remdesivir (Rx)

Brand and Other Names:Veklury
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

injection, lyophilized powder for reconstitution

  • 100mg/vial

injection, concentrated solution

  • 100mg/20mL (5mg/mL)

Coronavirus Disease 2019 (COVID-19)

Indicated for adults and pediatric patients aged ≥12 years who weigh ≥40 kg for treatment of COVID-19 requiring hospitalization

Day 1 loading dose: 200 mg IV infused over 30-120 min, THEN

Day 2 and thereafter: 100 mg IV qDay

Treatment duration

  • Not requiring invasive mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO): 5 days; if clinical improvement not demonstrated, treatment may be extended up to 10 days total
  • Requires invasive mechanical ventilation and/or ECMO: 10 days

Dosage Modifications

Renal impairment

  • Pharmacokinetics have not been evaluated in patients with renal impairment
  • eGFR ≥30 mL/min: No dose adjustment
  • eGFR <30 mL/min: Not recommended; sulfobutylether-beta-cyclodextrin sodium salt (SBECD) excipient in the concentrated solution is renally cleared and accumulates in patients with decreased renal function

Hepatic impairment

  • Not evaluated; unknown if dosage adjustment required

Dosing Considerations

Laboratory tests

  • Obtain before initiating in all patients and while receiving as clinically appropriate
  • Determine eGFR
  • Perform hepatic laboratory testing
  • Determine prothrombin time

Additional Resources

Dosage Forms & Strengths

injection, lyophilized powder for reconstitution

  • 100mg/vial
  • Note: Use lyophilized powder to prepare dose for children aged <12 years or weight <40 kg according to EUA for this group

injection, concentrated solution

  • 100mg/20mL (5mg/mL)

Coronavirus Disease 2019 (COVID-19)

Indicated for adults and pediatric patients aged ≥12 years who weigh ≥40 kg for treatment of COVID-19 requiring hospitalization

Day 1 loading dose: 200 mg IV infused over 30-120 min, THEN

Day 2 and thereafter: 100 mg IV qDay

Treatment duration

  • Not requiring invasive mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO): 5 days; if clinical improvement not demonstrated, treatment may be extended up to 10 days total
  • Requires invasive mechanical ventilation and/or ECMO: 10 days

COVID-19 in Younger Children (Investigational)

Emergency Use Authorization (EUA) issued for hospitalized pediatric patients weighing 3.5 kg to <40 kg or children aged <12 years who weigh at least 3.5 kg

Weight 3.5-40 kg

  • Day 1 loading dose: 5 mg/kg mg IV infused over 30-120 min, THEN
  • Day 2 and thereafter: 2.5 mg/kg IV qDay

Age <12 years and weight 40 kg or more

  • Day 1 loading dose: 200 mg IV infused over 30-120 min, THEN
  • Day 2 and thereafter: 100 mg IV qDay

Treatment duration

  • Not requiring invasive mechanical ventilation and/or ECMO: 5 days; if clinical improvement not demonstrated, treatment may be extended up to 10 days total
  • Requires invasive mechanical ventilation and/or ECMO: 10 days

Dosage Modifications

Renal impairment

  • eGFR ≥30 mL/min: No dose adjustment
  • Pediatric patients (aged >28 days) with eGFR <30 mL/min: Not recommended
  • Full-term neonates (aged ≥7 days to ≤28 days) with serum creatinine >1 mg/dL: Not recommended
  • Sulfobutylether-beta-cyclodextrin sodium salt (SBECD) excipient in the concentrated solution is renally cleared and accumulates in patients with decreased renal function

Hepatic impairment

  • Not evaluated; unknown if dosage adjustment required

Dosing Considerations

Administer only in a hospital or healthcare setting capable of providing acute care comparable to inpatient hospital care

Use lyophilized powder to prepare dose for children aged <12 years or weight <40 kg according to EUA for this group

Laboratory tests

  • Obtain before initiating in all patients and while receiving as clinically appropriate
  • Determine eGFR for patients aged >28 days
  • Measure serum creatinine for all full-term neonates aged 7-28 days
  • Perform hepatic laboratory testing
  • Determine prothrombin time

Additional Resources

No dosage adjustment required in patients aged ≥65 yr

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Interactions

Interaction Checker

and remdesivir

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            Adverse Effects

            >10%

            eGFR decreased* (18%)

            Decreased CrCl* (calculated by Cockcroft-Gault) (10-18%)

            Creatinine increased* (5-15%)

            Hemoglobin decreased* (6-15%)

            Glucose increased* (11-12%)

            Lymphocytes decreased* (11%)

            1-10%

            Prothrombin time increased (9%)

            ALT increased* (3-8%)

            AST increased* (6-7%)

            Nausea (3-5%)

            Bilirubin increased* (2%)

            Hypersensitivity reactions (<2%)

            Generalized seizure (<2%)

            Rash (<2%)

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            Warnings

            Contraindications

            Hypersensitivity to drug or any ingredient

            Cautions

            Hypersensitivity, including infusion-related reactions

            • Hypersensitivity, including infusion-related reactions observed during and following administration

            • Signs and symptoms may include hypotension, hypertension, tachycardia, bradycardia, hypoxia, fever, dyspnea, wheezing, angioedema, rash, nausea, diaphoresis, and shivering

