remdesivir (Investigational)

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    Dosing & Uses

    AdultPediatric

    Dosage Forms & Strengths

    injection, lyophilized powder for reconstitution

    • 100mg/vial

    injection, solution

    • 100mg/20mL (5mg/mL)

    Coronavirus Disease 2019 (COVID-19) (Investigational)

    May 1, 2020: The FDA has granted an emergency use authorization (EUA) for remdesivir to treat hospitalized adults and children with suspected or laboratory-confirmed SARS CoV-2 infection and severe COVID-19 disease

    EUA facilitates broader use of remdesivir, enabling access at additional hospitals across the country

    Severe COVID-19 disease is defined as patients with an oxygen saturation (SpO2) ≤94% on room air or requiring supplemental oxygen or requiring mechanical ventilation or requiring extracorporeal membrane oxygenation (ECMO)

    Optimal treatment duration is unknown; for this EUA, dosing is as follows

    Dosage (weight 40 kg or more)

    • Requires mechanical ventilation and/or ECMO
      • Day 1 loading dose: 200 mg IV infused over 30-120 min, THEN
      • Days 2-10 maintenance dose: 100 mg IV qDay
    • Does not require mechanical ventilation and/or ECMO
      • Day 1 loading dose: 200 mg IV infused over 30-120 min, THEN
      • Days 2-5 maintenance dose: 100 mg IV qDay
      • If clinical improvement not demonstrated, treatment may be extended for up to 5 additional days (ie, up to 10 days total)

    Dosage Modifications

    Renal impairment

    • Pharmacokinetics have not been evaluated in patients with renal impairment
    • Use in patients with renal impairment is based on potential risk and potential benefit considerations
    • eGFR ≥30 mL/min: No dose adjustment
    • eGFR <30 mL/min: Not recommended unless the potential benefit outweighs potential risk

    Hepatic impairment

    • Not evaluated; unknown if dosage adjustment required
    • Use only if potential benefit outweighs risk

    Dosing Considerations

    Remdesivir can be used at any time after onset of symptoms in hospitalized patients

    Laboratory tests

    • Measure eGFR for all patients before dosing
    • Obtain hepatic laboratory testing in all patients before initiating remdesivir and daily while receiving remdesivir

    Trials currently investigating the use of remdesivir to treat hospitalized patients with COVID-19 and pneumonia in the United States (US)

    • Adaptive COVID-19 Treatment Trial (ACTT): NIH-sponsored double-blinded, placebo-controlled trial of remdesivir versus placebo in COVID-19 patients with pneumonia and hypoxia (link https://clinicaltrials.gov/ct2/show/NCT04280705)
    • Two phase 3 randomized open-label trials of remdesivir are comparing 5-day, 10-day, and standard-of-care treatments

    Additional Medscape COVID-19 references are available

    Dosage Forms & Strengths

    injection, lyophilized powder for reconstitution

    • 100mg/vial

    injection, solution

    • 100mg/20mL (5mg/mL)

    Coronavirus Disease 2019 (COVID-19) (Investigational)

    May 1, 2020: The FDA has granted an emergency use authorization (EUA) for remdesivir to treat hospitalized adults and children with suspected or laboratory-confirmed SARS CoV-2 infection and severe COVID-19 disease

    EUA facilitates broader use of remdesivir, enabling access at additional hospitals across the country

    Severe COVID-19 disease is defined as patients with an oxygen saturation (SpO2) ≤94% on room air or requiring supplemental oxygen or requiring mechanical ventilation or requiring extracorporeal membrane oxygenation (ECMO)

    Optimal treatment duration is unknown; for this EUA, dosing is as follows

    Safety and effectiveness have not been assessed in pediatric patients; pediatric dosing derived based on pharmacokinetic data from adult healthy volunteers

    Dosage (weight 3.5-40 kg)

