Sovaldi

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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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 
 
Sovaldi 400 mg film-coated tablets 
Sovaldi 200 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Sovaldi 400 mg film-coated tablets 
Each film-coated tablet contains 400 mg of sofosbuvir. 
 
Sovaldi 200 mg film-coated tablets 
Each film-coated tablet contains 200 mg of sofosbuvir. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
Sovaldi 400 mg film-coated tablets 
Yellow, capsule-shaped, film-coated tablet of dimensions of approximately 20 mm x 9 mm, debossed 
on one side with “GSI” and “7977” on the other side. 
 
Sovaldi 200 mg film-coated tablets 
Yellow, oval-shaped, film-coated tablet of dimensions of approximately 15 mm x 8 mm, debossed on 
one side with “GSI” and “200” on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Sovaldi is indicated in combination with other medicinal products for the treatment of chronic 
hepatitis C (CHC) in adults and paediatric patients aged 3 years and above (see sections 4.2, 4.4 and 
5.1). 
 
For hepatitis C virus (HCV) genotype specific activity, see sections 4.4 and 5.1. 
 
4.2 Posology and method of administration 
 
Sovaldi treatment should be initiated and monitored by a physician experienced in the management of 
patients with CHC. 
 
Posology 
 
The recommended dose of Sovaldi in adults is one 400 mg tablet, taken orally, once daily with food 
(see section 5.2). 
 
The recommended dose of Sovaldi in paediatric patients aged 3 years and above is based on weight (as 
detailed in Table 2). Sovaldi should be taken with food (see section 5.2). 



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Sovaldi oral granules are available for the treatment of chronic HCV-infection in paediatric patients 
aged 3 years and above having difficulty in swallowing film-coated tablets. Please refer to the 
Summary of Product Characteristics for Sovaldi 150 mg or 200 mg granules. 
 
Sovaldi should be used in combination with other medicinal products. Monotherapy of Sovaldi is not 
recommended (see section 5.1). Refer also to the Summary of Product Characteristics of the medicinal 
products that are used in combination with Sovaldi. The recommended co-administered medicinal 
product(s) and treatment duration for Sovaldi combination therapy are provided in Table 1. 
 
Table 1: Recommended co-administered medicinal product(s) and treatment duration for adults 
and paediatric patients treated with Sovaldi combination therapy 

Patient population* Treatment Duration 
Adult patients with 
genotype 1, 4, 5 or 6 
CHC 

Sovaldi + ribavirinc + 
peginterferon alfa 

12 weeksa,b 

Sovaldi + ribavirinc 
 
Only for use in patients ineligible or 
intolerant to peginterferon alfa (see 
section 4.4) 

24 weeks 

Adult and paediatric 
patients aged 3 years 
and above with 
genotype 2 CHC 

Sovaldid + ribavirinc, e 12 weeksb 

Adult patients with 
genotype 3 CHC 

Sovaldi + ribavirinc + 
peginterferon alfa 

12 weeksb 

Sovaldi + ribavirinc 24 weeks 
Paediatric patients aged 
3 years and above with 
genotype 3 CHC 

 
Sovaldid + ribavirine 

 
24 weeks 

Adult patients with 
CHC awaiting liver 
transplantation 

Sovaldi + ribavirinc Until liver 
transplantationf 

* Includes patients co-infected with human immunodeficiency virus (HIV). 
a. For previously treated patients with HCV genotype 1 infection, no data exists with the combination of Sovaldi, ribavirin 
and peginterferon alfa (see section 4.4). 
b. Consideration should be given to potentially extending the duration of therapy beyond 12 weeks and up to 24 weeks; 
especially for those subgroups who have one or more factors historically associated with lower response rates to 
interferon-based therapies (e.g. advanced fibrosis/cirrhosis, high baseline viral concentrations, black race, IL28B non 
CC genotype, prior null response to peginterferon alfa and ribavirin therapy). 
c. Adults: weight-based ribavirin (< 75 kg = 1,000 mg and ≥ 75 kg = 1,200 mg); administered orally in two divided doses 
with food. 
d. See Table 2 for weight-based Sovaldi dosing recommendations for paediatric patients aged 3 years and above. 
e. See Table 3 for weight-based ribavirin dosing recommendations for paediatric patients aged 3 years and above. 
f. See Special patient populations – Patients awaiting liver transplantation below. 
 
Table 2: Dosing for paediatric patients aged 3 years and above using Sovaldi tablets* 
Body Weight (kg)  Dosing of Sovaldi Tablets  Sofosbuvir Daily Dose 

 
≥ 35 one 400 mg tablet once daily  

or 
two 200 mg tablets once daily  
 

400 mg/day  
 

17 to < 35  one 200 mg tablet once daily  
 

200 mg/day  
 

*Sovaldi is also available as granules for use in paediatric patients with CHC aged 3 years and above (see section 5.1). 
Patients that weigh < 17 kg are not recommended to take tablets. Please refer to the Summary of Product Characteristics for 
Sovaldi 150 mg or 200 mg granules. 
 
In paediatric patients aged 3 years and above the following ribavirin dosing is recommended where 
ribavirin is divided into two daily doses and given with food: 
 



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Table 3: Guidance for ribavirin dosing when administered in combination with Sovaldi to HCV-
infected paediatric patients aged 3 years and above  
Body weight kg (lbs) RBV daily dose* 

< 47 (< 103) 15 mg/kg/day 

47-49 (103-108) 600 mg/day 

50-65 (110-143) 800 mg/day 

66-80 (145-176) 1000 mg/day 

> 81 (178) 1200 mg/day 
* The daily dosage of ribavirin is weight-based and is administered orally in two divided doses with food. 
 
Concerning co-administration with other direct-acting antivirals against HCV, see section 4.4. 
 
Dose modification in adults 
Dose reduction of Sovaldi is not recommended. 
 
If sofosbuvir is used in combination with peginterferon alfa, and a patient has a serious adverse 
reaction potentially related to this medicinal product, the peginterferon alfa dose should be reduced or 
discontinued. Refer to the peginterferon alfa Summary of Product Characteristics for additional 
information about how to reduce and/or discontinue the peginterferon alfa dose. 
 
If a patient has a serious adverse reaction potentially related to ribavirin, the ribavirin dose should be 
modified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity. 
Table 4 provides guidelines for dose modifications and discontinuation based on the patient’s 
haemoglobin concentration and cardiac status. 
 
Table 4: Ribavirin dose modification guideline for co-administration with Sovaldi in adults 

Laboratory values Reduce ribavirin dose to 
600 mg/day if: 

Discontinue ribavirin if: 

Haemoglobin in patients with no 
cardiac disease 

<10 g/dL <8.5 g/dL 

Haemoglobin in patients with 
history of stable cardiac disease 

≥2 g/dL decrease in haemoglobin 
during any 4 week treatment 
period 

<12 g/dL despite 4 weeks at 
reduced dose 

 
Once ribavirin has been withheld due to either a laboratory abnormality or clinical manifestation, an 
attempt may be made to restart ribavirin at 600 mg daily and further increase the dose to 800 mg daily. 
However, it is not recommended that ribavirin be increased to the original assigned dose (1,000 mg to 
1,200 mg daily). 
 
Dose modification in paediatric patients aged 3 years and above 
Dose reduction of Sovaldi is not recommended. 
 
If a patient has a serious adverse reaction potentially related to ribavirin, the ribavirin dose should be 
modified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity. 
Refer to the ribavirin prescribing information for guidance on dose modification or discontinuation. 
 
Discontinuation of dosing  
If the other medicinal products used in combination with Sovaldi are permanently discontinued, 
Sovaldi should also be discontinued (see section 4.4). 
 
Vomiting and missed doses 
Patients should be instructed that if vomiting occurs within 2 hours of dosing an additional dose 
should be taken. If vomiting occurs more than 2 hours after dosing, no further dose is needed. These 



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recommendations are based on the absorption kinetics of sofosbuvir and GS-331007 suggesting that 
the majority of the dose is absorbed within 2 hours after dosing. 
 
If a dose is missed and it is within 18 hours of the normal time, patients should be instructed to take 
the dose 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 at the usual time. Patients 
should be instructed not to take a double dose. 
 
Special patient populations 
 
Elderly 
No dose adjustment is warranted for elderly patients (see section 5.2). 
 
Renal impairment 
No dose adjustment of Sovaldi 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. Sovaldi 
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 Sovaldi is required for patients with mild, moderate or severe hepatic 
impairment (Child-Pugh-Turcotte [CPT] class A, B or C) (see section 5.2). The safety and efficacy of 
Sovaldi have not been established in patients with decompensated cirrhosis. 
 
Patients awaiting liver transplantation 
The duration of administration of Sovaldi in patients awaiting liver transplantation should be guided 
by an assessment of the potential benefits and risks for the individual patient (see section 5.1). 
 
Adult liver transplant recipients 
Sovaldi in combination with ribavirin is recommended for 24 weeks in liver transplant recipients. In 
adults a starting ribavirin dose of 400 mg administered orally in two divided doses with food is 
recommended. If the starting dose of ribavirin is well-tolerated, the dose can be titrated up to a 
maximum of 1,000-1,200 mg daily (1,000 mg for patients weighing <75 kg and 1,200 mg for patients 
weighing ≥75 kg). If the starting dose of ribavirin is not well-tolerated, the dose should be reduced as 
clinically indicated based on haemoglobin levels (see section 5.1). 
 
Paediatric population aged < 3 years 
The safety and efficacy of Sovaldi in children aged <3 years have not yet been established. No data are 
available. 
 
Method of administration 
 
Oral use. 
 
Patients should be instructed to swallow the tablet(s) whole. The film-coated tablet(s) should not be 
chewed or crushed, due to the bitter taste of the active substance. The tablet(s) should be taken with 
food (see section 5.2). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  
 
Medicinal products that are strong P-glycoprotein (P-gp) inducers in the intestine (carbamazepine, 
phenobarbital, phenytoin, rifampicin and St. John’s wort). Co-administration will significantly 



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decrease sofosbuvir plasma concentration and could result in loss of efficacy of Sovaldi (see 
section 4.5). 
 
4.4 Special warnings and precautions for use 
 
General 
 
Sovaldi is not recommended for administration as monotherapy and should be prescribed in 
combination with other medicinal products for the treatment of hepatitis C infection. If the other 
medicinal products used in combination with Sovaldi are permanently discontinued, Sovaldi should 
also be discontinued (see section 4.2). Consult the Summary of Product Characteristics for 
co-prescribed medicinal products before starting therapy with Sovaldi. 
 
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 Sovaldi 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 Sovaldi. 
 
All patients with concurrent or recent use of amiodarone should be warned of the symptoms of 
bradycardia and heart block and should be advised to seek medical advice urgently should they 
experience them. 
 
HCV/HBV (hepatitis B virus) co-infection 
 
Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after 
treatment with direct-acting antiviral agents. HBV screening should be performed in all patients before 
initiation of treatment. HBV/HCV co-infected patients are at risk of HBV reactivation, and should 
therefore be monitored and managed according to current clinical guidelines. 
 
Treatment-experienced patients with genotype 1, 4, 5 and 6 HCV infection 
 
Sovaldi has not been studied in a Phase 3 study in treatment-experienced patients with genotype 1, 4, 5 
and 6 HCV infection. Thus, the optimal treatment duration in this population has not been established 
(see also sections 4.2 and 5.1). 
 
Consideration should be given to treating these patients, and potentially extending the duration of 
therapy with sofosbuvir, peginterferon alfa and ribavirin beyond 12 weeks and up to 24 weeks; 
especially for those subgroups who have one or more factors historically associated with lower 
response rates to interferon-based therapies (advanced fibrosis/cirrhosis, high baseline viral 
concentrations, black race, IL28B non CC genotype). 
 



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Treatment of patients with genotype 5 or 6 HCV infection 
 
The clinical data to support the use of Sovaldi in patients with genotype 5 and 6 HCV infection is very 
limited (see section 5.1). 
 
Interferon-free therapy for genotype 1, 4, 5 and 6 HCV infection 
 
Interferon-free regimens for patients with genotype 1, 4, 5 and 6 HCV infection with Sovaldi have not 
been investigated in Phase 3 studies (see section 5.1). The optimal regimen and treatment duration 
have not been established. Such regimens should only be used for patients that are intolerant to or 
ineligible for interferon therapy, and are in urgent need of treatment. 
 
Co-administration with other direct-acting antivirals against HCV 
 
Sovaldi should only be co-administered with other direct-acting antiviral medicinal products if the 
benefit is considered to outweigh the risks based upon available data. There are no data to support the 
co-administration of Sovaldi and telaprevir or boceprevir. Such co-administration is not recommended 
(see also section 4.5). 
 
