EPCLUSA 400mg / 100mg tablets medication leaflet

Epclusa 400 mg/100 mg film-coated tablets

Epclusa 200 mg/50 mg film-coated tablets

Epclusa 400 mg/100 mg film-coated tablets

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

Epclusa 200 mg/50 mg film-coated tablets

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

For the full list of excipients, see section 6.1.

Film-coated tablet.

Epclusa 400 mg/100 mg film-coated tablets

Pink, diamond-shaped, film-coated tablet of dimensions 20 mm x 10 mm, debossed on one side with“GSI” and “7916” on the other side.

Epclusa 200 mg/50 mg film-coated tablets

Pink, oval-shaped, film-coated tablets of dimensions 14 mm x 7 mm, debossed on one side with “GSI”and “S/V” on the other side.

Epclusa is indicated for the treatment of chronic hepatitis C virus (HCV) infection in patients 3 yearsof age and older (see sections 4.2, pct. 4.4 and 5.1).

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

The recommended dose of Epclusa in adults is one 400 mg/100 mg tablet, taken orally, once dailywith or without food (see section 5.2).

The recommended dose of Epclusa in paediatric patients aged 3 years and above is based on weight asdetailed in Table 3.

A granule formulation of Epclusa is available for the treatment of chronic HCV infection in paediatricpatients aged 3 years and above having difficulty swallowing film-coated tablets. For patientsweighing < 17 kg, please refer to the Summary of Product Characteristics for Epclusa 200 mg/50 mgor 150 mg/37.5 mg granules.

Table 1: Recommended treatment and duration for adults regardless of HCV genotypes

Adult patient populationa Treatment and duration

Epclusa for 12 weeks

Patients without cirrhosis and patients withcompensated cirrhosis Addition of ribavirin may be considered for genotype 3 infectedpatients with compensated cirrhosis (see section 5.1)

Patients with decompensated cirrhosis Epclusa + ribavirin for 12 weeksa Includes patients co-infected with human immunodeficiency virus (HIV) and patients with recurrent HCV post-livertransplant (see section 4.4).

When used in combination with ribavirin, refer also to the Summary of Product Characteristics of themedicinal product containing ribavirin.

The following dosing is recommended for adults where ribavirin is divided in two daily doses andgiven with food:

Table 2: Guidance for ribavirin dosing when administered with Epclusa to adults withdecompensated cirrhosis

Adult patient Ribavirin dose

Child-Pugh-Turcotte (CPT) Class B 1,000 mg per day for patients < 75 kg and 1,200 mg for thosecirrhosis pre-transplant weighing ≥ 75 kg

CPT Class C cirrhosis pre-transplant Starting dose of 600 mg, which can be titrated up to a maximum of1,000/1,200 mg (1,000 mg for patients weighing < 75 kg and

CPT Class B or C post-transplant 1,200 mg for patients weighing ≥ 75 kg) if well tolerated. If thestarting dose is not well tolerated, the dose should be reduced asclinically indicated based on haemoglobin levels

If ribavirin is used in genotype 3 infected adult patients with compensated cirrhosis (pre- or post-transplant) the recommended dose of ribavirin is 1,000/1,200 mg (1,000 mg for adult patientsweighing < 75 kg and 1,200 mg for adult patients weighing ≥ 75 kg).

For ribavirin dose modifications, refer to the Summary of Product Characteristics of the medicinalproduct containing ribavirin.

Table 3: Recommended treatment and duration for paediatric patients aged 3 to < 18 Yearsregardless of HCV genotype using Epclusa Tablets*

Body weight (kg) Dosing of Epclusa tablets Sofosbuvir/Velpatasvir Recommended treatmentdaily dose regimen≥ 30 one 400 mg/100 mg tablet 400 mg/100 mg per dayonce dailyortwo 200 mg/50 mg tablets Epclusa for 12 weeksonce daily17 to < 30 one 200 mg/50 mg tablet 200 mg/50 mg per dayonce daily

*Epclusa is also available as granules for paediatric patients with chronic HCV infection aged 3 years and above. For patientsweighing < 17 kg, please refer to the Summary of Product Characteristics for Epclusa 200 mg/50 mg or 150 mg/37.5 mggranules.

Patients should be instructed that if vomiting occurs within 3 hours of dosing an additional tablet of

Epclusa should be taken. If vomiting occurs more than 3 hours after dosing, no further dose of Epclusais needed (see section 5.1).

If a dose of Epclusa is missed and it is within 18 hours of the normal time, patients should beinstructed to take the tablet as soon as possible and then patients should take the next dose at the usualtime. If it is after 18 hours then patients should be instructed to wait and take the next dose of Epclusaat the usual time. Patients should be instructed not to take a double dose of Epclusa.

Adult patients who have previously failed therapy with an NS5A-containing regimen

Epclusa + ribavirin for 24 weeks may be considered (see section 4.4).

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

No dose adjustment of Epclusa 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. Epclusacan be used in these patients with no dose adjustment when no other relevant treatment options areavailable (see sections 4.4, 5.1 and 5.2).

No dose adjustment of Epclusa is required for patients with mild, moderate, or severe hepaticimpairment (CPT Class A, B, or C) (see section 5.2). Safety and efficacy of Epclusa have beenassessed in patients with CPT Class B cirrhosis, but not in patients with CPT Class C cirrhosis (seesections 4.4 and 5.1).

The safety and efficacy of Epclusa in children aged less than 3 years have not been established. Nodata are available.

For oral use.

Patients should be instructed to swallow the tablet(s) whole with or without food (see section 5.2). Dueto the bitter taste, it is recommended that film-coated tablets are not chewed or crushed.

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

Medicinal products that are strong P-glycoprotein (P-gp) and/or strong cytochrome P450 (CYP)inducers (carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin and St. John’s wort) (seesection 4.5).

Epclusa should not be administered concurrently with other medicinal products containing sofosbuvir.

Life-threatening cases of severe bradycardia and heart block have been observed when sofosbuvir-containing 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 Epclusa 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 co-administration, 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 Epclusa.

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.

Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or aftertreatment with direct-acting antiviral medicinal products. HBV screening should be performed in allpatients before initiation of treatment. HBV/HCV co-infected patients are at risk of HBV reactivation,and should, therefore, be monitored and managed according to current clinical guidelines.

Patients who have previously failed therapy with an NS5A-containing regimen

There are no clinical data to support the efficacy of sofosbuvir/velpatasvir for the treatment of patientswho have failed treatment with a regimen containing another NS5A inhibitor. However, on the basisof NS5A resistance associated variants (RAVs) typically seen in patients who have failed therapy withother NS5A inhibitor containing regimens, the in vitro pharmacology of velpatasvir, and the outcomesof sofosbuvir/velpatasvir treatment in NS5A-naïve patients with baseline NS5A RAVs enrolled intothe ASTRAL-studies, treatment with Epclusa + RBV for 24 weeks can be considered for patients whohave failed therapy on an NS5A-containing regimen and who are deemed at high risk for clinicaldisease progression and who do not have alternative treatment options.

Safety data are limited in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2) and

ESRD requiring haemodialysis. Epclusa can be used in these patients with no dose adjustment whenno other relevant treatment options are available (see sections 5.1 and 5.2). When Epclusa is used incombination with ribavirin refer also to the Summary of Product Characteristics for ribavirin forpatients with creatinine clearance < 50 mL/min (see section 5.2).

Use with moderate P-gp inducers and/or moderate CYP inducers

Medicinal products that are moderate P-gp and/or moderate CYP inducers (e.g. efavirenz, modafinil,oxcarbazepine or rifapentine) may decrease sofosbuvir or velpatasvir plasma concentrations leading toreduced therapeutic effect of Epclusa. Co-administration of such medicinal products with Epclusa isnot recommended (see section 4.5).

Epclusa has been shown to increase tenofovir exposure, especially when used together with an HIVregimen containing tenofovir disoproxil fumarate and a pharmacokinetic enhancer (ritonavir orcobicistat). The safety of tenofovir disoproxil fumarate in the setting of Epclusa and a pharmacokineticenhancer has not been established. The potential risks and benefits associated with co-administrationof Epclusa with the fixed-dose combination tablet containingelvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or tenofovir disoproxil fumarategiven in conjunction with a boosted HIV protease inhibitor (e.g. atazanavir or darunavir) should beconsidered, particularly in patients at increased risk of renal dysfunction. Patients receiving Epclusaconcomitantly with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or withtenofovir disoproxil fumarate and a boosted HIV protease inhibitor should be monitored fortenofovir-associated adverse reactions. Refer to tenofovir disoproxil fumarate, emtricitabine/tenofovirdisoproxil fumarate, or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate Summary of

Product Characteristics for recommendations on renal monitoring.

Diabetics may experience improved glucose control, potentially resulting in symptomatichypoglycaemia, after initiating HCV direct-acting antiviral treatment. Glucose levels of diabeticpatients initiating direct-acting antiviral therapy should be closely monitored, particularly within thefirst 3 months, and their diabetic treatment modified when necessary. The physician in charge of thediabetic care of the patient should be informed when direct-acting antiviral therapy is initiated.

CPT Class C cirrhosis

Safety and efficacy of Epclusa has not been assessed in patients with CPT Class C cirrhosis (seesection 5.1).

