ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

Animal Toxicology and/or PharmacologyIntravenous administration (slow bolus) of remdesivir to male rhesus monkeys at dosage levels of 5, 10, and 20 mg/kg/day for days resulted, at all dose levels, in increased mean urea nitrogen and increased mean creatinine, renal tubular atrophy, and basophilia and casts.Intravenous administration (slow bolus) of remdesivir to rats at dosage levels of >=3 mg/kg/day for up to weeks resulted in findings indicative of kidney injury and/or dysfunction.Kidney-related effects in rats and monkeys were observed at exposures of the predominant circulating metabolite (GS-441524) that are lower than the exposure in humans at the RHD.

BOXED WARNING SECTION.

This EUA is for the use of VEKLURY to treat COVID-19 in pediatric patients weighing 3.5 kg to less than 40 kg or pediatric patients less than 12 years of age weighing at least 3.5 kg, with positive results of direct SARS-CoV-2 viral testing who are: Hospitalized, or Not hospitalized and have mild-to-moderate COVID-19, and are at high risk for progression to severe COVID-19, including hospitalization or death. VEKLURY must be administered by intravenous (IV) infusion.Healthcare providers must submit report on all medication errors and ALL SERIOUS ADVERSE EVENTS related to VEKLURY. See Sections and of the Full EUA Prescribing Information for reporting requirements. See the Full EUA Prescribing Information for complete dosage, preparation, and administration instructions.The only authorized dosage form of VEKLURY for pediatric patients weighing 3.5 kg to less than 40 kg or pediatric patients less than 12 years of age weighing at least 3.5 kg is VEKLURY for injection (supplied as 100 mg lyophilized powder in vial). The recommended dosage for pediatric patients weighing 3.5 kg to less than 40 kg is single loading dose of VEKLURY mg/kg on Day followed by VEKLURY 2.5 mg/kg once daily from Day [see Full EUA Prescribing Information, Recommended Dosage in Pediatric Patients (2.3)]. The recommended dosage for pediatric patients less than 12 years of age and weighing 40 kg and higher is single loading dose of 200 mg on Day followed by once-daily maintenance doses of 100 mg from Day 2. See the Full EUA Prescribing Information for complete dosage, preparation, and administration instructions.. The only authorized dosage form of VEKLURY for pediatric patients weighing 3.5 kg to less than 40 kg or pediatric patients less than 12 years of age weighing at least 3.5 kg is VEKLURY for injection (supplied as 100 mg lyophilized powder in vial). The recommended dosage for pediatric patients weighing 3.5 kg to less than 40 kg is single loading dose of VEKLURY mg/kg on Day followed by VEKLURY 2.5 mg/kg once daily from Day [see Full EUA Prescribing Information, Recommended Dosage in Pediatric Patients (2.3)]. The recommended dosage for pediatric patients less than 12 years of age and weighing 40 kg and higher is single loading dose of 200 mg on Day followed by once-daily maintenance doses of 100 mg from Day 2. The recommended dosage for pediatric patients weighing 3.5 kg to less than 40 kg is single loading dose of VEKLURY mg/kg on Day followed by VEKLURY 2.5 mg/kg once daily from Day [see Full EUA Prescribing Information, Recommended Dosage in Pediatric Patients (2.3)]. The recommended dosage for pediatric patients less than 12 years of age and weighing 40 kg and higher is single loading dose of 200 mg on Day followed by once-daily maintenance doses of 100 mg from Day 2. Hospitalized patients: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 days. If patient does not demonstrate clinical improvement, treatment may be extended for up to additional days for total treatment duration of up to 10 days.. 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 days. If patient does not demonstrate clinical improvement, treatment may be extended for up to additional days for 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 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 days.Administer VEKLURY via intravenous infusion over 30 to 120 minutes.For information on clinical trials that are testing the use of VEKLURY in COVID-19, please see www.clinicaltrials.gov.. 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 days.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

CarcinogenesisGiven the short-term administration of VEKLURY for the treatment of COVID-19, long-term animal studies to evaluate the carcinogenic potential of remdesivir were not conducted.

CLINICAL PHARMACOLOGY SECTION.

14.CLINICAL PHARMACOLOGY. 14.1 Mechanism of Action Remdesivir is an inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), which is essential for viral replication. Remdesivir is an adenosine nucleotide prodrug that distributes into cells where it is metabolized to nucleoside monophosphate intermediate by carboxyesterase and/or cathepsin A, depending upon the cell type. The nucleoside monophosphate is subsequently phosphorylated by cellular kinases to form the pharmacologically active nucleoside triphosphate metabolite (GS-443902). Remdesivir triphosphate (RDV TP) acts as an analog of adenosine triphosphate (ATP) and competes with high selectivity (3.65-fold) over the natural ATP substrate for incorporation into nascent RNA chains by the SARS-CoV-2 RNA-dependent RNA polymerase, which results in delayed chain termination (position i+3) during replication of the viral RNA. In biochemical assay assessing RDV-TP incorporation by the MERS-CoV RdRp complex, RDV-TP inhibited RNA synthesis with an IC50 value of 0.032 uM. RDV-TP can also inhibit viral RNA synthesis following its incorporation into the template viral RNA as result of read-through by the viral polymerase that may occur at higher nucleotide concentrations. When remdesivir nucleotide is present in the viral RNA template, the efficiency of incorporation of the complementary natural nucleotide is compromised, thereby inhibiting viral RNA synthesis. Remdesivir triphosphate is weak inhibitor of mammalian DNA and RNA polymerases, including human mitochondrial RNA polymerase.. 14.2 Pharmacokinetics. The pharmacokinetic (PK) properties of remdesivir and metabolites have been evaluated in adults in several Phase trials and are provided in Table 12. The multiple dose PK parameters of remdesivir and metabolites in healthy adults are provided in Table 13.Table 12 Pharmacokinetic Properties of Remdesivir and Metabolites (GS-441524 and GS-704277) in AdultsRemdesivirGS-441524GS-704277ND=not detectedAbsorptionTmax (h)Remdesivir administered as 30-minute IV infusion (Study GS-US-399-5505); range of median observed on Day and Day or 10. 0.67-0.681.51-2.000.75-0.75Distribution% bound to human plasma proteins88-93.6Range of protein binding for remdesivir from independent experiments show no evidence of concentration-dependent protein binding for remdesivir. 21Blood-to-plasma ratio0.68-1.01.190.56Eliminationt1/2 (h)Median (Study GS-US-399-4231). 1271.3Metabolism Metabolic pathway(s)CES1 (80%)Cathepsin (10%)CYP3A (10%)Not significantly metabolizedHINT1ExcretionMajor route of eliminationMetabolismGlomerular filtration and active tubular secretionMetabolism% of dose excreted in urineMean (Study GS-US-399-4231). 10492.9% of dose excreted in feces ND0.5NDTable 13 Multiple Dose PK ParametersRemdesivir administered as 30-minute IV infusion (Study GS-US-399-5505). of Remdesivir and Metabolites (GS-441524 and GS-704277) Following IV Administration of VEKLURY 100 mg to Healthy AdultsParameterMean (CV%)RemdesivirGS-441524GS-704277CV=Coefficient of Variation; ND=Not detectable (at 24 hours post-dose)Cmax (nanogram per mL)2229 (19.2)145 (19.3)246 (33.9)AUCtau (nanogramh per mL)1585 (16.6)2229 (18.4)462 (31.4)Ctrough (nanogram per mL)ND69.2 (18.2)ND. Specific PopulationsPharmacokinetic differences based on sex, race, and age have not been evaluated.The pharmacokinetics of VEKLURY in pediatric patients have not been evaluated.Using modeling and simulation, the recommended dosing regimen is expected to result in comparable steady-state plasma exposures of remdesivir and metabolites in pediatric patients weighing 3.5 kg to less than 40 kg or pediatric patients less than 12 years of age weighing at least 3.5 kg as observed in healthy adults.

CONTRAINDICATIONS SECTION.

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

DESCRIPTION SECTION.