Pregnancy and concomitant use with ribavirin 
 
When Sovaldi is used in combination with ribavirin or peginterferon alfa/ribavirin, women of 
childbearing potential or their male partners must use an effective form of contraception during the 
treatment and for a period of time after the treatment as recommended in the Summary of Product 
Characteristics for ribavirin. Refer to the Summary of Product Characteristics for ribavirin for 
additional information. 
 
Use with moderate P-gp inducers 
 
Medicinal products that are moderate P-gp inducers in the intestine (e.g. modafinil, oxcarbazepine and 
rifapentine) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of 
Sovaldi. Co-administration of such medicinal products is not recommended with Sovaldi (see 
section 4.5). 
 
Use in diabetic patients  
 
Diabetics may experience improved glucose control, potentially resulting in symptomatic 
hypoglycaemia, after initiating HCV direct-acting antiviral treatment. Glucose levels of diabetic 
patients initiating direct-acting antiviral therapy should be closely monitored, particularly within the 
first 3 months, and their diabetic medication modified when necessary. The physician in charge of the 
diabetic care of the patient should be informed when direct-acting antiviral therapy is initiated. 
 
Renal impairment 
 
Safety data are limited in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2) and 
ESRD requiring haemodialysis. Sovaldi can be used in these patients with no dose adjustment when 
no other relevant treatment options are available (see sections 4.8, 5.1 and 5.2). When Sovaldi is used 
in combination with ribavirin or peginterferon alfa/ribavirin, refer also to the Summary of Product 
Characteristics for ribavirin for patients with creatinine clearance (CrCl) <50 mL/min (see also 
section 5.2). 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Sofosbuvir is a nucleotide prodrug. After oral administration of Sovaldi, sofosbuvir is rapidly 
absorbed and subject to extensive first-pass hepatic and intestinal metabolism. Intracellular hydrolytic 
prodrug cleavage catalysed by enzymes including carboxylesterase 1 and sequential phosphorylation 
steps catalysed by nucleotide kinases result in formation of the pharmacologically active uridine 



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nucleoside analogue triphosphate. The predominant inactive circulating metabolite GS-331007 that 
accounts for greater than 90% of drug-related material systemic exposure is formed through pathways 
sequential and parallel to formation of active metabolite. The parent sofosbuvir accounts for 
approximately 4% of drug-related material systemic exposure (see section 5.2). In clinical 
pharmacology studies, both sofosbuvir and GS-331007 were monitored for purposes of 
pharmacokinetic analyses. 
 
Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while 
GS-331007 is not. 
 
Medicinal products that are strong P-gp inducers in the intestine (carbamazepine, phenobarbital, 
phenytoin, rifampicin and St. John’s wort) may significantly decrease sofosbuvir plasma concentration 
leading to reduced therapeutic effect of Sovaldi and thus are contraindicated with Sovaldi (see 
section 4.3). Medicinal products that are moderate P-gp inducers in the intestine (e.g. modafinil, 
oxcarbazepine and rifapentine) may decrease sofosbuvir plasma concentration leading to reduced 
therapeutic effect of Sovaldi. Co-administration with such medicinal products is not recommended 
with Sovaldi (see section 4.4). Co-administration of Sovaldi with medicinal products that inhibit P-gp 
and/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasma 
concentration, thus Sovaldi may be co-administered with P-gp and/or BCRP inhibitors. Sofosbuvir and 
GS-331007 are not inhibitors of P-gp and BCRP and thus are not expected to increase exposures of 
medicinal products that are substrates of these transporters. 
 
The intracellular metabolic activation pathway of sofosbuvir is mediated by generally low affinity and 
high capacity hydrolase and nucleotide phosphorylation pathways that are unlikely to be affected by 
concomitant medicinal products (see section 5.2). 
 
Patients treated with vitamin K antagonists 
 
As liver function may change during treatment with Sovaldi, a close monitoring of International 
Normalised Ratio (INR) values is recommended. 
 
Impact of DAA therapy on drugs metabolized by the liver 
 
The pharmacokinetics of drugs that are metabolized by the liver (e.g. immunosuppressive agents such 
as calcineurin inhibitors) may be impacted by changes in liver function during DAA therapy, related to 
clearance of HCV. 
 
Other interactions 
 
Drug interaction information for Sovaldi with potential concomitant medicinal products is summarised 
in Table 5 below (where 90% confidence interval (CI) of the geometric least-squares mean (GLSM) 
ratio were within “↔”, extended above “↑”, or extended below “↓” the predetermined equivalence 
boundaries). The table is not all-inclusive. 
 
Table 5: Interactions between Sovaldi and other medicinal products 
Medicinal product by 

therapeutic areas 
Effects on drug levels. 

Mean ratio (90% 
confidence interval) for 

AUC, Cmax, Cmina,b 

Recommendation concerning co-administration 
with Sovaldi 

ANALEPTICS 
Modafinil Interaction not studied. 

Expected: 
↓ Sofosbuvir 
↔ GS-331007 
 
(Induction of P-gp) 

Co-administration of Sovaldi with modafinil is 
expected to decrease the concentration of 
sofosbuvir, leading to reduced therapeutic effect of 
Sovaldi. Such co-administration is not 
recommended. 



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Medicinal product by 
therapeutic areas 

Effects on drug levels. 
Mean ratio (90% 

confidence interval) for 
AUC, Cmax, Cmina,b 

Recommendation concerning co-administration 
with Sovaldi 

ANTIARRHYTHMICS 
Amiodarone Effect on amiodarone 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 Sovaldi (see 
sections 4.4 and 4.8). 

ANTICOAGULANTS 
Vitamin K antagonists Interaction not studied Close monitoring of INR is recommended with all 

vitamin K antagonists. This is due to liver function 
changes during treatment with Sovaldi. 

ANTICONVULSANTS 
Phenobarbital 
Phenytoin 

Interaction not studied. 
Expected: 
↓ Sofosbuvir 
↔ GS-331007 
 
(Induction of P-gp) 

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

Carbamazepine Sofosbuvir 
↓ Cmax 0.52 (0.43, 0.62) 
↓ AUC 0.52 (0.46, 0.59) 
Cmin (NA) 
 
GS 331007 
↔ Cmax 1.04 (0.97, 1.11) 
↔ AUC 0.99 (0.94, 1.04) 
Cmin (NA) 
 
(Induction of P-gp) 

Sovaldi is contraindicated with carbamazepine (see 
section 4.3). 

Oxcarbazepine Interaction not studied. 
Expected: 
↓ Sofosbuvir 
↔ GS-331007 
 
(Induction of P-gp) 

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

ANTIMYCOBACTERIALS 
Rifampicinf 
(600 mg single dose) 

Sofosbuvir 
↓ Cmax 0.23 (0.19, 0.29) 
↓ AUC 0.28 (0.24, 0.32) 
Cmin (NA) 
 
GS-331007 
↔ Cmax 1.23 (1.14, 1.34) 
↔ AUC 0.95 (0.88, 1.03) 
Cmin (NA) 
 
(Induction of P-gp) 

Sovaldi is contraindicated with rifampicin (see 
section 4.3). 



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Medicinal product by 
therapeutic areas 

Effects on drug levels. 
Mean ratio (90% 

confidence interval) for 
AUC, Cmax, Cmina,b 

Recommendation concerning co-administration 
with Sovaldi 

Rifabutin Sofosbuvir 
↓ Cmax 0.64 (0.53, 0.77) 
↓ AUC 0.76 (0.63, 0.91) 
Cmin (NA) 
 
GS 331007 
↔ Cmax 1.15 (1.03, 1.27) 
↔ AUC 1.03 (0.95, 1.12) 
Cmin (NA) 
 
(Induction of P-gp) 

No dose adjustment of Sovaldi is required when 
concomitantly used with rifabutin. 

Rifapentine Interaction not studied. 
Expected: 
↓ Sofosbuvir 
↔ GS-331007 
 
(Induction of P-gp) 

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

HERBAL SUPPLEMENTS 
St. John’s wort Interaction not studied. 

Expected: 
↓ Sofosbuvir 
↔ GS-331007 
 
(Induction of P-gp) 

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

HCV ANITIVIRAL AGENTS: HCV PROTEASE INHIBITORS 
Boceprevir (BOC) 
Telaprevir (TPV) 

Interaction not studied. 
Expected: 
↑ Sofosbuvir (TPV) 
↔ Sofosbuvir (BOC) 
↔ GS-331007 (TPV or 
BOC) 

No drug-drug interaction data exists regarding the 
co-administration of Sovaldi with boceprevir or 
telaprevir. 

NARCOTIC ANALGESICS 
Methadonef 
(Methadone 
maintenance therapy 
[30 to 130 mg/daily]) 

R-methadone 
↔ Cmax 0.99 (0.85, 1.16) 
↔ AUC 1.01 (0.85, 1.21) 
↔ Cmin 0.94 (0.77, 1.14) 
 
S-methadone 
↔ Cmax 0.95 (0.79, 1.13) 
↔ AUC 0.95 (0.77, 1.17) 
↔ Cmin 0.95 (0.74, 1.22) 
 
Sofosbuvir 
↓ Cmax 0.95c (0.68, 1.33) 
↑ AUC 1.30c (1.00, 1.69) 
Cmin (NA) 
 
GS-331007 
↓ Cmax 0.73c (0.65, 0.83) 
↔ AUC 1.04c (0.89, 1.22) 
Cmin (NA) 

No dose adjustment of sofosbuvir or methadone is 
required when sofosbuvir and methadone are used 
concomitantly. 



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Medicinal product by 
therapeutic areas 

Effects on drug levels. 
Mean ratio (90% 

confidence interval) for 
AUC, Cmax, Cmina,b 

Recommendation concerning co-administration 
with Sovaldi 

IMMUNOSUPPRESSANTS 
Ciclosporine 
(600 mg single dose) 

Ciclosporin 
↔ Cmax 1.06 (0.94, 1.18) 
↔ AUC 0.98 (0.85, 1.14) 
Cmin (NA) 
 
Sofosbuvir 
↑ Cmax 2.54 (1.87, 3.45) 
↑ AUC 4.53 (3.26, 6.30) 
Cmin (NA) 
 
GS-331007 
↓ Cmax 0.60 (0.53, 0.69) 
↔ AUC 1.04 (0.90, 1.20) 
Cmin (NA) 

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

Tacrolimuse 
(5 mg single dose) 

Tacrolimus 
↓ Cmax 0.73 (0.59, 0.90) 
↔ AUC 1.09 (0.84, 1.40) 
Cmin (NA) 
 
Sofosbuvir 
↓ Cmax 0.97 (0.65, 1.43) 
↑ AUC 1.13 (0.81, 1.57) 
Cmin (NA) 
 
GS-331007 
↔ Cmax 0.97 (0.83, 1.14) 
↔ AUC 1.00 (0.87, 1.13) 
Cmin (NA) 

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

HIV ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS 
Efavirenzf 
(600 mg once daily)d 

Efavirenz 
↔ Cmax 0.95 (0.85, 1.06) 
↔ AUC 0.96 (0.91, 1.03) 
↔ Cmin 0.96 (0.93, 0.98) 
 
Sofosbuvir 
↓ Cmax 0.81 (0.60, 1.10) 
↔ AUC 0.94 (0.76, 1.16) 
Cmin (NA) 
 
GS-331007 
↓ Cmax 0.77 (0.70, 0.84) 
↔ AUC 0.84 (0.76, 0.92) 
Cmin (NA) 

No dose adjustment of sofosbuvir or efavirenz is 
required when sofosbuvir and efavirenz are used 
concomitantly. 

Emtricitabinef 
(200 mg once daily)d 

Emtricitabine 
↔ Cmax 0.97 (0.88, 1.07) 
↔ AUC 0.99 (0.94, 1.05) 
↔ Cmin 1.04 (0.98, 1.11) 
 
Sofosbuvir 
↓ Cmax 0.81 (0.60, 1.10) 
↔ AUC 0.94 (0.76, 1.16) 
Cmin (NA) 
 
GS-331007 
↓ Cmax 0.77 (0.70, 0.84) 
↔ AUC 0.84 (0.76, 0.92) 
Cmin (NA) 

No dose adjustment of sofosbuvir or emtricitabine 
is required when sofosbuvir and emtricitabine are 
used concomitantly. 



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Medicinal product by 
therapeutic areas 

Effects on drug levels. 
Mean ratio (90% 

confidence interval) for 
AUC, Cmax, Cmina,b 

Recommendation concerning co-administration 
with Sovaldi 

Tenofovir disoproxilf 
(245 mg once daily)d 

Tenofovir 
↑ Cmax 1.25 (1.08, 1.45) 
↔ AUC 0.98 (0.91, 1.05) 
↔ Cmin 0.99 (0.91, 1.07) 
 
Sofosbuvir 
↓ Cmax 0.81 (0.60, 1.10) 
↔ AUC 0.94 (0.76, 1.16) 
Cmin (NA) 
 
GS-331007 
↓ Cmax 0.77 (0.70, 0.84) 
↔ AUC 0.84 (0.76, 0.92) 
Cmin (NA) 

No dose adjustment of sofosbuvir or tenofovir 
disoproxil is required when sofosbuvir and 
tenofovir disoproxil are used concomitantly. 

