Vosevi

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 
 
Vosevi 400 mg/100 mg/100 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 400 mg sofosbuvir, 100 mg velpatasvir and 100 mg voxilaprevir. 
 
Excipients with known effect 
 
Each film-coated tablet contains 111 mg of lactose (as monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
Beige, capsule-shaped, film-coated tablet of dimensions 10 mm x 20 mm, debossed with “GSI” on one 
side and “3” on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Vosevi 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 
 
Vosevi treatment should be initiated and monitored by a physician experienced in the management of 
patients with HCV infection. 
 
Posology 
 
The recommended dose of Vosevi is one tablet, taken orally, once daily with food (see section 5.2). 
 
The recommended durations of treatment applicable to all HCV genotypes are shown in Table 1. 
 



3 

Table 1: Recommended treatment durations for Vosevi for all HCV genotypes 
Patient population Treatment duration 
DAA naïve patients without cirrhosis 8 weeks 

DAA naïve patients with compensated cirrhosis 

12 weeks 
 
8 weeks may be considered in genotype 3 
infected patients (see section 5.1) 

DAA experienced patients* without cirrhosis or with 
compensated cirrhosis 12 weeks 

DAA: direct-acting antiviral agent 
 
* In clinical trials the DAA experienced patients had been exposed to combination regimens containing any of the following: 
daclatasvir, dasabuvir, elbasvir, grazoprevir, ledipasvir, ombitasvir, paritaprevir, sofosbuvir, velpatasvir, voxilaprevir 
(administered with sofosbuvir and velpatasvir for less than 12 weeks) 
 
Missed dose 
If a dose of Vosevi 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 Vosevi at the usual 
time.  Patients should be instructed not to take a double dose of Vosevi. 
 
Patients should be instructed that if vomiting occurs within 4 hours of dosing an additional tablet of 
Vosevi should be taken.  If vomiting occurs more than 4 hours after dosing, no further dose of Vosevi 
is needed (see section 5.1). 
 
Elderly 
No dose adjustment is warranted for elderly patients (see section 5.2). 
 
Renal impairment 
No dose adjustment of Vosevi is required for patients with mild or moderate renal impairment.   
 
Safety data are limited in patients with severe renal impairment (estimated Glomerular Filtration Rate 
[eGFR] < 30 mL/min/1.73 m2) and end stage renal disease (ESRD) requiring haemodialysis.  Vosevi 
has not been studied in patients with ESRD requiring dialysis.  Vosevi 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 Vosevi is required for patients with mild hepatic impairment (Child-Pugh-
Turcotte [CPT] Class A).  Vosevi is not recommended in patients with moderate or severe hepatic 
impairment (CPT Class B or C) (see section 5.2). 
 
Paediatric population 
The safety and efficacy of Vosevi in children and adolescents aged less than 18 years have not yet 
been established.  No data are available. 
 
Method of administration 
 
For oral use. 
 
Patients should be instructed to swallow the tablet whole with 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. 
 



4 

Concomitant use with medicinal products that are strong P-glycoprotein (P-gp) and/or strong 
cytochrome P450 (CYP) inducers (e.g. carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin 
and St. John’s wort) (see section 4.5). 
 
Concomitant use with rosuvastatin or dabigatran etexilate (see section 4.5). 
 
Concomitant use with ethinylestradiol-containing medicinal products such as combined oral 
contraceptives or contraceptive vaginal rings (see section 4.5). 
 
4.4 Special warnings and precautions for use 
 
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 Vosevi 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 Vosevi. 
 
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 co-infection 
 
There are no data on the use of Vosevi in patients with HCV/hepatitis B virus (HBV) co-infection.  
Cases of HBV reactivation, some of them fatal, have been reported during or after treatment with 
DAAs.  HBV screening should be performed in all patients before initiation of treatment.  HCV/HBV 
co-infected patients are at risk of HBV reactivation, and should therefore be monitored and managed 
according to current clinical guidelines. 
 
Renal impairment 
 
Safety data are limited in patients with severe renal impairment (estimated glomerular filtration rate 
[eGFR] < 30 mL/min/1.73 m2) and ESRD requiring haemodialysis.  Vosevi can be used in these 
patients with no dose adjustment when no other relevant treatment options are available (see 
sections 4.8, 5.1 and 5.2). 
 
Hepatic impairment 
 
No dose adjustment of Vosevi is required for patients with mild hepatic impairment (CPT Class A).  
Vosevi is not recommended in patients with moderate or severe hepatic impairment (CPT Class B 
or C) (see section 5.2). 
 



5 

Liver transplant patients 
 
The safety and efficacy of Vosevi in the treatment of HCV infection in patients who are post-liver 
transplant have not been assessed.  Treatment with Vosevi, 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. 
 
Use with moderate P-gp inducers 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, velpatasvir and/or voxilaprevir plasma 
concentrations leading to reduced therapeutic effect of Vosevi.  Co-administration of such medicinal 
products with Vosevi is not recommended (see section 4.5). 
 
Use with strong OATP1B inhibitors 
 
Medicinal products that are strong OATP1B inhibitors (e.g. ciclosporin) may substantially increase 
voxilaprevir plasma concentrations, the safety of which has not been established.  Co-administration 
of strong OATP1B inhibitors with Vosevi is not recommended (see section 4.5). 
 
Use with certain HIV antiretroviral regimens 
 
Vosevi has been shown to increase tenofovir exposure 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 Vosevi and a pharmacokinetic enhancer 
has not been established.  The potential risks and benefits associated with co-administration of Vosevi 
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. darunavir) should be considered, particularly in patients at increased risk of renal 
dysfunction.  Patients receiving Vosevi 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 DAA treatment. Glucose levels of diabetic patients initiating 
DAA 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 DAA therapy is initiated. 
 
Excipients 
 
Vosevi contains lactose.  Consequently, patients with rare hereditary problems of galactose 
intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this 
medicinal product. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
As Vosevi contains sofosbuvir, velpatasvir and voxilaprevir, any interactions that have been identified 
with these active substances individually may occur with Vosevi. 
 



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Pharmacokinetic interactions 
 
Potential for Vosevi to affect other medicinal products 
 
Velpatasvir and voxilaprevir are inhibitors of drug transporters P-gp, breast cancer resistance protein 
(BCRP), organic anion-transporting polypeptide (OATP) 1B1 and OATP1B3.  Co-administration of 
Vosevi with medicinal products that are substrates of these transporters may increase the exposure of 
such medicinal products.  Medicinal products that are sensitive substrates of these transporters and for 
which elevated plasma levels are associated with serious events are contraindicated (see Table 2). 
Dabigatran etexilate (P-gp substrate) and rosuvastatin (OATP1B and BCRP substrate) are 
contraindicated (see section 4.3 and Table 2).  
 
Potential for other medicinal products to affect Vosevi 
 
Sofosbuvir, velpatasvir and voxilaprevir are substrates of drug transporters P-gp and BCRP.  
Velpatasvir and voxilaprevir are substrates of drug transporters OATP1B1 and OATP1B3.  In vitro, 
slow metabolic turnover of velpatasvir primarily by CYP2B6, CYP2C8 and CYP3A4 and of 
voxilaprevir primarily by CYP3A4 was observed. 
 
Medicinal products that may decrease plasma exposure of Vosevi 
Medicinal products that are strong inducers of P-gp and/or strong inducers of CYP2B6, CYP2C8, or 
CYP3A4 (e.g. carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin and St. John’s wort) 
may decrease plasma concentrations of sofosbuvir, velpatasvir and/or voxilaprevir leading to reduced 
therapeutic effect of Vosevi.  The use of such medicinal products with Vosevi is contraindicated (see 
section 4.3 and Table 2). 
 
Medicinal products that are moderate P-gp inducers and/or moderate CYP inducers (e.g. efavirenz, 
modafinil, oxcarbazepine or rifapentine) may decrease sofosbuvir, velpatasvir and/or voxilaprevir 
plasma concentrations leading to reduced therapeutic effect of Vosevi.  Co-administration with such 
medicinal products is not recommended with Vosevi (see section 4.4 and Table 2). 
 
Medicinal products that may increase plasma exposure of Vosevi 
Co-administration with medicinal products that inhibit P-gp or BCRP may increase sofosbuvir, 
velpatasvir or voxilaprevir plasma concentrations.  Medicinal products that inhibit OATP1B, 
CYP2B6, CYP2C8, or CYP3A4 may increase plasma concentrations of velpatasvir or voxilaprevir.  
The use of strong inhibitors of OATP1B (e.g. ciclosporin) with Vosevi is not recommended (see 
section 4.4 and Table 2).  Clinically significant medicinal product interactions with Vosevi mediated 
by P-gp, BCRP and CYP inhibitors are not expected.  Vosevi may be co-administered with P-gp, 
BCRP and CYP inhibitors. 
 
Pharmacodynamic interactions 
 
Patients treated with vitamin K antagonists 
 
As liver function may change during treatment with Vosevi, 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. 
 
Patients treated with ethinylestradiol-containing medicinal products 
 
Concomitant use with ethinylestradiol-containing medicinal products may increase the risk of alanine 
aminotransferase (ALT) elevations and is contraindicated (see section 4.3 and Table 2). 



7 

 
Interactions between Vosevi and other medicinal products 
 
Table 2 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/voxilaprevir, its components (sofosbuvir, velpatasvir, and/or voxilaprevir), or 
are predicted medicinal product interactions that may occur with Vosevi.  The table is not 
all-inclusive. 
 
Table 2: Interactions between Vosevi and other medicinal products 
Medicinal product by 
therapeutic areas/Possible 
Mechanism of Interaction 

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

co-administration with Vosevi Active Cmax AUC Cmin 
ACID REDUCING AGENTS 
Antacids 
e.g. Aluminium or 
magnesium hydroxide; 
calcium carbonate 
 
(Increase in gastric pH 
decreases velpatasvir 
solubility) 

Interaction not studied. 
Expected: 
↔ Sofosbuvir 
↓ Velpatasvir 
↔ Voxilaprevir 

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

H2-receptor antagonists 
Famotidine 
(40 mg single dose) + 
sofosbuvir/velpatasvir/ 
voxilaprevir 
(400/100/100 mg single 
dose)c 
 
Famotidine dosed 
simultaneously with Vosevi 
 
Cimetidined 
Nizatidined 
Ranitidined 
 
(Increase in gastric pH 
decreases velpatasvir 
solubility) 

Observed: 
Sofosbuvir 

 
↔ 

 
↔ 

 H2-receptor antagonists may be 
administered simultaneously with 
or staggered from Vosevi at a 
dose that does not exceed doses 
comparable with famotidine 
40 mg twice daily. 