13.PRODUCT DESCRIPTION. VEKLURY contains remdesivir, SARS-CoV-2 nucleotide analog RNA polymerase inhibitor. The chemical name for remdesivir is 2-ethylbutyl N-(S)-[2-C-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,5-anhydro-d-altrononitril-6-O-yl]phenoxyphosphoryl-L-alaninate. It has molecular formula of C27H35N6O8P and molecular weight of 602.6 g/mol. Remdesivir has the following structural formula:. 13.1 Physical Appearance. VEKLURY for injection contains 100 mg of remdesivir as sterile, preservative-free lyophilized white to off-white to yellow powder in single-dose clear glass vial. It requires reconstitution and then further dilution prior to administration by intravenous infusion [see Dosage and Administration (2.5, 2.6)]. 13.2 Inactive Ingredients. The inactive ingredients are g betadex sulfobutyl ether sodium, and may include hydrochloric acid and/or sodium hydroxide for pH adjustment. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2.DOSAGE AND ADMINISTRATION. 2.1 Dosage and Administration Overview. VEKLURY may only be administered in settings in which healthcare providers have immediate access to medications to treat severe infusion or hypersensitivity reaction, such as anaphylaxis, and the ability to activate the emergency medical system (EMS), as necessary [see Warnings and Precautions (5.1)].Administer VEKLURY by intravenous infusion only. Do not administer by any other route.. VEKLURY may only be administered in settings in which healthcare providers have immediate access to medications to treat severe infusion or hypersensitivity reaction, such as anaphylaxis, and the ability to activate the emergency medical system (EMS), as necessary [see Warnings and Precautions (5.1)].. Administer VEKLURY by intravenous infusion only. Do not administer by any other route.. 2.2 Important Testing Before and During Treatment Pediatric patients (greater than 28 days old) must have an eGFR determined and full-term neonates (at least days to less than or equal to 28 days old) must have serum creatinine determined before starting VEKLURY and during treatment as clinically appropriate [see Dosage and Administration (2.4), Use in Specific Populations (11.4)].Perform hepatic laboratory testing in all patients before starting VEKLURY and during treatment as clinically appropriate [see Warnings and Precautions (5.2), Use in Specific Populations (11.5)].Determine prothrombin time in all patients before starting VEKLURY and monitor during treatment as clinically appropriate [see Overall Safety Summary (6.1)].. Pediatric patients (greater than 28 days old) must have an eGFR determined and full-term neonates (at least days to less than or equal to 28 days old) must have serum creatinine determined before starting VEKLURY and during treatment as clinically appropriate [see Dosage and Administration (2.4), Use in Specific Populations (11.4)].. Perform hepatic laboratory testing in all patients before starting VEKLURY and during treatment as clinically appropriate [see Warnings and Precautions (5.2), Use in Specific Populations (11.5)].. Determine prothrombin time in all patients before starting VEKLURY and monitor during treatment as clinically appropriate [see Overall Safety Summary (6.1)].. 2.3 Recommended Dosage in Pediatric Patients. The only authorized dosage form of VEKLURY for pediatric patients weighing 3.5 kg to less than 40 kg or pediatric patients less than 12 years of age weighing at least 3.5 kg is VEKLURY for injection (supplied as 100 mg lyophilized powder in vial).For pediatric patients weighing 3.5 kg to less than 40 kg, administer body weight-based dosing regimen of VEKLURY via intravenous (IV) infusion. The dosage should be calculated using the mg/kg dose according to the patients weight.For pediatric patients less than 12 years of age and weighing 40 kg and higher, administer single loading dose of VEKLURY 200 mg on Day followed by once-daily maintenance doses of VEKLURY 100 mg from Day 2.Refer to Table below for recommended dosage form and dosage in pediatric patients according to weight [see Dosage and Administration (2.5), Use in Specific Populations (11.3)]. Table Recommended Dosage Form and Dosage in Pediatric PatientsBody weightRecommended dosage formLoading dose(on Day 1)Maintenance dose(from Day 2)3.5 kg to less than 40 kgVEKLURY Lyophilized Powder for Injection Only mg/kg2.5 mg/kg40 kg and higher200 mg100 mg. Hospitalized patients: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 days. If patient does not demonstrate clinical improvement, treatment may be extended for up to additional days for total treatment duration of up to 10 days.. 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 days. If patient does not demonstrate clinical improvement, treatment may be extended for up to additional days for 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 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 days.VEKLURY for injection must be reconstituted and further diluted prior to administration via intravenous infusion.. 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 days.. 2.4 Renal Impairment. VEKLURY is not recommended in pediatric patients (greater than 28 days old) with eGFR less than 30 mL/min or in full-term neonates (at least days and less than or equal to 28 days old) with serum creatinine greater than or equal to mg/dL.. 2.5 Dose Preparation and Administration, VEKLURY for Injection The authorized dosage form of VEKLURY for pediatric patients weighing 3.5 kg to less than 40 kg or pediatric patients less than 12 years of age weighing at least 3.5 kg is VEKLURY for injection (supplied as 100 mg lyophilized powder) only.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Discard the vial if the lyophilized powder is discolored or contains particulate matter. Prior to dilution in 0.9% sodium chloride, reconstituted VEKLURY for injection should be clear, colorless to yellow solution, free of visible particles.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.. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Discard the vial if the lyophilized powder is discolored or contains particulate matter. Prior to dilution in 0.9% sodium chloride, reconstituted VEKLURY for injection should be clear, colorless to yellow solution, free of visible particles.. 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.. Reconstitution InstructionsRemove the required number of single-dose vial(s) from storage. For each vial:Aseptically reconstitute VEKLURY lyophilized powder by addition of 19 mL of Sterile Water for Injection using suitably sized syringe and needle per vial.Only use Sterile Water for Injection to reconstitute VEKLURY lyophilized powder.Discard the vial if 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 to minutes. 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 to 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 VEKLURY for injection immediately to prepare the diluted solution.. Aseptically reconstitute VEKLURY lyophilized powder by addition of 19 mL of Sterile Water for Injection using suitably sized syringe and needle per vial.. Only use Sterile Water for Injection to reconstitute VEKLURY lyophilized powder.. Discard the vial if 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 to minutes. 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 to 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 VEKLURY for injection immediately to prepare the diluted solution.. Dilution and Administration Instructions, Pediatric Patients Weighing 3.5 kg to Less Than 40 kg. Dilution InstructionsFor pediatric patients weighing 3.5 kg to less than 40 kg, the 100 mg/20 mL (5 mg/mL) remdesivir reconstituted solution should be further diluted to fixed concentration of 1.25 mg/mL using 0.9% sodium chloride.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 of mg/kg for the Loading Dose and 2.5 mg/kg for each Maintenance Dose.Small 0.9% sodium chloride 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 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.Refer to Table for recommended rate of infusion.. For pediatric patients weighing 3.5 kg to less than 40 kg, the 100 mg/20 mL (5 mg/mL) remdesivir reconstituted solution should be further diluted to fixed concentration of 1.25 mg/mL using 0.9% sodium chloride.. 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 of mg/kg for the Loading Dose and 2.5 mg/kg for each Maintenance Dose.. Small 0.9% sodium chloride 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 total volume dependent on the dose to yield the target remdesivir concentration of 1.25 mg/mL.. syringe and syringe pump may be used for infusion volumes less than 50 mL.. Refer to Table for recommended rate of infusion.. Infusion with IV BagDetermine the total infusion volume needed to achieve final infusion volume concentration of 1.25 mg/mL of remdesivir diluted solution based on the patients calculated dose.Select an appropriately sized infusion bag (either prefilled with 0.9% sodium chloride or empty) to prepare VEKLURY diluted solution.If using prefilled 0.9% sodium chloride infusion bag, withdraw and discard the amount of diluent equal to the volume of reconstituted VEKLURY solution needed per patients dose plus quantity sufficient to achieve 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 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 volume of 0.9% sodium chloride sufficient to achieve 1.25 mg/mL final volume concentration of remdesivir diluted solution.The prepared infusion solution is stable for 24 hours at room temperature (20C to 25C [68F to 77F]) or 48 hours at refrigerated temperature (2C to 8C [36F to 46F]).. Determine the total infusion volume needed to achieve final infusion volume concentration of 1.25 mg/mL of remdesivir diluted solution based on the patients calculated dose.. Select an appropriately sized infusion bag (either prefilled with 0.9% sodium chloride or empty) to prepare VEKLURY diluted solution.. If using prefilled 0.9% sodium chloride infusion bag, withdraw and discard the amount of diluent equal to the volume of reconstituted VEKLURY solution needed per patients dose plus quantity sufficient to achieve 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 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 volume of 0.9% sodium chloride sufficient to achieve 1.25 mg/mL final volume concentration of remdesivir diluted solution.. The prepared infusion solution is stable for 24 hours at room temperature (20C to 25C [68F to 77F]) or 48 hours at refrigerated temperature (2C to 8C [36F to 46F]).. Infusion with SyringeDetermine the total infusion volume needed to achieve final infusion volume concentration of 1.25 mg/mL of remdesivir diluted solution based on patients 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 patients calculated dose, followed by the required volume of 0.9% sodium chloride needed to achieve 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.. Determine the total infusion volume needed to achieve final infusion volume concentration of 1.25 mg/mL of remdesivir diluted solution based on patients 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 patients calculated dose, followed by the required volume of 0.9% sodium chloride needed to achieve 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.. Administration InstructionsThe 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 the diluted solution with the infusion rate described in Table 2.Table Recommended Rate of Infusion--Diluted VEKLURY for Injection Lyophilized Powder for Pediatric Patients Weighing 3.5 kg to Less Than 40 kgInfusion volumeInfusion timeRate of infusionNote: Rate of infusion may be adjusted based on total volume to be infused. 100 mL30 min3.33 mL/min60 min1.67 mL/min120 min0.83 mL/min50 mL30 min1.67 mL/min60 min0.83 mL/min120 min0.42 mL/min25 mL30 min0.83 mL/min60 min0.42 mL/min120 min0.21 mL/min7 mL30 min0.23 mL/min60 min0.12 mL/min120 min0.06 mL/minAdministration 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.. Dilution and Administration Instructions, Pediatric Patients Less Than 12 Years of Age and Weighing 40 kg and Higher. Dilution InstructionsFor pediatric patients less than 12 years of age and weighing 40 kg and higher, refer to the dilution instructions in Table 3.Table Recommended Dilution Instructions Using Reconstituted VEKLURY for Injection Lyophilized Powder in Pediatric Patients Less Than 12 Years of Age and Weighing 40 kg and HigherVEKLURY dose0.9% sodium chloride infusion bag volume to be usedVolume to be withdrawn and discarded from 0.9% sodium chloride infusion bagRequired volume of reconstituted VEKLURY for injectionLoading dose200 mg(2 vials)250 mL40 mL40 mL (2 20 mL)100 mL40 mL40 mL (2 20 mL)Maintenance dose100 mg(1 vial)250 mL20 mL20 mL100 mL20 mL20 mLWithdraw and discard the required volume of 0.9% sodium chloride from the infusion bag following instructions in Table 3, using an appropriately sized syringe and needle.Withdraw the required volume of reconstituted VEKLURY for injection from the VEKLURY vial following instructions in Table 3. 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 diluted solution is stable for 24 hours at room temperature (20C to 25C [68F to 77F]) or 48 hours at refrigerated temperature (2C to 8C [36F to 46F]).. Withdraw and discard the required volume of 0.9% sodium chloride from the infusion bag following instructions in Table 3, using an appropriately sized syringe and needle.. Withdraw the required volume of reconstituted VEKLURY for injection from the VEKLURY vial following instructions in Table 3. 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 diluted solution is stable for 24 hours at room temperature (20C to 25C [68F to 77F]) or 48 hours at refrigerated temperature (2C to 8C [36F to 46F]).. Administration InstructionsThe 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 the diluted solution with the infusion rate described in Table 4.Table Recommended Rate of Infusion -- Diluted VEKLURY for Injection Lyophilized Powder in Pediatric Patients Less Than 12 Years of Age and Weighing 40 kg and HigherInfusion volumeInfusion timeRate of infusion250 mL30 min8.33 mL/min60 min4.17 mL/min120 min2.08 mL/min100 mL30 min3.33 mL/min60 min1.67 mL/min120 min0.83 mL/minAdministration 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.. 2.6 Storage of Prepared Dosages. After reconstitution, use vials immediately to prepare diluted solution.The diluted VEKLURY solution in syringe should be used immediately.The diluted VEKLURY solution in the infusion bags can be stored up to 24 hours at room temperature (20C to 25C [68F to 77F]) or 48 hours at refrigerated temperature (2C to 8C [36F to 46F]) prior to administration.IMPORTANT:This product contains no preservative. Any unused portion of single-dose VEKLURY vial should be discarded after diluted solution is prepared. Maintain adequate records showing receipt, use, and disposition of VEKLURY. For unused intact vials, maintain adequate records showing disposition of VEKLURY; do not discard unused intact vials.