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

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

As Epclusa contains sofosbuvir and velpatasvir, any interactions that have been identified with theseactive substances individually may occur with Epclusa.

Potential for Epclusa to affect other medicinal products

Velpatasvir is an inhibitor of drug transporter P-gp, breast cancer resistance protein (BCRP), organicanion-transporting polypeptide (OATP) 1B1 and OATP1B3. Co-administration of Epclusa withmedicinal products that are substrates of these transporters may increase the exposure of suchmedicinal products. See Table 4 for examples of interactions with sensitive substrates of P-gp(digoxin), BCRP (rosuvastatin), and OATP (pravastatin).

Potential for other medicinal products to affect Epclusa

Sofosbuvir and velpatasvir are substrates of drug transporters P-gp and BCRP. Velpatasvir is also asubstrate of drug transporter OATP1B. In vitro, slow metabolic turnover of velpatasvir by CYP2B6,

CYP2C8 and CYP3A4 was observed. Medicinal products that are strong inducers of P-gp and/orstrong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g. carbamazepine, phenobarbital and phenytoin,rifampicin, rifabutin and St. John’s wort) may decrease plasma concentrations of sofosbuvir orvelpatasvir leading to reduced therapeutic effect of sofosbuvir/velpatasvir. The use of such medicinalproducts with Epclusa is contraindicated (see section 4.3). Medicinal products that are moderate

P-gp inducers and/or moderate CYP inducers (e.g. efavirenz, modafinil, oxcarbazepine or rifapentine)may decrease sofosbuvir or velpatasvir plasma concentration leading to reduced therapeutic effect of

Epclusa. Co-administration with such medicinal products is not recommended with Epclusa (seesection 4.4). Co-administration with medicinal products that inhibit P-gp or BCRP may increasesofosbuvir or velpatasvir plasma concentrations. Medicinal products that inhibit OATP, CYP2B6,

CYP2C8, or CYP3A4 may increase plasma concentration of velpatasvir. Clinically significantmedicinal product interactions with Epclusa mediated by P-gp, BCRP, OATP, or CYP450 inhibitorsare not expected; Epclusa may be co-administered with P-gp, BCRP, OATP and CYP inhibitors.

As liver function may change during treatment with Epclusa, a 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 medicinal products such as calcineurin inhibitors) may be impacted by changes inliver function during DAA therapy, related to clearance of HCV.

Interactions between Epclusa and other medicinal products

Table 4 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 or velpatasvir and sofosbuvir as individual agents, or are predicted medicinalproduct interactions that may occur with sofosbuvir/velpatasvir. The table is not all-inclusive.

Table 4: Interactions between Epclusa and other medicinal products

Medicinal product by Effects on medicinal product levels.therapeutic areas/Possible Mean ratio (90% confidence interval)a,b Recommendation concerning

Mechanism of Interaction Active Cmax AUC Cmin co-administration with Epclusa

ACID REDUCING AGENTS

Velpatasvir solubility decreases aspH increases. Medicinal productsthat increase gastric pH areexpected to decrease theconcentration of velpatasvir.

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

Medicinal product by Effects on medicinal product levels.therapeutic areas/Possible Mean ratio (90% confidence interval)a,b Recommendation concerning

Mechanism of Interaction Active Cmax AUC Cmin co-administration with Epclusa

H2-receptor antagonists

Famotidine Sofosbuvir ↔ ↔ H2-receptor antagonists may be(40 mg single dose)/ administered simultaneously withsofosbuvir/ velpatasvir or staggered from Epclusa at a(400/ 100 mg single dose)c dose that does not exceed dosescomparable to famotidine 40 mg

Famotidine dosed Velpatasvir ↓ ↓ twice daily.simultaneously withd 0.80 0.81

Epclusa (0.70, (0.71,0.91) 0.91)

Cimetidinee

Nizatidinee

Ranitidinee(Increase in gastric pH)

Famotidine Sofosbuvir ↓ ↓(40 mg single dose)/ 0.77 0.80sofosbuvir/ velpatasvir (0.68, (0.73,(400/ 100 mg single dose)c 0.87) 0.88)

Famotidine dosed 12 hours Velpatasvir ↔ ↔prior to Epclusad(Increase in gastric pH)

Omeprazole Sofosbuvir ↓ ↓ Co-administration with proton(20 mg once daily)/ 0.66 0.71 pump inhibitors is notsofosbuvir/ velpatasvir (0.55, (0.60, recommended. If it is considered(400/ 100 mg single dose 0.78) 0.83) necessary to co-administer, thenfasted)c Epclusa should be administeredwith food and taken 4 hours before

Omeprazole dosed Velpatasvir ↓ ↓ proton pump inhibitor at maxsimultaneously with 0.63 0.64 doses comparable to omeprazole

Epclusad (0.50, (0.52, 20 mg.0.78) 0.79)

Lansoprazolee

Rabeprazolee

Pantoprazolee

Esomeprazolee(Increase in gastric pH)

Omeprazole Sofosbuvir ↓ ↔(20 mg once daily)/ 0.79sofosbuvir/ velpatasvir (0.68,(400/ 100 mg single dose 0.92)fed)c

Omeprazole dosed 4 hours Velpatasvir ↓ ↓after Epclusad 0.67 0.74(0.58, (0.63,(Increase in gastric pH) 0.78) 0.86)

Medicinal product by Effects on medicinal product levels.therapeutic areas/Possible Mean ratio (90% confidence interval)a,b Recommendation concerning

Mechanism of Interaction Active Cmax AUC Cmin co-administration with Epclusa

ANTIARRHYTHMICS

Amiodarone Effect on amiodarone, velpatasvir, and Co-administration of amiodaronesofosbuvir concentrations unknown. with a sofosbuvir containingregimen may result in serioussymptomatic bradycardia.

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

Epclusa (see sections 4.4 and 4.8).

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

Expected: digoxin may increase the↔ Sofosbuvir concentration of digoxin. Caution

Digoxin (0.25 mg single Effect on velpatasvir exposure not studied is warranted and therapeuticdose)f/ velpatasvir (100 mg Expected: concentration monitoring ofsingle dose) ↔ Velpatasvir digoxin is recommended whenco-administered with Epclusa.(Inhibition of P-gp) Observed:

Digoxin ↑ ↑1.9 1.3(1.7, (1.1,2.1) 1.6)

ANTICOAGULANTS

Dabigatran etexilate Interaction not studied. Clinical monitoring, looking for

Expected: signs of bleeding and anaemia, is↑ Dabigatran recommended when dabigatran↔ Sofosbuvir etexilate is co-administered with↔ Velpatasvir Epclusa. A coagulation test helps(Inhibition of P-gp) to identify patients with anincreased bleeding risk due toincreased dabigatran exposure.

Vitamin K antagonists Interaction not studied Close monitoring of INR isrecommended with all vitamin Kantagonists. This is due to liverfunction changes during treatmentwith Epclusa.

ANTICONVULSANTS

Phenytoin Interaction not studied. Epclusa is contraindicated with

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

CYPs)

Carbamazepine Interaction not studied. Epclusa is contraindicated with

Expected: carbamazepine (see section 4.3).↓ Velpatasvir(Induction of P-gp and Observed: ↓0.52 ↓ 0.52

CYPs) Sofosbuvir (0.43, (0.46,0.62) 0.59)

Oxcarbazepine Interaction not studied. Co-administration of Epclusa with

Expected: oxcarbazepine is expected to↓ Sofosbuvir decrease the concentration of(Induction of P-gp and ↓ Velpatasvir sofosbuvir and velpatasvir, leading

CYPs) to reduced therapeutic effect of

Epclusa. Co-administration is notrecommended (see section 4.4).

Medicinal product by Effects on medicinal product levels.therapeutic areas/Possible Mean ratio (90% confidence interval)a,b Recommendation concerning

Mechanism of Interaction Active Cmax AUC Cmin co-administration with Epclusa

ANTIFUNGALS

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

Expected: ketoconazole is required.↔ Sofosbuvir

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

Observed:

Velpatasvir ↑ ↑(Inhibition of P-gp and 1.3 1.7

CYPs) (1.0, (1.4,1.6) 2.2)

Itraconazolee

Voriconazolee

Posaconazolee

Isavuconazolee

ANTIMYCOBACTERIALS

Rifampicin (600 mg once Effect on rifampicin exposure not studied. Epclusa is contraindicated withdaily)/ sofosbuvir (400 mg rifampicin (see section 4.3).single dose)d Expected:↔ Rifampicin

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

CYPs) 0.23 0.28(0.19, (0.24,0.29) 0.32)

Rifampicin (600 mg once Effect on rifampicin exposure not studied.daily)/ velpatasvir (100 mgsingle dose) Expected:↔ Rifampicin

Observed:

Velpatasvir ↓ ↓0.29 0.18(Induction of P-gp and (0.23, (0.15,

CYPs) 0.37) 0.22)

Rifabutin Interaction not studied. Epclusa is contraindicated with

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

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

Medicinal product by Effects on medicinal product levels.therapeutic areas/Possible Mean ratio (90% confidence interval)a,b Recommendation concerning

Mechanism of Interaction Active Cmax AUC Cmin co-administration with Epclusa

Rifapentine Interaction not studied. Co-administration of Epclusa with

Expected: rifapentine is expected to decrease↓ Sofosbuvir the concentration of sofosbuvir and↓ Velpatasvir velpatasvir, leading to reduced(Induction of P-gp and therapeutic effect of Epclusa.

