VEKLURY 100mg 5mg / ml perfusive solution concentrate medication leaflet

Veklury 100 mg powder for concentrate for solution for infusion

Each vial contains 100 mg of remdesivir. After reconstitution, each vial contains 5 mg/mL ofremdesivir solution.

Each vial contains 3 g betadex sulfobutyl ether sodium.

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion (powder for concentrate).

White to off-white to yellow powder.

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) withpneumonia requiring supplemental oxygen (low- or high-flow oxygen or other non-invasive ventilation at start of treatment)

* adults and paediatric patients (weighing at least 40 kg) who do not require supplementaloxygen 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 medicalpractice. Use under conditions where treatment of severe hypersensitivity reactions, includinganaphylaxis, is possible.

Table 1: Recommended dose in adults and paediatric patients

Given by intravenous infusion

Adults Paediatric patients Paediatric patients at least(weighing at least 4 weeks old (weighing at40 kg) least 3 kg but less than40 kg)

Day 1 200 mg 200 mg 5 mg/kg(single loading dose)

Day 2 and onwards 100 mg 100 mg 2.5 mg/kg(once daily)

Table 2: Treatment duration

Adults Paediatric patients Paediatric patients at least(weighing at least 4 weeks old (weighing at40 kg) least 3 kg but less than40 kg)

Patients with pneumonia Daily for at least Daily for at least Daily for up to a total ofand requiring 5 days and not 5 days and not more 10 days.supplemental oxygen more than than 10 days.

10 days.

Patients who do not Daily for 3 days, Daily for 3 days, Not applicable.require supplemental starting as soon as starting as soon asoxygen and are at possible after possible after diagnosisincreased risk for diagnosis of of COVID-19 andprogressing to severe COVID-19 and within 7 days of the

COVID-19 within 7 days of onset of symptoms.

the onset ofsymptoms.

No dose adjustment of remdesivir is required in patients over the age of 65 years (see sections 5.1 and5.2).

No dose adjustment of remdesivir is required in patients with renal impairment, including those ondialysis. 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 ofadministration of remdesivir is without regard to dialysis (see section 5.2).

The pharmacokinetics of remdesivir have not been evaluated in patients with hepatic impairment. It isnot known if dosage adjustment is appropriate in patients with hepatic impairment (see sections 4.4and 5.2).

The safety and efficacy of remdesivir in children less than 4 weeks of age and weighing less than 3 kghave not yet been established. No data are available.

The safety and efficacy of remdesivir in immunocompromised patients have not yet been established.

Only limited data are available (see section 4.4).

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, seesection 6.6.

Table 3: Recommended rate of infusion - for reconstituted and diluted remdesivir powderfor concentrate for solution for infusion in adults and paediatric patients weighingat least 40 kg

Infusion Bag Volume Infusion Time Rate of Infusion30 min 8.33 mL/min250 mL 60 min 4.17 mL/min120 min 2.08 mL/min30 min 3.33 mL/min100 mL 60 min 1.67 mL/min120 min 0.83 mL/min

Table 4: Recommended rate of infusion - for reconstituted and diluted remdesivir powderfor concentrate for solution for infusion in paediatric patients at least 4 weeks of ageand weighing at least 3 kg but less than 40 kg

Infusion Bag Volume Infusion Time Rate of Infusiona30 min 3.33 mL/min100 mL 60 min 1.67 mL/min120 min 0.83 mL/min30 min 1.67 mL/min50 mL 60 min 0.83 mL/min120 min 0.42 mL/min30 min 0.83 mL/min25 mL 60 min 0.42 mL/min120 min 0.21 mL/mina 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.

Hypersensitivity reactions including infusion-related and anaphylactic reactions have been observedduring 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 ofup to 120 minutes, can be considered to potentially prevent these signs and symptoms. Monitorpatients for hypersensitivity reactions during and following administration of remdesivir as clinicallyappropriate. Patients receiving remdesivir in an outpatient setting should be monitored afteradministration according to local medical practice. If signs and symptoms of a clinically significanthypersensitivity reaction occur, immediately discontinue administration of remdesivir and initiateappropriate treatment.

Transaminase elevations have been observed in the remdesivir clinical trials, including in healthyvolunteers and patients with COVID-19. Liver function should be determined in all patients prior tostarting remdesivir and should be monitored while receiving it as clinically appropriate. No clinicalstudies with remdesivir have been conducted in patients with hepatic impairment. Remdesivir shouldonly be used in patients with hepatic impairment if the potential benefit outweighs the potential risk.

* Remdesivir should not be initiated in patients with alanine aminotransferase (ALT) ≥ 5 timesthe upper limit of normal at baseline

* Remdesivir should be discontinued in patients who develop:

◦ ALT ≥ 5 times the upper limit of normal during treatment with remdesivir. It may berestarted when ALT is < 5 times the upper limit of normal.

OR◦ ALT elevation accompanied by signs or symptoms of liver inflammation or increasingconjugated bilirubin, alkaline phosphatase, or international normalised ratio (INR) (seesections 4.8 and 5.2).

As clinically appropriate, patients should have eGFR determined prior to starting remdesivir and whilereceiving 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 arelimited safety data in this patient population. Therefore, taking the significant higher exposure of themetabolite GS-441524 into account, patients with severe renal impairment and ESRD should beclosely monitored for adverse events during treatment with remdesivir (see section 5.2).

Coadministration of remdesivir and chloroquine phosphate or hydroxychloroquine sulphate is notrecommended based on in vitro data demonstrating an antagonistic effect of chloroquine on theintracellular metabolic activation and antiviral activity of remdesivir (see sections 4.5 and 5.1)

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

This medicine contains 212 mg sodium (main component of cooking/table salt) in each 100 mg doseunit. This is equivalent to 10.6% of the recommended maximum daily dietary intake of sodium for anadult.