DOSAGE FORMS & STRENGTHS SECTION.

3.DOSAGE FORMS AND STRENGTHS. VEKLURY for injection,100 mg, available as sterile, preservative-free white to off-white to yellow lyophilized powder in single-dose vial for reconstitution.

DRUG INTERACTIONS SECTION.

10.DRUG INTERACTIONS 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), Microbiology/Resistance Information (15)].Clinical drug-drug interaction studies have not been performed with VEKLURY.In vitro, remdesivir is substrate for drug metabolizing enzyme CYP3A4, and is substrate for Organic Anion Transporting Polypeptides 1B1 (OATP1B1) and P-glycoprotein (P-gp) transporters. In vitro, remdesivir is an inhibitor of CYP3A4, OATP1B1, OATP1B3, and MATE1. GS-704277 is substrate for OATP1B1 and OATP1B3. The clinical relevance of these in vitro assessments has not been established.Remdesivir is not substrate for CYP1A1, 1A2, 2B6, 2C9, 2C19, or OATP1B3. GS-704277 and GS-441524 are not substrates for CYP1A1, 1A2, 2B6, 2C8, 2C9, 2D6, or 3A5. GS-441524 is also not substrate for CYP2C19 or 3A4. GS-704277 and GS 441524 are not substrates for OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2K. GS 441524 is also not substrate for OATP1B1 or OATP1B3.

HEALTH CARE PROVIDER LETTER SECTION.