CYPs) Co-administration is notrecommended (see section 4.4).

HIV ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS

Tenofovir disoproxil Epclusa has been shown to increase tenofovir exposure (P-gp-inhibition). Thefumarate increase in tenofovir exposure (AUC and Cmax) was around 40-80% during co-treatment with Epclusa and tenofovir disoproxil fumarate/emtricitabine as part ofvarious HIV regimens.

Patients receiving tenofovir disoproxil fumarate and Epclusa 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).

Efavirenz/ emtricitabine/ Efavirenz ↔ ↔ ↔ Co-administration of Epclusa withtenofovir disoproxil Sofosbuvir ↑ ↔ efavirenz/ emtricitabine/ tenofovirfumarate 1.4 disoproxil fumarate is expected to(600/ 200/ 300 mg once (1.1, decrease the concentration ofdaily)/ sofosbuvir/ 1.7) velpatasvir. Co-administration ofvelpatasvir (400/ 100 mg Velpatasvir ↓ ↓ ↓ Epclusa with efavirenz-containingonce daily)c, d 0.53 0.47 0.43 regimens is not recommended (see(0.43, (0.39, (0.36, section 4.4).0.64) 0.57) 0.52)

Emtricitabine/ rilpivirine/ Rilpivirine ↔ ↔ ↔ No dose adjustment of Epclusa ortenofovir disoproxil Sofosbuvir ↔ ↔ emtricitabine/ rilpivirine/ tenofovirfumarate Velpatasvir ↔ ↔ ↔ disoproxil fumarate is required.(200/ 25/ 300 mg oncedaily)/ sofosbuvir/velpatasvir (400/ 100 mgonce daily)c, d

HIV ANTIVIRAL AGENTS: HIV PROTEASE INHIBITORS

Atazanavir boosted with Atazanavir ↔ ↔ ↑ No dose adjustment of Epclusa,ritonavir (300/ 100 mg once 1.4 atazanavir (ritonavir boosted) ordaily) + emtricitabine/ (1.2, emtricitabine/ tenofovir disoproxiltenofovir disoproxil 1.6) fumarate is required.fumarate (200/ 300 mg once Ritonavir ↔ ↑daily)/ sofosbuvir/ 1.3velpatasvir (400/ 100 mg (1.5,once daily)c, d 1.4)

Sofosbuvir ↔ ↔

Velpatasvir ↑ ↑ ↑1.6 2.4 4.0(1.4, (2.2, (3.6,1.7) 2.6) 4.5)

Darunavir boosted with Darunavir ↔ ↔ ↔ No dose adjustment of Epclusa,ritonavir (800/ 100 mg once Ritonavir ↔ ↔ ↔ darunavir (ritonavir boosted) ordaily) + emtricitabine/ Sofosbuvir ↓ ↓ emtricitabine/ tenofovir disoproxiltenofovir disoproxil 0.62 0.72 fumarate is required.fumarate (200/ 300 mg once (0.54, (0.66,daily)/ sofosbuvir/ 0.71) 0.80)velpatasvir (400/ 100 mg Velpatasvir ↓ ↔ ↔once daily)c, d 0.76(0.65,0.89)

Medicinal product by Effects on medicinal product levels.therapeutic areas/Possible Mean ratio (90% confidence interval)a,b Recommendation concerning

Mechanism of Interaction Active Cmax AUC Cmin co-administration with Epclusa

Lopinavir boosted with Lopinavir ↔ ↔ ↔ No dose adjustment of Epclusa,ritonavir (4x200 mg/ 50 mg Ritonavir ↔ ↔ ↔ lopinavir (ritonavir boosted) oronce daily) + emtricitabine/ Sofosbuvir ↓ ↓ emtricitabine/ tenofovir disoproxiltenofovir disoproxil 0.59 0.7 fumarate is required.fumarate (200/ 300 mg once (0.49 (0.6,daily)/ sofosbuvir/ 0.71) 0.8)velpatasvir (400/ 100 mg Velpatasvir ↓ ↔ ↑once daily)c, d 0.70 1.6(0.59, (1.4,0.83) 1.9)

HIV ANTIVIRAL AGENTS: INTEGRASE INHIBITORS

Raltegravir (400 mg twice Raltegravir ↔ ↔ ↓ No dose adjustment of Epclusa,daily)g + emtricitabine/ 0.79 raltegravir or emtricitabine/tenofovir disoproxil (0.42, tenofovir disoproxil fumarate isfumarate (200/ 300 mg once 1.5) required.daily)/ sofosbuvir/ Sofosbuvir ↔ ↔velpatasvir (400/ 100 mg Velpatasvir ↔ ↔ ↔once daily)c, d

Elvitegravir/ cobicistat/ Elvitegravir ↔ ↔ ↔ No dose adjustment of Epclusa oremtricitabine/ tenofovir Cobicistat ↔ ↔ ↑ elvitegravir/ cobicistat/alafenamide fumarate 2.0 emtricitabine/ tenofovir(150/ 150/ 200/ 10 mg once (1.7, alafenamide fumarate is required.daily)/ sofosbuvir/ 2.5)velpatasvir (400/ 100 mg Tenofovir ↔ ↔once daily)c, d alafenamide

Sofosbuvir ↔ ↑1.4(1.2,1.5)

Velpatasvir ↑ ↑ ↑1.3 1.5 1.6(1.2, (1.4, (1.4,1.5) 1.7) 1.8)

Elvitegravir/ cobicistat/ Elvitegravir ↔ ↔ ↔ No dose adjustment of Epclusa oremtricitabine/ tenofovir Cobicistat ↔ ↔ ↑ elvitegravir/ cobicistat/disoproxil fumarate 1.7 emtricitabine/ tenofovir disoproxil(150/ 150/ 200/ 300 mg (1.5, fumarate is required.once daily)/ sofosbuvir/ 1.9)velpatasvir (400/ 100 mg Sofosbuvir ↔ ↔once daily)c, d Velpatasvir ↔ ↔ ↑1.4(1.2,1.5)

Dolutegravir (50 mg once Dolutegravir ↔ ↔ ↔ No dose adjustment of Epclusa ordaily)/ sofosbuvir/ Sofosbuvir ↔ ↔ dolutegravir is required.velpatasvir (400/ 100 mgonce daily) Velpatasvir ↔ ↔ ↔

HERBAL SUPPLEMENTS

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

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

CYPs)

Medicinal product by Effects on medicinal product levels.therapeutic areas/Possible Mean ratio (90% confidence interval)a,b Recommendation concerning

Mechanism of Interaction Active Cmax AUC Cmin co-administration with Epclusa

HMG-CoA REDUCTASE INHIBITORS

Atorvastatin (40 mg single Observed: ↑ ↑ No dose adjustment of Epclusa ordose) + sofosbuvir/Atorvastatin 1.7 1.5 atorvastatin is required.velpatasvir (400/ 100 mg (1.5, (1.5,once daily)d 1.9) 1.6)

Rosuvastatin Interaction only studied with velpatasvir Co-administration of Epclusa with

Expected: rosuvastatin increases the↔ Sofosbuvir concentration of rosuvastatin,

Rosuvastatin (10 mg single Observed: which is associated with increaseddose)/ velpatasvir (100 mg Rosuvastatin ↑ ↑ risk of myopathy, includingonce daily)d 2.6 2.7 rhabdomyolysis. Rosuvastatin, at a(2.3, (2.5, dose that does not exceed 10 mg,2.9) 2.9) may be administered with Epclusa.

Effect on velpatasvir exposure not studied(Inhibition of OATP1B and Expected:

BCRP) ↔ Velpatasvir

Pravastatin Interaction only studied with velpatasvir No dose adjustment of Epclusa or

Expected: pravastatin is required.↔ Sofosbuvir

Pravastatin (40 mg single Observed:dose)/ velpatasvir (100 mg Pravastatin ↑ ↑once daily)d 1.3 1.4(1.1, (1.2,1.5) 1.5)(Inhibition of OATP1B) Effect on velpatasvir exposure not studied

Expected:↔ Velpatasvir

Other statins Expected: Interactions cannot be excluded↑ Statins with other HMG-CoA reductaseinhibitors. When co-administeredwith Epclusa, careful monitoringfor statin adverse reactions shouldbe undertaken and a reduced doseof statins should be considered ifrequired.

NARCOTIC ANALGESICS

Methadone R-methadone ↔ ↔ ↔ No dose adjustment of Epclusa or(Methadone maintenance methadone is required.therapy [30 to 130 mg S-methadone ↔ ↔ ↔daily])/ sofosbuvir (400 mgonce daily)d Sofosbuvir ↔ ↑1.3(1.0,1.7)

Methadone Interaction only studied with sofosbuvir

Expected:↔ Velpatasvir

Medicinal product by Effects on medicinal product levels.therapeutic areas/Possible Mean ratio (90% confidence interval)a,b Recommendation concerning

Mechanism of Interaction Active Cmax AUC Cmin co-administration with Epclusa

IMMUNOSUPPRESSANTS

Ciclosporin Ciclosporin ↔ ↔ No dose adjustment of Epclusa or(600 mg single dose)/ ciclosporin is required at initiationsofosbuvir (400 mg single Sofosbuvir ↑ ↑ of co-administration. Afterwards,dose)f 2.5 4.5 close monitoring and potential(1.9, (3.3, dose adjustment of ciclosporin may3.5) 6.3) be required.

