Epclusa

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



2 

This medicinal product is subject to additional monitoring.  This will allow quick identification of 
new safety information.  Healthcare professionals are asked to report any suspected adverse reactions.  
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Epclusa 400 mg/100 mg film-coated tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 400 mg sofosbuvir and 100 mg velpatasvir. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
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. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Epclusa is indicated for the treatment of chronic hepatitis C virus (HCV) infection in adults (see 
sections 4.2, 4.4 and 5.1). 
 
4.2 Posology and method of administration 
 
Epclusa treatment should be initiated and monitored by a physician experienced in the management of 
patients with HCV infection. 
 
Posology 
The recommended dose of Epclusa is one tablet, taken orally, once daily with or without food (see 
section 5.2). 
 
Table 1: Recommended treatment and duration for all HCV genotypes 
Patient populationa Treatment and duration 

Patients without cirrhosis and patients with 
compensated cirrhosis 

Epclusa for 12 weeks 
 
Addition of ribavirin may be considered for genotype 3 infected 
patients with compensated cirrhosis (see section 5.1.) 

Patients with decompensated cirrhosis Epclusa + ribavirin for 12 weeks 
a Includes patients co-infected with human immunodeficiency virus (HIV) and patients with recurrent HCV post-liver 

transplant (see section 4.4.). 
 
When used in combination with ribavirin, refer also to the Summary of Product Characteristics of the 
medicinal product containing ribavirin. 
 



3 

The following dosing is recommended where ribavirin is divided in two daily doses and given with 
food: 
 
Table 2: Guidance for ribavirin dosing when administered with Epclusa to patients with 
decompensated cirrhosis 
Patient Ribavirin Dose 
Child-Pugh-Turcotte (CPT) Class B 
cirrhosis pre-transplant 

1,000 mg per day for patients < 75 kg and 1,200 mg for those 
weighing ≥ 75 kg 

CPT Class C cirrhosis pre-transplant 
 
CPT Class B or C post-transplant 

Starting dose of 600 mg, which can be titrated up to a maximum of 
1,000/1,200 mg (1,000 mg for patients weighing < 75 kg and 
1,200 mg for patients weighing ≥ 75 kg) if well tolerated.  If the 
starting dose is not well tolerated, the dose should be reduced as 
clinically indicated based on haemoglobin levels 

 
If ribavirin is used in genotype 3 infected patients with compensated cirrhosis (pre- or post-transplant) 
the recommended dose of ribavirin is 1,000/1,200 mg (1,000 mg for patients weighing < 75 kg and 
1,200 mg for patients weighing ≥ 75 kg). 
 
For ribavirin dose modifications, refer to the Summary of Product Characteristics of the medicinal 
product containing ribavirin. 
 
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 
Epclusa is needed (see section 5.1). 
 
If a dose of Epclusa is missed and it is within 18 hours of the normal time, patients should be 
instructed to take the tablet as soon as possible and then patients should take the next dose at the usual 
time.  If it is after 18 hours then patients should be instructed to wait and take the next dose of Epclusa 
at the usual time.  Patients should be instructed not to take a double dose of Epclusa. 
 
Patients who have previously failed therapy with an NS5A-containing regimen 
Epclusa + ribavirin for 24 weeks may be considered (see section 4.4). 
 
Elderly 
No dose adjustment is warranted for elderly patients (see section 5.2). 
 
Renal impairment 
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.  Epclusa 
can be used in these patients with no dose adjustment when no other relevant treatment options are 
available (see section 4.4, 4.8, 5.1 and 5.2). 
 
Hepatic impairment 
No dose adjustment of Epclusa is required for patients with mild, moderate, or severe hepatic 
impairment (CPT Class A, B, or C) (see section 5.2).  Safety and efficacy of Epclusa have been 
assessed in patients with CPT Class B cirrhosis, but not in patients with CPT Class C cirrhosis (see 
sections 4.4, 4.8 and 5.1). 
 
Paediatric population 
The safety and efficacy of Epclusa in children and adolescents aged less than 18 years have not yet 
been established.  No data are available. 
 
Method of administration 
For oral use. 
 



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Patients should be instructed to swallow the tablet whole with or without food (see section 5.2).  Due 
to the bitter taste, it is recommended that the film-coated tablet is not chewed or crushed. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. 
 
Use with strong P-gp and strong CYP inducers 
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).  
Co-administration will significantly decrease sofosbuvir or velpatasvir plasma concentrations and 
could result in loss of efficacy of Epclusa (see section 4.5). 
 
4.4 Special warnings and precautions for use 
 
Epclusa should not be administered concurrently with other medicinal products containing sofosbuvir. 
 
Severe bradycardia and heart block 
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 occurred 
within hours to days, but cases with a longer time to onset have been observed mostly up to 2 weeks 
after initiating HCV treatment. 
 
Amiodarone should only be used in patients on Epclusa when other alternative anti-arrhythmic 
treatments are not tolerated or are contraindicated. 
 
Should concomitant use of amiodarone be considered necessary, it is recommended that patients 
undergo cardiac monitoring in an in-patient setting for the first 48 hours of coadministration, after 
which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the 
first 2 weeks of treatment. 
 
Due to the long half-life of amiodarone, cardiac monitoring as outlined above should also be carried 
out for patients who have discontinued amiodarone within the past few months and are to be initiated 
on Epclusa. 
 
All patients with concurrent or recent use of amiodarone should be warned of the symptoms of 
bradycardia and heart block and should be advised to seek medical advice urgently should they 
experience them. 
 
HCV/HBV (hepatitis B virus) co-infection 
Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after 
treatment with direct-acting antiviral agents.  HBV screening should be performed in all patients 
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 patients 
who have failed treatment with a regimen containing another NS5A inhibitor.  However, on the basis 
of NS5A resistance associated variants (RAVs) typically seen in patients who have failed therapy with 
other NS5A inhibitor containing regimens, the in vitro pharmacology of velpatasvir, and the outcomes 
of sofosbuvir/velpatasvir treatment in NS5A-naïve patients with baseline NS5A RAVs enrolled into 
the ASTRAL-studies, treatment with Epclusa + RBV for 24 weeks can be considered for patients who 
have failed therapy on an NS5A-containing regimen and who are deemed at high risk for clinical 
disease progression and who do not have alternative treatment options. 
 



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Renal impairment 
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 when 
no other relevant treatment options are available (see sections 4.8, 5.1 and 5.2).  When Epclusa is used 
in combination with ribavirin refer also to the Summary of Product Characteristics for ribavirin for 
patients 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 to 
reduced therapeutic effect of Epclusa.  Co-administration of such medicinal products with Epclusa is 
not recommended (see section 4.5). 
 
Use with certain HIV antiretroviral regimens 
Epclusa has been shown to increase tenofovir exposure, especially when used together with an HIV 
regimen containing tenofovir disoproxil fumarate and a pharmacokinetic enhancer (ritonavir or 
cobicistat).  The safety of tenofovir disoproxil fumarate in the setting of Epclusa and a 
pharmacokinetic enhancer has not been established.  The potential risks and benefits associated with 
co-administration of Epclusa with the fixed-dose combination tablet containing 
elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or tenofovir disoproxil fumarate 
given in conjunction with a boosted HIV protease inhibitor (e.g. atazanavir or darunavir) should be 
considered, particularly in patients at increased risk of renal dysfunction.  Patients receiving Epclusa 
concomitantly with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or with 
tenofovir disoproxil fumarate and a boosted HIV protease inhibitor should be monitored for 
tenofovir-associated adverse reactions.  Refer to tenofovir disoproxil fumarate, emtricitabine/tenofovir 
disoproxil fumarate, or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate Summary of 
Product Characteristics for recommendations on renal monitoring. 
 
Use in diabetic patients  
Diabetics may experience improved glucose control, potentially resulting in symptomatic 
hypoglycaemia, after initiating HCV direct-acting antiviral treatment. Glucose levels of diabetic 
patients initiating direct-acting antiviral therapy should be closely monitored, particularly within the 
first 3 months, and their diabetic medication modified when necessary. The physician in charge of the 
diabetic 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 (see 
sections 4.8 and 5.1). 
 
Liver transplant patients 
The safety and efficacy of Epclusa in the treatment of HCV infection in patients who are post-liver 
transplant have not been assessed.  Treatment with Epclusa in accordance with the recommended 
posology (see section 4.2) should be guided by an assessment of the potential benefits and risks for the 
individual patient. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
As Epclusa contains sofosbuvir and velpatasvir, any interactions that have been identified with these 
active 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), organic 
anion-transporting polypeptide (OATP) 1B1 and OATP1B3.  Co-administration of Epclusa with 
medicinal products that are substrates of these transporters may increase the exposure of such 
medicinal products.  See Table 3 for examples of interactions with sensitive substrates of P-gp 
(digoxin), BCRP (rosuvastatin), and OATP (pravastatin). 
 



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Potential for other medicinal products to affect Epclusa 
Sofosbuvir and velpatasvir are substrates of drug transporters P-gp and BCRP.  Velpatasvir is also a 
substrate 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/or 
strong 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 or 
velpatasvir leading to reduced therapeutic effect of sofosbuvir/velpatasvir.  The use of such medicinal 
products 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 (see 
section 4.4).  Co-administration with medicinal products that inhibit P-gp or BCRP may increase 
sofosbuvir or velpatasvir plasma concentrations.  Medicinal products that inhibit OATP, CYP2B6, 
CYP2C8, or CYP3A4 may increase plasma concentration of velpatasvir.  Clinically significant 
medicinal product interactions with Epclusa mediated by P-gp, BCRP, OATP, or CYP450 inhibitors 
are not expected; Epclusa may be co-administered with P-gp, BCRP, OATP and CYP inhibitors. 
 
Patients treated with vitamin K antagonists 
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 drugs metabolized by the liver 
The pharmacokinetics of drugs that are metabolized by the liver (e.g. immunosuppressive agents such 
as calcineurin inhibitors) may be impacted by changes in liver function during DAA therapy, related to 
clearance of HCV. 
 
