VOSEVI 400mg / 100mg / 100mg film-coated tablets medication leaflet

Each film-coated tablet contains 400 mg sofosbuvir, 100 mg velpatasvir and 100 mg voxilaprevir.

Each film-coated tablet contains 111 mg of lactose (as monohydrate).

Each film-coated tablet contains 200 mg sofosbuvir, 50 mg velpatasvir and 50 mg voxilaprevir.

Each film-coated tablet contains 55 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet.

Beige, capsule-shaped, film-coated tablet of dimensions 10 mm x 20 mm, debossed with “GSI” on oneside and “3” on the other side.

Beige, oval-shaped, film-coated tablet of dimensions 8 mm x 15 mm, debossed with “GSI” on oneside and “SVV” on the other side.

Vosevi is indicated for the treatment of chronic hepatitis C virus (HCV) infection in patients aged12 years and older and weighing at least 30 kg (see sections 4.2, pct. 4.4 and 5.1).

Vosevi treatment should be initiated and monitored by a physician experienced in the management ofpatients with HCV infection.

The recommended dose of Vosevi in patients aged 12 years and older and weighing at least 30 kg isone 400 mg/100 mg/100 mg tablet or two 200 mg/50 mg/50 mg tablets, taken orally, once daily withfood (see section 5.2).

The recommended durations of treatment applicable to all HCV genotypes are shown in Table 1.

Table 1: Recommended treatment durations for Vosevi for all HCV genotypes in patients12 years and older and weighing at least 30 kg

Patient population Treatment duration

DAA naïve patients without cirrhosis 8 weeks12 weeks

DAA naïve patients with compensated cirrhosis8 weeks may be considered in genotype 3infected patients (see section 5.1)

DAA experienced patients* without cirrhosis or withcompensated cirrhosis 12 weeks

DAA: direct-acting antiviral agent

* In clinical studies the DAA experienced patients had been exposed to combination regimens containing any of thefollowing: daclatasvir, dasabuvir, elbasvir, grazoprevir, ledipasvir, ombitasvir, paritaprevir, sofosbuvir, velpatasvir,voxilaprevir (administered with sofosbuvir and velpatasvir for less than 12 weeks).

If a dose of Vosevi is missed and it is within 18 hours of the normal time, patients should be instructedto take the tablet(s) as soon as possible and then patients should take the next dose at the usual time. Ifit is after 18 hours then patients should be instructed to wait and take the next dose of Vosevi at theusual time. Patients should be instructed not to take a double dose of Vosevi.

Patients should be instructed that if vomiting occurs within 4 hours of dosing an additional dose of

Vosevi should be taken. If vomiting occurs more than 4 hours after dosing, no further dose of Voseviis needed (see section 5.1).

No dose adjustment is warranted for elderly patients (see section 5.2).

No dose adjustment of Vosevi is required for patients with mild or moderate renal impairment.

Safety data are limited in patients with severe renal impairment (estimated Glomerular Filtration Rate[eGFR] < 30 mL/min/1.73 m2) and end stage renal disease (ESRD) requiring haemodialysis. Vosevihas not been studied in patients with ESRD requiring dialysis. Vosevi can be used in these patientswith no dose adjustment when no other relevant treatment options are available (see section 4.4,4.8,5.1 and 5.2).

No dose adjustment of Vosevi is required for patients with mild hepatic impairment (Child-Pugh-

Turcotte [CPT] Class A). Vosevi is not recommended in patients with moderate or severe hepaticimpairment (CPT Class B or C) (see section 5.2).

The safety and efficacy of Vosevi in children aged less than 12 years and weighing less than 30 kghave not yet been established. No data are available.

For oral use.

Patients should be instructed to swallow the tablet(s) whole with food (see section 5.2). Due to thebitter taste, it is recommended that the film-coated tablet is not chewed or crushed.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Concomitant use with medicinal products that are strong P-glycoprotein (P-gp) and/or strongcytochrome P450 (CYP) inducers (e.g. carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutinand St. John’s wort) (see section 4.5).

Concomitant use with rosuvastatin or dabigatran etexilate (see section 4.5).

Concomitant use with ethinylestradiol-containing medicinal products such as combined oralcontraceptives or contraceptive vaginal rings or transdermal patches (see section 4.5).

Life-threatening cases of severe bradycardia and heart block have been observed when sofosbuvircontaining regimens are used in combination with amiodarone. Bradycardia has generally occurredwithin hours to days, but cases with a longer time to onset have been observed mostly up to 2 weeksafter initiating HCV treatment.

Amiodarone should only be used in patients on Vosevi when other alternative anti-arrhythmictreatments are not tolerated or are contraindicated.

Should concomitant use of amiodarone be considered necessary, it is recommended that patientsundergo cardiac monitoring in an in-patient setting for the first 48 hours of coadministration, afterwhich outpatient or self-monitoring of the heart rate should occur on a daily basis through at least thefirst 2 weeks of treatment.

Due to the long half-life of amiodarone, cardiac monitoring as outlined above should also be carriedout for patients who have discontinued amiodarone within the past few months and are to be initiatedon Vosevi.

All patients with concurrent or recent use of amiodarone should be warned of the symptoms ofbradycardia and heart block and should be advised to seek medical advice urgently should theyexperience them.

There are no data on the use of Vosevi in patients with HCV/hepatitis B virus (HBV) co-infection.

Cases of HBV reactivation, some of them fatal, have been reported during or after treatment with

DAAs. HBV screening should be performed in all patients before initiation of treatment. HCV/HBVco-infected patients are at risk of HBV reactivation, and should therefore be monitored and managedaccording to current clinical guidelines.

Safety data are limited in patients with severe renal impairment (estimated glomerular filtration rate[eGFR] < 30 mL/min/1.73 m2) and ESRD requiring haemodialysis. Vosevi can be used in thesepatients with no dose adjustment when no other relevant treatment options are available (seesections 4.8, 5.1 and 5.2).

No dose adjustment of Vosevi is required for patients with mild hepatic impairment (CPT Class A).

Vosevi is not recommended in patients with moderate or severe hepatic impairment (CPT Class Bor C) (see section 5.2).

The safety and efficacy of Vosevi in the treatment of HCV infection in patients who are post-livertransplant have not been assessed. Treatment with Vosevi, in accordance with the recommendedposology (see section 4.2), should be guided by an assessment of the potential benefits and risks forthe individual patient.

Medicinal products that are moderate P-gp and/or moderate CYP inducers (e.g. efavirenz, modafinil,oxcarbazepine or rifapentine) may decrease sofosbuvir, velpatasvir and/or voxilaprevir plasmaconcentrations leading to reduced therapeutic effect of Vosevi. Co-administration of such medicinalproducts with Vosevi is not recommended (see section 4.5).

Medicinal products that are strong OATP1B inhibitors (e.g. ciclosporin) may substantially increasevoxilaprevir plasma concentrations, the safety of which has not been established. Co-administration ofstrong OATP1B inhibitors with Vosevi is not recommended (see section 4.5).

Vosevi has been shown to increase tenofovir exposure when used together with an HIV regimencontaining tenofovir disoproxil fumarate and a pharmacokinetic enhancer (ritonavir or cobicistat). Thesafety of tenofovir disoproxil fumarate in the setting of Vosevi and a pharmacokinetic enhancer hasnot been established. The potential risks and benefits associated with co-administration of Vosevi withthe fixed-dose combination tablet containing elvitegravir/cobicistat/emtricitabine/tenofovir disoproxilfumarate or tenofovir disoproxil fumarate given in conjunction with a boosted HIV protease inhibitor(e.g. darunavir) should be considered, particularly in patients at increased risk of renal dysfunction.

Patients receiving Vosevi concomitantly with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxilfumarate or with tenofovir disoproxil fumarate and a boosted HIV protease inhibitor should bemonitored for tenofovir-associated adverse reactions. Refer to tenofovir disoproxil fumarate,emtricitabine/tenofovir disoproxil fumarate, or elvitegravir/cobicistat/emtricitabine/tenofovirdisoproxil fumarate Summary of Product Characteristics for recommendations on renal monitoring.

Diabetics may experience improved glucose control, potentially resulting in symptomatichypoglycaemia, after initiating HCV DAA treatment. Glucose levels of diabetic patients initiating

DAA therapy should be closely monitored, particularly within the first 3 months, and their diabetictreatment modified when necessary. The physician in charge of the diabetic care of the patient shouldbe informed when DAA therapy is initiated.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

As Vosevi contains sofosbuvir, velpatasvir and voxilaprevir, any interactions that have been identifiedwith these active substances individually may occur with Vosevi.

Velpatasvir and voxilaprevir are inhibitors of drug transporters P-gp, breast cancer resistance protein(BCRP), organic anion-transporting polypeptide (OATP) 1B1 and OATP1B3. Co-administration of

Vosevi with medicinal products that are substrates of these transporters may increase the exposure ofsuch medicinal products. Medicinal products that are sensitive substrates of these transporters and forwhich elevated plasma levels are associated with serious events are contraindicated (see Table 2).

Dabigatran etexilate (P-gp substrate) and rosuvastatin (OATP1B and BCRP substrate) arecontraindicated (see section 4.3 and Table 2).

Sofosbuvir, velpatasvir and voxilaprevir are substrates of drug transporters P-gp and BCRP.

Velpatasvir and voxilaprevir are substrates of drug transporters OATP1B1 and OATP1B3. In vitro,slow metabolic turnover of velpatasvir primarily by CYP2B6, CYP2C8 and CYP3A4 and ofvoxilaprevir primarily by CYP3A4 was observed.

Medicinal products that are strong inducers of P-gp and/or strong inducers of CYP2B6, CYP2C8, or

CYP3A4 (e.g. carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin and St. John’s wort)may decrease plasma concentrations of sofosbuvir, velpatasvir and/or voxilaprevir leading to reducedtherapeutic effect of Vosevi. The use of such medicinal products with Vosevi is contraindicated (seesection 4.3 and Table 2).

Medicinal products that are moderate P-gp inducers and/or moderate CYP inducers (e.g. efavirenz,modafinil, oxcarbazepine or rifapentine) may decrease sofosbuvir, velpatasvir and/or voxilaprevirplasma concentrations leading to reduced therapeutic effect of Vosevi. Co-administration with suchmedicinal products is not recommended with Vosevi (see section 4.4 and Table 2).