Rilpivirinef 
(25 mg once daily) 

Rilpivirine 
↔ Cmax 1.05 (0.97, 1.15) 
↔ AUC 1.06 (1.02, 1.09) 
↔ Cmin 0.99 (0.94, 1.04) 
 
Sofosbuvir 
↑ Cmax 1.21 (0.90, 1.62) 
↔ AUC 1.09 (0.94, 1.27) 
Cmin (NA) 
 
GS-331007 
↔ Cmax 1.06 (0.99, 1.14) 
↔ AUC 1.01 (0.97, 1.04) 
Cmin (NA) 

No dose adjustment of sofosbuvir or rilpivirine is 
required when sofosbuvir and rilpivirine are used 
concomitantly. 

HIV ANTIVIRAL AGENTS: HIV PROTEASE INHIBITORS 
Darunavir boosted with 
ritonavirf 
(800/100 mg once 
daily) 

Darunavir 
↔ Cmax 0.97 (0.94, 1.01) 
↔ AUC 0.97 (0.94, 1.00) 
↔ Cmin 0.86 (0.78, 0.96) 
 
Sofosbuvir 
↑ Cmax 1.45 (1.10, 1.92) 
↑ AUC 1.34 (1.12, 1.59) 
Cmin (NA) 
 
GS-331007 
↔ Cmax 0.97 (0.90, 1.05) 
↔ AUC 1.24 (1.18, 1.30) 
Cmin (NA) 

No dose adjustment of sofosbuvir or darunavir 
(ritonavir boosted) is required when sofosbuvir and 
darunavir are used concomitantly. 

HIV ANTIVIRAL AGENTS: INTEGRASE INHIBITORS 
Raltegravirf 
(400 mg twice daily) 

Raltegravir 
↓ Cmax 0.57 (0.44, 0.75) 
↓ AUC 0.73 (0.59, 0.91) 
↔ Cmin 0.95 (0.81, 1.12) 
 
Sofosbuvir 
↔ Cmax 0.87 (0.71, 1.08) 
↔ AUC 0.95 (0.82, 1.09) 
Cmin (NA) 
 
GS-331007 
↔ Cmax 1.09 (0.99, 1.20) 
↔ AUC 1.03 (0.97, 1.08) 
Cmin (NA) 

No dose adjustment of sofosbuvir or raltegravir is 
required when sofosbuvir and raltegravir are used 
concomitantly. 



13 

Medicinal product by 
therapeutic areas 

Effects on drug levels. 
Mean ratio (90% 

confidence interval) for 
AUC, Cmax, Cmina,b 

Recommendation concerning co-administration 
with Sovaldi 

ORAL CONTRACEPTIVES 
Norgestimate/ethinyl 
estradiol 

Norgestromin 
↔ Cmax 1.06 (0.93, 1.22) 
↔ AUC 1.05 (0.92, 1.20) 
Cmin (NA) 
 
Norgestrel 
↔ Cmax 1.18 (0.99, 1.41) 
↔ AUC 1.19 (0.98, 1.44) 
Cmin (NA) 
 
Ethinyl estradiol 
↔ Cmax 1.14 (0.96, 1.36) 
↔ AUC 1.08 (0.93, 1.25) 
Cmin (NA) 

No dose adjustment of norgestimate/ethinyl 
estradiol is required when sofosbuvir and 
norgestimate/ethinyl estradiol are used 
concomitantly. 

NA = not available/not applicable 
a. Mean ratio (90% CI) of co-administered drug pharmacokinetics with/without sofosbuvir and mean ratio of sofosbuvir and 
GS-331007 with/without co-administered drug. No effect = 1.00 
b. All interaction studies conducted in healthy volunteers 
c. Comparison based on historical control 
d. Administered as Atripla 
e. Bioequivalence boundary 80%-125% 
f. Equivalence boundary 70%-143% 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential / contraception in males and females 
 
When Sovaldi is used in combination with ribavirin or peginterferon alfa/ribavirin, extreme care must 
be taken to avoid pregnancy in female patients and in female partners of male patients. Significant 
teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to 
ribavirin (see section 4.4). Women of childbearing potential or their male partners must use an 
effective form of contraception during treatment and for a period of time after the treatment has 
concluded as recommended in the Summary of Product Characteristics for ribavirin. Refer to the 
Summary of Product Characteristics for ribavirin for additional information. 
 
Pregnancy 
 
There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of sofosbuvir 
in pregnant women. 
 
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. 
No effects on foetal development have been observed in rats and rabbits at the highest doses tested. 
However, 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). 
 
As a precautionary measure, it is preferable to avoid the use of Sovaldi during pregnancy. 
 
However, if ribavirin is co-administered with sofosbuvir, the contraindications regarding use of 
ribavirin during pregnancy apply (see also the Summary of Product Characteristics for ribavirin). 
 
Breast-feeding 
 
It is unknown whether sofosbuvir and its metabolites are excreted in human milk. 
 



14 

Available pharmacokinetic data in animals have shown excretion of metabolites in milk (for details 
see section 5.3). 
 
A risk to newborns/infants cannot be excluded. Therefore, Sovaldi should not be used during 
breast-feeding. 
 
Fertility 
 
No human data on the effect of Sovaldi on fertility are available. Animal studies do not indicate 
harmful effects on fertility. 
 
4.7 Effects on ability to drive and use machines 
 
Sovaldi has moderate influence on the ability to drive and use machines. Patients should be informed 
that fatigue and disturbance in attention, dizziness and blurred vision have been reported during 
treatment with sofosbuvir in combination with peginterferon alfa and ribavirin (see section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile in adults 
 
Assessment of adverse reactions is based on pooled data from five Phase 3 clinical studies (both 
controlled and uncontrolled). 
 
Sovaldi has been studied in combination with ribavirin, with or without peginterferon alfa. In this 
context, no adverse drug reactions specific to sofosbuvir have been identified. The most common 
adverse drug reactions occurring in patients receiving sofosbuvir and ribavirin or sofosbuvir, ribavirin 
and peginterferon alfa were fatigue, headache, nausea and insomnia. 
 
Tabulated summary of adverse reactions 
 
The following adverse drug reactions have been identified with sofosbuvir in combination with 
ribavirin or in combination with peginterferon alfa and ribavirin (Table 6). The adverse reactions are 
listed below by body system organ class and frequency. Frequencies are defined as follows: very 
common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to 
<1/1,000) or very rare (<1/10,000). 
 
Table 6: Adverse drug reactions identified with sofosbuvir in combination with ribavirin or 
peginterferon alfa and ribavirin 

Frequency SOFa + RBVb SOF + PEGc + RBV 
Infections and infestations: 
Common nasopharyngitis  
Blood and lymphatic system disorders: 
Very common haemoglobin decreased anaemia, neutropenia, lymphocyte count 

decreased, platelet count decreased 
Common anaemia  
Metabolism and nutrition disorders: 
Very common decreased appetited decreased appetite 
Common  weight decreased 
Psychiatric disorders: 
Very common insomnia insomnia 
Common depression depression, anxiety, agitation 
Nervous system disorders: 
Very common headache dizziness, headache 
Common disturbance in attention migraine, memory impairment, 

disturbance in attention 
Eye disorders: 
Common  vision blurred 



15 

Respiratory, thoracic and mediastinal disorders: 
Very common  dyspnoea, cough 
Common dyspnoea, dyspnoea 

exertional, cough 
dyspnoea exertional 

Gastrointestinal disorders: 
Very common nausea diarrhoea, nausea, vomiting 
Common abdominal discomfort, 

constipation, dyspepsia 
constipation, dry mouth, 
gastroesophageal reflux 

Hepatobiliary disorders: 
Very common blood bilirubin increased blood bilirubin increased 
Skin and subcutaneous tissue disorders: 
Very common  rash, pruritus 
Common alopecia, dry skin, pruritus alopecia, dry skin 
Musculoskeletal and connective tissue disorders: 
Very common  arthralgia, myalgia 
Common arthralgia, back pain, 

muscle spasms, myalgia 
back pain, muscle spasms 

General disorders and administration site conditions: 
Very common fatigue, irritability chills, fatigue, influenza-like illness, 

irritability, pain, pyrexia 
Common pyrexia, asthenia chest pain, asthenia 
a. SOF = sofosbuvir; b. RBV = ribavirin; c. PEG = peginterferon alfa; d. Decreased appetite was identified as an adverse drug 
reaction to Sovaldi in combination with ribavirin oral solution in paediatric patients aged 3 to < 12 years 
 
Description of selected adverse reactions 
 
Cardiac arrhythmias 
Cases of severe bradycardia and heart block have been observed when sofosbuvir containing-regimes 
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 
 
Other special population(s) 
 
HIV/HCV co-infection 
The safety profile of sofosbuvir and ribavirin in HCV/HIV co-infected adult patients was similar to 
that observed in mono-infected HCV patients treated with sofosbuvir and ribavirin in Phase 3 clinical 
studies (see section 5.1). 
 
Patients awaiting liver transplantation 
The safety profile of sofosbuvir and ribavirin in HCV infected adult patients prior to liver 
transplantation was similar to that observed in patients treated with sofosbuvir and ribavirin in Phase 3 
clinical studies (see section 5.1). 
 
Patients with Renal Impairment  
Sofosbuvir in a fixed dose combination with ledipasvir was administered for 12 weeks to 18 patients 
with genotype 1 CHC and severe renal impairment in an open-label study (Study 0154). 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. 
 
Adult liver transplant recipients 
The safety profile of sofosbuvir and ribavirin in liver transplant adult recipients with chronic 
hepatitis C was similar to that observed in patients treated with sofosbuvir and ribavirin in Phase 3 
clinical studies (see section 5.1). In study 0126, decreases in haemoglobin during treatment were very 



16 

common with 32.5% (13/40 patients) experiencing a decline in haemoglobin to <10 g/dL, 1 of whom 
also had a decline to <8.5 g/dL. Eight patients (20%) received epoetin and/or a blood product. In 
5 patients (12.5%), study drugs were discontinued, modified or interrupted due to adverse events. 
 
Paediatric population 
The safety and efficacy of Sovaldi in paediatric patients aged 3 years and above are based on data 
from 106 patients who were treated with Sovaldi and ribavirin for 12 weeks (genotype 2 patients) and 
for 24 weeks (genotype 3 patients) in a Phase 2, open-label clinical trial. No adverse drug reactions 
specific to Sovaldi have been identified. The adverse reactions observed were generally consistent 
with those observed in clinical studies of Sovaldi plus ribavirin in adults (see Table 6). Decreased 
appetite was observed as a very common adverse drug reaction to Sovaldi when given in combination 
with ribavirin oral solution in paediatric patients aged 3 to < 12 years. 
 
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 dose of sofosbuvir was a single supratherapeutic dose of sofosbuvir 1,200 mg 
administered to 59 healthy subjects. In that study, there were no untoward effects observed at this dose 
level, and adverse reactions were similar in frequency and severity to those reported in the placebo and 
sofosbuvir 400 mg treatment groups. The effects of higher doses are unknown. 
 
No specific antidote is available for overdose with Sovaldi. If overdose occurs the patient must be 
monitored for evidence of toxicity. Treatment of overdose with Sovaldi 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 (53% extraction ratio) the predominant circulating metabolite 
GS-331007. A 4-hour haemodialysis session removed 18% of the administered dose. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antivirals for systemic use, direct-acting antiviral; ATC code: J05AP08 
 
Mechanism of action 
 
Sofosbuvir is a pan-genotypic inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is 
essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular 
metabolism to form the pharmacologically active uridine analog 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 with a 50% inhibitory concentration (IC50) value ranging from 0.7 to 
2.6 μM. GS-461203 (the active metabolite of sofosbuvir) is not an inhibitor of human DNA and 
RNA polymerases nor an inhibitor of mitochondrial RNA polymerase. 
 
Antiviral activity 
 
In HCV replicon assays, the effective concentration (EC50) values of sofosbuvir against full-length 
replicons from genotype 1a, 1b, 2a, 3a and 4a were 0.04, 0.11, 0.05, 0.05 and 0.04 μM, respectively, 
and EC50 values of sofosbuvir against chimeric 1b replicons encoding NS5B from genotype 2b, 5a or 
6a were 0.014 to 0.015 μM. The mean ± SD EC50 of sofosbuvir against chimeric replicons encoding 

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


17 

NS5B sequences from clinical isolates was 0.068 ± 0.024 μM for genotype 1a (n = 67), 
0.11 ± 0.029 μM for genotype 1b (n = 29), 0.035 ± 0.018 μM for genotype 2 (n = 15) and 
0.085 ± 0.034 μM for genotype 3a (n = 106). In these assays, the in vitro antiviral activity of 
sofosbuvir against the less common genotypes 4, 5 and 6 was similar to that observed for genotypes 1, 
2 and 3. 
 