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

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 thepharmacokinetic 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

Co-administered Drug Interaction Recommendation

Dose (mg) Geometric mean change (%) concerning co-administrationremdesivir: Cmax ↑49%

Cyclosporin AUCinf ↑89% No dose adjustment of400 single dose GS-704277: Cmax ↑151% remdesivir is required

AUCinf ↑197% when it is co-administered

GS-441524: C ↑17% with inhibitors ofmax

AUC ↔ OATP1B1 and OATP1B3.inf

No interactions are expected when co-administeringremdesivir with inhibitors of OATP1B1/1B3 and/or P-gp.

remdesivir: Cmax ↓13%

Carbamazepine AUCinf ↓8% No dose adjustment of300 twice daily GS-704277: Cmax ↔ remdesivir is required

AUCinf ↔ when it is co-administered

GS-441524: C ↔ with strong CYP3A4max

AUC ↓17% and/or P-gp inducers.inf

No interactions are expected when co-administeringremdesivir with strong CYP3A4 inducers or CYP3A4inhibitors.

NOTE: Interaction study conducted in healthy volunteers.

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 substratesof 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 CYP3A4substrates with narrow therapeutic index may lead to loss of their efficacy.

Dexamethasone is a substrate of CYP3A4 and although remdesivir inhibits CYP3A4, due toremdesivir's rapid clearance after IV administration, remdesivir is unlikely to have a significant effecton dexamethasone exposure.

There is a limited amount of data from the use of remdesivir in pregnant women (less than300 pregnancy outcomes). Most of the exposures occurred in the second, third or an unknowntrimester and available data do not indicate any risk.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity atexposures of the major metabolite of remdesivir that were around human therapeutic exposures (seesection 5.3).

Due to very limited experience, remdesivir should not be used during first trimester in pregnancyunless the clinical condition of the woman requires treatment with it. Use in the second and thirdtrimester of pregnancy may be considered.

Use of effective contraception during treatment should be considered in women of child-bearingpotential.

Remdesivir and its major metabolite are excreted into breast milk in very small amounts afterintravenous administration. No clinical effect on the infant is expected due to low breast milk transferand poor oral bioavailability.

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

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

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

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

The adverse reactions in Table 6 are listed below by system organ class and frequency. Frequenciesare 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

Frequency Adverse reaction

Rare hypersensitivity

Not known anaphylactic reaction, anaphylactic shock

Common headache

Not known sinus bradycardia*

Common nausea

Very common transaminases increased

Common rash

Very common prothrombin time prolonged

Rare infusion-related reaction

*Reported in post-marketing, usually normalised within 4 days following last remdesivir administration without additionalintervention

In healthy volunteer studies, increases in ALT, aspartate aminotransferase (AST) or both in subjectswho received remdesivir were grade 1 (10%) or grade 2 (4%). In a randomised, double-blind, placebo-controlled clinical study of patients with COVID-19 (NIAID ACTT-1), any grade (≥ 1.25 × upperlimit of normal (ULN)) laboratory abnormalities of increased AST and increased ALT occurred in33% and 32% of patients, respectively, receiving remdesivir compared with 44% and 43% of patients,respectively, receiving placebo. Grade ≥ 3 (≥ 5.0 × ULN) laboratory abnormalities of increased ASTand increased ALT occurred in 6% and 3% of patients, respectively, receiving remdesivir comparedwith 8% and 6% of patients, respectively, receiving placebo. In a randomised, open-label multi-centreclinical trial (Study GS-US-540-5773) in hospitalised patients with severe COVID-19 receivingremdesivir for 5 (n=200) or 10 days (n=197), any grade laboratory abnormalities of increased AST andincreased ALT occurred in 40% and 42% of patients, respectively, receiving remdesivir. Grade ≥ 3laboratory abnormalities of increased AST and increased ALT both occurred in 7% of patientsreceiving remdesivir. In a randomised, open-label multi-centre clinical trial (Study GS-US-540-5774)in hospitalised patients with moderate COVID-19 receiving remdesivir for 5 (n=191) or 10 days(n=193) compared to standard of care (n=200), any grade laboratory abnormalities of increased ASTand increased ALT occurred in 32% and 33% of patients, respectively, receiving remdesivir, and 33%and 39% of patients, respectively, receiving standard of care. Grade ≥ 3 laboratory abnormalities ofincreased AST and increased ALT occurred in 2% and 3% of patients, respectively, receivingremdesivir and 6% and 8%, respectively, receiving standard of care.

In a clinical study (NIAID ACTT-1) of patients with COVID-19, the incidence of prolongedprothrombin time or INR (predominantly Grades 1-2) was higher in subjects who received remdesivircompared to placebo, with no difference observed in the incidence of bleeding events between the twogroups. Prothrombin time should be monitored while receiving remdesivir as clinically appropriate.

In Study GS-US-540-9012, the incidence of increased prothrombin time or INR was similar in patientstreated with remdesivir compared to placebo.

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

The safety assessment of remdesivir in children 4 weeks of age and older and weighing at least 3 kgwith 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 reactionsobserved were consistent with those observed in clinical trials of remdesivir in adults.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Treatment of overdose with remdesivir should consist of general supportive measures includingmonitoring of vital signs and observation of the clinical status of the patient. There is no specificantidote for overdose with remdesivir.

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

Remdesivir is an adenosine nucleotide prodrug that is metabolized within host cells to form thepharmacologically active nucleoside triphosphate metabolite. Remdesivir triphosphate acts as ananalog of adenosine triphosphate (ATP) and competes with the natural ATP substrate for incorporationinto nascent RNA chains by the SARS-CoV-2 RNA-dependent RNA polymerase, which results indelayed chain termination during replication of the viral RNA. As an additional mechanism,remdesivir triphosphate can also inhibit viral RNA synthesis following its incorporation into thetemplate viral RNA as a result of read-through by the viral polymerase that may occur in the presenceof higher nucleotide concentrations. When remdesivir nucleotide is present in the viral RNA template,the efficiency of incorporation of the complementary natural nucleotide is compromised, therebyinhibiting viral RNA synthesis.

Remdesivir exhibited in vitro activity against a clinical isolate of SARS-CoV-2 in primary humanairway 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 celllines Calu-3 and A549-hACE2 with EC50 values of 280 nM after 72 hours of treatment and 115 nMafter 48 hours of treatment, respectively. The EC50 values of remdesivir against SARS-CoV-2 in Verocells 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-dependentmanner when the two drugs were co-incubated at clinically relevant concentrations in HEp-2 cellsinfected with respiratory syncytial virus (RSV). Higher remdesivir EC50 values were observed withincreasing concentrations of chloroquine phosphate. Increasing concentrations of chloroquinephosphate reduced formation of remdesivir triphosphate in A549-hACE2, HEp-2 and normal humanbronchial epithelial cells.

