Veklury

1 INDICATIONS AND USAGE VEKLURY 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 [see Clinical Studies (14) ] : 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. ( 1 )

2 DOSAGE AND ADMINISTRATION Testing: In all patients, before starting VEKLURY and during treatment as clinically appropriate, perform hepatic laboratory testing. Assess prothrombin time before starting VEKLURY and monitor as clinically appropriate. ( 2.2 ) Recommended dosage: Adults and pediatric patients weighing at least 40 kg: a single loading dose of VEKLURY 200 mg on Day 1 followed by once-daily maintenance doses of VEKLURY 100 mg from Day 2 via intravenous infusion. ( 2.3 ) Pediatric patients (birth to less than 18 years of age) weighing 1.5 kg to less than 40 kg: Recommended dosage is based on weight. Refer to Table 1 of the full prescribing information for specific dosing guidelines based on body weight. ( 2.3 ) Hospitalized patients: The treatment course of VEKLURY should be initiated as soon as possible after diagnosis of symptomatic COVID-19 has been made. ( 2.3 ) For hospitalized patients requiring invasive mechanical ventilation and/or ECMO, the recommended total treatment duration is 10 days. ( 2.3 ) For hospitalized patients not requiring invasive mechanical ventilation and/or ECMO, the recommended 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. ( 2.3 ) Non-hospitalized patients: The treatment course of VEKLURY should be initiated as soon as possible after diagnosis of symptomatic COVID-19 has been made and within 7 days of symptom onset. ( 2.3 ) For non-hospitalized patients diagnosed with mild-to-moderate COVID-19 who are at high risk for progression to severe COVID-19, including hospitalization or death, the recommended total treatment duration is 3 days ( 2.3 ). Renal impairment: No dosage adjustment of VEKLURY is recommended in patients with any degree of renal impairment, including those on dialysis. ( 2.4 ) Administer VEKLURY via intravenous (IV) infusion over 30 to 120 minutes. ( 2.5 ) Dose preparation and administration: Refer to the full prescribing information for further details. ( 2.5 ) Storage of prepared dosages: VEKLURY contains no preservative. ( 2.6 ) 2.1 Dosage and Administration Overview VEKLURY may only be administered in settings in which healthcare providers have immediate access to medications to treat a severe infusion or hypersensitivity reaction, such as anaphylaxis, and the ability to activate the emergency medical system (EMS), as necessary [see Dosage and Administration (2.5) , Warnings and Precautions (5.1) ] . Administer VEKLURY for the treatment of COVID-19 in adults and pediatric patients (birth to less than 18 years of age weighing at least 1.5 kg) by intravenous infusion only. Do not administer by any other route. VEKLURY for injection must be reconstituted with Sterile Water for Injection prior to diluting with 0.9% sodium chloride injection. 2.2 Testing Before Starting and During Treatment with VEKLURY Perform hepatic laboratory testing in all patients before starting VEKLURY and while receiving VEKLURY as clinically appropriate [see Warnings and Precautions (5.2) and Use in Specific Populations (8.7) ]. Determine prothrombin time in all patients before starting VEKLURY and monitor while receiving VEKLURY as clinically appropriate [see Adverse Reactions (6.1) ]. 2.3 Recommended Dosage in Adults and Pediatric Patients (Birth to Less than 18 Years of Age Weighing at Least 1.5 kg) The recommended dosage for adults and pediatric patients weighing at least 40 kg is a single loading dose of VEKLURY 200 mg on Day 1 via intravenous infusion followed by once-daily maintenance doses of VEKLURY 100 mg from Day 2 via intravenous infusion. The recommended dosage for pediatric patients weighing 1.5 kg to less than 40 kg is presented in Table 1. Table 1 Recommended Dosage in Pediatric Patients Including Term Gestational age greater than 37 weeks. Neonates and Infants Weighing 1.5 kg to Less than 40 kg Pediatric Patient Population Loading Dose Via Intr…

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 chl…

4 CONTRAINDICATIONS VEKLURY is contraindicated in patients with a history of clinically significant hypersensitivity reactions to VEKLURY or any components of the product [see Warnings and Precautions (5.1) ]. VEKLURY is contraindicated in patients with a history of clinically significant hypersensitivity reactions to VEKLURY or any components of the product. ( 4 )

7 DRUG INTERACTIONS 7.1 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 [see Warnings and Precautions (5.3) and Microbiology (12.4) ]. 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) [see Clinical Pharmacology (12.3) ]. 7.2 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 [see Clinical Pharmacology (12.3) ].

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 w…

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), hypertrans…