The presence of 40% human serum had no effect on the anti-HCV activity of sofosbuvir. 
 
Resistance 
 
In cell culture 
HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple 
genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced susceptibility to sofosbuvir was associated 
with the primary NS5B substitution S282T in all replicon genotypes examined. Site-directed 
mutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2- to 18-fold reduced 
susceptibility to sofosbuvir and reduced the replication viral capacity by 89% to 99% compared to the 
corresponding wild-type. In biochemical assays, recombinant NS5B polymerase from genotypes 1b, 
2a, 3a and 4a expressing the S282T substitution showed reduced susceptibility to GS-461203 
compared to respective wild-types. 
 
In clinical studies - Adults 
In a pooled analysis of 991 patients who received sofosbuvir in Phase 3 studies, 226 patients qualified 
for resistance analysis due to virologic failure or early study drug discontinuation and having 
HCV RNA >1,000 IU/mL. Post-baseline NS5B sequences were available for 225 of the 226 patients, 
with deep sequencing data (assay cutoff of 1%) from 221 of these patients. The sofosbuvir-associated 
resistance substitution S282T was not detected in any of these patients by deep sequencing or 
population sequencing. The S282T substitution in NS5B was detected in a single subject receiving 
Sovaldi monotherapy in a Phase 2 study. This subject harboured <1% HCV S282T at baseline and 
developed S282T (>99%) at 4 weeks post-treatment which resulted in a 13.5-fold change in sofosbuvir 
EC50 and reduced viral replication capacity. The S282T substitution reverted to wild-type over the next 
8 weeks and was no longer detectable by deep sequencing at 12 weeks post-treatment. 
 
Two NS5B substitutions, L159F and V321A, were detected in post-treatment relapse samples from 
multiple genotype 3 HCV infected patients in the Phase 3 clinical studies. No shift in the phenotypic 
susceptibility to sofosbuvir or ribavirin of subject isolates with these substitutions was detected. In 
addition, S282R and L320F substitutions were detected on treatment by deep sequencing in a 
pre-transplant subject with a partial treatment response. The clinical significance of these findings is 
unknown. 
 
Effect of baseline HCV polymorphisms on treatment outcome 
 
Adult population 
Baseline NS5B sequences were obtained for 1,292 patients from Phase 3 studies by population 
sequencing and the S282T substitution was not detected in any subject with available baseline 
sequence. In an analysis evaluating the effect of baseline polymorphisms on treatment outcome, no 
statistically significant association was observed between the presence of any HCV NS5B variant at 
baseline and treatment outcome. 
 
Paediatric population 
The presence of NS5B RAVs did not impact treatment outcome; all patients with baseline NS5B 
nucleoside inhibitor RAVs achieved SVR following treatment with sofosbuvir. 
 
Cross-resistance 
 
HCV replicons expressing the sofosbuvir-associated resistance substitution S282T were fully 
susceptible to other classes of anti-HCV agents. Sofosbuvir retained activity against the 
NS5B substitutions L159F and L320F associated with resistance to other nucleoside inhibitors. 



18 

Sofosbuvir was fully active against substitutions associated with resistance to other direct-acting 
antivirals with different mechanisms of actions, such as NS5B non-nucleoside inhibitors, NS3 protease 
inhibitors and NS5A inhibitors. 
 
Clinical efficacy and safety 
 
The efficacy of sofosbuvir was evaluated in five Phase 3 studies in a total of 1,568 adult patients with 
genotypes 1 to 6 chronic hepatitis C. One study was conducted in treatment-naïve patients with 
genotype 1, 4, 5 or 6 chronic hepatitis C in combination with peginterferon alfa 2a and ribavirin and 
the other four studies were conducted in patients with genotype 2 or 3 chronic hepatitis C in 
combination with ribavirin including one in treatment-naïve patients, one in interferon intolerant, 
ineligible or unwilling patients, one in patients previously treated with an interferon-based regimen, 
and one in all patients irrespective of prior treatment history or ability to receive treatment with 
interferon. Patients in these studies had compensated liver disease including cirrhosis. Sofosbuvir was 
administered at a dose of 400 mg once daily. The ribavirin dose was weight-based at 1,000-1,200 mg 
daily administered in two divided doses, and the peginterferon alfa 2a dose, where applicable, was 
180 μg per week. Treatment duration was fixed in each study and was not guided by patients’ 
HCV RNA levels (no response guided algorithm). 
 
Plasma HCV RNA values were measured during the clinical studies using the COBAS TaqMan 
HCV test (version 2.0), for use with the High Pure System. The assay had a lower limit of 
quantification (LLOQ) of 25 IU/mL. Sustained virologic response (SVR) was the primary endpoint to 
determine the HCV cure rate for all studies which was defined as HCV RNA less than LLOQ at 
12 weeks after the end of treatment (SVR12). 
 
Clinical studies in patients with genotype 1, 4, 5 and 6 chronic hepatitis C 
Treatment-naïve adult patients - NEUTRINO (study 110) 
NEUTRINO was an open-label, single-arm study that evaluated 12 weeks of treatment with sofosbuvir 
in combination with peginterferon alfa 2a and ribavirin in treatment-naïve patients with genotype 1, 4, 
5 or 6 HCV infection. 
 
Treated patients (n = 327) had a median age of 54 years (range: 19 to 70); 64% of the patients were 
male; 79% were White; 17% were Black; 14% were Hispanic or Latino; mean body mass index was 
29 kg/m2 (range: 18 to 56 kg/m2); 78% had baseline HCV RNA greater than 6 log10 IU/mL; 17% had 
cirrhosis; 89% had HCV genotype 1 and 11% had HCV genotype 4, 5 or 6. Table 7 presents the 
response rates for the treatment group of sofosbuvir + peginterferon alfa + ribavirin. 
 
Table 7: Response rates in study NEUTRINO 
 SOF+PEG+RBV 

12 weeks 
(n = 327) 

Overall SVR12 91% (296/327) 
Outcome for patients without SVR12  

On-treatment virologic failure 0/327 
Relapsea 9% (28/326) 
Otherb 1% (3/327) 

a. The denominator for relapse is the number of patients with HCV RNA <LLOQ at their last on-treatment assessment. 
b. Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up). 
 
Response rates for selected subgroups are presented in Table 8. 
 



19 

Table 8: SVR12 rates for selected subgroups in NEUTRINO 
 SOF+PEG+RBV 

12 weeks 
(n = 327) 

Genotype  
Genotype 1 90% (262/292) 
Genotype 4, 5 or 6 97% (34/35) 

Cirrhosis  
No 93% (253/273) 
Yes 80% (43/54) 

Race  
Black 87% (47/54) 
Non-Black 91% (249/273) 

 
SVR12 rates were similarly high in patients with baseline IL28B C/C allele [94/95 (99%)] and 
non-C/C (C/T or T/T) allele [202/232 (87%)]. 
 
27/28 patients with genotype 4 HCV achieved SVR12. A single subject with genotype 5 and all 
6 patients with genotype 6 HCV infection in this study achieved SVR12. 
 
Clinical studies in patients with genotype 2 and 3 chronic hepatitis C 
Treatment-naïve adults - FISSION (study 1231) 
FISSION was a randomised, open-label, active-controlled study that evaluated 12 weeks of treatment 
with sofosbuvir and ribavirin compared to 24 weeks of treatment with peginterferon alfa 2a and 
ribavirin in treatment-naïve patients with genotype 2 or 3 HCV infection. The ribavirin doses used in 
the sofosbuvir + ribavirin and peginterferon alfa 2a + ribavirin arms were weight-based 
1,000-1,200 mg/day and 800 mg/day regardless of weight, respectively. Patients were randomised in a 
1:1 ratio and stratified by cirrhosis (presence versus absence), HCV genotype (2 versus 3) and baseline 
HCV RNA level (<6 log10 IU/mL versus ≥6 log10 IU/mL). Patients with genotype 2 or 3 HCV were 
enrolled in an approximately 1:3 ratio. 
 
Treated patients (n = 499) had a median age of 50 years (range: 19 to 77); 66% of the patients were 
male; 87% were White; 3% were Black; 14% were Hispanic or Latino; mean body mass index was 
28 kg/m2 (range: 17 to 52 kg/m2); 57% had baseline HCV RNA levels greater than 6 log10 IU/mL; 
20% had cirrhosis; 72% had HCV genotype 3. Table 9 presents the response rates for the treatment 
groups of sofosbuvir + ribavirin and peginterferon alfa + ribavirin. 
 
Table 9: Response rates in study FISSION 
 SOF+RBV PEG+RBV 

12 weeks 24 weeks 
(n = 256)a (n = 243) 

Overall SVR12 67% (171/256) 67% (162/243) 
Genotype 2 95% (69/73) 78% (52/67) 
Genotype 3 56% (102/183) 63% (110/176) 

Outcome for patients without 
SVR12 

  

On-treatment virologic failure < 1% (1/256) 7% (18/243) 
Relapseb 30% (76/252) 21% (46/217) 
Otherc 3% (8/256) 7% (17/243) 

a. The efficacy analysis includes 3 patients with recombinant genotype 2/1 HCV infection. 
b. The denominator for relapse is the number of patients with HCV RNA <LLOQ at their last on-treatment assessment. 
c. Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up). 
 
The difference in the overall SVR12 rates between sofosbuvir + ribavirin and peginterferon alfa + 
ribavirin treatment groups was 0.3% (95% confidence interval: -7.5% to 8.0%) and the study met the 
predefined non-inferiority criterion. 
 
Response rates for patients with cirrhosis at baseline are presented in Table 10 by HCV genotype. 
 



20 

Table 10: SVR12 rates by cirrhosis and genotype in study FISSION 
 Genotype 2 Genotype 3 

SOF+RBV PEG+RBV SOF+RBV PEG+RBV 
12 weeks 24 weeks 12 weeks 24 weeks 
(n = 73)a (n = 67) (n = 183) (n = 176) 

Cirrhosis     
No 97% (59/61) 81% (44/54) 61% (89/145) 71% (99/139) 
Yes 83% (10/12) 62% (8/13) 34% (13/38) 30% (11/37) 

a. The efficacy analysis includes 3 patients with recombinant genotype 2/1 HCV infection. 
 
Interferon intolerant, ineligible or unwilling adults - POSITRON (study 107) 
POSITRON was a randomised, double-blinded, placebo-controlled study that evaluated 12 weeks of 
treatment with sofosbuvir and ribavirin (n = 207) compared to placebo (n = 71) in patients who are 
interferon intolerant, ineligible or unwilling. Patients were randomised in 3:1 ratio and stratified by 
cirrhosis (presence versus absence). 
 
Treated patients (n = 278) had a median age of 54 years (range: 21 to 75); 54% of the patients were 
male; 91% were White; 5% were Black; 11% were Hispanic or Latino; mean body mass index was 
28 kg/m2 (range: 18 to 53 kg/m2); 70% had baseline HCV RNA levels greater than 6 log10 IU/mL; 
16% had cirrhosis; 49% had HCV genotype 3. The proportions of patients who were interferon 
intolerant, ineligible, or unwilling were 9%, 44%, and 47%, respectively. Most patients had no prior 
HCV treatment (81.3%). Table 11 presents the response rates for the treatment groups of sofosbuvir + 
ribavirin and placebo. 
 
Table 11: Response rates in study POSITRON 
 SOF+RBV Placebo 

12 weeks 12 weeks 
(n = 207) (n = 71) 

Overall SVR12 78% (161/207) 0/71 
Genotype 2 93% (101/109) 0/34 
Genotype 3 61% (60/98) 0/37 

Outcome for patients without 
SVR12 

  

On-treatment virologic failure 0/207 97% (69/71) 
Relapsea 20% (42/205) 0/0 
Otherb 2% (4/207) 3% (2/71) 

a. The denominator for relapse is the number of patients with HCV RNA <LLOQ at their last on-treatment assessment. 
b. Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up). 
 
The SVR12 rate in the sofosbuvir + ribavirin treatment group was statistically significant when 
compared to placebo (p <0.001). 
 
Table 12 presents the subgroup analysis by genotype for cirrhosis and interferon classification. 
 