Velpatasvir ↔ ↔  
Voxilaprevir ↔ ↔  

Famotidine 
(40 mg single dose) + 
sofosbuvir/velpatasvir/ 
voxilaprevir (400/100/ 
100 mg single dose)c 
 
Famotidine dosed 12 hours 
prior to Vosevi 
 
(Increase in gastric pH 
decreases velpatasvir 
solubility) 
 

Observed: 
Sofosbuvir 

 
↔ 

 
↔ 

  

Velpatasvir ↔ ↔  
Voxilaprevir ↔ ↔  



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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 Vosevi Active Cmax AUC Cmin 
Proton pump inhibitors 
Omeprazole 
(20 mg once daily) + 
sofosbuvir/velpatasvir/ 
voxilaprevir (400/100/ 
100 mg single dose)c 
 
Omeprazole dosed 2 hours 
prior to Vosevi 
 
Lansoprazoled 
Rabeprazoled 
Pantoprazoled 
Esomeprazoled 
 
(Increase in gastric pH 
decreases velpatasvir 
solubility) 

Observed: 
Sofosbuvir 

 
↓ 
0.77 
(0.65, 
0.91) 

 
↓ 
0.73 
(0.67, 
0.79) 

 Proton pump inhibitors may be 
administered with Vosevi at a 
dose that does not exceed doses 
comparable with omeprazole 
20 mg. 

Velpatasvir ↓ 
0.43 
(0.38, 
0.49) 

↓ 
0.46 
(0.41, 
0.52) 

 

Voxilaprevir ↓ 
0.76 
(0.69, 
0.85) 

↔  

Omeprazole 
(20 mg once daily) + 
sofosbuvir/velpatasvir/ 
voxilaprevir (400/100/ 
100 mg single dose)c 
 
Omeprazole dosed 4 hours 
after Vosevi 
 
(Increase in gastric pH 
decreases velpatasvir 
solubility) 

Observed: 
Sofosbuvir 

 
↔ 

 
↔ 

 

Velpatasvir ↓ 
0.49 
(0.43, 
0.55) 

↓ 
0.49 
(0.43, 
0.55) 

 

Voxilaprevir ↔ ↔  

ANTIARRHYTHMICS 
Amiodarone Effect on amiodarone, voxilaprevir, 

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 
Vosevi (see sections 4.4 and 4.8). 

Digoxin Interaction only studied with velpatasvir.  
Expected: 
↔ Sofosbuvir 
↔ Voxilaprevir 

Co-administration of Vosevi with 
digoxin may increase the 
concentration of digoxin.  Caution 
is warranted and therapeutic 
concentration monitoring of 
digoxin is recommended. 

Digoxin (0.25 mg single 
dose)e + velpatasvir 
(100 mg single dose) 
 
(Inhibition of P-gp) 

Effect on velpatasvir exposure not studied 
Expected: 
↔ Velpatasvir 
Observed: 
Digoxin 

 
↑ 
1.88 
(1.71, 
2.08) 

 
↑ 
1.34 
(1.13, 
1.60) 

 



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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 Vosevi Active Cmax AUC Cmin 
ANTICOAGULANTS 
Dabigatran etexilate (75 mg 
single dose) + 
sofosbuvir/velpatasvir/ 
voxilaprevir (400/100/ 
100 mg single dose) + 
voxilaprevir (100 mg single 
dose)f 
 
(Inhibition of P-gp) 

Effect on sofosbuvir, velpatasvir and 
voxilaprevir concentrations not studied 
Expected: 
↔ Sofosbuvir 
↔ Velpatasvir 
↔ Voxilaprevir 

Vosevi is contraindicated with 
dabigatran etexilate (see 
section 4.3). 

Observed: 
Dabigatran 

 
↑ 
2.87 
(2.61, 
3.15) 

 
↑ 
2.61 
(2.41, 
2.82) 

 

Edoxaban 
 
(Inhibition of OATP1B1) 

Interaction not studied. 
Expected: 
↑ Edoxaban (active metabolite) 
↔ Sofosbuvir 
↔ Velpatasvir 
↔ Voxilaprevir 

Co-administration of Vosevi with 
edoxaban is not recommended.  
Should direct Xa inhibitor use be 
deemed necessary, apixaban or 
rivaroxaban may be considered. 

Vitamin K antagonists 
 
(Liver function changes 
during treatment with 
Vosevi). 

Interaction not studied. Close monitoring of INR is 
recommended when Vosevi is co-
administered with all vitamin K 
antagonists.  

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

Interaction not studied. 
Expected: 
↓ Sofosbuvir 
↓ Velpatasvir 
↓ Voxilaprevir 

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

Carbamazepine 
 
(Induction of P-gp and 
CYPs) 

Interaction not studied. 
Expected: 
↓ Velpatasvir 
↓ Voxilaprevir 

Vosevi is contraindicated with 
carbamazepine (see section 4.3). 

Observed: 
Sofosbuvir 

 
↓  
0.52 
(0.43, 
0.62) 
 

 
↓  
0.52 
(0.46, 
0.59) 
 

 

ANTIFUNGALS 
Ketoconazole 
 
(Inhibition of P-gp and 
CYP3A) 

Interaction only studied with velpatasvir  
Expected: 
↔ Sofosbuvir 
↑ Voxilaprevir 

No dose adjustment of Vosevi or 
ketoconazole is required. 

Ketoconazole (200 mg 
twice daily) + velpatasvir 
(100 mg single dose)f 
 
Itraconazoled 
Posaconazoled 
Isavuconazoled 
 
 
(Inhibition of P-gp and 
CYP3A) 

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

 
↑ 
1.29 
(1.02, 
1.64) 

 
↑ 
1.71 
(1.35, 
2.18) 

 



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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 Vosevi Active Cmax AUC Cmin 
Voriconazole 
 
(Inhibition of CYP3A) 

Interaction only studied with voxilaprevir. 
Expected: 
↔ Sofosbuvir 
↑ Velpatasvir 

No dose adjustment of Vosevi or 
voriconazole is required. 

Voriconazole (200 mg twice 
daily) + voxilaprevir 
(100 mg single dose)f 

Observed: 
Voxilaprevir 

 
↔ 

 
↑ 
1.84 
(1.66, 
2.03) 

 

ANTIMYCOBACTERIALS 
Rifampicin (single dose) 
 
(Inhibition of OATP1B) 

Interaction only studied with velpatasvir 
and voxilaprevir. 
 
Expected: 
↔ Rifampicin 
↔ Sofosbuvir 

Vosevi is contraindicated with 
rifampicin (see section 4.3). 

Rifampicin (600 mg single 
dose) + velpatasvir (100 mg 
single dose)f 
 

Observed: 
Velpatasvir 

 
↑ 
1.28 
(1.05, 
1.56) 

 
↑ 
1.46 
(1.17, 
1.83) 

 

Rifampicin (600 mg single 
dose) + voxilaprevir 
(100 mg single dose)f 
 

Voxilaprevir ↑ 
11.10 
(8.23, 
14.98) 

↑ 
7.91 
(6.20, 
10.09) 

 

Rifampicin (multiple dose) 
 
(Induction of P-gp and 
CYPs) 

Effect on rifampicin exposure not studied. 
 
Expected: 
↔ Rifampicin 

Rifampicin (600 mg once 
daily) + sofosbuvir (400 mg 
single dose)f 

Observed: 
Sofosbuvir 

 
↓ 
0.23 
(0.19, 
0.29) 

 
↓ 
0.28 
(0.24, 
0.32) 

 

Rifampicin (600 mg once 
daily) + velpatasvir (100 mg 
single dose)f 

Velpatasvir ↓ 
0.29 
(0.23, 
0.37) 

↓ 
0.18 
(0.15, 
0.22) 

 

Rifampicin (600 mg once 
daily) + voxilaprevir 
(100 mg single dose)f 

Voxilaprevir ↔ ↓ 
0.27 
(0.23, 
0.31) 

 

Rifabutin 
 
 
 
 
(Induction of P-gp and 
CYPs) 

Interaction not studied. 
Expected: 
↓ Velpatasvir 
↓ Voxilaprevir 

Vosevi is contraindicated with 
rifabutin (see section 4.3). 

Observed:  
Sofosbuvir 

 
↓ 
0.64 
(0.53, 
0.77) 

 
↓ 
0.76 
(0.63, 
0.91) 

 



11 

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 Vosevi Active Cmax AUC Cmin 
Rifapentine 
 
(Induction of P-gp and 
CYPs) 

Interaction not studied. 
Expected: 
↓ Sofosbuvir 
↓ Velpatasvir 
↓ Voxilaprevir 

Co-administration of Vosevi with 
rifapentine is not recommended 
(see section 4.4). 

HIV ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS 
Tenofovir disoproxil 
fumarate 
 
(Inhibition of P-gp) 

Vosevi has been shown to increase tenofovir exposure (P-gp inhibition).  There 
was an increase in tenofovir exposure (AUC and Cmax) of around 40% during co-
treatment with Vosevi and darunavir + ritonavir + tenofovir disoproxil 
fumarate/emtricitabine. 
 
Patients receiving tenofovir disoproxil fumarate and Vosevi 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)g + sofosbuvir/ 
velpatasvir (400/100 mg 
once daily)f, h 
 
(Induction of CYPs) 

Interaction only studied with 
sofosbuvir/velpatasvir 
Expected: 
↓ Voxilaprevir 

Co-administration of Vosevi with 
efavirenz/emtricitabine/tenofovir 
disoproxil fumarate is not 
recommended (see section 4.4). 

Observed: 
Efavirenz 

 
↔ 

 
↔ 

 
↔ 

Sofosbuvir ↑ 
1.38 
(1.14, 
1.67) 

↔  

Velpatasvir ↓ 
0.53 
(0.43, 
0.64) 

↓ 
0.47 
(0.39, 
0.57) 

↓ 
0.43 
(0.36, 
0.52) 

Emtricitabine/rilpivirine/ 
tenofovir alafenamide 
(200/25/25 mg once daily)i 
+ sofosbuvir/velpatasvir/ 
voxilaprevir (400/100/ 
100 mg once 
daily) + voxilaprevir 
(100 mg once daily)f 

Observed: 
Rilpivirine 

 
↔ 

 
↔ 

 
↔ 

No dose adjustment of Vosevi or 
emtricitabine/rilpivirine/tenofovir 
alafenamide is required. Sofosbuvir ↔ ↔  

Velpatasvir ↔ ↔ ↔ 
Voxilaprevir ↔ ↔ ↔ 



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 Vosevi Active Cmax AUC Cmin 
HIV ANTIVIRAL AGENTS: HIV PROTEASE INHIBITORS 
Atazanavir boosted with 
ritonavir (300 + 100 mg 
single dose) + sofosbuvir/ 
velpatasvir/voxilaprevir 
(400/100/100 mg single 
dose)f 
 
(Inhibition of OATP1B, 
P-gp  and CYP3A) 

Effect on atazanavir and ritonavir exposure 
not studied. 
 
