Remdesivir

Remdesivir is used for: Coronavirus Disease 2019 (COVID-19)

Coronavirus Disease 2019 (COVID-19) Injection Indicated for adults and pediatric patients aged >12 years who weigh >40 kg for treatment of COVID-19 requiring hospitalization Day 1 loading dose: 200 mg IV infused over 30-120 min, THEN Day 2 and thereafter: 100 mg IV qDay Treatment duration Not requiring invasive mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO): 5 days; if clinical improvement not demonstrated, treatment may be extended up to 10 days total Requires invasive mechanical ventilation and/or ECMO: 10 days Hepatic impairment Not evaluated; unknown if dosage adjustment required Use only if potential benefit outweighs risk

Injection, lyophilized powder for reconstitution 100mg/vial Note: Use lyophilized powder to prepare dose for children aged <12 years or weight <40 kg according to EUA for this group COVID-19 in Younger Children (Investigational) Emergency Use Authorization (EUA) issued for hospitalized pediatric patients weighing 3.5 kg to <40 kg or children aged <12 years who weigh at least 3.5 kg Weight 3.5-40 kg Day 1 loading dose: 5 mg/kg mg IV infused over 30-120 min, THEN Day 2 and thereafter: 2.5 mg/kg IV qDay Age <12 years and weight 40 kg or more Day 1 loading dose: 200 mg IV infused over 30-120 min, THEN Day 2 and thereafter: 100 mg IV qDay Treatment duration Not requiring invasive mechanical ventilation and/or ECMO: 5 days; if clinical improvement not demonstrated, treatment may be extended up to 10 days total Requires invasive mechanical ventilation and/or ECMO: 10 days

Renal impairment Pharmacokinetics have not been evaluated in patients with renal impairment Use in patients with renal impairment are based on potential risk and potential benefit considerations eGFR >30 mL/min: No dose adjustment eGFR <30 mL/min: Not recommended unless the potential benefit outweighs potential risk

IV Preparation Pediatric patients weighing 3.5 kg to <40 kg: Prepare dose with only lyophilized powder product Do not use concentrated solution 100 mg/20 mL (5 mg/mL) for pediatric patients <40 kg or patients with eGFR <30 mL/min owing to the higher amount of sulfobutylether-beta-cyclodextrin sodium salt (SBECD) present and resulting higher tonicity compared with the lyophilized powder formulation Reconstitution of lyophilized powder Aseptically reconstitute lyophilized powder by adding 19 mL of sterile water for injection (SWI) Discard vial if a vacuum does not pull the SWI into the vial Immediately shake vial for 30 seconds Allow vial contents to settle for 2-3 minutes; resulting solution should appear clear If not completely dissolved, shake vial again for 30 seconds and allow the contents to settle for 2-3 minutes; repeat this procedure as necessary until the contents of the vial are completely dissolved Following reconstitution, resulting concentration/vial is 100 mg/20 mL (5 mg/mL) Inspected visually for particulate matter and discoloration Use reconstituted product immediately to prepare diluted solution Further dilution required Adults and pediatric patients weighing ?40 kg Dilute further by adding reconstituted solution or concentrated solution to 0.9% NaCl infusion bag (100-mL or 250-mL volume) to reconstituted solution or concentrated solution Withdraw 20 mL (for 100-mg dose) or 40 mL (for 200-mg dose) of saline from the IV bag using an appropriately sized syringe and needle; discard the saline withdrawn from bag Withdraw required dosage volume of reconstituted or concentrated remdesivir solution from vial; discard any unused portion remaining in the vial Transfer required dosage volume to selected infusion bag Gently invert the bag 20 times to mix the solution in the bag; do not shake Pediatric patients weighing <40 kg Prepare an IV bag or infusion syringe of 0.9% NaCl with volume equal to the total infusion volume minus the volume of reconstituted remdesivir solution to achieve a 1.25-mg/mL solution Gently invert IV bag or infusion syringe 20 times to mix; do not shake IV Administration Do not administer simultaneously in IV line with any other medication Infuse IV over 30-120 minutes Also see prescribing information for infusion rate charts Rate of infusion may be adjusted based on total volume infused