Interactions between Epclusa and other medicinal products 
Table 3 provides a listing of established or potentially clinically significant medicinal product 
interactions (where 90% confidence interval [CI] of the geometric least-squares mean [GLSM] ratio 
were within “↔”, extended above “↑”, or extended below “↓” the predetermined interaction 
boundaries).  The medicinal product interactions described are based on studies conducted with either 
sofosbuvir/velpatasvir or velpatasvir and sofosbuvir as individual agents, or are predicted medicinal 
product interactions that may occur with sofosbuvir/velpatasvir.  The table is not all-inclusive. 
 
Table 3: Interactions between Epclusa and other medicinal products 
Medicinal product by 
therapeutic areas/Possible 
Mechanism of Interaction 

Effects on medicinal product levels. 
Mean ratio (90% confidence interval)a,b Recommendation concerning 

co-administration with Epclusa Active Cmax AUC Cmin 
ACID REDUCING AGENTS 
  Velpatasvir solubility decreases as 

pH increases.  Medicinal products 
that increase gastric pH are 
expected to decrease the 
concentration of velpatasvir. 

Antacids 
e.g. Aluminium or 
magnesium hydroxide; 
calcium carbonate 
 
(Increase in gastric pH) 

Interaction not studied. 
Expected. 
↔ Sofosbuvir 
↓ Velpatasvir 

It is recommended to separate 
antacid and Epclusa administration 
by 4 hours. 



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Medicinal product by 
therapeutic areas/Possible 
Mechanism of Interaction 

Effects on medicinal product levels. 
Mean ratio (90% confidence interval)a,b Recommendation concerning 

co-administration with Epclusa Active Cmax AUC Cmin 
H2-receptor antagonists 
Famotidine 
(40 mg single dose)/ 
sofosbuvir/ velpatasvir 
(400/ 100 mg single dose)c 
 
Famotidine dosed 
simultaneously with 
Epclusad 
 
Cimetidinee 
Nizatidinee 
Ranitidinee 
 
(Increase in gastric pH) 

Sofosbuvir ↔ ↔  H2-receptor antagonists may be 
administered simultaneously with 
or staggered from Epclusa at a 
dose that does not exceed doses 
comparable to famotidine 40 mg 
twice daily. Velpatasvir ↓ 

0.80 
(0.70, 
0.91) 

↓ 
0.81 
(0.71, 
0.91) 

 

Famotidine 
(40 mg single dose)/ 
sofosbuvir/ velpatasvir 
(400/ 100 mg single dose)c 
 
Famotidine dosed 12 hours 
prior to Epclusad 
 
(Increase in gastric pH) 

Sofosbuvir ↓ 
0.77 
(0.68, 
0.87) 

↓ 
0.80 
(0.73, 
0.88) 

  

Velpatasvir ↔ ↔  

Proton pump inhibitors 
Omeprazole 
(20 mg once daily)/ 
sofosbuvir/ velpatasvir 
(400/ 100 mg single dose 
fasted)c 
 
Omeprazole dosed 
simultaneously with 
Epclusad 
 
Lansoprazolee 
Rabeprazolee 
Pantoprazolee 
Esomeprazolee 
 
(Increase in gastric pH) 

Sofosbuvir ↓ 
0.66 
(0.55, 
0.78) 

↓ 
0.71 
(0.60, 
0.83) 

 Co-administration with proton 
pump inhibitors is not 
recommended.  If it is considered 
necessary to co-administer, then 
Epclusa should be administered 
with food and taken 4 hours before 
proton pump inhibitor at max 
doses comparable to omeprazole 
20 mg. 

Velpatasvir ↓ 
0.63 
(0.50, 
0.78) 

↓ 
0.64 
(0.52, 
0.79) 

 

Omeprazole 
(20 mg once daily)/ 
sofosbuvir/ velpatasvir 
(400/ 100 mg single dose 
fed)c 
 
Omeprazole dosed 4 hours 
after Epclusad 
 
(Increase in gastric pH) 

Sofosbuvir ↓ 
0.79 
(0.68, 
0.92) 

↔   

Velpatasvir ↓ 
0.67 
(0.58, 
0.78) 

↓ 
0.74 
(0.63, 
0.86) 

 



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Medicinal product by 
therapeutic areas/Possible 
Mechanism of Interaction 

Effects on medicinal product levels. 
Mean ratio (90% confidence interval)a,b Recommendation concerning 

co-administration with Epclusa Active Cmax AUC Cmin 
ANTIARRHYTHMICS 
Amiodarone Effect on amiodarone, velpatasvir, and 

sofosbuvir concentrations unknown. 
Coadministration of amiodarone 
with a sofosbuvir containing 
regimen may result in serious 
symptomatic bradycardia. 
Use only if no other alternative is 
available.  Close monitoring is 
recommended if this medicinal 
product is administered with 
Epclusa (see sections 4.4 and 4.8). 

Digoxin Interaction only studied with velpatasvir. 
Expected: 
↔ Sofosbuvir 

Co-administration of Epclusa with 
digoxin may increase the 
concentration of digoxin.  Caution 
is warranted and therapeutic 
concentration monitoring of 
digoxin is recommended when 
co-administered with Epclusa. 

Digoxin (0.25 mg single 
dose)f/ velpatasvir (100 mg 
single dose) 
 
(Inhibition of P-gp) 

Effect on velpatasvir exposure not studied 
Expected: 
↔ Velpatasvir 

Observed: 
Digoxin 

 
↑ 
1.9 
(1.7, 
2.1) 

 
↑ 
1.3 
(1.1, 
1.6) 

 

ANTICOAGULANTS 
Dabigatran etexilate 
 
 
 
 
(Inhibition of P-gp) 

Interaction not studied. 
Expected: 
↑ Dabigatran 
↔ Sofosbuvir 
↔ Velpatasvir 

Clinical monitoring, looking for 
signs of bleeding and anaemia, is 
recommended when dabigatran 
etexilate is co-administered with 
Epclusa.  A coagulation test helps 
to identify patients with an 
increased bleeding risk due to 
increased dabigatran exposure. 

Vitamin K antagonists Interaction not studied Close monitoring of INR is 
recommended with all vitamin K 
antagonists.  This is due to liver 
function changes during treatment 
with Epclusa. 

ANTICONVULSANTS 
Phenytoin 
Phenobarbital 
 
(Induction of P-gp and 
CYPs) 

Interaction not studied. 
Expected: 
↓ Sofosbuvir 
↓ Velpatasvir 

Epclusa is contraindicated with 
phenobarbital and phenytoin (see 
section 4.3). 

Carbamazepine 
 
 
 
(Induction of P-gp and 
CYPs) 

Interaction not studied. 
Expected: 
↓ Velpatasvir 
 

Epclusa is contraindicated with 
carbamazepine (see section 4.3). 

Observed: 
Sofosbuvir 

↓0.52 
(0.43, 
0.62) 
 

↓ 0.52 
(0.46, 
0.59) 

 
 

Oxcarbazepine 
 
 
(Induction of P-gp and 
CYPs) 

Interaction not studied. 
Expected: 
↓ Sofosbuvir 
↓ Velpatasvir 

Co-administration of Epclusa with 
oxcarbazepine is expected to 
decrease the concentration of 
sofosbuvir and velpatasvir, leading 
to reduced therapeutic effect of 
Epclusa.  Co-administration is not 
recommended (see section 4.4). 



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Medicinal product by 
therapeutic areas/Possible 
Mechanism of Interaction 

Effects on medicinal product levels. 
Mean ratio (90% confidence interval)a,b Recommendation concerning 

co-administration with Epclusa Active Cmax AUC Cmin 
ANTIFUNGALS 
Ketoconazole Interaction only studied with velpatasvir 

Expected: 
↔ Sofosbuvir 

No dose adjustment of Epclusa or 
ketoconazole is required. 

Ketoconazole (200 mg 
twice daily)/ velpatasvir 
(100 mg single dose)d 
 
 
 
(Inhibition of P-gp and 
CYPs) 
 
Itraconazolee 
Voriconazolee 
Posaconazolee 
Isavuconazolee 

Effect on ketoconazole exposure not 
studied. 
Expected: 
↔ Ketoconazole 
Observed: 
Velpatasvir 

 
↑ 
1.3 
(1.0, 
1.6) 

 
↑ 
1.7 
(1.4, 
2.2) 

 

ANTIMYCOBACTERIALS 
Rifampicin (600 mg once 
daily)/ sofosbuvir (400 mg 
single dose)d 
 
 
(Induction of P-gp and 
CYPs) 

Effect on rifampicin exposure not studied. 
 
Expected: 
↔ Rifampicin 

Epclusa is contraindicated with 
rifampicin (see section 4.3). 

Observed: 
Sofosbuvir 

 
↓ 
0.23 
(0.19, 
0.29) 

 
↓ 
0.28 
(0.24, 
0.32) 

 

Rifampicin (600 mg once 
daily)/ velpatasvir (100 mg 
single dose) 
 
 
 
 
(Induction of P-gp and 
CYPs) 

Effect on rifampicin exposure not studied. 
 
Expected: 
↔ Rifampicin 
Observed: 
Velpatasvir 

 
↓ 
0.29 
(0.23, 
0.37) 

 
↓ 
0.18 
(0.15, 
0.22) 

 

Rifabutin 
 
 
 
(Induction of P-gp and 
CYPs) 

Interaction not studied. 
Expected: 
↓ Velpatasvir 
 

Epclusa is contraindicated with 
rifabutin (see section 4.3). 
 