Expected: 
↔ Atazanavir 
↔ Ritonavir 

Co-administration of Vosevi with 
atazanavir is expected to increase 
the concentration of voxilaprevir.  
Co-administration of Vosevi with 
atazanavir-containing regimens is 
not recommended. 

Observed: 
Sofosbuvir 

 
↑ 
1.29 
(1.09, 
1.52) 

 
↑ 
1.40 
(1.25, 
1.57) 

 

Velpatasvir ↑ 
1.29 
(1.07, 
1.56) 

↑ 
1.93 
(1.58, 
2.36) 

 

Voxilaprevir ↑ 
4.42 
(3.65, 
5.35) 

↑ 
4.31 
(3.76, 
4.93) 

 

Darunavir boosted with 
ritonavir (800 + 100 mg 
once daily) + emtricitabine/ 
tenofovir disoproxil 
fumarate (200/300 mg once 
daily)j + sofosbuvir/ 
velpatasvir/voxilaprevir 
(400/100/100 mg once 
daily) + voxilaprevir 
(100 mg once daily)f 
 
(Inhibition of OATP1B, 
P-gp, and CYP3A) 

Observed: 
Darunavir 

 
↔ 

 
↔ 

 
↓ 
0.66 
(0.58, 
0.74) 

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

Ritonavir ↑ 
1.60 
(1.47, 
1.75) 

↑ 
1.45 
(1.35, 
1.57) 

↔ 

Sofosbuvir ↓ 
0.70 
(0.62, 
0.78) 

↔  

Velpatasvir ↔ ↔ ↔ 
Voxilaprevir ↑ 

1.72 
(1.51, 
1.97) 

↑ 
2.43 
(2.15, 
2.75) 

↑ 
4.00 
(3.44, 
4.65) 

Lopinavir 
 
(Inhibition of OATP1B) 

Interaction not studied. 
Expected: 
↔ Lopinavir 
↔ Sofosbuvir 
↔ Velpatasvir 
↑ Voxilaprevir 

Co-administration of Vosevi with 
lopinavir-containing regimens is 
not recommended. 

HIV ANTIVIRAL AGENTS: INTEGRASE INHIBITORS 
Raltegravir (400 mg twice 
daily)k + emtricitabine/ 
tenofovir disoproxil 
fumarate (200/300 mg once 
daily)j + sofosbuvir/ 
velpatasvir (400/100 mg 
once daily)f, h 

Interaction only studied with 
sofosbuvir/velpatasvir 
Expected: 
↔ Voxilaprevir 

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

Observed: 
Raltegravir 

 
↔ 

 
↔ 

 
↓ 
0.79 
(0.42, 
1.48) 

Sofosbuvir ↔ ↔  
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 Vosevi Active Cmax AUC Cmin 
Elvitegravir/cobicistat/ 
emtricitabine/tenofovir 
alafenamide fumarate 
(150/150/200/10 mg once 
daily)l + 
sofosbuvir/velpatasvir/ 
voxilaprevir (400/100/ 
100 mg once daily) + 
voxilaprevir (100 mg once 
daily)f 
 
(Inhibition of OATP1B, 
P-gp/BCRP and CYP3A) 

Observed: 
Elvitegravir 

 
↔ 

 
↔ 

 
↑ 
1.32 
(1.17, 
1.49) 

No dose adjustment of Vosevi or 
elvitegravir/cobicistat/ 
emtricitabine/tenofovir 
alafenamide fumarate is required. 

Cobicistat ↔ ↑ 
1.50 
(1.44, 
1.58) 

↑ 
3.50 
(3.01, 
4.07) 

Tenofovir  ↓ 
0.79 
(0.68, 
0.92) 

↔  

Sofosbuvir ↑ 
1.27 
(1.09, 
1.48)  

↔  

Velpatasvir ↔ ↔ ↑ 
1.46 
(1.30, 
1.64) 

Voxilaprevir ↑ 
1.92 
(1.63, 
2.26) 

↑ 
2.71 
(2.30, 
3.19) 

↑ 
4.50 
(3.68, 
5.50) 

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

Interaction only studied with 
sofosbuvir/velpatasvir 
Expected: 
↔ Voxilaprevir 

No dose adjustment of Vosevi or 
dolutegravir is required. 

Observed: 
Dolutegravir 

 
↔ 

 
↔ 

 
↔ 

Sofosbuvir ↔ ↔  
Velpatasvir ↔ ↔ ↔ 



14 

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 Vosevi Active Cmax AUC Cmin 
HERBAL SUPPLEMENTS 
St. John’s wort 
 
(Induction of P-gp and 
CYPs) 

Interaction not studied. 
Expected: 
↓ Sofosbuvir 
↓ Velpatasvir 
↓ Voxilaprevir 

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

HMG-CoA REDUCTASE INHIBITORS 
Atorvastatin  Interaction only studied with sofosbuvir/ 

velpatasvir. 
Expected: 
↔ Voxilaprevir 

Atorvastatin may be administered 
with Vosevi at a dose that does 
not exceed atorvastatin 20 mg. 

Atorvastatin (40 mg single 
dose) + sofosbuvir/ 
velpatasvir (400/100 mg 
once daily)f 

Observed: 
atorvastatin  

↑ 
1.7 
(1.5, 
1.9) 

↑ 
1.5 
(1.5, 
1.6) 

 

Rosuvastatin Effect on sofosbuvir, velpatasvir and 
voxilaprevir not studied. 
Expected: 
↔ Sofosbuvir 
↔ Velpatasvir 
↔ Voxilaprevir 

Vosevi is contraindicated with 
rosuvastatin (see section 4.3). 

Rosuvastatin (10 mg single 
dose) + sofosbuvir/ 
velpatasvir/voxilaprevir 
(400/100/100 mg once 
daily) + voxilaprevir 
(100 mg once daily)f 
 
(Inhibition of OATP1B and 
BCRP) 

Observed: 
Rosuvastatin 

 
↑ 
18.9 
(16.2, 
22.0) 

 
↑ 
7.4 
(6.7, 
8.2) 

 

Pravastatin Effect on sofosbuvir, velpatasvir and 
voxilaprevir not studied. 
Expected: 
↔ Sofosbuvir 
↔ Velpatasvir 
↔ Voxilaprevir 

Pravastatin may be administered 
with Vosevi at a dose that does 
not exceed pravastatin 40 mg. 

Pravastatin (40 mg single 
dose) + sofosbuvir/ 
velpatasvir/voxilaprevir 
(400/100/100 mg once 
daily) + voxilaprevir 
(100 mg once daily)f 
 
(Inhibition of OATP1B) 

Observed: 
Pravastatin 

 
↑ 
1.89 
(1.53, 
2.34) 

 
↑ 
2.16 
(1.79, 
2.60) 

 

Other statins 
 
(Inhibition of OATP1B) 

Effect on fluvastatin, lovastatin, pitavastatin 
and simvastatin not studied. 
 

Interactions cannot be excluded 
with other HMG-CoA reductase 
inhibitors.  Co-administration 
with Vosevi is not recommended. 



15 

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 Vosevi Active Cmax AUC Cmin 
NARCOTIC ANALGESICS 
Methadone Interaction only studied with sofosbuvir  

Expected: 
↔ Velpatasvir 
↔ Voxilaprevir 

No dose adjustment of Vosevi or 
methadone is required. 

Methadone 
(Methadone maintenance 
therapy [30 to 130 mg 
daily]) + sofosbuvir 
(400 mg once daily)f 

Observed: 
R-methadone 

 
↔ 

 
↔ 

 
↔ 

S-methadone ↔ ↔ ↔ 
Sofosbuvir ↔ ↑ 

1.30 
(1.00, 
1.69) 

 

IMMUNOSUPPRESSANTS 
Ciclosporin 
(600 mg single dose)f + 
sofosbuvir (400 mg single 
dose)e 
 
(Inhibition of OATP1B or 
P-gp or BCRP) 

Observed: 
Ciclosporin 

 
↔ 

 
↔ 

 Co-administration of Vosevi with 
ciclosporin is not recommended 
(see section 4.4). Sofosbuvir ↑ 

2.54 
(1.87, 
3.45) 

↑ 
4.53 
(3.26, 
6.30) 

 

Ciclosporin 
(600 mg single dose)e + 
velpatasvir (100 mg single 
dose)f 

Ciclosporin ↔ ↓ 
0.88 
(0.78, 
1.0) 

 

Velpatasvir ↑ 
1.56 
(1.22, 
2.01) 

↑ 
2.03 
(1.51, 
2.71) 

 

Ciclosporin 
(600 mg single dose)e + 
voxilaprevir (100 mg single 
dose)f 

Ciclosporin ↔ ↔  
Voxilaprevir ↑ 

19.0 
(14.1, 
25.6) 

↑ 
9.4 
(7.4, 
12.0) 

 

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

No dose adjustment of Vosevi or 
tacrolimus is required at initiation 
of co-administration. Afterwards, 
close monitoring and potential 
dose adjustment of tacrolimus 
may be required. Tacrolimus (5 mg single 

dose)e + sofosbuvir (400 mg 
single dose)f 

Observed: 
Tacrolimus 

 
↓ 
0.73 
(0.59, 
0.90) 

 
↑ 
1.09 
(0.84, 
1.40) 

 

Sofosbuvir ↓ 
0.97 
(0.65, 
1.43) 

↑ 
1.13 
(0.81, 
1.57) 

 

ORAL CONTRACEPTIVES 
Norgestimate/ethinyl 
estradiol (norgestimate 
0.180 mg/0.215 mg/0.25 mg
/ethinyl estradiol 0.025 mg) 
+ sofosbuvir/velpatasvir/ 
voxilaprevir (400/100/ 
100 mg once daily) + 
voxilaprevir (100 mg once 
daily)f 

Observed: 
Norelgestrom
in 

 
↔ 

 
↔ 

 
↔ 

Vosevi is contraindicated with 
ethinylestradiol-containing 
medicinal products (see 
section 4.3).  Alternative methods 
of contraception (e.g. progestin 
only contraception or non-
hormonal methods) should be 
considered. 

Norgestrel ↔ ↔ ↔ 
Ethinyl 
estradiol 

↔ ↔ ↔ 



16 

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 Vosevi Active Cmax AUC Cmin 
STIMULANTS 
Modafinil 
 
(Induction of P-gp and 
CYPs) 

Interaction not studied. 
Expected: 
↔ Modafinil 
↓ Sofosbuvir 
↓ Velpatasvir 
↓ Voxilaprevir 

Co-administration of Vosevi with 
modafinil is not recommended 
(see section 4.4). 

