Veklury^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Gilead Sciences International, Ltd. (United Kingdom)

Manufactured By

Jubilant HollisterStier, LLC (USA)

Packaging and Quality Control Release

GILEAD SCIENCES IRELAND, UC (Ireland)

Or

PHARMSTANDARD-LEKSREDSTVA, JSC (Russia)

ATC Code

J05AB16 (Remdesivir)

Active Substance

Remdesivir (Rec.INN registered by WHO)

Dosage Form

Veklury®

Lyophilisate for preparation of concentrate for preparation of solution for infusion, 100 mg: fl. 1 pc.

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of concentrate for preparation of solution for infusion in the form of a lyophilized powder or compacted mass from white or almost white to yellow.

Excipients: sulfobutyl ether beta-cyclodextrin sodium – 3000 mg, hydrochloric acid or sodium hydroxide – q.s. to target pH.

* The amount of active and auxiliary substances is indicated without a 5% overfill.

100 mg – vial of transparent colorless type I glass with a capacity of 30 ml, sealed with a rubber stopper, crimped with an aluminum cap with a flip-off plastic cap (1) – cardboard box.
100 mg – vial of transparent colorless type I glass with a capacity of 30 ml, sealed with a rubber stopper, crimped with an aluminum cap with a flip-off plastic cap (1) – cardboard box with first opening control*.

* During secondary packaging of the drug at PHARMSTANDARD-LEKSREDSTVA, JSC.

Clinical-Pharmacological Group

Antiviral drug

Pharmacotherapeutic Group

Systemic antiviral agents; direct-acting antiviral agents; nucleosides and nucleotides, excluding reverse transcriptase inhibitors

Pharmacological Action

Antiviral agent. Remdesivir is an adenosine nucleotide prodrug that is metabolized in body cells to form the pharmacologically active nucleoside triphosphate metabolite. Remdesivir triphosphate acts as an ATP analog and competes with the natural ATP substrate for incorporation into nascent RNA chains by the SARS-CoV-2 virus RNA-dependent RNA polymerase, resulting in delayed chain termination during viral RNA replication.

Remdesivir exhibited antiviral activity in vitro against a clinical isolate of the SARS-CoV-2 virus in primary human airway epithelial cells with a half-maximal effective concentration (EC₅₀) of 9.9 nM at 48 hours after treatment initiation. The EC₅₀ values of remdesivir against SARS-CoV-2 in Vero cells were 137 nM at 24 hours and 750 nM at 48 hours after treatment initiation. Chloroquine phosphate exerted a dose-dependent antagonistic effect on the antiviral activity of remdesivir when the two drugs were co-incubated at clinically relevant concentrations in HEp-2 cells infected with respiratory syncytial virus. Higher EC₅₀ values of remdesivir were observed with increasing chloroquine phosphate concentration. Increasing the concentration of chloroquine phosphate reduced the formation of remdesivir triphosphate in normal human bronchial epithelial cells.

There are no clinical data on the development of resistance of the SARS-CoV-2 virus to remdesivir.

Medicinal products containing Remdesivir are registered under the procedure for registration of medicinal products intended for use in the context of a threat of occurrence, occurrence and liquidation of emergencies. The instructions are prepared based on a limited amount of clinical data on the use of the drugs and will be supplemented as new data become available. The use of drugs containing Remdesivir is possible only in inpatient healthcare settings.

Pharmacokinetics

There are no pharmacokinetic data in patients with COVID-19.

Pharmacokinetic parameters of remdesivir and its predominant circulating metabolite GS-441524 were evaluated in healthy adult volunteers. After IV administration of remdesivir to adults, C_max in plasma was observed at the end of the infusion regardless of dose and then decreased rapidly with a T_1/2 of about 1 hour. C_max of the metabolite GS-441524 in plasma were observed 1.5-2.0 hours after the start of a 30-minute infusion. The binding of remdesivir to human plasma proteins is about 88%. The binding of the metabolite GS-441524 to human plasma proteins is low – 2%. After a single administration of 150 mg of ¹⁴C-labeled remdesivir to healthy volunteers, the ratio of ¹⁴C-radioactivity in blood to plasma was about 0.68 at 15 minutes after the start of infusion, increased over time, reaching a ratio of 1.0 at 5 hours, indicating differential distribution of remdesivir and its metabolites in plasma or cellular components of blood.

Remdesivir is extensively metabolized to the pharmacologically active nucleoside triphosphate analog GS-443902 (formed intracellularly). The metabolic activation pathway involves hydrolysis by esterases, which leads to the formation of the intermediate metabolite GS-704277. Cleavage of the phosphoramidate followed by phosphorylation leads to the formation of the active triphosphate GS-443902. Dephosphorylation of all phosphorylated metabolites may lead to the formation of the nucleoside metabolite GS-441524, which may not be efficiently re-phosphorylated. A human mass balance study also indicates the presence of an unidentified major metabolite (M27) in plasma.

