Remdesivir Other names: GS-5734

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.

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.

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.

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.

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.

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. 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 the table below are listed 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).

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. 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.

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. The adverse reactions observed were consistent with those observed in clinical trials of remdesivir in adults.