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. Lack of pharmacokinetics interaction lower bound 70%. 
d. These are medicinal products within class where similar interactions could be predicted. 
e. Bioequivalence/Equivalence boundary 80-125%. 
f. Lack of pharmacokinetics interaction bounds 70-143%. 
g. Administered as efavirenz, emtricitabine and tenofovir DF fixed-dose combination. 
h. Administered as sofosbuvir, velpatasvir fixed-dose combination. 
i. Administered as emtricitabine, rilpivirine, and tenofovir alafenamide fixed-dose combination. 
j. Administered as emtricitabine, tenofovir disoproxil fumarate fixed-dose combination. 
k. Lack of pharmacokinetics interaction bounds 50-200%. 
l. Administered as elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide fixed-dose combination. 
 
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, voxilaprevir or Vosevi 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). 
 
Voxilaprevir 
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity 
(see section 5.3). 
 
As a precautionary measure, Vosevi use is not recommended during pregnancy. 
 
Breast-feeding 
 
It is unknown whether sofosbuvir, metabolites of sofosbuvir, velpatasvir or voxilaprevir are excreted 
in human milk. 
 
Available pharmacokinetic data in animals have shown excretion of velpatasvir and metabolites of 
sofosbuvir in milk.  When administered to lactating rats, voxilaprevir was detected in the plasma of 
nursing pups. 
 
A risk to the newborns/infants cannot be excluded.  Therefore, Vosevi should not be used during 
breast-feeding. 
 



17 

Fertility 
 
No human data on the effect of Vosevi on fertility are available.  Animal studies do not indicate 
harmful effects of sofosbuvir, velpatasvir or voxilaprevir on fertility. 
 
4.7 Effects on ability to drive and use machines 
 
Vosevi has no or negligible influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
In Phase 2 and 3 clinical trials, the proportion of patients who permanently discontinued treatment due 
to adverse reactions was 0.1% for patients receiving sofosbuvir/velpatasvir/voxilaprevir for 8 weeks.  
There were no patients receiving sofosbuvir/velpatasvir/voxilaprevir for 12 weeks who permanently 
discontinued treatment due to adverse reactions in the Phase 2 and 3 pivotal clinical studies. 
 
Tabulated summary of adverse reactions 
 
Assessment of adverse reactions for Vosevi is based on safety data from clinical studies and 
postmarketing experience. All adverse reactions are presented in Table 3. 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 3: Adverse drug reactions identified with Vosevi 
Frequency Adverse drug reaction 
Nervous system disorders: 
Very common headache 
Gastrointestinal disorders: 
Very common diarrhoea, nausea 
Common abdominal pain, decreased appetite, vomiting 
Skin and subcutaneous tissue disorders: 
Common rash 
Uncommon angioedemaa 
Musculoskeletal and connective tissue disorders: 
Common myalgia 
Uncommon muscle spasm 
Laboratory investigations: 
Common total bilirubin increased  
a. Adverse reaction identified through post-marketing surveillance for sofosbuvir/velpatasvir-containing products 
 
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 
 
Laboratory abnormalities 
 
Total bilirubin 
In the Phase 3 trials increases in total bilirubin less than or equal to 1.5 x the upper limit of normal 
were observed in 4% of patients without cirrhosis and 10% of patients with compensated cirrhosis, due 



18 

to inhibition of OATP1B1 and OATP1B3 by voxilaprevir.  Total bilirubin levels decreased after 
completing Vosevi treatment. 
 
Patients with renal impairment  
 
The safety of sofosbuvir in a fixed dose combination with either ledipasvir or velpatasvir has been 
studied in 154 patients with ESRD requiring dialysis (Study 4062 and Study 4063). In this setting, 
exposure of sofosbuvir metabolite GS-331007 is 20-fold increased, exceeding levels where 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. 
 
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, velpatasvir and voxilaprevir were single doses of 
1,200 mg, 500 mg, and 900 mg, respectively.  In healthy volunteer studies with sofosbuvir and 
velpatasvir, 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 most common adverse 
reactions in patients receiving voxilaprevir 900 mg were diarrhoea (34%), nausea (17%) and headache 
(9%). 
 
No specific antidote is available for overdose with Vosevi.  If overdose occurs the patient must be 
monitored for evidence of toxicity.  Treatment of overdose with Vosevi 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 or voxilaprevir since velpatasvir and voxilaprevir are highly bound to plasma 
proteins. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Direct-acting antiviral, ATC code: J05AP56 
 
Mechanism of action 
 
Sofosbuvir is a pan-genotypic inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is 
required 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.  In a 
biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV 
genotype 1b, 2a, 3a, and 4a.  GS-461203 is neither an inhibitor of human DNA and RNA polymerases 
nor an inhibitor of mitochondrial RNA polymerase. 
 
Velpatasvir is a pan-genotypic HCV inhibitor targeting the HCV NS5A protein, which is required for 
viral replication. 
 
Voxilaprevir is a pan-genotypic inhibitor of the HCV NS3/4A protease.  Voxilaprevir acts as a 
noncovalent, reversible inhibitor of the NS3/4A protease. 

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


19 

 
Antiviral activity 
 
The 50% effective concentration (EC50) values of sofosbuvir, velpatasvir and voxilaprevir against 
full-length or chimeric replicons encoding NS5B, NS5A and NS3 protease sequences from the 
laboratory strains are presented in Table 4.  The EC50 values of sofosbuvir, velpatasvir and 
voxilaprevir against clinical isolates are presented in Table 5. 
 
Table 4: Activity of sofosbuvir, velpatasvir and voxilaprevir against full-length or chimeric 
laboratory replicons 
Replicon 
genotype 

Sofosbuvir EC50, nMa Velpatasvir EC50, nMa Voxilaprevir EC50, nMa 

1a 40 0.014 3.9e 
1b 110 0.016 3.3e 
2a 50 0.005-0.016c 3.7-4.5e 
2b 15b 0.002-0.006c 1.8-6.6f 
3a 50 0.004 6.1f 
4a 40 0.009 2.9e 
4d 33 0.004 3.2e 
5a 15b 0.021-0.054d 1.9f 
6a 14-25b 0.006-0.009 3.0-4.0e 
6e NA 0.130d 0.33f 
6n NA NA 2.9f 
NA: Not available 
a. Mean value from multiple experiments of same laboratory replicon. 
b. Stable chimeric 1b replicons carrying NS5B genes from genotype 2b, 5a or 6a were used for testing. 
c. Data from various strains of full length NS5A replicons or chimeric NS5A replicons carrying full-length NS5A genes that 
contain L31 or M31 polymorphisms. 
d. Data from a chimeric NS5A replicon carrying NS5A amino acids 9-184. 
e. Stable cell lines expressing Renilla luciferase-encoding replicons. 
f. Data obtained from transiently transfected replicons. 
 
Table 5: Activity of sofosbuvir, velpatasvir and voxilaprevir against transient replicons 
containing NS5A, NS5B or NS3 protease from clinical isolates 
Replicon 
genotype 

Replicons containing 
NS5B from clinical 
isolates 

Replicons containing NS5A 
from clinical isolates 

Replicons containing NS3 
protease from clinical 
isolates 

Number of 
clinical 
isolates 

Median 
sofosbuvir 
EC50, nM 
(range) 

Number 
of clinical 
isolates 

Median 
velpatasvir 
EC50, nM 
(range) 

Number 
of clinical 
isolates 

Median 
voxilaprevir 
EC50, nM 
(range) 

1a 67 62 
(29-128) 

23 0.019 
(0.011-0.078) 

58 0.59 
(0.14-19.16) 

1b 29 102 
(45-170) 

34 0.012 
(0.005-0.500) 

29 0.50 
(0.19-2.87) 

2a 1 28 8 0.011 
(0.006-0.364) 

18 2.8 
(1.78-6.72) 

2b 14 30 
(14-81) 

16 0.002 
(0.0003-0.007) 

43 2.1 
(0.92-8.3) 

3a 106 81 
(24-181) 

38 0.005 
(0.002-1.871) 

32 6.3 
(1.3-21.48) 

4a NA NA 5 0.002 
(0.001-0.004) 

58 0.52 
(0.12-1.7) 

4d NA NA 10 0.007 
(0.004-0.011) 

11 0.85 
(0.41-1.1) 

4r NA NA 7 0.003 
(0.002-0.006) 

1 1.15 
NA 

5a NA NA 42 0.005 
(0.001-0.019) 

16 1.8 
(0.87-5.63) 

6a NA NA 26 0.007 
(0.0005-0.113) 

15 2.7 
(0.23-7.35) 



20 

Replicon 
genotype 

Replicons containing 
NS5B from clinical 
isolates 

Replicons containing NS5A 
from clinical isolates 

Replicons containing NS3 
protease from clinical 
isolates 

Number of 
clinical 
isolates 

Median 
sofosbuvir 
EC50, nM 
(range) 

Number 
of clinical 
isolates 

Median 
velpatasvir 
EC50, nM 
(range) 

Number 
of clinical 
isolates 

Median 
voxilaprevir 
EC50, nM 
(range) 

6e NA NA 15 0.024 
(0.005-0.433) 

12 0.2 
(0.12-0.43) 

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 and voxilaprevir by 13- and 6.8-fold, respectively, against 
genotype 1a HCV replicons. 
 
Resistance 
 
In cell culture 
For sofosbuvir, the NS5B substitution S282T was selected in genotype 1-6 replicons and was 
associated with 2- to 18-fold reduced susceptibility to sofosbuvir. 
 
For velpatasvir in genotype 1-6 replicons, resistance-associated substitutions selected in 2 or more 
genotypes were L31I/V and Y93H.  Site directed mutagenesis of NS5A resistance associated variants 
(RAVs) showed that substitutions conferring a > 100-fold reduction in velpatasvir susceptibility are 
M28G, A92K and Y93H/N/R/W in genotype 1a, A92K in genotype 1b, C92T and Y93H/N in 
genotype 2b, Y93H in genotype 3, and L31V and P32A/L/Q/R in genotype 6.  No individual RAV 
tested in genotypes 2a, 4a or 5a conferred a > 100-fold reduction in velpatasvir susceptibility. 
 
For voxilaprevir in genotype 1-6 replicons, resistance-associated substitutions selected in 2 or more 
genotypes were Q41H, A156V/T/L and D168E/H/Y.  Site directed mutagenesis of known NS3 RAVs 
showed that substitutions conferring a > 100-fold reduction in voxilaprevir susceptibility are A156V, 
A156T or A156L in genotype 1a, 1b, 2a, 3a and 4.  No individual RAV tested in genotypes 2b, 5a or 
6a conferred a > 100-fold reduction in voxilaprevir susceptibility. 
 
For both velpatasvir and voxilaprevir, combinations of RAVs often showed greater reductions in 
susceptibility than individual RAVs alone. 
 