Co-administration with medicinal products that inhibit P-gp or BCRP may increase sofosbuvir,velpatasvir or voxilaprevir plasma concentrations. Medicinal products that inhibit OATP1B, CYP2B6,

CYP2C8, or CYP3A4 may increase plasma concentrations of velpatasvir or voxilaprevir. The use ofstrong inhibitors of OATP1B (e.g. ciclosporin) with Vosevi is not recommended (see section 4.4 and

Table 2). Clinically significant medicinal product interactions with Vosevi mediated by P-gp, BCRPand CYP inhibitors are not expected. Vosevi may be co-administered with P-gp, BCRP and CYPinhibitors.

As liver function may change during treatment with Vosevi, close monitoring of International

Normalised Ratio (INR) values is recommended.

Impact of DAA therapy on medicinal products metabolized by the liver

The pharmacokinetics of medicinal products that are metabolized by the liver (e.g.immunosuppressive agents such as calcineurin inhibitors) may be impacted by changes in liverfunction during DAA therapy, related to clearance of HCV.

Concomitant use with ethinylestradiol-containing medicinal products may increase the risk of alanineaminotransferase (ALT) elevations and is contraindicated (see section 4.3 and Table 2).

Table 2 provides a listing of established or potentially clinically significant medicinal productinteractions (where 90% confidence interval [CI] of the geometric least-squares mean [GLSM] ratiowere within “↔”, extended above “↑”, or extended below “↓” the predetermined interactionboundaries). The medicinal product interactions described are based on studies conducted with eithersofosbuvir/velpatasvir/voxilaprevir, its components (sofosbuvir, velpatasvir, and/or voxilaprevir), orare predicted medicinal product interactions that may occur with Vosevi. The table is not all-inclusive.

Table 2: Interactions between Vosevi and other medicinal products

Medicinal product by Effects on medicinal product levels.therapeutic areas/Possible Mean ratio (90% confidence interval)a,b Recommendation concerningmechanism of interaction Active Cmax AUC Cmin co-administration with Vosevi

ACID REDUCING AGENTS

Antacidse.g. Aluminium or Interaction not studied. It is recommended to separatemagnesium hydroxide; Expected: antacid and Vosevi administrationcalcium carbonate ↔ Sofosbuvir by 4 hours.↓ Velpatasvir(Increase in gastric pH ↔ Voxilaprevirdecreases velpatasvirsolubility)

H2-receptor antagonists

Famotidine Observed: H2-receptor antagonists may be(40 mg single dose) + Sofosbuvir ↔ ↔ administered simultaneously withsofosbuvir/velpatasvir/ Velpatasvir ↔ ↔ or staggered from Vosevi at avoxilaprevir Voxilaprevir ↔ ↔ dose that does not exceed doses(400/100/100 mg single comparable with famotidinedose)c 40 mg twice daily.

Famotidine dosedsimultaneously with Vosevi

Cimetidined

Nizatidined

Ranitidined(Increase in gastric pHdecreases velpatasvirsolubility)

Medicinal product by Effects on medicinal product levels.therapeutic areas/Possible Mean ratio (90% confidence interval)a,b Recommendation concerningmechanism of interaction Active Cmax AUC Cmin co-administration with Vosevi

Famotidine Observed:(40 mg single dose) + Sofosbuvir ↔ ↔sofosbuvir/velpatasvir/ Velpatasvir ↔ ↔voxilaprevir (400/100/ Voxilaprevir ↔ ↔100 mg single dose)c

Famotidine dosed 12 hoursprior to Vosevi(Increase in gastric pHdecreases velpatasvirsolubility)

Omeprazole Observed: Proton pump inhibitors may be(20 mg once daily) + Sofosbuvir ↓ ↓ administered with Vosevi at asofosbuvir/velpatasvir/ 0.77 0.73 dose that does not exceed dosesvoxilaprevir (400/100/ (0.65, (0.67, comparable with omeprazole100 mg single dose)c 0.91) 0.79) 20 mg.

Velpatasvir ↓ ↓

Omeprazole dosed 2 hours 0.43 0.46prior to Vosevi (0.38, (0.41,0.49) 0.52)

Lansoprazoled Voxilaprevir ↓ ↔

Rabeprazoled 0.76

Pantoprazoled (0.69,

Esomeprazoled 0.85)(Increase in gastric pHdecreases velpatasvirsolubility)

Omeprazole Observed:(20 mg once daily) + Sofosbuvir ↔ ↔sofosbuvir/velpatasvir/ Velpatasvir ↓ ↓voxilaprevir (400/100/ 0.49 0.49100 mg single dose)c (0.43, (0.43,0.55) 0.55)

Omeprazole dosed 4 hours Voxilaprevir ↔ ↔after Vosevi(Increase in gastric pHdecreases velpatasvirsolubility)

ANTIARRHYTHMICS

Amiodarone Effect on amiodarone, voxilaprevir, Coadministration of amiodaronevelpatasvir, and sofosbuvir concentrations with a sofosbuvir-containingunknown. regimen may result in serioussymptomatic bradycardia.

Use only if no other alternative isavailable. Close monitoring isrecommended if this medicinalproduct is administered with

Vosevi (see sections 4.4 and 4.8).

Medicinal product by Effects on medicinal product levels.therapeutic areas/Possible Mean ratio (90% confidence interval)a,b Recommendation concerningmechanism of interaction Active Cmax AUC Cmin co-administration with Vosevi

Digoxin Interaction only studied with velpatasvir. Co-administration of Vosevi with

Expected: digoxin may increase the↔ Sofosbuvir concentration of digoxin. Caution↔ Voxilaprevir is warranted and therapeutic

Digoxin (0.25 mg single Effect on velpatasvir exposure not studied concentration monitoring ofdose)e + velpatasvir Expected: digoxin is recommended.(100 mg single dose) ↔ Velpatasvir

Observed:(Inhibition of P-gp) Digoxin ↑ ↑1.88 1.34(1.71, (1.13,2.08) 1.60)

ANTICOAGULANTS

Dabigatran etexilate (75 mg Effect on sofosbuvir, velpatasvir and Vosevi is contraindicated withsingle dose) + voxilaprevir concentrations not studied dabigatran etexilate (seesofosbuvir/velpatasvir/ Expected: section 4.3).voxilaprevir (400/100/ ↔ Sofosbuvir100 mg single dose) + ↔ Velpatasvirvoxilaprevir (100 mg single ↔ Voxilaprevirdose)f Observed:

Dabigatran ↑ ↑(Inhibition of P-gp) 2.87 2.61(2.61, (2.41,3.15) 2.82)

Edoxaban Interaction not studied. Co-administration of Vosevi with

Expected: edoxaban is not recommended.(Inhibition of OATP1B1) ↑ Edoxaban (active metabolite) Should direct Xa inhibitor use be↔ Sofosbuvir deemed necessary, apixaban or↔ Velpatasvir rivaroxaban may be considered.↔ Voxilaprevir

Vitamin K antagonists Interaction not studied. Close monitoring of INR isrecommended when Vosevi is co-(Liver function changes administered with all vitamin Kduring treatment with antagonists.

Vosevi).

ANTICONVULSANTS

Phenytoin Interaction not studied. Vosevi is contraindicated with

Phenobarbital Expected: phenobarbital and phenytoin (see↓ Sofosbuvir section 4.3).(Induction of P-gp and ↓ Velpatasvir

CYPs) ↓ Voxilaprevir

Carbamazepine Interaction not studied. Vosevi is contraindicated with

Expected: carbamazepine (see section 4.3).(Induction of P-gp and ↓ Velpatasvir

CYPs) ↓ Voxilaprevir

Observed:

Sofosbuvir ↓ ↓0.52 0.52(0.43, (0.46,0.62) 0.59)

Medicinal product by Effects on medicinal product levels.therapeutic areas/Possible Mean ratio (90% confidence interval)a,b Recommendation concerningmechanism of interaction Active Cmax AUC Cmin co-administration with Vosevi

ANTIFUNGALS

Ketoconazole Interaction only studied with velpatasvir No dose adjustment of Vosevi or

Expected: ketoconazole is required.(Inhibition of P-gp and ↔ Sofosbuvir

CYP3A) ↑ Voxilaprevir

Ketoconazole (200 mg Effect on ketoconazole exposure nottwice daily) + velpatasvir studied.(100 mg single dose)f Expected:↔ Ketoconazole

Itraconazoled Observed:

Posaconazoled Velpatasvir ↑ ↑

Isavuconazoled 1.29 1.71(1.02, (1.35,1.64) 2.18)(Inhibition of P-gp and

CYP3A)

Voriconazole Interaction only studied with voxilaprevir. No dose adjustment of Vosevi or

Expected: voriconazole is required.(Inhibition of CYP3A) ↔ Sofosbuvir↑ Velpatasvir

Voriconazole (200 mg twice Observed:daily) + voxilaprevir Voxilaprevir ↔ ↑(100 mg single dose)f 1.84(1.66,2.03)

Medicinal product by Effects on medicinal product levels.therapeutic areas/Possible Mean ratio (90% confidence interval)a,b Recommendation concerningmechanism of interaction Active Cmax AUC Cmin co-administration with Vosevi

ANTIMYCOBACTERIALS

Rifampicin (single dose) Interaction only studied with velpatasvir Vosevi is contraindicated withand voxilaprevir. rifampicin (see section 4.3).(Inhibition of OATP1B)

Expected:↔ Rifampicin↔ Sofosbuvir

Rifampicin (600 mg single Observed:dose) + velpatasvir (100 mg Velpatasvir ↑ ↑single dose)f 1.28 1.46(1.05, (1.17,1.56) 1.83)

Rifampicin (600 mg single Voxilaprevir ↑ ↑dose) + voxilaprevir 11.10 7.91(100 mg single dose)f (8.23, (6.20,14.98) 10.09)

Rifampicin (multiple dose) Effect on rifampicin exposure not studied.

(Induction of P-gp and Expected:

CYPs) ↔ Rifampicin

Rifampicin (600 mg once Observed:daily) + sofosbuvir (400 mg Sofosbuvir ↓ ↓single dose)f 0.23 0.28(0.19, (0.24,0.29) 0.32)

Rifampicin (600 mg once Velpatasvir ↓ ↓daily) + velpatasvir (100 mg 0.29 0.18single dose)f (0.23, (0.15,0.37) 0.22)

Rifampicin (600 mg once Voxilaprevir ↔ ↓daily) + voxilaprevir 0.27(100 mg single dose)f (0.23,0.31)

Rifabutin Interaction not studied. Vosevi is contraindicated with

Expected: rifabutin (see section 4.3).↓ Velpatasvir↓ Voxilaprevir

Observed:(Induction of P-gp and Sofosbuvir ↓ ↓

CYPs) 0.64 0.76(0.53, (0.63,0.77) 0.91)

Rifapentine Interaction not studied. Co-administration of Vosevi with

Expected: rifapentine is not recommended(Induction of P-gp and ↓ Sofosbuvir (see section 4.4).