After a single IV administration of 150 mg of ¹⁴C-labeled remdesivir, the mean total recovery of the dose was 92%, with renal and intestinal excretion accounting for about 74% and 18%, respectively. The main part of the remdesivir dose excreted in the urine consisted of the metabolite GS-441524 (49%) and 10% was Remdesivir. These data show that renal clearance is the main route of elimination for the metabolite GS-441524. The median terminal T_1/2 of remdesivir and the metabolite GS-441524 was approximately 1 hour and 27 hours, respectively.

Special patient groups

Sex, race and age. Pharmacokinetic differences by sex, race, and age have not been evaluated.

Children. The pharmacokinetics of the drug in pediatric patients is unknown.

Renal impairment. Evaluation of the pharmacokinetics of remdesivir and the metabolite GS-441524 in patients with renal impairment has not been conducted. Remdesivir is largely not excreted unchanged in the urine, but its main metabolite GS-441524 is excreted by the kidneys, and the plasma levels of metabolites may theoretically increase in patients with impaired renal function. The excipient sulfobutyl ether beta-cyclodextrin sodium is excreted by the kidneys and accumulates in patients with reduced renal function. The drug Veklury^® should not be prescribed to patients with an estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m².

Hepatic impairment. Evaluation of the pharmacokinetics of remdesivir and the metabolite GS-441524 in patients with hepatic impairment has not been conducted. The role of the liver in the metabolism of remdesivir is unknown.

Drug interactions

The potential for interaction of remdesivir regarding inhibition of the hydrolytic pathway (esterase) has not been studied. The possibility of clinically significant interaction is unknown.

Remdesivir inhibited the CYP3A4 isoenzyme in vitro (see section “Drug Interactions”). Remdesivir or its metabolites GS-441524 and GS-704277 at physiologically active concentrations (at steady state) did not inhibit the CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2D6 isoenzymes in vitro. However, Remdesivir may temporarily inhibit the CYP2B6, CYP2C8, CYP2C9 and CYP2D6 isoenzymes on the first day of administration. The clinical significance of this inhibition has not been studied. The possibility of time-dependent inhibition of CYP450 isoenzymes by remdesivir has not been studied.

Remdesivir induced the CYP1A2 isoenzyme and possibly CYP3A4, but not CYP2B6 in vitro (see section “Drug Interactions”).

In vitro data indicate no clinically significant inhibition of uridine diphosphate glucuronosyltransferase UGT1A1, UGT1A3; UGT1A4, UGT1A6, UGT1A9 or UGT2B7 by remdesivir or its metabolites GS-441524 and GS-704277. Remdesivir inhibited the organic anion transporting polypeptides OATP1B1 and OATP1B3 in vitro (see section “Drug Interactions”). There are no data on inhibition of OAT1, OAT3 or OCT2 by remdesivir.

Remdesivir and its metabolites at physiologically active concentrations did not inhibit P-glycoprotein and breast cancer resistance protein (BCRP) in vitro.

Indications

Treatment of novel coronavirus infection (COVID-19) in adults with pneumonia requiring supplemental oxygen.

ICD codes

Dosage Regimen

For IV administration.

It is prohibited to administer drugs containing Remdesivir intramuscularly.

The use of remdesivir is permitted only in medical institutions where patients can be under close supervision.

The recommended dose for adults is 200 mg of remdesivir as a single IV dose on the first day of treatment, followed by intravenous administration of 100 mg of remdesivir once daily, starting from the second day.

Adverse Reactions

From the immune system rarely – hypersensitivity.

From the nervous system often – headache.

From the digestive system often – nausea.

From the liver and biliary tract very often – increased activity of hepatic transaminases; frequency unknown – hepatic failure.

From the skin and subcutaneous tissues: often – rash.

From the kidneys and urinary tract: frequency unknown – acute renal failure.

General disorders: rarely – infusion reactions (arterial hypotension, nausea, vomiting, sweating, tremor).

Contraindications

Hypersensitivity to remdesivir; eGFR<30 ml/min/1.73 m²; ALT ≥5 ULN; pregnancy, breastfeeding period; children under 18 years of age.

With caution

Elderly patients over 65 years of age.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Contraindicated for use when ALT ≥5 ULN.

Given the possible development of hepatic failure, it is necessary to assess liver function daily before and during remdesivir administration, as well as carefully monitor the patient’s condition. If the patient has symptoms of hepatic failure or abnormalities in laboratory parameters (changes in INR, conjugated bilirubin or ALP) together with an increase in ALT, then treatment with remdesivir should be discontinued.