Cross resistance in cell culture 
Voxilaprevir is active in vitro against most of the NS3 RAVs that confer resistance to first generation 
NS3/4A protease inhibitors.  Additionally, velpatasvir is active in vitro against most of the 
NS5A RAVs that confer resistance to ledipasvir and daclatasvir.  Sofosbuvir, velpatasvir, and 
voxilaprevir were fully active against substitutions associated with resistance to other classes of DAAs 
with different mechanisms of actions, e.g. voxilaprevir was fully active against NS5A and NS5B 
NI RAVs. 
 
In clinical studies 
Studies in DAA-experienced patients 
Of the 263 NS5A inhibitor-experienced patients treated with sofosbuvir/velpatasvir/voxilaprevir for 
12 weeks in POLARIS-1 (see Table 10), 7 of 263 (3%) patients (2 with genotype 1, 4 with genotype 3, 
and 1 with genotype 4) did not achieve sustained virologic response (SVR12) and qualified for 
resistance analysis; 6 relapsed and 1 experienced virologic breakthrough with pharmacokinetic data 
consistent with nonadherence.  The patient with genotype 1a and virologic breakthrough developed the 
NS5A RAVs L31M and Y93H.  One patient with genotype 4d who relapsed developed the NS5A 
RAV Y93H.  No NS3, NS5A, or NS5B nucleoside inhibitor (NI) RAVs emerged in the other 
5 patients who relapsed. 
 



21 

Of the 182 DAA-experienced patients treated with sofosbuvir/velpatasvir/voxilaprevir for 12 weeks in 
POLARIS-4 (see Table 11), 1 of 182 (1%) patients relapsed and qualified for resistance analysis.  
No NS3, NS5A, or NS5B NI RAVs emerged in this patient infected with genotype 1a HCV. 
 
Studies in DAA-naïve patients 
In the POLARIS-2 sofosbuvir/velpatasvir/voxilaprevir 8-week treatment group (see Table 12), a total 
of 21 of 501 (4%) patients (16 with genotype 1, 2 with genotype 2, 2 with genotype 4, and 1 with 
genotype 5) qualified for resistance analysis due to relapse.  Of these 21 patients, 1 patient had virus 
with emergent NS5A RAVs Q30R and L31M at failure.  No NS3 and NS5B NI RAVs emerged in any 
of these 21 patients at failure.  In the sofosbuvir/velpatasvir 12-week treatment group, a total of 3 of 
440 (1%) patients (2 with genotype 1, 1 with genotype 4) qualified for resistance analysis due to 
relapse.  Of these 3 patients, 1 patient (33%) had virus with emergent NS5A RAV Y93N at failure.  
No NS3 and NS5B NI RAVs emerged in any of these 3 patients. 
 
In the POLARIS-3 sofosbuvir/velpatasvir/voxilaprevir 8-week treatment group (see Table 14), 
2 of 110 (2%) patients (genotype 3) qualified for resistance analysis due to relapse.  No NS3, NS5A, 
or NS5B NI RAVs emerged in either of these patients.  In the sofosbuvir/velpatasvir 12-week 
treatment group, 2 of 109 (2%) patients qualified for resistance analysis due to virologic failure.  Both 
of these patients had virus with emergent NS5A RAV Y93H at failure.  No NS3 or NS5B NI RAVs 
emerged in either of these patients. 
 
Effect of baseline HCV resistance-associated variants on treatment outcome 
 
Studies in DAA-experienced patients 
Analyses were conducted to explore the association between pre-existing baseline NS3 and 
NS5A RAVs and treatment outcome for patients that had previously been treated with DAA regimens 
and received sofosbuvir/velpatasvir/voxilaprevir for 12 weeks in POLARIS-1 and POLARIS-4.  These 
are shown in Table 6. 
 
Table 6: SVR12 in DAA-experienced patients with or without baseline NS3 or NS5A RAVs by 
study 
 sofosbuvir/velpatasvir/voxilaprevir 12 weeks 

POLARIS-1 (n = 260) POLARIS-4 (n = 179) 
No NS3 or NS5A RAVs 98% (42/43) 99% (85/86) 
Any NS3 or NS5A RAV 97% (199/205) 100% (83/83) 

NS3 Only 100% (9/9) 100% (39/39) 
NS5A Only 97% (120/124) 100% (40/40) 
NS3 and NS5A 97% (70/72) 100% (4/4) 

RAVs not determined for both NS3 
and NS5Aa 

100% (12/12) 100% (10/10) 

a. Patients with NS3 and/or NS5A gene sequencing failure. 
 
SVR12 was achieved in 18 of 19 (95%) patients who had baseline NS5B NI RAVs in POLARIS-1, 
including 2 patients who had virus with the S282T NS5B NI RAV in addition to NS5A RAVs at 
baseline.  In POLARIS-4, a total of 14 patients had virus with NS5B NI RAVs at baseline and all 
achieved SVR12. 
 
Studies in DAA-naïve patients 
Analyses were conducted to explore the association between pre-existing baseline NS3 and 
NS5A RAVs and treatment outcome for patients that had not previously been treated with DAA 
regimens and received sofosbuvir/velpatasvir/voxilaprevir for 8 weeks in POLARIS-2 and 
POLARIS-3.  These are shown in Table 7. 
 



22 

Table 7: SVR12 in DAA-naïve patients with or without baseline NS3 or NS5A RAVs by study 

 

sofosbuvir/velpatasvir/voxilaprevir 8 weeks 
POLARIS-2 
(n = 498) 

POLARIS-3 
(n = 108) 

No NS3 or NS5A RAVs 98% (224/229) 98% (80/82) 
Any NS3 or NS5A RAV 94% (234/250) 100% (23/23) 

NS3 only 91% (100/110) 100% (2/2) 
NS5A only 95% (114/120) 100% (20/20) 
NS3 and NS5A 100% (20/20) 100% (1/1) 

RAVs not determined for both 
NS3 and NS5Aa 

100% (19/19) 100% (3/3) 

a. Patients with NS3 and/or NS5A gene sequencing failure. 
 
SVR12 was achieved in all 39 patients who had baseline NS5B NI RAVs in POLARIS-2 and 2 of 
3 (67%) patients in POLARIS-3.  The NS5B NI RAV S282T was not detected in any patient in 
POLARIS-2 and POLARIS-3 studies.  Among subjects with genotype 1a in POLARIS-2, SVR12 was 
87% (53/61) for those with Q80K/L/R RAVs and 94% (99/105) for those without Q80K/L/R RAVs. 
 
Clinical efficacy 
 
The efficacy of Vosevi (sofosbuvir [SOF]/velpatasvir [VEL]/voxilaprevir [VOX]) was evaluated in 
four Phase 3 studies, two studies in DAA-experienced patients and two studies in DAA-naïve patients 
with, genotype 1 to 6 HCV infection without cirrhosis or with compensated cirrhosis, as summarised 
in Table 8.  Demographics and baseline characteristics for all studies are detailed in Table 9. 
 
Table 8: Studies conducted with Vosevi 
Study Population Study arms and duration 

(Number of patients treated) 
Additional study details 

POLARIS-1 
(randomised 
double blind) 

NS5A inhibitor-
experienced patients, 
GT1-6, with or without 
cirrhosis 

• SOF/VEL/VOX 12 weeks 
(N=263) 

• Placebo 12 weeks   
(N=152) 

Placebo-controlled study in which 
patients with GT1 infection were 
randomised in a 1:1 ratio to 
SOF/VEL/VOX or placebo for 
12 weeks.  Patients with GT2-6 
infection were enrolled into the 
SOF/VEL/VOX 12 week group 
only. 

POLARIS-4 
(open label) 

DAA-experienced 
patients (who have not 
received an NS5A 
inhibitor), GT1-6, with 
or without cirrhosis 

• SOF/VEL/VOX 12 weeks 
(N=182) 

• SOF/VEL 12 weeks 
(N=151) 

Patients with GT1-3 infection were 
randomised in a 1:1 ratio to 
SOF/VEL/VOX or SOF/VEL for 
12 weeks.  Patients with GT4-6 
infection were enrolled into the 
SOF/VEL/VOX 12 week group 
only. 

POLARIS-2 
(open label) 

DAA-naïve patients, 
GT 1, 2, 4, 5, or 6, with 
or without cirrhosis 
GT 3 without cirrhosis 

• SOF/VEL/VOX 8 weeks 
(N=501) 

• SOF/VEL 12 weeks 
(N=440) 

Patients with GT1-4 were 
randomised in a 1:1 ratio to 
SOF/VEL/VOX for 8 weeks or 
SOF/VEL for 12 weeks.  Patients 
with GT5-6 infection were enrolled 
into the SOF/VEL/VOX 8 week 
group only. 

POLARIS-3 
(open label) 

DAA-naïve patients 
with GT 3 and cirrhosis 

• SOF/VEL/VOX 8 weeks 
(N=110) 

• SOF/VEL 12 weeks 
(N=109) 

Patients were randomised in a 1:1 
ratio to SOF/VEL/VOX for 
8 weeks or SOF/VEL for 12 weeks. 

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



23 

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

Patients 
Studies with DAA-naïve Patients 

Patient disposition POLARIS-1 
(n =415) 

POLARIS-4 
(n =333) 

POLARIS-2 
(n =941) 

POLARIS-3 
(n =219) 

Age (years) median (range) 59 (27-84) 58 (24-85) 55 (18-82) 56 (25-75) 
Male Gender 77% (321) 77% (257) 52% (492) 72% (157) 
Race 

Black/African American 14% (60) 9% (29) 10% (95) < 1% (1) 
White 81% (335) 87% (291) 80% (756) 90% (197) 
Hispanic/Latino 6% (25) 8% (27) 9% (84) 8% (17) 

Genotype 
 Genotype 1a 53% (218) 29% (98) 36% (341) 0 
 Genotype 1b 18% (76) 14% (46) 13% (122) 0 
 Genotype 2 1% (5) 19% (64) 12% (116) 0 
 Genotype 3 19% (78) 32% (106) 19% (181) 100% (219) 
 Genotype 4 5% (22) 5.7% (19) 13% (120) 0 
 Genotype 5 < 1% (1) 0 2% (18) 0 
 Genotype 6 2% (8) 0 4% (39) 0 
IL28B CC 18% (74) 19% (62) 32% (302) 42% (93) 
HCV RNA ≥ 800,000 IU/mL 74% (306) 75% (249) 69% (648) 69% (151) 
Compensated cirrhosis 41% (172) 46% (153) 18% (174) 100% (219) 
Site 
 US 57% (236) 56% (188) 59% (552) 44% (96) 
 Non-US 43% (179) 44% (145) 41% (389) 56% (123) 
 
Serum HCV RNA values were measured during the clinical studies using the COBAS 
AmpliPrep/COBAS Taqman HCV test (version 2.0) with a lower limit of quantification (LLOQ) of 
15 IU per 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 DAA-experienced patients 
NS5A inhibitor-experienced adults (POLARIS-1) 
Table 10 presents the SVR12 by HCV genotype for the POLARIS-1 trial.  The median time between 
prior DAA failure and first dose of Vosevi for patients enrolled into POLARIS-1 was 39 weeks 
(range: 11 to 299 weeks).  No patients in the placebo group achieved SVR4. 
 