CYPs) ↓ Velpatasvir↓ Voxilaprevir

HIV ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS

Tenofovir disoproxil Vosevi has been shown to increase tenofovir exposure (P-gp inhibition). Therefumarate was an increase in tenofovir exposure (AUC and Cmax) of around 40% during co-treatment with Vosevi and darunavir + ritonavir + tenofovir disoproxil(Inhibition of P-gp) fumarate/emtricitabine.

Patients receiving tenofovir disoproxil fumarate and Vosevi concomitantlyshould be monitored for adverse reactions associated with tenofovir disoproxilfumarate. Refer to the tenofovir disoproxil fumarate-containing product’s

Summary of Product Characteristics for recommendations on renal monitoring(see section 4.4).

Medicinal product by Effects on medicinal product levels.therapeutic areas/Possible Mean ratio (90% confidence interval)a,b Recommendation concerningmechanism of interaction Active Cmax AUC Cmin co-administration with Vosevi

Efavirenz/emtricitabine/ Interaction only studied with Co-administration of Vosevi withtenofovir disoproxil sofosbuvir/velpatasvir efavirenz/emtricitabine/tenofovirfumarate (600/200/300 mg Expected: disoproxil fumarate is notonce daily)g + sofosbuvir/ ↓ Voxilaprevir recommended (see section 4.4).velpatasvir (400/100 mg Observed:once daily)f, h Efavirenz ↔ ↔ ↔

Sofosbuvir ↑ ↔(Induction of CYPs) 1.38(1.14,1.67)

Velpatasvir ↓ ↓ ↓0.53 0.47 0.43(0.43, (0.39, (0.36,0.64) 0.57) 0.52)

Emtricitabine/rilpivirine/ Observed: No dose adjustment of Vosevi ortenofovir alafenamide Rilpivirine ↔ ↔ ↔ emtricitabine/rilpivirine/tenofovir(200/25/25 mg once daily)i Sofosbuvir ↔ ↔ alafenamide is required.+ sofosbuvir/velpatasvir/ Velpatasvir ↔ ↔ ↔voxilaprevir (400/100/ Voxilaprevir ↔ ↔ ↔100 mg oncedaily) + voxilaprevir(100 mg once daily)f

HIV ANTIVIRAL AGENTS: HIV PROTEASE INHIBITORS

Atazanavir boosted with Effect on atazanavir and ritonavir exposure Co-administration of Vosevi withritonavir (300 + 100 mg not studied. atazanavir is expected to increasesingle dose) + sofosbuvir/ the concentration of voxilaprevir.velpatasvir/voxilaprevir Expected: Co-administration of Vosevi with(400/100/100 mg single ↔ Atazanavir atazanavir-containing regimens isdose)f ↔ Ritonavir not recommended.

Observed:(Inhibition of OATP1B, Sofosbuvir ↑ ↑

P-gp and CYP3A) 1.29 1.40(1.09, (1.25,1.52) 1.57)

Velpatasvir ↑ ↑1.29 1.93(1.07, (1.58,1.56) 2.36)

Voxilaprevir ↑ ↑4.42 4.31(3.65, (3.76,5.35) 4.93)

Medicinal product by Effects on medicinal product levels.therapeutic areas/Possible Mean ratio (90% confidence interval)a,b Recommendation concerningmechanism of interaction Active Cmax AUC Cmin co-administration with Vosevi

Darunavir boosted with Observed: No dose adjustment of Vosevi,ritonavir (800 + 100 mg Darunavir ↔ ↔ ↓ darunavir (ritonavir boosted) oronce daily) + emtricitabine/ 0.66 emtricitabine/tenofovir disoproxiltenofovir disoproxil (0.58, fumarate is required.fumarate (200/300 mg once 0.74)daily)j + sofosbuvir/ Ritonavir ↑ ↑ ↔velpatasvir/voxilaprevir 1.60 1.45(400/100/100 mg once (1.47, (1.35,daily) + voxilaprevir 1.75) 1.57)(100 mg once daily)f Sofosbuvir ↓ ↔0.70(Inhibition of OATP1B, (0.62,

P-gp, and CYP3A) 0.78)

Velpatasvir ↔ ↔ ↔

Voxilaprevir ↑ ↑ ↑1.72 2.43 4.00(1.51, (2.15, (3.44,1.97) 2.75) 4.65)

Lopinavir Interaction not studied. Co-administration of Vosevi with

Expected: lopinavir-containing regimens is(Inhibition of OATP1B) ↔ Lopinavir not recommended.

↔ Sofosbuvir↔ Velpatasvir↑ Voxilaprevir

HIV ANTIVIRAL AGENTS: INTEGRASE INHIBITORS

Raltegravir (400 mg twice Interaction only studied with No dose adjustment of Vosevi,daily)k + emtricitabine/ sofosbuvir/velpatasvir raltegravir ortenofovir disoproxil Expected: emtricitabine/tenofovir disoproxilfumarate (200/300 mg once ↔ Voxilaprevir fumarate is required.daily)j + sofosbuvir/ Observed:velpatasvir (400/100 mg Raltegravir ↔ ↔ ↓once daily)f, h 0.79(0.42,1.48)

Sofosbuvir ↔ ↔

Velpatasvir ↔ ↔ ↔

Medicinal product by Effects on medicinal product levels.therapeutic areas/Possible Mean ratio (90% confidence interval)a,b Recommendation concerningmechanism of interaction Active Cmax AUC Cmin co-administration with Vosevi

Elvitegravir/cobicistat/ Observed: No dose adjustment of Vosevi oremtricitabine/tenofovir Elvitegravir ↔ ↔ ↑ elvitegravir/cobicistat/alafenamide fumarate 1.32 emtricitabine/tenofovir(150/150/200/10 mg once (1.17, alafenamide fumarate is required.daily)l + 1.49)sofosbuvir/velpatasvir/ Cobicistat ↔ ↑ ↑voxilaprevir (400/100/ 1.50 3.50100 mg once daily) + (1.44, (3.01,voxilaprevir (100 mg once 1.58) 4.07)daily)f Tenofovir ↓ ↔0.79(Inhibition of OATP1B, (0.68,

P-gp/BCRP and CYP3A) 0.92)

Sofosbuvir ↑ ↔1.27(1.09,1.48)

Velpatasvir ↔ ↔ ↑1.46(1.30,1.64)

Voxilaprevir ↑ ↑ ↑1.92 2.71 4.50(1.63, (2.30, (3.68,2.26) 3.19) 5.50)

Dolutegravir (50 mg once Interaction only studied with No dose adjustment of Vosevi ordaily) + sofosbuvir/ sofosbuvir/velpatasvir dolutegravir is required.velpatasvir (400/100 mg Expected:once daily)h ↔ Voxilaprevir

Observed:

Dolutegravir ↔ ↔ ↔

Sofosbuvir ↔ ↔

Velpatasvir ↔ ↔ ↔

HERBAL SUPPLEMENTS

St. John’s wort Interaction not studied. Vosevi is contraindicated with

Expected: St. John’s wort (see section 4.3).(Induction of P-gp and ↓ Sofosbuvir

CYPs) ↓ Velpatasvir↓ Voxilaprevir

HMG-CoA REDUCTASE INHIBITORS

Atorvastatin Interaction only studied with sofosbuvir/ Atorvastatin may be administeredvelpatasvir. with Vosevi at a dose that does

Expected: not exceed atorvastatin 20 mg.↔ Voxilaprevir

Atorvastatin (40 mg single Observed: ↑ ↑dose) + sofosbuvir/ atorvastatin 1.7 1.5velpatasvir (400/100 mg (1.5, (1.5,once daily)f 1.9) 1.6)

Medicinal product by Effects on medicinal product levels.therapeutic areas/Possible Mean ratio (90% confidence interval)a,b Recommendation concerningmechanism of interaction Active Cmax AUC Cmin co-administration with Vosevi

Rosuvastatin Effect on sofosbuvir, velpatasvir and Vosevi is contraindicated withvoxilaprevir not studied. rosuvastatin (see section 4.3).

Expected:↔ Sofosbuvir↔ Velpatasvir↔ Voxilaprevir

Rosuvastatin (10 mg single Observed:dose) + sofosbuvir/ Rosuvastatin ↑ ↑velpatasvir/voxilaprevir 18.9 7.4(400/100/100 mg once (16.2, (6.7,daily) + voxilaprevir 22.0) 8.2)(100 mg once daily)f(Inhibition of OATP1B and

BCRP)

Pravastatin Effect on sofosbuvir, velpatasvir and Pravastatin may be administeredvoxilaprevir not studied. with Vosevi at a dose that does

Expected: not exceed pravastatin 40 mg.↔ Sofosbuvir↔ Velpatasvir↔ Voxilaprevir

Pravastatin (40 mg single Observed:dose) + sofosbuvir/ Pravastatin ↑ ↑velpatasvir/voxilaprevir 1.89 2.16(400/100/100 mg once (1.53, (1.79,daily) + voxilaprevir 2.34) 2.60)(100 mg once daily)f(Inhibition of OATP1B)

Other statins Effect on fluvastatin, lovastatin, pitavastatin Interactions cannot be excludedand simvastatin not studied. with other HMG-CoA reductase(Inhibition of OATP1B) inhibitors. Co-administration with

Vosevi is not recommended.