IMPORTANT PRESCRIBING INFORMATIONSubject:Updated Emergency Use Authorization (EUA) for treatment of coronavirus disease 2019 (COVID-19) in pediatric patients weighing 3.5 kg to less than 40 kg or pediatric patients less than 12 years of age weighing at least 3.5 kg with positive results of direct severe acute respiratory syndrome coronavirus (SARS-CoV-2) viral testing, 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, and variations in carton and vial labeling of VEKLURY(R) (remdesivir) Dear Healthcare Provider:Gilead Sciences, Inc., would like to clarify the appropriate use and the variable packaging and labeling of the antiviral VEKLURY(R) (remdesivir).Gileads remdesivir (brand name VEKLURY) was approved by the US Food and Drug Administration (FDA) on January 21, 2022 for adults and pediatric patients (12 years of age and older and weighing at least 40 kg) for the treatment of coronavirus disease 2019 (COVID-19) with positive results of direct severe acute respiratory syndrome coronavirus (SARS-CoV-2) viral testing, who are:Hospitalized, orNot hospitalized and have mild-to-moderate COVID-19, and are at high risk for progression to severe COVID-19, including hospitalization or death.Healthcare providers should administer VEKLURY in these patients per the current US Prescribing Information available at www.gilead.com/science-and-medicine/medicines; please also see Important Safety Information at the end of this letter.Emergency use of Gileads remdesivir (brand name VEKLURY) for treatment of COVID-19 in pediatric patients weighing 3.5 kg to less than 40 kg or pediatric patients less than 12 years of age weighing at least 3.5 kg with positive results of direct SARS-CoV-2 viral testing, 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.On January 21, 2022, FDA revised the Emergency Use Authorization (EUA) for VEKLURY, which now authorizes VEKLURY for use by healthcare providers to treat COVID-19 in pediatric patients weighing 3.5 kg to less than 40 kg or pediatric patients less than 12 years of age weighing at least 3.5 kg with positive results of direct SARS-CoV-2 viral testing, 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. Only Gileads VEKLURY (remdesivir) for injection (supplied as 100 mg lyophilized powder in vial) is authorized for emergency use under the terms and conditions set forth in the Letter of Authorization for the EUA. The safety and efficacy of VEKLURY to treat COVID-19 in pediatric patients weighing 3.5 kg to less than 40 kg or pediatric patients less than 12 years of age weighing at least 3.5 kg with positive results of direct SARS-CoV-2 viral testing has not been established, and VEKLURY is not FDA approved for this use. For information about the authorized use of VEKLURY in pediatric patients weighing 3.5 kg to less than 40 kg or pediatric patients less than 12 years of age weighing at least 3.5 kg, including dosing, administration, and preparation instructions, please review the EUA Fact Sheet for Healthcare Providers and FDA Letter of Authorization available at www.gilead.com/remdesivir.Variations in packaging and labeling of Gileads remdesivir (brand name VEKLURY)Gileads VEKLURY (remdesivir) has been manufactured for use under an EUA, and for commercial use. As such, VEKLURY has different packaging, labeling, and expiration dates depending on the date of manufacture. Packaging and labeling for Gileads remdesivir EUA use may not necessarily include the brand name, VEKLURY.To help avoid potential drug shortage, hospitals should continue to use all unexpired, unopened vials of Gileads remdesivir whether or not the vial includes the brand name VEKLURY or is labeled for use under EUA. Refer to the attached chart at the end of this letter that outlines what hospitals should do with unexpired, unopened vials of Gileads remdesivir.Authentic VEKLURY or remdesivir, manufactured by Gilead Sciences, Inc., will include the GILEAD name and logo on the carton and vial label. All packaging includes the drug name remdesivir. Current packaging variations for the two formulations are described below. Both formulations are for intravenous infusion only.VEKLURY(R) (remdesivir) for injection (supplied as 100 mg lyophilized powder in vial). The lyophilized powder formulation is always supplied with red cap and the package and labeling may be marked for use under Emergency Use Authorization (EUA).VEKLURY(R) (remdesivir) injection (supplied as 100 mg/20 mL [5 mg/mL], solution in vial). The solution formulation is supplied with blue cap and the package and labeling may be marked for use under Emergency Use Authorization (EUA). The solution should only be used in adults and pediatric patients 12 years of age and older and weighing at least 40 kg.Veklury (remdesivir) injection (solution; left) and Veklury (remdesivir) for injection (lyophilized powder; right) now approved by FDA for use in accordance with the prescribing information (PI).Veklury (remdesivir) injection (solution; left) and Veklury (remdesivir) for injection (lyophilized powder; right) previously authorized for emergency use.Reporting Adverse Events and Medication ErrorsHealthcare providers should direct questions on VEKLURY packaging or use to Gilead Sciences at 1-866-633-4474 or www.askgileadmedical.com.Under the Emergency Use Authorization, the prescribing healthcare provider and/or the providers designee are/is responsible for mandatory reporting of all serious adverse events and medication errors potentially related to VEKLURY treatment within calendar days from the healthcare providers awareness of the event using FDA Form 3500. Healthcare providers must report all serious adverse events and medication errors to FDA when utilizing VEKLURY under the EUA in accordance with the Healthcare Provider Fact Sheet.For additional information about VEKLURY, including the full Prescribing Information, please visit www.vekluryhcp.com.Information and reports of suspicious, counterfeit, or unregistered remdesivir can be submitted to Gilead anticounterfeitinggilead.com and/or www.fraud.org/fakerx. SignatorySignatory DepartmentAppropriate use of Gileads remdesivir (brand name VEKLURY), including vials labeled for Emergency Use Authorization (EUA) useProductRemdesivir for injection, 100 mg, lyophilized powderRemdesivir injection, 100 mg/20 mL (5 mg/mL), solutionLabeled For use under Emergency Use Authorization (EUA) (vials and cartons do not include the brand name, VEKLURY)Continue use in: Adults and pediatric patients (12 years of age and older and weighing at least 40 kg) requiring hospitalization or non-hospitalized patients with mild-to-moderate COVID-19 who are at high risk for progression to severe COVID-19, including hospitalization or death.Pediatric patients weighing 3.5 kg to less than 40 kg or hospitalized pediatric patients less than 12 years of age weighing at least 3.5 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 under the provisions of the Emergency Use Authorization (EUA) Please review the EUA Fact Sheet for Healthcare Providers and FDA Letter of Authorization, available at gilead.com/remdesivir. Continue use in: Adults and pediatric patients (12 years of age and older and weighing at least 40 kg) requiring hospitalization or non-hospitalized patients with mild-to-moderate COVID-19 who are at high risk for progression to severe COVID-19, including hospitalization or death. FDA-approved VEKLURY (carton and vials will include the brand name, VEKLURY)Use in:Adults and pediatric patients (12 years of age and older and weighing at least 40 kg) requiring hospitalization or non-hospitalized patients with mild-to-moderate COVID-19 who are at high risk for progression to severe COVID-19, including hospitalization or death.Pediatric patients weighing 3.5 kg to less than 40 kg or hospitalized pediatric patients less than 12 years of age weighing at least 3.5 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 under the provisions of the Emergency Use Authorization (EUA) Please review the EUA Fact Sheet for Healthcare Providers and FDA Letter of Authorization, available at gilead.com/remdesivir. Use in: Adults and pediatric patients (12 years of age and older and weighing at least 40 kg) requiring hospitalization or non-hospitalized patients with mild-to-moderate COVID-19 who are at high risk for progression to severe COVID-19, including hospitalization or death. U.S. Indication and Important Safety Information for VEKLURY(R) (remdesivir)IndicationVEKLURY is indicated for the treatment of COVID-19 in adults and pediatric patients >=12 years old and weighing >=40 kg with positive results of SARS-CoV-2 viral testing, who are:Hospitalized, orNot hospitalized and have mild-to-moderate COVID-19 and are at high risk for progression to severe COVID-19, including hospitalization or death.Important Safety InformationContraindicationVEKLURY is contraindicated in patients with history of clinically significant hypersensitivity reactions to VEKLURY or any of its components. Warnings and precautions Hypersensitivity, including infusion-related and anaphylactic reactions: Hypersensitivity, including infusion-related and anaphylactic reactions, has been observed during and following administration of VEKLURY; most occurred within hour. Monitor patients during infusion and observe for at least hour after infusion is complete for signs and symptoms of hypersensitivity as clinically appropriate. Symptoms may include hypotension, hypertension, tachycardia, bradycardia, hypoxia, fever, dyspnea, wheezing, angioedema, rash, nausea, diaphoresis, and shivering. Slower infusion rates (maximum infusion time of up to120 minutes) can potentially prevent these reactions. If severe infusion-related hypersensitivity reaction occurs, immediately discontinue VEKLURY and initiate appropriate treatment (see Contraindications).Increased risk of transaminase elevations: Transaminase elevations have been observed in healthy volunteers and in patients with COVID-19 who received VEKLURY; these elevations have also been reported as clinical feature of COVID-19. Perform hepatic laboratory testing in all patients (see Dosage and administration). Consider discontinuing VEKLURY if ALT levels increase to >10x ULN. Discontinue VEKLURY if ALT elevation is accompanied by signs or symptoms of liver inflammation.Risk of reduced antiviral activity when coadministered with chloroquine or hydroxychloroquine: Coadministration of VEKLURY with chloroquine phosphate or hydroxychloroquine sulfate is not recommended based on data from cell culture experiments, demonstrating potential antagonism, which may lead to decrease in the antiviral activity of VEKLURY.Adverse reactionsThe most common adverse reaction (>=5% all grades) was nausea.The most common lab abnormalities (>=5% all grades) were increases in ALT and AST.Drug interactionsDrug interaction trials of VEKLURY and other concomitant medications have not been conducted in humans. Dosage and administration Dosage: For adults and pediatric patients >=12 years old and weighing >=40 kg: 200 mg on Day 1, followed by once-daily maintenance doses of 100 mg from Day administered only via intravenous infusion. VEKLURY should be initiated as soon as possible after diagnosis of symptomatic COVID-19.Treatment duration:-For hospitalized patients requiring invasive mechanical ventilation and/or ECMO, the recommended total treatment duration is 10 days.-For hospitalized patients not requiring invasive mechanical ventilation and/or ECMO, the recommended treatment duration is days. If patient does not demonstrate clinical improvement, treatment may be extended for up to additional days, for total treatment duration of up to 10 days.-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 days.Testing prior to and during treatment: Perform eGFR, hepatic laboratory, and prothrombin time testing prior to initiating VEKLURY and during use as clinically appropriate.Renal impairment: VEKLURY is not recommended in individuals with eGFR <30 mL/min.Dose preparation and administration: See full Prescribing Information.Pregnancy and lactationPregnancy: pregnancy registry has been established. There are insufficient human data on the use of VEKLURY during pregnancy. COVID-19 is associated with adverse maternal and fetal outcomes, including preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic disease, and fetal death.Lactation: It is not known whether VEKLURY can pass into breast milk. Breastfeeding individuals with COVID-19 should follow practices according to clinical guidelines to avoid exposing the infant to COVID-19. Please see full Prescribing Information for VEKLURY, available at www.gilead.com.. 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(R) (remdesivir) for injection (supplied as 100 mg lyophilized powder in vial). The lyophilized powder formulation is always supplied with red cap and the package and labeling may be marked for use under Emergency Use Authorization (EUA).. VEKLURY(R) (remdesivir) injection (supplied as 100 mg/20 mL [5 mg/mL], solution in vial). The solution formulation is supplied with blue cap and the package and labeling may be marked for use under Emergency Use Authorization (EUA). The solution should only be used in adults and pediatric patients 12 years of age and older and weighing at least 40 kg.. Adults and pediatric patients (12 years of age and older and weighing at least 40 kg) requiring hospitalization or non-hospitalized patients with mild-to-moderate COVID-19 who are at high risk for progression to severe COVID-19, including hospitalization or death.. Pediatric patients weighing 3.5 kg to less than 40 kg or hospitalized pediatric patients less than 12 years of age weighing at least 3.5 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 under the provisions of the Emergency Use Authorization (EUA) Please review the EUA Fact Sheet for Healthcare Providers and FDA Letter of Authorization, available at gilead.com/remdesivir.. Adults and pediatric patients (12 years of age and older and weighing at least 40 kg) requiring hospitalization or non-hospitalized patients with mild-to-moderate COVID-19 who are at high risk for progression to severe COVID-19, including hospitalization or death.. Adults and pediatric patients (12 years of age and older and weighing at least 40 kg) requiring hospitalization or non-hospitalized patients with mild-to-moderate COVID-19 who are at high risk for progression to severe COVID-19, including hospitalization or death.. Pediatric patients weighing 3.5 kg to less than 40 kg or hospitalized pediatric patients less than 12 years of age weighing at least 3.5 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 under the provisions of the Emergency Use Authorization (EUA) Please review the EUA Fact Sheet for Healthcare Providers and FDA Letter of Authorization, available at gilead.com/remdesivir.. Adults and pediatric patients (12 years of age and older and weighing at least 40 kg) requiring hospitalization or non-hospitalized patients with mild-to-moderate COVID-19 who are at high risk for progression to severe COVID-19, including hospitalization or death.. 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 contraindicated in patients with history of clinically significant hypersensitivity reactions to VEKLURY or any of its components. Hypersensitivity, including infusion-related and anaphylactic reactions: Hypersensitivity, including infusion-related and anaphylactic reactions, has been observed during and following administration of VEKLURY; most occurred within hour. Monitor patients during infusion and observe for at least hour after infusion is complete for signs and symptoms of hypersensitivity as clinically appropriate. Symptoms may include hypotension, hypertension, tachycardia, bradycardia, hypoxia, fever, dyspnea, wheezing, angioedema, rash, nausea, diaphoresis, and shivering. Slower infusion rates (maximum infusion time of up to120 minutes) can potentially prevent these reactions. If severe infusion-related hypersensitivity reaction occurs, immediately discontinue VEKLURY and initiate appropriate treatment (see Contraindications).. Increased risk of transaminase elevations: Transaminase elevations have been observed in healthy volunteers and in patients with COVID-19 who received VEKLURY; these elevations have also been reported as clinical feature of COVID-19. Perform hepatic laboratory testing in all patients (see Dosage and administration). Consider discontinuing VEKLURY if ALT levels increase to >10x ULN. Discontinue VEKLURY if ALT elevation is accompanied by signs or symptoms of liver inflammation.. Risk of reduced antiviral activity when coadministered with chloroquine or hydroxychloroquine: Coadministration of VEKLURY with chloroquine phosphate or hydroxychloroquine sulfate is not recommended based on data from cell culture experiments, demonstrating potential antagonism, which may lead to decrease in the antiviral activity of VEKLURY.. The most common adverse reaction (>=5% all grades) was nausea.. The most common lab abnormalities (>=5% all grades) were increases in ALT and AST.. Drug interaction trials of VEKLURY and other concomitant medications have not been conducted in humans. Dosage: For adults and pediatric patients >=12 years old and weighing >=40 kg: 200 mg on Day 1, followed by once-daily maintenance doses of 100 mg from Day administered only via intravenous infusion. VEKLURY should be initiated as soon as possible after diagnosis of symptomatic COVID-19.. Treatment duration:-For hospitalized patients requiring invasive mechanical ventilation and/or ECMO, the recommended total treatment duration is 10 days.-For hospitalized patients not requiring invasive mechanical ventilation and/or ECMO, the recommended treatment duration is days. If patient does not demonstrate clinical improvement, treatment may be extended for up to additional days, for total treatment duration of up to 10 days.-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 days.. -For hospitalized patients requiring invasive mechanical ventilation and/or ECMO, the recommended total treatment duration is 10 days.. -For hospitalized patients not requiring invasive mechanical ventilation and/or ECMO, the recommended treatment duration is days. If patient does not demonstrate clinical improvement, treatment may be extended for up to additional days, for total treatment duration of up to 10 days.. -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 days.. Testing prior to and during treatment: Perform eGFR, hepatic laboratory, and prothrombin time testing prior to initiating VEKLURY and during use as clinically appropriate.. Renal impairment: VEKLURY is not recommended in individuals with eGFR <30 mL/min.. Dose preparation and administration: See full Prescribing Information.. Pregnancy: pregnancy registry has been established. There are insufficient human data on the use of VEKLURY during pregnancy. COVID-19 is associated with adverse maternal and fetal outcomes, including preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic disease, and fetal death.. Lactation: It is not known whether VEKLURY can pass into breast milk. Breastfeeding individuals with COVID-19 should follow practices according to clinical guidelines to avoid exposing the infant to COVID-19. Image. Image.