Table 10: SVR12 in NS5A-inhibitor experienced patients by HCV genotype in study 
POLARIS-1* 

 

SOF/VEL/VOX 12 weeks (n = 263) 
Total 
(all 
GTs)a 
(n = 263) 

GT-1 
GT-2 
(n = 5) 

GT-3 
(n = 78) 

GT-4 
(n = 22) 

GT-5 
(n = 1) 

GT-6 
(n = 6) GT-1a (n = 101) 

GT-1b 
(n = 45) 

Totalb 
(n = 150) 

SVR12 96% (253/263) 
96% 
(97/101) 

100% 
(45/45) 

97% 
(146/150) 

100% 
(5/5)  

95% 
(74/78) 

91% 
(20/22) 

100% 
(1/1) 

100% 
(6/6) 

Outcome for patients without SVR 
On-
treatment 
virologic 
failurec 

<1% 
(1/263) 

1% 
(1/101) 

0/45 1% 
(1/150) 

0/5 0/78 0/22 0/1 0/6 

Relapsed 2% 
(6/261) 

1% 
(1/100) 

0/45 1%  
(1/149) 

0/5 5% 
(4/78) 

5% 
(1/21) 

0/1 0/6 

Othere 1% 
(3/263) 

2% 
(2/101) 

0/45 1% 
(2/150) 

0/5 0/78 5% 
(1/22) 

0/1 0/6 

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



24 

a. One patient with undetermined genotype achieved SVR12. 
b. Four patients had genotype 1 subtypes other than genotype 1a or genotype 1b; all 4 patients achieved SVR12. 
c. Pharmacokinetic data for the 1 patient with on-treatment virologic failure was consistent with non-adherence. 
d. The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment. 
e. Other includes patients with missing data and those who discontinued treatment prior to virologic suppression. 
 
DAA-experienced adults who had not received an NS5A inhibitor (POLARIS-4) 
Table 11 presents the SVR12 by HCV genotype and virologic outcome for the POLARIS-4 trial.  The 
median time between prior DAA failure and first dose of Vosevi or sofosbuvir/velpatasvir for patients 
enrolled into POLARIS-4 was 76 weeks (range: 10 to 549 weeks).   
 
Table 11: SVR12 by HCV genotype and virologic outcome in study POLARIS-4 
 SOF/VEL/VOX 12 weeks 

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

Overall SVR12 98% (178/182) 90% (136/151) 
Genotype 1 97% (76/78) 91% (60/66) 

Genotype 1a 98% (53/54) 89% (39/44) 
Genotype 1b 96% (23/24) 95% (21/22) 

Genotype 2 100% (31/31) 97% (32/33) 
Genotype 3 96% (52/54) 85% (44/52) 
Genotype 4 100% (19/19) 0/0 
Outcome for patients without SVR 
On-treatment 
virologic failurea 

0/182 1% (1/151) 

Relapseb 1% (1/182) 9% (14/150) 
Otherc 2% (3/182) 0/151 
a. The majority (85%) of patients previously failed a regimen containing sofosbuvir. 
b. The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment. 
c. Other includes patients with missing data and those who discontinued treatment prior to virologic suppression. 
 
Clinical studies in DAA-naïve patients 
DAA-naïve adults with genotype 1, 2, 3, 4, 5, or 6 HCV infection (POLARIS-2) 
Table 12 presents the SVR12 by HCV genotype and virologic outcome for the POLARIS-2 trial. 
 
Table 12: SVR12 by HCV genotype and virologic outcome in study POLARIS-2* 
 SOF/VEL/VOX 

8 weeks 
(n = 501) 

SOF/VEL 
12 weeks 
(n = 440) 

Overall SVR12a 95% (477/501) 98% (432/440) 
Genotype 1b 93% (217/233) 98% (228/232) 

Genotype 1a 92% (155/169) 99% (170/172) 
Genotype 1b 97% (61/63) 97% (57/59) 

Genotype 2 97% (61/63) 100% (53/53) 
Genotype 3 99% (91/92) 97% (86/89) 
Genotype 4 94% (59/63) 98% (56/57) 
Genotype 5 94% (17/18) 0/0 
Genotype 6 100% (30/30) 100% (9/9) 
Outcome for patients without SVR 
On-treatment virologic 
failure 0/501 0/440 

Relapsec 4% (21/498) 1% (3/439) 
Otherd 1% (3/501) 1% (5/440) 
* 23% of patients enrolled into POLARIS-2 had received prior treatment with an interferon-based regimen. 
a. Two patients with undetermined genotype in the SOF/VEL/VOX group achieved SVR12. 
b. Two patients had genotype 1 subtypes other than genotype 1a or genotype 1b; both patients achieved SVR12. 
c. The denominator for relapse is the number of patients with HCV RNA <LLOQ at their last on-treatment assessment. 
d. Other includes patients with missing data and those who discontinued treatment prior to virologic suppression. 
 



25 

Treatment with Vosevi for 8 weeks in POLARIS-2 did not demonstrate noninferiority to treatment 
with sofosbuvir/velpatasvir for 12 weeks with a prespecified margin of -5%.  The difference in SVR12 
was driven by a lower response rate in patients with genotype 1a infection and/or cirrhosis.  In patients 
with genotype 1a without cirrhosis treated with Vosevi for 8 weeks, outcome was influenced by the 
following baseline factors: BMI ≥ 30 kg/m2, Q80K/L/R RAVs, IL28B non-CC, HCV RNA 
≥ 800,000 IU/mL.  The SVR12 was 98% among those with two or fewer factors and 81% among those 
with three or four factors.  Table 13 presents the SVR12 by HCV genotype by cirrhosis status for the 
POLARIS-2 trial. 
 
Table 13: SVR12 by HCV genotype and virologic outcome in patients who received Vosevi 8 
weeks without cirrhosis or with cirrhosis in study POLARIS-2 
 SOF/VEL/VOX 8 weeks 
 Without Cirrhosis 

(411/501) 
With Cirrhosis 
(90/501) 

Overall SVR12a 96% (395/411) 91% (82/90) 
Genotype 1b 94% (162/172) 90% (55/61) 

Genotype 1a 92% (109/118)c 90% (46/51) 
Genotype 1b 98% (52/53) 90% (9/10) 

Genotype 2 96% (47/49) 100% (14/14) 
Genotype 3 99% (90/91) 100% (1/1) 
Genotype 4 96% (51/53) 80% (8/10) 
Genotype 5 94% (16/17) 100% (1/1) 
Genotype 6 100% (27/27) 100% (3/3) 
Outcome for patients without SVR 
On-treatment virologic 
failure 0/411 0/90 

Relapsed 3% (14/409) 8% (7/89) 
Othere < 1% (2/411) 1% (1/90) 
a. Two patients without cirrhosis with undetermined genotype in the SOF/VEL/VOX group achieved SVR12. 
b. One patient without cirrhosis had genotype 1 subtype other than genotype 1a or genotype 1b; the patient achieved SVR12. 
c. SVR12 is 89% in genotype 1a patients enrolled at sites in the US and 97% in genotype 1a patients enrolled at sites outside the US 
d. The denominator for relapse is the number of patients with HCV RNA <LLOQ at their last on-treatment assessment. 
e. Other includes patients with missing data and those who discontinued treatment prior to virologic suppression. 
 
DAA-naïve adults with genotype 3 HCV infection and compensated cirrhosis (POLARIS-3) 
Table 14 presents the SVR12 and virologic outcome for the POLARIS-3 study. 
 
Table 14: SVR12 and virologic outcome in study POLARIS-3 (HCV genotype 3 with 
compensated cirrhosis)* 
 SOF/VEL/VOX 

8 weeks 
(n = 110) 

SOF/VEL 
12 weeks 
(n = 109) 

SVR12 96% (106/110) 96% (105/109) 
Outcome for patients without SVR 
On-treatment virologic 
failure  

0/110 1% (1/109) 

Relapsea 2% (2/108) 1% (1/107) 
Otherb 2% (2/110) 2% (2/109) 
* 29% of patients enrolled into POLARIS-3 had received prior treatment with an interferon-based regimen. 
a. The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment. 
b. Other includes patients with missing data and those who discontinued treatment prior to virologic suppression. 
 
Adults previously treated with sofosbuvir/velpatasvir-containing regimens 
Vosevi for 12 weeks was evaluated in patients who were previously treated with a 
sofosbuvir/velpatasvir-containing regimen. The median time to re-treatment was 414 days (range 198-
1271). Of the 31 patients enrolled, 74% (23/31) were male, 81% (25/31) were white, 71% (22/31) had 
a baseline body mass index < 30 kg/m2, 48% (15/31) had compensated cirrhosis, 58% (18/31) had 
previously received sofosbuvir, velpatasvir and voxilaprevir, and 42% (13/31) had previously received 
sofosbuvir and velpatasvir. Most subjects had genotype 1 (61% (19/31) [1a, 48% (15/31); 1b, 13% 
(4/31)]) or genotype 3 (26% (8/31)) HCV infection. The overall SVR12 rate was 100% (31/31).  



26 

 
Elderly 
Clinical studies of Vosevi included 189 patients aged 65 and over (17% of total number of patients in 
the Phase 2 and 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. 
 
Paediatric population 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
sofosbuvir/velpatasvir/voxilaprevir 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). 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
The pharmacokinetic properties of sofosbuvir, GS-331007, velpatasvir and voxilaprevir have been 
evaluated in healthy adult subjects and in patients with chronic hepatitis C. 
 
Sofosbuvir 
Following oral administration of Vosevi, sofosbuvir was absorbed quickly and the peak median 
plasma concentration was observed 2 hours post-dose.  Median peak plasma concentration of 
GS-331007 was observed 4 hours post-dose.  Based on the population pharmacokinetic analysis in 
HCV-infected patients, mean steady-state AUC0-24 and Cmax for sofosbuvir (n = 1038) were 
1665 ng•hr/mL and 678 ng/mL, respectively; mean steady-state AUC0-24 and Cmax for GS-331007 
(n = 1593) were 12834 ng•hr/mL and 744 ng/mL, respectively.  Sofosbuvir and GS-331007 AUC0-24 
and Cmax were similar in healthy adult subjects and patients with HCV infection.   
 
Velpatasvir 
Velpatasvir median peak concentrations were observed at 4 hours post-dose.  Based on the population 
pharmacokinetic analysis in HCV-infected patients mean steady-state AUC0-24 and Cmax for velpatasvir 
(n = 1595) were 4041 ng•hr/mL and 311 ng/mL, respectively.  Relative to healthy subjects (n = 137), 
velpatasvir AUC0-24 and Cmax were 41% lower and 39% lower, respectively, in HCV-infected patients. 
 