Based on in vitro testing, remdesivir retained similar antiviral activity (< 2.5-fold change in EC50value) against clinical isolates of SARS-CoV-2 variants including Alpha (B.1.1.7), Beta (B.1.351),

Gamma (P.1), Epsilon (B.1.429), Kappa (B.1.617.1), Lambda (C.37), Iota (B.1.526), Zeta (P.2), and

Delta (B.1.617.2) variants compared to earlier lineage SARS-CoV-2 (lineage A) isolates. Similarly,for the clinical isolates of Omicron variant (including B.1.1.529/BA.1, BA.2, BA.2.12.1, BA.2.75,

BA.4, BA.4.6, BA.5, BF.5, BQ.1.1 and XBB), remdesivir also maintained antiviral activity (≤ 1.1-foldchange in EC50 value) relative to the lineage A SARS-CoV-2 isolate. The antiviral activity ofremdesivir against SARS-CoV-2 variants is presented in Table 7.

Table 7: Remdesivir antiviral activity against clinical isolates of SARS-CoV-2 variants

SARS-CoV-2 WHO Key Remdesivir Fold Change Change in

Lineage Nomenclature Substitutions EC50 (nM) in Susceptibility

Susceptibility

A - - 110 1.0

B.1.1.7 Alpha P323L 192 1.58 No changea

B.1.351 Beta P323L 141 1.19 No changea

P.1 Gamma P323L 97 0.82 No changea

B.1.617.2 Delta P323L, G671S 70 0.59 No changea

B.1.429 Epsilon P323L 210 1.94 No changea

P.2 Zeta P323L 151 1.17 No changea

B.1.526 Iota P323L 258 2.33 No changea

B.1.617.1 Kappa P323L 77 0.63 No changea

SARS-CoV-2 WHO Key Remdesivir Fold Change Change in

Lineage Nomenclature Substitutions EC50 (nM) in Susceptibility

Susceptibility

C.37 Lambda P323L 175 1.37 No changea

B.1.1.529/BA.1 Omicron P323L 44 0.45 No changea

BA.2 P323L 25 0.23 No changea

BA.2.12.1 P323L 33 0.20 No changea

BA.2.75 P323L, G671S 32 0.30 No changea

BA.4 P323L 25 0.15 No changea

BA.4.6 P323L 92 0.64 No changea

BA.5 P323L 106 0.66 No changea

BF.5 P323L 134 0.94 No changea

BQ.1.1 Y273H, P323L 90 1.12 No changea

XBB P323L, G671S 86 1.07 No changeaa Fold-change: < 2.5- is not significant. All variants show no reduction in susceptibility.

In Cell Culture

SARS-CoV-2 isolates with reduced susceptibility to remdesivir have been selected in cell culture. Inone selection with GS-441524, the parent nucleoside of remdesivir, virus pools emerged expressingcombinations of amino acid substitutions at V166A, N198S, S759A, V792I, C799F, and C799R in theviral RNA-dependent RNA polymerase, conferring EC50 fold-changes of 2.7 up to 10.4. Whenindividually introduced into a wild-type recombinant virus by site-directed mutagenesis, 1.7- to 3.5-fold reduced susceptibility to remdesivir was observed. In a second selection with remdesivir using a

SARS-CoV-2 isolate containing the P323L substitution in the viral polymerase, a single amino acidsubstitution at V166L emerged. Recombinant viruses with substitutions at P323L alone or

P323L+V166L in combination exhibited 1.3- and 1.5-fold changes in remdesivir susceptibility,respectively.

Cell culture resistance profiling of remdesivir using the rodent CoV murine hepatitis virus identifiedtwo substitutions (F476L and V553L) in the viral RNA-dependent RNA polymerase at residuesconserved across CoVs that conferred 5.6-fold reduced susceptibility to remdesivir. Introduction of thecorresponding substitutions (F480L and V557L) into SARS-CoV resulted in 6-fold reducedsusceptibility to remdesivir in cell culture and attenuated SARS-CoV pathogenesis in a mouse model.

When individually introduced into a SARS-CoV-2 recombinant virus, the corresponding substitutionsat F480L and V557L each conferred 2-fold reduced susceptibility to remdesivir.

In Clinical Trials

In NIAID ACTT-1 Study (CO-US-540-5776), among 61 patients with baseline and post-baselinesequencing data available, the rate of emerging substitutions in the viral RNA-dependent RNApolymerase was similar in patients treated with remdesivir compared to placebo. In 2 patients treatedwith remdesivir, substitutions in the RNA-dependent RNA polymerase previously identified inresistance selection experiments (V792I or C799F) and associated with low fold change in remdesivirsusceptibility (≤3.4-fold) were observed. No other RNA-dependent RNA polymerase substitutionsobserved in patients treated with remdesivir were associated with resistance to remdesivir.

In Study GS-US-540-5773, among 19 patients treated with remdesivir who had baseline and post-baseline sequencing data available, substitutions in the viral RNA-dependent RNA polymerase (nsp12)were observed in 4 patients. The substitutions T76I, A526V, A554V and C697F were not associatedwith resistance to remdesivir (≤ 1.45-fold change in susceptibility). The effect of substitution E665K onsusceptibility to remdesivir could not be determined due to lack of replication.

In GS-US-540-9012 Study, among 244 patients with baseline and post-baseline sequencing dataavailable, the rate of emerging substitutions in the viral RNA-dependent RNA polymerase was similarin patients treated with remdesivir compared to placebo. In one patient treated with remdesivir, onesubstitution in the RNA-dependent RNA polymerase (A376V) emerged and was associated with adecrease in remdesivir susceptibility in vitro (12.6-fold). No other substitutions in the RNA-dependent

RNA polymerase or other proteins of the replication-transcription complex observed in patients treatedwith remdesivir were associated with resistance to remdesivir.

In Study GS-US-540-5912, among 60 patients with baseline and post-baseline sequencing dataavailable, substitutions in the viral RNA-dependent RNA polymerase emerged in 8 patients treatedwith remdesivir. In 4 patients treated with remdesivir, substitutions in the RNA-dependent RNApolymerase (M794I, C799F, or E136V) emerged and were associated with reduced susceptibility toremdesivir in vitro (≤3.5-fold). No other substitutions in the RNA-dependent RNA polymerasedetected in patients treated with remdesivir were associated with resistance to remdesivir.