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

Velpatasvir ↑ ↑1.6 2.0(1.2, (1.5,2.0) 2.7)

Tacrolimus Tacrolimus ↓ ↑ No dose adjustment of Epclusa or(5 mg single dose)f/ 0.73 1.1 tacrolimus is required at initiationsofosbuvir (400 mg single (0.59, (0.84, of co-administration. Afterwards,dose)d 0.90) 1.4) close monitoring and potential

Sofosbuvir ↓ ↑ dose adjustment of tacrolimus may0.97 1.1 be required.(0.65, (0.81,1.4) 1.6)

Tacrolimus Effect on velpatasvir exposure not studied.

Expected:↔ Velpatasvir

ORAL CONTRACEPTIVES

Norgestimate/ ethinyl Norel- ↔ ↔ ↔ No dose adjustment of oralestradiol (norgestimate gestromin contraceptives is required.0.180 mg/ 0.215 mg/0.25 mg/ ethinyl estradiol0.025 mg)/ sofosbuvir(400 mg once daily)d

Norgestrel ↔ ↑ ↑1.2 1.2(0.98, (1.0,1.5) 1.5)

Ethinyl ↔ ↔ ↔estradiol

Norgestimate/ ethinyl Norel- ↔ ↔ ↔estradiol (norgestimate gestromin0.180 mg/ 0.215 mg/ Norgestrel ↔ ↔ ↔0.25 mg/ ethinyl estradiol0.025 mg)/ velpatasvir Ethinyl ↑ ↔ ↓(100 mg once daily)d estradiol 1.4 0.83(1.2, (0.65,1.7) 1.1)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 Administered as Epclusa.d Lack of pharmacokinetics interaction bounds 70-143%.e These are medicinal products within class where similar interactions could be predicted.f Bioequivalence/Equivalence boundary 80-125%.g Lack of pharmacokinetics interaction bounds 50-200%.

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of sofosbuvir,velpatasvir or Epclusa 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).

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

It is unknown whether sofosbuvir, metabolites of sofosbuvir or velpatasvir are excreted in humanmilk.

Available pharmacokinetic data in animals have shown excretion of velpatasvir and metabolites ofsofosbuvir in milk.

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

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

If ribavirin is co-administered with Epclusa, refer to the Summary of Product Characterisitics forribavirin for detailed recommendations regarding pregnancy, contraception, and breast-feeding.

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

The safety profile of Epclusa has been determined in pooled Phase 3 clinical studies of patients withgenotype 1, 2, 3, 4, 5 or 6 HCV infection and in the postmarketing setting. No adverse drug reactionsto Epclusa were identified from clinical studies. In the postmarketing setting, cases of severebradycardia and heart block have been observed when SOF-containing products are used incombination with amiodarone, and HBV reactivation has been observed in patients coinfected with

HCV/HBV following treatment with DAAs (see section 4.4).

Assessment of adverse reactions for Epclusa is based on safety data from clinical studies andpostmarketing experience. All adverse reactions are presented in Table 5. The adverse reactions arelisted below 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 5: Adverse drug reactions identified with Epclusa

Frequency Adverse drug reaction

Very common vomitinga

Common rashb

Uncommon angioedemab

a. Adverse reaction was observed in paediatric patients aged 3 to < 6 years

b. 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

The adverse reactions observed were consistent with those observed in clinical studies of Epclusa inadults. Vomiting was observed as a very common adverse drug reaction to Epclusa in paediatricpatients aged 3 to < 6 years. The safety assessment of Epclusa in paediatric patients aged 3 years andolder is based on data from a Phase 2, open-label clinical study (study 1143) that enrolled 216 patientswho were treated with sofosbuvir/velpatasvir for 12 weeks.

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 and velpatasvir were a single dose of 1,200 mg and asingle dose of 500 mg, respectively. In these healthy adult volunteer studies, there were no untowardeffects observed at these dose levels. The effects of higher doses/exposures are not known.

No specific antidote is available for overdose with Epclusa. If overdose occurs the patient must bemonitored for evidence of toxicity. Treatment of overdose with Epclusa 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, since velpatasvir is highly bound to plasma protein.

Pharmacotherapeutic group: Antivirals for systemic use; Direct acting antiviral, ATC code: J05AP55

Sofosbuvir is a pan-genotypic inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which isessential 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.

GS-461203 (the active metabolite of sofosbuvir) is neither an inhibitor of human DNA and

RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.

Velpatasvir is a HCV inhibitor targeting the HCV NS5A protein, which is essential for both RNAreplication and the assembly of HCV virions. In vitro resistance selection and cross-resistance studiesindicate velpatasvir targets NS5A as its mode of action.

The 50% effective concentration (EC50) values of sofosbuvir and velpatasvir against full-length orchimeric replicons encoding NS5B and NS5A sequences from the laboratory strains are presented in

Table 6. The EC50 values of sofosbuvir and velpatasvir against clinical isolates are presented in

Table 7.

Table 6: Activity of sofosbuvir and velpatasvir against full-length or chimeric laboratoryreplicons

Replicon genotype Sofosbuvir EC50, nMa Velpatasvir EC50, nMa1a 40 0.0141b 110 0.0162a 50 0.005-0.016c2b 15b 0.002-0.006c3a 50 0.0044a 40 0.0094d NA 0.0045a 15b 0.021-0.054d6a 14b 0.006-0.0096e NA 0.130d

NA = Not availablea 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.

Table 7: Activity of sofosbuvir and velpatasvir against transient replicons containing NS5A or

NS5B from clinical isolates

Replicon Replicons containing NS5B from clinical Replicons containing NS5A from clinicalgenotype isolates isolates

Number of clinical Median sofosbuvir Number of clinical Median velpatasvirisolates EC50, nM (range) isolates EC50, nM (range)1a 67 62 (29-128) 23 0.019 (0.011-0.078)1b 29 102 (45-170) 34 0.012 (0.005-0.500)2a 15 29 (14-81) 8 0.011 (0.006-0.364)2b NA NA 16 0.002 (0.0003-0.007)3a 106 81 (24-181) 38 0.005 (0.002-1.871)4a NA NA 5 0.002 (0.001-0.004)4d NA NA 10 0.007 (0.004-0.011)4r NA NA 7 0.003 (0.002-0.006)5a NA NA 42 0.005 (0.001-0.019)6a NA NA 26 0.007 (0.0005-0.113)6e NA NA 15 0.024 (0.005-0.433)

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 by 13-fold against genotype 1a HCV replicons.

Evaluation of sofosbuvir in combination with velpatasvir showed no antagonistic effect in reducing

HCV RNA levels in replicon cells.

HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiplegenotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced susceptibility to sofosbuvir was associatedwith the primary NS5B substitution S282T in all replicon genotypes examined. Site-directedmutagenesis of the S282T substitution in replicons of genotype 1 to 6 conferred 2- to 18-fold reducedsusceptibility to sofosbuvir and reduced the replication viral capacity by 89% to 99% compared to thecorresponding wild-type. In biochemical assays, the ability of the active triphosphate of sofosbuvir(GS-461203) to inhibit recombinant NS5B polymerase from genotypes 1b, 2a, 3a and 4a expressingthe S282T substitution was reduced compared to its ability to inhibit wild-type recombinant NS5Bpolymerase, as indicated by a 8.5- to 24-fold increase in the 50% inhibitory concentration (IC50).

In vitro selection of HCV replicons with reduced susceptibility to velpatasvir was performed in cellculture for multiple genotypes including 1a, 1b, 2a, 3a, 4a, 5a and 6a. Variants were selected at NS5Aresistance associated positions 24, 28, 30, 31, 32, 58, 92 and 93. The resistance associated variants(RAVs) selected in 2 or more genotypes were F28S, L31I/V and Y93H. Site-directed mutagenesis ofknown NS5A RAVs showed that substitutions conferring a > 100-fold reduction in velpatasvirsusceptibility are M28G, A92K and Y93H/N/R/W in genotype 1a, A92K in genotype 1b, C92T and

Y93H/N in genotype 2b, Y93H in genotype 3, and L31V and P32A/L/Q/R in genotype 6. Noindividual substitutions tested in genotypes 2a, 4a, or 5a conferred a > 100-fold reduction invelpatasvir susceptibility. Combinations of these variants often showed greater reductions insusceptibility to velpatasvir than single RAVs alone.

Studies in patients without cirrhosis and patients with compensated cirrhosis

In a pooled analysis of patients without cirrhosis or with compensated cirrhosis who received Epclusafor 12 weeks in three Phase 3 studies, 12 patients (2 with genotype 1 and 10 with genotype 3) qualifiedfor resistance analysis due to virologic failure. One additional patient with genotype 3 HCV infectionat baseline was reinfected with genotype 1a HCV at virologic failure and was excluded from thevirological analysis. No patients with genotype 2, 4, 5, or 6 HCV infection experienced virologicfailure.