NARCOTIC ANALGESICS

Methadone Interaction only studied with sofosbuvir No dose adjustment of Vosevi or

Expected: methadone is required.↔ Velpatasvir↔ Voxilaprevir

Methadone Observed:(Methadone maintenance R-methadone ↔ ↔ ↔therapy [30 to 130 mg S-methadone ↔ ↔ ↔daily]) + sofosbuvir Sofosbuvir ↔ ↑(400 mg once daily)f 1.30(1.00,1.69)

Medicinal product by Effects on medicinal product levels.therapeutic areas/Possible Mean ratio (90% confidence interval)a,b Recommendation concerningmechanism of interaction Active Cmax AUC Cmin co-administration with Vosevi

IMMUNOSUPPRESSANTS

Ciclosporin Observed: Co-administration of Vosevi with(600 mg single dose)f + Ciclosporin ↔ ↔ ciclosporin is not recommendedsofosbuvir (400 mg single Sofosbuvir ↑ ↑ (see section 4.4).dose)e 2.54 4.53(1.87, (3.26,(Inhibition of OATP1B or 3.45) 6.30)

P-gp or BCRP)

Ciclosporin Ciclosporin ↔ ↓(600 mg single dose)e + 0.88velpatasvir (100 mg single (0.78,dose)f 1.0)

Velpatasvir ↑ ↑1.56 2.03(1.22, (1.51,2.01) 2.71)

Ciclosporin Ciclosporin ↔ ↔(600 mg single dose)e + Voxilaprevir ↑ ↑voxilaprevir (100 mg single 19.0 9.4dose)f (14.1, (7.4,25.6) 12.0)

Tacrolimus Effect on velpatasvir or voxilaprevir No dose adjustment of Vosevi orexposure not studied. tacrolimus is required at initiation

Expected: of co-administration. Afterwards,↔ Velpatasvir close monitoring and potential↔ Voxilaprevir dose adjustment of tacrolimus

Tacrolimus (5 mg single Observed: may be required.dose)e + sofosbuvir (400 mg Tacrolimus ↓ ↑single dose)f 0.73 1.09(0.59, (0.84,0.90) 1.40)

Sofosbuvir ↓ ↑0.97 1.13(0.65, (0.81,1.43) 1.57)

HORMONAL CONTRACEPTIVES

Oral norgestimate/ethinyl Observed: Vosevi is contraindicated withestradiol (norgestimate Norelgestrom ↔ ↔ ↔ ethinylestradiol-containing0.180 mg/0.215 mg/0.25 mg in medicinal products (see/ethinyl estradiol 0.025 mg) Norgestrel ↔ ↔ ↔ section 4.3). Alternative methods+ sofosbuvir/velpatasvir/ Ethinyl ↔ ↔ ↔ of contraception (e.g. progestinvoxilaprevir (400/100/ estradiol only contraception or non-100 mg once daily) + hormonal methods) should bevoxilaprevir (100 mg once considered.daily)f

STIMULANTS

Modafinil Interaction not studied. Co-administration of Vosevi with

Expected: modafinil is not recommended(Induction of P-gp and ↔ Modafinil (see section 4.4).

CYPs) ↓ Sofosbuvir↓ Velpatasvir↓ Voxilaprevir

a. Mean ratio (90% CI) of co-administered drug pharmacokinetics of study medicinal products alone or in combination. Noeffect = 1.00.

b. All interaction studies conducted in healthy volunteers.

c. Lack of pharmacokinetics interaction lower bound 70%.

d. These are medicinal products within class where similar interactions could be predicted.

e. Bioequivalence/Equivalence boundary 80-125%.

f. Lack of pharmacokinetics interaction bounds 70-143%.g. Administered as efavirenz, emtricitabine and tenofovir DF fixed-dose combination.

h. Administered as sofosbuvir, velpatasvir fixed-dose combination.i. Administered as emtricitabine, rilpivirine, and tenofovir alafenamide fixed-dose combination.j. Administered as emtricitabine, tenofovir disoproxil fumarate fixed-dose combination.k. Lack of pharmacokinetics interaction bounds 50-200%.l. Administered as elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide fixed-dose combination.

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of sofosbuvir,velpatasvir, voxilaprevir or Vosevi in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity(see section 5.3).

It has not been possible to fully estimate exposure margins achieved for sofosbuvir in the rat relativeto the exposure in humans at the recommended clinical dose (see section 5.3).

Animal studies have shown a possible link to reproductive toxicity (see section 5.3).

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity(see section 5.3).

As a precautionary measure, Vosevi use is not recommended during pregnancy.

It is unknown whether sofosbuvir, metabolites of sofosbuvir, velpatasvir or voxilaprevir are excretedin human milk.

Available pharmacokinetic data in animals have shown excretion of velpatasvir and metabolites ofsofosbuvir in milk. When administered to lactating rats, voxilaprevir was detected in the plasma ofnursing pups.

A risk to the newborns/infants cannot be excluded. Therefore, Vosevi should not be used duringbreast-feeding.

No human data on the effect of Vosevi on fertility are available. Animal studies do not indicateharmful effects of sofosbuvir, velpatasvir or voxilaprevir on fertility.

Vosevi has no or negligible influence on the ability to drive and use machines.

In Phase 2 and 3 clinical studies, the proportion of patients who permanently discontinued treatmentdue to adverse reactions was 0.1% for patients receiving sofosbuvir/velpatasvir/voxilaprevir for8 weeks. There were no patients receiving sofosbuvir/velpatasvir/voxilaprevir for 12 weeks whopermanently discontinued treatment due to adverse reactions in the Phase 2 and 3 pivotal clinicalstudies.

Assessment of adverse reactions for Vosevi is based on safety data from clinical studies and post-marketing experience. All adverse reactions are presented in Table 3. The adverse reactions are listedbelow by system organ class and frequency. Frequencies are defined as follows: very common(≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000)or very rare (< 1/10,000).

Table 3: Adverse reactions identified with Vosevi

Frequency Adverse reaction

Very common headache

Very common diarrhoea, nausea

Common abdominal pain, decreased appetite, vomiting

Common rash

Uncommon angioedemaa

Common myalgia

Uncommon muscle spasm

Laboratory investigations:

Common total bilirubin increased

a. Adverse reaction identified through post-marketing surveillance for sofosbuvir/velpatasvir-containing products

Cases of severe bradycardia and heart block have been observed when sofosbuvir containing regimensare used in combination with amiodarone and/or other medicinal products that lower heart rate (seesections 4.4 and 4.5).

Frequency not known: Stevens-Johnson syndrome

In the Phase 3 studies increases in total bilirubin less than or equal to 1.5 x the upper limit of normalwere observed in 4% of patients without cirrhosis and 10% of patients with compensated cirrhosis, dueto inhibition of OATP1B1 and OATP1B3 by voxilaprevir. Total bilirubin levels decreased aftercompleting Vosevi treatment.

The safety of sofosbuvir in a fixed dose combination with either ledipasvir or velpatasvir has beenstudied in 154 patients with ESRD requiring dialysis (Study 4062 and Study 4063). In this setting,exposure of sofosbuvir metabolite GS-331007 is 20-fold increased, exceeding levels where adversereactions have been observed in preclinical studies. In this limited clinical safety data set, the rate ofadverse events and deaths was not clearly elevated from what is expected in ESRD patients.

The safety assessment of Vosevi in paediatric patients aged 12 years and older is based on data from21 DAA-naïve patients with genotype 1, 2, 3, or 4 HCV infection (without cirrhosis) who were treatedwith Vosevi for 8 weeks in a Phase 2, open-label clinical study (study 1175). The adverse reactionsobserved were consistent with those observed in clinical studies of Vosevi 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.

The highest documented doses of sofosbuvir, velpatasvir and voxilaprevir were single doses of1,200 mg, 500 mg, and 900 mg, respectively. In healthy adult volunteer studies with sofosbuvir andvelpatasvir, there were no untoward effects observed at these dose levels, and adverse events weresimilar in frequency and severity to those reported in the placebo groups. The most common adversereactions in patients receiving voxilaprevir 900 mg were diarrhoea (34%), nausea (17%) and headache(9%).

No specific antidote is available for overdose with Vosevi. If overdose occurs the patient must bemonitored for evidence of toxicity. Treatment of overdose with Vosevi consists of general supportivemeasures including monitoring of vital signs, as well as observation of the clinical status of the patient.

Haemodialysis can efficiently remove the predominant circulating metabolite of sofosbuvir,

GS-331007, with an extraction ratio of 53%. Haemodialysis is unlikely to result in significant removalof velpatasvir or voxilaprevir since velpatasvir and voxilaprevir are highly bound to plasma proteins.

Pharmacotherapeutic group: Antivirals for systemic use; Direct-acting antivirals, ATC code: J05AP56

Sofosbuvir is a pan-genotypic inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which isrequired for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellularmetabolism to form the pharmacologically active uridine analogue triphosphate (GS-461203), whichcan be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. In abiochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCVgenotype 1b, 2a, 3a, and 4a. GS-461203 is neither an inhibitor of human DNA and RNA polymerasesnor an inhibitor of mitochondrial RNA polymerase.

Velpatasvir is a pan-genotypic HCV inhibitor targeting the HCV NS5A protein, which is required forviral replication.

Voxilaprevir is a pan-genotypic inhibitor of the HCV NS3/4A protease. Voxilaprevir acts as anoncovalent, reversible inhibitor of the NS3/4A protease.

The 50% effective concentration (EC50) values of sofosbuvir, velpatasvir and voxilaprevir againstfull-length or chimeric replicons encoding NS5B, NS5A and NS3 protease sequences from thelaboratory strains are presented in Table 4. The EC50 values of sofosbuvir, velpatasvir and voxilapreviragainst clinical isolates are presented in Table 5.

Table 4: Activity of sofosbuvir, velpatasvir and voxilaprevir against full-length or chimericlaboratory replicons

Replicon Sofosbuvir EC50, nMa Velpatasvir EC50, nMa Voxilaprevir EC50, nMagenotype1a 40 0.014 3.9e1b 110 0.016 3.3e2a 50 0.005-0.016c 3.7-4.5e2b 15b 0.002-0.006c 1.8-6.6f3a 50 0.004 6.1f4a 40 0.009 2.9e4d 33 0.004 3.2e5a 15b 0.021-0.054d 1.9f6a 14-25b 0.006-0.009 3.0-4.0e6e NA 0.130d 0.33f6n NA NA 2.9f

NA: Not available

a. Mean value from multiple experiments of same laboratory replicon.

b. Stable chimeric 1b replicons carrying NS5B genes from genotype 2b, 5a or 6a were used for testing.

c. Data from various strains of full length NS5A replicons or chimeric NS5A replicons carrying full-length NS5A genesthat contain L31 or M31 polymorphisms.

d. Data from a chimeric NS5A replicon carrying NS5A amino acids 9-184.

e. Stable cell lines expressing Renilla luciferase-encoding replicons.

f. Data obtained from transiently transfected replicons.