In Study GS-US-540-5823, among patients with baseline and post-baseline sequencing data available,substitutions in the viral RNA-dependent RNA polymerase (A656P and G670V) were observed in oneof 23 patients treated with remdesivir. The substitutions observed have not been associated withresistance to remdesivir.

A randomised, double-blind, placebo-controlled clinical trial evaluated remdesivir 200 mg once dailyfor 1 day followed by remdesivir 100 mg once daily for up to 9 days (for a total of up to 10 days ofintravenously administered therapy) in hospitalised adult patients with COVID-19 with evidence oflower respiratory tract involvement. The trial enrolled 1,062 hospitalised patients: 159 (15%) patientswith mild/moderate disease (15% in both treatment groups) and 903 (85%) patients with severedisease (85% in both treatment groups). Mild/moderate disease was defined as SpO2 > 94% andrespiratory rate < 24 breaths/minute without supplemental oxygen; severe disease was defined as

SpO2 ≤ 94% on room air, a respiratory rate ≥ 24 breaths/min, and an oxygen requirement, or arequirement for mechanical ventilation. A total of 285 patients (26.8%) (n=131 received remdesivir)were on mechanical ventilation/Extracorporeal Membrane Oxygenation (ECMO). Patients wererandomised 1:1, stratified by disease severity at enrolment, to receive remdesivir (n=541) or placebo(n=521), plus standard of care.

The baseline mean age was 59 years and 36% of patients were aged 65 or older. Sixty-four percentwere male, 53% were White, 21% were Black, 13% were Asian. The most common comorbiditieswere hypertension (51%), obesity (45%) and type 2 diabetes mellitus (31%); the distribution ofcomorbidities was similar between the two treatment groups.

Approximately 38.4% (208/541) of the patients received a 10-day treatment course with remdesivir.

The primary clinical endpoint was time to recovery within 29 days after randomisation, defined aseither discharged from hospital (with or without limitations of activity and with or without homeoxygen requirements) or hospitalised but not requiring supplemental oxygen and no longer requiringongoing medical care. The median time to recovery was 10 days in the remdesivir group compared to15 days in the placebo group (recovery rate ratio 1.29; [95% CI 1.12 to 1.49], p < 0.001).

No difference in time to recovery was seen in the stratum of patients with mild-moderate disease atenrolment (n=159). The median time to recovery was 5 days in the remdesivir and 7 days in theplacebo groups (recovery rate ratio 1.10; [95% CI 0.8 to 1.53]); the odds of improvement in theordinal scale in the remdesivir group at Day 15 when compared to the placebo group were as follows:odds ratio, 1.2; [95% CI 0.7 to 2.2, p = 0.562].

Among patients with severe disease at enrolment (n=903), the median time to recovery was 12 days inthe remdesivir group compared to 19 days in the placebo group (recovery rate ratio, 1.34; [95% CI1.14 to 1.58]; p < 0.001); the odds of improvement in the ordinal scale in the remdesivir group at Day15 when compared to the placebo group were as follows: odds ratio, 1.6; [95% CI 1.3 to 2.0].

Overall, the odds of improvement in the ordinal scale were higher in the remdesivir group at Day 15when compared to the placebo group (odds ratio, 1.6; [95% CI 1.3 to 1.9], p < 0.001).

The 29-day mortality in the overall population was 11.6% for the remdesivir group vs 15.4% for theplacebo group (hazard ratio, 0.73; [95% CI 0.52 to 1.03]; p=0.07). A post-hoc analysis of 29-daymortality by ordinal scale is reported in Table 8.

Table 8: 29-Day mortality outcomes by ordinal scalea at baseline—NIAID ACTT-1 trial

Ordinal Score at Baseline5 6

Requiring low-flow oxygen Requiring high-flow oxygen or non-invasive mechanical ventilation

Remdesivir Placebo Remdesivir Placebo(N=232) (N=203) (N=95) (N=98)29-day mortality 4.1 12.8 21.8 20.6

Hazard ratiob (95% CI) 0.30 (0.14, 0.64) 1.02 (0.54, 1.91)a Not a pre-specified analysis.b Hazard ratios for baseline ordinal score subgroups are from unstratified Cox proportional hazards models.

A randomised, open-label multi-centre clinical trial (Study 5773) of patients at least 12 years of agewith confirmed SARS-CoV-2 infection, oxygen saturation of ≤ 94% on room air, and radiologicalevidence of pneumonia compared 200 patients who received remdesivir for 5 days with 197 patientswho received remdesivir for 10 days. All patients received 200 mg of remdesivir on Day 1 and 100 mgonce daily on subsequent days, plus standard of care. The primary endpoint was clinical status on Day14 assessed on a 7-point ordinal scale ranging from hospital discharge to increasing levels of oxygenand ventilatory support to death.

The odds of improvement at Day 14 for patients randomized to a 10-day course of remdesivircompared with those randomized to a 5-day course was 0.67 (odds ratio); [95% CI 0.46 to 0.98].

Statistically significant imbalances in baseline clinical status were observed in this study. Afteradjusting for between-group differences at baseline, the odds of improvement at Day 14 was 0.75(odds ratio); [95% CI 0.51 to 1.12]. In addition, there were no statistically significant differences inrecovery rates or mortality rates in the 5-day and 10-day groups once adjusted for between groupdifferences at baseline. All-cause 28-day mortality was 12% vs 14% in the 5- and 10-day treatmentgroups, respectively.

Study GS-US-540-9012 in patients with confirmed COVID-19 at increased risk for diseaseprogression

A randomised, double-blind, placebo-controlled, multi-centre clinical trial to evaluate treatment withremdesivir in an outpatient setting in 562 patients including 8 adolescents (12 years of age and olderand weighing at least 40 kg) with confirmed COVID-19 and at least one risk factor for diseaseprogression to hospitalisation. Risk factors for disease progression were: aged ≥ 60 years, chronic lungdisease, hypertension, cardiovascular or cerebrovascular disease, diabetes mellitus, obesity,immunocompromised state, chronic mild or moderate kidney disease, chronic liver disease, currentcancer, or sickle cell disease. Vaccinated patients were excluded from the study.