Use in Renal Impairment

Contraindicated for use when eGFR<30 ml/min/1.73 m².

Given the possible development of acute renal failure, it is necessary to assess renal function daily before and during remdesivir administration, as well as carefully monitor the patient’s condition.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age

Geriatric Use

In elderly patients, Remdesivir should be used with caution and under constant clinical supervision.

Special Precautions

Use is possible only in inpatient healthcare settings.

If adverse effects occur, it is necessary to report them in the established manner for pharmacovigilance measures.

Before starting the use of drugs containing Remdesivir, it is necessary to provide the patient with written information about the effectiveness of the drug and the risks associated with its use (including the risk of effects on the embryo and fetus) and obtain written consent for the use of the drug.

Due to the limited clinical experience with remdesivir and the possibility of developing adverse reactions (including serious adverse reactions) that have not been previously reported, the condition of patients should be carefully monitored through clinical observation and monitoring of laboratory parameters (white blood cell count, leukocyte formula, hemoglobin level, hematocrit, platelet count, creatinine concentration, blood glucose, total bilirubin, ALT, AST, ALP, prothrombin time, etc.) during treatment with remdesivir. Laboratory test data should be evaluated on a daily basis. If any adverse reactions are detected during treatment, administration of the drug should be continued only if the established therapeutic benefit outweighs the risks.

Given the possible development of acute renal failure, it is necessary to assess renal function daily before and during remdesivir administration, as well as carefully monitor the patient’s condition.

Given the possible development of hepatic failure, it is necessary to assess liver function daily before and during remdesivir administration, as well as carefully monitor the patient’s condition. If the patient has symptoms of hepatic failure or abnormalities in laboratory parameters (changes in INR, conjugated bilirubin or ALP) together with an increase in ALT, then treatment with remdesivir should be discontinued.

Given the possible development of infusion reactions (arterial hypotension, nausea, vomiting, sweating, tremor), it is necessary to carefully monitor the patient’s condition and immediately discontinue the use of remdesivir and take necessary measures if any abnormalities are observed.

In accordance with the majority of cases of remdesivir use in clinical studies to date, this agent should generally be used for the treatment of severe COVID-19 infection in patients whose blood oxygen saturation is ≤94% (while breathing room air) and who require supplemental oxygen, also when undergoing ECMO or mechanical ventilation.

In elderly patients, Remdesivir should be used with caution and under constant clinical supervision. In general, elderly patients may have reduced physiological functions, a higher frequency of concomitant diseases or previous diseases.

Drug Interactions

Studies to evaluate interactions with remdesivir have not been conducted. The overall interaction potential is currently unknown; patients should be closely monitored throughout the period of remdesivir use.

Concomitant use of remdesivir with chloroquine phosphate or hydroxychloroquine sulfate is not recommended due to the antagonism observed in vitro. There is a risk of reduced antiviral activity when remdesivir is co-administered with chloroquine or hydroxychloroquine.

The interaction of remdesivir with inhibitors/inducers of the hydrolytic pathway (esterase) or with CYP2C8, CYP2D6 and CYP3A4 isoenzymes has not been studied. The likelihood of clinically significant interaction is unknown. Strong inhibitors of these isoenzymes may lead to increased exposure to remdesivir. The use of strong inducers (e.g., rifampicin) may reduce the plasma concentration of remdesivir, so it is not recommended.

Dexamethasone is reported to be a moderate inducer of the CYP3A isoenzyme and P-glycoprotein. Induction is dose-dependent and occurs after multiple doses. Dexamethasone is unlikely to have a clinically significant effect on Remdesivir, since Remdesivir has a moderately high hepatic extraction ratio and is used for a short period of time for the treatment of COVID-19.

Remdesivir may temporarily increase the plasma concentration of drugs that are substrates of the CYP3A isoenzyme or OATP 1B1/1B3. Data are lacking, but it is assumed that medicinal products that are substrates of the CYP3A4 isoenzyme or OATP 1B1/1B3 should be administered at least 2 hours after remdesivir administration. Remdesivir induced the CYP1A2 isoenzyme and possibly CYP3A in vitro. Concomitant use of remdesivir with drugs that are substrates of the CYP1A2 or CYP3A4 isoenzymes with a narrow therapeutic index may lead to loss of their efficacy.

Dexamethasone is a substrate of the CYP3A4 isoenzyme, and although Remdesivir inhibits the CYP3A4 isoenzyme, due to the rapid elimination of remdesivir after IV administration, it is unlikely to have a significant effect on the concentration of dexamethasone.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.