Table 12: SVR12 rates for selected subgroups by genotype in POSITRON 
 SOF+RBV 

12 weeks 
Genotype 2 Genotype 3 

(n = 109) (n = 98) 
Cirrhosis   

No 92% (85/92) 68% (57/84) 
Yes 94% (16/17) 21% (3/14) 

Interferon classification   
Ineligible 88% (36/41) 70% (33/47) 
Intolerant 100% (9/9) 50% (4/8) 
Unwilling 95% (56/59) 53% (23/43) 

 



21 

Previously treated adults - FUSION (study 108) 
FUSION was a randomised, double-blinded study that evaluated 12 or 16 weeks of treatment with 
sofosbuvir and ribavirin in patients who did not achieve SVR with prior interferon-based treatment 
(relapsers and nonresponders). Patients were randomised in a 1:1 ratio and stratified by cirrhosis 
(presence versus absence) and HCV genotype (2 versus 3). 
 
Treated patients (n = 201) had a median age of 56 years (range: 24 to 70); 70% of the patients were 
male; 87% were White; 3% were Black; 9% were Hispanic or Latino; mean body mass index was 
29 kg/m2 (range: 19 to 44 kg/m2); 73% had baseline HCV RNA levels greater than 6 log10 IU/mL; 
34% had cirrhosis; 63% had HCV genotype 3; 75% were prior relapsers. Table 13 presents the 
response rates for the treatment groups of sofosbuvir + ribavirin for 12 weeks and 16 weeks. 
 
Table 13: Response rates in study FUSION 
 SOF+RBV SOF+RBV 

12 weeks 16 weeks 
(n = 103)a (n = 98)a 

Overall SVR12 50% (51/103) 71% (70/98) 
Genotype 2 82% (32/39) 89% (31/35) 
Genotype 3 30% (19/64) 62% (39/63) 

Outcome for patients without 
SVR12 

  

On-treatment virologic failure 0/103 0/98 
Relapseb 48% (49/103) 29% (28/98) 
Otherc 3% (3/103) 0/98 

a. The efficacy analysis includes 6 patients with recombinant genotype 2/1 HCV infection. 
b. The denominator for relapse is the number of patients with HCV RNA <LLOQ at their last on-treatment assessment. 
c. Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up). 
 
Table 14 presents the subgroup analysis by genotype for cirrhosis and response to prior 
HCV treatment. 
 
Table 14: SVR12 rates for selected subgroups by genotype in study FUSION 
 Genotype 2 Genotype 3 

SOF+RBV SOF+RBV SOF+RBV SOF+RBV 
12 weeks 16 weeks 12 weeks 16 weeks 
(n = 39) (n = 35) (n = 64) (n = 63) 

Cirrhosis     
No 90% (26/29) 92% (24/26) 37% (14/38) 63% (25/40) 
Yes 60% (6/10) 78% (7/9) 19% (5/26) 61% (14/23) 

Response to prior 
HCV treatment 

    

Relapser 86% (25/29) 89% (24/27) 31% (15/49) 65% (30/46) 
Nonresponder 70% (7/10) 88% (7/8) 27% (4/15) 53% (9/17) 

 
Treatment-naïve and previously treated adults - VALENCE (study 133) 
VALENCE was a Phase 3 study that evaluated sofosbuvir in combination with weight-based ribavirin 
for the treatment of genotype 2 or 3 HCV infection in treatment-naïve patients or patients who did not 
achieve SVR with prior interferon-based treatment, including patients with compensated cirrhosis. The 
study was designed as a direct comparison of sofosbuvir and ribavirin versus placebo for 12 weeks. 
However, based on emerging data, the study was unblinded and all HCV genotype 2 patients 
continued to receive sofosbuvir and ribavirin for 12 weeks, whilst treatment for HCV genotype 3 
patients was extended to 24 weeks. Eleven HCV genotype 3 patients had already completed treatment 
with sofosbuvir and ribavirin for 12 weeks at the time of the amendment. 
 
Treated patients (n = 419) had a median age of 51 years (range: 19 to 74); 60% of the patients were 
male; median body mass index was 25 kg/m2 (range: 17 to 44 kg/m2); the mean baseline HCV RNA 
level was 6.4 log10 IU/mL; 21% had cirrhosis; 78% had HCV genotype 3; 65% were prior relapsers. 
Table 15 presents the response rates for the treatment groups of sofosbuvir + ribavirin for 12 weeks 
and 24 weeks. 



22 

 
Placebo recipients are not included in the tables since none achieved SVR12. 
 
Table 15: Response rates in study VALENCE 
 Genotype 2 Genotype 3 Genotype 3 

SOF+RBV 12 weeks SOF+RBV 12 weeks SOF+RBV 24 weeks 
(n = 73) (n = 11) (n = 250) 

Overall SVR12 93% (68/73) 27% (3/11) 84% (210/250) 
Outcome for patients without 
SVR12 

   

On-treatment virologic 
failure 

0% (0/73) 0% (0/11) 0.4% (1/250) 

Relapsea 7% (5/73) 55% (6/11) 14% (34/249) 
Otherb 0% (0/73) 18% (2/11) 2% (5/250) 

a. The denominator for relapse is the number of patients with HCV RNA <LLOQ at their last on-treatment assessment. 
b. Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up). 
 
Table 16 presents the subgroup analysis by genotype for cirrhosis and exposure to prior 
HCV treatment. 
 
Table 16: SVR12 rates for selected subgroups by genotype in study VALENCE 
 Genotype 2 Genotype 3 

SOF+RBV 12 weeks SOF+RBV 24 weeks 
(n = 73) (n = 250) 

Treatment-naïve 97% (31/32) 93% (98/105) 
Non-cirrhotic 97% (29/30) 93% (86/92) 
Cirrhotic 100% (2/2) 92% (12/13) 

Treatment-experienced 90% (37/41) 77% (112/145) 
Non-cirrhotic 91% (30/33) 85% (85/100) 
Cirrhotic 88% (7/8) 60% (27/45) 

 
SVR12 to SVR24 concordance 
The concordance between SVR12 and SVR24 (SVR 24 weeks after the end of the treatment) 
following treatment with sofosbuvir in combination with ribavirin or ribavirin and pegylated interferon 
demonstrates a positive predictive value of 99% and a negative predictive value of 99%. 
 
Clinical efficacy and safety in special populations 
HCV/HIV co-infected adult patients - PHOTON-1 (study 123) 
Sofosbuvir was studied in an open-label clinical study evaluating the safety and efficacy of 12 or 
24 weeks of treatment with sofosbuvir and ribavirin in patients with genotype 1, 2 or 3 chronic 
hepatitis C co-infected with HIV-1. Genotype 2 and 3 patients were either treatment-naïve or 
experienced, whereas genotype 1 patients were naïve to prior treatment. Treatment duration was 
12 weeks in treatment-naïve patients with genotype 2 or 3 HCV infection, and 24 weeks in 
treatment-experienced patients with genotype 3 HCV infection, as well as patients with genotype 1 
HCV infection. Patients received 400 mg sofosbuvir and weight-based ribavirin (1,000 mg for patients 
weighing <75 kg or 1,200 mg for patients weighing ≥75 kg). Patients were either not on antiretroviral 
therapy with a CD4+ cell count >500 cells/mm3 or had virologically suppressed HIV-1 with a CD4+ 
cell count >200 cells/mm3. 95% of patients received antiretroviral therapy at the time of enrolment. 
Preliminary SVR12 data are available for 210 patients. 
 
Table 17 presents the response rates by genotype and exposure to prior HCV treatment. 
 



23 

Table 17: Response rates in study PHOTON-1 
 Genotype 2/3 Genotype 2/3 Genotype 1 

treatment-naïve treatment-experienced treatment-naïve 
SOF+RBV SOF+RBV SOF+RBV 
12 weeks 24 weeks 24 weeks 
(n = 68) (n = 28) (n = 114) 

Overall SVR12 75% (51/68) 93% (26/28) 76% (87/114) 
Outcome for patients 
without SVR12 

   

On-treatment 
virologic failure 

1% (1/68) 0/28 1% (1/114) 

Relapsea 18% (12/67) 7% (2/28) 22% (25/113) 
Otherb 6% (4/68) 0/28 1% (1/114) 

a. The denominator for relapse is the number of patients with HCV RNA <LLOQ at their last on-treatment assessment. 
b. Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up). 
 
Table 18 presents the subgroup analysis by genotype for cirrhosis. 
 
Table 18: SVR12 rates for selected subgroups by genotype in study PHOTON-1 
 HCV genotype 2 HCV genotype 3 

SOF+RBV SOF+RBV SOF+RBV SOF+RBV 
12 weeks 24 weeks 12 weeks 24 weeks 

TN (n = 26) TE (n = 15) TN (n = 42) TE (n = 13) 
Overall 88% (23/26) 93% (14/15) 67% (28/42) 92% (12/13) 

No cirrhosis 88% (22/25) 92% (12/13) 67% (24/36) 100% (8/8) 
Cirrhosis 100% (1/1) 100% (2/2) 67% (4/6) 80% (4/5) 

TN = treatment-naïve; TE = treatment-experienced. 
 
Adult patients awaiting liver transplantation - Study 2025 
Sofosbuvir was studied in HCV infected patients prior to undergoing liver transplantation in an 
open-label clinical study evaluating the safety and efficacy of sofosbuvir and ribavirin administered 
pre-transplant to prevent post-transplant HCV reinfection. The primary endpoint of the study was 
post-transplant virologic response (pTVR, HCV RNA <LLOQ at 12 weeks post-transplant). 
HCV infected patients, regardless of genotype, with hepatocellular carcinoma (HCC) meeting the 
MILAN criteria received 400 mg sofosbuvir and 1,000-1,200 mg ribavirin daily for a maximum of 
24 weeks, subsequently amended to 48 weeks, or until the time of liver transplantation, whichever 
occurred first. An interim analysis was conducted on 61 patients who received sofosbuvir and 
ribavirin; the majority of patients had HCV genotype 1, 44 patients were CPT class A and 17 patients 
were CPT class B. Of these 61 patients, 44 patients underwent liver transplantation following up to 
48 weeks of treatment with sofosbuvir and ribavirin; 41 had HCV RNA <LLOQ at the time of 
transplantation. The virologic response rates of the 41 patients transplanted with HCV RNA <LLOQ is 
described in Table 19. Duration of viral suppression prior to transplantation was the most predictive 
factor for pTVR in those who were HCV RNA <LLOQ at the time of transplantation. 
 
Table 19: Virologic response post-transplant in patients with HCV RNA <LLOQ at the time of 
liver transplantation 
 Week 12 

post-transplant 
(pTVR)b 

Virologic response in 
evaluable patientsa 

23/37 (62%) 

a. Evaluable patients are defined as those who have reached the specified time point at the time of the interim analysis. 
b. pTVR: post-transplant virologic response (HCV RNA <LLOQ at 12 weeks post-procedure). 
 
In patients that discontinued therapy at 24 weeks, according to protocol, the relapse rate was 11/15. 
 
Adult liver transplant recipients - Study 0126 
Sofosbuvir was studied in an open-label clinical study evaluating the safety and efficacy of 24 weeks 
of treatment with sofosbuvir and ribavirin in liver transplant recipients with chronic hepatitis C. 



24 

Eligible patients were ≥18 years old and had undergone liver transplantation 6 to 150 months prior to 
screening. Patients had HCV RNA ≥104 IU/mL at screening and documented evidence of chronic 
HCV infection pre-transplantation. The starting dose of ribavirin was 400 mg given in a divided daily 
dose. If patients maintained haemoglobin levels ≥12 g/dL, ribavirin dose was increased at weeks 2, 4, 
and up to every 4 weeks until the appropriate weight-based dose was reached (1,000 mg daily in 
patients <75 kg, 1,200 mg daily in patients ≥75 kg). The median ribavirin dose was 600 mg-800 mg 
daily at weeks 4-24. 
 
Forty patients (33 with HCV genotype 1 infection, 6 with HCV genotype 3 infection, and 1 with HCV 
genotype 4 infection) were enrolled, 35 of whom had previously failed interferon-based treatment, and 
16 of whom had cirrhosis. 28 out of 40 (70%) patients achieved SVR12: 22/33 (73%) with HCV 
genotype 1 infection, 6/6 (100%) with HCV genotype 3 infection, and 0/1 (0%) with HCV genotype 4 
infection. All patients who achieved SVR12 achieved SVR24 and SVR48. 
 
Overview of outcomes by therapeutic regimen and treatment duration, a comparison across studies 
The following tables (Table 20 to Table 23) present data from Phase 2 and Phase 3 studies relevant to 
the dosing to help clinicians determine the best regimen for individual patients. 
 