Table 5: Activity of sofosbuvir, velpatasvir and voxilaprevir against transient repliconscontaining NS5A, NS5B or NS3 protease from clinical isolates

Replicon Replicons containing Replicons containing NS5A Replicons containing NS3genotype NS5B from clinical from clinical isolates protease from clinicalisolates isolates

Number of Median Number Median Number Medianclinical sofosbuvir of clinical velpatasvir of clinical voxilaprevirisolates EC50, nM isolates EC50, nM isolates EC50, nM(range) (range) (range)1a 67 62 23 0.019 58 0.59(29-128) (0.011-0.078) (0.14-19.16)1b 29 102 34 0.012 29 0.50(45-170) (0.005-0.500) (0.19-2.87)2a 1 28 8 0.011 18 2.8(0.006-0.364) (1.78-6.72)2b 14 30 16 0.002 43 2.1(14-81) (0.0003-0.007) (0.92-8.3)3a 106 81 38 0.005 32 6.3(24-181) (0.002-1.871) (1.3-21.48)4a NA NA 5 0.002 58 0.52(0.001-0.004) (0.12-1.7)4d NA NA 10 0.007 11 0.85(0.004-0.011) (0.41-1.1)4r NA NA 7 0.003 1 1.15(0.002-0.006) NA5a NA NA 42 0.005 16 1.8(0.001-0.019) (0.87-5.63)

Replicon Replicons containing Replicons containing NS5A Replicons containing NS3genotype NS5B from clinical from clinical isolates protease from clinicalisolates isolates

Number of Median Number Median Number Medianclinical sofosbuvir of clinical velpatasvir of clinical voxilaprevirisolates EC50, nM isolates EC50, nM isolates EC50, nM(range) (range) (range)6a NA NA 26 0.007 15 2.7(0.0005-0.113) (0.23-7.35)6e NA NA 15 0.024 12 0.2(0.005-0.433) (0.12-0.43)

NA: Not available

The presence of 40% human serum had no effect on the anti-HCV activity of sofosbuvir but reducedthe anti-HCV activity of velpatasvir and voxilaprevir by 13- and 6.8-fold, respectively, againstgenotype 1a HCV replicons.

For sofosbuvir, the NS5B substitution S282T was selected in genotype 1-6 replicons and wasassociated with 2- to 18-fold reduced susceptibility to sofosbuvir.

For velpatasvir in genotype 1-6 replicons, resistance-associated substitutions selected in 2 or moregenotypes were L31I/V and Y93H. Site directed mutagenesis of NS5A resistance associated variants(RAVs) showed that substitutions conferring a > 100-fold reduction in velpatasvir susceptibility are

M28G, A92K and Y93H/N/R/W in genotype 1a, A92K in genotype 1b, C92T and Y93H/N ingenotype 2b, Y93H in genotype 3, and L31V and P32A/L/Q/R in genotype 6. No individual RAVtested in genotypes 2a, 4a or 5a conferred a > 100-fold reduction in velpatasvir susceptibility.

For voxilaprevir in genotype 1-6 replicons, resistance-associated substitutions selected in 2 or moregenotypes were Q41H, A156V/T/L and D168E/H/Y. Site directed mutagenesis of known NS3 RAVsshowed that substitutions conferring a > 100-fold reduction in voxilaprevir susceptibility are A156V,

A156T or A156L in genotype 1a, 1b, 2a, 3a and 4. No individual RAV tested in genotypes 2b, 5a or6a conferred a > 100-fold reduction in voxilaprevir susceptibility.

For both velpatasvir and voxilaprevir, combinations of RAVs often showed greater reductions insusceptibility than individual RAVs alone.

Voxilaprevir is active in vitro against most of the NS3 RAVs that confer resistance to first generation

NS3/4A protease inhibitors. Additionally, velpatasvir is active in vitro against most of the

NS5A RAVs that confer resistance to ledipasvir and daclatasvir. Sofosbuvir, velpatasvir, andvoxilaprevir were fully active against substitutions associated with resistance to other classes of DAAswith different mechanisms of actions, e.g. voxilaprevir was fully active against NS5A and NS5B

NI RAVs.

Of the 263 NS5A inhibitor-experienced patients treated with sofosbuvir/velpatasvir/voxilaprevir for12 weeks in POLARIS-1 (see Table 10), 7 of 263 (3%) patients (2 with genotype 1, 4 with genotype 3,and 1 with genotype 4) did not achieve sustained virologic response (SVR12) and qualified forresistance analysis; 6 relapsed and 1 experienced virologic breakthrough with pharmacokinetic dataconsistent with nonadherence. The patient with genotype 1a and virologic breakthrough developed the

NS5A RAVs L31M and Y93H. One patient with genotype 4d who relapsed developed the NS5A RAV

Y93H. No NS3, NS5A, or NS5B nucleoside inhibitor (NI) RAVs emerged in the other 5 patients whorelapsed.

Of the 182 DAA-experienced patients treated with sofosbuvir/velpatasvir/voxilaprevir for 12 weeks in

POLARIS-4 (see Table 11), 1 of 182 (1%) patients relapsed and qualified for resistance analysis.

No NS3, NS5A, or NS5B NI RAVs emerged in this patient infected with genotype 1a HCV.

In the POLARIS-2 sofosbuvir/velpatasvir/voxilaprevir 8-week treatment group (see Table 12), a totalof 21 of 501 (4%) patients (16 with genotype 1, 2 with genotype 2, 2 with genotype 4, and 1 withgenotype 5) qualified for resistance analysis due to relapse. Of these 21 patients, 1 patient had viruswith emergent NS5A RAVs Q30R and L31M at failure. No NS3 and NS5B NI RAVs emerged in anyof these 21 patients at failure. In the sofosbuvir/velpatasvir 12-week treatment group, a total of 3 of440 (1%) patients (2 with genotype 1, 1 with genotype 4) qualified for resistance analysis due torelapse. Of these 3 patients, 1 patient (33%) had virus with emergent NS5A RAV Y93N at failure. No

NS3 and NS5B NI RAVs emerged in any of these 3 patients.

In the POLARIS-3 sofosbuvir/velpatasvir/voxilaprevir 8-week treatment group (see Table 14),2 of 110 (2%) patients (genotype 3) qualified for resistance analysis due to relapse. No NS3, NS5A, or

NS5B NI RAVs emerged in either of these patients. In the sofosbuvir/velpatasvir 12-week treatmentgroup, 2 of 109 (2%) patients qualified for resistance analysis due to virologic failure. Both of thesepatients had virus with emergent NS5A RAV Y93H at failure. No NS3 or NS5B NI RAVs emerged ineither of these patients.

Analyses were conducted to explore the association between pre-existing baseline NS3 and

NS5A RAVs and treatment outcome for patients that had previously been treated with DAA regimensand received sofosbuvir/velpatasvir/voxilaprevir for 12 weeks in POLARIS-1 and POLARIS-4. Theseare shown in Table 6.

Table 6: SVR12 in DAA-experienced patients with or without baseline NS3 or NS5A RAVs bystudysofosbuvir/velpatasvir/voxilaprevir 12 weeks

POLARIS-1 (n = 260) POLARIS-4 (n = 179)

No NS3 or NS5A RAVs 98% (42/43) 99% (85/86)

Any NS3 or NS5A RAV 97% (199/205) 100% (83/83)

NS3 Only 100% (9/9) 100% (39/39)

NS5A Only 97% (120/124) 100% (40/40)

NS3 and NS5A 97% (70/72) 100% (4/4)

RAVs not determined for both NS3 100% (12/12) 100% (10/10)and NS5Aa

a. Patients with NS3 and/or NS5A gene sequencing failure.

SVR12 was achieved in 18 of 19 (95%) patients who had baseline NS5B NI RAVs in POLARIS-1,including 2 patients who had virus with the S282T NS5B NI RAV in addition to NS5A RAVs atbaseline. In POLARIS-4, a total of 14 patients had virus with NS5B NI RAVs at baseline and allachieved SVR12.

Analyses were conducted to explore the association between pre-existing baseline NS3 and

NS5A RAVs and treatment outcome for patients that had not previously been treated with DAAregimens and received sofosbuvir/velpatasvir/voxilaprevir for 8 weeks in POLARIS-2 and

POLARIS-3. These are shown in Table 7.

Table 7: SVR12 in DAA-naïve patients with or without baseline NS3 or NS5A RAVs by studysofosbuvir/velpatasvir/voxilaprevir 8 weeks

POLARIS-2 POLARIS-3(n = 498) (n = 108)

No NS3 or NS5A RAVs 98% (224/229) 98% (80/82)

Any NS3 or NS5A RAV 94% (234/250) 100% (23/23)

NS3 only 91% (100/110) 100% (2/2)

NS5A only 95% (114/120) 100% (20/20)

NS3 and NS5A 100% (20/20) 100% (1/1)

RAVs not determined for both 100% (19/19) 100% (3/3)

NS3 and NS5Aa

a. Patients with NS3 and/or NS5A gene sequencing failure.

SVR12 was achieved in all 39 patients who had baseline NS5B NI RAVs in POLARIS-2 and 2 of3 (67%) patients in POLARIS-3. The NS5B NI RAV S282T was not detected in any patient in

POLARIS-2 and POLARIS-3 studies. Among patients with genotype 1a in POLARIS-2, SVR12 was87% (53/61) for those with Q80K/L/R RAVs and 94% (99/105) for those without Q80K/L/R RAVs.

Study in paediatric patients

Baseline NS3, NS5A, and NS5B sequences were obtained for 21 paediatric patients aged 12 years toless than 18 years who had not previously been treated with DAA regimens in a Phase 2 study. Of the21 patients, baseline NS3, NS5A and/or NS5B NI RAVs were detected in 1, 10, and 3 patients,respectively. Following treatment with Vosevi for 8 weeks, SVR12 was achieved in all 21 patients,including all patients who had baseline NS3, NS5A, and/or NS5B NI RAVs.

The efficacy of Vosevi (sofosbuvir [SOF]/velpatasvir [VEL]/voxilaprevir [VOX]) was evaluated infour Phase 3 studies in adults, two studies in DAA-experienced patients and two studies in DAA-naïvepatients with, genotype 1 to 6 HCV infection without cirrhosis or with compensated cirrhosis, assummarised in Table 8. Demographics and baseline characteristics for all studies are detailed in

Table 9.