HEPATIC IMPAIRMENT SUBSECTION.

11.5 Hepatic Impairment. The pharmacokinetics of VEKLURY have not been evaluated in patients with hepatic impairment [see Warnings and Precautions (5.2)]. Perform hepatic laboratory testing in all patients before starting VEKLURY and during treatment as clinically appropriate [see Dosage and Administration (2.2)].

HOW SUPPLIED SECTION.

19.HOW SUPPLIED/STORAGE AND HANDLING How SuppliedVEKLURY for injection, 100 mg, is supplied as single-dose vial containing sterile, preservative-free white to off-white to yellow lyophilized powder. It requires reconstitution and further dilution prior to administration by intravenous infusion [see Dosage and Administration (2.5)]. Discard unused portion.The container closure is not made with natural rubber latex.. Storage and HandlingDo not reuse or save reconstituted or diluted VEKLURY for future use. This product contains no preservative; therefore, partially used vials should be discarded [see Dosage and Administration (2.6)]. Store VEKLURY for injection, 100 mg, vials below 30C (below 86F) until required for use.After reconstitution, use vials immediately to prepare diluted solution. Dilute the reconstituted solution in 0.9% sodium chloride injection, USP within the same day as administration.The diluted VEKLURY solution in syringe should be used immediately.The diluted VEKLURY solution in the infusion bags can be stored up to 24 hours at room temperature (20C to 25C [68F to 77F]) or 48 hours at refrigerated temperature (2C to 8C [36F to 46F]) prior to administration.

LACTATION SECTION.

11.2 Lactation. Risk SummaryThere are no available data on the presence of remdesivir in human milk, the effects on the breastfed infant, or the effects 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. The developmental and health benefits of breastfeeding should be considered along with the mothers 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.. Animal DataRemdesivir 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 to Lactation Day 20. Exposures in nursing pups were approximately 1% that of maternal exposure on Lactation Day 10.

MECHANISM OF ACTION SECTION.

14.1 Mechanism of Action Remdesivir is an inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), which is essential for viral replication. Remdesivir is an adenosine nucleotide prodrug that distributes into cells where it is metabolized to nucleoside monophosphate intermediate by carboxyesterase and/or cathepsin A, depending upon the cell type. The nucleoside monophosphate is subsequently phosphorylated by cellular kinases to form the pharmacologically active nucleoside triphosphate metabolite (GS-443902). Remdesivir triphosphate (RDV TP) acts as an analog of adenosine triphosphate (ATP) and competes with high selectivity (3.65-fold) over the natural ATP substrate for incorporation into nascent RNA chains by the SARS-CoV-2 RNA-dependent RNA polymerase, which results in delayed chain termination (position i+3) during replication of the viral RNA. In biochemical assay assessing RDV-TP incorporation by the MERS-CoV RdRp complex, RDV-TP inhibited RNA synthesis with an IC50 value of 0.032 uM. RDV-TP can also inhibit viral RNA synthesis following its incorporation into the template viral RNA as result of read-through by the viral polymerase that may occur at higher nucleotide concentrations. When remdesivir nucleotide is present in the viral RNA template, the efficiency of incorporation of the complementary natural nucleotide is compromised, thereby inhibiting viral RNA synthesis. Remdesivir triphosphate is weak inhibitor of mammalian DNA and RNA polymerases, including human mitochondrial RNA polymerase.

MICROBIOLOGY SECTION.