Patients treated with remdesivir received 200 mg on Day 1 and 100 mg once daily on subsequent daysfor a total of 3 days of intravenously administered therapy. Patients were randomized in a 1:1 manner,stratified by residence in a skilled nursing facility (yes/no), age (< 60 vs ≥ 60 years), and region (USvs ex-US) to receive remdesivir (n=279) or placebo (n=283), plus standard of care.

At baseline, mean age was 50 years (with 30% of patients aged 60 or older); 52% were male, 80%were White, 8% were Black, 2% were Asian, 44% were Hispanic or Latino; median body mass indexwas 30.7 kg/m2. The most common comorbidities were diabetes mellitus (62%), obesity (56%), andhypertension (48%). Median (Q1, Q3) duration of symptoms prior to treatment was 5 (3,6) days;median viral load was 6.3 log10 copies/mL at baseline. The baseline demographics and diseasecharacteristics were balanced across the remdesivir and placebo treatment groups. Post-hocexploratory analysis of optional biomarker samples showed 14.8% of patients were serologicalpositive at baseline and 37.7% were serological negative (47.5% did not consent to optional biomarkercollection).

The primary endpoint was the proportion of patients with COVID-19 related hospitalisation (definedas at least 24 hours of acute care) or all-cause 28-day mortality. Events (COVID-19-relatedhospitalisation or all-cause 28-day mortality) occurred in 2 (0.7%) patients treated with remdesivircompared to 15 (5.3%) patients concurrently randomized to placebo, demonstrating an 87% reductionin COVID-19-related hospitalisation or all-cause mortality compared to placebo (hazard ratio, 0.134[95% CI, 0.031 to 0.586]; p=0.0076). The absolute risk reduction was 4.6% (95% CI, 1.8% to 7.5%).

No deaths were observed at Day 28. Six of the 17 hospitalisation events occurred in participants withknown baseline serostatus (serological positive: n=0 in remdesivir group and n=2 in placebo group;serological negative: n=2 in remdesivir group and n=2 in placebo group). Eleven of the 17hospitalisation events occurred in participants with unknown baseline serostatus in placebo group andnone in the remdesivir group. No conclusion can be made on efficacy in the subgroups stratified byserostatus due to the small number of patients with known serostatus and overall low event rates.

Study GS-US-540-5912 in patients with COVID-19 and renal impairment

A randomised, double-blind, placebo-controlled clinical study (Study GS-US-540-5912) evaluatedremdesivir 200 mg once daily for 1 day followed by remdesivir 100 mg once daily for 4 days (for atotal of up to 5 days of intravenously administered therapy) in 243 hospitalised adult patients withconfirmed COVID-19 and renal impairment. The trial included 90 patients (37%) with AKI (definedas a 50% increase in serum creatinine within a 48-hour period that was sustained for ≥6 hours despitesupportive care), 64 patients (26%) with CKD (eGFR <30 mL/minute), and 89 patients (37%) with

ESRD (eGFR <15 mL/minute) requiring haemodialysis. Patients were randomised in a 2:1 manner,stratified by ESRD, high-flow oxygen requirement, and region (US vs ex-US) to receive remdesivir(n=163) or placebo (n=80), plus standard of care.

At baseline, mean age was 69 years (with 62% of patients aged 65 or older); 57% of patients weremale, 67% were White, 26% were Black, and 3% were Asian. The most common baseline risk factorswere hypertension (89%), diabetes mellitus (79%), and cardiovascular or cerebrovascular disease(51%); the distribution of risk factors was similar between the two treatment groups. A total of 45patients (19%) were on high-flow oxygen, 144 (59%) were on low-flow oxygen, and 54 (22%) wereon room air at baseline; no patients were on invasive mechanical ventilation (IMV). A total of 182patients (75%) were not on renal replacement therapy, and 31 patients (13%) had received a COVID-19 vaccine. The study closed prematurely due to feasibility issues and was underpowered to assessprimary (all-cause death or IMV by Day 29) and secondary efficacy endpoints because of lower thanexpected enrolment.

Current non-clinical and clinical data do not suggest a risk of QT prolongation, but QT prolongationhas not been fully evaluated in humans.

Study GS-US-540-5823 is a single-arm, open-label study where the pharmacokinetics and safety ofremdesivir in paediatric patients at least 28 days of age and weighing at least 3 kg with COVID-19(n=53) was assessed. Efficacy endpoints were secondary and descriptively analysed and thereforethese should be interpreted with caution. The study is ongoing.

Patients weighing ≥ 40 kg received 200 mg of remdesivir on Day 1 followed by remdesivir 100 mgonce daily on subsequent days (i.e., the adult dose); patients weighing ≥ 3 kg to < 40 kg receivedremdesivir 5 mg/kg on Day 1 followed by remdesivir 2.5 mg/kg once daily on subsequent days.

Median (range) exposure to remdesivir was 5 (1, 10) days.

At baseline, median age was 7 years (range: 0.1 to 17 years); 57% were female; median weight was24.6 kg (range: 4 kg to 192 kg). A total of 19 patients (37%) were obese (BMI-for-age ≥ 95thpercentile); 7 (58%), 2 (17%), 3 (27%), 3 (27%), and 4 (80%) patients in Cohorts 1, 2, 3, 4 and 8respectively. A total of 12 patients (23%) were on invasive mechanical ventilation (score of 2 in a 7-point ordinal scale), 18 (34%) were on non-invasive ventilation or high-flow oxygen (score of 3);10 (19%) were on low-flow oxygen (score of 4); and 13 (25%) were on room air (score of 5), atbaseline. The overall median (Q1, Q3) duration of symptoms and hospitalisation prior to first dose ofremdesivir was 5 (3, 7) days and 1 (1, 3) day, respectively.

In the overall population of the study, the median (Q1, Q3) change from baseline in clinical status(assessed on a 7-point ordinal scale ranging from death [score of 1] to hospital discharge [score of 7])was +2.0 (1.0, 4.0) points on Day 10. Among those with an ordinal score of ≤ 5 points at baseline, theproportion who had a ≥ 2-point improvement in clinical status on Day 10 was 75.0% (39/52); median(Q1, Q3) time to recovery was 7 (5, 16) days. Overall, 60% of patients were discharged by Day 10.

Most patients 92% (49/53) received at least 1 concomitant medication other than remdesivir for thetreatment of COVID-19 including immune modulator and anti-inflammatory agents. Three patientsdied during the study.

