaCl Injection, withdraw and discard 40 mL.
    • 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).
    • Transfer a total of 40 mL remdesivir 5 mg/mL solution from the 2 vials into the 0.9% NaCl Injection bag.
    • Gently invert bag 20 times to mix the solution. Do not shake.
    • Storage: The prepared diluted solution is stable for 4 hours at room temperature (20 to 25 degrees C; 68 to 77 degrees F) or 24 hours under refrigeration (2 to 8 degrees C; 36 to 46 degrees F).

     

    Dilution of the 100 mg Maintenance Doses using a single Solution for Injection 100 mg/20 mL vial (patients weighing 40 kg or more):

    • The injection solution must be further diluted in 250 mL of 0.9% NaCl Injection.
    • From a 250 mL infusion bag of 0.9% NaCl Injection, withdraw and discard 20 mL.
    • 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.
    • Transfer 20 mL remdesivir 5 mg/mL solution from the vial into the 0.9% NaCl Injection bag.
    • Gently invert bag 20 times to mix the solution. Do not shake.
    • Storage: The prepared diluted solution is stable for 4 hours at room temperature (20 to 25 degrees C; 68 to 77 degrees F) or 24 hours under refrigeration (2 to 8 degrees C; 36 to 46 degrees F).

     

    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% NaCl 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% NaCl 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% NaCl 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% NaCl infusion bag.
      • Gently invert the bag 20 times to mix the solution in the bag. Do not shake.
    • 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% NaCl needed to achieve a 1.25 mg/mL remdesivir solution.
      • Mix the syringe by inversion 20 times.
    • Storage: The prepared solution is stable for 4 hours at room temperature (20 to 25 degrees C; 68 to 77 degrees F) or 24 hours under refrigeration (2 to 8 degrees C; 36 to 46 degrees F).
      • For solutions prepared using the reconstituted lyophilized powder, total storage time from reconstitution to administration should not exceed 4 hours at room temperature or 24 hours under refrigeration.

     

    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% NaCl 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% NaCl 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% NaCl 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% NaCl infusion bag.
      • Gently invert the bag 20 times to mix the solution in the bag. Do not shake.
    • 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% NaCl needed to achieve a 1.25 mg/mL remdesivir solution.
      • Mix the syringe by inversion 20 times.
    • Storage: The prepared solution is stable for 4 hours at room temperature (20 to 25 degrees C; 68 to 77 degrees F) or 24 hours under refrigeration (2 to 8 degrees C; 36 to 46 degrees F).
      • For solutions prepared using the reconstituted lyophilized powder, total storage time from reconstitution to administration should not exceed 4 hours at room temperature or 24 hours under refrigeration.

     

    Intermittent IV Infusion:

    • Infuse over 30 to 120 minutes.
    • After the infusion is complete, flush with at least 30 mL 0.9% NaCl Injection.
    • Do not mix with or administer simultaneously with other IV medications.

    Clinical Pharmaceutics Information

    From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database
      Revision Date: 06/24/2020, 07:26:07 PM

      References

      65365 - Food and Drug Administration (FDA). Fact sheet for health care providers: emergency use authorization (EUA) of remdesivir (GS-5734). Retrieved June 15, 2020. Available on the World Wide Web at https://www.fda.gov/media/137566/download.

      Adverse Reactions

      Moderate

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

      Mild

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

      Severe

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

      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]

      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]

      Hypersensitivity reactions including infusion-related reactions and anaphylactoid reactions have occurred during remdesivir infusion. Signs and symptoms may include hypotension, sinus tachycardia, bradycardia, dyspnea, wheezing, angioedema, rash, nauseous feeling, vomiting, diaphoresis, and shivering. Monitor patients during 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]

      Safety data from a clinical trial involving hospitalized patients with severe COVID-19 found 10% of patients who received remdesivir for 5 days (n = 200) and 9% of patients treated for 10 days (n = 197) experienced nausea. In the same study, 7% of drug recipients in both treatment groups developed constipation.[65365] 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 4% (n = 22/541) of remdesivir recipients and 6% (n = 31/522) of those receiving placebo developed elevated hepatic enzymes. Data from another clinical trial involving hospitalized patients with severe COVID-19 found 6% to 8% of patients treated with remdesivir developed increased hepatic enzymes.[65365] 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 in 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]