Voxilaprevir 
Voxilaprevir median peak concentrations were observed 4 hours post-dose.  Based on the population 
pharmacokinetic analysis in HCV-infected patients mean steady-state AUC0-24 and Cmax for 
voxilaprevir (n = 1591) were 2577 ng•hr/mL and 192 ng/mL, respectively.  Relative to healthy 
subjects (n = 63), voxilaprevir AUC0-24 and Cmax were both 260% higher in HCV-infected patients. 
 
Effects of food 
When Vosevi or its components taken together were administered with food, sofosbuvir AUC0-inf and 
Cmax were 64% to 144% and 9% to 76% higher, respectively; velpatasvir AUC0-inf and Cmax were 40% 
to 166% and 37% to 187% higher, respectively; and voxilaprevir AUC0-inf and Cmax were 112% to 
435% and 147% to 680% higher, respectively.  GS-331007 AUC0-inf did not change and Cmax was 19% 
to 35% lower when Vosevi or its components together were administered with food. 
 
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% 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 
0.5 and 0.7. 



27 

 
Voxilaprevir is approximately > 99% bound to human plasma proteins.  After a single 100 mg dose of 
[14C]-voxilaprevir in healthy subjects, the blood to plasma ratio of [14C]-radioactivity ranged between 
0.5 and 0.8. 
 
Biotransformation 
 
Sofosbuvir is extensively metabolised in the liver to form the pharmacologically active nucleoside 
analogue 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.  After a single 400 mg oral dose of [14C]-sofosbuvir, GS-331007 accounted 
for approximately > 90% of total systemic exposure. 
 
Velpatasvir is primarily a substrate of CYP2B6, CYP2C8, and CYP3A4 with slow turnover.  
Following a single dose of 100 mg [14C]-velpatasvir, the majority (> 98%) of radioactivity in 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. 
 
Voxilaprevir is primarily a substrate of CYP3A4 with slow turnover.  Following a single dose of 
100 mg [14C]-voxilaprevir, the majority (approximately 91%) of radioactivity in plasma was parent 
drug.  The hydrolysed and dehydrogenated voxilaprevir were the major metabolites identified in 
human plasma.  Unchanged voxilaprevir is the major species present in faeces. 
 
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 Vosevi were 0.5 and 29 hours, respectively. 
 
Following a single 100 mg oral dose of [14C]-velpatasvir, mean total recovery of the 
[14C]-radioactivity was 95%, consisting of approximately 94% and 0.4% recovered from the 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 Vosevi was approximately 17 hours. 
 
Following a single 100 mg oral dose of [14C]-voxilaprevir, mean total recovery of the 
[14C]-radioactivity was 94%, with all radioactivity measured in the faeces and none in the urine.  
Unchanged voxilaprevir was the major species in faeces accounting for a mean of 40% of the 
administered dose.  Voxilaprevir metabolites also identified in faeces included des-
[methylcyclopropylsulphonamide]-voxilaprevir (22.1%), which is formed intestinally, dehydro-
voxilaprevir (7.5%), and two des-[methylcyclopropylsulphonamide]-oxy-voxilaprevir metabolites 
(5.4% and 3.9%).  Biliary excretion of parent drug was the major route of elimination for voxilaprevir.  
The median terminal half-life of voxilaprevir following administration of Vosevi was approximately 
33 hours. 
 
Linearity/non-linearity 
 
Sofosbuvir and GS-331007 AUCs are near dose-proportional over the dose range of 200 mg to 
1200 mg.  Velpatasvir AUC increases in a greater than proportional manner from 5 to 50 mg and in a 



28 

less than proportional manner from 50 to 450 mg, indicating velpatasvir absorption is solubility 
limited.  Voxilaprevir (studied under fed conditions) AUC increases in a greater than dose-
proportional manner over the dose range of 100 to 900 mg. 
 
In vitro potential for sofosbuvir/velpatasvir/voxilaprevir drug-drug interactions 
 
Sofosbuvir, velpatasvir and voxilaprevir are substrates of drug transporters P-gp and BCRP while 
GS-331007 is not.  Voxilaprevir, and to a lesser extent velpatasvir, are also substrates of OATP1B1 
and OATP1B3.  In vitro, slow metabolic turnover of velpatasvir primarily by CYP2B6, CYP2C8, and 
CYP3A4 and of voxilaprevir primarily by CYP3A4 was observed. 
 
Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, multidrug resistance-
associated protein 2 (MRP2), bile salt export pump (BSEP), OATP1B1, OATP1B3 and organic cation 
transporter (OCT) 1 and GS-331007 is not an inhibitor of OAT1, OAT3, OCT2, and multidrug and 
toxin extrusion protein (MATE) 1.  Sofosbuvir and GS-331007 are not inhibitors or inducers of CYP 
or uridine glucuronosyltransferase (UGT) 1A1 enzymes. 
 
Velpatasvir is an inhibitor of drug transporter P-gp, BCRP, OATP1B1, OATP1B3 and OATP2B1, and 
its involvement in drug interactions with these transporters is primarily limited to the process of 
absorption.  At clinically relevant concentrations, velpatasvir is not an inhibitor of hepatic transporters 
BSEP, sodium taurocholate cotransporter protein (NTCP), OATP1A2 or OCT1, renal transporters 
OCT2, OAT1, OAT3, MRP2 or MATE1, or CYP or UGT1A1 enzymes. 
 
Voxilaprevir is an inhibitor of drug transporters P-gp, BCRP, OATP1B1 and OATP1B3, and its 
involvement in drug interactions with these transporters is primarily limited to the process of 
absorption.  At clinically relevant concentrations, voxilaprevir is not an inhibitor of hepatic 
transporters OCT1, renal transporters OCT2, OAT1, OAT3 or MATE1, or CYP or UGT1A1 enzymes. 
 
Pharmacokinetics in special populations 
 
Race and gender 
No clinically relevant pharmacokinetic differences due to race or gender have been identified for 
sofosbuvir, GS-331007, velpatasvir or voxilaprevir. 
 
Elderly 
Population pharmacokinetic analysis in HCV-infected patients showed that within the age range 
(18 to 85 years) analysed, age did not have a clinically relevant effect on the exposure to sofosbuvir, 
GS-331007, velpatasvir or voxilaprevir.  In the 13 patients aged 75 to 84 years with available 
pharmacokinetic data, mean exposure to voxilaprevir was 93% higher than the mean exposure 
observed in patients aged 18 to 64 years. 
 
Renal impairment 
A summary of the effect of varying degrees of renal impairment (RI) on the exposures of the 
components of Vosevi compared to subjects with normal renal function, as described in the text 
below, are provided in Table 15. 
 
Table 15: Effect of Varying Degrees of Renal Impairment on Exposures (AUC) of SOF, GS -
 331007, Velpatasvir and Voxilaprevir Compared to Subjects with Normal Renal Function 
 HCV-Negative Subjects HCV-Infected 

Subjects 
Mild RI 
(eGFR 

≥50 and 
<80 mL/m
in/1.73m2) 

Moderate RI 
(eGFR ≥30 

and 
<50 mL/min/

1.73m2) 

Severe RI 
(eGFR 

<30 mL/min/ 
1.73m2) 

ESRD Requiring 
Dialysis 

Severe RI 
(eGFR 

<30 mL/m
in/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↑ 



29 

 HCV-Negative Subjects HCV-Infected 
Subjects 

Mild RI 
(eGFR 

≥50 and 
<80 mL/m
in/1.73m2) 

Moderate RI 
(eGFR ≥30 

and 
<50 mL/min/

1.73m2) 

Severe RI 
(eGFR 

<30 mL/min/ 
1.73m2) 

ESRD Requiring 
Dialysis 

Severe RI 
(eGFR 

<30 mL/m
in/1.73m2) 

ESRD 
Requiring 
Dialysis Dosed 1 

hr Before 
Dialysis 

Dosed 1 
hr After 
Dialysis 

Velpatasvir - - 1.5-fold↑ - - - 1.4-fold↑ 
Voxilaprevir - - 1.7-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 were studied with a single dose of 100 mg velpatasvir in HCV 
negative patients with severe renal impairment (eGFR < 30 mL/min by Cockcroft-Gault).  
Voxilaprevir is not renally eliminated. 
 
Additionally, the pharmacokinetics of voxilaprevir were studied with a single dose of 100 mg 
voxilaprevir in HCV negative patients with severe renal impairment (eGFR < 30 mL/min by 
Cockcroft-Gault).  The pharmacokinetics of voxilaprevir have not been studied in subjects with ESRD 
requiring dialysis (see section 4.2). 
 
The pharmacokinetics of sofosbuvir, GS-331007, and velpatasvir were studied in HCV-infected 
patients with ESRD requiring dialysis treated with once daily sofosbuvir/velpatasvir 400/100 mg for 
12 weeks, and compared to patients without renal impairment in the sofosbuvir/velpatasvir Phase 2/3 
trials. 
 
Although exposures of the fixed-dose combination sofosbuvir, GS-331007, velpatasvir, and 
voxilaprevir were not directly evaluated in HCV-infected patients with ESRD requiring dialysis after 
administration of Vosevi, the exposures of sofosbuvir, GS-331007, and velpatasvir are expected to be 
similar to those observed after administration of sofosbuvir/velpatasvir 400/100 mg in HCV-infected 
patients with ESRD requiring dialysis. 
 
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 
patients with 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 (CPT Class A) had no clinically relevant effect on the exposure to sofosbuvir and 
GS-331007. 
 



30 

The pharmacokinetics of velpatasvir were studied with a single dose of 100 mg velpatasvir in HCV 
negative patients with moderate and severe hepatic impairment (CPT Class B and C).  Velpatasvir 
plasma exposure (AUCinf) was similar in patients with moderate hepatic impairment, severe hepatic 
impairment, and control subjects with normal hepatic function.  Population pharmacokinetic analysis 
in HCV-infected patients indicated that cirrhosis (CPT Class A) had no clinically relevant effect on the 
exposure of velpatasvir. 
 
The pharmacokinetics of voxilaprevir were studied with a single dose of 100 mg voxilaprevir in HCV 
negative patients with moderate and severe hepatic impairment (CPT Class B and C).  Relative to 
patients with normal hepatic function, the voxilaprevir AUCinf was 299% and 500% higher in patients 
with moderate and severe hepatic impairment, respectively.  The unbound fraction of voxilaprevir was 
approximately 2-fold higher in severe hepatic impairment compared with moderate hepatic 
impairment or normal hepatic function.  Population pharmacokinetic analysis in HCV-infected 
patients indicated that patients with cirrhosis (CPT Class A) had 73% higher exposure of voxilaprevir 
than those without cirrhosis (see section 4.2). 
 
