Veklury Drug Information

is indicated for the treatment of coronavirus disease 2019 (COVID-19) in adults and pediatric patients (birth to less than 18 years of age weighing at least 1.5 kg) who are : Hospitalized, or Not hospitalized and have mild-to-moderate COVID-19, and are at high risk for progression to severe COVID-19, including hospitalization or death. VEKLURY is a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleotide analog RNA polymerase inhibitor indicated for the treatment of coronavirus disease 2019 (COVID-19) in adults and pediatric patients (birth to less than 18 years of age weighing at least 1.5 kg) who are: Hospitalized, or Not hospitalized and have mild-to-moderate COVID-19, and are at high risk for progression to severe COVID-19, including hospitalization or death.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials in Adult Subjects The safety of VEKLURY is based on data from four Phase 3 studies in 1,476 hospitalized adult subjects with COVID-19, one Phase 3 study in 279 non-hospitalized adult and pediatric subjects (12 years of age and older weighing at least 40 kg) with mild-to-moderate COVID-19, four Phase 1 studies in 131 healthy adults, and from patients with COVID-19 who received VEKLURY under the Emergency Use Authorization or in a compassionate use program. Clinical Trials Experience in Adults with COVID-19 NIAID ACTT-1 was a randomized, double-blind, placebo-controlled clinical trial in hospitalized subjects with mild, moderate, and severe COVID-19 treated with VEKLURY (n=532) or placebo (n=516) for up to 10 days.

Subjects treated with VEKLURY received 200 mg on Day 1 and 100 mg once daily on subsequent days . The collection of adverse event data in this trial was limited to severe (Grade 3) or potentially life-threatening (Grade 4) adverse events, serious adverse events, adverse events leading to study drug discontinuation, and moderate (Grade 2) severity or higher hypersensitivity reactions. Rates of adverse reactions (≥ Grade 3), serious adverse reactions, and adverse reactions leading to treatment discontinuation are presented in Table 4. Table 4 Summary of Adverse Reaction Rates in Hospitalized Subjects with Mild, Moderate, or Severe COVID-19 in NIAID ACTT-1 Types of Adverse Reactions VEKLURY N=532 n (%) Placebo N=516 n (%) Adverse reactions, Grades ≥3 41 (8%) 46 (9%) Serious adverse reactions 2 (0.4%) Seizure (n=1), infusion-related reaction (n=1). 3 (0.6%) Adverse reactions leading to treatment discontinuation 11 (2%) Seizure (n=1), infusion-related reaction (n=1), transaminases increased (n=3), ALT increased and AST increased (n=1), GFR decreased (n=2), acute kidney injury (n=3). 15 (3%) Study GS-US-540-5773 was a randomized, open-label clinical trial in hospitalized subjects with severe COVID-19 treated with VEKLURY 200 mg on Day 1 and 100 mg once daily for 5 (n=200) or 10 days (n=197). Adverse reactions were reported in 33 (17%) subjects in the 5-day group and 40 (20%) subjects in the 10-day group . The most common adverse reactions occurring in at least 5% of subjects in either the VEKLURY 5-day or 10-day group, respectively, were nausea (5% vs 3%), AST increased (3% vs 6%), and ALT increased (2% vs 7%). Rates of any adverse reactions, serious adverse reactions, and adverse reactions leading to treatment discontinuation are presented in Table 5. Table 5 Summary of Adverse Reaction Rates in Hospitalized Subjects with Severe COVID-19 in Study 5773 Types of Adverse Reactions VEKLURY 5 Days N=200 n (%) VEKLURY 10 Days N=197 n (%) Any adverse reaction, all Grades 33 (17%) 40 (20%) Serious adverse reactions 3 (2%) Transaminases increased (n=5), hepatic enzyme increased (n=1), hypertransaminasaemia (n=1). 4 (2%) Adverse reactions leading to treatment discontinuation 5 (3%) Transaminases increased (n=4), hepatic enzyme increased (n=2), LFT increased (n=2), hypertransaminasaemia (n=1), ALT increased (n=1), ALT increased and AST increased (n=2), injection site erythema (n=1), rash (n=1). 9 (5%) Study GS-US-540-5774 was a randomized, open-label clinical trial in hospitalized subjects with moderate COVID-19 treated with VEKLURY 200 mg on Day 1 and 100 mg daily for 5 (n=191) or 10 days (n=193), or standard of care (SOC) only (n=200) . Adverse reactions were reported in 36 (19%) subjects in the 5-day group and 25 (13%) subjects in the 10-day group. The most common adverse reaction occurring in at least 5% of subjects in the VEKLURY groups was nausea (7% in the 5-day group, 4% in the 10-day group). Rates of any adverse reactions, serious adverse reactions, and adverse reactions leading to treatment discontinuation are presented in Table 6. Table 6 Summary of Adverse Reaction Attribution of events to study drug was not performed for the SOC group.