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

      Safety data from the Adaptive COVID-19 Treatment Trial (ACTT-1) identified adverse events (Grade 3 or higher) in 29% of patients treated with remdesivir (n = 541) and 33% of patients who received a placebo (n = 522). The most frequently reported adverse events for remdesivir and placebo were anemia (8% vs. 9%, respectively), acute renal injury (7% vs. 7%), respiratory arrest or failure (5% vs. 8%), fever (5% vs. 3%), and hyperglycemia (4% vs. 3%). Data from another clinical trial found 6% to 11% of remdesivir recipients developed acute respiratory failure.[65365]

      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]

      In pooled data from Gilead-sponsored studies (n = 138), phlebitis was reported in 8 patients.[65247]

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

      In pooled data from Gilead-sponsored studies (n = 138), headache was reported in 6 patients and extremity pain was reported in 5 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]

      Revision Date: 06/16/2020, 04:15:08 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 remdesivir (GS-5734). Retrieved June 15, 2020. Available on the World Wide Web at https://www.fda.gov/media/137566/download.

      Contraindications/Precautions

      Absolute contraindications are italicized.

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

      There are limited clinical data available for remdesivir; serious and unexpected adverse events may occur that have not yet been reported. Health care providers administering remdesivir under the Emergency Use Authorization must report all medication errors and serious adverse events to the FDA within 7 calendar days of occurrence.[65365]

       

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

       

      Study protocols for remdesivir exclude patients with evidence of multiorgan failure and the use of more than 1 pressor for septic shock. This contraindication is based on a lack of safety data for patients with end-organ failure. However, once a patient initiates treatment with remdesivir, subsequent use of pressors is not a reason for discontinuation. The use of 1 pressor at low/medium doses for inotropic support due to the use of sedation and paralytics while on the ventilator is allowed.[65247][65248]

      Hypersensitivity reactions including infusion-related reactions and anaphylaxis have occurred during remdesivir infusion. Monitor patients during administration for the following adverse reactions: hypotension, tachycardia, bradycardia, dyspnea, wheezing, angioedema, rash, nausea, vomiting, 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]

      All potential recipients of remdesivir must have their renal function monitored prior to and daily during treatment. 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 unless the potential benefit outweighs the potential risk. 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. Both IV 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]

      It is unknown if dosage adjustments are needed in patients with hepatic disease; therefore, remdesivir should only be used in patients with hepatic impairment if the potential benefit outweighs the potential risk. Conduct liver function testing (LFT) in all patients before starting remdesivir and daily while receiving remdesivir. Avoid starting treatment in patients with a baseline ALT greater than or equal to 5-times the upper limit of normal (ULN). For elevated hepatic enzymes developing during therapy, discontinue treatment if the increase in ALT is accompanied by signs or symptoms of hepatic inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR or the ALT increases to 5-times ULN or more. Remdesivir may be restarted when ALT drops below 5-times ULN.[65365]

      There are no data regarding the use of remdesivir during pregnancy to determine the drug-associated risk for major birth defects, miscarriages, or adverse maternal or fetal outcomes. Study protocols state the use of remdesivir in pregnant women is not recommended based on lack of safety data; however, remdesivir has been used from the treatment of Ebola in a few pregnant women.[65247] [65248] In animal studies involving rats and rabbits, no adverse effects on embryofetal development were observed following exposure to the predominant circulating metabolite (GS-441524) that were 4-times the exposure at the recommended human dose. Administer during pregnancy only if the potential benefit to the mother justifies the potential risks to the fetus.[65365]

      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]

      Revision Date: 06/16/2020, 02:18:12 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.65365 - Food and Drug Administration (FDA). Fact sheet for health care providers: emergency use authorization (EUA) of remdesivir (GS-5734). Retrieved June 15, 2020. Available on the World Wide Web at https://www.fda.gov/media/137566/download.

      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]

      Revision Date: 05/04/2020, 03:14:37 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 remdesivir (GS-5734). Retrieved June 15, 2020. Available on the World Wide Web at https://www.fda.gov/media/137566/download.

