Veklury · 4.6 Fertility, pregnancy and lactation · 1

HOS-099865 · has-adverse-reaction-information · PDF-Seite 8

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 8 (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 S

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HOS-099861 · has-contraindication-information · PDF-Seite 4

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

HOS-099860 · has-indication-information · PDF-Seite 2

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)

HOS-099863 · has-interaction-information · PDF-Seite 5

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. 5 Table 5: Effect of other drugs on remdesivir and metabolites GS-704277 and GS-441524 Co-administered Drug Interaction Recommendation Dose (mg) Geometric mean change (%) concerning co- administration remdesivir: Cmax ↑49% Cyclosporin AUCinf ↑89% No dose adjustment of 400 single dose GS-704277: Cmax ↑151% remdesivir is required AUCinf ↑197% when it is co-administered GS-441524: Cmax ↑17% with inhibitors of AUCinf ↔ OATP1B1 and OATP1B3. No interactions are expected when co-administering remdesivir with inhibitors of OATP1B1/1B3 and/or P-gp. remdesivir: Cmax ↓13% Carbamazepine AUCinf ↓8% No dose adjustment of 300 twice daily GS-704277: Cmax ↔ remdesivir is required AUCinf ↔ when it is co-administered GS-441524: maxC ↔ with strong CYP3A4

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HOS-099864 · has-pregnancy-information · PDF-Seite 7

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. 7 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.

HOS-099862 · has-warning-information · PDF-Seite 4

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 4 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.