Table 20: Outcomes by therapeutic regimen and treatment duration, a comparison across 
studies in genotype 1 HCV infection 

Patient population 
(Study number/name) 

Regimen/Duration Subgroup SVR12 rate % 
(n/N) 

Treatment-naïvea 
(NEUTRINO) 

SOF+PEG+RBV 12 weeks Overall 90% (262/292) 
Genotype 1a 92% (206/225) 
Genotype 1b 83% (55/66) 
No cirrhosis 93% (253/273) 
Cirrhosis 80% (43/54) 

Treatment-naïve and 
co-infected with HIV 
(PHOTON-1) 

SOF+RBV 24 weeks Overall 76% (87/114) 
Genotype 1a 82% (74/90) 
Genotype 1b 54% (13/24) 
No cirrhosis 77% (84/109) 
Cirrhosis 60% (3/5) 

Treatment-naïve 
(QUANTUMb and 
11-1-0258b) 

SOF+RBV 24 weeks Overallc 65% (104/159) 
Genotype 1ac 69% (84/121) 
Genotype 1bc 53% (20/38) 
No cirrhosisc 68% (100/148) 
Cirrhosisc 36% (4/11) 

n = number of patients with SVR12 response; N = total number of patients per group. 
a. For previously treated patients with genotype 1 HCV infection, no data exists with the combination of sofosbuvir, 
peginterferon alfa and ribavirin. Consideration should be given to treating these patients, and potentially extending the 
duration of therapy with sofosbuvir, peginterferon alfa and ribavirin beyond 12 weeks and up to 24 weeks; especially for 
those subgroups who have one or more factors historically associated with lower response rates to interferon-based therapies 
(prior null response to peginterferon alfa and ribavirin therapy, advanced fibrosis/cirrhosis, high baseline viral concentrations, 
black race, IL28B non CC genotype). 
b. These are exploratory or Phase 2 studies. The outcomes should be interpreted with caution, as subject numbers are small 
and SVR rates may be impacted by the selection of patients. 
c. Summary data from both studies. 
 
Table 21: Outcomes by therapeutic regimen and treatment duration, a comparison across 
studies in genotype 2 HCV infection 

Patient population (Study 
number/name) 

Regimen/Duration Subgroup SVR12 rate % (n/N) 

Treatment-naïve 
(FISSION) 

SOF+RBV 12 weeks Overall 95% (69/73) 
No cirrhosis 97% (59/61) 
Cirrhosis 83% (10/12) 

Interferon intolerant, ineligible 
or unwilling 
(POSITRON) 

SOF+RBV 12 weeks Overall 93% (101/109) 
No cirrhosis 92% (85/92) 
Cirrhosis 94% (16/17) 



25 

Patient population (Study 
number/name) 

Regimen/Duration Subgroup SVR12 rate % (n/N) 

Treatment-experienced 
(FUSION) 

SOF+RBV 12 weeks Overall 82% (32/39) 
No cirrhosis 90% (26/29) 
Cirrhosis 60% (6/10) 

Treatment-naïve 
(VALENCE) 

SOF+RBV 12 weeks Overall 97% (31/32) 
No cirrhosis 97% (29/30) 
Cirrhosis 100% (2/2) 

Treatment-experienced 
(VALENCE) 

SOF+RBV 12 weeks Overall 90% (37/41) 
No cirrhosis 91% (30/33) 
Cirrhosis 88% (7/8) 

Treatment-experienced 
(FUSION) 

SOF+RBV 16 weeks Overall 89% (31/35) 
No cirrhosis 92% (24/26) 
Cirrhosis 78% (7/9) 

Treatment-naïve co-infected 
with HIV 
(PHOTON-1) 

SOF+RBV 12 weeks Overall 88% (23/26) 
No cirrhosis 88% (22/25) 
Cirrhosis 100% (1/1) 

Treatment-experienced 
co-infected with HIV 
(PHOTON-1) 

SOF+RBV 24 weeks Overalla 93% (14/15) 
No cirrhosisa 92% (12/13) 
Cirrhosisa 100% (2/2) 

Treatment-naïve 
(ELECTRONb and PROTONb) 

SOF+PEG+RBV 
12 weeks 

Overallc 96% (25/26) 

Treatment-experienced 
(LONESTAR-2b) 

SOF+PEG+RBV 
12 weeks 

Overall 96% (22/23) 
No cirrhosis 100% (9/9) 
Cirrhosis 93% (13/14) 

n = number of patients with SVR12 response; N = total number of patients per group. 
a. These data are preliminary. 
b. These are exploratory or Phase 2 studies. The outcomes should be interpreted with caution, as subject numbers are small 
and SVR rates may be impacted by the selection of patients. In the ELECTRON study (N = 11), the duration of 
peginterferon alfa ranged from 4-12 weeks in combination with sofosbuvir + ribavirin. 
c. All patients were non-cirrhotic in these two studies. 
 
Table 22: Outcomes by therapeutic regimen and treatment duration, a comparison across 
studies in genotype 3 HCV infection 

Patient population (Study 
number/name) 

Regimen/Duration Subgroup SVR12 rate % (n/N) 

Treatment-naïve 
(FISSION) 

SOF+RBV 12 weeks Overall 56% (102/183) 
No cirrhosis 61% (89/145) 
Cirrhosis 34% (13/38) 

Interferon intolerant, ineligible 
or unwilling 
(POSITRON) 

SOF+RBV 12 weeks Overall 61% (60/98) 
No cirrhosis 68% (57/84) 
Cirrhosis 21% (3/14) 

Treatment-experienced 
(FUSION) 

SOF+RBV 12 weeks Overall 30% (19/64) 
No cirrhosis 37% (14/38) 
Cirrhosis 19% (5/26) 

Treatment-experienced 
(FUSION) 

SOF+RBV 16 weeks Overall 62% (39/63) 
No cirrhosis 63% (25/40) 
Cirrhosis 61% (14/23) 

Treatment-naïve 
(VALENCE) 

SOF+RBV 24 weeks Overall 93% (98/105) 
No cirrhosis 94% (86/92) 
Cirrhosis 92% (12/13) 

Treatment-experienced 
(VALENCE) 

SOF+RBV 24 weeks Overall 77% (112/145) 
No cirrhosis 85% (85/100) 
Cirrhosis 60% (27/45) 

Treatment-naïve co-infected 
with HIV 
(PHOTON-1) 

SOF+RBV 12 weeks Overall 67% (28/42) 
No cirrhosis 67% (24/36) 
Cirrhosis 67% (4/6) 

Treatment-experienced 
co-infected with HIV 
(PHOTON-1) 

SOF+RBV 24 weeks Overalla 92% (12/13) 
No cirrhosisa 100% (8/8) 
Cirrhosisa 80% (4/5) 



26 

Patient population (Study 
number/name) 

Regimen/Duration Subgroup SVR12 rate % (n/N) 

Treatment-naïve 
(ELECTRONb and 
PROTONb) 

SOF+PEG+RBV 12 weeks Overallc 97% (38/39) 

Treatment-experienced 
(LONESTAR-2b) 

SOF+PEG+RBV 12 weeks Overall 83% (20/24) 
No cirrhosis 83% (10/12) 
Cirrhosis 83% (10/12) 

n = number of patients with SVR12 response; N = total number of patients per group. 
a. These data are preliminary. 
b. These are exploratory or Phase 2 studies. The outcomes should be interpreted with caution, as subject numbers are small 
and SVR rates may be impacted by the selection of patients. In the ELECTRON study (N = 11), the duration of 
peginterferon alfa ranged from 4-12 weeks in combination with sofosbuvir + ribavirin. 
c. All patients were non-cirrhotic in these two studies. 
 
Table 23: Outcomes by therapeutic regimen and treatment duration, a comparison across 
studies in genotype 4, 5 and 6 HCV infection 

Patient population 
(Study number/name) 

Regimen/Duration Subgroup SVR12 rate % (n/N) 

Treatment-naïve 
(NEUTRINO) 

SOF+PEG+RBV 
12 weeks 

Overall 97% (34/35) 
No cirrhosis 100% (33/33) 
Cirrhosis 50% (1/2) 

n = number of patients with SVR12 response; N = total number of patients per group. 
 
Patients with renal impairment 
Study 0154 was an open-label clinical study that evaluated the safety and efficacy of 24 weeks of 
treatment with sofosbuvir in combination with ribavirin in 20 genotype 1 or 3 HCV-infected patients 
with severe renal impairment not requiring dialysis. Following treatment with sofosbuvir 200 mg or 
400 mg in combination with ribavirin the SVR12 rate in patients with ESRD was 40% and 60%, 
respectively. The safety and efficacy of 12 weeks of treatment with ledipasvir/sofosbuvir in 18 
genotype 1 HCV-infected patients with severe renal impairment not requiring dialysis was also studied 
in Study 0154. At baseline, two patients had cirrhosis and the mean eGFR was 24.9 mL/min (range: 
9.0-39.6). SVR12 was achieved in 100 % (18/18) of patients treated with ledipasvir/sofosbuvir.  
 
Study 4063 was an open-label study that evaluated a fixed dose combination of sofosbuvir and 
ledipasvir in 95 patients with HCV-infection and ESRD requiring dialysis. The SVR rates for the 8, 
12, and 24 week ledipasvir/sofosbuvir treatment groups were 93% (42/45), 100% (31/31), and 79% 
(15/19), respectively. Of the seven patients who did not achieve SVR12, none experienced virologic 
failure or relapsed. 
 
Study 4062 was an open-label study that evaluated a fixed dose combination of sofosbuvir and 
velpatasvir in 59 HCV-infected patients with ESRD requiring dialysis. The SVR rate was 95% 
(56/59); of the three patients that did not achieve SVR12, one had completed sofosbuvir with 
velpatasvir treatment and relapsed.  
 
Paediatric population 
The efficacy of sofosbuvir in HCV-infected patients aged 3 years and above was evaluated in a 
Phase 2, open label clinical trial that enrolled 106 patients with genotype 2 (n = 31) or genotype 3 
(n = 75) chronic HCV infection. Patients with HCV genotype 2 or 3 infection in the trial were treated 
with sofosbuvir with ribavirin for 12 or 24 weeks, respectively. 
 
Patients aged 12 to < 18 Years: 
Sofosbuvir was evaluated in 52 patients 12 to < 18 years with genotype 2 (n = 13) or genotype 3 (n = 
39) HCV infection. The median age was 15 years (range: 12 to 17); 40% of the patients were female; 
90% were White, 4% were Black, and 2% were Asian; 4% were Hispanic/Latino; mean weight was 
60.4 kg (range: 29.6 to 75.6 kg); 17% were treatment experienced; 65% had baseline HCV RNA 
levels greater than or equal to 800,000 IU/mL; and no patients had known cirrhosis. The majority of 
patients (69%) had been infected through vertical transmission. 
 



27 

The SVR12 rate was 98% overall (100% [13/13] in genotype 2 patients and 97% [38/39]) in 
genotype 3 patients. No patient experienced on-treatment virologic failure or relapse; one patient with 
genotype 3 HCV infection achieved SVR4 but did not return for the SVR12 visit. 
 
Patients aged 6 to < 12 Years:  
Sofosbuvir was evaluated in 41 patients 6 to < 12 years of age with genotype 2 (n = 13), or genotype 3 
(n = 28) HCV infection. The median age was 9 years (range: 6 to 11); 73% of the patients were 
female; 71% were White and 20% were Asian; 15% were Hispanic/Latino; mean weight was 33.7 kg 
(range: 15.1 to 80.0 kg); 98% were treatment naive; 46% had baseline HCV RNA levels greater than 
or equal to 800,000 IU /mL; and no patients had known cirrhosis. The majority of patients (98%) had 
been infected through vertical transmission. 
 
The SVR12 rate was 100% (100% [13/13] in genotype 2 patients and 100% [28/28] in genotype 3 
patients). No patients experienced on-treatment virologic failure or relapse. 
 
Patients aged 3 to < 6 Years:  
Sofosbuvir was evaluated in 13 patients 3 to < 6 years with genotype 2 (n = 5) or genotype 3 (n = 8) 
HCV infection. The median age was 4 years (range: 3 to 5); 77% of the patients were female; 69% 
were White, 8% were Black, and 8% were Asian; 8% were Hispanic/Latino; mean weight was 16.8 kg 
(range: 13.0 to 19.2 kg); 100% were treatment naive; 23% had baseline HCV RNA levels greater than 
or equal to 800,000 IU/mL; and no patients had known cirrhosis. The majority of patients (85%) had 
been infected through vertical transmission. 
 
The SVR12 rate was 92% overall (80% [4/5] in genotype 2 patients and 100% [8/8] in genotype 3 
patients). No patients experienced on-treatment virologic failure or relapse; one patient with 
genotype 2 HCV prematurely discontinued study treatment after three days due to abnormal taste of 
the medication and did not return for post-treatment Week 12. 
 
5.2 Pharmacokinetic properties 
 
Sofosbuvir is a nucleotide prodrug that is extensively metabolised. The active metabolite is formed in 
hepatocytes and not observed in plasma. The predominant (>90%) metabolite, GS-331007, is inactive. 
It is formed through sequential and parallel pathways to the formation of active metabolite. 
 