Observed: 
Sofosbuvir 

↓ 
0.64 
(0.53, 
0.77) 

↓  
0.76 
(0.63, 
0.91) 

 



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Medicinal product by 
therapeutic areas/Possible 
Mechanism of Interaction 

Effects on medicinal product levels. 
Mean ratio (90% confidence interval)a,b Recommendation concerning 

co-administration with Epclusa Active Cmax AUC Cmin 
Rifapentine 
 
 
 
(Induction of P-gp and 
CYPs) 

Interaction not studied. 
Expected: 
↓ Sofosbuvir 
↓ Velpatasvir 

Co-administration of Epclusa with 
rifapentine is expected to decrease 
the concentration of sofosbuvir and 
velpatasvir, leading to reduced 
therapeutic effect of Epclusa.  
Co-administration is not 
recommended (see section 4.4). 

HIV ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS 
Tenofovir disoproxil 
fumarate 

Epclusa has been shown to increase tenofovir exposure (P-gp-inhibition).  The 
increase in tenofovir exposure (AUC and Cmax) was around 40-80% during co-
treatment with Epclusa and tenofovir disoproxil fumarate/emtricitabine as part of 
various HIV regimens. 
 
Patients receiving tenofovir disoproxil fumarate and Epclusa concomitantly 
should be monitored for adverse reactions associated with tenofovir disoproxil 
fumarate.  Refer to the tenofovir disoproxil fumarate-containing product’s 
Summary of Product Characteristics for recommendations on renal monitoring 
(see section 4.4). 

Efavirenz/ emtricitabine/ 
tenofovir disoproxil 
fumarate 
(600/ 200/ 300 mg once 
daily)/ sofosbuvir/ 
velpatasvir (400/ 100 mg 
once daily)c, d 

Efavirenz ↔ ↔ ↔ Co-administration of Epclusa with 
efavirenz/ emtricitabine/ tenofovir 
disoproxil fumarate is expected to 
decrease the concentration of 
velpatasvir.  Co-administration of 
Epclusa with efavirenz-containing 
regimens is not recommended (see 
section 4.4). 

Sofosbuvir ↑ 
1.4 
(1.1, 
1.7) 

↔  

Velpatasvir ↓ 
0.53 
(0.43, 
0.64) 

↓ 
0.47 
(0.39, 
0.57) 

↓ 
0.43 
(0.36, 
0.52) 

Emtricitabine/ rilpivirine/ 
tenofovir disoproxil 
fumarate 
(200/ 25/ 300 mg once 
daily)/ sofosbuvir/ 
velpatasvir (400/ 100 mg 
once daily)c, d 

Rilpivirine ↔ ↔ ↔ No dose adjustment of Epclusa or 
emtricitabine/ rilpivirine/ tenofovir 
disoproxil fumarate is required. 

Sofosbuvir ↔ ↔  
Velpatasvir ↔ ↔ ↔ 

HIV ANTIVIRAL AGENTS: HIV PROTEASE INHIBITORS 
Atazanavir boosted with 
ritonavir (300/ 100 mg once 
daily) + emtricitabine/ 
tenofovir disoproxil 
fumarate (200/ 300 mg once 
daily)/ sofosbuvir/ 
velpatasvir (400/ 100 mg 
once daily)c, d 

Atazanavir ↔ ↔ ↑ 
1.4 
(1.2, 
1.6) 

No dose adjustment of Epclusa, 
atazanavir (ritonavir boosted) or 
emtricitabine/ tenofovir disoproxil 
fumarate is required. 

Ritonavir ↔  ↑ 
1.3 
(1.5, 
1.4) 

Sofosbuvir ↔ ↔  

Velpatasvir ↑ 
1.6 
(1.4, 
1.7) 

↑ 
2.4 
(2.2, 
2.6) 

↑ 
4.0 
(3.6, 
4.5) 

Darunavir boosted with 
ritonavir (800/ 100 mg once 
daily) + emtricitabine/ 
tenofovir disoproxil 
fumarate (200/ 300 mg once 
daily)/ sofosbuvir/ 
velpatasvir (400/ 100 mg 
once daily)c, d 

Darunavir ↔ ↔ ↔ No dose adjustment of Epclusa, 
darunavir (ritonavir boosted) or 
emtricitabine/ tenofovir disoproxil 
fumarate is required. 

Ritonavir ↔ ↔ ↔ 
Sofosbuvir ↓ 

0.62 
(0.54, 
0.71) 

↓ 
0.72 
(0.66, 
0.80) 

 

Velpatasvir ↓ 
0.76 
(0.65, 
0.89) 

↔ ↔ 



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Medicinal product by 
therapeutic areas/Possible 
Mechanism of Interaction 

Effects on medicinal product levels. 
Mean ratio (90% confidence interval)a,b Recommendation concerning 

co-administration with Epclusa Active Cmax AUC Cmin 
Lopinavir boosted with 
ritonavir (4x200 mg/ 50 mg 
once daily) + emtricitabine/ 
tenofovir disoproxil 
fumarate (200/ 300 mg once 
daily)/ sofosbuvir/ 
velpatasvir (400/ 100 mg 
once daily)c, d 

Lopinavir ↔ ↔ ↔ No dose adjustment of Epclusa, 
lopinavir (ritonavir boosted) or 
emtricitabine/ tenofovir disoproxil 
fumarate is required. 

Ritonavir ↔ ↔ ↔ 
Sofosbuvir ↓ 

0.59 
(0.49 
0.71) 

↓ 
0.7 
(0.6, 
0.8) 

 

Velpatasvir ↓ 
0.70 
(0.59, 
0.83) 

↔ ↑ 
1.6 
(1.4, 
1.9) 

HIV ANTIVIRAL AGENTS: INTEGRASE INHIBITORS 
Raltegravir (400 mg twice 
daily)g + emtricitabine/ 
tenofovir disoproxil 
fumarate (200/ 300 mg once 
daily)/ sofosbuvir/ 
velpatasvir (400/ 100 mg 
once daily)c, d 

Raltegravir ↔ ↔ ↓ 
0.79 
(0.42, 
1.5) 

No dose adjustment of Epclusa, 
raltegravir or emtricitabine/ 
tenofovir disoproxil fumarate is 
required. 

Sofosbuvir ↔ ↔  
Velpatasvir ↔ ↔ ↔ 

Elvitegravir/ cobicistat/ 
emtricitabine/ tenofovir 
alafenamide fumarate 
(150/ 150/ 200/ 10 mg once 
daily)/ sofosbuvir/ 
velpatasvir (400/ 100 mg 
once daily)c, d 

Elvitegravir ↔ ↔ ↔ No dose adjustment of Epclusa or 
elvitegravir/ cobicistat/ 
emtricitabine/ tenofovir 
alafenamide fumarate is required. 

Cobicistat ↔ ↔ ↑ 
2.0 
(1.7, 
2.5) 

Tenofovir 
alafenamide 

↔ ↔  

Sofosbuvir ↔ ↑ 
1.4 
(1.2, 
1.5) 

 

Velpatasvir ↑ 
1.3 
(1.2, 
1.5) 

↑ 
1.5 
(1.4, 
1.7) 

↑ 
1.6 
(1.4, 
1.8) 

Elvitegravir/ cobicistat/ 
emtricitabine/ tenofovir 
disoproxil fumarate 
(150/ 150/ 200/ 300 mg 
once daily)/ sofosbuvir/ 
velpatasvir (400/ 100 mg 
once daily)c, d 

Elvitegravir ↔ ↔ ↔ No dose adjustment of Epclusa or 
elvitegravir/ cobicistat/ 
emtricitabine/ tenofovir disoproxil 
fumarate is required. 

Cobicistat ↔ ↔ ↑ 
1.7 
(1.5, 
1.9) 

Sofosbuvir ↔ ↔  
Velpatasvir ↔ ↔ ↑ 

1.4 
(1.2, 
1.5) 

Dolutegravir (50 mg once 
daily)/ sofosbuvir/ 
velpatasvir (400/ 100 mg 
once daily) 

Dolutegravir ↔ ↔ ↔ No dose adjustment of Epclusa or 
dolutegravir is required. Sofosbuvir ↔ ↔  

Velpatasvir ↔ ↔ ↔ 

HERBAL SUPPLEMENTS 
St. John’s wort 
 
 
 
(Induction of P-gp and 
CYPs) 

Interaction not studied. 
Expected: 
↓ Sofosbuvir 
↓ Velpatasvir 

Epclusa is contraindicated with 
St. John’s wort (see section 4.3). 



12 

Medicinal product by 
therapeutic areas/Possible 
Mechanism of Interaction 

Effects on medicinal product levels. 
Mean ratio (90% confidence interval)a,b Recommendation concerning 

co-administration with Epclusa Active Cmax AUC Cmin 
HMG-CoA REDUCTASE INHIBITORS 
Atorvastatin (40 mg single 
dose)  + sofosbuvir / 
velpatasvir (400/ 100  mg 
once daily)d  

Observed: 
Atorvastatin 

↑ 
1.7  
(1.5, 
1.9)  

↑ 
1.5  
(1.5, 
1.6)  

 No dose adjustment of Epclusa or 
atorvastatin is required. 

Rosuvastatin Interaction only studied with velpatasvir 
Expected: 
↔ Sofosbuvir 

Co-administration of Epclusa with 
rosuvastatin increases the 
concentration of rosuvastatin, 
which is associated with increased 
risk of myopathy, including 
rhabdomyolysis.  Rosuvastatin, at a 
dose that does not exceed 10 mg, 
may be administered with Epclusa. 

Rosuvastatin (10 mg single 
dose)/ velpatasvir (100 mg 
once daily)d 
 
 
 
(Inhibition of OATP1B and 
BCRP) 

Observed: 
Rosuvastatin 

 
↑ 
2.6 
(2.3, 
2.9) 

 
↑ 
2.7 
(2.5, 
2.9) 

 

Effect on velpatasvir exposure not studied 
Expected: 
↔ Velpatasvir 

Pravastatin Interaction only studied with velpatasvir 
Expected: 
↔ Sofosbuvir 

No dose adjustment of Epclusa or 
pravastatin is required. 

