Veklury Lyophilised 100 Mg/20 ml/5 mg Injection

VEKLURY is indicated for the treatment of coronavirus disease 2019 (COVID-19/ SARS- CoV-2) in adult patients with pneumonia requiring supplemental oxygen (see section 5.1).

Use of VEKLURY is confined to healthcare facilities in which patients can be monitored closely (see section 4.4).

Posology

The recommended dosage of VEKLURY is:

• Day 1 u2013 single loading dose of remdesivir 200 mg given by intravenous infusion
• Day 2 onwards u2013 100 mg given once daily by intravenous infusion.

The total duration of treatment should be at least 5 days and not more than 10 days.

Special populations

Elderly

No dose adjustment of VEKLURY is required in patients over the age of 65 years (see sections 5.1 and 5.2).

Renal impairment

No dose adjustment of remdesivir is required in patients with renal impairment, including those on dialysis. However, safety data in patients with severe renal impairment and end stage renal disease (ESRD) are limited (see section 4.4) and based on a 5-day treatment duration. The timing of administration of remdesivir is without regard to dialysis (see section 5.2).

Hepatic impairment

No dose adjustment of VEKLURY is required in patients with mild, moderate and severe hepatic impairment (Child-Pugh Class A, B, C) (see section 5.2). However, safety data in patients with severe hepatic impairment are limited and only based on a single 100 mg dose administration.

Paediatric population

The safety and efficacy of VEKLURY in children under the age of 18 years have not yet been established. No data are available.

Method of administration

For intravenous use. VEKLURY is for administration by intravenous infusion after reconstitution and further dilution. It must not be given as an intramuscular (IM) injection. For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

Table 1: Recommended rate of infusion u2013 for reconstituted and diluted remdesivir powder for concentrate for solution for infusion

Hypersensitivity to remdesivir or to any of the excipients listed in section 6.1.

Hypersensitivity including infusion-related and anaphylactic reactions

Hypersensitivity reactions including infusion-related and anaphylactic reactions have been observed during and following administration of VEKLURY. Signs and symptoms may include hypotension, hypertension, tachycardia, bradycardia, hypoxia, fever, dyspnoea, wheezing, angioedema, rash, nausea, vomiting, diaphoresis, and shivering. Slower infusion rates, with a maximum infusion time of up to 120 minutes, can be considered to potentially prevent these signs and symptoms. Monitor patients for hypersensitivity reactions during and following administration of VEKLURY. If signs and symptoms of a clinically significant hypersensitivity reaction occur, immediately discontinue administration of VEKLURY and initiate appropriate treatment.

Renal impairment

As clinically appropriate, patients should have eGFR determined prior to starting remdesivir and while receiving it. Safety data from patients with severe renal impairment and ESRD reported during Study GS-US-540-5912 were comparable to the known safety profile of VEKLURY. However, there are limited safety data in this patient population. Therefore, taking the significant higher exposure of the metabolite GS-441524 into account, patients with severe renal impairment and ESRD should be closely monitored for adverse events during treatment with VEKLURY (see section 5.2).

Excipients

This medicinal product contains 212 mg sodium per 100 mg dose equivalent to 10.6 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Risk of reduced antiviral activity when coadministered with chloroquine or hydroxychloroquine

Coadministration of VEKLURY and chloroquine phosphate or hydroxychloroquine sulphate is not recommended based on in vitro data demonstrating an antagonistic effect of chloroquine on the intracellular metabolic activation and antiviral activity of VEKLURY (see sections 4.5 and 5.1) Concomitant use of remdesivir and dexamethasone, interferon and other medicines have not been investigated.

Due to antagonism observed in vitro, concomitant use of remdesivir with chloroquine phosphate or hydroxychloroquine sulphate is not recommended.

Effects of other medicinal products on VEKLURY

In vitro, remdesivir is a substrate for esterases in plasma and tissue, drug metabolizing enzyme CYP3A4 and is a substrate for Organic Anion Transporting Polypeptides 1B1 (OATP1B1) and P-glycoprotein (P-gp) transporters. GS-704277 (a metabolite of remdesivir) is a substrate for OATP1B1 and OATP1B3.