Absorption 
 
The pharmacokinetic properties of sofosbuvir and the predominant circulating metabolite GS-331007 
have been evaluated in healthy adult subjects and in patients with chronic hepatitis C. Following oral 
administration, sofosbuvir was absorbed quickly and the peak plasma concentration was observed 
~0.5-2 hour post-dose, regardless of dose level. Peak plasma concentration of GS-331007 was 
observed between 2 to 4 hours post-dose. Based on population pharmacokinetic analysis in patients 
with genotypes 1 to 6 HCV infection (n = 986), steady-state AUC0-24 for sofosbuvir and GS-331007 
was 1,010 ng•h/mL and 7,200 ng•h/mL, respectively. Relative to healthy subjects (n = 284), the 
sofosbuvir and GS-331007 AUC0-24 was 57% higher and 39% lower, respectively in HCV infected 
patients. 
 
Effects of food 
Relative to fasting conditions, the administration of a single dose of sofosbuvir with a standardised 
high fat meal slowed the rate of absorption of sofosbuvir. The extent of absorption of sofosbuvir was 
increased approximately 1.8-fold, with little effect on peak concentration. The exposure to GS-331007 
was not altered in the presence of a high-fat meal. 
 
Distribution 
 
Sofosbuvir is not a substrate for hepatic uptake transporters, organic anion-transporting polypeptide 
(OATP) 1B1 or 1B3, and organic cation transporter (OCT) 1. While subject to active tubular secretion, 
GS-331007 is not a substrate for renal transporters including organic anion transporter (OAT) 1 or 3, 



28 

OCT2, MRP2, P-gp, BCRP or MATE1. Sofosbuvir and GS-331007 are not inhibitors of drug 
transporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3 and OCT1. GS-331007 is not an 
inhibitor of OAT1, OCT2, and MATE1. 
 
Sofosbuvir is approximately 85% bound to human plasma proteins (ex vivo data) 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. 
 
Biotransformation 
 
Sofosbuvir is extensively metabolised in the liver to form the pharmacologically active nucleoside 
analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of 
the carboxyl ester moiety catalysed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and 
phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by 
phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the 
formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks 
anti-HCV activity in vitro. Sofosbuvir and GS-331007 are not substrates or inhibitors of UGT1A1 or 
CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 enzymes. 
 
After a single 400 mg oral dose of [14C]-sofosbuvir, sofosbuvir and GS-331007 accounted for 
approximately 4% and >90% of drug-related material (sum of molecular weight-adjusted AUC of 
sofosbuvir and its metabolites) systemic exposure, respectively. 
 
Elimination 
 
Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose 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. This data indicate that renal clearance is the major elimination 
pathway for GS-331007 with a large part actively secreted. The median terminal half-lives of 
sofosbuvir and GS-331007 were 0.4 and 27 hours respectively. 
 
Linearity/non-linearity 
 
The dose linearity of sofosbuvir and its primary metabolite, GS-331007, was evaluated in fasted 
healthy subjects. Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of 
200 mg to 400 mg. 
 
Pharmacokinetics in special populations 
 
Gender and race 
No clinically relevant pharmacokinetic differences due to gender or race have been identified for 
sofosbuvir and GS-331007. 
 
Elderly 
Population pharmacokinetic analysis in HCV infected patients showed that within the age range (19 to 
75 years) analysed, age did not have a clinically relevant effect on the exposure to sofosbuvir and 
GS-331007. Clinical studies of sofosbuvir included 65 patients aged 65 and over. The response rates 
observed for patients over 65 years of age were similar to that of younger patients across treatment 
groups. 
 
Renal impairment 
A summary of the effect of varying degrees of renal impairment (RI) on the exposures of sofosbuvir 
and GS-331007 compared to subjects with normal renal function, as described in the text below, are 
provided in Table 24.  
 



29 

Table 24: Effect of varying degrees of renal impairment on exposures (AUC) of sofosbuvir and 
GS-331007 compared to subjects with normal renal function 
 HCV-Negative Subjects HCV-Infected Subjects 

Mild RI 
(eGFR 
≥50 and 
<80 mL/min/ 
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/min/ 
1.73m2) 

ESRD 
Requiring 
Dialysis Dosed 

1 hr 
Before 
Dialysis 

Dosed 
1 hr 
After 
Dialysis 

Sofosbuvir 1.6-fold↑ 2.1-fold↑ 2.7-fold↑ 1.3-fold↑ 1.6-fold↑ ~2-fold↑ 1.9-fold↑ 
GS-331007 1.6-fold↑ 1.9-fold↑ 5.5-fold↑ ≥10-fold↑ ≥20-fold↑ ~7-fold↑ 21-fold↑ 
 
The pharmacokinetics of sofosbuvir were studied in adult 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 adult 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 sofosbuvir dose. 
 
In HCV-infected adult 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 adult patients with severe renal impairment.  
 
The pharmacokinetics of sofosbuvir, and GS-331007 were studied in HCV-infected adult patients with 
ESRD requiring dialysis treated with ledipasvir/sofosbuvir (n = 94) for 8, 12, or 24 weeks or 
sofosbuvir/velpatasvir (n = 59) for 12 weeks, and compared to patients without renal impairment in the 
ledipasvir/sofosbuvir and sofosbuvir/velpatasvir Phase 2/3 trials (see section 4.4). 
 
Hepatic impairment 
The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in 
adult HCV-infected patients with moderate and severe hepatic impairment (CPT class B and C). 
Relative to patients with normal hepatic function, the sofosbuvir AUC0-24 was 126% and 143% higher 
in moderate and severe hepatic impairment, while the GS-331007 AUC0-24 was 18% and 9% higher, 
respectively. Population pharmacokinetics analysis in adult HCV-infected patients indicated that 
cirrhosis had no clinically relevant effect on the exposure to sofosbuvir and GS-331007. No dose 
adjustment of sofosbuvir is recommended for patients with mild, moderate and severe hepatic 
impairment (see section 4.2). 
 
Paediatric population 
Sofosbuvir and GS-331007 exposures in paediatric patients aged 3 years and above were similar to 
those in adults from Phase 2/3 studies following administration of sofosbuvir. The pharmacokinetics 
of sofosbuvir and GS-331007 have not been established in paediatric patients aged < 3 years (see 
section 4.2). 
 
Pharmacokinetic/pharmacodynamic relationship(s) 
 
Efficacy, in terms of rapid virologic response, has been shown to correlate with exposure to sofosbuvir 
as well as GS 331007. However, neither of these entities has been evidenced to be a general surrogate 
marker for efficacy (SVR12) at the therapeutic 400 mg dose. 
 
5.3 Preclinical safety data 
 
In repeat dose toxicology studies in rat and dog, high doses of the 1:1 diastereomeric mixture caused 
adverse liver (dog) and heart (rat) effects and gastrointestinal reactions (dog). Exposure to sofosbuvir 
in rodent studies could not be detected likely due to high esterase activity; however, exposure to the 
major metabolite GS-331007 at the adverse dose was 29 times (rat) and 123 times (dog) higher than 



30 

the clinical exposure at 400 mg sofosbuvir. No liver or heart findings were observed in chronic 
toxicity studies at exposures 9 times (rat) and 27 times (dog) higher than the clinical exposure. 
 
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. 
 
Carcinogenicity studies in mice and rats do not indicate any carcinogenicity potential of sofosbuvir 
administered at doses up to 600 mg/kg/day in mouse and 750 mg/kg/day in rat. Exposure to 
GS-331007 in these studies was up to 30 times (mouse) and 15 times (rat) higher than the clinical 
exposure at 400 mg sofosbuvir. 
 
Sofosbuvir had no effects on embryo-foetal viability or on fertility in rat and was not teratogenic in rat 
and rabbit development studies. No adverse effects on behaviour, reproduction or development of 
offspring in rat were reported. In rabbit studies exposure to sofosbuvir was 9 times the expected 
clinical exposure. In the rat studies, exposure to sofosbuvir could not be determined but exposure 
margins based on the major human metabolite ranged from 8 to 28 times higher than the clinical 
exposure at 400 mg sofosbuvir. 
 
Sofosbuvir-derived material was transferred through the placenta in pregnant rats and into the milk of 
lactating rats. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
 
Mannitol (E421) 
Microcrystalline cellulose  
Croscarmellose sodium 
Colloidal anhydrous silica  
Magnesium stearate  
 
Film-coating 
 
Polyvinyl alcohol  
Titanium dioxide  
Macrogol   
Talc  
Iron oxide yellow  
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
6 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 



31 

6.5 Nature and contents of container 
 
Sovaldi 400 mg tablets are supplied in high density polyethylene (HDPE) bottles with a polypropylene 
child-resistant closure containing 28 film-coated tablets with a silica gel desiccant and polyester coil. 
 
Sovaldi 200 mg tablets are supplied in high density polyethylene (HDPE) bottles with a polypropylene 
child-resistant closure containing 28 film-coated tablets and a polyester coil. 
 
The following pack sizes are available:  

• outer cartons containing 1 bottle of 28 film-coated tablets  
• and for the 400 mg tablets only; outer cartons containing 84 (3 bottles of 28) film-coated 

tablets. 
 
Not all pack sizes may be marketed. 
 
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/1/13/894/001 
EU/1/13/894/002 
EU/1/13/894/003 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 16 January 2014 
Date of latest renewal: 17 September 2018 
 
 
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 
 
 



32 

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 
 
Sovaldi 150 mg coated granules in sachet 
Sovaldi 200 mg coated granules in sachet 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Sovaldi 150 mg coated granules in sachet 
Each sachet contains 150 mg sofosbuvir.  
 
Excipients with known effect: 
Each 150 mg sachet contains 173 mg of lactose (as monohydrate).  
 
Sovaldi 200 mg coated granules in sachet 
Each sachet contains 200 mg sofosbuvir. 
 
Excipients with known effect: 
Each 200 mg sachet contains 231 mg of lactose (as monohydrate).  
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Coated granules in sachet. 
 
White to off-white coated granules in sachet. 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Sovaldi is indicated in combination with other medicinal products for the treatment of chronic 
hepatitis C (CHC) in adult and paediatric patients aged 3 years and above (see sections 4.2, 4.4 and 
5.1). 
 
For hepatitis C virus (HCV) genotype specific activity, see sections 4.4 and 5.1. 
 
4.2 Posology and method of administration 
 
Sovaldi treatment should be initiated and monitored by a physician experienced in the management of 
patients with CHC. 
 
Posology 
 
The recommended dose of Sovaldi in paediatric patients aged 3 years and above is based on weight (as 
detailed in Table 2). Sovaldi should be taken with food (see section 5.2). 
 
Sovaldi should be used in combination with other medicinal products.  Monotherapy of Sovaldi is not 
recommended (see section 5.1). Refer also to the Summary of Product Characteristics of the medicinal 



33 

products that are used in combination with Sovaldi. The recommended co-administered medicinal 
product(s) and treatment duration for Sovaldi combination therapy are provided in Table 1. 
 
Table 1: Recommended co-administered medicinal product(s) and treatment duration for adults 
and paediatric patients treated Sovaldi combination therapy 
Patient population* Treatment Duration 

Adult patients with genotype 1, 4, 
5 or 6 CHC 

Sovaldi + ribavirinc + peginterferon alfa 12 weeksa,b 

Sovaldi + ribavirinc 
 
Only for use in patients ineligible or intolerant to 
peginterferon alfa (see section 4.4) 

24 weeks 

Adult and paediatric patients aged 
3 years and above with 
genotype 2 CHC 

Sovaldid + ribavirinc,e 12 weeksb 

Adult patients with genotype 3 
CHC 

Sovaldi + ribavirinc + peginterferon alfa 12 weeksb 

Sovaldi + ribavirinc 24 weeks 

Paediatric patients aged 3 years 
and above with genotype 3 CHC Sovaldi

d + ribavirine 24 weeks 

Adult patients with CHC awaiting 
liver transplantation Sovaldi + ribavirin

c Until liver transplantationf 
* Includes patients co-infected with human immunodeficiency virus (HIV). 
a. For previously treated patients with HCV genotype 1 infection, no data exists with the combination of Sovaldi, ribavirin 
and peginterferon alfa (see section 4.4). 
b. Consideration should be given to potentially extending the duration of therapy beyond 12 weeks and up to 24 weeks; 
especially for those subgroups who have one or more factors historically associated with lower response rates to 
interferon-based therapies (e.g. advanced fibrosis/cirrhosis, high baseline viral concentrations, black race, IL28B non 
CC genotype, prior null response to peginterferon alfa and ribavirin therapy). 
c. Adults: weight-based ribavirin (<75 kg = 1,000 mg and ≥75 kg = 1,200 mg); administered orally in two divided doses with 
food. Paediatric Patients: for ribavirin dosing recommendations see Table 3 below. 
d. See Table 2 for weight-based Sovaldi dosing recommendations for paediatric patients aged 3 years and above. 
e. See Table 3 for weight-based ribavirin dosing recommendations for paediatric patients aged 3 years and above. 
f. See Special patient populations – Patients awaiting liver transplantation below. 
 