    • Requires mechanical ventilation and/or ECMO
      • Day 1 loading dose: 5 mg/kg mg IV infused over 30-120 min, THEN
      • Days 2-10 maintenance dose: 2.5 mg/kg IV qDay
    • Does not require mechanical ventilation and/or ECMO
      • Day 1 loading dose: 5 mg/kg IV infused over 30-120 min, THEN
      • Days 2-5 maintenance dose: 2.5 mg/kg IV qDay
      • If clinical improvement not demonstrated, treatment may be extended for up to 5 additional days (ie, up to 10 days total)

    Dosage (weight 40 kg or more)

    • Requires mechanical ventilation and/or ECMO
      • Day 1 loading dose: 200 mg IV infused over 30-120 min, THEN
      • Days 2-10 maintenance dose: 100 mg IV qDay
    • Does not require mechanical ventilation and/or ECMO
      • Day 1 loading dose: 200 mg IV infused over 30-120 min, THEN
      • Days 2-5 maintenance dose: 100 mg IV qDay
      • If clinical improvement not demonstrated, treatment may be extended for up to 5 additional days (ie, up to 10 days total)

    Dosage Modifications

    Renal impairment

    • eGFR ≥30 mL/min: No dose adjustment
    • Pediatric patients (aged >28 days) with eGFR <30 mL/min: Not recommended unless the potential benefit outweighs potential risk
    • Full-term neonates (aged ≥7 days to ≤28 days) with serum creatinine >1 mg/dL: Not recommended unless the potential benefit outweighs potential risk

    Hepatic impairment

    • Not evaluated; unknown if dosage adjustment required
    • Use only if potential benefit outweighs risk

    Dosing Considerations

    Remdesivir can be used at any time after onset of symptoms in hospitalized patients

    Use of adult dose in pediatric patients is expected to maintain exposures of both remdesivir and the nucleoside analog GS-441524 generally within the expected adult steady-state exposure range following administration of the adult therapeutic dosage regimen in healthy volunteers

    Laboratory tests

    • Measure eGFR for all patients before dosing
    • Obtain hepatic laboratory testing in all patients before initiating remdesivir and daily while receiving remdesivir

    Trials currently investigating the use of remdesivir to treat hospitalized patients with COVID-19 and pneumonia in the United States (US)

    Adaptive COVID-19 Treatment Trial (ACTT): NIH-sponsored double-blinded, placebo-controlled trial of remdesivir versus placebo in COVID-19 patients with pneumonia and hypoxia (link https://clinicaltrials.gov/ct2/show/NCT04280705)

    • Two phase 3 randomized open-label trials of remdesivir are comparing 5-day, 10-day, and standard-of-care treatments

    Additional Medscape COVID-19 references are available

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    Interactions

    Interaction Checker

    and remdesivir

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      Interactions Found

      Contraindicated

        Serious - Use Alternative

          Significant - Monitor Closely

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              Adverse Effects

              Mandatory requirement: Completion of FDA MedWatch form to report all medication errors and adverse effects

              Data compared with placebo not yet available

              1-10%

              ALT/AST Grade 3 (4-6%)

              ALT/AST Grade 4 (2-3%)

              Total bilirubin Grade 4 (1%)

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              Warnings

              Contraindications

              Hypersensitivity to drug or any ingredient

              Cautions

              Limited data are available

              Infusion-related reactions

              • Infusion-related reactions observed during, and/or been temporally associated with, administration
              • Signs and symptoms may include hypotension, nausea, vomiting, diaphoresis, and shivering
              • If these symptoms occur, discontinue immediately and implement appropriate treatment

              Hepatic transaminases

              • Increased hepatic transaminases reported in healthy volunteers and patients with COVID-19
              • ALT ≥5 x ULN at baseline: Do not initiate drug
              • Discontinue drug if
                • ALT ≥5 x ULN during treatment; may resume when ALT <5 X ULN, OR
                • ALT elevation accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR

              Drug interaction overview

              • Drug-drug interaction trials of remdesivir and other concomitant medications have not been conducted in humans
              • In vitro, remdesivir is a substrate of CYP2C8, CYP2D6, and CYP3A4 enzymes; and a substrate of OAPT1B1 and P-glycoprotein transporters
              • In vitro, remdesivir is an inhibitor of CYP3A4, OATP1B1, OATP1B3, BSEP, MRP4, and NTCP
              • Clinical relevance of these in vitro assessments has not been established
              • Coadministration with chloroquine or hydroxychloroquine
                • Coadministration of remdesivir is not recommended with chloroquine or hydroxychloroquine
                • Based on in vitro data, chloroquine demonstrated an antagonistic effect on the intracellular metabolic activation and antiviral activity of remdesivir
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              Pregnancy & Lactation

              Pregnancy

              No studies have been conducted in pregnant women

              Remdesivir should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and fetus

              Animal studies

              • In nonclinical reproductive toxicity studies, remdesivir demonstrated no adverse effect on embryofetal development when administered to pregnant animals at systemic exposures of the predominant circulating metabolite of remdesivir (GS-441524) that were 4 times (rats and rabbits) the exposure in humans at the recommended human dose

              Lactation

              Data are not available regarding the presence of remdesivir in human milk, effects on breastfed infants, or effects on milk production

              Animal studies

              • Remdesivir and metabolites have been detected in the nursing pups of mothers given remdesivir, likely due to the presence of remdesivir in milk

              Pregnancy Categories

              A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

              B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

              C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

              D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

              X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

              NA: Information not available.

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              Pharmacology

              Mechanism of Action

              Adenosine nucleotide prodrug that distributes into cells where it is metabolized to form the pharmacologically active nucleoside triphosphate metabolite

              Metabolism of remdesivir to remdesivir triphosphate has been demonstrated in multiple cell types

              Remdesivir triphosphate acts as an analog of adenosine triphosphate (ATP) and competes with the natural ATP substrate for incorporation into nascent RNA chains by the SARS-CoV-2 RNA-dependent RNA polymerase, which results in delayed chain termination during replication of the viral RNA

              Remdesivir triphosphate is a weak inhibitor of mammalian DNA and RNA polymerases with low potential for mitochondrial toxicity

              Metabolism

              Metabolized to remdesivir triphosphate

              Elimination

              Excretion: Urine (~74%; 49% as metabolite); feces (18%)

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              Administration

              IV Preparation

              Reconstitution

              • Aseptically reconstitute lyophilized powder by adding 19 mL of sterile water for injection (SWI)
              • Discard vial if a vacuum does not pull the SWI into the vial
              • Immediately shake vial for 30 seconds
              • Allow vial contents to settle for 2-3 minutes; resulting solution should appear clear
              • If not completely dissolved, shake vial again for 30 seconds and allow the contents to settle for 2-3 minutes; repeat this procedure as necessary until the contents of the vial are completely dissolved
              • Following reconstitution, resulting concentration/vial is 100 mg/20 mL (5 mg/mL)
              • Inspected visually for particulate matter and discoloration

              Further dilution required

              • Dilute further by adding to 0.9% NaCl infusion bag (100 mL or 250 mL volume)
              • Withdraw 20 mL (for 100-mg dose) or 40 mL (for 200-mg dose) volume of saline from the IV bag using an appropriately sized syringe and needle; discard the saline withdrawn from bag
              • Withdraw the required volume of reconstituted remdesivir from vial; discard any unused portion remaining in the vial
              • Transfer required dosage volume to selected infusion bag
              • Gently invert the bag 20 times to mix the solution in the bag; do not shake

              IV Administration

              Do not administer simultaneously in IV line with any other medication

              Storage

              Unopened vials

              • Lyophilized powder
                • Store <30ºC (<86ºF)
              • Solution for injection
                • Refrigerate at 2-8ºC (36-46ºF)
                • Further dilute within the same day as administration

              Reconstituted or diluted drug

              • Does not contain preservatives
              • Room temperature: Do not exceed 4 hr total storage time before administration
              • Refrigerated at 2-8ºC (36-46ºF): Do not exceed 24 hr total storage time before administration
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              Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.