remdesivir: prescribing information – dosing, contraindications, interactions, side effects

Veklury is indicated for the treatment of coronavirus disease 2019 (COVID-19) in adults and paediatric patients (at least 4 weeks of age and weighing at least 3 kg):
- with pneumonia requiring supplemental oxygen (low- or high-flow oxygen or other non- invasive ventilation at start of treatment)
- who do not require supplemental oxygen and who are at increased risk of progressing to severe COVID-19 (see section 5.1)

Patients should be monitored when receiving remdesivir (see section 4.4).

Patients receiving remdesivir in an outpatient setting should be monitored according to local medical practice. Use under conditions where treatment of severe hypersensitivity reactions, including anaphylaxis, is possible.

Posology

Table 1:
Recommended dose in adults and paediatric patients

Given by intravenous infusion
Adults
Paediatric patients
(weighing at least
40 kg)
Paediatric patients at least
4 weeks old (weighing at least
3 kg but less than 40 kg)
Day 1
(single loading dose)
200 mg
200 mg
5 mg/kg
Day 2 and onwards
(once daily)
100 mg
100 mg
2.5 mg/kg

Table 2:
Treatment duration

Adults

Paediatric patients
(weighing at least
40 kg)
Paediatric patients at least
4 weeks old (weighing at least
3 kg but less than 40 kg)
Patients with pneumonia and requiring supplemental oxygen
Daily for at least
5 days and not more than
10 days.
Daily for at least
5 days and not more than 10 days.
Daily for up to a total of 10 days
Patients who do not require supplemental oxygen and are at increased risk for progressing to severe COVID-19 Daily for 3 days, starting as soon as possible after diagnosis of COVID-19 and within 7 days of the onset of symptoms.
Daily for 3 days, starting as soon as possible after diagnosis of COVID-19 and within 7 days of the onset of symptoms.
Daily for 3 days, starting as soon as possible after diagnosis of
COVID-19 and within 7 days of the onset of symptoms.

Special populations

Elderly
No dose adjustment of remdesivir 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 remdesivir 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 remdesivir in children less than 4 weeks of age and weighing less than 3 kg have not yet been established (see section 5.1).

Immunocompromised population
The safety and efficacy of remdesivir in immunocompromised patients have not yet been established.
Only limited data are available (see section 4.4).

Method of administration

For intravenous use.

Remdesivir 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 3:
Recommended rate of infusion – for reconstituted and diluted remdesivir powder for concentrate for solution for infusion in adults and paediatric patients weighing at least 40 kg Infusion Bag Volume Infusion Time Rate of Infusion 250 mL 30 min 8.33 mL/min 60 min 4.17 mL/min 120 min 2.08 mL/min 100 mL 30 min 3.33 mL/min 60 min 1.67 mL/min 120 min 0.83 mL/min

Table 4:
Recommended rate of infusion – for reconstituted and diluted remdesivir powder for concentrate for solution for infusion in paediatric patients at least 4 weeks of age and weighing at least 3 kg but less than 40 kg Infusion Bag Volume Infusion Time Rate of Infusiona 100 mL 30 min 3.33 mL/min 60 min 1.67 mL/min 120 min 0.83 mL/min 50 mL 30 min 1.67 mL/min 60 min 0.83 mL/min 120 min 0.42 mL/min 25 mL 30 min 0.83 mL/min 60 min 0.42 mL/min 120 min 0.21 mL/min a Rate of infusion may be adjusted based on total volume to be infused.

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

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 7 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 7:
Tabulated list of adverse reactions
Frequency
Adverse reaction
Immune system disorders
Rare hypersensitivity
Not known anaphylactic reaction, anaphylactic shock
Nervous system disorders
Common headache
Cardiac disorders
Not known sinus bradycardia*
Gastrointestinal disorders
Common nausea
Hepatobiliary disorders
Very common transaminases increased
Skin and subcutaneous tissue disorders
Common rash
Investigations
Very common prothrombin time prolonged
Injury, poisoning and procedural complications
Rare infusion-related reaction
*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) in 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.

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
Remdesivir is not a clinically relevant inhibitor of CYP3A4, OATP1B1, and OATP1B3. In vitro, remdesivir is an inhibitor of UGT1A1, MATE1, OAT3, and OCT1; however no clinically significant drug interactions are expected with remdesivir and substrates of these enzymes or transporters.

Remdesivir is not a clinically relevant inducer of CYP3A4. Remdesivir induced CYP1A2 in vitro;
however no clinically significant drug interaction is expected with remdesivir and CYP1A2 substrates.

Drug-drug interaction studies were conducted with remdesivir. Table 6 summarises the effect of remdesivir on the pharmacokinetics of studied drugs.

Co-administered Drug
Dose (mg)
Interaction
Geometric mean change (%)
Recommendation concerning co- administration

Cyclosporin
400 single dose remdesivir:
Cmax
↑49%

AUCinf
↑89%

No dose adjustment of remdesivir is required when it is co-administered with inhibitors of OATP1B1 and OATP1B3.
GS-704277: Cmax
↑151%

AUCinf
↑197%
GS-441524: Cmax
↑17%

AUCinf
↔
No interactions are expected when co-administering remdesivir with inhibitors of OATP1B1/1B3 and/or P-gp.

