Veklury Drug Information

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: 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.

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. 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.

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. Determine prothrombin time in all patients before starting VEKLURY and monitor while receiving VEKLURY as clinically appropriate.

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 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 for detailed preparation and administration instructions.

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.

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. 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. 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 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. 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 ) or 48 hours at refrigerated temperature (2°C to 8°C ) 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. Administer the diluted solution with the infusion rate described in Table 3.

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. 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. Do not shake.

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. 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 rate of infusion (mL/min) should be calculated based on the total infusion volume and total infusion time.

Storage of Prepared Dosages

After reconstitution, use vials immediately to prepare diluted solution. IMPORTANT: This product contains no preservative. Any unused portion of a single-dose VEKLURY vial should be discarded after a diluted solution is prepared.

Clinical Trials Experience

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

Subjects treated with VEKLURY received 200 mg on Day 1 and 100 mg once daily on subsequent days. The collection of adverse event data in this trial was limited to severe (Grade 3) or potentially life-threatening (Grade 4) adverse events, serious adverse events, adverse events leading to study drug discontinuation, and moderate (Grade 2) severity or higher hypersensitivity reactions. Rates of adverse reactions (≥ Grade 3), serious adverse reactions, and adverse reactions leading to treatment discontinuation are presented in Table 4.

Table 4 Summary of Adverse Reaction Rates in Hospitalized Subjects with Mild, Moderate, or Severe COVID-19 in NIAID ACTT-1 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). Rates of any adverse reactions, serious adverse reactions, and adverse reactions leading to treatment discontinuation are presented in Table 5. 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).

Table 6 Summary of Adverse Reaction Attribution of events to study drug was not performed for the SOC group. 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. 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. No subjects (0 of 9) who received 5 days of VEKLURY had graded increases in ALT.

The adverse reactions observed were consistent with those observed in clinical trials of VEKLURY in adults. 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. The most common adverse reaction occurring in at least 5% of subjects was ALT increased (6%).

Two (4%) subjects permanently discontinued treatment due to adverse reactions (ALT increased, ALT increased and AST increased and hyperbilirubinemia ). Laboratory abnormalities (Grades 3–4) occurring in at least 3% of subjects with COVID-19 receiving VEKLURY in Trial 5823 and who had at least one post-baseline value for the specified test were hemoglobin decreased (, 2/52). Emergency Use Authorization Experience in Subjects with COVID-19 The following adverse reactions have been identified during use of VEKLURY under Emergency Use Authorization: General disorders and administration site conditions: Administration site extravasation Skin and subcutaneous tissue disorders: Rash Immune system disorders: Anaphylaxis, angioedema, infusion-related reactions, hypersensitivity Investigations: Transaminase elevations

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

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

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

No dose adjustments are recommended in patients who receive VEKLURY during pregnancy (see Data ) and. In nonclinical reproductive toxicity studies, remdesivir demonstrated no adverse effect on embryo-fetal development when administered to pregnant animals at systemic exposures (AUC) of the predominant circulating metabolite of remdesivir (GS-441524) that were 4 times (rats and rabbits) the exposure in humans at the recommended human dose (RHD) (see Data ). There are maternal and fetal risks associated with untreated COVID-19 in pregnancy (see Clinical Considerations ).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 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. Three subjects (12%) did not have data available on baseline oxygen status. The overall median (Q1, Q3) duration of symptoms prior to hospitalization was 7 days.

The overall median (Q1, Q3) duration of symptoms prior to first dose of VEKLURY was 8 days. Of the 25 pregnant subjects, median gestational age was 28 weeks at baseline (range 22 to 33 weeks) and about half of subjects were in each of the second and third trimester of pregnancy. No clinically relevant differences in the pharmacokinetics of remdesivir or its metabolites (GS-704277 and GS-441524) were observed between pregnant (n=21) and non-pregnant (n=22) individuals.

No difference in pharmacokinetics of remdesivir or its metabolites is expected between the first and second/third trimesters. The adverse reactions observed were consistent with those observed in clinical trials of VEKLURY in adults. There were no adverse reactions in infants born during the study (n=16).

No adverse effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed in rats and rabbits at nontoxic doses in pregnant animals. During organogenesis, exposures to the predominant circulating metabolite (GS-441524) were 4 times higher (rats and rabbits) than the exposure in humans at the RHD. In a pre/postnatal development study, exposures to the predominant circulating metabolite of remdesivir (GS-441524) were similar to the human exposures at the RHD.

Pediatric Use The safety and effectiveness of VEKLURY for the treatment of COVID-19 have been established in pediatric patients from birth to less than 18 years of age and weighing at least 1.5 kg, who are: Hospitalized, or Not hospitalized and have mild-to-moderate COVID-19, and are at high risk for progression to severe COVID-19, including hospitalization or death. Use in this age group is supported by the following: Trials in adults An open-label trial (Study 5823) in 58 hospitalized pediatric subjects. The safety and pharmacokinetic results in pediatric subjects were similar to those in adults.

The safety in this weight group was comparable to adult subjects weighing greater than 50 kg. Thirty-nine pediatric patients 12 years and older and weighing at least 40 kg received VEKLURY in a compassionate use program in hospitalized subjects; the available clinical data from these patients are limited. Use of VEKLURY in pediatric patients with renal impairment is supported by safety data in adults.

Limited data are available regarding the safety of VEKLURY in pediatric patients with mild or moderate renal impairment. No data are available regarding the safety of VEKLURY in pediatric patients with severe renal impairment. In adults with severe renal impairment, including those requiring dialysis, exposures of GS-441524 and GS-704277, the metabolites of remdesivir, and betadex sulfobutyl ether sodium (SBECD) are increased.

VEKLURY contains SBECD which, when administered intravenously, is eliminated through glomerular filtration and therefore when administered to pediatric patients with renal immaturity or renal impairment, may result in higher exposure to SBECD.

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

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