Table 8: Studies conducted with Vosevi

Study Population Study arms and duration Additional study details(Number of patients treated)

Placebo-controlled study in whichpatients with GT1 infection were

POLARIS-1 NS5A inhibitor- * SOF/VEL/VOX 12 weeks randomised in a 1:1 ratio to(randomised experienced patients, (N=263) SOF/VEL/VOX or placebo fordouble blind) GT1-6, with or without * Placebo 12 weeks 12 weeks. Patients with GT2-6cirrhosis (N=152) infection were enrolled into the

SOF/VEL/VOX 12 week grouponly.

Patients with GT1-3 infection were

DAA-experiencedpatients (who have not * SOF/VEL/VOX 12 weeks randomised in a 1:1 ratio to

POLARIS-4 received an NS5A (N=182) SOF/VEL/VOX or SOF/VEL for(open label) SOF/VEL 12 weeks 12 weeks. Patients with GT4-6inhibitor), GT1-6, with * infection were enrolled into theor without cirrhosis (N=151) SOF/VEL/VOX 12 week grouponly.

Patients with GT1-4 were

DAA-naïve patients, * SOF/VEL/VOX 8 weeks randomised in a 1:1 ratio to

POLARIS-2 GT 1, 2, 4, 5, or 6, with (N=501) SOF/VEL/VOX for 8 weeks or(open label) or without cirrhosis SOF/VEL 12 weeks SOF/VEL for 12 weeks. Patients

*

GT 3 without cirrhosis (N=440) with GT5-6 infection were enrolledinto the SOF/VEL/VOX 8 weekgroup only.

* SOF/VEL/VOX 8 weeks

POLARIS-3 DAA-naïve patients (N=110) Patients were randomised in a 1:1(open label) with GT 3 and cirrhosis SOF/VEL 12 weeks ratio to SOF/VEL/VOX for

*(N=109) 8 weeks or SOF/VEL for 12 weeks.

DAA: direct-acting antiviral; GT: genotype; SOF: sofosbuvir; VEL: velpatasvir; VOX: voxilaprevir

Table 9: Demographics and baseline characteristics for patients enrolled into POLARIS-1, -2, -3and -4

Studies with DAA-experienced Studies with DAA-naïve Patients

Patients

Patient disposition POLARIS-1 POLARIS-4 POLARIS-2 POLARIS-3(n =415) (n =333) (n =941) (n =219)

Age (years) median (range) 59 (27-84) 58 (24-85) 55 (18-82) 56 (25-75)

Male Gender 77% (321) 77% (257) 52% (492) 72% (157)

Black/African American 14% (60) 9% (29) 10% (95) < 1% (1)

White 81% (335) 87% (291) 80% (756) 90% (197)

Hispanic/Latino 6% (25) 8% (27) 9% (84) 8% (17)

Genotype

Genotype 1a 53% (218) 29% (98) 36% (341) 0

Genotype 1b 18% (76) 14% (46) 13% (122) 0

Genotype 2 1% (5) 19% (64) 12% (116) 0

Genotype 3 19% (78) 32% (106) 19% (181) 100% (219)

Genotype 4 5% (22) 5.7% (19) 13% (120) 0

Genotype 5 < 1% (1) 0 2% (18) 0

Genotype 6 2% (8) 0 4% (39) 0

IL28B CC 18% (74) 19% (62) 32% (302) 42% (93)

HCV RNA ≥ 800,000 IU/mL 74% (306) 75% (249) 69% (648) 69% (151)

Compensated cirrhosis 41% (172) 46% (153) 18% (174) 100% (219)

Site

US 57% (236) 56% (188) 59% (552) 44% (96)

Non-US 43% (179) 44% (145) 41% (389) 56% (123)

Serum HCV RNA values were measured during the clinical studies using the COBAS

AmpliPrep/COBAS Taqman HCV test (version 2.0) with a lower limit of quantification (LLOQ) of15 IU per mL. Sustained virologic response (SVR12), defined as HCV RNA less than LLOQ at12 weeks after the cessation of treatment, was the primary endpoint to determine the HCV cure rate.

Clinical studies in DAA-experienced patients

Table 10 presents the SVR12 by HCV genotype for the POLARIS-1 study. The median time betweenprior DAA failure and first dose of Vosevi for patients enrolled into POLARIS-1 was 39 weeks(range: 11 to 299 weeks). No patients in the placebo group achieved SVR4.

Table 10: SVR12 in NS5A-inhibitor experienced patients by HCV genotype in study

POLARIS-1*

SOF/VEL/VOX 12 weeks (n = 263)

Total GT-1(all GT-1a GT-1b Totalb GT-2 GT-3 GT-4 GT-5 GT-6

GTs)a (n = 101) (n = 45) (n = 150) (n = 5) (n = 78) (n = 22) (n = 1) (n = 6)(n = 263)

SVR12 96% 96% 100% 97% 100% 95% 91% 100% 100%(253/263) (97/101) (45/45) (146/150) (5/5) (74/78) (20/22) (1/1) (6/6)

Outcome for patients without SVR

On-treatment <1% 1% 1%virologic (1/263) (1/101) 0/45 (1/150) 0/5 0/78 0/22 0/1 0/6failurec

Relapsed 2% 1% 1% 5% 5%(6/261) (1/100) 0/45 (1/149) 0/5 (4/78) (1/21) 0/1 0/6

Othere 1% 2% 1% 5%(3/263) (2/101) 0/45 (2/150) 0/5 0/78 (1/22) 0/1 0/6

GT = genotype

* The most common prior NS5A inhibitors were ledipasvir (LDV) (51%), daclatasvir (27%), and ombitasvir (11%).

a. One patient with undetermined genotype achieved SVR12.

b. Four patients had genotype 1 subtypes other than genotype 1a or genotype 1b; all 4 patients achieved SVR12.

c. Pharmacokinetic data for the 1 patient with on-treatment virologic failure was consistent with non-adherence.

d. The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment.

e. Other includes patients with missing data and those who discontinued treatment prior to virologic suppression.

Table 11 presents the SVR12 by HCV genotype and virologic outcome for the POLARIS-4 study. Themedian time between prior DAA failure and first dose of Vosevi or sofosbuvir/velpatasvir for patientsenrolled into POLARIS-4 was 76 weeks (range: 10 to 549 weeks).

Table 11: SVR12 by HCV genotype and virologic outcome in study POLARIS-4

SOF/VEL/VOX 12 weeks SOF/VEL(n = 182) 12 weeks(n = 151)

Overall SVR12 98% (178/182) 90% (136/151)

Genotype 1 97% (76/78) 91% (60/66)

Genotype 1a 98% (53/54) 89% (39/44)

Genotype 1b 96% (23/24) 95% (21/22)

Genotype 2 100% (31/31) 97% (32/33)

Genotype 3 96% (52/54) 85% (44/52)

Genotype 4 100% (19/19) 0/0

Outcome for patients without SVR

On-treatment 0/182 1% (1/151)virologic failurea

Relapseb 1% (1/182) 9% (14/150)

Otherc 2% (3/182) 0/151

a. The majority (85%) of patients previously failed a regimen containing sofosbuvir.

b. The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment.

c. Other includes patients with missing data and those who discontinued treatment prior to virologic suppression.

Clinical studies in DAA-naïve patients

Table 12 presents the SVR12 by HCV genotype and virologic outcome for the POLARIS-2 study.

Table 12: SVR12 by HCV genotype and virologic outcome in study POLARIS-2*

SOF/VEL/VOX SOF/VEL8 weeks 12 weeks(n = 501) (n = 440)

Overall SVR12a 95% (477/501) 98% (432/440)

Genotype 1b 93% (217/233) 98% (228/232)

Genotype 1a 92% (155/169) 99% (170/172)

Genotype 1b 97% (61/63) 97% (57/59)

Genotype 2 97% (61/63) 100% (53/53)

Genotype 3 99% (91/92) 97% (86/89)

Genotype 4 94% (59/63) 98% (56/57)

Genotype 5 94% (17/18) 0/0

Genotype 6 100% (30/30) 100% (9/9)

Outcome for patients without SVR

On-treatment virologicfailure 0/501 0/440

Relapsec 4% (21/498) 1% (3/439)

Otherd 1% (3/501) 1% (5/440)

* 23% of patients enrolled into POLARIS-2 had received prior treatment with an interferon-based regimen.

a. Two patients with undetermined genotype in the SOF/VEL/VOX group achieved SVR12.

b. Two patients had genotype 1 subtypes other than genotype 1a or genotype 1b; both patients achieved SVR12.

c. The denominator for relapse is the number of patients with HCV RNA <LLOQ at their last on-treatment assessment.

d. Other includes patients with missing data and those who discontinued treatment prior to virologic suppression.

Treatment with Vosevi for 8 weeks in POLARIS-2 did not demonstrate noninferiority to treatmentwith sofosbuvir/velpatasvir for 12 weeks with a prespecified margin of -5%. The difference in SVR12was driven by a lower response rate in patients with genotype 1a infection and/or cirrhosis. In patientswith genotype 1a without cirrhosis treated with Vosevi for 8 weeks, outcome was influenced by thefollowing baseline factors: Body Mass Index (BMI) ≥ 30 kg/m2, Q80K/L/R RAVs, IL28B non-CC,

HCV RNA ≥ 800,000 IU/mL. The SVR12 was 98% among those with two or fewer factors and 81%among those with three or four factors. Table 13 presents the SVR12 by HCV genotype by cirrhosisstatus for the POLARIS-2 study.

Table 13: SVR12 by HCV genotype and virologic outcome in patients who received Vosevi 8weeks without cirrhosis or with cirrhosis in study POLARIS-2

SOF/VEL/VOX 8 weeks

Without Cirrhosis With Cirrhosis(411/501) (90/501)

Overall SVR12a 96% (395/411) 91% (82/90)

Genotype 1b 94% (162/172) 90% (55/61)

Genotype 1a 92% (109/118)c 90% (46/51)

Genotype 1b 98% (52/53) 90% (9/10)

Genotype 2 96% (47/49) 100% (14/14)

Genotype 3 99% (90/91) 100% (1/1)

Genotype 4 96% (51/53) 80% (8/10)

Genotype 5 94% (16/17) 100% (1/1)

Genotype 6 100% (27/27) 100% (3/3)

Outcome for patients without SVR

On-treatment virologicfailure 0/411 0/90

Relapsed 3% (14/409) 8% (7/89)

Othere < 1% (2/411) 1% (1/90)

a. Two patients without cirrhosis with undetermined genotype in the SOF/VEL/VOX group achieved SVR12.

b. One patient without cirrhosis had genotype 1 subtype other than genotype 1a or genotype 1b; the patient achieved

SVR12.

c. SVR12 is 89% in genotype 1a patients enrolled at sites in the US and 97% in genotype 1a patients enrolled at sitesoutside the US

d. The denominator for relapse is the number of patients with HCV RNA <LLOQ at their last on-treatment assessment.

e. Other includes patients with missing data and those who discontinued treatment prior to virologic suppression.