Carbamazepine
300 twice daily remdesivir:
Cmax
↓13%

AUCinf
↓8%

No dose adjustment of remdesivir is required when it is co-administered with strong CYP3A4 and/or P-gp inducers.
GS-704277: Cmax
↔

AUCinf
↔
GS-441524: Cmax
↔

AUCinf
↓17%

No interactions are expected when co-administering remdesivir with strong CYP3A4 inducers or CYP3A4 inhibitors.

Table 6:
Effect of remdesivir on other drugs
NOTE: Interaction study conducted in healthy volunteers.
a.
No effect = 1.00 (0.80-1.25).
b.
Midazolam administered with last dose of remdesivir.
c.
No effect = 1.00 (0.70-1.43)

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.

Co-administered
Drug
Dose (mg)
Remdesivir
Dose (mg)
Interaction
Geometric mean change (%)
Recommendation concerning co-administration
Midazolam

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

Treatment of overdose with remdesivir 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 remdesivir. In one clinical pharmacology trial, remdesivir 600 mg as a single dose over 30 minutes, equivalent to 3 times the therapeutic loading dose of 200 mg, was administered to 60 healthy subjects. Nausea and/or vomiting (Grades 1-2) was reported for 33 (55%) subjects. One subject (2%) had increased AST and ALT (Grade 4) without elevation of bilirubin.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antivirals for systemic use, direct acting antivirals, ATC code: J05AB16

Mechanism of action

Remdesivir is an adenosine nucleotide prodrug that is metabolized within host cells to form the pharmacologically active nucleoside triphosphate metabolite. Remdesivir triphosphate 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. As an additional mechanism, remdesivir triphosphate can also inhibit viral RNA synthesis following its incorporation into the template viral RNA as a result of read-through by the viral polymerase that may occur in the presence of higher nucleotide concentrations. When remdesivir nucleotide is present in the viral RNA template, the efficiency of incorporation of the complementary natural nucleotide is compromised, thereby inhibiting viral RNA synthesis.

Antiviral activity

Remdesivir exhibited in vitro activity against a clinical isolate of SARS-CoV-2 in primary human airway epithelial cells with a 50% effective concentration (EC50) of 9.9 nM after 48 hours of treatment.
Remdesivir inhibited the replication of SARS-CoV-2 in the continuous human lung epithelial cell lines Calu-3 and A549-hACE2 with EC50 values of 280 nM after 72 hours of treatment and 115 nM after 48 hours of treatment, respectively. The EC50 values of remdesivir against SARS-CoV-2 in Vero cells were 137 nM at 24 hours and 750 nM at 48 hours post-treatment.

The antiviral activity of remdesivir was antagonised by chloroquine phosphate in a dose-dependent manner when the two drugs were co-incubated at clinically relevant concentrations in HEp-2 cells infected with respiratory syncytial virus (RSV). Higher remdesivir EC50 values were observed with increasing concentrations of chloroquine phosphate. Increasing concentrations of chloroquine phosphate reduced formation of remdesivir triphosphate in A549-hACE2, HEp-2 and normal human bronchial epithelial cells.

The pharmacokinetic properties of remdesivir have been investigated in healthy volunteers and patients with COVID-19.

Absorption

The pharmacokinetic properties of remdesivir and the predominant circulating metabolite GS-441524 have been evaluated in healthy adult subjects. Following intravenous administration of remdesivir adult dosage regimen, peak plasma concentration was observed at end of infusion, regardless of dose level, and declined rapidly thereafter with a half-life of approximately 1 hour. Peak plasma concentrations of GS-441524 were observed at 1.5 to 2.0 hours post start of a 30 minutes infusion.

Distribution

Remdesivir is approximately 93% bound to human plasma proteins (ex-vivo data) with free fraction ranging from 6.4% to 7.4%. The binding is independent of drug concentration over the range of 1 to 10 μM, with no evidence for saturation of remdesivir binding. After a single 150 mg dose of [14C]-

remdesivir in healthy subjects, the blood to plasma ratio of [14C]-radioactivity was approximately 0.68 at 15 minutes from start of infusion, increased over time reaching ratio of 1.0 at 5 hours, indicating differential distribution of remdesivir and its metabolites to plasma or cellular components of blood.

Biotransformation

Remdesivir is extensively metabolized to the pharmacologically active nucleoside analog triphosphate GS-443902 (formed intracellularly). The metabolic activation pathway involves hydrolysis by esterases, which leads to the formation of the intermediate metabolite, GS-704277. In the liver, carboxylesterase 1 and cathepsin A are the esterases responsible for 80% and 10% of remdesivir metabolism, respectively. Phosphoramidate cleavage followed by phosphorylation forms the active triphosphate, GS-443902. Dephosphorylation of all phosphorylated metabolites can result in the formation of nucleoside metabolite GS-441524 that itself is not efficiently re-phosphorylated.