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 Intravenous Infusion Maintenance Dose Via Intravenous Infusion Less than 28 days old and at least 1.5 kg VEKLURY 2.5 mg/kg on Day 1 VEKLURY 1.25 mg/kg once daily from Day 2 At least 28 days old and 1.5 kg to less than 3 kg At least 28 days old and 3 kg to less than 40 kg VEKLURY 5 mg/kg on Day 1 VEKLURY 2.5 mg/kg once daily from Day 2 The treatment course of VEKLURY should be initiated as soon as possible after diagnosis of symptomatic COVID-19 has been made. The recommended total treatment duration for hospitalized patients requiring invasive mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO) is 10 days. The recommended treatment duration for hospitalized patients not requiring invasive mechanical ventilation and/or ECMO 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. 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. The recommended total treatment duration 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, is 3 days. VEKLURY must be diluted prior to intravenous infusion. Refer to Dosage and Administration (2.5) for detailed preparation and administration instructions. 2.4 Renal Impairment No dosage adjustment of VEKLURY is recommended in patients with any degree of renal impairment, including patients on dialysis. VEKLURY may be administered without regard to the timing of dialysis [see Dosage and Administration (2.3) and Use in Specific Populations (8.4 , 8.6) ]. 2.5 Dosage Preparation and Administration Reconstitution Instructions Remove the required number of single-dose vial(s) from storage. For each vial: Inspect the vial to ensure the container closure is free from defects. Aseptically reconstitute VEKLURY lyophilized powder by adding 19 mL of Sterile Water for Injection using a suitably sized syringe and needle per vial, and insert the needle in the center of the vial stopper. Only use Sterile Water for Injection to reconstitute VEKLURY lyophilized powder. Discard the vial if a vacuum does not pull the Sterile Water for Injection into the vial. Immediately shake the vial for 30 seconds. Allow the contents of the vial to settle for 2 to 3 minutes. A clear, colorless to yellow solution, free of visible particles, should result. If the contents of the vial are not completely dissolved, shake the vial again for 30 seconds and allow the contents to settle for 2 to 3 minutes. Repeat this procedure as necessary until the contents of the vial are completely dissolved. Discard the vial if the contents are not completely dissolved. Following reconstitution, each vial contains 100 mg/20 mL (5 mg/mL) of remdesivir solution. Use reconstituted product immediately to prepare the diluted drug product. Detailed dilution and administration instruction based on patient’s weight is provided below. Dilution Instructions for Adults and Pediatric Patients Weighing at Least 40 kg Care should be taken during admixture to prevent inadvertent microbial contamination. As there is no preservative or bacteriostatic agent present in this product, aseptic technique must be used in preparation of the final parenteral solution. It is always recommended to administer intravenous medication immediately after preparation when possible. Reconstituted VEKLURY for injection, containing 100 mg/20 mL remdesivir solution, must be further diluted in either a 100 mL or 250 mL 0.9% sodium chloride injection infusion bag. Refer to Table 2 for instructions. Table 2 Recommended Dilution Instructions—Reconstituted VEKLURY for Injection in Adults and Pediatric Patients Weighing at Least 40 kg VEKLURY dose 0.9% sodium chloride injection infusion bag volume to be used Volume to be withdrawn and discarded from 0.9% sodium chloride injection infusion bag Required volume of reconstituted VEKLURY for injection Loading dose 200 mg (2 vials) 250 mL 40 mL 40 mL (2 × 20 mL) 100 mL 40 mL 40 mL (2 × 20 mL) Maintenance dose 100 mg (1 vial) 250 mL 20 mL 20 mL 100 mL 20 mL 20 mL Withdraw and discard the required volume of 0.9% sodium chloride injection from the bag following instructions in Table 2, using an appropriately sized syringe and needle. Inspect the reconstituted VEKLURY for injection vial to ensure the solution is free of particulate matter. Withdraw the required volume of reconstituted VEKLURY for injection from the VEKLURY vial following instructions in Table 2, using an appropriately sized syringe. Discard any unused portion remaining in the reconstituted vial. Transfer the required volume of reconstituted VEKLURY for injection to the selected infusion bag. Gently invert the bag 20 times to mix the solution in the bag. Do not shake. The prepared infusion solution can be stored for 24 hours at room temperature (20°C to 25°C [68°F to 77°F]) or 48 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]) prior to administration. Administration Instructions for Adults and Pediatric Patients Weighing at Least 40 kg Do not administer the prepared diluted solution simultaneously with any other medication. The compatibility of VEKLURY injection with intravenous solutions and medications other than 0.9% sodium chloride injection, USP is not known. Administer VEKLURY via intravenous infusion over 30 to 120 minutes. Administration should be under conditions where management of severe hypersensitivity reactions, such as anaphylaxis, is possible. 