Pravastatin (40 mg single 
dose)/ velpatasvir (100 mg 
once daily)d 
 
 
(Inhibition of OATP1B) 

Observed: 
Pravastatin 

 
↑ 
1.3 
(1.1, 
1.5) 

 
↑ 
1.4 
(1.2, 
1.5) 

 

Effect on velpatasvir exposure not studied 
Expected: 
↔ Velpatasvir 

Other statins Expected: 
↑ Statins 

Interactions cannot be excluded 
with other HMG-CoA reductase 
inhibitors.  When co-administered 
with Epclusa, careful monitoring 
for statin adverse reactions should 
be undertaken and a reduced dose 
of statins should be considered if 
required. 

NARCOTIC ANALGESICS 
Methadone 
(Methadone maintenance 
therapy [30 to 130 mg 
daily])/ sofosbuvir (400 mg 
once daily)d 

R-methadone 
 

↔ 
 

↔ 
 

↔ 
 

No dose adjustment of Epclusa or 
methadone is required. 

S-methadone 
 

↔ 
 

↔ 
 

↔ 
 

Sofosbuvir ↔ ↑ 
1.3 
(1.0, 
1.7) 

 

Methadone Interaction only studied with sofosbuvir 
Expected: 
↔ Velpatasvir 



13 

Medicinal product by 
therapeutic areas/Possible 
Mechanism of Interaction 

Effects on medicinal product levels. 
Mean ratio (90% confidence interval)a,b Recommendation concerning 

co-administration with Epclusa Active Cmax AUC Cmin 
IMMUNOSUPPRESSANTS 
Ciclosporin 
(600 mg single dose)/ 
sofosbuvir (400 mg single 
dose)f 

Ciclosporin ↔ 
 

↔ 
 

 No dose adjustment of Epclusa or 
ciclosporin is required at initiation 
of co-administration.  Afterwards, 
close monitoring and potential 
dose adjustment of ciclosporin may 
be required. 

Sofosbuvir ↑ 
2.5 
(1.9, 
3.5) 

↑ 
4.5 
(3.3, 
6.3) 

 

Ciclosporin 
(600 mg single dose)f/ 
velpatasvir (100 mg single 
dose)d 

Ciclosporin ↔ ↓ 
0.88 
(0.78, 
1.0) 

 

Velpatasvir ↑ 
1.6 
(1.2, 
2.0) 

↑ 
2.0 
(1.5, 
2.7) 

 

Tacrolimus 
(5 mg single dose)f/ 
sofosbuvir (400 mg single 
dose)d 

Tacrolimus ↓ 
0.73 
(0.59, 
0.90) 

↑ 
1.1 
(0.84, 
1.4) 

 No dose adjustment of Epclusa or 
tacrolimus is required at initiation 
of co-administration.  Afterwards, 
close monitoring and potential 
dose adjustment of tacrolimus may 
be required. 

Sofosbuvir ↓ 
0.97 
(0.65, 
1.4) 

↑ 
1.1 
(0.81, 
1.6) 

 

Tacrolimus Effect on velpatasvir exposure not studied. 
Expected: 
↔ Velpatasvir 

ORAL CONTRACEPTIVES 
Norgestimate/ ethinyl 
estradiol (norgestimate 
0.180 mg/ 0.215 mg/ 
0.25 mg/ ethinyl estradiol 
0.025 mg)/ sofosbuvir 
(400 mg once daily)d 

Norel-
gestromin 

↔ 
 

↔ 
 

↔ 
 

No dose adjustment of oral 
contraceptives is required. 

Norgestrel ↔ ↑ 
1.2 
(0.98, 
1.5) 

↑ 
1.2 
(1.0, 
1.5) 

Ethinyl 
estradiol 

↔ 
 

↔ 
 

↔ 
 

Norgestimate/ ethinyl 
estradiol (norgestimate 
0.180 mg/ 0.215 mg/ 
0.25 mg/ ethinyl estradiol 
0.025 mg)/ velpatasvir 
(100 mg once daily)d 

Norel-
gestromin 

↔ 
 

↔ 
 

↔ 
 

Norgestrel ↔ 
 

↔ 
 

↔ 
 

Ethinyl 
estradiol 

↑ 
1.4 
(1.2, 
1.7) 

↔ ↓ 
0.83 
(0.65, 
1.1) 

a Mean ratio (90% CI) of co-administered drug pharmacokinetics of study medicinal products alone or in combination.  No 
effect = 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%. 
 



14 

4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of sofosbuvir, 
velpatasvir or Epclusa in pregnant women. 
 
Sofosbuvir 
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 relative 
to the exposure in humans at the recommended clinical dose (see section 5.3). 
 
Velpatasvir 
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. 
 
Breast-feeding 
It is unknown whether sofosbuvir, metabolites of sofosbuvir or velpatasvir are excreted in human 
milk. 
 
Available pharmacokinetic data in animals have shown excretion of velpatasvir and metabolites of 
sofosbuvir in milk. 
 
A risk to the newborns/infants cannot be excluded.  Therefore, Epclusa should not be used during 
breast-feeding. 
 
Fertility 
No human data on the effect of Epclusa on fertility are available.  Animal studies do not indicate 
harmful effects of sofosbuvir or velpatasvir on fertility. 
 
If ribavirin is co-administered with Epclusa, refer to the Summary of Product Characterisitics for 
ribavirin for detailed recommendations regarding pregnancy, contraception, and breast-feeding. 
 
4.7 Effects on ability to drive and use machines 
 
Epclusa has no or negligible influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
In pooled Phase 3 clinical studies of patients with genotype 1, 2, 3, 4, 5 or 6 HCV infection the 
proportion of patients who permanently discontinued treatment due to adverse events was 0.2% and 
the proportion of patients who experienced any severe adverse events was 3.2% for patients receiving 
Epclusa for 12 weeks.  In clinical studies, headache, fatigue and nausea were the most common 
(incidence ≥ 10%) treatment emergent adverse events reported in patients treated with 12 weeks of 
Epclusa.  These and other adverse events were reported at a similar frequency in placebo treated 
patients compared with Epclusa treated patients in the Phase 3 pivotal clinical studies. 
 



15 

Tabulated summary of adverse reactions 
 
Assessment of adverse reactions for Epclusa is based on safety data from clinical studies and 
postmarketing experience. All adverse reactions are presented in Table 4. The adverse reactions are 
listed below by system organ class and frequency.  Frequencies are defined as follows: very common 
(≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000) 
or very rare (< 1/10,000). 
 
Table 4: Adverse drug reactions identified with Epclusa 
Frequency Adverse drug reaction 
Skin and subcutaneous tissue disorders: 
Common rasha 
Uncommon angioedemaa 
a. Adverse reaction identified through post-marketing surveillance for sofosbuvir/velpatasvir-containing products 
 
Patients with decompensated cirrhosis 
The safety profile of Epclusa has been evaluated in one open-label study in which patients with CPT 
Class B cirrhosis received Epclusa for 12 weeks (n = 90), Epclusa + RBV for 12 weeks (n = 87) or 
Epclusa for 24 weeks (n = 90).  The adverse events observed were consistent with expected clinical 
sequelae of decompensated liver disease, or the known toxicity profile of ribavirin for patients 
receiving Epclusa in combination with ribavirin. 
 
Among the 87 patients who were treated with Epclusa + RBV for 12 weeks, decreases in haemoglobin 
to less than 10 g/dL and 8.5 g/dL during treatment were experienced by 23% and 7% patients, 
respectively.  Ribavirin was discontinued in 15% of patients treated with Epclusa + RBV for 12 weeks 
due to adverse events. 
 
Patients with renal impairment  
The safety of Epclusa has been evaluated in a 12-week non-controlled study including 59 subjects 
with ESRD requiring dialysis (Study 4062). In this setting, exposure of sofosbuvir metabolite GS-
331007 was 20-fold increased, exceeding levels where adverse reactions have been observed in 
preclinical trials. In this limited clinical safety data set, the rate of adverse events and deaths was not 
clearly elevated from what is expected in ESRD patients. 
 
Description of selected adverse reactions 
Cardiac arrhythmias 
Cases of severe bradycardia and heart block have been observed when sofosbuvir-containing regimens 
are used in combination with amiodarone and/or other medicinal products that lower heart rate (see 
sections 4.4 and 4.5). 
 
Skin disorders 
Frequency not known: Stevens-Johnson syndrome 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important.  It 
allows continued monitoring of the benefit/risk balance of the medicinal product.  Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
The highest documented doses of sofosbuvir and velpatasvir were a single dose of 1,200 mg and a 
single dose of 500 mg, respectively.  In these healthy volunteer studies, there were no untoward effects 
observed at these dose levels, and adverse events were similar in frequency and severity to those 
reported in the placebo groups.  The effects of higher doses/exposures are not known. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


16 

No specific antidote is available for overdose with Epclusa.  If overdose occurs the patient must be 
monitored for evidence of toxicity.  Treatment of overdose with Epclusa consists of general supportive 
measures 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 
removal of velpatasvir, since velpatasvir is highly bound to plasma protein. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Direct acting antiviral, ATC code: J05AP55 
 
Mechanism of action 
Sofosbuvir is a pan-genotypic inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is 
essential for viral replication.  Sofosbuvir is a nucleotide prodrug that undergoes intracellular 
metabolism to form the pharmacologically active uridine analogue triphosphate (GS-461203), which 
can 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 RNA 
replication and the assembly of HCV virions.  In vitro resistance selection and cross-resistance studies 
indicate velpatasvir targets NS5A as its mode of action. 
 
Antiviral activity 
The 50% effective concentration (EC50) values of sofosbuvir and velpatasvir against full-length or 
chimeric replicons encoding NS5B and NS5A sequences from the laboratory strains are presented in 
Table 5.  The EC50 values of sofosbuvir and velpatasvir against clinical isolates are presented in 
Table 6. 
 
