Remdesivir

5 WARNINGS AND PRECAUTIONS Hypersensitivity including infusion-related and anaphylactic reactions: Hypersensitivity reactions have been observed during and following administration of VEKLURY. Slower infusion rates, with a maximum infusion time of up to 120 minutes, can be considered to potentially prevent signs and symptoms of hypersensitivity. Monitor patients during infusion and observe patients for at least one hour after infusion is complete for signs and symptoms of hypersensitivity as clinically appropriate. If signs and symptoms of a clinically significant hypersensitivity reaction occur, immediately discontinue administration of VEKLURY and initiate appropriate treatment. ( 5.1 ) Increased risk of transaminase elevations: Transaminase elevations have been observed in healthy volunteers and have also been reported in patients with COVID-19 who received VEKLURY. Perform hepatic laboratory testing in all patients before starting VEKLURY and while receiving VEKLURY as clinically appropriate. Consider discontinuing VEKLURY if ALT levels increase to greater than 10 times the upper limit of normal. Discontinue VEKLURY if ALT elevation is accompanied by signs or symptoms of liver inflammation. ( 5.2 ) Risk of reduced antiviral activity when coadministered with chloroquine phosphate or hydroxychloroquine sulfate: Coadministration of VEKLURY and chloroquine phosphate or hydroxychloroquine sulfate is not recommended based on data from cell culture experiments demonstrating a potential antagonistic effect of chloroquine on the intracellular metabolic activation and antiviral activity of VEKLURY. ( 5.3 ) 5.1 Hypersensitivity Including Infusion-related and Anaphylactic Reactions Hypersensitivity reactions, including infusion-related and anaphylactic reactions, have been observed during and following administration of VEKLURY; most occurred within one hour. Signs and symptoms may include hypotension, hypertension, tachycardia, bradycardia, hypoxia, fever, dyspnea, wheezing, angioedema, rash, nausea, diaphoresis, and shivering. Slower infusion rates, with a maximum infusion time of up to 120 minutes, can be considered to potentially prevent these signs and symptoms. Monitor patients during infusion and observe patients for at least one hour after infusion is complete for signs and symptoms of hypersensitivity as clinically appropriate. If signs and symptoms of a clinically significant hypersensitivity reaction occur, immediately discontinue administration of VEKLURY and initiate appropriate treatment. The use of VEKLURY is contraindicated in patients with known hypersensitivity to VEKLURY or any components of the product [see Contraindications (4) ] . 5.2 Increased Risk of Transaminase Elevations Transaminase elevations have been observed in healthy volunteers who received 200 mg of VEKLURY followed by 100 mg doses for up to 10 days; the transaminase elevations were mild (Grade 1) to moderate (Grade 2) in severity and resolved upon discontinuation of VEKLURY. Transaminase elevations have also been reported in patients with COVID-19 who received VEKLURY [see Adverse Reactions (6.1) ] . Because transaminase elevations have been reported as a clinical feature of COVID-19, and the incidence was similar in patients receiving placebo versus VEKLURY in clinical trials of VEKLURY, discerning the contribution of VEKLURY to transaminase elevations in patients with COVID-19 can be challenging. Perform hepatic laboratory testing in all patients before starting VEKLURY and while receiving VEKLURY as clinically appropriate [see Dosage and Administration (2.1) and Use in Specific Populations (8.7) ] . Consider discontinuing VEKLURY if ALT levels increase to greater than 10 times the upper limit of normal. Discontinue VEKLURY if ALT elevation is accompanied by signs or symptoms of liver inflammation. 5.3 Risk of Reduced Antiviral Activity When Coadministered with Chloroquine Phosphate or Hydroxychloroquine Sulfate Coadministration of VEKLURY and chloroquine phosphate or hydroxychloroquine sulfate is not recommended based on data from cell culture experiments demonstrating a potential antagonistic effect of chloroquine on the intracellular metabolic activation and antiviral activity of VEKLURY [see Drug Interactions (7) and Microbiology (12.4) ].