Of the 2 genotype 1 virologic failure patients, one patient had virus with emergent NS5A RAV Y93Nand the other patient had virus with emergent NS5A RAVs L31I/V and Y93H at virologic failure.

Both patients had virus at baseline harbouring NS5A RAVs. No NS5B nucleoside inhibitor (NI)

RAVs were observed at failure in the 2 patients.

Of the 10 genotype 3 virologic failure patients, Y93H was observed in all 10 patients at failure (6 had

Y93H emerge post-treatment and 4 patients had Y93H at baseline and post-treatment). No

NS5B NI RAVs were observed at failure in the 10 patients.

Studies in patients with decompensated cirrhosis

In one Phase 3 study in patients with decompensated cirrhosis who received Epclusa + RBV for12 weeks, 3 patients (1 with genotype 1 and 2 with genotype 3) qualified for resistance analysis due tovirologic failure. No patients with genotype 2 or 4 HCV infection in the Epclusa + RBV 12 weeksgroup experienced virologic failure.

The 1 virologic failure patient with genotype 1 HCV had no NS5A or NS5B RAVs at failure.

Of the 2 genotype 3 virologic failure patients, one had NS5A RAV Y93H emerge at failure. Anotherpatient had virus with Y93H at baseline and virologic failure and also developed low levels (< 5%) of

NS5B NI RAVs N142T and E237G at failure. Pharmacokinetic data from this patient was consistentwith non-adherence to treatment.

In this study, 2 patients treated with Epclusa for 12 or 24 weeks without ribavirin had emergent NS5B

S282T at low levels (< 5%) along with L159F.

Studies in patients without cirrhosis and patients with compensated cirrhosis

Analyses were conducted to explore the association between pre-existing baseline NS5A RAVs andtreatment outcome for patients without cirrhosis or with compensated cirrhosis in three Phase 3clinical studies (ASTRAL-1, ASTRAL-2 and ASTRAL-3). Of the 1,035 patients treated withsofosbuvir/velpatasvir in the three Phase 3 clinical studies, 1,023 patients were included in the analysisof NS5A RAVs; 7 patients were excluded as they neither achieved sustained virologic response(SVR12) nor had virologic failure and 5 additional patients were excluded as NS5A gene sequencingfailed. In the pooled analysis of the Phase 3 studies, 380/1,023 (37%) patients’ virus had baseline

NS5A RAVs. Genotype 2, 4, and 6 HCV-infected patients had a higher prevalence of NS5A RAVs(70%, 63% and 52%, respectively) compared to genotype 1 (23%), genotype 3 (16%), and genotype 5(18%) HCV-infected patients.

Baseline RAVs had no relevant impact on SVR12 rates in patients infected with genotype 1, 2, 4, 5and 6 HCV, as summarised in Table 8. Genotype 3 infected patients with the NS5A RAV Y93H atbaseline had a lower SVR12 rate than patients without Y93H after treatment with Epclusa for12 weeks, as summarised in Table 9. In the ASTRAL-3 study, the Y93H RAV was detected atbaseline in 9% of patients treated with Epclusa.

Table 8: SVR12 in patients with or without baseline NS5A RAVs by HCV genotype (studies

ASTRAL-1, ASTRAL-2 and ASTRAL-3)

Epclusa 12 weeks

Genotype 1 Genotype 3 Genotypes 2, 4, 5 or 6 Total

With any baseline NS5A RAVs 97% (73/75) 88% (38/43) 100% (262/262) 98% (373/380)

Without baseline NS5A RAVs 100% (251/251) 97% (225/231) 100% (161/161) 99% (637/643)

Table 9: SVR12 in patients with and without baseline Y93H, 1% Cut-off (Resistance Analysis

Population Set) ASTRAL 3

Epclusa 12 Weeks

All Subjects Cirrhotic Non-Cirrhotic(n = 274) (n = 80) (n = 197)

O verall 95.3% (263/274) 91.3% (73/80) 97.9% (190/194)95% CI 92.9% to 98.0% 82.8% to 96.4% 92.8% to 98.6%

SVR with Y93H 84.0% (21/25) 50.0% (2/4) 90.5% (19/21)95% CI 63.9% to 95.5% 6.8% to 93.2% 69.6% to 98.8%

SVR without Y93H 96.4% (242/249) 93.4% (71/76) 98.8% (171/173)95% CI 94.3% to 98.9% 85.3% to 97.8% 95.9% to 99.9%

The NS5B NI RAV S282T was not detected in the baseline NS5B sequence of any patient in Phase 3studies. SVR12 was achieved in all 77 patients who had baseline NS5B NI RAVs including N142T,

L159F, E/N237G, C/M289L/I, L320F/I/V, V321A/I, and S282G+V321I.

Studies in patients with decompensated cirrhosis (CPT Class B)

Analyses were conducted to explore the association between pre-existing baseline NS5A RAVs andtreatment outcome for patients with decompensated cirrhosis in one Phase 3 study (ASTRAL-4). Ofthe 87 patients treated with Epclusa + RBV, 85 patients were included in the analysis of NS5A RAVs;2 patients were excluded as they neither achieved SVR12 nor had virologic failure. Among thepatients who received treatment with Epclusa + RBV for 12 weeks, 29% (25/85) of patients hadbaseline virus with NS5A RAVs: 29% (19/66), 75% (3/4), 15% (2/13), and 50% (1/2) for patients withgenotype 1, 2, 3 and 4 HCV, respectively.

SVR12 in patients with or without baseline NS5A RAVs in the Epclusa + RBV 12 week group for thisstudy is shown in Table 10.

Table 10: SVR12 in patients with or without baseline NS5A RAVs by HCV genotype (study

ASTRAL-4)

Epclusa + RBV 12 weeks

Genotype 1 Genotype 3 Genotypes 2 or 4 Total

With any baseline NS5A RAVs 100% (19/19) 50% (1/2) 100% (4/4) 96% (24/25)

Without baseline NS5A RAVs 98% (46/47) 91% (10/11) 100% (2/2) 98% (58/60)

The single genotype 3 patient who had baseline NS5A RAVs and failed to achieve SVR12 had NS5Asubstitution Y93H at baseline; pharmacokinetic data from this patient was consistent withnon-adherence to treatment.

Three patients in the Epclusa + RBV 12 week group had baseline NS5B NI RAVs (N142T and

L159F) and all three patients achieved SVR12.

The presence of NS5A and NS5B RAVs did not impact treatment outcome; all patients with baseline

NS5A (n=29) or NS5B NI (n=6) RAVs achieved SVR following 12 weeks treatment with Epclusa.

In vitro data suggests that the majority of NS5A RAVs that confer resistance to ledipasvir anddaclatasvir remained susceptible to velpatasvir. Velpatasvir was fully active against the sofosbuvirresistance-associated substitution S282T in NS5B while all velpatasvir resistance-associatedsubstitutions in NS5A were fully susceptible to sofosbuvir. Both sofosbuvir and velpatasvir were fullyactive against substitutions associated with resistance to other classes of direct-acting antivirals withdifferent mechanisms of actions, such as NS5B non-nucleoside inhibitors and NS3 protease inhibitors.

The efficacy of Epclusa has not been assessed in patients who have previously failed treatment withother regimens that include an NS5A inhibitor.

The efficacy of Epclusa was evaluated in three Phase 3 studies in patients with genotype 1 to 6 HCVinfection with or without compensated cirrhosis, one Phase 3 study in patients with genotype 1 to 6

HCV infection with decompensated cirrhosis, one Phase 3 study in HCV/HIV-1 co-infected patientswith genotype 1 to 6 HCV infection and one Phase 2 study in patients with HCV infection and ESRDrequiring dialysis, as summarised in Table 11.

Table 11: Studies conducted with Epclusa in patients with genotype 1, 2, 3, 4, 5 or 6 HCVinfection

Study Population Study arms(Number of patients treated)

Genotype 1, 2, 4, 5 and 6

ASTRAL-1 TN and TE, without cirrhosis or with compensated Epclusa 12 weeks (624)cirrhosis Placebo 12 weeks (116)

Genotype 2

ASTRAL-2 TN and TE, without cirrhosis or with compensated Epclusa 12 weeks (134)cirrhosis SOF+RBV 12 weeks (132)

Genotype 3

ASTRAL-3 TN and TE, without cirrhosis or with compensated Epclusa 12 weeks (277)cirrhosis SOF+RBV 24 weeks (275)

Genotype 1, 2, 3, 4, 5 and 6 Epclusa 12 weeks (90)

ASTRAL-4 TN and TE, with CPT Class B decompensated Epclusa + RBV 12 weeks (87)cirrhosis Epclusa 24 weeks (90)

Genotype 1, 2, 3, 4, 5 and 6

ASTRAL-5 TN and TE, without cirrhosis or with compensated Epclusa 12 weeks (106)cirrhosis, with HCV/HIV-1 co-infection

GS-US-342-4062 TN and TE with or without cirrhosis, with ESRD Epclusa 12 weeks (59)requiring dialysis

TN = treatment-naïve patients; TE = treatment-experienced patients (including those who have failed a peginterferon alfa +ribavirin based regimen with or without an HCV protease inhibitor)

The ribavirin dose was weight-based (1,000 mg daily administered in two divided doses for patients< 75 kg and 1,200 mg for those ≥ 75 kg) and administered in two divided doses when used incombination with sofosbuvir in the ASTRAL-2 and ASTRAL-3 studies or in combination with

Epclusa in the ASTRAL-4 study. Ribavirin dose adjustments were performed according to theribavirin prescribing information. Serum HCV RNA values were measured during the clinical studiesusing the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) with a lower limit ofquantification (LLOQ) of 15 IU/mL. Sustained virologic response (SVR12), defined as HCV RNAless than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint to determinethe HCV cure rate.