Rates in Hospitalized Subjects with Moderate COVID-19 in Study 5774 Types of Adverse Reactions VEKLURY 5 Days N=191 n (%) VEKLURY 10 Days N=193 n (%) Any adverse reaction, all Grades 36 (19%) 25 (13%) Serious adverse reactions 1 (<1%) Heart rate decreased. 0 Adverse reactions leading to treatment discontinuation 4 (2%) ALT increased (n=2), ALT increased and AST increased (n=1), hypertransaminasaemia (n=1), blood alkaline phosphatase increased (n=1), rash (n=2), heart rate decreased (n=1). 4 (2%) Study GS-US-540-9012 was a randomized, double-blind, placebo-controlled clinical trial in subjects who were non-hospitalized, were symptomatic for COVID-19 for ≤7 days, had confirmed SARS-CoV-2 infection, and had at least one risk factor for progression to hospitalization treated with VEKLURY (n=279; 276 adults and 3 pediatric subjects 12 years of age and older weighing at least 40 kg) or placebo (n=283; 278 adults and 5 pediatric subjects 12 years of age and older weighing at least 40 kg) for 3 days. Of the 279 subjects treated with VEKLURY, 227 subjects received at least one dose of VEKLURY at an outpatient facility, 44 subjects received at least one dose of VEKLURY in a home healthcare setting, and 8 subjects received at least one dose of VEKLURY at a skilled nursing facility. Subjects treated with VEKLURY received 200 mg on Day 1 and 100 mg once daily on subsequent days . Adverse reactions (all grades) were reported in 34 (12%) subjects in the VEKLURY group and 25 (9%) subjects in the placebo group.

The most common adverse reaction occurring in at least 5% of subjects in the VEKLURY group was nausea (6%). There were no serious adverse reactions or adverse reactions leading to treatment discontinuation in either treatment group. Safety in subjects who received VEKLURY in a home healthcare setting was comparable to that observed in the overall GS-US-540-9012 study population, but these findings are based on limited data. Less Common Adverse Reactions in Adults from Clinical Trials Clinically significant adverse reactions that were reported in <2% of subjects exposed to VEKLURY in clinical trials are listed below: Hypersensitivity reactions.

Generalized seizure Rash Laboratory Abnormalities Study GS-US-399-5505 was a Phase 1, randomized, blinded, placebo-controlled clinical trial in healthy volunteers administered VEKLURY 200 mg on Day 1 and 100 mg for either 4 days or 9 days. Mild (Grade 1, n=8) to moderate (Grade 2, n=1) elevations in ALT were observed in 9 of 20 subjects receiving 10 days of VEKLURY; the elevations in ALT resolved upon discontinuation of VEKLURY. No subjects (0 of 9) who received 5 days of VEKLURY had graded increases in ALT. The frequencies of laboratory abnormalities (Grades 3–4) occurring in at least 3% of subjects with COVID-19 receiving VEKLURY in Trials NIAID ACTT-1, 5773, and 5774 are presented in Table 7, Table 8, and Table 9, respectively. Table 7 Laboratory Abnormalities (Grades 3–4) Reported in ≥3% of Hospitalized Subjects with Mild, Moderate, or Severe COVID-19 in NIAID ACTT-1 Laboratory Parameter Abnormality Frequencies are based on treatment-emergent laboratory abnormalities.