Body weight 
Body weight did not have a clinically significant effect on sofosbuvir, velpatasvir or voxilaprevir 
exposure according to a population pharmacokinetic analysis. 
 
Paediatric population 
The pharmacokinetics of Vosevi in paediatric patients have not been established (see section 4.2). 
 
5.3 Preclinical safety data 
 
Sofosbuvir 
 
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 carcinogenic in the 2-year mouse and rat carcinogenicity studies at GS-331007 
exposures up to 17 and 10-times higher, respectively 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 26-week transgenic mouse and 2-year rat carcinogenicity 
studies at exposures up to 67- and 5-times higher than human exposure, respectively. 
 
Velpatasvir had no adverse effects on mating and fertility.  No teratogenic effects were observed in the 
mouse and rat developmental toxicity studies with velpatasvir at AUC exposures approximately 
23- and 4-fold higher, respectively, than the human exposure at the recommended clinical dose.  
However, a possible teratogenic effect was indicated in rabbits where an increase in total visceral 
malformations was seen in exposed animals at AUC exposures up to 0.5 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 3-fold higher than the human exposure 
at the recommended clinical dose. 
 



31 

Voxilaprevir 
 
Voxilaprevir 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. 
 
Carcinogenicity studies for voxilaprevir have not been conducted. 
 
Voxilaprevir had no adverse effects on mating and fertility.  No teratogenic effects were observed in 
the rat and rabbit developmental toxicity studies with voxilaprevir at AUC exposures approximately 
141- and 4-times higher, respectively, than the human exposure at the recommended clinical dose.  
Voxilaprevir had no adverse effects on behavior, reproduction, or development of the offspring in the 
rat pre- and post-natal development study at AUC exposures approximately 238-times higher than the 
human exposure at the recommended clinical dose. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
 
Colloidal anhydrous silica 
Copovidone 
Croscarmellose sodium 
Lactose monohydrate 
Magnesium stearate 
Microcrystalline cellulose 
 
Film-coating 
 
Iron oxide black (E172) 
Iron oxide red (E172) 
Iron oxide yellow (E172) 
Macrogol 
Polyvinyl alcohol 
Talc 
Titanium dioxide (E171) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
4 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special temperature storage conditions. 
Store in the original package in order to protect from moisture.  Keep the bottle tightly closed. 
 
6.5 Nature and contents of container 
 
High density polyethylene (HDPE) bottle with a polypropylene child-resistant closure containing 
28 film-coated tablets with polyester coil and a silica gel desiccant. 
 



32 

Pack size: outer carton 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/1/17/1223/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 26 July 2017 
 
 
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. 

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


33 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) 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 



34 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) 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 requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates 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 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 
Non-interventional post-authorisation safety study (PASS): 
In order to evaluate the recurrence of hepatocellular carcinoma associated with 
Vosevi, 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 



35 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



36 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



37 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
BOTTLE AND CARTON LABELLING 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Vosevi 400 mg/100 mg/100 mg film-coated tablets 
sofosbuvir/velpatasvir/voxilaprevir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 400 mg sofosbuvir, 100 mg velpatasvir and 100 mg voxilaprevir. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose.  See leaflet for further information. 
 
 
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 
 
Store in the original package in order to protect from moisture.  Keep the bottle tightly closed. 
 
 



38 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
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/1/17/1223/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Vosevi [Outer packaging only] 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
 



39 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



40 

Package leaflet: Information for the user 
 

Vosevi 400 mg/100 mg/100 mg film-coated tablets 
sofosbuvir/velpatasvir/voxilaprevir 

 
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 Vosevi is and what it is used for 
2. What you need to know before you take Vosevi 
3. How to take Vosevi 
4. Possible side effects 
5. How to store Vosevi 
6. Contents of the pack and other information 
 
 
1. What Vosevi is and what it is used for 
 
Vosevi is a medicine that contains the active substances sofosbuvir, velpatasvir and voxilaprevir in a 
single tablet.  It is given to adults of 18 years and older to treat a chronic (long-term) viral infection of 
the liver called hepatitis C. 
 
The active substances in this medicine work together by blocking three different proteins that the 
hepatitis C virus needs to grow and reproduce itself, causing the infection to be eliminated from the 
body. 
 
 
2. What you need to know before you take Vosevi 
 
Do not take Vosevi 
• If you are allergic to sofosbuvir, velpatasvir, voxilaprevir or any of the other ingredients of this 

medicine (listed in section 6 of this leaflet). 
 

If this applies to you, do not take Vosevi 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 (a herbal medicine used to treat depression); 
• carbamazepine, phenobarbital and phenytoin (medicines used to treat epilepsy and 

prevent seizures); 
• rosuvastatin (a medicine used to treat high blood cholesterol or decrease the risk of 

certain cardiovascular events); 
• dabigatran (a medicine used to prevent blood clots); 
• ethinylestradiol containing medicines, including many contraceptives. 



41 

 
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. 
• 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 Vosevi 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 Vosevi is 
needed, you may required 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 Vosevi. Some diabetic patients have 
experienced low sugar levels in the blood (hypoglycaemia) after starting treatment with 
medicines like Vosevi. 

 
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 Vosevi.  This is so that: 
• Your doctor can decide if you should take Vosevi 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 Vosevi in 
children and adolescents has not yet been studied. 
 
Other medicines and Vosevi 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
If you are not sure talk to your doctor or pharmacist. 
 
Some medicines must not be taken with Vosevi.  Taking Vosevi with any of these may stop your 
medicines from working properly, or make any side effects worse: 
• rifampicin and rifabutin (antibiotics used to treat infections, including tuberculosis); 
• St. John’s wort (a herbal medicine used to treat depression); 
• carbamazepine, phenobarbital and phenytoin (medicines used to treat epilepsy and prevent 

seizures); 
• rosuvastatin (a medicine used to treat high blood cholesterol or decrease the risk of certain 

cardiovascular events); 
• dabigatran (a medicine used to prevent blood clots); 
• ethinylestradiol containing medicines, including many contraceptives. 
 



42 

Tell your doctor or pharmacist if you are taking any of the medicines below: 
 
• amiodarone, used to treat irregular heartbeats; 
• rifapentine (an 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; 
• atazanavir, efavirenz or lopinavir, used to treat HIV infection; 
• digoxin, used to treat heart conditions; 
• modafinil, used to treat sleep disorders; 
• atorvastatin, pravastatin, or other statins, used to treat high cholesterol; 
• ciclosporin, used to suppress the immune system. 
Taking Vosevi 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. 
 
• 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 Vosevi; 
• proton pump inhibitors (such as omeprazole, lansoprazole, rabeprazole, pantoprazole and 

esomeprazole).  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; 

• 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 Vosevi 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. 
 
• Get advice from a doctor or pharmacist if you take warfarin or 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 Vosevi. 

 
Pregnancy, breast-feeding and fertility 
If you are pregnant, think you may be pregnant, are breast-feeding your baby, or are planning to have 
a baby ask your doctor for advice before taking this medicine. 
 
Pregnancy 
Vosevi is not recommended during pregnancy.  The effects of Vosevi during pregnancy are not 
known. 
 
Breast-feeding 
Do not breast-feed during treatment with Vosevi.  Some of the active substances of Vosevi may 
pass into human breast milk. 
 
Driving and using machines 
Vosevi should not affect your ability to drive or use any tools or machinery. 
 



43 

Vosevi contains lactose 
• Tell your doctor if you are lactose intolerant or intolerant to other sugars.  Vosevi 

contains lactose monohydrate.  If you are lactose intolerant, or if you have been told that you 
have an intolerance to other sugars, talk to your doctor before taking this medicine. 

 
3. How to take Vosevi 
 
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 8 or 12 weeks. 
 
Swallow the tablet whole with food.  Do not chew, crush or split the tablet as it has a very bitter taste. 
 
Kidney problems 
Tell your doctor if you have kidney problems or if you are on kidney dialysis, since Vosevi has not 
been fully tested in patients with severe kidney problems. 
 
Liver problems 
Vosevi should not be used if you have moderate or severe liver problems. 
 
If you are taking an antacid, take it at least 4 hours before or at least 4 hours after Vosevi. 
 
If you are sick (vomit) after taking Vosevi it may affect the amount of Vosevi in your blood.  This 
may make Vosevi work less well. 
• If you are sick (vomit) less than 4 hours after taking Vosevi, take another tablet. 
• If you are sick (vomit) more than 4 hours after taking Vosevi, you do not need to take another 

tablet until your next scheduled tablet. 
 
If you take more Vosevi than you should 
If you accidentally take more than the recommended dose of Vosevi you may be at increased risk of 
side effects with this medicine (see section 4 Possible side effects). 
 
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 Vosevi 
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 Vosevi: 
• If you notice within 18 hours of the time you usually take Vosevi, you must take the tablet as 

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

your usual time.  Do not take a double dose (two doses close together). 
 
Do not stop taking Vosevi 
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. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine may cause side effects, although not everybody gets them. 



44 

 
Very common side effects 
(may affect more than 1 in 10 people) 
• headache 
• diarrhoea 
• feeling sick (nausea) 
 
Common side effects 
(may affect up to 1 in 10 people) 
• stomach pain 
• decreased appetite 
• being sick (vomiting) 
• muscle pain (myalgia) 
• abnormality in a laboratory test of liver function (total bilirubin) 
• rash 
 
Uncommon side effects 
(may affect up to 1 in 100 people) 
• muscle spasms 
• 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). 
 
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 Vosevi 
 
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 temperature storage conditions.  Store in the original 
package in order to protect from moisture.  Keep the bottle tightly closed. 
 
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 Vosevi contains 
 
• The active substances are sofosbuvir, velpatasvir and voxilaprevir.  Each film-coated tablet 

contains 400 mg sofosbuvir, 100 mg velpatasvir and 100 mg voxilaprevir. 
 

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


45 

• The other ingredients are 
Tablet core: 
Colloidal anhydrous silica, copovidone, croscarmellose sodium, lactose monohydrate, 
magnesium stearate, microcrystalline cellulose 

 
Film-coating: 
Iron oxide black (E172), iron oxide red (E172), iron oxide yellow (E172), macrogol, polyvinyl 
alcohol, talc, titanium dioxide (E171) 

 
What Vosevi looks like and contents of the pack 
The film-coated tablets are beige, capsule-shaped tablets debossed with “GSI” on one side and “3” on 
the other side.  The tablet is 20 mm long and 10 mm wide. 
 
The tablets are packed in plastic bottles with child resistant caps.  Each bottle contains a silica gel 
desiccant (drying agent) that must be kept in the bottle to help protect your tablets.  The silica gel 
desiccant is contained in a separate sachet or canister and should not be swallowed. 
 
The following pack size is 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 
 



46 

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 
 

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/

	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