15.MICROBIOLOGY/RESISTANCE INFORMATION Antiviral ActivityRemdesivir exhibited cell culture antiviral activity against clinical isolate of SARS-CoV-2 in primary human airway epithelial (HAE) cells with 50% effective concentration (EC50) of 9.9 nM after 48 hours of treatment. Remdesivir inhibited the replication of SARS-CoV-2 in the continuous human lung epithelial cell lines Calu-3 and A549-hACE2 with EC50 values of 280 nM after 72 hours of treatment and 115 nM after 48 hours of treatment, respectively.Remdesivir EC50 values for SARS-CoV-2 in A549-hACE2 cells were not different when combined with chloroquine phosphate or hydroxychloroquine sulfate at concentrations up to 2.5 uM. In separate study, the antiviral activity of remdesivir was antagonized by chloroquine phosphate in dose-dependent manner when the two drugs were co-incubated at clinically relevant concentrations in HEp-2 cells infected with respiratory syncytial virus (RSV). Higher remdesivir EC50 values were observed with increasing concentrations of chloroquine phosphate. Increasing concentrations of chloroquine phosphate or hydroxychloroquine sulfate reduced formation of remdesivir triphosphate in A549-hACE2, HEp-2, and normal human bronchial epithelial cells.Based on cell culture susceptibility testing by plaque assay and/or protein ELISA assay, remdesivir retained similar antiviral activity (<=1.5-fold change) against clinical isolates of SARS-CoV-2 variants containing the P323L substitution in the viral polymerase including the Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), Gamma (P.1), and Epsilon (B.1.429) variants compared to earlier lineage SARS-CoV-2 (lineage A) isolates.SARS-CoV-2 RNA shedding results from GS-US-540-5776 (ACTT-1) indicate that remdesivir does not significantly reduce the amount of detectable SARS-CoV-2 RNA in oropharyngeal or nasopharyngeal swabs or plasma samples in hospitalized patients compared to placebo, and SARS-CoV-2 RNA shedding results from GS-US-540-9012 indicate that remdesivir does not significantly reduce the amount of detectable SARS-CoV-2 RNA in nasopharyngeal swabs in non-hospitalized patients compared to placebo.. Resistance SARS-CoV-2 isolates with reduced susceptibility to remdesivir have been selected in cell culture. In selection with GS-441524, the parent nucleoside of remdesivir, virus pools emerged expressing amino acid substitutions at V166A, N198S, S759A, V792I, C799F, and C799R in the viral RNA-dependent RNA polymerase (nsp12). When these substitutions were individually introduced into wild-type recombinant virus by site-directed mutagenesis, 1.7- to 3.5-fold reductions in susceptibility to remdesivir were observed. In cell culture resistance selection experiment with remdesivir, nsp12 amino acid substitution E802D emerged, resulting in 2.5-fold reduction in susceptibility to remdesivir. In another selection with remdesivir using SARS-CoV-2 isolate containing the P323L substitution in the viral polymerase, single amino acid substitution at V166L emerged. Recombinant SARS-CoV-2 with substitutions at P323L alone or P323L+V166L in combination exhibited 1.3- and 1.5-fold reductions in remdesivir susceptibility, respectively.Cell culture resistance profiling of remdesivir using the rodent CoV murine hepatitis virus identified two substitutions (F476L and V553L) in the viral RNA-dependent RNA polymerase at residues conserved across CoVs. Introduction of the corresponding substitutions (F480L and V557L) into SARS-CoV resulted in 6-fold reduction in susceptibility to remdesivir in cell culture and attenuated SARS-CoV pathogenesis in mouse model. When individually introduced into SARS-CoV-2 recombinant virus, the corresponding substitutions at F480L and V557L each conferred 2-fold reduced susceptibility to remdesivir. When individually introduced into SARS-CoV-2 recombinant virus, the corresponding substitutions at F480L and V557L each conferred 2-fold reduced susceptibility to remdesivir.SARS-CoV-2 nsp12 E802D substitution has emerged in one individual treated with remdesivir. The E802D substitution resulted in 2.5-fold increase in the remdesivir EC50 value.

NONCLINICAL TOXICOLOGY SECTION.

16.NONCLINICAL TOXICOLOGY. CarcinogenesisGiven the short-term administration of VEKLURY for the treatment of COVID-19, long-term animal studies to evaluate the carcinogenic potential of remdesivir were not conducted.. MutagenesisRemdesivir was not genotoxic in battery of assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes, and in vivo rat micronucleus assays.. Impairment of FertilityNonclinical toxicity studies in rats demonstrated no adverse effect on male fertility at exposures of the predominant circulating metabolite (GS-441524) approximately times the exposure in humans at the RHD.Reproductive toxicity, including decreases in corpora lutea, numbers of implantation sites, and viable embryos, was seen when remdesivir was administered intravenous daily at systemically toxic dose (10 mg/kg) in female rats 14 days prior to mating and during conception; exposures of the predominant circulating metabolite (GS-441524) were 1.3 times the exposure in humans at the RHD.. Animal Toxicology and/or PharmacologyIntravenous administration (slow bolus) of remdesivir to male rhesus monkeys at dosage levels of 5, 10, and 20 mg/kg/day for days resulted, at all dose levels, in increased mean urea nitrogen and increased mean creatinine, renal tubular atrophy, and basophilia and casts.Intravenous administration (slow bolus) of remdesivir to rats at dosage levels of >=3 mg/kg/day for up to weeks resulted in findings indicative of kidney injury and/or dysfunction.Kidney-related effects in rats and monkeys were observed at exposures of the predominant circulating metabolite (GS-441524) that are lower than the exposure in humans at the RHD.

OVERDOSAGE SECTION.

12.OVERDOSAGE. 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 100 mg/20 mL Vial Label. remdesivir injection 100 mg/20 mL (5 mg/mL)For Intravenous Use OnlySingle-Dose Vial: Discard Unused PortionFor use under Emergency Use Authorization (EUA)90286902Rx only. PRINCIPAL DISPLAY PANEL 100 mg/20 mL Vial Label.

PEDIATRIC USE SECTION.

11.3 Pediatric Use. The safety and effectiveness of VEKLURY have not been established in pediatric patients weighing 3.5 kg to less than 40 kg or pediatric patients less than 12 years of age weighing at least 3.5 kg, with positive results of direct SARS-CoV-2 viral testing, and who are:Hospitalized, orNot hospitalized and have mild-to-moderate COVID-19, and are at high risk for progression to severe COVID-19, including hospitalization or death.VEKLURY for injection (supplied as 100 mg lyophilized powder in vial) [see Dosage and Administration (2.2, 2.3, 2.4, 2.5)] is the only authorized dosage form of VEKLURY for pediatric patients in this age group.Use in this age group is based on extrapolation of pediatric efficacy from adequate and well-controlled studies in adults [see Overall Safety Summary (6), Clinical Pharmacology (14), Clinical Trial Results and Supporting Data for EUA (18)]. Pediatric patients (older than 28 days) must have eGFR determined and full-term neonates (at least days to less than or equal to 28 days) must have serum creatinine determined before dosing and daily while receiving VEKLURY. Pediatric patients should be monitored for renal function and consideration given for stopping therapy in the setting of substantial decline [see Dosage and Administration (2.2, 2.4)]. 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.

PHARMACOKINETICS SECTION.

14.2 Pharmacokinetics. The pharmacokinetic (PK) properties of remdesivir and metabolites have been evaluated in adults in several Phase trials and are provided in Table 12. The multiple dose PK parameters of remdesivir and metabolites in healthy adults are provided in Table 13.Table 12 Pharmacokinetic Properties of Remdesivir and Metabolites (GS-441524 and GS-704277) in AdultsRemdesivirGS-441524GS-704277ND=not detectedAbsorptionTmax (h)Remdesivir administered as 30-minute IV infusion (Study GS-US-399-5505); range of median observed on Day and Day or 10. 0.67-0.681.51-2.000.75-0.75Distribution% bound to human plasma proteins88-93.6Range of protein binding for remdesivir from independent experiments show no evidence of concentration-dependent protein binding for remdesivir. 21Blood-to-plasma ratio0.68-1.01.190.56Eliminationt1/2 (h)Median (Study GS-US-399-4231). 1271.3Metabolism Metabolic pathway(s)CES1 (80%)Cathepsin (10%)CYP3A (10%)Not significantly metabolizedHINT1ExcretionMajor route of eliminationMetabolismGlomerular filtration and active tubular secretionMetabolism% of dose excreted in urineMean (Study GS-US-399-4231). 10492.9% of dose excreted in feces ND0.5NDTable 13 Multiple Dose PK ParametersRemdesivir administered as 30-minute IV infusion (Study GS-US-399-5505). of Remdesivir and Metabolites (GS-441524 and GS-704277) Following IV Administration of VEKLURY 100 mg to Healthy AdultsParameterMean (CV%)RemdesivirGS-441524GS-704277CV=Coefficient of Variation; ND=Not detectable (at 24 hours post-dose)Cmax (nanogram per mL)2229 (19.2)145 (19.3)246 (33.9)AUCtau (nanogramh per mL)1585 (16.6)2229 (18.4)462 (31.4)Ctrough (nanogram per mL)ND69.2 (18.2)ND. Specific PopulationsPharmacokinetic differences based on sex, race, and age have not been evaluated.The pharmacokinetics of VEKLURY in pediatric patients have not been evaluated.Using modeling and simulation, the recommended dosing regimen is expected to result in comparable steady-state plasma exposures of remdesivir and metabolites in pediatric patients weighing 3.5 kg to less than 40 kg or pediatric patients less than 12 years of age weighing at least 3.5 kg as observed in healthy adults.