      Pharmacokinetics

      Remdesivir is administered intravenously. Remdesivir is a single diastereomer monophosphoramidate prodrug of a monophosphate nucleoside analog (GS-441524). Remdesivir has moderate protein binding, with a free fraction in humans of 12.1%.[65247]

       

      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-702477 and the nucleoside metabolite GS-44152. Within cells, the GS-44152 monophosphate undergoes rapid conversion to the pharmacologically active analog of adenosine triphosphate, GS-443902. Although remdesivir is a substrate of CYP2C8, CYP2D6, and CYP3A4, metabolism is likely to be predominantly mediated by hydrolase activity. Metabolism of the metabolites has not been reported. In radiolabeled studies, the total combined mean recovery of [14C]-radioactivity in feces and urine was approximately 92%, with most of the radioactive dose recovered from the urine (approximately 74%). Unchanged remdesivir is not present in the urine to any substantial extent, but its main metabolite, GS-441524, is found in urine. GS-44152 was predominately recovered in the urine (49%), with remdesivir (10%) and other metabolites (6%) accounting for less of the total radioactive dose.[65365] In single-dose studies in healthy adults, the half-life ranged from 0.66 to 1.05 hours. After multiple doses, the half-life was consistent at approximately 1 hour. The half-life of the metabolite GS-44152 was approximately 24.5 hours. Based on peripheral blood mononuclear cell pharmacokinetic parameters, the half-life for metabolite GS-443902 ranged from 35.95 to 48.79 hours. Based on peripheral blood mononuclear cell pharmacokinetic parameters, the half-life for metabolite GS-4431524 ranged from 32.23 to 48.38 hours.[65247]

       

      Affected cytochrome P450 isoenzymes and drug transporters: CYP2C8, CYP2D6, CYP3A4, OATP1B1, OATP1B3, BSEP, MRP4, NTCP, P-gp

      In vitro, remdesivir is a substrate for CYP2C8, CYP2D6, CYP3A4, and the transporters organic anion transporting polypeptide 1B1 (OATP1B1) and p-glycoprotein (P-gp). The impact of the transporters on remdesivir disposition is likely minimized by the parenteral route of administration. Remdesivir is an in vitro inhibitor of CYP3A4 and the transporters OATP1B1, OATP1B3, bile salt export pump (BSEP), multidrug resistance protein 4 (MRP4), and sodium taurocholate cotransporting polypeptide (NTCP); however, its potential to be the perpetrator of clinically significant interactions is limited by its rapid clearance. Hepatocyte donor-dependent induction of mRNA levels of CYP1A2 and CYP2B6 was observed.[65247]

       

      Some in vitro interaction results may indicate a potential for drug interactions, but in vivo relevance is likely low given the transient exposure to remdesivir after IV infusion. The interaction potential of metabolites is largely unknown.[65247]

      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 a single dose in healthy adults, the AUC0-24 values were 4.8 microM x hour for remdesivir and 7.7 microM x hour for GS-441524. The Tmax for remdesivir after a single dose was approximately 2 hours. Pharmacokinetic parameters after multiple doses were consistent with those observed with single-dose administration.[65247]

      Special Populations

      Hepatic Impairment

      There are no data available on the pharmacokinetics of remdesivir in patients with hepatic impairment.[65247] [65365]

      Renal Impairment

      There are no data available on the pharmacokinetics of remdesivir in patients with renal impairment.[65365] 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. 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: 06/25/2020, 09:28:58 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.65365 - Food and Drug Administration (FDA). Fact sheet for health care providers: emergency use authorization (EUA) of remdesivir (GS-5734). Retrieved June 15, 2020. Available on the World Wide Web at https://www.fda.gov/media/137566/download.

      Pregnancy/Breast-feeding

      pregnancy

      There are no data regarding the use of remdesivir during pregnancy to determine the drug-associated risk for major birth defects, miscarriages, or adverse maternal or fetal outcomes. Study protocols state the use of remdesivir in pregnant women is not recommended based on lack of safety data; however, remdesivir has been used from the treatment of Ebola in a few pregnant women.[65247] [65248] In animal studies involving rats and rabbits, no adverse effects on embryofetal development were observed following exposure to the predominant circulating metabolite (GS-441524) that were 4-times the exposure at the recommended human dose. Administer during pregnancy only if the potential benefit to the mother justifies the potential risks to the fetus.[65365]

      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]

      Revision Date: 05/04/2020, 12:27:13 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.65365 - Food and Drug Administration (FDA). Fact sheet for health care providers: emergency use authorization (EUA) of remdesivir (GS-5734). Retrieved June 15, 2020. Available on the World Wide Web at https://www.fda.gov/media/137566/download.