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Hypersensitivity Including Infusion-related and Anaphylactic Reactions [see Warnings and Precautions (5.1) ] Increased Risk of Transaminase Elevations [see Warnings and Precautions (5.2) ] 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 [see Clinical Studies (14.1) ] . 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 [see Clinical Studies (14.2) ] . 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) [see Clinical Studies (14.3) ] . 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 [see Clinical Studies (14.4) ] . 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 [see Warnings and Precautions (5.1) ]. 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 [see Use in Specific Populations (8.6) ]. 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 [see Clinical Studies (14.6) ] : 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 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 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 [n=1], ALT increased and AST increased and hyperbilirubinemia [n=1]). 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

8 USE IN SPECIFIC POPULATIONS 8.1 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 [see Clinical Pharmacology (12.3) ] . 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 (6, 9) days. The overall median (Q1, Q3) duration of symptoms prior to first dose of VEKLURY was 8 (6, 9) 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 [see Clinical Pharmacology (12.3) ] . 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 [see Adverse Reactions (6.1) ] . 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. 8.2 Lactation Risk Summary A published case report describes the presence of remdesivir and active metabolite GS-441524 in human milk. Available data (n=11) from pharmacovigilance reports do not indicate adverse effects on breastfed infants from exposure to remdesivir and its metabolite through breastmilk. There are no available data on the effects of remdesivir on milk production. In 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 (see Data ). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VEKLURY and any potential adverse effects on the breastfed child from VEKLURY or from the underlying maternal condition. Breastfeeding individuals with COVID-19 should follow practices according to clinical guidelines to avoid exposing the infant to COVID-19. Data Remdesivir and its metabolites were detected in the plasma of nursing rat pups, likely due to the presence of remdesivir and/or its metabolites in milk, following daily intravenous administration of remdesivir to pregnant rats from Gestation Day 6 to Lactation Day 20. Exposures in nursing pups were approximately 1% that of maternal exposure on Lactation Day 10. The concentration of remdesivir in animal milk does not necessarily predict the concentration of drug in human milk. 8.4 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 [see Clinical Studies (14.1 , 14.2 , 14.3 , 14.4 , 14.5) ] An open-label trial (Study 5823) in 58 hospitalized pediatric subjects [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.6) ]. 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 37 weeks, and weighing ≥2.5 kg (n=3); subjects 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 [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , Clinical Studies (14.6) ]. 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 [see Adverse Reactions (6.1) and Clinical Studies (14) ]. Use of VEKLURY in pediatric patients with renal impairment is supported by safety data in adults [see Adverse Reactions (6.1) , Use in Specific Populations (8.6) ]. 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 [see Clinical Pharmacology (12.3) ] . 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. 8.5 Geriatric Use Of the 1,062 hospitalized subjects with SARS-CoV-2 infection randomized in ACTT-1, 36% were 65 years or older. Of the 397 hospitalized subjects with SARS-CoV-2 infection randomized in Study GS-US-540-5773, 42% were 65 years or older. Of the 584 hospitalized subjects with SARS-CoV-2 infection randomized in Study GS-US-540-5774, 27% were 65 years or older. Of the 562 non-hospitalized subjects with SARS-CoV-2 infection randomized in Study GS-US-540-9012, 17% were 65 years or older. Reported clinical experience has not identified differences in responses between the elderly and younger patients [see Clinical Studies (14) ] . No dosage adjustment is required in patients over the age of 65 years. In general, appropriate caution should be exercised in the administration of VEKLURY and monitoring of elderly patients, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Renal Impairment Use of VEKLURY in patients with COVID-19 and renal impairment, including those on dialysis, is supported by safety and pharmacokinetic data from the following: a randomized, double-blind, placebo-controlled trial (Study 5912) in adults [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3) ]. an open-label, parallel-group, single-dose trial in subjects with normal renal function and renal impairment (Study 9015) [see Clinical Pharmacology (12.3) ]. The pharmacokinetics and safety of VEKLURY in patients with COVID-19 and renal impairment, including those on dialysis, were evaluated in 163 subjects in a randomized, double-blind, placebo-controlled trial, Study GS-US-540-5912 [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3) ]. Study GS-US-540-5912 evaluated VEKLURY 200 mg once daily for 1 day followed by VEKLURY 100 mg once daily for 4 days (for a total of up to 5 days of intravenously administered therapy) in 243 hospitalized adult subjects with confirmed COVID-19 and renal impairment. The trial included 90 subjects (37%) with AKI (defined as a 50% increase in serum creatinine within a 48-hour period that was sustained for ≥6 hours despite supportive care), 64 subjects (26%) with CKD (eGFR <30 mL/minute/1.73m 2 ), and 89 subjects (37%) with ESRD (eGFR <15 mL/minute/1.73m 2 ) requiring hemodialysis. Subjects were randomized in a 2:1 manner, stratified by ESRD, high-flow oxygen requirement, and region (US vs ex-US) to receive VEKLURY (n=163) or placebo (n=80), plus standard of care. At baseline, mean age was 69 years (with 62% of subjects aged 65 or older); 57% of subjects were male, 67% were White, 26% were Black, and 3% were Asian. The most common baseline risk factors were hypertension (89%), diabetes mellitus (79%), and cardiovascular or cerebrovascular disease (51%); the distribution of risk factors was similar between the two treatment groups. A total of 45 subjects (19%) were on high-flow oxygen, 144 (59%) were on low-flow oxygen, and 54 (22%) were on room air at baseline; no subjects were on invasive mechanical ventilation (IMV). A total of 182 subjects (75%) were not on renal replacement therapy, and 31 subjects (13%) had received a COVID-19 vaccine. The safety results in subjects with COVID-19 and renal impairment, including those on dialysis, were consistent with those observed in clinical trials of VEKLURY in adults [see Adverse Reactions (6.1) ]. Study GS-US-540-5912 closed prematurely due to feasibility issues and was underpowered to assess for efficacy because of lower than expected enrollment. The pharmacokinetics and safety of VEKLURY in subjects with normal renal function and renal impairment, including those on dialysis, were evaluated in 75 subjects (43 subjects with renal impairment plus 32 matched control subjects with normal renal function) in an open-label, parallel-group, single-dose trial, Study GS-US-540-9015 [see Clinical Pharmacology (12.3) ]. In studies GS-US-540-5912 and GS-US-540-9015, exposures of GS-441524 and GS-704277, the metabolites of remdesivir, and SBECD are increased in subjects with mild to severe renal impairment, including those requiring dialysis, relative to subjects with normal renal function [see Clinical Pharmacology (12.3) ] . No dosage adjustment of VEKLURY is recommended for patients with any degree of renal impairment, including those on dialysis [see Dosage and Administration (2.2 , 2.4) , Use in Specific Populations (8.4) ]. 8.7 Hepatic Impairment No dosage adjustment of VEKLURY is recommended for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C) [see Clinical Pharmacology (12.3) ] . Perform hepatic laboratory testing in all patients before starting VEKLURY and while receiving VEKLURY as clinically appropriate [see Dosage and Administration (2.2) and Warnings and Precautions (5.2) ].

8.1 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 [see Clinical Pharmacology (12.3) ] . 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 (6, 9) days. The overall median (Q1, Q3) duration of symptoms prior to first dose of VEKLURY was 8 (6, 9) 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 [see Clinical Pharmacology (12.3) ] . 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 [see Adverse Reactions (6.1) ] . 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.

8.4 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 [see Clinical Studies (14.1 , 14.2 , 14.3 , 14.4 , 14.5) ] An open-label trial (Study 5823) in 58 hospitalized pediatric subjects [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.6) ]. 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 37 weeks, and weighing ≥2.5 kg (n=3); subjects 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 [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , Clinical Studies (14.6) ]. 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 [see Adverse Reactions (6.1) and Clinical Studies (14) ]. Use of VEKLURY in pediatric patients with renal impairment is supported by safety data in adults [see Adverse Reactions (6.1) , Use in Specific Populations (8.6) ]. 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 [see Clinical Pharmacology (12.3) ] . 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.