PREGNANCY SECTION.

11.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to VEKLURY during pregnancy. Pregnant and recently pregnant individuals can go to https://covid-pr.pregistry.com to enroll or call 1-800-616-3791 to obtain information about the registry.. Risk SummaryAvailable data from published case reports and compassionate use of remdesivir in pregnant women are insufficient to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. 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 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 estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 to 4% and 15 to 20%, respectively.. Clinical Considerations. Disease-associated maternal and/or embryo-fetal riskCOVID-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.. Animal DataRemdesivir was administered via intravenous injection to pregnant rats and rabbits (up to 20 mg/kg/day) on Gestation Days through 17, and through 20, respectively, and also to rats from Gestation Day 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 times higher (rats and rabbits) than the exposure in humans at the RHD. In pre/postnatal development study, exposures to the predominant circulating metabolite of remdesivir (GS-441524) were similar to the human exposures at the RHD.

RENAL IMPAIRMENT SUBSECTION.

11.4 Renal Impairment. The pharmacokinetics of VEKLURY have not been evaluated in patients with renal impairment. Patients with eGFR greater than or equal to 30 mL/min have received VEKLURY for the treatment of COVID-19 with no dose adjustment of VEKLURY.Pediatric patients (greater than 28 days old) must have eGFR determined and full-term neonates (at least days to less than or equal to 28 days old) must have serum creatinine determined before dosing and while receiving VEKLURY. VEKLURY is not recommended in pediatric patients (at least 28 days old) with eGFR less than 30 mL/min or in full-term neonates (at least days and less than or equal to 28 days old) with serum creatinine greater than or equal to mg/dL [see Dosage and Administration (2.2, 2.4)].

SPL PATIENT PACKAGE INSERT SECTION.

Fact Sheet for Parents and CaregiversEmergency Use Authorization (EUA) of VEKLURY(R) (remdesivir) for Coronavirus Disease 2019 (COVID-19) for Children Weighing pounds (3.5 kg) to Less Than 88 pounds (40 kg) or for Children Less Than 12 Years of Age Weighing at least pounds (3.5 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 You are being given this Fact Sheet because your healthcare provider believes it is necessary to provide your child with VEKLURY for use for the treatment of coronavirus disease 2019 (COVID-19). The United States Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) for VEKLURY for use in children weighing pounds (3.5 kg) to less than 88 pounds (40 kg) or children less than 12 years of age weighing at least pounds (3.5 kg) with positive results of direct severe acute respiratory syndrome coronavirus (SARS-CoV-2) viral testing, 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.This Fact Sheet contains information to help you understand the risks and benefits of your child receiving VEKLURY.The FDA has issued an EUA to make VEKLURY available for this use during the COVID-19 pandemic (for more details about an EUA please see What is an Emergency Use Authorization at the end of this document). VEKLURY is not approved for use as treatment for COVID-19 for the pediatric population covered under this EUA. Read this Fact Sheet for information about VEKLURY. Talk to your healthcare provider about your options or if you have any questions. It is your choice for your child to receive VEKLURY or stop it at any time.What is COVID-19COVID-19 is caused by virus called coronavirus. You can get COVID-19 through close contact with another person who has the virus. COVID-19 illnesses have ranged from very mild to severe, including illness with no reported symptoms and illness resulting in death. While information so far suggests that most COVID-19 illness is mild, serious illness can happen and may cause some of childs other medical conditions to become worse. Older people and people of all ages with severe, long-lasting (chronic) medical conditions like heart disease, lung disease, and diabetes, for example, seem to be at higher risk of being hospitalized for COVID-19. What is VEKLURYVEKLURY is prescription medicine that is investigational for use for the treatment of COVID-19 in children weighing pounds (3.5 kg) to less than 88 pounds (40 kg) or children less than 12 years of age weighing at least pounds (3.5 kg) with positive results of direct SARS-CoV-2 viral testing, who are:hospitalized, or not hospitalized and have mild-to-moderate COVID-19, and are at high risk for progression to severe COVID-19, including hospitalization or death.VEKLURY is investigational for this use because it is still being studied and there is limited information about the safety and effectiveness of using VEKLURY for the treatment of COVID-19 in this population.VEKLURY is an FDA-approved prescription medicine used to treat COVID-19 in adults and children (12 years of age and older and weighing at least 88 pounds (40 kg), with positive results of direct SARS-CoV-2 viral testing, who are:hospitalized, or not hospitalized and have mild-to-moderate COVID-19, and at high risk for progression to severe COVID-19, including hospitalization or death.What should tell my healthcare provider before my child receives VEKLURYTell your healthcare provider about all of your childs medical conditions, including if your child: Has any allergies Has kidney or liver disease Has any serious illnessesTell your healthcare provider about all the medicines your child takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VEKLURY may interact with other medicines and may cause serious side effects.Especially tell your healthcare provider if your child is taking the medicines chloroquine phosphate or hydroxychloroquine sulfate.How will my child receive VEKLURYHospitalized: VEKLURY is given to your child through vein by intravenous (IV) infusion one time each day for up to 10 days. Your healthcare provider will decide how many doses your child needs. Not hospitalized: VEKLURY is given to your child through vein by intravenous (IV) infusion one time each day for days.Your healthcare provider will do certain blood tests before starting and during treatment with VEKLURY.Who should generally not receive VEKLURYYour child should not receive VEKLURY if your child is allergic to remdesivir or any of the ingredients in VEKLURY.What are the important possible side effects of VEKLURYPossible side effects of VEKLURY are: Allergic reactions. Allergic reactions can happen during and after infusion with VEKLURY. Your healthcare provider will monitor your child for signs and symptoms of allergic reactions during their infusion and for at least hour after their infusion. Tell your healthcare provider right away if your child gets any of the following signs and symptoms of allergic reactions:changes to heart rate fevershortness of breath or wheezing shiveringswelling of the lips, face, or throatrashnauseasweatingIncreases in levels of liver enzymes. Increases in liver enzymes are common in people who have received VEKLURY and may be sign of liver injury. Your healthcare provider will do blood tests to check your childs liver enzymes before receiving VEKLURY and as needed while receiving VEKLURY. Your healthcare provider may stop treatment with VEKLURY if your child develops liver problems.The most common side effect of VEKLURY is nausea. These are not all the possible side effects of VEKLURY. VEKLURY is still being studied so it is possible that all of the risks are not known at this time. What other treatment choices are thereLike VEKLURY, FDA may allow for the emergency use of other medicines to treat people with COVID-19. Go to https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization for information on the emergency use of other medicines that are not approved by the FDA to treat people with COVID-19. Your healthcare provider may talk with you about clinical trials your child may be eligible for.It is your choice for your child to be treated or not to be treated with VEKLURY. Should you decide for your child not to receive it, it will not change your childs standard medical care.How do report side effects with VEKLURYContact your healthcare provider if your child has any side effect that bothers them or does not go away.Report side effects to FDA MedWatch at www.fda.gov/medwatch or call 1-800-FDA-1088 and to Gilead by calling 1-800-445-3235.How can learn more about COVID-19Ask your healthcare provider.Visit https://www.cdc.gov/COVID19.Contact your local or state public health department.What is an Emergency Use Authorization (EUA)The United States FDA has made VEKLURY available under an emergency access mechanism called an Emergency Use Authorization (EUA) for the treatment of coronavirus disease 2019 (COVID-19) in children weighing pounds (3.5 kg) to less than 88 pounds (40 kg) or children less than 12 years of age weighing at least pounds (3.5 kg), with positive results of direct severe acute respiratory syndrome coronavirus (SARS-CoV-2) viral testing, 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.The EUA is supported by Secretary of Health and Human Service (HHS) declaration that circumstances exist to justify the emergency use of drugs and biological products during the COVID-19 pandemic.VEKLURY for the authorized use has not undergone the same type of review as an FDA-approved product. In issuing an EUA under the COVID-19 public health emergency, the FDA has determined, among other things, that based on the total amount of scientific evidence available including data from adequate and well controlled clinical trials, it is reasonable to believe that the product may be effective for diagnosing, treating, or preventing COVID-19, or serious or life threatening disease or condition caused by COVID-19; that the known and potential benefits of the product, when used to diagnose, treat, or prevent such disease or condition, outweigh the known and potential risks of such product; and that there are no adequate, approved, and available alternatives.All of these criteria must be met to allow for the product to be used in the treatment of the authorized patient population during the COVID-19 pandemic. The EUA for VEKLURY is in effect for the duration of the COVID-19 declaration justifying emergency use of VEKLURY, unless terminated or revoked (after which VEKLURY may no longer be used under the EUA).(C) 2022 Gilead Sciences, Inc. All rights reserved.Revised: 01/2022. 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.. 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.. hospitalized, or not hospitalized and have mild-to-moderate COVID-19, and at high risk for progression to severe COVID-19, including hospitalization or death.. Has any allergies. Has kidney or liver disease. Has any serious illnesses. Hospitalized: VEKLURY is given to your child through vein by intravenous (IV) infusion one time each day for up to 10 days. Your healthcare provider will decide how many doses your child needs. Not hospitalized: VEKLURY is given to your child through vein by intravenous (IV) infusion one time each day for days.. Your healthcare provider will do certain blood tests before starting and during treatment with VEKLURY.. Allergic reactions. Allergic reactions can happen during and after infusion with VEKLURY. Your healthcare provider will monitor your child for signs and symptoms of allergic reactions during their infusion and for at least hour after their infusion. Tell your healthcare provider right away if your child gets any of the following signs and symptoms of allergic reactions:changes to heart rate fevershortness of breath or wheezing shiveringswelling of the lips, face, or throatrashnauseasweating. changes to heart rate fever. shortness of breath or wheezing shivering. swelling of the lips, face, or throat. rash. nausea. sweating. Increases in levels of liver enzymes. Increases in liver enzymes are common in people who have received VEKLURY and may be sign of liver injury. Your healthcare provider will do blood tests to check your childs liver enzymes before receiving VEKLURY and as needed while receiving VEKLURY. Your healthcare provider may stop treatment with VEKLURY if your child develops liver problems.. Ask your healthcare provider.. Visit https://www.cdc.gov/COVID19.. Contact your local or state public health department.. 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.