Graded per Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 dated July 2017. VEKLURY 10 Days N=532 Placebo N=516 ALT increased 3% 6% AST increased 6% 8% Bilirubin increased 2% 5% Creatinine clearance decreased Based on the Cockcroft-Gault formula. 18% 20% Creatinine increased 15% 16% eGFR decreased 18% 24% Glucose increased 12% 13% Hemoglobin decreased 15% 22% Lymphocytes decreased 11% 18% Prothrombin time increased 9% 4% Table 8 Laboratory Abnormalities (Grades 3–4) Reported in ≥3% of Hospitalized Subjects with Severe COVID-19 in Trial 5773 Laboratory Parameter Abnormality Frequencies are based on treatment-emergent laboratory abnormalities. Graded per Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 dated July 2017. VEKLURY 5 Days N=200 VEKLURY 10 Days N=197 ALT increased 6% 8% AST increased 7% 6% Creatinine clearance decreased Based on the Cockcroft-Gault formula. 10% 19% Creatinine increased 5% 15% Glucose increased 11% 8% Hemoglobin decreased 6% 8% Table 9 Laboratory Abnormalities (Grades 3–4) Reported in ≥3% of Hospitalized Subjects with Moderate COVID-19 in Trial 5774 Laboratory Parameter Abnormality Frequencies are based on treatment-emergent laboratory abnormalities. Graded per Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 dated July 2017. VEKLURY 5 Days N=191 VEKLURY 10 Days N=193 SOC N=200 SOC=Standard of care.

ALT increased 2% 3% 8% Creatinine clearance decreased Based on the Cockcroft-Gault formula. 2% 5% 8% Glucose increased 4% 3% 2% Hemoglobin decreased 3% 1% 6% The frequencies of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects with COVID-19 receiving VEKLURY in Trial GS-US-540-9012 are presented in Table 10. Table 10 Laboratory Abnormalities (Grades 3–4) Reported in ≥2% of Non-Hospitalized Subjects in Trial 9012 Laboratory Parameter Abnormality Frequencies are based on treatment-emergent laboratory abnormalities. Graded per Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 dated July 2017. VEKLURY 3 Days N=279 Placebo N=283 Creatinine clearance decreased Based on the Cockcroft-Gault formula. 6% 2% Creatinine increased 3% 1% Glucose increased 6% 6% Lymphocytes decreased 2% 1% Prothrombin time increased 1% 2% Clinical Trials Experience in Adults with COVID-19 and Renal Impairment Study GS-US-540-5912 was a randomized, double-blind, placebo-controlled clinical trial in which 163 hospitalized subjects with confirmed COVID-19 and acute kidney injury (AKI; N=60), chronic kidney disease (CKD; eGFR <30 mL/minute/1.73m 2 ; N=44), or end-stage renal disease (ESRD; eGFR <15 mL/minute/1.73m 2 ; N=59) on hemodialysis received VEKLURY for up to 5 days. The adverse reactions observed were consistent with those observed in clinical trials of VEKLURY in adults.

Adverse reactions (all grades) were reported in 13 (8%) subjects in the VEKLURY group and 3 (4%) subjects in the placebo group. The most common adverse reactions were nausea (1%), abdominal pain (1%), and diarrhea (1%). No subjects experienced serious adverse reactions. One subject permanently discontinued treatment due to an adverse reaction: lipase increased.