The European Medicines Agency has deferred the obligation to submit the results of studies withremdesivir in one or more subsets of the paediatric population (see sections 4.2 and 5.2 for informationon paediatric use).

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

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

Remdesivir is approximately 93% bound to human plasma proteins (ex-vivo data) with free fractionranging from 6.4% to 7.4%. The binding is independent of drug concentration over the range of 1 to10 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 0.68at 15 minutes from start of infusion, increased over time reaching ratio of 1.0 at 5 hours, indicatingdifferential distribution of remdesivir and its metabolites to plasma or cellular components of blood.

Remdesivir is extensively metabolized to the pharmacologically active nucleoside analog triphosphate

GS-443902 (formed intracellularly). The metabolic activation pathway involves hydrolysis byesterases, 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 remdesivirmetabolism, respectively. Phosphoramidate cleavage followed by phosphorylation forms the activetriphosphate, GS-443902. Dephosphorylation of all phosphorylated metabolites can result in theformation of nucleoside metabolite GS-441524 that itself is not efficiently re-phosphorylated.

Decyanation of remdesivir and/or its metabolites, followed by subsequent rhodanese mediatedconversion generates thiocyanate anion. The levels of thiocyanate detected following administration of100 mg and 200 mg remdesivir were observed to be significantly below endogenous levels in humanplasma.

Following a single 150 mg IV dose of [14C]-remdesivir, mean total recovery of the dose was 92%,consisting of approximately 74% and 18% recovered in urine and feces, respectively. The majority ofthe remdesivir dose recovered in urine was GS-441524 (49%), while 10% was recovered asremdesivir. These data indicate that renal clearance is the major elimination pathway for GS-441524.

The median terminal half-lives of remdesivir and GS-441524 were approximately 1 and 27 hours,respectively.

Pharmacokinetics of remdesivir and metabolites in adults with COVID-19

Pharmacokinetic exposures for remdesivir and its metabolites in adults with COVID-19 are providedin Table 9.

Table 9: Multiple dose PK parametersa of remdesivir and metabolites (GS-441524 and

GS-704277) following IV administration of remdesivir 100 mg to adults with

COVID-19

Parameters

Meanb (95%CI) Remdesivir GS-441524 GS-704277

Cmax(ng/mL) 2700 (2440, 2990) 143 (135, 152) 198 (180, 218)

AUCtau(ng*h/mL) 1710 (1480, 1980) 2410 (2250, 2580) 392 (348, 442)

Ctau(ng/mL) ND 61.5 (56.5, 66.8) ND

CI=Confidence Interval; ND=Not detectable (at 24 hours post-dose)

a. Population PK estimates for 30-minute IV infusion of remdesivir for 3 days (Study GS-US-540-9012, n=147).

b. Geometric mean estimates

Based on gender, race and age, pharmacokinetic differences on the exposures of remdesivir wereevaluated using population pharmacokinetic analysis. Gender and race did not affect thepharmacokinetics of remdesivir and its metabolites (GS-704277 and GS-441524). Pharmacokineticexposures of the GS-441524 metabolite were modestly increased in hospitalised COVID-19 patients≥ 60 years of age, however no dose adjustment is needed in these patients.

In CO-US-540-5961 (IMPAACT 2032) study, mean exposures (AUCtau, Cmax, and Ctau) of remdesivirand its metabolites (GS-441524 and GS-704277) were comparable between pregnant and non-pregnant women of child-bearing potential.

Population pharmacokinetic models for remdesivir and its circulating metabolites (GS-704277 and

GS-441524), developed using pooled data from studies in healthy subjects and in adult and paediatricpatients with COVID-19, were used to predict pharmacokinetic exposures in 50 paediatric patientsaged ≥ 28 days to < 18 years and weighing ≥ 3 kg (Study GS-US-540-5823) (Table 10). Geometricmean exposures (AUCtau, Cmax and Ctau) for these patients at the doses administered were higher forremdesivir (44% to 147%), GS-441524 (-21% to 25%), and GS-704277 (7% to 91%) as compared tothose in adult hospitalised patients with COVID-19. The increases were not considered clinicallysignificant.

Table 10: Pharmacokinetic parametersa estimate of steady-state plasma remdesivir,

GS-441524 and GS-704277 in paediatric and adult hospitalised COVID-19 patients

Parameters Paediatric patients Adult

Meanb Cohort 1 Cohort 8 Cohort 2 Cohort 3 Cohort 4 hospitalised12 to <18 <12 Years 28 Days to 28 Days to 28 Days to patients

Years and and <18 Years <18 Years <18 Years (N=277)

Weighing Weighing and and and≥40 kg ≥40 kg Weighing Weighing Weighing(N=12) (N=5) 20 to 12 to 3 to <12 kg<40 kg <20 kg (N=10)(N=12) (N=11)

Remdesivir

Cmax (ng/mL) 3910 3920 5680 5530 4900 2650

AUCtau (h*ng/mL) 2470 2280 3500 3910 2930 1590

GS-441524

Parameters Paediatric patients Adult

Meanb Cohort 1 Cohort 8 Cohort 2 Cohort 3 Cohort 4 hospitalised12 to <18 <12 Years 28 Days to 28 Days to 28 Days to patients

Years and and <18 Years <18 Years <18 Years (N=277)

Weighing Weighing and and and≥40 kg ≥40 kg Weighing Weighing Weighing(N=12) (N=5) 20 to 12 to 3 to <12 kg<40 kg <20 kg (N=10)(N=12) (N=11)

Cmax (ng/mL) 197 162 181 158 202 170

AUCtau (h*ng/mL) 3460 2640 2870 2400 2770 3060

Ctau (ng/mL) 98.3 76.2 73.8 69.4 78.4 78.4

GS-704277

Cmax (ng/mL) 307 278 423 444 390 233

AUCtau (h*ng/mL) 815 537 754 734 691 501a PK parameters were simulated using PopPK modeling with 0.5 hour of duration for remdesivir infusions.b Geometric mean estimates.

Paediatric hospitalised patients are from Study GS-US-540-5823; patients received 200 mg on Day 1 followed by remdesivir100 mg once daily on subsequent days (Cohort 1 and 8), or 5 mg/kg on Day 1 followed by remdesivir 2.5 mg/kg once dailyon subsequent days (Cohort 2-4) for a total treatment duration of up to 10 days.