      Interactions

      Level 2 (Major)

      • Atropine; Hyoscyamine; Phenobarbital; Scopolamine
      • Belladonna Alkaloids; Ergotamine; Phenobarbital
      • Carbamazepine
      • Chloroquine
      • Fosphenytoin
      • Hydroxychloroquine
      • Isoniazid, INH; Pyrazinamide, PZA; Rifampin
      • Isoniazid, INH; Rifampin
      • Phenobarbital
      • Phenytoin
      • Primidone
      • Rifampin
      • Rifapentine
      • St. John's Wort, Hypericum perforatum

      Level 3 (Moderate)

      • Bosentan
      • Dexamethasone
      • Eslicarbazepine
      • Omeprazole; Amoxicillin; Rifabutin
      • Oxcarbazepine
      • Rifabutin
      • Rufinamide
      Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid concurrent administration of remdesivir and phenobarbital. Taking these drugs together is expected to reduce the systemic exposure to remdesivir and potentially reduce its antiviral activity. Although drug-drug interaction studies involving remdesivir have not been conducted, in vitro data show remdesivir is a substrate for CYP3A4 and the drug transporter P-glycoprotein (P-gp). Phenobarbital is a strong CYP3A4 inducer and a moderate inducer of P-gp. [22005] [55436] [57046] [57048] [57080] [65210] [65365] Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid concurrent administration of remdesivir and phenobarbital. Taking these drugs together is expected to reduce the systemic exposure to remdesivir and potentially reduce its antiviral activity. Although drug-drug interaction studies involving remdesivir have not been conducted, in vitro data show remdesivir is a substrate for CYP3A4 and the drug transporter P-glycoprotein (P-gp). Phenobarbital is a strong CYP3A4 inducer and a moderate inducer of P-gp. [22005] [55436] [57046] [57048] [57080] [65210] [65365] Bosentan: (Moderate) The systemic exposure to remdesivir may be reduced when administered concurrently with bosentan; close monitoring for reduced remdesivir efficacy is advised if these drugs are used together. Although drug-drug interaction studies involving remdesivir have not been conducted, in vitro data show remdesivir is a substrate for CYP3A4. Bosentan is a moderate CYP3A4 inducer. [28496] [65210] [65365] Carbamazepine: (Major) Avoid concurrent administration of remdesivir and carbamazepine. Taking these drugs together is expected to reduce the systemic exposure to remdesivir and potentially reduce its antiviral activity. Although drug-drug interaction studies involving remdesivir have not been conducted, in vitro data show remdesivir is a substrate for CYP3A4 and the drug transporter P-glycoprotein (P-gp). Carbamazepine is a strong CYP3A4 inducer and a moderate inducer of P-gp. [56579] [65210] [65365] 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] Dexamethasone: (Moderate) The systemic exposure to remdesivir may be reduced when administered concurrently with dexamethasone; close monitoring for reduced remdesivir efficacy is advised if these drugs are used together. Although drug-drug interaction studies involving remdesivir have not been conducted, in vitro data show remdesivir is a substrate for CYP3A4. Dexamethasone is a moderate CYP3A4 inducer. [54286] [65210] [65365] Eslicarbazepine: (Moderate) The systemic exposure to remdesivir may be reduced when administered concurrently with eslicarbazepine; close monitoring for reduced remdesivir efficacy is advised if these drugs are used together. Although drug-drug interaction studies involving remdesivir have not been conducted, in vitro data show remdesivir is a substrate for CYP3A4. Eslicarbazepine is a moderate CYP3A4 inducer. [56436] [65210] [65365] Fosphenytoin: (Major) Avoid concurrent administration of remdesivir and fosphenytoin. Taking these drugs together is expected to reduce the systemic exposure to remdesivir and potentially reduce its antiviral activity. Although drug-drug interaction studies involving remdesivir have not been conducted, in vitro data show remdesivir is a substrate for CYP3A4 and the drug transporter P-glycoprotein (P-gp). Phenytoin, the active metabolite of fosphenytoin, is a strong CYP3A4 inducer and a weak inducer of P-gp. [22005] [55436] [56579] [57046] [57048] [57080] [57105] [65210] [65365] 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] Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concurrent administration of remdesivir and rifampin. Taking these drugs together is expected to reduce the systemic exposure to remdesivir and potentially reduce its antiviral activity. Although drug-drug interaction studies involving remdesivir have not been conducted, in vitro data show remdesivir is a substrate for CYP3A4, CYP2C8, and the drug transporter P-glycoprotein (P-gp). Rifampin is a strong inducer of CYP3A4 and moderate CYP2C8 and P-gp inducer. [34733] [65210] [65365] Isoniazid, INH; Rifampin: (Major) Avoid concurrent administration of remdesivir and rifampin. Taking these drugs together is expected to reduce the systemic exposure to remdesivir and potentially reduce its antiviral activity. Although drug-drug interaction studies involving remdesivir have not been