SPL UNCLASSIFIED SECTION.

FACT SHEET FOR HEALTHCARE PROVIDERS EMERGENCY USE AUTHORIZATION (EUA) OF VEKLURY(R) (remdesivir) FOR THE TREATMENT OF CORONAVIRUS DISEASE 2019 (COVID-19) IN PEDIATRIC PATIENTS WEIGHING 3.5 KG TO LESS THAN 40 KG OR PEDIATRIC PATIENTS LESS THAN 12 YEARS OF AGE WEIGHING AT LEAST 3.5 KG, WITH POSITIVE RESULTS OF DIRECT SARS-CoV-2 VIRAL TESTING 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. The U.S. Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) to permit the emergency use of VEKLURY for the treatment of coronavirus disease 2019 (COVID-19) in pediatric patients weighing 3.5 kg to less than 40 kg or pediatric patients less than 12 years of age weighing at least 3.5 kg, with positive results of direct severe acute respiratory syndrome coronavirus (SARS-CoV-2) viral testing, who are:Hospitalized, orNot hospitalized and have mild-to-moderate COVID-19, and are at high risk for progression to severe COVID-19, including hospitalization or death. Refer to CDC websitehttps://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html. Healthcare providers should consider the benefit-risk for an individual patient. for additional details.VEKLURY has been authorized by FDA for the emergency uses described above. VEKLURY is not FDA-approved for these uses.VEKLURY is authorized only for the duration of the declaration that circumstances exist justifying the authorization of the emergency use of VEKLURY under section 564(b)(1) of the Act, 21 U.S.C. 360bbb-3(b)(1), unless the authorization is terminated or revoked sooner.. 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. Refer to CDC websitehttps://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html. Healthcare providers should consider the benefit-risk for an individual patient. for additional details.

STORAGE AND HANDLING SECTION.

Storage and HandlingDo not reuse or save reconstituted or diluted VEKLURY for future use. This product contains no preservative; therefore, partially used vials should be discarded [see Dosage and Administration (2.6)]. Store VEKLURY for injection, 100 mg, vials below 30C (below 86F) until required for use.After reconstitution, use vials immediately to prepare diluted solution. Dilute the reconstituted solution in 0.9% sodium chloride injection, USP within the same day as administration.The diluted VEKLURY solution in syringe should be used immediately.The diluted VEKLURY solution in the infusion bags can be stored up to 24 hours at room temperature (20C to 25C [68F to 77F]) or 48 hours at refrigerated temperature (2C to 8C [36F to 46F]) prior to administration.

USE IN SPECIFIC POPULATIONS SECTION.

11.USE IN SPECIFIC POPULATIONS. 11.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to VEKLURY during pregnancy. Pregnant and recently pregnant individuals can go to https://covid-pr.pregistry.com to enroll or call 1-800-616-3791 to obtain information about the registry.. Risk SummaryAvailable data from published case reports and compassionate use of remdesivir in pregnant women are insufficient to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. 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 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 estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 to 4% and 15 to 20%, respectively.. Clinical Considerations. Disease-associated maternal and/or embryo-fetal riskCOVID-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.. Animal DataRemdesivir was administered via intravenous injection to pregnant rats and rabbits (up to 20 mg/kg/day) on Gestation Days through 17, and through 20, respectively, and also to rats from Gestation Day 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 times higher (rats and rabbits) than the exposure in humans at the RHD. In pre/postnatal development study, exposures to the predominant circulating metabolite of remdesivir (GS-441524) were similar to the human exposures at the RHD.. 11.2 Lactation. Risk SummaryThere are no available data on the presence of remdesivir in human milk, the effects on the breastfed infant, or the effects 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. The developmental and health benefits of breastfeeding should be considered along with the mothers 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.. Animal DataRemdesivir 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 to Lactation Day 20. Exposures in nursing pups were approximately 1% that of maternal exposure on Lactation Day 10.. 11.3 Pediatric Use. The safety and effectiveness of VEKLURY have not been established in pediatric patients weighing 3.5 kg to less than 40 kg or pediatric patients less than 12 years of age weighing at least 3.5 kg, with positive results of direct SARS-CoV-2 viral testing, and who are:Hospitalized, orNot hospitalized and have mild-to-moderate COVID-19, and are at high risk for progression to severe COVID-19, including hospitalization or death.VEKLURY for injection (supplied as 100 mg lyophilized powder in vial) [see Dosage and Administration (2.2, 2.3, 2.4, 2.5)] is the only authorized dosage form of VEKLURY for pediatric patients in this age group.Use in this age group is based on extrapolation of pediatric efficacy from adequate and well-controlled studies in adults [see Overall Safety Summary (6), Clinical Pharmacology (14), Clinical Trial Results and Supporting Data for EUA (18)]. Pediatric patients (older than 28 days) must have eGFR determined and full-term neonates (at least days to less than or equal to 28 days) must have serum creatinine determined before dosing and daily while receiving VEKLURY. Pediatric patients should be monitored for renal function and consideration given for stopping therapy in the setting of substantial decline [see Dosage and Administration (2.2, 2.4)]. 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.. 11.4 Renal Impairment. The pharmacokinetics of VEKLURY have not been evaluated in patients with renal impairment. Patients with eGFR greater than or equal to 30 mL/min have received VEKLURY for the treatment of COVID-19 with no dose adjustment of VEKLURY.Pediatric patients (greater than 28 days old) must have eGFR determined and full-term neonates (at least days to less than or equal to 28 days old) must have serum creatinine determined before dosing and while receiving VEKLURY. VEKLURY is not recommended in pediatric patients (at least 28 days old) with eGFR less than 30 mL/min or in full-term neonates (at least days and less than or equal to 28 days old) with serum creatinine greater than or equal to mg/dL [see Dosage and Administration (2.2, 2.4)]. 11.5 Hepatic Impairment. The pharmacokinetics of VEKLURY have not been evaluated in patients with hepatic impairment [see Warnings and Precautions (5.2)]. Perform hepatic laboratory testing in all patients before starting VEKLURY and during treatment as clinically appropriate [see Dosage and Administration (2.2)].

WARNINGS AND PRECAUTIONS SECTION.

5.WARNINGS AND PRECAUTIONS. There are limited clinical data available for VEKLURY in pediatric patients weighing 3.5 kg to less than 40 kg or pediatric patients less than 12 years of age weighing at least 3.5 kg. Serious and unexpected adverse events may occur that have not been previously reported with VEKLURY use.. 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 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 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)].. 5.2Increased 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. Because transaminase elevations have been reported as clinical feature of COVID-19, including in patients receiving placebo in clinical trials of VEKLURY, 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.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.. 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 potential antagonistic effect of chloroquine on the intracellular metabolic activation and antiviral activity of VEKLURY [see Drug Interactions (10), Microbiology/Resistance Information (15)].