Clinical studies in patients without cirrhosis and patients with compensated cirrhosis

Genotype 1, 2, 4, 5 and 6 HCV-infected adults - ASTRAL-1 (study 1138)

ASTRAL-1 was a randomised, double-blind, placebo-controlled study that evaluated 12 weeks oftreatment with Epclusa compared with 12 weeks of placebo in patients with genotype 1, 2, 4, 5, or 6

HCV infection. Patients with genotype 1, 2, 4 or 6 HCV infection were randomised in a 5:1 ratio totreatment with Epclusa for 12 weeks or placebo for 12 weeks. Patients with genotype 5 HCVinfection were enrolled to the Epclusa group. Randomisation was stratified by HCV genotype (1, 2, 4,6, and indeterminate) and the presence or absence of cirrhosis.

Demographics and baseline characteristics were balanced between the Epclusa and placebo group. Ofthe 740 treated patients, the median age was 56 years (range: 18 to 82); 60% of the patients were male;79% were White, 9% were Black; 21% had a baseline body mass index of at least 30 kg/m2; theproportions of patients with genotype 1, 2, 4, 5, or 6 HCV infection were 53%, 17%, 19%, 5% and7%, respectively; 69% had non-CC IL28B alleles (CT or TT); 74% had baseline HCV RNA levels ofat least 800,000 IU/mL; 19% had compensated cirrhosis; and 32% were treatment-experienced.

Table 12 presents the SVR12 for the ASTRAL-1 study by HCV genotypes. No patients in the placebogroup achieved SVR12.

Table 12: SVR12 in study ASTRAL-1 by HCV genotype

Epclusa 12 weeks(n = 624)

Total GT-1 GT-2 GT-4 GT-5 GT-6(all GTs) GT-1a GT-1b Total (n = 104) (n = 116) (n = 35) (n = 41)(n = 624) (n = 210) (n = 118) (n = 328)

SVR12 99% 98% 99% 98% 100% 100% 97% 100%(618/624) (206/210) (117/118) (323/328) (104/104) (116/116) (34/35) (41/41)

Outcome for patients without SVR12

On-treatmentvirologic 0/624 0/210 0/118 0/328 0/104 0/116 0/35 0/41failure

Relapsea < 1% < 1% 1% 1%(2/623) (1/209) (1/118) (2/327) 0/104 0/116 0/35 0/41

Otherb 1% 1%(4/624) (3/210) 0/118 1%(3/328) 0/104 0/116 3%(1/35) 0/41

GT = genotypea The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment.b Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria.

Genotype 2 HCV-infected adults - ASTRAL-2 (study 1139)

ASTRAL-2 was a randomised, open-label study that evaluated 12 weeks of treatment with Epclusacompared with 12 weeks of treatment with SOF+RBV in patients with genotype 2 HCV infection.

Patients were randomised in a 1:1 ratio to treatment with Epclusa for 12 weeks or SOF+RBV for12 weeks. Randomisation was stratified by the presence or absence of cirrhosis and prior treatmentexperience (treatment-naïve versus treatment-experienced).

Demographics and baseline characteristics were balanced across the two treatment groups. Of the 266treated patients, the median age was 58 years (range: 23 to 81); 59% of the patients were male; 88%were White, 7% were Black; 33% had a baseline body mass index of at least 30 kg/m2; 62% hadnon-CC IL28B alleles (CT or TT); 80% had baseline HCV RNA levels of at least 800,000 IU/mL;14% had compensated cirrhosis and 15% were treatment-experienced.

Table 13 presents the SVR12 for the ASTRAL-2 study.

Table 13: SVR12 in study ASTRAL-2 (HCV genotype 2)

Epclusa SOF+RBV12 weeks 12 weeks(n = 134) (n = 132)

SVR12 99% (133/134) 94% (124/132)

Outcome for patients without SVR12

On-treatment virologic failure 0/134 0/132

Relapsea 0/133 5% (6/132)

Otherb 1% (1/134) 2% (2/132)a The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment.b Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria.

Treatment with Epclusa for 12 weeks demonstrated the statistical superiority (p = 0.018) overtreatment with SOF+RBV for 12 weeks (treatment difference +5.2%; 95% confidence interval: +0.2%to +10.3%).

Genotype 3 HCV-infected adults - ASTRAL-3 (study 1140)

ASTRAL-3 was a randomised, open-label study that evaluated 12 weeks of treatment with Epclusacompared with 24 weeks of treatment with SOF+RBV in patients with genotype 3 HCV infection.

Patients were randomised in a 1:1 ratio to treatment with Epclusa for 12 weeks or SOF+RBV for24 weeks. Randomisation was stratified by the presence or absence of cirrhosis and prior treatmentexperience (treatment-naïve versus treatment-experienced).

Demographics and baseline characteristics were balanced across the two treatment groups. Of the 552treated patients, the median age was 52 years (range: 19 to 76); 62% of the patients were male; 89%were White, 9% were Asian; 1% were Black; 20% had a baseline body mass index of at least30 kg/m2; 61% had non-CC IL28B alleles (CT or TT); 70% had baseline HCV RNA levels of at least800,000 IU/mL, 30% had compensated cirrhosis and 26% were treatment-experienced.

Table 14 presents the SVR12 for the ASTRAL-3 study.

Table 14: SVR12 in study ASTRAL-3 (HCV genotype 3)

Epclusa SOF+RBV12 weeks 24 weeks(n = 277) (n = 275)

SVR12 95% (264/277) 80% (221/275)

Outcome for patients without SVR12

On-treatment virologic failure 0/277 < 1% (1/275)

Relapsea 4% (11/276) 14% (38/272)

Otherb 1% (2/277) 5% (15/275)a The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment.b Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria.

Treatment with Epclusa for 12 weeks demonstrated the statistical superiority (p < 0.001) compared totreatment with SOF+RBV for 24 weeks (treatment difference +14.8%; 95% confidence interval:+9.6% to +20.0%).

SVR12 for selected subgroups are presented in Table 15.

Table 15: SVR12 for selected subgroups in study ASTRAL-3 (HCV genotype 3)

Epclusa SOF+RBV12 weeks 24 weeksa

SVR12 Treatment-naïve Treatment- Treatment-naïve Treatment-(n = 206) experienced (n = 201) experienced(n = 71) (n = 69)

Without cirrhosis 98% (160/163) 91% (31/34) 90% (141/156) 71% (22/31)

With cirrhosis 93% (40/43) 89% (33/37) 73% (33/45) 58% (22/38)a Five patients with missing cirrhosis status in the SOF+RBV 24 week group were excluded from this subgroup analysis.

Clinical studies in patients with decompensated cirrhosis - ASTRAL-4 (study 1137)

ASTRAL-4 was a randomised, open-label study in patients with genotype 1, 2, 3, 4, 5 or 6 HCVinfection and CPT Class B cirrhosis. Patients were randomised in a 1:1:1 ratio to treatment with

Epclusa for 12 weeks, Epclusa + RBV for 12 weeks or Epclusa for 24 weeks. Randomisation wasstratified by HCV genotype (1, 2, 3, 4, 5, 6 and indeterminate).

Demographics and baseline characteristics were balanced across the treatment groups. Of the 267treated patients, the median age was 59 years (range: 40 to 73); 70% of the patients were male; 90%were White, 6% were Black; 42% had a baseline body mass index of at least 30 kg/m2. Theproportions of patients with genotype 1, 2, 3, 4 or 6 HCV were 78%, 4%, 15%, 3%, and < 1%(1 patient), respectively. No patients with genotype 5 HCV infection were enrolled. 76% of thepatients had non-CC IL28B alleles (CT or TT); 56% had baseline HCV RNA levels of at least800,000 IU/mL, 55% were treatment-experienced; 90% and 95% of patients had CPT Class Bcirrhosis and Model for End Stage Liver Disease (MELD) score ≤ 15 at baseline, respectively.

Table 16 presents the SVR12 for the ASTRAL-4 study by HCV genotype.