The frequencies of laboratory abnormalities (Grades 3–4) occurring in at least 3% of subjects with COVID-19 receiving VEKLURY in Trial GS-US-540-5912 are presented in Table 11. Table 11 Laboratory Abnormalities (Grades 3–4) Reported in ≥3% of Hospitalized Subjects in Trial 5912 Laboratory Parameter Abnormality Frequencies are based on treatment-emergent laboratory abnormalities. Graded per Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 dated July 2017. VEKLURY 5 Days N=163 Placebo N=80 Lymphocytes decreased 27% 27% Hemoglobin decreased 25% 25% Glucose increased 15% 19% Uric acid increased 11% 4% Creatinine increased 12% 14% Albumin decreased 12% 10% Lipase increased 12% 7% Prothrombin time increased 11% 4% Prothrombin INR increased 7% 4% AST increased 6% 4% Thromboplastin time increased 5% 4% ALT increased 5% 6% Sodium increased 3% 3% Calcium increased 3% 0 Clinical Trials in Pediatric Subjects Study GS-US-540-5823 was a Phase 2/3, single-arm, open-label clinical trial in hospitalized subjects from birth to <18 years of age and weighing at least 1.5 kg with mild, moderate, and severe COVID-19 treated with weight-based VEKLURY (n=58) for up to 10 days : Cohorts 1, 8: Subjects ≥12 years and weighing ≥40 kg (n=12) and subjects <12 years and weighing ≥40 kg (n=5): Received 200 mg on Day 1 and 100 mg once daily on subsequent days. Cohorts 2–4: Subjects ≥28 days and weighing ≥20 to <40 kg (n=12); subjects ≥28 days and weighing ≥12 to <20 kg (n=12); and subjects ≥28 days and weighing ≥3 to <12 kg (n=12): Received 5 mg/kg on Day 1 and 2.5 mg/kg once daily on subsequent days.

Cohort 5: Subjects 14 to <28 days old, gestational age (GA) >37 weeks, and weighing ≥2.5 kg (n=3): Received 5 mg/kg on Day 1 and 2.5 mg/kg once daily on subsequent days. Cohorts 6–7: Subjects <14 days old, GA >37 weeks, and weighing ≥2.5 kg at birth (n=1); and subjects <56 days old, GA ≤ 37 weeks, and weighing ≥1.5 kg at birth (n=1): Received 2.5 mg/kg on Day 1 and 1.25 mg/kg once daily on subsequent days. The adverse reactions observed were consistent with those observed in clinical trials of VEKLURY in adults.

Infants, children, and adolescents; Cohorts 1–4, 8: Adverse reactions (all grades) were reported in 8 (15%) subjects. The most common adverse reaction occurring in at least 5% of subjects was ALT increased (6%). No subjects experienced serious adverse reactions. Two (4%) subjects permanently discontinued treatment due to adverse reactions (ALT increased, ALT increased and AST increased and hyperbilirubinemia ). Laboratory abnormalities (Grades 3–4) occurring in at least 3% of subjects with COVID-19 receiving VEKLURY in Trial 5823 and who had at least one post-baseline value for the specified test were hemoglobin decreased (18%, 9/51), eGFR decreased (18%, 7/40), creatinine increased (10%, 5/52), direct bilirubin increased (9%, 2/23), prothrombin time increased (7%, 3/46), APTT increased (7%, 3/45), lymphocytes decreased (6% 2/33), proteinuria (6%, 2/36), WBC decreased (4%, 2/51), ALT increased (4%, 2/51), glucose increased (4%, 2/52), glycosuria (4%, 2/46), potassium decreased (4%, 2/52). Neonates and infants; Cohorts 5–7: Laboratory abnormalities (Grades 3–4) were reported in 3/5 subjects: APTT increased (2/5); direct bilirubin increased (1/5); creatinine increased (1/5); prothrombin time increased (1/5); prothrombin/INR increased (1/5); and potassium increased (1/5). Emergency Use Authorization Experience in Subjects with COVID-19 The following adverse reactions have been identified during use of VEKLURY under Emergency Use Authorization: General disorders and administration site conditions: Administration site extravasation Skin and subcutaneous tissue disorders: Rash Immune system disorders: Anaphylaxis, angioedema, infusion-related reactions, hypersensitivity Investigations: Transaminase elevations