Table 5: Activity of sofosbuvir and velpatasvir against full-length or chimeric laboratory 
replicons 
Replicon 
genotype 

Sofosbuvir EC50, nMa Velpatasvir EC50, nMa 

1a 40 0.014 
1b 110 0.016 
2a 50 0.005-0.016c 
2b 15b 0.002-0.006c 
3a 50 0.004 
4a 40 0.009 
4d NA 0.004 
5a 15b 0.021-0.054d 
6a 14b 0.006-0.009 
6e NA 0.130d 
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 genes 

that contain L31 or M31 polymorphisms. 
d Data from a chimeric NS5A replicon carrying NS5A amino acids 9-184. 
 



17 

Table 6: Activity of sofosbuvir and velpatasvir against transient replicons containing NS5A or 
NS5B from clinical isolates 
Replicon 
genotype 

Replicons containing NS5B from clinical 
isolates 

Replicons containing NS5A from clinical 
isolates 

Number of clinical 
isolates 

Median sofosbuvir 
EC50, nM (range) 

Number of 
clinical isolates 

Median velpatasvir 
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 reduced 
the 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. 
 
Resistance 
In cell culture 
HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple 
genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a.  Reduced susceptibility to sofosbuvir was associated 
with the primary NS5B substitution S282T in all replicon genotypes examined.  Site-directed 
mutagenesis of the S282T substitution in replicons of genotype 1 to 6 conferred 2- to 18-fold reduced 
susceptibility to sofosbuvir and reduced the replication viral capacity by 89% to 99% compared to the 
corresponding 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 expressing 
the S282T substitution was reduced compared to its ability to inhibit wild-type recombinant NS5B 
polymerase, 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 cell 
culture for multiple genotypes including 1a, 1b, 2a, 3a, 4a, 5a and 6a.  Variants were selected at NS5A 
resistance 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 of 
known NS5A 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 in genotype 2b, Y93H in genotype 3, and L31V and P32A/L/Q/R in genotype 6.  No 
individual substitutions tested in genotypes 2a, 4a, or 5a conferred a > 100-fold reduction in 
velpatasvir susceptibility.  Combinations of these variants often showed greater reductions in 
susceptibility to velpatasvir than single RAVs alone. 
 
In clinical studies 
Studies in patients without cirrhosis and patients with compensated cirrhosis 
In a pooled analysis of patients without cirrhosis or with compensated cirrhosis who received Epclusa 
for 12 weeks in three Phase 3 studies, 12 patients (2 with genotype 1 and 10 with genotype 3) qualified 
for resistance analysis due to virologic failure.  One additional patient with genotype 3 HCV infection 
at baseline was reinfected with genotype 1a HCV at virologic failure and was excluded from the 
virological analysis.  No patients with genotype 2, 4, 5, or 6 HCV infection experienced virologic 
failure. 
 



18 

Of the 2 genotype 1 virologic failure patients, one patient had virus with emergent NS5A RAV Y93N 
and the other patient had virus with emergent NS5A RAVs L31I/V and Y93H at virologic failure.  
Both patients had virus at baseline harboring 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 for 
12 weeks, 3 patients (1 with genotype 1 and 2 with genotype 3) qualified for resistance analysis due to 
virologic failure.  No patients with genotype 2 or 4 HCV infection in the Epclusa + RBV 12 weeks 
group 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.  Another 
patient 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 consistent 
with 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. 
 
Effect of baseline HCV resistance-associated variants on treatment outcome 
Studies in patients without cirrhosis and patients with compensated cirrhosis 
Analyses were conducted to explore the association between pre-existing baseline NS5A RAVs and 
treatment outcome for patients without cirrhosis or with compensated cirrhosis in three Phase 3 
clinical studies (ASTRAL-1, ASTRAL-2 and ASTRAL-3).  Of the 1,035 patients treated with 
sofosbuvir/velpatasvir in the three Phase 3 clinical studies, 1,023 patients were included in the analysis 
of 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 sequencing 
failed.  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, 5 
and 6 HCV, as summarised in Table 7.  Genotype 3 infected patients with the NS5A RAV Y93H at 
baseline had a lower SVR12 rate than patients without Y93H after treatment with Epclusa for 
12 weeks, as summarised in Table 8.  In the ASTRAL-3 study, the Y93H RAV was detected at 
baseline in 9% of patients treated with Epclusa. 
 
Table 7: 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) 

 



19 

Table 8: SVR12 in patients with and without baseline Y93H, 1% Cut-off (Resistance Analysis 
Population Set) ASTRAL 3 

 

Epclusa 12 Weeks 

All Subjects 
(n = 274) 

Cirrhotic 
(n = 80) 

Non-Cirrhotic 
(n = 197) 

Overall 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 3 
studies.  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 and 
treatment outcome for patients with decompensated cirrhosis in one Phase 3 study (ASTRAL-4).  Of 
the 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 the 
patients who received treatment with Epclusa + RBV for 12 weeks, 29% (25/85) of patients had 
baseline virus with NS5A RAVs: 29% (19/66), 75% (3/4), 15% (2/13), and 50% (1/2) for patients with 
genotype 1, 2, 3 and 4 HCV, respectively. 
 
SVR12 in patients with or without baseline NS5A RAVs in the Epclusa + RBV 12 week group for this 
study is shown in Table 9. 
 
Table 9: 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 NS5A 
substitution Y93H at baseline; pharmacokinetic data from this patient was consistent with 
non-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. 
 
Cross-resistance 
In vitro data suggests that the majority of NS5A RAVs that confer resistance to ledipasvir and 
daclatasvir remained susceptible to velpatasvir.  Velpatasvir was fully active against the sofosbuvir 
resistance-associated substitution S282T in NS5B while all velpatasvir resistance-associated 
substitutions in NS5A were fully susceptible to sofosbuvir.  Both sofosbuvir and velpatasvir were fully 
active against substitutions associated with resistance to other classes of direct-acting antivirals with 
different 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 with 
other regimens that include an NS5A inhibitor. 
 



20 

Clinical efficacy and safety 
The efficacy of Epclusa was evaluated in three Phase 3 studies in patients with genotype 1 to 6 HCV 
infection 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 patients 
with genotype 1 to 6 HCV infection and one Phase 2 trial in patients with HCV infection and ESRD 
requiring dialysis, as summarised in Table 10. 
 
Table 10: Studies conducted with Epclusa in patients with genotype 1, 2, 3, 4, 5 or 6 HCV 
infection 
Study Population Study arms 

(Number of patients treated) 

ASTRAL-1 
Genotype 1, 2, 4, 5 and 6 
TN and TE, without cirrhosis or with 
compensated cirrhosis 

Epclusa 12 weeks (624) 
Placebo 12 weeks (116) 

ASTRAL-2 
Genotype 2 
TN and TE, without cirrhosis or with 
compensated cirrhosis 

Epclusa 12 weeks (134) 
SOF+RBV 12 weeks (132) 

ASTRAL-3 
Genotype 3 
TN and TE, without cirrhosis or with 
compensated cirrhosis 

Epclusa 12 weeks (277) 
SOF+RBV 24 weeks (275) 

ASTRAL-4 
Genotype 1, 2, 3, 4, 5 and 6 
TN and TE, with CPT Class B 
decompensated cirrhosis  

Epclusa 12 weeks (90) 
Epclusa + RBV 12 weeks (87) 
Epclusa 24 weeks (90) 

ASTRAL-5 

Genotype 1, 2, 3, 4, 5 and 6 
TN and TE, without cirrhosis or with 
compensated cirrhosis, with 
HCV/HIV-1 co-infection 

Epclusa 12 weeks (106) 

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

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 in 
combination 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 the 
ribavirin prescribing information.  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) of 15 IU/mL.  Sustained virologic response (SVR12), defined as HCV RNA 
less than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint to determine 
the 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 of 
treatment 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 to 
treatment with Epclusa for 12 weeks or placebo for 12 weeks.  Patients with genotype 5 HCV 
infection 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.  Of 
the 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; the 
proportions of patients with genotype 1, 2, 4, 5, or 6 HCV infection were 53%, 17%, 19%, 5% and 
7%, respectively; 69% had non-CC IL28B alleles (CT or TT); 74% had baseline HCV RNA levels of 
at least 800,000 IU/mL; 19% had compensated cirrhosis; and 32% were treatment-experienced. 
 



21 

Table 11 presents the SVR12 for the ASTRAL-1 study by HCV genotypes.  No patients in the placebo 
group achieved SVR12. 
 
Table 11: SVR12 in study ASTRAL-1 by HCV genotype 
 Epclusa 12 weeks 

(n = 624) 
Total 
(all GTs) 
(n = 624) 

GT-1 GT-2 
(n = 104) 

GT-4 
(n = 116) 

GT-5 
(n = 35) 

GT-6 
(n = 41) GT-1a 

(n = 210) 
GT-1b 
(n = 118) 

Total 
(n = 328) 

SVR12 99% (618/624) 
98% 
(206/210) 

99% 
(117/118) 

98% 
(323/328) 

100% 
(104/104) 

100% 
(116/116) 

97% 
(34/35) 

100% 
(41/41) 

Outcome for patients without SVR12 
On-
treatment 
virologic 
failure 

0/624 0/210 0/118 0/328 0/104 0/116 0/35 0/41 

Relapsea < 1% (2/623) 
< 1% 
(1/209) 

1% 
(1/118) 

1% 
(2/327) 0/104 0/116 0/35 0/41 

Otherb 1% (4/624) 
1% 
(3/210) 0/118 

1% 
(3/328) 0/104 0/116 

3% 
(1/35) 0/41 

GT = genotype 
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. 
 
Genotype 2 HCV-infected adults – ASTRAL-2 (study 1139) 
ASTRAL-2 was a randomised, open-label study that evaluated 12 weeks of treatment with Epclusa 
compared 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 for 
12 weeks.  Randomisation was stratified by the presence or absence of cirrhosis and prior treatment 
experience (treatment-naïve versus treatment-experienced). 
 
Demographics and baseline characteristics were balanced across the two treatment groups.  Of the 266 
treated 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% had 
non-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 12 presents the SVR12 for the ASTRAL-2 study. 
 