Table 16: SVR12 in study ASTRAL-4 by HCV genotype

Epclusa Epclusa + RBV Epclusa12 weeks 12 weeks 24 weeks(n = 90) (n = 87) (n = 90)

Overall SVR12 83% (75/90) 94% (82/87) 86% (77/90)

Genotype 1 88% (60/68) 96% (65/68) 92% (65/71)

Genotype 1a 88% (44/50) 94% (51/54) 93% (51/55)

Genotype 1b 89% (16/18) 100% (14/14) 88% (14/16)

Genotype 3 50% (7/14) 85% (11/13) 50% (6/12)

Genotype 2, 4 and 6 100% (8/8)a 100% (6/6)b 86% (6/7)ca n = 4 for genotype 2 and n = 4 for genotype 4.b n = 4 for genotype 2 and n = 2 for genotype 4.c n = 4 for genotype 2, n = 2 for genotype 4 and n = 1 for genotype 6.

Table 17 presents the virologic outcome for patients with genotype 1 or 3 HCV infection in the

ASTRAL-4 study.

No patients with genotype 2, 4 or 6 HCV infection experienced virologic failure.

Table 17: Virologic outcome for patients with genotype 1 and 3 HCV infection in study

ASTRAL-4

Epclusa 12 weeks Epclusa + RBV 12 weeks Epclusa 24 weeks

Virologic failure (relapse and on-treatment failure)

Genotype 1a 7% (5/68) 1% (1/68) 4% (3/71)

Genotype 1a 6% (3/50) 2% (1/54) 4% (2/55)

Genotype 1b 11% (2/18) 0% (0/14) 6% (1/16)

Genotype 3 43% (6/14) 15% (2b/13) 42% (5c/12)

Otherd 5% (4/82) 2% (2/81) 5% (4/83)a No patients with genotype 1 HCV had on-treatment virologic failure.b One patient had on-treatment virologic failure; pharmacokinetic data from this patient was consistent with non-adherenceto treatment.c One patient had on-treatment virologic failure.d Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria.

Changes in the parameters found in the CPT score system in patients achieving SVR12 in ASTRAL-4(all 3 regimens) are shown in Table 18.

Table 18: Changes in CPT score parameters from baseline to week 12 and 24 post-treatment inpatients achieving SVR12, ASTRAL-4

Albumin Bilirubin INR Ascites Encephalopathy

Post-treatment Week 12 (N = 236), % (n/N)

Decreased score 34.5% 17.9% 7.9%(Improvement) (79/229) (41/229) 2.2% (5/229) (18/229) 5.2% (12/229)

No change 60.3% 76.4% 96.5% 89.1%(138/229) (175/229) (221/229) (204/229) 91.3% (209/229)

Increased score(Worsening) 5.2% (12/229) 5.7% (13/229) 1.3% (3/229) 3.1%(7/229) 3.5% (8/229)

No assessment 7 7 7 7 7

Albumin Bilirubin INR Ascites Encephalopathy

Post-treatment Week 24 (N = 236), % (n/N)

Decreased score 39.4% 16.4%(Improvement) (84/213) (35/213) 2.3% (5/213) 15.0%(32/213) 9.4% (20/213)

No change 54.0% 80.8% 94.8% 81.2%(115/213) (172/213) (202/213) (173/213) 88.3% (188/213)

Increased score(Worsening) 6.6% (14/213) 2.8% (6/213) 2.8% (6/213) 3.8%(8/213) 2.3% (5/213)

No assessment 23 23 23 23 23

Note: Baseline frequency of ascites was: 20% none, 77% mild/moderate, 3% severe

Baseline frequency of encephalopathy was: 38% none, 62% grade 1-2.

Clinical studies in patients with HCV/HIV-1 Co-infection - ASTRAL-5 (study 1202)

ASTRAL-5 evaluated 12 weeks of treatment with Epclusa in patients with genotype 1, 2, 3, or 4 HCVinfection who were co-infected with HIV-1 (HCV genotype 5 and 6 allowed, but no such patientswere included). Patients were on a stable HIV-1 antiretroviral therapy that includedemtricitabine/tenofovir disoproxil fumarate or abacavir/lamivudine administered with a ritonavirboosted protease inhibitor (atazanavir, darunavir, or lopinavir), rilpivirine, raltegravir oremtricitabine/tenofovir disoproxil fumarate /elvitegravir/cobicistat.

Of the 106 treated patients, the median age was 57 years (range: 25 to 72); 86% of the patients weremale; 51% were White; 45% were Black; 22% had a baseline body mass index ≥ 30 kg/m2; 19 patients(18%) had compensated cirrhosis; and 29% were treatment experienced. The overall mean CD4+count was 598 cells/µL (range: 183−1513 cells/µL).

Table 19 presents the SVR12 for the ASTRAL-5 study by HCV genotype.

Table 19: SVR12 in study ASTRAL-5 by HCV genotype

Epclusa 12 weeks(n = 106)

Total GT-1 GT-2 GT-3 GT-4(all GTs) GT-1a GT-1b Total (n = 11) (n = 12) (n = 5)(n = 106) (n = 66) (n = 12) (n = 78)

SVR12 95% 95% 92% 95% 100% 92% 100%(101/106) (63/66) (11/12) (74/78) (11/11) (11/12) (5/5)

Outcome for patients without SVR

On-treatmentvirologic 0/106 0/66 0/12 0/78 0/11 0/12 0/5failure

Relapsea 2% 3% 3%(2/103) (2/65) 0/11 (2/76) 0/11 0/11 0/5

Otherb 3% 2% 8% 3% 8%(3/106) (1/66) (1/12) (2/78) 0/11 (1/12) 0/5

GT = genotypea The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment.b Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria.

SVR12 was achieved by 19/19 patients with cirrhosis. No patient had HIV-1 rebound during the study,and CD4+ counts were stable during treatment.

Clinical studies in patients with Renal Impairment - study 4062

Study 4062 was an open-label clinical study that evaluated 12 weeks of treatment with Epclusa in 59

HCV-infected patients with ESRD requiring dialysis. The proportions of patients with genotype 1, 2,3, 4, 6 or indeterminate HCV infection were 42%, 12%, 27%, 7%, 3%, and 9%, respectively. Atbaseline, 29% of patients had cirrhosis, 22% were treatment experienced, 32% had received a kidneytransplant, 92% were on haemodialysis, and 8% were on peritoneal dialysis; mean duration on dialysiswas 7.3 years (range: 0 to 40 years). The overall SVR rate was 95% (56/59); of the three patients thatdid not achieve SVR12, one had completed Epclusa treatment and relapsed and two did not meetvirologic failure criteria.

The efficacy of 12 weeks of treatment with sofosbuvir/velpatasvir in HCV-infected paediatric patientsaged 3 years and older was evaluated in a Phase 2, open-label clinical study in 214 patients with HCVinfection.

Patients aged 12 to < 18 Years:

Sofosbuvir/velpatasvir was evaluated in 102 patients aged 12 to <18 years with genotype 1, 2, 3, 4, or6 HCV infection. A total of 80 patients (78%) were treatment-naïve and 22 patients (22%) weretreatment-experienced. The median age was 15 years (range: 12 to 17); 51% of the patients werefemale; 73% were White, 9% were Black, and 11% were Asian; 14% were Hispanic/Latino; meanbody mass index was 22.7 kg/m2 (range: 12.9 to 48.9 kg/m2); mean weight was 61 kg(range 22 to 147 kg); 58% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; theproportions of subjects with genotype 1, 2, 3, 4, or 6 HCV infection were 74%, 6%, 12%, 2%, and 6%,respectively; no patients had known cirrhosis. The majority of patients (89%) had been infectedthrough vertical transmission.

The SVR rate was 95% overall (97/102), 93% (71/76) in patients with genotype 1 HCV infection, and100% in patients with genotype 2 (6/6), genotype 3 (12/12), genotype 4 (2/2), and genotype 6 (6/6)

HCV infection. One patient who discontinued treatment early relapsed; the other four patients who didnot achieve SVR12 did not meet virologic failure criteria (e.g., lost to follow-up).

Patients aged 6 to < 12 Years:

Sofosbuvir/velpatasvir was evaluated in 71 patients aged 6 to <12 years with genotype 1, 2, 3, and 4

HCV infection. A total of 67 patients (94%) were treatment-naïve and 4 patients (6%) were treatment-experienced. The median age was 8 years (range: 6 to 11); 54% of the patients were female; 90% were

White, 6% were Black, and 1% were Asian; 10% were Hispanic/Latino; mean body mass index was17.4 kg/m2 (range: 12.8 to 30.9 kg/m2); mean weight was 30 kg (range 18 to 78 kg); 48% had baseline

HCV RNA levels greater than or equal to 800,000 IU per mL; the proportions of patients withgenotype 1, 2, 3, or 4 HCV infection were 76%, 3%, 15%, and 6%, respectively; no patients hadknown cirrhosis. The majority of patients (94%) had been infected through vertical transmission.

The SVR rate was 93% overall (66/71), 93% (50/54) in patients with genotype 1 HCV infection, 91%(10/11) in patients with genotype 3 HCV infection, and 100% in patients with genotype 2 (2/2) andgenotype 4 (4/4) HCV infection. One subject had on-treatment virologic failure; the other four patientswho did not achieve SVR12 did not meet virologic failure criteria (e.g., lost to follow-up).