Adult hospitalised patients are from Study CO-US-540-5844 (a phase 3 randomised study to evaluate the safety and antiviralactivity of remdesivir in patients with severe COVID-19); patients received 200 mg on Day 1 followed by remdesivir 100 mgonce daily on subsequent days (10 days total treatment duration).

The pharmacokinetics of remdesivir and its metabolites (GS-441524 and GS-704277) and theexcipient SBECD were evaluated in healthy subjects, those with mild (eGFR 60-89 mL/minute),moderate (eGFR 30-59 mL/minute), severe (eGFR 15-29 mL/minute) renal impairment, or with ESRD(eGFR <15 mL/minute) on haemodialysis or not on haemodialysis following a single dose of up to100 mg of remdesivir (Table 11); and in a Phase 3 study in COVID-19 patients with severely reducedkidney function (eGFR <30 mL/minute) receiving remdesivir 200 mg on Day 1 followed by 100 mgfrom Day 2 to Day 5 (Table 12).

Pharmacokinetic exposures of remdesivir were not affected by renal function or timing of remdesiviradministration around dialysis. Exposures of GS-704277, GS-441524, and SBECD were up to 2.8-fold, 7.9-fold and 26-fold higher, respectively, in those with renal impairment than those with normalrenal function which is not considered clinically significant based on limited available safety data. Nodose adjustment of remdesivir is required for patients with renal impairment, including those ondialysis.

Table 11: Statistical comparison of single-dose pharmacokinetic parametersa of remdesivirand metabolites (GS-441524 and GS-704277) between adult subjects with decreasedrenal functionb (mild, moderate, severe renal impairment and ESRD) and adultsubjectsa with normal renal function60-89 mL 30-59 mL 15-29 mL <15 mL per minute

GLSM Ratioc per per per Pre-haemodialysis Post- No(90%CI) minute minute minute N=6 haemodialysis dialysis

N=10 N=10 N=10 N=6 N=3

Remdesivir

Cmax 96.0 120 97.1 89.1 (67.1, 118) 113 93.9(ng/mL) (70.5, 131) (101, 142) (83.3, 113) (79.4, 160) (65.4, 135)

AUCinf 99.5 122 94 79.6 (59.0, 108) 108 88.9(h*ng/mL) (75.3, 132) (97.5, (83.0, 107) (71.5, 163) (55.2, 143)152)

GS-441524

Cmax 107 144 168 227 (172, 299) 307 (221, 426) 300(ng/mL) (90, 126) (113, 185) (128, 220) (263, 342)

AUC dinf 119 202 326 497 (365, 677) 622 (444, 871) 787(h*ng/mL) (97, 147) (157, 262) (239, 446) (649, 953)

GS-704277

Cmax 225 183 127 143 (100, 205) 123 176(ng/mL) (120, 420) (134, 249) (96.1, 168) (83.6, 180) (119, 261)

AUCinf 139 201 178 218 (161, 295) 206 (142, 297) 281(h*ng/mL) (113, 171) (148, 273) (127, 249) (179, 443)

CI=Confidence Interval; GLSM = geometric least-squares meana Exposures were estimated using noncompartmental analysis from a dedicated Phase 1 renal impairment study GS-US-540-9015; single doses up to 100 mg were administered; each subject with renal impairment had a matched adult subjectenrolled with normal renal function (eGFR ≥90 mL/min/1.73m2), same sex, and similar body mass index (BMI (± 20%))and age (± 10 years)

Subjects with reduced renal function and matched adult subjects with normal renal function received the same remdesivirdoseb eGFR was calculated using Modification of Diet in Renal Disease equation and reported in mL/min/1.73 m^2c Ratio calculated for the comparison of PK parameters of test (subjects with reduced renal function) to reference (subjectswith normal renal function)d AUC0-72h for subjects on haemodialysis

Table 12: Pharmacokinetic parametersa of remdesivir and metabolites (GS-441524 and GS-704277) following IV administration of remdesivir (200 mg on day 1 followed by100 mg daily on days 2-5) to adults with COVID-19 and severely reduced kidneyfunction (eGFR <30 mL/min /1.73 m2)

Parameterb th th Remdesivir GS-441524 GS-704277

Mean (percentile, 5 , 95 )

Cmax 3850 703 378(ng/mL) (1530, 8720) (343, 1250) (127, 959)

AUCtau 2950 15400 1540(h*ng/mL) (1390, 8370) (7220, 27900) (767, 3880)a Population PK estimates for 30-minute IV infusion of remdesivir for 5 days (Study GS-US-540-5912, n=90).

b Geometric mean estimates.

The pharmacokinetics of remdesivir and GS-441524 in hepatic impairment have not been evaluated.

The role of the liver in the metabolism of remdesivir is unknown.

Hospitalisation

Pharmacokinetic exposures for remdesivir in hospitalised patients with severe COVID-19 pneumoniawere generally within the range of the exposures in non-hospitalised patients. The GS-704277 and

GS-441524 metabolite levels were modestly increased.

Remdesivir inhibited CYP3A4 in vitro (see section 4.5). At physiologically relevant concentrations(steady-state), remdesivir or its metabolites GS-441524 and GS-704277 did not inhibit CYP1A2, 2B6,2C8, 2C9, 2C19, and 2D6 in vitro. Remdesivir is not a time-dependent inhibitor of CYP450 enzymesin vitro.

Remdesivir induced CYP1A2 and potentially CYP3A4, but not CYP2B6 in vitro (see section 4.5).

In vitro data indicates no clinically relevant inhibition of UGT1A3, 1A4, 1A6, 1A9 or 2B7 byremdesivir or its metabolites GS-441524 and GS-704277. Remdesivir, but not its metabolites,inhibited UGT1A1 in vitro.

For GS-441524 and GS-704277, the only enzyme for which metabolism could be detected was

UGT1A3.

Remdesivir inhibited OAT3, MATE1, OCT1, OATP1B1 and OATP1B3 in vitro (see section 4.5).

At physiologically relevant concentrations, remdesivir and its metabolites did not inhibit P-gp and

BCRP in vitro.

