VEKLURY Powder for concentrate for solution for infusion Ref.[27515] Active ingredients: Remdesivir

Hypersensitivity including infusion-related and anaphylactic reactions

Hypersensitivity reactions including infusion-related and anaphylactic reactions have been observed during and following administration of remdesivir. 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 remdesivir as clinically appropriate. Patients receiving remdesivir in an outpatient setting should be monitored after administration according to local medical practice. If signs and symptoms of a clinically significant hypersensitivity reaction occur, immediately discontinue administration of remdesivir 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 remdesivir. 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 remdesivir (see section 5.2).

Risk of reduced antiviral activity when coadministered with chloroquine or hydroxychloroquine

Coadministration of remdesivir 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 remdesivir (see sections 4.5 and 5.1).

Immunocompromised patients

It is unclear if the treatment duration of three days is sufficient to clear the virus in immunocompromised patients, in whom prolonged viral shedding occurs. There is a potential risk of resistance development. Only limited data are available.

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.

Pharmacodynamic interactions

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

Pharmacokinetic interactions

Effects of other medicinal products on remdesivir

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 5 summarises the pharmacokinetic effects of studied drugs on remdesivir and metabolites GS-704277 and GS-441524.

Table 5. Effect of other drugs on remdesivir and metabolites GS-704277 and GS-441524:

NOTE: Interaction study conducted in healthy volunteers.

Effects of remdesivir on other medicinal products

In vitro, remdesivir 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. Remdesivir induced CYP1A2 and potentially CYP3A in vitro. Co-administration of remdesivir with CYP1A2 or CYP3A4 substrates with narrow therapeutic index may lead to loss of their efficacy.

Dexamethasone is a substrate of CYP3A4 and although remdesivir inhibits CYP3A4, due to remdesivir’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 remdesivir 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 unless the clinical condition of the woman requires treatment with it. 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. No clinical effect on the infant is expected due to low breast milk transfer and poor oral bioavailability.

As the clinical experience is limited, a decision about breast-feeding during treatment should be made after a careful individual benefit-risk assessment.

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 remdesivir treatment. In female rats, however, an impairment of fertility was observed (see section 5.3). The relevance for humans is unknown.

Remdesivir is predicted to have no or negligible influence on these abilities.

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 6 are listed below by system organ class and frequency. Frequencies are defined as follows: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); not known (cannot be estimated from the available data).

Table 6. Tabulated list of adverse reactions:

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

Description of selected adverse reactions

Transaminases Increased

In healthy volunteer studies, increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST) or both in subjects who received remdesivir 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 remdesivir 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).

Paediatric population

The safety assessment of remdesivir in children 4 weeks of age and older and weighing at least 3 kg with COVID-19 is based on data from a Phase 2/3, open-label clinical trial (Study GS-US-540-5823) that enrolled 53 patients who were treated with remdesivir (see Section 5.1). The adverse reactions observed were consistent with those observed in clinical trials of remdesivir in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

This medicinal product must not be mixed or administered simultaneously with other medicinal products in the same dedicated line except those mentioned in section 6.6.