Table 14 presents the SVR12 and virologic outcome for the POLARIS-3 study.

Table 14: SVR12 and virologic outcome in study POLARIS-3 (HCV genotype 3 withcompensated cirrhosis)*

SOF/VEL/VOX SOF/VEL8 weeks 12 weeks(n = 110) (n = 109)

SVR12 96% (106/110) 96% (105/109)

Outcome for patients without SVR

On-treatment virologic 0/110 1% (1/109)failure

Relapsea 2% (2/108) 1% (1/107)

Otherb 2% (2/110) 2% (2/109)

* 29% of patients enrolled into POLARIS-3 had received prior treatment with an interferon-based regimen.

a. The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment.

b. Other includes patients with missing data and those who discontinued treatment prior to virologic suppression.

Vosevi for 12 weeks was evaluated in patients who were previously treated with asofosbuvir/velpatasvir-containing regimen. The median time to re-treatment was 414 days (range 198-1271). Of the 31 patients enrolled, 74% (23/31) were male, 81% (25/31) were white, 71% (22/31) hada baseline body mass index < 30 kg/m2, 48% (15/31) had compensated cirrhosis, 58% (18/31) hadpreviously received sofosbuvir, velpatasvir and voxilaprevir, and 42% (13/31) had previously receivedsofosbuvir and velpatasvir. Most patients had genotype 1 (61% (19/31) [1a, 48% (15/31); 1b, 13%(4/31)]) or genotype 3 (26% (8/31)) HCV infection. The overall SVR12 rate was 100% (31/31).

Clinical studies of Vosevi included 189 patients aged 65 and over (17% of total number of patients inthe Phase 2 and 3 clinical studies). The response rates observed for patients ≥ 65 years of age weresimilar to that of patients < 65 years of age, across treatment groups.

The efficacy of 8 weeks of treatment with sofosbuvir/velpatasvir/voxilaprevir in HCV-infectedpaediatric patients aged 12 years and older was evaluated in a Phase 2, open-label clinical study(Study 1175) in 21 DAA-naïve patients.

Of the 21 treated patients, the median age was 14 years (range: 12-16); 62% of the patients werefemale; 76% were White, 5% were Black, and 10% were Asian; 10% were Hispanic/Latino. Meanweight was 54 kg (range: 38-86 kg); mean body mass index was 20.5 kg/m2 (range: 17-32 kg/m2); and52% had baseline HCV RNA levels ≥ 800,000 IU/mL. The proportions of patients with genotype 1, 2,3, and 4 HCV were 29%, 19%, 43%, and 10%; and no patients had known cirrhosis. The majority ofpatients (76%) had been infected through vertical transmission. The SVR12 rate was 100% overall.

The pharmacokinetic properties of sofosbuvir, GS-331007, velpatasvir and voxilaprevir have beenevaluated in healthy adult subjects and in patients with chronic hepatitis C.

Following oral administration of Vosevi, sofosbuvir was absorbed quickly and the peak medianplasma concentration was observed 2 hours post-dose. Median peak plasma concentration of

GS-331007 was observed 4 hours post-dose. Based on the population pharmacokinetic analysis in

HCV-infected patients, mean steady-state AUC0-24 and Cmax for sofosbuvir (n = 1038) were1665 ng*hr/mL and 678 ng/mL, respectively; mean steady-state AUC0-24 and Cmax for GS-331007(n = 1593) were 12834 ng*hr/mL and 744 ng/mL, respectively. Sofosbuvir and GS-331007 AUC0-24and Cmax were similar in healthy adult subjects and patients with HCV infection.

Velpatasvir median peak concentrations were observed at 4 hours post-dose. Based on the populationpharmacokinetic analysis in HCV-infected patients mean steady-state AUC0-24 and Cmax for velpatasvir(n = 1595) were 4041 ng*hr/mL and 311 ng/mL, respectively. Relative to healthy subjects (n = 137),velpatasvir AUC0-24 and Cmax were 41% lower and 39% lower, respectively, in HCV-infected patients.

Voxilaprevir median peak concentrations were observed 4 hours post-dose. Based on the populationpharmacokinetic analysis in HCV-infected patients mean steady-state AUC0-24 and Cmax forvoxilaprevir (n = 1591) were 2577 ng*hr/mL and 192 ng/mL, respectively. Relative to healthy subjects(n = 63), voxilaprevir AUC0-24 and Cmax were both 260% higher in HCV-infected patients.

When Vosevi or its components taken together were administered with food, sofosbuvir AUC0-inf and

Cmax were 64% to 144% and 9% to 76% higher, respectively; velpatasvir AUC0-inf and Cmax were 40%to 166% and 37% to 187% higher, respectively; and voxilaprevir AUC0-inf and Cmax were 112% to435% and 147% to 680% higher, respectively. GS-331007 AUC0-inf did not change and Cmax was 19%to 35% lower when Vosevi or its components together were administered with food.

Sofosbuvir is approximately 61-65% bound to human plasma proteins and the binding is independentof drug concentration over the range of 1 μg/mL to 20 μg/mL. Protein binding of GS-331007 wasminimal in human plasma. After a single 400 mg dose of [14C]-sofosbuvir in healthy subjects, theblood to plasma ratio of [14C]-radioactivity was approximately 0.7.

Velpatasvir is > 99% bound to human plasma proteins and binding is independent of drugconcentration over the range of 0.09 μg/mL to 1.8 μg/mL. After a single 100 mg dose of[14C]-velpatasvir in healthy subjects, the blood to plasma ratio of [14C]-radioactivity ranged between0.5 and 0.7.

Voxilaprevir is approximately > 99% bound to human plasma proteins. After a single 100 mg dose of[14C]-voxilaprevir in healthy subjects, the blood to plasma ratio of [14C]-radioactivity ranged between0.5 and 0.8.

Sofosbuvir is extensively metabolised in the liver to form the pharmacologically active nucleosideanalogue triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis ofthe carboxyl ester moiety catalysed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) andphosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed byphosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in theformation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacksanti-HCV activity in vitro. After a single 400 mg oral dose of [14C]-sofosbuvir, GS-331007 accountedfor approximately > 90% of total systemic exposure.

Velpatasvir is primarily a substrate of CYP2B6, CYP2C8, and CYP3A4 with slow turnover.

Following a single dose of 100 mg [14C]-velpatasvir, the majority (> 98%) of radioactivity in plasmawas parent drug. The monohydroxylated and desmethylated velpatasvir were the metabolites identifiedin human plasma. Unchanged velpatasvir is the major species present in faeces.

Voxilaprevir is primarily a substrate of CYP3A4 with slow turnover. Following a single dose of100 mg [14C]-voxilaprevir, the majority (approximately 91%) of radioactivity in plasma was parentdrug. The hydrolysed and dehydrogenated voxilaprevir were the major metabolites identified in humanplasma. Unchanged voxilaprevir is the major species present in faeces.

Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the [14C]-radioactivitywas greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, faeces,and expired air, respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007(78%) while 3.5% was recovered as sofosbuvir. These data indicate that renal clearance is the majorelimination pathway for GS-331007. The median terminal half-lives of sofosbuvir and GS-331007following administration of Vosevi were 0.5 and 29 hours, respectively.

Following a single 100 mg oral dose of [14C]-velpatasvir, mean total recovery of the[14C]-radioactivity was 95%, consisting of approximately 94% and 0.4% recovered from the faecesand urine, respectively. Unchanged velpatasvir was the major species in faeces accounting for a meanof 77% of the administered dose, followed by monohydroxylated velpatasvir (5.9%) anddesmethylated velpatasvir (3.0%). These data indicate that biliary excretion of parent drug was a majorroute of elimination for velpatasvir. The median terminal half-life of velpatasvir followingadministration of Vosevi was approximately 17 hours.

Following a single 100 mg oral dose of [14C]-voxilaprevir, mean total recovery of the[14C]-radioactivity was 94%, with all radioactivity measured in the faeces and none in the urine.

Unchanged voxilaprevir was the major species in faeces accounting for a mean of 40% of theadministered dose. Voxilaprevir metabolites also identified in faeces included des-[methylcyclopropylsulphonamide]-voxilaprevir (22.1%), which is formed intestinally, dehydro-voxilaprevir (7.5%), and two des-[methylcyclopropylsulphonamide]-oxy-voxilaprevir metabolites(5.4% and 3.9%).Biliary excretion of parent drug was the major route of elimination for voxilaprevir.

The median terminal half-life of voxilaprevir following administration of Vosevi was approximately33 hours.

Sofosbuvir and GS-331007 AUCs are near dose-proportional over the dose range of 200 mg to1200 mg. Velpatasvir AUC increases in a greater than proportional manner from 5 to 50 mg and in aless than proportional manner from 50 to 450 mg, indicating velpatasvir absorption is solubilitylimited. Voxilaprevir (studied under fed conditions) AUC increases in a greater than dose-proportionalmanner over the dose range of 100 to 900 mg.

Sofosbuvir, velpatasvir and voxilaprevir are substrates of drug transporters P-gp and BCRP while

GS-331007 is not. Voxilaprevir, and to a lesser extent velpatasvir, are also substrates of OATP1B1and OATP1B3. In vitro, slow metabolic turnover of velpatasvir primarily by CYP2B6, CYP2C8, and

CYP3A4 and of voxilaprevir primarily by CYP3A4 was observed.

Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, multidrug resistance-associated protein 2 (MRP2), bile salt export pump (BSEP), OATP1B1, OATP1B3 and organic cationtransporter (OCT) 1 and GS-331007 is not an inhibitor of OAT1, OAT3, OCT2, and multidrug andtoxin extrusion protein (MATE) 1. Sofosbuvir and GS-331007 are not inhibitors or inducers of CYP oruridine glucuronosyltransferase (UGT) 1A1 enzymes.

