FDA Approves VEKLURY (Remdesivir)

FDA
  • Kelly Wilson
  • October 25, 2020

On October 22, 2020, the U.S. Food and Drug Administration (FDA) approved VEKLURY (remdesivir) for adults and pediatric patients (12 years of age and older and weighing at least 40 kg) for the treatment of coronavirus disease 2019 (COVID-19) requiring hospitalization. VEKLURY should only be administered intravenously (IV) in a hospital or in a healthcare setting capable of providing acute care comparable to inpatient hospital care. Perform renal and hepatic laboratory testing and assess prothrombin time in all patients before initiating VEKLURY and during treatment as clinically appropriate.

The approved recommended dosage of VEKLURY in adults and pediatric patients 12 years of age and older and weighing at least 40 kg is a single loading dose of VEKLURY 200 mg IV on Day 1 followed by once-daily maintenance doses of VEKLURY 100 mg IV from Day 2 infused over 30 to 120 minutes. For patients not requiring invasive mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO), the recommended total treatment duration is 5 days. If a patient does not demonstrate clinical improvement, treatment may be extended for up to 5 additional days for a total treatment duration of up to 10 days. For patients requiring invasive mechanical ventilation and/or ECMO, the recommended total treatment duration is 10 days.

Additional information regarding dosage and administration as well as warnings and precautions about hypersensitivity including infusion-related and anaphylactic reactions, increased risk of transaminase elevations, and risk of reduced antiviral activity when coadministered with chloroquine phosphate or hydroxychloroquine sulfate can be found in the full prescribing information linked below.

Mechanism of Action (MOA) and Pharmacokinetics (PK)

MOA: Remdesivir is an antiviral drug with activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

PK: The PK properties of remdesivir and metabolites are provided in Table 1. The multiple dose PK parameters of remdesivir and metabolites in healthy adults are provided in Table 2.

Table 1: Pharmacokinetic Properties of Remdesivir and Metabolites (GS-441524 and GS-704277)

 

Remdesivir

GS-441524

GS-704277

Absorption

Tmax (h)a 

0.67-0.68

1.51-2.00

0.75-0.75

Distribution

% bound to human plasma proteins  

88-93.6

2

1

Blood-to-plasma ratio

0.68-1.0

1.19

0.56

Elimination

t1/2 (h)c   

1

27

1.3

Metabolism

Metabolic pathway(s) 

CES1 (80%)
Cathepsin A (10%)
CYP3A (10%)

Not significantly metabolized

 HINT1

Excretion

Major route of elimination 

Metabolism 

Glomerular filtration and active tubular secretion 

Metabolism

% of dose excreted in urined 

10 

49 

2.9

% of dose excreted in fecesd

ND

0.5

ND

ND=not detected

a Remdesivir administered as a 30-minute IV infusion (Study GS-US-399-5505); range of median observed on Day 1 and Day 5 or 10.
b Range of protein binding for remdesivir from 2 independent experiments show no evidence of concentration-dependent protein binding for remdesivir.
c Median (Study GS-US-399-4231).
d Mean (Study GS-US-399-4231).

 

Table 2: Multiple Dose PK Parametersa of Remdesivir and Metabolites (GS-441524 and GS-704277) Following IV Administration of VEKLURY 100 mg to Healthy Adults

Parameter
Mean (CV%) 

Remdesivir 

GS-441524 

GS-704277

Cmax
(nanogram per mL) 

2229 (19.2) 

145 (19.3) 

246 (33.9)

AUCtau
(nanogram•h per mL) 

1585 (16.6) 

2229 (18.4) 

462 (31.4)

Ctrough
(nanogram per mL) 

ND 

69.2 (18.2)

ND

CV=Coefficient of Variation; ND=not detectable (at 24 hours post-dose)
a Remdesivir administered as a 30-minute IV infusion (Study GS-US-399-5505).

Drug Interactions

Concomitant use of VEKLURY with chloroquine phosphate or hydroxychloroquine sulfate is not recommended due to antagonism observed in cell culture. Drug-drug interaction trials of VEKLURY and other concomitant medications have not been conducted in humans.

Use in Specific Populations

Pharmacokinetic differences based on sex, race, or age on the exposures of remdesivir have not been evaluated.

Renal Impairment: The pharmacokinetics of VEKLURY have not been evaluated in patients with renal impairment. Determine eGFR in all patients before starting VEKLURY and monitor while receiving VEKLURY as clinically appropriate. VEKLURY is not recommended in patients with eGFR less than 30 mL per minute because the excipient betadex sulfobutyl ether sodium is renally cleared and accumulates in patients with decreased renal function. Patients with eGFR greater than or equal to 30 mL per minute have received VEKLURY for treatment of COVID-19 with no dose adjustment of VEKLURY.

Hepatic Impairment: The pharmacokinetics of VEKLURY have not been evaluated in patients with hepatic impairment. Perform hepatic laboratory testing in all patients before starting VEKLURY and while receiving VEKLURY as clinically appropriate.

Pediatric Patients: The pharmacokinetics of VEKLURY in pediatric patients have not been evaluated. Using modeling and simulation, the recommended dosing regimen is expected to result in comparable steady-state plasma exposures of remdesivir and metabolites in patients 12 years of age and older and weighing at least 40 kg as observed in healthy adults.

Efficacy and Safety

Subjects with Mild/Moderate and Severe COVID-19: Efficacy of VEKLURY was demonstrated in a randomized, double-blind, placebo-controlled clinical trial of hospitalized adult subjects with confirmed SARS-CoV-2 infection and mild, moderate, or severe COVID-19 compared treatment with VEKLURY for 10 days with placebo. The primary clinical endpoint was time to recovery within 29 days after randomization.

Pediatrics: The safety and effectiveness of VEKLURY for the treatment of COVID-19 have been established in pediatric patients 12 years and older and weighing at least 40 kg. Use in this age group is based on extrapolation of pediatric efficacy from adequate and well-controlled studies in adults. Clinical trials of VEKLURY included 30 adult subjects weighing 40-50 kg. The safety in this weight group was comparable to adult subjects weighing greater than 50 kg. Thirty-nine pediatric patients 12 years and older and weighing at least 40 kg received VEKLURY in a compassionate use program; the available clinical data from these patients are limited. The safety and effectiveness of VEKLURY have not been established in pediatric patients younger than 12 years of age or weighing less than 40 kg.

Additional information regarding the efficacy trials can be found in the full prescribing information linked below.

The most common adverse reactions (incidence greater than or equal to 5%, all grades) observed with treatment with VEKLURY are nausea, ALT increased, and AST increased.

Full prescribing information is available at https://go.usa.gov/x7YVW.

Visit [email protected] at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at https://www.fda.gov/safety/medwatch/default.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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