conducted, in vitro data show remdesivir is a substrate for CYP3A4, CYP2C8, and the drug transporter P-glycoprotein (P-gp). Rifampin is a strong inducer of CYP3A4 and moderate CYP2C8 and P-gp inducer. [34733] [65210] [65365] Omeprazole; Amoxicillin; Rifabutin: (Moderate) The systemic exposure to remdesivir may be reduced when administered concurrently with rifabutin; close monitoring for reduced remdesivir efficacy is advised if these drugs are used together. Although drug-drug interaction studies involving remdesivir have not been conducted, in vitro data show remdesivir is a substrate for CYP3A4. Rifabutin is a moderate CYP3A4 inducer. [29210] [29812] [34549] [34550] [65210] [65365] Oxcarbazepine: (Moderate) The systemic exposure to remdesivir may be reduced when administered concurrently with oxcarbazepine; close monitoring for reduced remdesivir efficacy is advised if these drugs are used together. Although drug-drug interaction studies involving remdesivir have not been conducted, in vitro data show remdesivir is a substrate for CYP3A4. Oxcarbazepine is a weak CYP3A4 inducer. [29014] [65210] [65365] Phenobarbital: (Major) Avoid concurrent administration of remdesivir and phenobarbital. Taking these drugs together is expected to reduce the systemic exposure to remdesivir and potentially reduce its antiviral activity. Although drug-drug interaction studies involving remdesivir have not been conducted, in vitro data show remdesivir is a substrate for CYP3A4 and the drug transporter P-glycoprotein (P-gp). Phenobarbital is a strong CYP3A4 inducer and a moderate inducer of P-gp. [22005] [55436] [57046] [57048] [57080] [65210] [65365] Phenytoin: (Major) Avoid concurrent administration of remdesivir and phenytoin. Taking these drugs together is expected to reduce the systemic exposure to remdesivir and potentially reduce its antiviral activity. Although drug-drug interaction studies involving remdesivir have not been conducted, in vitro data show remdesivir is a substrate for CYP3A4 and the drug transporter P-glycoprotein (P-gp). Phenytoin is a strong CYP3A4 inducer and a weak inducer of P-gp. [22005] [55436] [56579] [57046] [57048] [57080] [57105] [65210] [65365] Primidone: (Major) Avoid concurrent administration of remdesivir and primidone. Taking these drugs together is expected to reduce the systemic exposure to remdesivir and potentially reduce its antiviral activity. Although drug-drug interaction studies involving remdesivir have not been conducted, in vitro data show remdesivir is a substrate for CYP3A4 and the drug transporter P-glycoprotein (P-gp). Primidone is a strong CYP3A4 inducer and a moderate inducer of P-gp. [22005] [57046] [57048] [57080] [65210] [65365] Rifabutin: (Moderate) The systemic exposure to remdesivir may be reduced when administered concurrently with rifabutin; close monitoring for reduced remdesivir efficacy is advised if these drugs are used together. Although drug-drug interaction studies involving remdesivir have not been conducted, in vitro data show remdesivir is a substrate for CYP3A4. Rifabutin is a moderate CYP3A4 inducer. [29210] [29812] [34549] [34550] [65210] [65365] Rifampin: (Major) Avoid concurrent administration of remdesivir and rifampin. Taking these drugs together is expected to reduce the systemic exposure to remdesivir and potentially reduce its antiviral activity. Although drug-drug interaction studies involving remdesivir have not been conducted, in vitro data show remdesivir is a substrate for CYP3A4, CYP2C8, and the drug transporter P-glycoprotein (P-gp). Rifampin is a strong inducer of CYP3A4 and moderate CYP2C8 and P-gp inducer. [34733] [65210] [65365] Rifapentine: (Major) Avoid concurrent administration of remdesivir and rifapentine. Taking these drugs together is expected to reduce the systemic exposure to remdesivir and potentially reduce its antiviral activity. Although drug-drug interaction studies involving remdesivir have not been conducted, in vitro data show remdesivir is a substrate for the enzymes CYP3A4 and CYP2C8. Rifapentine is a moderate inducer of CYP3A4 and CYP2C8. [28483] [65210] [65365] Rufinamide: (Moderate) The systemic exposure to remdesivir may be reduced when administered concurrently with rufinamide; close monitoring for reduced remdesivir efficacy is advised if these drugs are used together. Although drug-drug interaction studies involving remdesivir have not been conducted, in vitro data show remdesivir is a substrate for CYP3A4. Rufinamide is a weak CYP3A4 inducer. [34590] [65210] [65365] St. John's Wort, Hypericum perforatum: (Major) Avoid concurrent administration of remdesivir and St. Johns Wort. Taking these drugs together is expected to reduce the systemic exposure to remdesivir and potentially reduce its antiviral activity. Although drug-drug interaction studies involving remdesivir have not been conducted, in vitro data show remdesivir is a substrate for CYP3A4 and the drug transporter P-glycoprotein (P-gp). St. Johns Wort is a strong CYP3A4 inducer and a moderate inducer of P-gp. [57202] [65210] [65365]
      Revision Date: 07/10/2020, 02:28:00 AM