Effects of Other Drugs on

VEKLURY Due to potential antagonism based on data from cell culture experiments, concomitant use of VEKLURY with chloroquine phosphate or hydroxychloroquine sulfate is not recommended. Based on drug interaction studies conducted with VEKLURY, no clinically significant drug interactions are expected with inducers of cytochrome P450 (CYP) 3A4 or inhibitors of Organic Anion Transporting Polypeptides (OATP) 1B1/1B3 and, P-glycoprotein (P-gp).

Effects of

VEKLURY on Other Drugs Based on drug interaction studies conducted with VEKLURY, it is a weak inhibitor of CYP3A and does not inhibit OATP1B1/1B3.

Pregnancy Risk Summary Available data from a clinical trial (IMPAACT 2032), published reports, the COVID-PR pregnancy exposure registry, and compassionate use of remdesivir in pregnant individuals have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes following exposure in the second and third trimester. However, there are insufficient pregnancy data available to evaluate the risk of remdesivir exposure during the first trimester. A study evaluating the pharmacokinetics of remdesivir during pregnancy demonstrated no clinically relevant differences between pregnant and non-pregnant individuals.

No dose adjustments are recommended in patients who receive VEKLURY during pregnancy (see Data ) and . In nonclinical reproductive toxicity studies, remdesivir demonstrated no adverse effect on embryo-fetal development when administered to pregnant animals at systemic exposures (AUC) 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 (RHD) (see Data ). There are maternal and fetal risks associated with untreated COVID-19 in pregnancy (see Clinical Considerations ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations Disease-associated maternal and/or embryo-fetal risk COVID-19 in pregnancy is associated with adverse maternal and fetal outcomes, including preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic disease, and fetal death. Data Human Data A non-randomized, open-label clinical study (IMPAACT 2032) evaluated pharmacokinetics and safety of up to 10 days of treatment with VEKLURY in 25 hospitalized pregnant and 28 hospitalized non-pregnant individuals of childbearing potential. Subjects received VEKLURY 200 mg once daily for 1 day followed by VEKLURY 100 mg once daily on subsequent days via intravenous infusion.

Subjects were enrolled prior to their fourth VEKLURY infusion. Assessments occurred at the following intervals: Screening; Pre-infusion (defined as 48 hours prior to start of first infusion); each infusion day; 48 hours after the last infusion; 7 days after the last infusion; 4 weeks after the last infusion. Assessments also occurred 24 hours post-delivery in subjects who delivered.

Treatment with VEKLURY was stopped in subjects who were discharged from the hospital prior to the completion of 10 days of treatment. Of the 25 pregnant subjects, median age was 33 years (Q1, Q3: 27 years, 37 years); 40% were White, 24% were Black, and 48% were Hispanic or Latino. A total of 9 subjects (36%) were on high-flow oxygen; 12 subjects (48%) were on low-flow oxygen; and 1 subject (4%) was on room air, at baseline.

Three subjects (12%) did not have data available on baseline oxygen status. The overall median (Q1, Q3) duration of symptoms prior to hospitalization was 7 days. The overall median (Q1, Q3) duration of symptoms prior to first dose of VEKLURY was 8 days.