Velpatasvir is an inhibitor of drug transporter P-gp, BCRP, OATP1B1, OATP1B3 and OATP2B1, andits involvement in drug interactions with these transporters is primarily limited to the process ofabsorption. At clinically relevant concentrations, velpatasvir is not an inhibitor of hepatic transporters

BSEP, sodium taurocholate cotransporter protein (NTCP), OATP1A2 or OCT1, renal transporters

OCT2, OAT1, OAT3, MRP2 or MATE1, or CYP or UGT1A1 enzymes.

Voxilaprevir is an inhibitor of drug transporters P-gp, BCRP, OATP1B1 and OATP1B3, and itsinvolvement in drug interactions with these transporters is primarily limited to the process ofabsorption. At clinically relevant concentrations, voxilaprevir is not an inhibitor of hepatic transporters

OCT1, renal transporters OCT2, OAT1, OAT3 or MATE1, or CYP or UGT1A1 enzymes.

No clinically relevant pharmacokinetic differences due to race or gender have been identified forsofosbuvir, GS-331007, velpatasvir or voxilaprevir.

Population pharmacokinetic analysis in HCV-infected patients showed that within the age range(18 to 85 years) analysed, age did not have a clinically relevant effect on the exposure to sofosbuvir,

GS-331007, velpatasvir or voxilaprevir. In the 13 patients aged 75 to 84 years with availablepharmacokinetic data, mean exposure to voxilaprevir was 93% higher than the mean exposureobserved in patients aged 18 to 64 years.

A summary of the effect of varying degrees of renal impairment (RI) on the exposures of thecomponents of Vosevi compared to subjects with normal renal function, as described in the textbelow, are provided in Table 15.

Table 15: Effect of varying degrees of renal impairment on exposures (AUC) of SOF, GS -331007, velpatasvir and voxilaprevir compared to subjects with normal renal function

HCV-negative subjects HCV-infected subjects

Mild RI Moderate RI Severe RI ESRD Requiring Severe RI ESRD(eGFR (eGFR ≥30 (eGFR Dialysis (eGFR Requiring≥50 and and <30 mL/min/ Dosed 1 Dosed 1 <30 mL/m Dialysis<80 mL/m <50 mL/min/ 1.73m2) hr Before hr After in/1.73m2)in/1.73m2) 1.73m2) Dialysis Dialysis

Sofosbuvir 1.6-fold↑ 2.1-fold↑ 2.7-fold↑ 1.3-fold↑ 1.6-fold↑ ~2-fold↑ 1.8-fold↑

GS-331007 1.6-fold↑ 1.9-fold↑ 5.5-fold↑ ≥10-fold↑ ≥20-fold↑ ~7-fold↑ 18-fold↑

Velpatasvir - - 1.5-fold↑ - - - 1.4-fold↑

Voxilaprevir - - 1.7-fold↑ - - - -

The pharmacokinetics of sofosbuvir was studied in HCV negative adult patients with mild (eGFR ≥ 50and < 80 mL/min/1.73 m2), moderate (eGFR ≥ 30 and < 50 mL/min/1.73 m2), severe renal impairment(eGFR < 30 mL/min/1.73 m2) and patients with ESRD requiring haemodialysis following a single400 mg dose of sofosbuvir, relative to patients with normal renal function (eGFR> 80 mL/min/1.73 m2). GS-331007 is efficiently removed by haemodialysis with an extractioncoefficient of approximately 53%. Following a single 400 mg dose of sofosbuvir, a 4-hourhaemodialysis removed 18% of administered dose.

In HCV-infected adult patients with severe renal impairment treated with sofosbuvir 200 mg withribavirin (n=10) or sofosbuvir 400 mg with ribavirin (n=10) for 24 weeks or ledipasvir/sofosbuvir90/400 mg (n=18) for 12 weeks, the pharmacokinetics of sofosbuvir and GS-331007 were consistentwith that observed in HCV negative adult patients with severe renal impairment.

The pharmacokinetics of velpatasvir were studied with a single dose of 100 mg velpatasvir in HCVnegative adult patients with severe renal impairment (eGFR < 30 mL/min by Cockcroft-Gault).

Voxilaprevir is not renally eliminated.

Additionally, the pharmacokinetics of voxilaprevir were studied with a single dose of 100 mgvoxilaprevir in HCV negative adult patients with severe renal impairment (eGFR < 30 mL/min by

Cockcroft-Gault). The pharmacokinetics of voxilaprevir have not been studied in subjects with ESRDrequiring dialysis (see section 4.2).

The pharmacokinetics of sofosbuvir, GS-331007, and velpatasvir were studied in HCV-infectedpatients with ESRD requiring dialysis treated with once daily sofosbuvir/velpatasvir 400/100 mg for12 weeks, and compared to patients without renal impairment in the sofosbuvir/velpatasvir Phase 2/3studies.

Although exposures of the fixed-dose combination sofosbuvir, GS-331007, velpatasvir, andvoxilaprevir were not directly evaluated in HCV-infected adult patients with ESRD requiring dialysisafter administration of Vosevi, the exposures of sofosbuvir, GS-331007, and velpatasvir are expectedto be similar to those observed after administration of sofosbuvir/velpatasvir 400/100 mg in HCV-infected patients with ESRD requiring dialysis.

The pharmacokinetics of sofosbuvir was studied following 7-day dosing of 400 mg sofosbuvir in

HCV-infected adult patients with moderate and severe hepatic impairment (CPT Class B and C).

Relative to patients with normal hepatic function, the sofosbuvir AUC0-24 was 126% and 143% higherin patients with moderate and severe hepatic impairment, while the GS-331007 AUC0-24 was 18% and9% higher, respectively. Population pharmacokinetics analysis in HCV-infected adult patientsindicated that cirrhosis (CPT Class A) had no clinically relevant effect on the exposure to sofosbuvirand GS-331007.

The pharmacokinetics of velpatasvir were studied with a single dose of 100 mg velpatasvir in HCVnegative adult patients with moderate and severe hepatic impairment (CPT Class B and C).

Velpatasvir plasma exposure (AUCinf) was similar in patients with moderate hepatic impairment,severe hepatic impairment, and control subjects with normal hepatic function. Populationpharmacokinetic analysis in HCV-infected adult patients indicated that cirrhosis (CPT Class A) had noclinically relevant effect on the exposure of velpatasvir.

The pharmacokinetics of voxilaprevir were studied with a single dose of 100 mg voxilaprevir in HCVnegative adult patients with moderate and severe hepatic impairment (CPT Class B and C). Relative topatients with normal hepatic function, the voxilaprevir AUCinf was 299% and 500% higher in patientswith moderate and severe hepatic impairment, respectively. The unbound fraction of voxilaprevir wasapproximately 2-fold higher in severe hepatic impairment compared with moderate hepaticimpairment or normal hepatic function. Population pharmacokinetic analysis in HCV-infected adultpatients indicated that patients with cirrhosis (CPT Class A) had 73% higher exposure of voxilaprevirthan those without cirrhosis (see section 4.2).

In adults, body weight did not have a clinically significant effect on sofosbuvir, velpatasvir orvoxilaprevir exposure according to a population pharmacokinetic analysis.

Sofosbuvir, GS-331007, velpatasvir, and voxilaprevir exposures in paediatric patients aged 12 yearsand older receiving oral once daily doses of sofosbuvir/velpatasvir/voxilaprevir400 mg/100 mg/100 mg were similar to those in adults.

The pharmacokinetics of Vosevi in paediatric patients aged less than 12 years and weighing less than30 kg have not been established (see section 4.2).

Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterialmutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mousemicronucleus assays. No teratogenic effects were observed in the rat and rabbit developmental toxicitystudies with sofosbuvir. Sofosbuvir had no adverse effects on behaviour, reproduction, or developmentof the offspring in the rat pre- and post-natal development study.

Sofosbuvir was not carcinogenic in the 2-year mouse and rat carcinogenicity studies at GS-331007exposures up to 17 and 10-times higher, respectively than human exposure.

Velpatasvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterialmutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo ratmicronucleus assays.

Velpatasvir was not carcinogenic in the 26-week transgenic mouse and 2-year rat carcinogenicitystudies at exposures up to 67- and 5-times higher than human exposure, respectively.

Velpatasvir had no adverse effects on mating and fertility. No teratogenic effects were observed in themouse and rat developmental toxicity studies with velpatasvir at AUC exposures approximately 23-and 4-fold higher, respectively, than the human exposure at the recommended clinical dose. However,a possible teratogenic effect was indicated in rabbits where an increase in total visceral malformationswas seen in exposed animals at AUC exposures up to 0.5 fold the human exposure at recommendedclinical dose. The human relevance of this finding is not known. Velpatasvir had no adverse effects onbehaviour, reproduction, or development of the offspring in the rat pre- and post-natal developmentstudy at AUC exposures approximately 3-fold higher than the human exposure at the recommendedclinical dose.

Voxilaprevir was not genotoxic in a battery of in vitro or in vivo assays, including bacterialmutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo ratmicronucleus assays.

Carcinogenicity studies for voxilaprevir have not been conducted.

Voxilaprevir had no adverse effects on mating and fertility. No teratogenic effects were observed inthe rat and rabbit developmental toxicity studies with voxilaprevir at AUC exposures approximately141- and 4-times higher, respectively, than the human exposure at the recommended clinical dose.

Voxilaprevir had no adverse effects on behavior, reproduction, or development of the offspring in therat pre- and post-natal development study at AUC exposures approximately 238-times higher than thehuman exposure at the recommended clinical dose.

Colloidal anhydrous silica

Copovidone

Croscarmellose sodium (E468)

Lactose monohydrate

Magnesium stearate

Microcrystalline cellulose (E460)

Iron oxide black (E172)

Iron oxide red (E172)

Iron oxide yellow (E172)

Macrogol (E1521)

Polyvinyl alcohol (E1203)

Talc (E553b)

Titanium dioxide (E171)

Not applicable.

4 years.

This medicinal product does not require any special temperature storage conditions.

Store in the original package in order to protect from moisture. Keep the bottle tightly closed.

High density polyethylene (HDPE) bottle with a polypropylene child-resistant closure containing28 film-coated tablets with polyester coil and a silica gel desiccant.

Pack size: outer carton containing 1 bottle of 28 film-coated tablets.

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/1/17/1223/001

EU/1/17/1223/002

Date of first authorisation: 26 July 2017

Date of latest renewal: 29 April 2022

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

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