A drug-drug interaction study was conducted with remdesivir. Table 2 summarises the pharmacokinetic effects of studied drugs on remdesivir and metabolites GS-704277 and GS-441524.

Table 2: Effect of other drugs on remdesivir and metabolites GS-704277 and GS-441524

NOTE: Interaction study conducted in healthy volunteers.

Effects of VEKLURY on other medicinal products

In vitro, VEKLURY is an inhibitor of CYP3A4, UGT1A1, MATE1, OAT3, OCT1, OATP1B1 and OATP1B3. Until respective clinical data become available, the coadministration of sensitive substrates of these enzymes and/or transporters should be considered with caution. VEKLURY induced CYP1A2 and potentially CYP3A in vitro. Co-administration of VEKLURY with CYP1A2 or CYP3A4 substrates with narrow therapeutic index may lead to loss of their efficacy. Dexamethasone is a substrate of CYP3A4 and although VEKLURY inhibits CYP3A4, due to VEKLURY's rapid clearance after IV administration, remdesivir is unlikely to have a significant effect on dexamethasone exposure.

Pregnancy

There is a limited amount of data from the use of VEKLURY in pregnant women (less than 300- pregnancy outcomes). Most of the exposures occurred in the second, third or an unknown trimester and available data do not indicate any risk.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at exposures of the major metabolite of remdesivir that were around human therapeutic exposures (see section 5.3). Due to very limited experience, remdesivir should not be used during first trimester in pregnancy. Use in the second and third trimester of pregnancy may be considered. Use of effective contraception during treatment should be considered in women of child-bearing potential.

Breast-feeding

Remdesivir and its major metabolite are excreted into breast milk in very small amounts after intravenous administration. Because of the potential for viral transmission to SARS-CoV-2-negative infants and the limited clinical experience, mothers receiving VEKLURY should not breastfeed their infants.

Fertility

No human data on the effect of remdesivir on fertility are available. In male rats, there was no effect on mating or fertility with VEKLURY treatment. In female rats, however, an impairment of fertility was observed (see section 5.3). The relevance for humans is unknown.

Patients receiving VEKURY must not drive or use machines until all side effects of the medicine and the symptoms of SARS-CoV-2 infection, have resolved.

Summary of the safety profile

The most common adverse reaction in healthy volunteers is increased transaminases (14 %). The most common adverse reaction in patients with COVID-19 is nausea (4 %).

Tabulated summary of adverse reactions

The adverse reactions in Table 3 are listed below by system organ class and frequency. Frequencies are defined as follows: Very common (u22651/10); common (u22651/100 to <1/10); uncommon (u22651/1,000 to <1/100); rare (u22651/10,000 to <1/1,000). Not known (cannot be estimated from the available data)

Table 3: Tabulated list of adverse reactions

*Reported in post-marketing, usually normalised within 4 days following last VEKLURY administration without additional intervention

Description of selected adverse reactions

Transaminases increased

In healthy volunteer studies, increases in alanine transaminase (ALT), aspartate aminotransferase (AST) or both in subjects who received VEKLURY were 1,25 to 2,5 times the upper limit of normal (ULN) (10 %) or 2,5 to 5 times ULN (4 %). In clinical studies of patients with COVID-19, the incidence of increased transaminases was similar in patients treated with VEKLURY compared to placebo or standard of care.

Prothrombin time prolonged

In a clinical study (NIAID ACTT-1) of patients with COVID-19, the incidence of prolonged prothrombin time or INR (predominantly less than 2 times ULN) was higher in subjects who received remdesivir compared to placebo, with no difference observed in the incidence of bleeding events between the two groups. In Study GS-US-540-9012, the incidence of increased prothrombin time or INR was similar in patients treated with remdesivir compared to placebo.

Patients with renal impairment

In Study GS-US-540-5912, 163 hospitalised patients with confirmed COVID-19 and acute kidney injury, chronic kidney disease or ESRD on haemodialysis received remdesivir for up to 5 days (see sections 4.4 and 5.2). Safety data from these patients were comparable to the known safety profile of remdesivir. In this same study, the incidence of increased prothrombin time or INR was higher in patients treated with remdesivir compared to placebo, with no difference observed in the incidence of bleeding events between the two groups (see section 5.1).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-ucm.org) found on SAHPRA website.

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.