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 [see Warnings and Precautions (5.1) ] . Administer the diluted solution with the infusion rate described in Table 3. Table 3 Recommended Rate of Infusion—Diluted VEKLURY for Injection in Adults and Pediatric Patients Weighing at Least 40 kg Infusion bag volume Infusion time Rate of infusion 250 mL 30 min 8.33 mL/min 60 min 4.17 mL/min 120 min 2.08 mL/min 100 mL 30 min 3.33 mL/min 60 min 1.67 mL/min 120 min 0.83 mL/min Dilution Instructions for Pediatric Patients (Birth to Less than 18 Years of Age) Weighing 1.5 kg to Less than 40 kg Care should be taken during admixture to prevent inadvertent microbial contamination. As there is no preservative or bacteriostatic agent present in this product, aseptic technique must be used in preparation of the final parenteral solution. It is always recommended to administer intravenous medication immediately after preparation when possible. Inspect the reconstituted VEKLURY for injection vial to ensure the reconstituted solution is free of particulate matter. For pediatric patients (birth to less than 18 years of age) weighing 1.5 kg to less than 40 kg, the 100 mg/20 mL (5 mg/mL) remdesivir reconstituted solution should be further diluted to a fixed concentration of 1.25 mg/mL using 0.9% sodium chloride injection. The final required infusion volume concentration of 1.25 mg/mL remdesivir diluted solution for infusion is based on the pediatric weight-based dosing regimens. Small 0.9% sodium chloride injection infusion bags (e.g., 25, 50, or 100 mL) or an appropriately sized syringe should be used for pediatric dosing. The recommended dose is administered via intravenous infusion in a total volume dependent on the dose to yield the target remdesivir concentration of 1.25 mg/mL. A syringe and syringe pump may be used for infusion volumes less than 50 mL. Infusion with IV Bag Determine the total infusion volume needed to achieve a final infusion volume concentration of 1.25 mg/mL of remdesivir diluted solution based on the patient's calculated dose. Select an appropriately sized infusion bag (either prefilled with 0.9% sodium chloride injection or empty) to prepare VEKLURY diluted solution. If using a prefilled 0.9% sodium chloride injection infusion bag, withdraw and discard the amount of diluent equal to the volume of reconstituted VEKLURY solution needed per patient's dose plus a quantity sufficient to achieve a 1.25 mg/mL final volume concentration of remdesivir diluted solution. Withdraw the required volume of reconstituted VEKLURY solution into an appropriately sized syringe. Transfer the required volume of reconstituted VEKLURY solution to the 0.9% sodium chloride injection infusion bag. Gently invert the bag 20 times to mix the solution in the bag. Do not shake. If using an empty infusion bag, transfer the required volume of reconstituted VEKLURY solution to the bag, followed by a volume of 0.9% sodium chloride injection sufficient to achieve a 1.25 mg/mL final volume concentration of remdesivir diluted solution. The prepared infusion solution is stable for 24 hours at room temperature (20°C to 25°C [68°F to 77°F]) or 48 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]). Infusion with Syringe Determine the total infusion volume needed to achieve a final infusion volume concentration of 1.25 mg/mL of remdesivir diluted solution based on patient's calculated dose. Select an appropriately sized syringe equal to or larger than the calculated total infusion volume of 1.25 mg/mL remdesivir solution needed. Withdraw the required volume of reconstituted VEKLURY solution from the vial into the syringe based on patient's calculated dose, followed by the required volume of 0.9% sodium chloride injection needed to achieve a 1.25 mg/mL final volume concentration of remdesivir diluted solution. Gently invert the syringe 20 times to mix the solution in the syringe. Do not shake. The prepared diluted solution should be used immediately. Administration Instructions for Pediatric Patients (Birth to Less than 18 Years of Age) Weighing 1.5 kg to Less than 40 kg The prepared diluted solution should not be administered simultaneously with any other medication. The compatibility of VEKLURY with IV solutions and medications other than 0.9% sodium chloride injection, USP is not known. Administer VEKLURY via intravenous infusion over 30 to 120 minutes. The rate of infusion (mL/min) should be calculated based on the total infusion volume and total infusion time. Administration should be under conditions where management of severe hypersensitivity reactions, such as anaphylaxis, is possible. 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 [see Warnings and Precautions (5.1) ] . 2.6 Storage of Prepared Dosages After reconstitution, use vials immediately to prepare diluted solution. The diluted VEKLURY solution in the infusion bags can be stored up to 24 hours at room temperature (20°C to 25°C [68°F to 77°F]) prior to administration or 48 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]). IMPORTANT: This product contains no preservative. Any unused portion of a single-dose VEKLURY vial should be discarded after a diluted solution is prepared.

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 )

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) ].

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) ].

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 <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 [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

8.1 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.