Hypersensitivity to drug or any ingredient

Hypersensitivity, including infusion-related reactions Hypersensitivity, including infusion-related reactions observed during and following administration Signs and symptoms may include hypotension, hypertension, tachycardia, bradycardia, hypoxia, fever, dyspnea, wheezing, angioedema, rash, nausea, diaphoresis, and shivering Consider slowing infusion rate (up to 120 minutes) to potentially prevent these signs and symptoms If clinically significant reaction occurs, discontinue immediately and implement appropriate treatment Hepatic transaminases Increased hepatic transaminases reported in healthy volunteers and patients with COVID-19 Because transaminase elevations are reported as a clinical feature of COVID-19, and the incidence in clinical trials was similar in patients receiving placebo versus remdesivir, it is challenging to discern the contribution of remdesivir to transaminase elevations in patients with COVID-19 ALT levels increase to >10x ULN: Consider discontinuing remdesivir ALT elevation accompanied by signs or symptoms of liver inflammation: Discontinue remdesivir

Pregnancy Available data from published case reports and compassionate use of remdesivir in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes Animal studies In nonclinical reproductive toxicity studies, remdesivir demonstrated no adverse effect on embryofetal development when administered to pregnant animals at systemic exposures of the predominant circulating metabolite of remdesivir (GS-441524) that were 4 times (rats and rabbits) the exposure in humans at the recommended human dose Clinical considerations Pregnant women hospitalized with COVID-19 are at risk for serious morbidity and mortality Lactation Data are not available regarding the presence of remdesivir in human milk, effects on breastfed infants, or effects on milk production Animal studies Remdesivir and metabolites detected in plasma of nursing rat pups, likely owing to presence of remdesivir in milk following daily IV remdesivir to pregnant rats from gestation day 6 to lactation day 20 Exposures in nursing pups were ~1% that of maternal exposure on lactation day 10 Lactation Data are not available regarding the presence of remdesivir in human milk, effects on breastfed infants, or effects on milk production 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

Drug-drug interaction trials of remdesivir and other concomitant medications have not been conducted in humans In vitro, remdesivir is a substrate of CYP2C8, CYP2D6, and CYP3A4 enzymes; and a substrate of OAPT1B1 and P-glycoprotein transporters In vitro, remdesivir is an inhibitor of CYP3A4, OATP1B1, OATP1B3, BSEP, MRP4, and NTCP Clinical relevance of these in vitro assessments has not been established Coadministration with chloroquine or hydroxychloroquine Coadministration of remdesivir is not recommended with chloroquine or hydroxychloroquine Based on in vitro data, chloroquine demonstrated an antagonistic effect on the intracellular metabolic activation and antiviral activity of remdesivir

Side effects of Remdesivir : >10% eGFR decreased* (18%) Decreased CrCl* (calculated by Cockcroft-Gault) (10-18%) Creatinine increased* (5-15%) Hemoglobin decreased* (6-15%) Glucose increased* (11-12%) Lymphocytes decreased* (11%) 1-10% Prothrombin time increased (9%) ALT increased* (3-8%) AST increased* (6-7%) Nausea (3-5%) Bilirubin increased* (2%) Hypersensitivity reactions (<2%) Generalized seizure (<2%) Rash (<2%)

Inhibits SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), which is essential for viral replication Adenosine nucleotide prodrug that distributes into cells, where it is metabolized to form the pharmacologically active nucleoside triphosphate metabolite Metabolism of remdesivir to remdesivir triphosphate (RDV-TP) demonstrated in multiple cell types RDV-TP acts as an analog of adenosine triphosphate (ATP) and competes with 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 during replication of the viral RNA Remdesivir triphosphate is a weak inhibitor of mammalian DNA and RNA polymerases with low potential for mitochondrial toxicity