            • Consider slowing infusion rate (up to 120 minutes) to potentially prevent these signs and symptoms

            • If clinically significant reaction occurs, discontinue immediately and implement appropriate treatment

            Hepatic transaminases

            • Increased hepatic transaminases reported in healthy volunteers and patients with COVID-19
            • Because transaminase elevations are reported as a clinical feature of COVID-19, and the incidence in clinical trials was similar in patients receiving placebo versus remdesivir, it is challenging to discern the contribution of remdesivir to transaminase elevations in patients with COVID-19
            • ALT levels increase to >10x ULN: Consider discontinuing remdesivir
            • ALT elevation accompanied by signs or symptoms of liver inflammation: Discontinue remdesivir

            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

            Available data from published case reports and compassionate use of remdesivir in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes

            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

            Clinical considerations

            • Pregnant women hospitalized with COVID-19 are at risk for serious morbidity and mortality

            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 detected in plasma of nursing rat pups, likely owing to presence of remdesivir in milk following daily IV remdesivir to pregnant rats from gestation day 6 to lactation day 20
            • Exposures in nursing pups were ~1% that of maternal exposure on lactation day 10

            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

            Inhibits SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), which is essential for viral replication

            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 (RDV-TP) demonstrated in multiple cell types

            RDV-TP 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

            Absorption

            Peak plasma time

            • Remdesivir: 0.67-0.68 hr
            • GS-441524: 1.51-2 hr
            • GS-704277: 0.75 hr

            Peak plasma concentration

            • Remdesivir: 2229 ng/mL
            • GS-441524: 145 ng/mL
            • GS-704277: 246 ng/mL

            Trough concentration

            • Remdesivir: Not detectable (24-hr post dose)
            • GS-441524: 69.2 ng/mL
            • GS-704277: Not detectable (24-hr post dose)

            AUC

            • Remdesivir: 1585 nghr/mL
            • GS-441524: 2229 nghr/mL
            • GS-704277: 452 nghr/mL

            Distribution

            Protein bound

            • Remdesivir: 88-93.6%
            • GS-441524: 2%
            • GS-704277: 1%

            Metabolism

            Remdesivir: CES1 (80%); cathepsin A (10%); CYP3A (10%)

            GS-441524: Not significantly metabolized

            GS-704277: HINT1

            Elimination

            Half-life

            • Remdesivir: 1 hr
            • GS-441524: 27 hr
            • GS-704277: 1.3 hr

            Excretion

            • Major route
              • Remdesivir: Metabolism
              • GS-441524: Glomerular filtration and active tubular secretion
              • GS-704277: Metabolism
            • Urine
              • Remdesivir: 10%
              • GS-441524: 49%
              • GS-704277: 2.9%
            • Feces
              • Remdesivir: Not detected
              • GS-441524: 0.5%
              • GS-704277: Not detected
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            Administration

            IV Preparation

            Pediatric patients weighing 3.5 kg to <40 kg: Prepare dose with only lyophilized powder product

            Do not use concentrated solution 100 mg/20 mL (5 mg/mL) for pediatric patients <40 kg or patients with eGFR <30 mL/min owing to the higher amount of sulfobutylether-beta-cyclodextrin sodium salt (SBECD) present and resulting higher tonicity compared with the lyophilized powder formulation

            Reconstitution of lyophilized powder

            • 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
            • Use reconstituted product immediately to prepare diluted solution

            Further dilution required

            • Adults and pediatric patients weighing ≥40 kg
              • Dilute further by adding reconstituted solution or concentrated solution to 0.9% NaCl infusion bag (100-mL or 250-mL volume) to reconstituted solution or concentrated solution
              • Withdraw 20 mL (for 100-mg dose) or 40 mL (for 200-mg dose) of saline from the IV bag using an appropriately sized syringe and needle; discard the saline withdrawn from bag
              • Withdraw required dosage volume of reconstituted or concentrated remdesivir solution 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
            • Pediatric patients weighing <40 kg
              • Prepare an IV bag or infusion syringe of 0.9% NaCl with volume equal to the total infusion volume minus the volume of reconstituted remdesivir solution to achieve a 1.25-mg/mL solution
              • Gently invert IV bag or infusion syringe 20 times to mix; do not shake

            IV Administration

            Do not administer simultaneously in IV line with any other medication

            Infuse IV over 30-120 minutes

            Also see prescribing information for infusion rate charts

            Rate of infusion may be adjusted based on total volume infused

            Storage

            Does not contain preservatives

            Lyophilized powder

            • Unopened vial: Store <30ºC (<86ºF)
            • Reconstituted vial: Use reconstituted product immediately to prepare diluted solution
            • Diluted solution: Stable for 24 hr at 20-25ºC (68-77ºF) or 48 hr refrigerated at temperature 2-8ºC (36-46ºF)

            Solution for injection

            • Unopened vial: Refrigerate at 2-8ºC (36-46ºF); may store at room temperature up to 12 hr before dilution
            • Diluted solution: Stable for 24 hr at 20-25ºC (68-77ºF) or 48 hr refrigerated at temperature 2-8ºC (36-46ºF)
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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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