      References

      22005 - Perucca E. Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol 2006;61(3):246-255.28483 - Priftin (rifapentine) package insert. Bridgewater, NJ: Sanofi-Aventis Pharmaceuticals Inc.; 2020 Jun.28496 - Tracleer (bosentan) package insert. South San Francisco, CA: Actelion Pharmaceuticals US, Inc.; 2019 May.29014 - Trileptal (oxcarbazepine) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2019 Jan.29210 - Mycobutin (rifabutin) package insert. New York, NY: Pharmacia and Upjohn, Co.; 2018 Apr.29812 - Burman WJ, Gallicano K, Peloquin C. Comparative pharmacokinetics and pharmacodynamics of the rifamycin antibacterials. Clin Pharmacokinet. 2001;40:327-41.34549 - Reinach B, de Sousa G, Dostert P, et al. Comparative effects of rifabutin and rifampicin on cytochromes P450 and UDP-glucuronosyl-transferases expression in fresh and cryopreserved human hepatocytes. Chem Biol Interact 1999;121:37-48.34550 - Kuper JI, DAprile M. Drug-Drug interactions of clinical significance in the treatment of patients with Mycobacterium avium complex disease. Clin Pharmacokinet 2000;39:203-14.34590 - Banzel (rufinamide) package insert. Woodcliff Lake, NJ: Eisai Co., Ltd.; 2019 Nov.34733 - Niemi M, Backman JT, Neuvonen PJ. Effects of trimethoprim and rifampin on the pharmacokinetics of the cytochrome P450 2C8 substrate rosiglitazone. Clin Pharmacol Ther 2004;76:239-49.54286 - Dexamethasone tablets USP, Dexamethasone oral solution, and Dexamethasone Intensol (oral solution concentrate) package insert. Eatontown, NJ: West-Ward Pharmaceuticals Corp; 2016 March.55436 - Patsalos PN, Berry DJ, Bourgeois BF. Antiepileptic drugs--best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia 2008;49:1239-1276.56436 - Aptiom (eslicarbazepine acetate) package insert. Marlborough, MA: Sunovion Pharmaceuticals Inc.; 2019 Mar.56579 - Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Updated Mar 10, 2020. Retrieved from the World Wide Web at www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm57046 - Perucca E, Hedges A, Makki KA, et al. A comparative study of the relative enzyme inducing properties of anticonvulsant drugs in epileptic patients. Br J Clin Pharmacol 1984;18:401-10.57048 - Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Retrieved from the World Wide Web December 27, 2013. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm#major57080 - de Leon J, Santoro V, D'Arrigo C, et al. Interactions between antiepileptics and second generation antipsychotics. Expert Opin Drug Metab Toxicol 2012;8:311-34.57105 - Schuetz EG, Beck WT, Schuetz JD. Modulators and substrates of P-glycoprotein and cytochrome P4503A coordinately up-regulate these proteins in human colon carcinoma cells. Mol Pharmacol 1996;49:311-318.57202 - Zhou S, Chan E, Pan S, et al. Pharmacokinetic interactions of drugs with St John's wort. J Psychopharmacol 2004;18:262-76.65210 - University of Liverpool. COVID-19 Drug Interactions. Retrived April 6, 2020. Available on the World Wide Web at https://www.covid19-druginteractions.org/.65365 - Food and Drug Administration (FDA). Fact sheet for health care providers: emergency use authorization (EUA) of remdesivir (GS-5734). Retrieved June 15, 2020. Available on the World Wide Web at https://www.fda.gov/media/137566/download.

      Monitoring Parameters

      • CBC with differential
      • LFTs
      • serum creatinine/BUN
      • serum electrolytes