Table 12: SVR12 in study ASTRAL-2 (HCV genotype 2) 
 Epclusa 

12 weeks 
(n = 134) 

SOF+RBV 
12 weeks 
(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) over 
treatment 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 Epclusa 
compared with 24 weeks of treatment with SOF+RBV in patients with genotype 3 HCV infection.  



22 

Patients were randomised in a 1:1 ratio to treatment with Epclusa for 12 weeks or SOF+RBV for 
24 weeks.  Randomisation was stratified by the presence or absence of cirrhosis and prior treatment 
experience (treatment-naïve versus treatment-experienced). 
 
Demographics and baseline characteristics were balanced across the two treatment groups.  Of the 552 
treated 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 least 
30 kg/m2; 61% had non-CC IL28B alleles (CT or TT); 70% had baseline HCV RNA levels of at least 
800,000 IU/mL, 30% had compensated cirrhosis and 26% were treatment-experienced. 
 
Table 13 presents the SVR12 for the ASTRAL-3 study. 
 
Table 13: SVR12 in study ASTRAL-3 (HCV genotype 3) 
 Epclusa 

12 weeks 
(n = 277) 

SOF+RBV 
24 weeks 
(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 to 
treatment 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 14. 
 
Table 14: SVR12 for selected subgroups in study ASTRAL-3 (HCV genotype 3) 
 Epclusa 

12 weeks 
SOF+RBV 
24 weeksa 

SVR12 Treatment-naïve 
(n = 206) 

Treatment-
experienced 
(n = 71) 

Treatment-naïve 
(n = 201) 

Treatment-
experienced 
(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 HCV 
infection 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 was 
stratified by HCV genotype (1, 2, 3, 4, 5, 6 and indeterminate). 
 
Demographics and baseline characteristics were balanced across the treatment groups.  Of the 267 
treated 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.  The 
proportions 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 the 
patients had non-CC IL28B alleles (CT or TT); 56% had baseline HCV RNA levels of at least 
800,000 IU/mL, 55% were treatment-experienced; 90% and 95% of patients had CPT Class B 
cirrhosis and Model for End Stage Liver Disease (MELD) score ≤ 15 at baseline, respectively. 
 
Table 15 presents the SVR12 for the ASTRAL-4 study by HCV genotype. 
 



23 

Table 15: SVR12 in study ASTRAL-4 by HCV genotype 
 Epclusa 

12 weeks 
(n = 90) 

Epclusa + RBV 
12 weeks 
(n = 87) 

Epclusa 
24 weeks 
(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)c 

a 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 16 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 16: 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-adherence 

to 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 17. 
 
Table 17: Changes in CPT score parameters from baseline to week 12 and 24 post-treatment in 
patients achieving SVR12, ASTRAL-4 
 Albumin Bilirubin INR Ascites Encephalopathy 
Post-treatment Week 12 (N = 236), % (n/N)  
Decreased score 
(Improvement) 34.5% (79/229) 17.9% (41/229) 2.2% (5/229) 

7.9% 
(18/229) 5.2% (12/229) 

No change 60.3% 
(138/229) 

76.4% 
(175/229) 

96.5% 
(221/229) 

89.1% 
(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 
Post-treatment Week 24 (N = 236), % (n/N) 
Decreased score 
(Improvement) 39.4% (84/213) 16.4% (35/213) 2.3% (5/213) 

15.0% 
(32/213) 9.4% (20/213) 

No change 54.0% 
(115/213) 

80.8% 
(172/213) 

94.8% 
(202/213) 

81.2% 
(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. 
 



24 

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 HCV 
infection who were co-infected with HIV-1 (HCV genotype 5 and 6 allowed, but no such patients 
were included).  Patients were on a stable HIV-1 antiretroviral therapy that included 
emtricitabine/tenofovir disoproxil fumarate or abacavir/lamivudine administered with a ritonavir 
boosted protease inhibitor (atazanavir, darunavir, or lopinavir), rilpivirine, raltegravir or 
emtricitabine/tenofovir disoproxil fumarate /elvitegravir/cobicistat. 
 
Of the 106 treated patients, the median age was 57 years (range: 25 to 72); 86% of the patients were 
male; 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 18 presents the SVR12 for the ASTRAL-5 study by HCV genotype. 
 
Table 18: SVR12 in study ASTRAL-5 by HCV genotype 
 Epclusa 12 weeks 

(n = 106) 
Total 
(all GTs) 
(n = 106) 

GT-1 GT-2 
(n = 11) 

GT-3 
(n = 12) 

GT-4 
(n = 5) GT-1a 

(n = 66) 
GT-1b 
(n = 12) 

Total 
(n = 78) 

SVR12 95% (101/106) 
95% 
(63/66) 

92% 
(11/12) 

95% 
(74/78) 

100% 
(11/11) 

92% 
(11/12) 

100% 
(5/5) 

Outcome for patients without SVR 
On-
treatment 
virologic 
failure 

0/106 0/66 0/12 0/78 0/11 0/12 0/5 

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

3% 
(2/76) 0/11 0/11 0/5 

Otherb 3% (3/106) 
2% 
(1/66) 

8% 
(1/12) 

3% 
(2/78) 0/11 

8% 
(1/12) 0/5 

GT = genotype 
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. 
 
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 trial 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.  At 
baseline, 29% of patients had cirrhosis, 22% were treatment experienced, 32% had received a kidney 
transplant, 92% were on haemodialysis, and 8% were on peritoneal dialysis; mean duration on dialysis 
was 7.3 years (range: 0 to 40 years).  The overall SVR rate was 95% (56/59); of the three patients that 
did not achieve SVR12, one had completed Epclusa treatment and relapsed and two did not meet 
virologic failure criteria. 
 
Paediatric population 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Epclusa in one or more subsets of the paediatric population in the treatment of chronic hepatitis C (see 
section 4.2 for information on paediatric use). 
 
Elderly 
Clinical studies of Epclusa included 156 patients aged 65 and over (12% of total number of patients in 
the Phase 3 clinical studies).  The response rates observed for patients ≥ 65 years of age were similar 
to that of patients < 65 years of age, across treatment groups. 
 



25 

5.2 Pharmacokinetic properties 
 
Absorption 
The pharmacokinetic properties of sofosbuvir, GS-331007 and velpatasvir have been evaluated in 
healthy 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 observed 
1 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 velpatasvir 
were 566, 868 and 259 ng/mL, respectively.  Sofosbuvir and GS-331007 AUC0-24 and Cmax were 
similar 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-infected 
patients. 
 
Effects of food 
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 in 
velpatasvir AUC0-inf, respectively, and a 31% and 5% increase in velpatasvir Cmax, respectively.  The 
moderate or high fat meal increased sofosbuvir AUC0-inf by 60% and 78%, respectively, but did not 
substantially 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 without 
food.  Epclusa can be administered without regard to food. 
 
Distribution 
Sofosbuvir is approximately 61-65% bound to human plasma proteins and the binding is independent 
of drug concentration over the range of 1 µg/mL to 20 µg/mL.  Protein binding of GS-331007 was 
minimal in human plasma.  After a single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the 
blood to plasma ratio of [14C]-radioactivity was approximately 0.7. 
 
Velpatasvir is > 99.5% bound to human plasma proteins and binding is independent of drug 
concentration 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 between 
0.52 and 0.67. 
 
Biotransformation 
Sofosbuvir is extensively metabolised in the liver to form the pharmacologically active nucleoside 
analog triphosphate GS-461203.  The metabolic activation pathway involves sequential hydrolysis of 
the carboxyl ester moiety catalysed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and 
phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by 
phosphorylation by the pyrimidine nucleotide biosynthesis pathway.  Dephosphorylation results in the 
formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks 
anti-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 single 
400 mg oral dose of [14C]-sofosbuvir, GS-331007 accounted for approximately > 90% of total 
systemic exposure. 
 
Velpatasvir is 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 plasma was parent drug.  
The monohydroxylated and desmethylated velpatasvir were the metabolites identified in human 
plasma.  Unchanged velpatasvir is the major species present in faeces. 
 



26 

Elimination 
Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the [14C]-radioactivity 
was 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 major 
elimination pathway for GS-331007.  The median terminal half-lives of sofosbuvir and GS-331007 
following 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 faeces 
and urine, respectively.  Unchanged velpatasvir was the major species in faeces accounting for a mean 
of 77% of the administered dose, followed by monohydroxylated velpatasvir (5.9%) and 
desmethylated velpatasvir (3.0%).  These data indicate that biliary excretion of parent drug was a 
major route of elimination for velpatasvir.  The median terminal half-life of velpatasvir following 
administration of Epclusa was approximately 15 hours. 
 
Linearity/non-linearity 
Velpatasvir AUC increases in a nearly dose proportional manner over the dose range of 25 mg to 
150 mg.  Sofosbuvir and GS-331007 AUCs are near dose-proportional over the dose range of 200 mg 
to 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 its 
involvement in drug interactions with these transporters is primarily limited to the process of 
absorption.  At clinically relevant plasma concentration, velpatasvir is not an inhibitor of hepatic 
transporters 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. 
 
Pharmacokinetics in special populations 
Race and gender 
No clinically relevant pharmacokinetic differences due to race or gender have been identified for 
sofosbuvir, GS-331007 or velpatasvir. 
 
Elderly 
Population pharmacokinetic analysis in HCV-infected patients showed that within the age range (18 to 
82 years) analysed, age did not have a clinically relevant effect on the exposure to sofosbuvir, 
GS-331007, or velpatasvir. 
 
Renal impairment 
A summary of the effect of varying degrees of renal impairment (RI) on the exposures of the 
components of Epclusa compared to subjects with normal renal function, as described in the text 
below, are provided in Table 19.  
 



27 

Table 19: 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 

(eGFR ≥50 
and <80 

mL/min/1.7
3m2) 

Moderate RI 
(eGFR ≥30 

and <50 
mL/min/1.73

m2) 

Severe RI 
(eGFR <30 
mL/min/1.7

3m2) 

ESRD Requiring 
Dialysis 

Severe RI 
(eGFR 

<30 
mL/min/1.