Patients aged 3 to < 6 Years:

Sofosbuvir/velpatasvir was evaluated in 41 treatment-naïve subjects 3 years to < 6 years of age withgenotype 1, 2, 3, and 4 HCV infection. The median age was 4 years (range: 3 to 5); 59% of thesubjects were female; 78% were White and 7% were Black; 10% were Hispanic/Latino; mean bodymass index was 17.0 kg/m2 (range: 13.9 to 22.0 kg/m2); mean weight was 19 kg (range: 13 to 35 kg);49% had baseline HCV RNA levels ≥ 800,000 IU per mL; the proportions of subjects with genotype 1,2, 3, or 4 HCV infection were 78%, 15%, 5%, and 2%, respectively; no subjects had known cirrhosis.

The majority of subjects (98%) had been infected through vertical transmission.

The SVR rate was 83% overall (34/41), 88% (28/32) in subjects with genotype 1 HCV infection, 50%(3/6) in subjects with genotype 2 HCV infection, and 100% in subjects with genotype 3 (2/2) andgenotype 4 (1/1) HCV infection. No subject experienced on-treatment virologic failure or relapse. Theseven subjects who did not achieve SVR12 did not meet virologic failure criteria (e.g., lost to follow-up).

Clinical studies of Epclusa included 156 patients aged 65 and over (12% of total number of patients inthe Phase 3 clinical studies). The response rates observed for patients ≥ 65 years of age were similar tothat of patients < 65 years of age, across treatment groups.

The pharmacokinetic properties of sofosbuvir, GS-331007 and velpatasvir have been evaluated inhealthy adult subjects and in patients with chronic hepatitis C. Following oral administration of

Epclusa, sofosbuvir was absorbed quickly and the peak median plasma concentration was observed1 hour post-dose. Median peak plasma concentration of GS-331007 was observed 3 hours post-dose.

Velpatasvir median peak concentrations were observed at 3 hours post-dose.

Based on the population pharmacokinetic analysis in HCV-infected patients, mean steady-state

AUC0-24 for sofosbuvir (n = 982), GS-331007 (n = 1,428) and velpatasvir (n = 1,425) were 1,260,13,970 and 2,970 ng*h/mL, respectively. Steady-state Cmax for sofosbuvir, GS-331007 and velpatasvirwere 566, 868 and 259 ng/mL, respectively. Sofosbuvir and GS-331007 AUC0-24 and Cmax weresimilar in healthy adult subjects and patients with HCV infection. Relative to healthy subjects(n = 331), velpatasvir AUC0-24 and Cmax were 37% lower and 41% lower, respectively in HCV-infectedpatients.

Relative to fasting conditions, the administration of a single dose of Epclusa with a moderate fat(~600 kcal, 30% fat) or high fat (~800 kcal, 50% fat) meal resulted in a 34% and 21% increase invelpatasvir AUC0-inf, respectively, and a 31% and 5% increase in velpatasvir Cmax, respectively. Themoderate or high fat meal increased sofosbuvir AUC0-inf by 60% and 78%, respectively, but did notsubstantially affect the sofosbuvir Cmax. The moderate or high fat meal did not alter GS-331007

AUC0-inf, but resulted in a 25% and 37% decrease in its Cmax, respectively. The response rates in

Phase 3 studies were similar in HCV-infected patients who received Epclusa with food or withoutfood. Epclusa can be administered without regard to 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 > 99.5% 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 between0.52 and 0.67.

Sofosbuvir is extensively metabolised in the liver to form the pharmacologically active nucleosideanalog 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. Sofosbuvir and GS-331007 are not substrates or inhibitors of UGT1A1 or

CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 enzymes. After a single400 mg oral dose of [14C]-sofosbuvir, GS-331007 accounted for approximately > 90% of totalsystemic exposure.

Velpatasvir is a substrate of CYP2B6, CYP2C8, and CYP3A4 with slow turnover. Following a singledose of 100 mg [14C]-velpatasvir, the majority (> 98%) of radioactivity in plasma was parent drug.

The monohydroxylated and desmethylated velpatasvir were the metabolites identified in humanplasma. Unchanged velpatasvir 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 Epclusa were 0.5 and 25 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 Epclusa was approximately 15 hours.

Velpatasvir AUC increases in a nearly dose proportional manner over the dose range of 25 mg to150 mg. Sofosbuvir and GS-331007 AUCs are near dose-proportional over the dose range of 200 mgto 1,200 mg.

In vitro potential for sofosbuvir/velpatasvir drug-drug interactions

Sofosbuvir and velpatasvir are substrates of drug transporters P-gp and BCRP while GS-331007 is not.

Velpatasvir is also a substrate of OATP1B. In vitro, slow metabolic turnover of velpatasvir by

CYP2B6, CYP2C8, and CYP3A4 was observed.

Velpatasvir is an inhibitor of drug transporter P-gp, BCRP, OATP1B1 and OATP1B3 and itsinvolvement in drug interactions with these transporters is primarily limited to the process ofabsorption. At clinically relevant plasma concentration, velpatasvir is not an inhibitor of hepatictransporters bile salt export pump (BSEP), sodium taurocholate cotransporter protein (NTCP),

OATP2B1, OATP1A2 or organic cation transporter (OCT) 1, renal transporters OCT2, OAT1, OAT3,multidrug resistance-associated protein 2 (MRP2) or multidrug and toxin extrusion protein (MATE) 1,or CYP or uridine glucuronosyltransferase (UGT) 1A1 enzymes.

Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, MRP2, BSEP,

OATP1B1, OATP1B3 and OCT1. GS-331007 is not an inhibitor of OAT1, OCT2, and MATE1.

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

Population pharmacokinetic analysis in HCV-infected patients showed that within the age range (18 to82 years) analysed, age did not have a clinically relevant effect on the exposure to sofosbuvir,

GS-331007, or velpatasvir.

A summary of the effect of varying degrees of renal impairment (RI) on the exposures of thecomponents of Epclusa compared to subjects with normal renal function, as described in the textbelow, are provided in Table 20.

Table 20: Effect of Varying Degrees of Renal Impairment on Exposures (AUC) of Sofosbuvir,

GS-331007, and Velpatasvir 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 ≥50 (eGFR ≥30 (eGFR Dialysis (eGFR Requiringand and <30 mL/min Dosed 1 Dosed 1 <30 mL/m Dialysis<80 mL/min <50 mL/min/ /1.73m2) hr Before hr After in/1.73m2)/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↑

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 patients with severe renal impairment treated with sofosbuvir 200 mg with ribavirin(n=10) or sofosbuvir 400 mg with ribavirin (n=10) for 24 weeks or ledipasvir/sofosbuvir 90/400 mg(n=18) for 12 weeks, the pharmacokinetics of sofosbuvir and GS-331007 were consistent with thatobserved in HCV negative adult patients with severe renal impairment.

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

The pharmacokinetics of sofosbuvir, GS-331007, and velpatasvir were studied in HCV-infectedpatients with ESRD requiring dialysis treated with Epclusa (n=59) for 12 weeks, and compared topatients without renal impairment in the sofosbuvir/velpatasvir Phase 2/3 studies.

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 moderate and severe hepatic impairment, while the GS-331007 AUC0-24 was 18% and 9% higher,respectively. Population pharmacokinetics analysis in HCV-infected adult patients indicated thatcirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure tosofosbuvir and GS-331007.

The pharmacokinetics of velpatasvir was studied with a single dose of 100 mg velpatasvir in HCVnegative adult patients with moderate and severe hepatic impairment (CPT Class B and C). Comparedto subjects with normal hepatic function velpatasvir total plasma exposure (AUCinf) was similar inpatients with moderate or severe hepatic impairment. Population pharmacokinetics analysis in

HCV-infected patients indicated that cirrhosis (including decompensated cirrhosis) had no clinicallyrelevant effect on the exposure to velpatasvir (see section 4.2).

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

Sofosbuvir, GS-331007 and velpatasvir exposures in paediatric patients aged 3 years and olderreceiving oral once daily doses of sofosbuvir/velpatasvir 400 mg/100 mg, 200 mg/50 mg or150 mg/37.5 mg per day were similar to those in adults receiving once daily doses ofsofosbuvir/velpatasvir 400 mg/100 mg.

The pharmacokinetics of sofosbuvir, GS-331007 and velpatasvir in paediatric patients aged less than3 years have not been established (see section 4.2).

Exposure to sofosbuvir in rodent studies could not be detected likely due to high esterase activity andexposure to the major metabolite GS-331007 was instead used to estimate exposure margins.

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 a carcinogen in the 2-year mouse and rat carcinogenicity studies at GS-331007exposures up to 15 and 9 times, respectively, higher 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 6-month rasH2 transgenic mouse and 2-year ratcarcinogenicity studies at exposures at least 50-times 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 31-and 6-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 0.7-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 5-fold higher than the human exposure at the recommendedclinical dose.

Copovidone (E1208)

Microcrystalline cellulose (E460)

Croscarmellose sodium (E468)

Magnesium stearate (E470b)

Poly(vinyl alcohol) (E1203)

Titanium dioxide (E171)

Macrogol (E1521)

Talc (E553b)

Iron oxide red (E172)

Not applicable.

4 years.

This medicinal product does not require any special storage conditions.

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

Pack size of 1 bottle containing 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/1/16/1116/001

EU/1/16/1116/002

Date of first authorisation: 06 July 2016

Date of latest renewal: 22 March 2021

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

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