Of the 25 pregnant subjects, median gestational age was 28 weeks at baseline (range 22 to 33 weeks) and about half of subjects were in each of the second and third trimester of pregnancy. No clinically relevant differences in the pharmacokinetics of remdesivir or its metabolites (GS-704277 and GS-441524) were observed between pregnant (n=21) and non-pregnant (n=22) individuals . No difference in pharmacokinetics of remdesivir or its metabolites is expected between the first and second/third trimesters. The adverse reactions observed were consistent with those observed in clinical trials of VEKLURY in adults . There were no adverse reactions in infants born during the study (n=16). Animal Data Remdesivir was administered via intravenous injection to pregnant rats and rabbits (up to 20 mg/kg/day) on Gestation Days 6 through 17, and 7 through 20, respectively, and also to rats from Gestation Day 6 to Lactation/Post-partum Day 20. No adverse effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed in rats and rabbits at nontoxic doses in pregnant animals.

During organogenesis, exposures to the predominant circulating metabolite (GS-441524) were 4 times higher (rats and rabbits) than the exposure in humans at the RHD. In a pre/postnatal development study, exposures to the predominant circulating metabolite of remdesivir (GS-441524) were similar to the human exposures at the RHD.

Pediatric Use The safety and effectiveness of VEKLURY for the treatment of COVID-19 have been established in pediatric patients from birth to less than 18 years of age and weighing at least 1.5 kg, who are: Hospitalized, or Not hospitalized and have mild-to-moderate COVID-19, and are at high risk for progression to severe COVID-19, including hospitalization or death. Use in this age group is supported by the following: Trials in adults An open-label trial (Study 5823) in 58 hospitalized pediatric subjects. Use of VEKLURY in pediatric patients from birth to less than 18 years of age and weighing at least 1.5 kg is supported by Study 5823 where 58 hospitalized pediatric subjects were treated with weight-based VEKLURY for up to 10 days in the following cohorts: Cohorts 1–4, 8; infants, children, and adolescents: Subjects ≥12 years and weighing ≥40 kg (n=12); subjects <12 years and weighing ≥40 kg (n=5); subjects ≥28 days and weighing ≥20 to <40 kg (n=12); subjects ≥28 days and weighing ≥12 to <20 kg (n=12); and subjects ≥28 days and weighing ≥3 to <12 kg (n=12); Cohorts 5–7; neonates and infants: Subjects 14 to <28 days old, GA >37 weeks, and weighing ≥2.5 kg (n=3); subjects <14 days old, GA >37 weeks, and weighing ≥2.5 kg at birth (n=1); and subjects <56 days old, GA ≤37 weeks, and weighing ≥1.5 kg at birth (n=1). The safety and pharmacokinetic results in pediatric subjects were similar to those in adults.

Use of VEKLURY in pediatric patients weighing at least 40 kg is further supported by a clinical trial of VEKLURY in non-hospitalized subjects that included 3 pediatric subjects 12 years and older, and by clinical trials in hospitalized subjects that included 30 adult subjects weighing 40 to 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 in hospitalized subjects; the available clinical data from these patients are limited.

Use of VEKLURY in pediatric patients with renal impairment is supported by safety data in adults. Limited data are available regarding the safety of VEKLURY in pediatric patients with mild or moderate renal impairment. No data are available regarding the safety of VEKLURY in pediatric patients with severe renal impairment.

In adults with severe renal impairment, including those requiring dialysis, exposures of GS-441524 and GS-704277, the metabolites of remdesivir, and betadex sulfobutyl ether sodium (SBECD) are increased . VEKLURY contains SBECD which, when administered intravenously, is eliminated through glomerular filtration and therefore when administered to pediatric patients with renal immaturity or renal impairment, may result in higher exposure to SBECD. The safety and effectiveness of VEKLURY have not been established in pediatric patients weighing less than 1.5 kg.

is contraindicated in patients with a history of clinically significant hypersensitivity reactions to VEKLURY or any components of the product. VEKLURY is contraindicated in patients with a history of clinically significant hypersensitivity reactions to VEKLURY or any components of the product.

There is no human experience of acute overdosage with VEKLURY. Treatment of overdose with VEKLURY should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with VEKLURY.