73m2) 

ESRD 
Requiring 
Dialysis Dosed 1 

hr Before 
Dialysis 

Dosed 1 
hr After 
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 patients with mild (eGFR ≥ 50 and 
< 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 single 
400 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 extraction 
coefficient of approximately 53%.  Following a single 400 mg dose of sofosbuvir, a 4 hour 
haemodialysis 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 that 
observed in HCV negative patients with severe renal impairment. 
 
The pharmacokinetics of velpatasvir was studied with a single dose of 100 mg velpatasvir in HCV 
negative patients with severe renal impairment (eGFR < 30 mL/min by Cockcroft-Gault).   
 
The pharmacokinetics of sofosbuvir, GS-331007, and velpatasvir were studied in HCV-infected 
patients with ESRD requiring dialysis treated with Epclusa (n=59) for 12 weeks, and compared to 
patients without renal impairment in the sofosbuvir/velpatasvir Phase 2/3 trials. 
 
Hepatic impairment 
The pharmacokinetics of sofosbuvir was studied following 7-day dosing of 400 mg sofosbuvir in 
HCV-infected 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% higher in 
moderate and severe hepatic impairment, while the GS-331007 AUC0-24 was 18% and 9% higher, 
respectively.  Population pharmacokinetics analysis in HCV-infected patients indicated that cirrhosis 
(including decompensated cirrhosis) had no clinically relevant effect on the exposure to sofosbuvir 
and GS-331007. 
 
The pharmacokinetics of velpatasvir was studied with a single dose of 100 mg velpatasvir in HCV 
negative patients with moderate and severe hepatic impairment (CPT Class B and C).  Compared to 
subjects with normal hepatic function velpatasvir total plasma exposure (AUCinf) was similar in 
patients with moderate or severe hepatic impairment.  Population pharmacokinetics analysis in 
HCV-infected patients indicated that cirrhosis (including decompensated cirrhosis) had no clinically 
relevant effect on the exposure to velpatasvir (see section 4.2).  
 
Body weight 
Body weight did not have a clinically significant effect on sofosbuvir or velpatasvir exposure 
according to a population pharmacokinetic analysis. 
 
Paediatric population 
The pharmacokinetics of sofosbuvir, GS-331007 and velpatasvir in paediatric patients have not been 
established (see section 4.2). 
 



28 

5.3 Preclinical safety data 
 
Sofosbuvir 
Exposure to sofosbuvir in rodent studies could not be detected likely due to high esterase activity and 
exposure 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 bacterial 
mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse 
micronucleus assays.  No teratogenic effects were observed in the rat and rabbit developmental 
toxicity studies with sofosbuvir.  Sofosbuvir had no adverse effects on behaviour, reproduction, or 
development of 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-331007 
exposures up to 15 and 9 times, respectively, higher than human exposure. 
 
Velpatasvir 
Velpatasvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial 
mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo rat 
micronucleus assays. 
 
Velpatasvir was not carcinogenic in the 6-month rasH2 transgenic mouse and 2-year rat 
carcinogenicity 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 the 
mouse 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 
malformations was seen in exposed animals at AUC exposures up to 0.7 fold the human exposure at 
recommended clinical dose.  The human relevance of this finding is not known.  Velpatasvir had no 
adverse effects on behaviour, reproduction, or development of the offspring in the rat pre- and 
post-natal development study at AUC exposures approximately 5-fold higher than the human exposure 
at the recommended clinical dose. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Copovidone 
Microcrystalline cellulose 
Croscarmellose sodium 
Magnesium stearate 
 
Film-coating 
Polyvinyl alcohol 
Titanium dioxide 
Polyethylene glycol 
Talc 
Iron oxide red 
 
6.2 Incompatibilities 
 
Not applicable. 
 



29 

6.3 Shelf life 
 
4 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Epclusa tablets are supplied in high density polyethylene (HDPE) bottle with a polypropylene 
child-resistant closure containing 28 film-coated tablets with polyester coil. 
 
The following pack sizes are available: outer cartons containing 1 bottle of 28 film-coated tablets. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/16/1116/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 06 July 2016 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 



30 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 



31 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Gilead Sciences Ireland UC 
IDA Business & Technology Park 
Carrigtohill 
County Cork 
IRELAND 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The marketing authorisation holder shall submit the first PSUR for this product within 6 months 
following authorisation. Subsequently, the marketing authorisation holder (MAH) shall submit PSUR 
for this product in accordance with the requirements set out in the list of Union reference dates (EURD 
list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European 
medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 
and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
• Obligation to conduct post-authorisation measures 
 
The MAH shall complete, within the stated timeframe, the below measures: 
 
Description Due date 
In order to evaluate the recurrence of hepatocellular carcinoma associated with 
Epclusa, the MAH shall conduct and submit the results of a prospective safety 
study using data deriving from a cohort of a well-defined group of patients, based 
on an agreed protocol.  The final study report shall be submitted by: 

Q2 2023 



32 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



33 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



34 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
BOTTLE AND CARTON LABELLING 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Epclusa 400 mg/100 mg film-coated tablets 
sofosbuvir/velpatasvir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 400 mg sofosbuvir and 100 mg velpatasvir. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



35 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/16/1116/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Epclusa [Outer packaging only] 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



36 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



37 

Package leaflet: Information for the user 
 

Epclusa 400 mg/100 mg film-coated tablets 
sofosbuvir/velpatasvir 

 
This medicine is subject to additional monitoring.  This will allow quick identification of new 

safety information.  You can help by reporting any side effects you may get.  See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet.  You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only.  Do not pass it on to others.  It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects talk to your doctor or pharmacist.  This includes any possible side 

effects not listed in this leaflet.  See section 4. 
 
What is in this leaflet 
1. What Epclusa is and what it is used for 
2. What you need to know before you take Epclusa 
3. How to take Epclusa 
4. Possible side effects 
5. How to store Epclusa 
6. Contents of the pack and other information 
 
 
1. What Epclusa is and what it is used for 
 
Epclusa is a medicine that contains the active substances sofosbuvir and velpatasvir in a single tablet.  
It is given to treat a chronic (long-term) viral infection of the liver called hepatitis C in adults of 
18 years and older. 
 
The active substances in this medicine work together by blocking two different proteins that the virus 
needs to grow and reproduce itself, allowing the infection to be permanently eliminated from the body. 
 
Epclusa is sometimes taken with another medicine, ribavirin. 
 
It is very important that you also read the leaflets for the other medicines that you will be taking with 
Epclusa.  If you have any questions about your medicines, please ask your doctor or pharmacist. 
 
 
2. What you need to know before you take Epclusa 
 
Do not take Epclusa 
• If you are allergic to sofosbuvir, velpatasvir or any of the other ingredients of this medicine 

(listed in section 6 of this leaflet). 
 
 If this applies to you, do not take Epclusa and tell your doctor immediately. 

 
• If you are currently taking any of the following medicines: 

• rifampicin and rifabutin (antibiotics used to treat infections, including tuberculosis); 
• St. John’s wort (herbal medicine used to treat depression); 
• carbamazepine, phenobarbital and phenytoin (medicines used to treat epilepsy and 

prevent seizures). 
 



38 

Warnings and precautions 
Talk to your doctor if you: 
• have liver problems other than from hepatitis C, for instance 

• if you have a current or previous infection with the hepatitis B virus, since your doctor 
may want to monitor you more closely; 

• if you have had a liver transplant 
• have kidney problems or if you are on kidney dialysis, since Epclusa has not been fully 

tested in patients with some severe kidney problems; 
• are taking treatment for human immunodeficiency virus (HIV) infection, since your doctor 

may want to monitor you more closely. 
 
Talk to your doctor or pharmacist before taking Epclusa if: 
• you currently take, or have taken in the last few months, the medicine amiodarone to treat 

irregular heartbeats, as it may result in a life-threatening slowing of your heart beat. Your doctor 
may consider alternative treatments if you have taken this medicine. If treatment with Epclusa is 
needed, you may require additional heart monitoring. 

• you have diabetes. You may need closer monitoring of your blood glucose levels and/or 
adjustment of your diabetes medication after starting Epclusa. Some diabetic patients have 
experienced low sugar levels in the blood (hypoglycaemia) after starting treatment with 
medicines like Epclusa. 

 
Tell your doctor immediately if you currently take, or have taken in the last months any medicines 
for heart problems and during treatment you experience: 
• slow or irregular heartbeat, or heart rhythm problems; 
• shortness of breath or worsening of existing shortness of breath; 
• chest pain; 
• light-headedness; 
• palpitations; 
• near fainting or fainting. 
 
Blood tests 
Your doctor will test your blood before, during and after your treatment with Epclusa.  This is so that: 
• Your doctor can decide if you should take Epclusa and for how long; 
• Your doctor can confirm that your treatment has worked and you are free of the hepatitis C 

virus. 
 
Children and adolescents 
Do not give this medicine to children and adolescents under 18 years of age.  The use of Epclusa in 
children and adolescents has not yet been studied. 
 
Other medicines and Epclusa 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Warfarin and other similar medicines called vitamin K antagonists used to thin the blood.  Your doctor 
may need to increase the frequency of your blood tests to check how well your blood can clot. 
 
Your liver function may change with treatment of hepatitis C and therefore may affect other 
medications (e.g. medicines used to suppress your immune system, etc.). Your doctor may need to 
closely monitor these other medicines you are taking and make adjustments after starting Epclusa. 
 
If you are not sure talk to your doctor or pharmacist. 
 



39 

Some medicines should not be taken with Epclusa. 
 
• Do not take any other medicine that contains sofosbuvir, one of the active substances in 

Epclusa. 
 