Following intravenous administration (slow bolus) of remdesivir to rhesus monkeys and rats, severerenal toxicity occurred after short treatment durations. In male rhesus monkeys at dosage levels of 5,10, and 20 mg/kg/day for 7 days resulted, at all dose levels, in increased mean urea nitrogen andincreased mean creatinine, renal tubular atrophy, and basophilia and casts, and an unscheduled deathof one animal at the 20 mg/kg/day dose level. In rats, dosage levels of >3 mg/kg/day for up to 4 weeksresulted in findings indicative of kidney injury and/or dysfunction. Systemic exposures (AUC) of thepredominant circulating metabolite of remdesivir (GS-441524) were 0.1 times (monkeys at5 mg/kg/day) and 0.3 times (rats at 3 mg/kg/day) the exposure in humans following intravenousadministration at the recommended human dose (RHD).

Long-term animal studies to evaluate the carcinogenic potential of remdesivir have not beenperformed.

Remdesivir was not genotoxic in a battery of assays, including bacterial mutagenicity, chromosomeaberration using human peripheral blood lymphocytes, and in vivo rat micronucleus assays.

In female rats, decreases in corpora lutea, numbers of implantation sites, and viable embryos, wereseen when remdesivir was administered intravenously daily at a systemically toxic dose(10 mg/kg/day) 14 days prior to mating and during conception; exposures of the predominantcirculating metabolite (GS-441524) were 1.3 times the exposure in humans at the RHD. There were noeffects on female reproductive performance (mating, fertility, and conception) at this dose level.

In rats and rabbits, remdesivir demonstrated no adverse effect on embryofoetal development whenadministered to pregnant animals at systemic exposures (AUC) of the predominant circulatingmetabolite of remdesivir (GS-441524) that were up to 4 times the exposure in humans at the RHD.

In rats, there were no adverse effects on pre- and post-natal development at systemic exposures (AUC)of the predominant circulating metabolite of remdesivir (GS-441524) that were similar to the exposurein humans at the RHD.

Betadex sulfobutyl ether sodium

Hydrochloric acid (to adjust pH) (E507)

Sodium hydroxide (to adjust pH) (E524)

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

Unopened vials4 years

Store diluted remdesivir solution for infusion up to 24 hours at below 25°C or 48 hours in arefrigerator (2°C - 8°C).

No special precautions for storage.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

Type I clear glass vial, an elastomeric closure, and an aluminium overseal with a flip-off cap.

Pack size: 1 vial

Prepare solution for infusion under aseptic conditions and on the same day as administration.

Remdesivir should be inspected visually for particulate matter and discolouration prior toadministration, whenever solution and container permit. Should either be observed, the solution shouldbe discarded and fresh solution prepared.

Remdesivir must be reconstituted with 19 mL sterile water for injections and diluted in sodiumchloride 9 mg/mL (0.9%) solution for injection before being administered via intravenous infusionover 30 to 120 minutes.

Remove the required number of single-use vial(s) from storage. For each vial:

* Aseptically reconstitute remdesivir powder for concentrate for solution for infusion by additionof 19 mL of sterile water for injections using a suitably sized syringe and needle per vial.◦ Discard the vial if a vacuum does not pull the sterile water for injections into the vial.

* Only use sterile water for injection to reconstitute remdesivir powder.

* Immediately shake the vial for 30 seconds.

* Allow the contents of the vial to settle for 2 to 3 minutes. A clear solution should result.

* If the contents of the vial are not completely dissolved, shake the vial again for 30 seconds andallow the contents to settle for 2 to 3 minutes. Repeat this procedure as necessary until thecontents of the vial are completely dissolved.

* Inspect the vial to ensure the container closure is free from defects and the solution is free ofparticulate matter.

* Dilute immediately after reconstitution.

Care should be taken to prevent inadvertent microbial contamination. As there is no preservative orbacteriostatic agent present in this product, aseptic technique must be used in preparation of the finalparenteral solution. It is recommended to administer immediately after preparation when possible.

Adults and paediatric patients (weighing at least 40 kg)

* Using Table 13, determine the volume of sodium chloride 9 mg/mL (0.9%) solution forinjection to withdraw from the infusion bag.

Table 13: Recommended dilution instructions - Reconstituted remdesivir powder forconcentrate for solution for infusion

Sodium chloride Volume to be withdrawn and

Remdesivir 9 mg/mL (0.9%) infusion discarded from sodium chloride Required volume ofdose bag volume to be used 9 mg/mL (0.9%) infusion bag reconstituted remdesivir200 mg 250 mL 40 mL 2 × 20 mL(2 vials) 100 mL 40 mL 2 × 20 mL100 mg 250 mL 20 mL 20 mL(1 vial) 100 mL 20 mL 20 mL

NOTE: 100 mL should be reserved for patients with severe fluid restriction, e.g. with ARDS or renal failure.

* Withdraw and discard the required volume of sodium chloride 9 mg/mL from the bag using anappropriately sized syringe and needle per Table 13.

* Withdraw the required volume of reconstituted remdesivir using an appropriately sized syringeper Table 13. Discard any unused portion remaining in the remdesivir vial.

* Transfer the required volume of reconstituted remdesivir to the selected infusion bag.

* Gently invert the bag 20 times to mix the solution in the bag. Do not shake.

* The prepared solution is stable for 24 hours at room temperature (20°C to 25°C) or 48 hours inthe refrigerator (2°C to 8°C).

Paediatric patients (at least 4 weeks of age and weighing 3 kg to less than 40 kg)

* Further dilute the 100 mg/20 mL (5 mg/mL) remdesivir concentrate to a fixed concentration of1.25 mg/mL using 0.9% sodium chloride.

* The total required infusion volume of the 1.25 mg/mL remdesivir solution for infusion iscalculated from the paediatric weight-based dosing regimens of 5 mg/kg for the Loading Doseand 2.5 mg/kg for each Maintenance Dose.

* Small 0.9% sodium chloride infusion bags (e.g., 25, 50, or 100 mL) or an appropriately sizedsyringe should be used for paediatric dosing. The recommended dose is administered via IVinfusion in a total volume dependent on the dose to yield the target remdesivir concentration of1.25 mg/mL.

* A syringe may be used for delivering volumes <50 mL.

After infusion is complete, flush with at least 30 mL of sodium chloride 9 mg/mL.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Gilead Sciences Ireland UC

Carrigtohill

County Cork, T45 DP77

Ireland

EU/1/20/1459/002

Date of first authorisation: 03 July 2020

Date of latest renewal: 12 April 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.