Tell your doctor or pharmacist if you are taking any of the medicines below: 
 
• amiodarone used to treat irregular heartbeats; 
• rifapentine (antibiotic used to treat infections, including tuberculosis); 
• oxcarbazepine (medicine used to treat epilepsy and prevent seizures); 
• tenofovir disoproxil fumarate or any medicine containing tenofovir disoproxil fumarate, used 

to treat HIV infection; 
• efavirenz used to treat HIV infection; 
• digoxin used to treat heart conditions; 
• dabigatran used to thin the blood; 
• modafinil used to treat sleep disorders; 
• rosuvastatin or other statins used to treat high cholesterol. 
Taking Epclusa with any of these may stop your medicines from working properly, or make any side 
effects worse.  Your doctor may need to give you a different medicine or adjust the dose of medicine 
you are taking.  This change could be to Epclusa or another medicine you are taking. 
 
• Get advice from a doctor or pharmacist if you take medicines used to treat stomach ulcers, 

heartburn or acid reflux as they can decrease the amount of velpatasvir in your blood.  These 
medicines include: 
• antacids (such as aluminium/magnesium hydroxide or calcium carbonate).  These should 

be taken at least 4 hours before or 4 hours after Epclusa; 
• proton pump inhibitors (such as omeprazole, lansoprazole, rabeprazole, pantoprazole and 

esomeprazole).  Epclusa should be taken with food 4 hours before using a proton pump 
inhibitor. 

• H2-receptor antagonists (such as famotidine, cimetidine, nizatidine or ranitidine).  If you 
need high doses of these medicines your doctor may give you a different medicine instead 
or adjust the dose of the medicine you are taking. 

These medicines can decrease the amount of velpatasvir in your blood.  If you are taking one of these 
medicines your doctor will either give you a different medicine for stomach ulcers, heartburn or acid 
reflux, or recommend how and when you take that medicine. 
 
Pregnancy and contraception 
The effects of Epclusa during pregnancy are not known.  If you are pregnant, think you may be 
pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. 
 
Epclusa is sometimes used together with ribavirin.  Ribavirin can harm your unborn baby.  It is 
therefore very important that you (or your partner) do not become pregnant during this treatment or for 
a period of time after completing treatment.  You must read the “Pregnancy” section in the ribavirin 
package leaflet very carefully.  Ask your doctor for effective contraception method suitable for you 
and your partner. 
 
Breast-feeding 
Do not breast-feed during treatment with Epclusa.  It is not known whether sofosbuvir or 
velpatasvir, the two active substances of Epclusa, pass into human breast milk. 
 
Driving and using machines 
Epclusa should not affect your ability to drive or use any tools or machinery. 
 
 



40 

3. How to take Epclusa 
 
Always take this medicine exactly as your doctor has told you.  Check with your doctor or pharmacist 
if you are not sure. 
 
Recommended dose 
The recommended dose is one tablet once a day for 12 weeks. 
 
Swallow the tablet whole with or without food.  Do not chew, crush or split the tablet as it has a very 
bitter taste. 
 
If you are taking an antacid, take it at least 4 hours before or at least 4 hours after Epclusa. 
 
If you are taking a proton pump inhibitor, take Epclusa with food 4 hours before using a proton 
pump inhibitor. 
 
If you are sick (vomit) after taking Epclusa it may affect the amount of Epclusa in your blood.  This 
may make Epclusa work less well. 
• If you are sick (vomit) less than 3 hours after taking Epclusa, take another tablet. 
• If you are sick (vomit) more than 3 hours after taking Epclusa, you do not need to take 

another tablet until your next scheduled tablet. 
 
If you take more Epclusa than you should 
If you accidentally take more than the recommended dose you should contact your doctor or nearest 
emergency department immediately for advice.  Keep the tablet bottle with you so that you can easily 
describe what you have taken. 
 
If you forget to take Epclusa 
It is important not to miss a dose of this medicine. 
 
If you do miss a dose, work out how long it is since you last took your Epclusa: 
• If you notice within 18 hours of the time you usually take Epclusa, you must take the tablet as 

soon as possible.  Then take the next dose at your usual time. 
• If it’s 18 hours or more after the time you usually take Epclusa, wait and take the next dose at 

your usual time.  Do not take a double dose (two doses close together). 
 
Do not stop taking Epclusa 
Do not stop taking this medicine unless your doctor tells you to.  It is very important that you complete 
the full course of treatment to give the medicine the best chance to treat your hepatitis C virus 
infection. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 



41 

4. Possible side effects 
 
Like all medicines, this medicine may cause side effects, although not everybody gets them. 
 
Common side effects 
(may affect up to 1 in 10 people) 
• rash 
 
Uncommon side effects 
(may affect up to 1 in 100 people) 
• swelling of the face, lips, tongue or throat (angioedema). 
 
Other effects that may be seen during treatment with sofosbuvir: 
The frequency of the following side effects is not known (frequency cannot be estimated from the 
available data). 
• a wide spread severe rash with peeling skin which may be accompanied by fever, flu like 

symptoms, blisters in the mouth, eyes, and/or genitals (Stevens Johnson syndrome). 
 
 If you get any side effects tell your doctor. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist.  This includes any possible side 
effects not listed in this leaflet.  You can also report side effects directly via the national reporting 
system listed in Appendix V.  By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Epclusa 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the bottle and carton after “EXP”.  
The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste.  Ask your pharmacist how to 
throw away medicines you no longer use.  These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Epclusa contains 
 
• The active substances are sofosbuvir and velpatasvir.  Each film-coated tablet contains 400 mg 

sofosbuvir and 100 mg velpatasvir. 
 
• The other ingredients are 

Tablet core: 
Copovidone, microcrystalline cellulose, croscarmellose sodium, magnesium stearate 

 
Film-coating: 
Polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide red 

 
What Epclusa looks like and contents of the pack 
The film-coated tablets are pink, diamond-shaped tablets debossed with “GSI” on one side and “7916” 
on the other side.  The tablet is 20 mm long and 10 mm wide. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


42 

 
The following pack sizes are available: 
• outer cartons containing 1 bottle of 28 film-coated tablets 
 
Marketing Authorisation Holder 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
Manufacturer 
Gilead Sciences Ireland UC 
IDA Business & Technology Park 
Carrigtohill 
County Cork 
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Gilead Sciences Belgium SPRL-BVBA 
Tél/Tel: + 32 (0) 24 01 35 50 
 

Lietuva 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

България 
Gilead Sciences Ireland UC 
Тел.: + 353 (0) 1 686 1888 
 

Luxembourg/Luxemburg 
Gilead Sciences Belgium SPRL-BVBA 
Tél/Tel: + 32 (0) 24 01 35 50 
 

Česká republika 
Gilead Sciences s.r.o. 
Tel: + 420 910 871 986 
 

Magyarország 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Danmark 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Malta 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Deutschland 
Gilead Sciences GmbH 
Tel: + 49 (0) 89 899890-0 
 

Nederland 
Gilead Sciences Netherlands B.V. 
Tel: + 31 (0) 20 718 36 98 
 

Eesti 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

Norge 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Ελλάδα 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Österreich 
Gilead Sciences GesmbH 
Tel: + 43 1 260 830 
 

España 
Gilead Sciences, S.L. 
Tel: + 34 91 378 98 30 
 

Polska 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

France 
Gilead Sciences 
Tél: + 33 (0) 1 46 09 41 00 
 

Portugal 
Gilead Sciences, Lda. 
Tel: + 351 21 7928790 
 



43 

Hrvatska 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

România 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Ireland 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 214 825 999 
 

Slovenija 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Ísland 
Gilead Sciences Sweden AB 
Sími: + 46 (0) 8 5057 1849 
 

Slovenská republika 
Gilead Sciences Slovakia s.r.o. 
Tel: + 421 232 121 210 
 

Italia 
Gilead Sciences S.r.l. 
Tel: + 39 02 439201 
 

Suomi/Finland 
Gilead Sciences Sweden AB 
Puh/Tel: + 46 (0) 8 5057 1849 
 

Κύπρος 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Sverige 
Gilead Sciences Sweden AB 
Tel: + 46 (0) 8 5057 1849 
 

Latvija 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

United Kingdom 
Gilead Sciences Ltd. 
Tel: + 44 (0) 8000 113 700 
 

 
This leaflet was last revised in  
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 

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


44 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX IV 

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS 
OF THE MARKETING AUTHORISATION(S) 



45 

Scientific conclusions 

Taking into account the PRAC Assessment Report on the PSUR(s) for sofosbuvir / velpatasvir, the 
scientific conclusions of CHMP are as follows:  

The MAH performed an updated cumulative review of bradyarrhythmia occurring when sofosbuvir-
containing products are co-administered with amiodarone, cumulative to 27 June 2019. The review 
identified 40 valid cases, of which 31 occurred after 5 March 2015, when warnings regarding 
bradyarrhythmia were implemented. Of these, 5 cases involved discontinuation of amiodarone prior to 
initiation of the sofosbuvir-containing regimen. While this suggests that some physicians are aware of 
the risk of bradyarrhythmia and discontinue amiodarone prior to initiation of the sofosbuvir-containing 
products, not all physicians appear to take into account the long half-life of amiodarone, despite the 
existing labelling. 

Of note, two cases reported discontinuation of amiodarone on the day of starting the sofosbuvir-
containing regimen, which would result in significant levels of amiodarone still being present in the 
patient’s plasma while on sofosbuvir. In the instances where amiodarone is coadministered, the 
reasons for coadministration were not reported in the majority of cases. However, when reported, 
prescribing error, patient error, medical need or the hepatologist not being aware of concomitant 
amiodarone treatment were cited as reasons for the concomitant use. In this context, it was considered 
that warnings regarding bradyarrhythmia and the recommendation of cardiac monitoring should be 
strengthened. 

The CHMP agrees with the scientific conclusions made by the PRAC. 

 

Grounds for the variation to the terms of the marketing authorisation(s) 

On the basis of the scientific conclusions for sofosbuvir / velpatasvir the CHMP is of the opinion that 
the benefit-risk balance of the medicinal product(s) containing sofosbuvir / velpatasvir is unchanged 
subject to the proposed changes to the product information 

The CHMP recommends that the terms of the marketing authorisation(s) should be varied. 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATION(S)