Table 2: Dosing for paediatric patients aged 3  years and above using Sovaldi oral granules* 
Body Weight (kg)  Dosing of Sovaldi Oral Granules  Sofosbuvir Daily Dose 

≥ 35 two 200 mg sachets of granules once 
daily 

400 mg/day  
 

17 to < 35  one 200 mg sachet of granules once 
daily 

200 mg/day  
 

< 17 
 

one 150 mg sachet of granules once 
daily  

150 mg/day 
 

*Sovaldi is also available as film-coated tablet for use in paediatric patients with CHC aged 3 years and above (see 
section 5.1). Please refer to the Summary of Product Characteristics for Sovaldi 200 mg or 400 mg tablets. 
 
In paediatric patients aged 3 years and above the following ribavirin dosing is recommended where 
ribavirin is divided into two daily doses and given with food: 
 



34 

Table 3: Guidance for ribavirin dosing when administered in combination with Sovaldi to HCV-infected 
paediatric patients aged 3 years and above. 

Body weight kg Ribavirin Dose* 
< 47 15 mg/kg/day 
47-49 600 mg/day 
50-65 800 mg/day 
66-80 1000 mg/day 
> 81 1200 mg/day 

* The daily dosage of ribavirin is weight-based and is administered orally in two divided doses with food. 
 
Concerning co-administration with other direct-acting antivirals against HCV, see section 4.4. 
 
Dose modification in adults 
Dose reduction of Sovaldi is not recommended. 
 
If sofosbuvir is used in combination with peginterferon alfa, and a patient has a serious adverse 
reaction potentially related to this medicinal product, the peginterferon alfa dose should be reduced or 
discontinued. Refer to the peginterferon alfa Summary of Product Characteristics for additional 
information about how to reduce and/or discontinue the peginterferon alfa dose. 
 
If a patient has a serious adverse reaction potentially related to ribavirin, the ribavirin dose should be 
modified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity. 
Table 4 provides guidelines for dose modifications and discontinuation based on the patient’s 
haemoglobin concentration and cardiac status. 
 
Table 4: Ribavirin dose modification guideline for co-administration with Sovaldi in adults 

Laboratory values Reduce ribavirin dose to 
600 mg/day if: 

Discontinue ribavirin if: 

Haemoglobin in patients with no 
cardiac disease 

<10 g/dL <8.5 g/dL 

Haemoglobin in patients with history 
of stable cardiac disease 

≥2 g/dL decrease in haemoglobin 
during any 4 week treatment 
period 

<12 g/dL despite 4 weeks at 
reduced dose 

 
Once ribavirin has been withheld due to either a laboratory abnormality or clinical manifestation, an 
attempt may be made to restart ribavirin at 600 mg daily and further increase the dose to 800 mg daily.  
However, it is not recommended that ribavirin be increased to the original assigned dose (1,000 mg to 
1,200 mg daily). 
 
Dose modification in paediatric patients aged 3 years and above  
Dose reduction of Sovaldi is not recommended. 
 
If a patient has a serious adverse reaction potentially related to ribavirin, the ribavirin dose should be 
modified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity. 
Refer to the ribavirin prescribing information for guidance on dose modification or discontinuation. 
 
Discontinuation of dosing  
If the other medicinal products used in combination with Sovaldi are permanently discontinued, 
Sovaldi should also be discontinued (see section 4.4). 
 
Vomiting and missed doses 
Patients should be instructed that if vomiting occurs within 2 hours of dosing an additional dose 
should be taken. If vomiting occurs more than 2 hours after dosing, no further dose is needed. These 
recommendations are based on the absorption kinetics of sofosbuvir and GS-331007 suggesting that 
the majority of the dose is absorbed within 2 hours after dosing. 
 



35 

If a dose is missed and it is within 18 hours of the normal time, patients should be instructed to take 
the dose 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 at the usual time. Patients 
should be instructed not to take a double dose. 
 
Special patient populations 
 
Elderly 
No dose adjustment is warranted for elderly patients (see section 5.2). 
 
Renal impairment 
No dose adjustment of Sovaldi 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. Sovaldi 
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 Sovaldi is required for patients with mild, moderate or severe hepatic 
impairment (Child-Pugh-Turcotte [CPT] class A, B or C) (see section 5.2). The safety and efficacy of 
Sovaldi have not been established in patients with decompensated cirrhosis. 
 
Patients awaiting liver transplantation 
The duration of administration of Sovaldi in patients awaiting liver transplantation should be guided 
by an assessment of the potential benefits and risks for the individual patient (see section 5.1). 
 
Adult liver transplant recipients 
Sovaldi in combination with ribavirin is recommended for 24 weeks in liver transplant recipients. In 
adults a starting ribavirin dose of 400 mg administered orally in two divided doses with food is 
recommended. If the starting dose of ribavirin is well-tolerated, the dose can be titrated up to a 
maximum of 1,000-1,200 mg daily (1,000 mg for patients weighing <75 kg and 1,200 mg for patients 
weighing ≥75 kg). If the starting dose of ribavirin is not well-tolerated, the dose should be reduced as 
clinically indicated based on haemoglobin levels (see section 5.1). 
 
Paediatric population aged < 3 years 
The safety and efficacy of Sovaldi in children aged <3 years have not yet been established. No data are 
available. 
 
Method of administration 
 
Oral use. 
 
Sovaldi must be taken shortly before food, shortly after food, or with food. 
 
To help with swallowing of the Sovaldi oral granules you can use food or water as detailed below. 
Alternatively, Sovaldi can be swallowed without food or water. 
 
Taking Sovaldi granules with food to aid swallowing 
To administer with food to aid swallowability of the granules, patients should be instructed to sprinkle 
the granules on one or more spoonfuls of non-acidic soft food at or below room temperature. Patients 
should be instructed to take the Sovaldi granules within 30 minutes of gently mixing with food and to 
swallow the entire contents without chewing to avoid a bitter taste. Examples of non-acidic foods 
include chocolate syrup, mashed potato, and ice-cream.  
 



36 

Taking Sovaldi granules with water to aid swallowing 
To administer with water, patients should be instructed that the granules can be taken directly into the 
mouth and swallowed with water.  
 
Taking Sovaldi granules without food or water 
To administer without food or water, patients should be instructed that the granules can be taken 
directly into the mouth and swallowed. Patients should be instructed to swallow the entire contents 
without chewing (see section 5.2). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  
 
Medicinal products that are strong P-glycoprotein (P-gp) inducers in the intestine (carbamazepine, 
phenobarbital, phenytoin, rifampicin and St. John’s wort). Co-administration will significantly 
decrease sofosbuvir plasma concentration and could result in loss of efficacy of Sovaldi (see 
section 4.5). 
 
4.4 Special warnings and precautions for use 
 
General 
 
Sovaldi is not recommended for administration as monotherapy and should be prescribed in 
combination with other medicinal products for the treatment of hepatitis C infection. If the other 
medicinal products used in combination with Sovaldi are permanently discontinued, Sovaldi should 
also be discontinued (see section 4.2). Consult the Summary of Product Characteristics for 
co-prescribed medicinal products before starting therapy with Sovaldi. 
 
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 Sovaldi 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 Sovaldi. 
 
All patients with concurrent or recent use of amiodarone should be warned of the symptoms of 
bradycardia and heart block and should be advised to seek medical advice urgently should they 
experience them. 
 
HCV/HBV (hepatitis B virus) co-infection 
 
Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after 
treatment with direct-acting antiviral agents. HBV screening should be performed in all patients before 
initiation of treatment.  HBV/HCV co-infected patients are at risk of HBV reactivation, and should 
therefore be monitored and managed according to current clinical guidelines. 



37 

Treatment-experienced patients with genotype 1, 4, 5 and 6 HCV infection 
 
Sovaldi has not been studied in a Phase 3 study in treatment-experienced patients with genotype 1, 4, 5 
and 6 HCV infection. Thus, the optimal treatment duration in this population has not been established 
(see also sections 4.2 and 5.1). 
 
Consideration should be given to treating these patients, and potentially extending the duration of 
therapy with sofosbuvir, peginterferon alfa and ribavirin beyond 12 weeks and up to 24 weeks; 
especially for those subgroups who have one or more factors historically associated with lower 
response rates to interferon-based therapies (advanced fibrosis/cirrhosis, high baseline viral 
concentrations, black race, IL28B non CC genotype). 
 
Treatment of patients with genotype 5 or 6 HCV infection 
 
The clinical data to support the use of Sovaldi in patients with genotype 5 and 6 HCV infection is very 
limited (see section 5.1). 
 
Interferon-free therapy for genotype 1, 4, 5 and 6 HCV infection 
 
Interferon-free regimens for patients with genotype 1, 4, 5 and 6 HCV infection with Sovaldi have not 
been investigated in Phase 3 studies (see section 5.1). The optimal regimen and treatment duration 
have not been established. Such regimens should only be used for patients that are intolerant to or 
ineligible for interferon therapy, and are in urgent need of treatment. 
 
Co-administration with other direct-acting antivirals against HCV 
 
Sovaldi should only be co-administered with other direct-acting antiviral medicinal products if the 
benefit is considered to outweigh the risks based upon available data. There are no data to support the 
co-administration of Sovaldi and telaprevir or boceprevir. Such co-administration is not recommended 
(see also section 4.5). 
 
Pregnancy and concomitant use with ribavirin 
 
When Sovaldi is used in combination with ribavirin or peginterferon alfa/ribavirin, women of 
childbearing potential or their male partners must use an effective form of contraception during the 
treatment and for a period of time after the treatment as recommended in the Summary of Product 
Characteristics for ribavirin. Refer to the Summary of Product Characteristics for ribavirin for 
additional information. 
 
Use with moderate P-gp inducers 
 
Medicinal products that are moderate P-gp inducers in the intestine (e.g. modafinil, oxcarbazepine and 
rifapentine) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of 
Sovaldi. Co-administration of such medicinal products is not recommended with Sovaldi (see 
section 4.5). 
 
Use in diabetic patients  
 
Diabetics may experience improved glucose control, potentially resulting in symptomatic 
hypoglycaemia, after initiating HCV direct-acting antiviral treatment. Glucose levels of diabetic 
patients initiating direct-acting antiviral therapy should be closely monitored, particularly within the 
first 3 months, and their diabetic medication modified when necessary. The physician in charge of the 
diabetic care of the patient should be informed when direct-acting antiviral therapy is initiated. 
 



38 

Renal impairment 
 
Safety data are limited in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2) and 
ESRD requiring haemodialysis. Sovaldi can be used in these patients with no dose adjustment when 
no other relevant treatment options are available (see sections 4.8, 5.1 and 5.2). When Sovaldi is used 
in combination with ribavirin or peginterferon alfa/ribavirin, refer also to the Summary of Product 
Characteristics for ribavirin for patients with creatinine clearance (CrCl) <50 mL/min (see also 
section 5.2). 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Sofosbuvir is a nucleotide prodrug. After oral administration of Sovaldi, sofosbuvir is rapidly 
absorbed and subject to extensive first-pass hepatic and intestinal metabolism.  Intracellular hydrolytic 
prodrug cleavage catalysed by enzymes including carboxylesterase 1 and sequential phosphorylation 
steps catalysed by nucleotide kinases result in formation of the pharmacologically active uridine 
nucleoside analogue triphosphate. The predominant inactive circulating metabolite GS-331007 that 
accounts for greater than 90% of drug-related material systemic exposure is formed through pathways 
sequential and parallel to formation of active metabolite. The parent sofosbuvir accounts for 
approximately 4% of drug-related material systemic exposure (see section 5.2). In clinical 
pharmacology studies, both sofosbuvir and GS-331007 were monitored for purposes of 
pharmacokinetic analyses. 
 
Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while 
GS-331007 is not. 
 
Medicinal products that are strong P-gp inducers in the intestine (carbamazepine, phenobarbital, 
phenytoin, rifampicin and St. John’s wort) may significantly decrease sofosbuvir plasma concentration 
leading to reduced therapeutic effect of Sovaldi and thus are contraindicated with Sovaldi (see 
section 4.3). Medicinal products that are moderate P-gp inducers in the intestine (e.g. modafinil, 
oxcarbazepine and rifapentine) may decrease sofosbuvir plasma concentration leading to reduced 
therapeutic effect of Sovaldi. Co-administration with such medicinal products is not recommended 
with Sovaldi (see section 4.4). Co-administration of Sovaldi with medicinal products that inhibit P-gp 
and/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasma 
concentration, thus Sovaldi may be co-administered with P-gp and/or BCRP inhibitors. Sofosbuvir and 
GS-331007 are not inhibitors of P-gp and BCRP and thus are not expected to increase exposures of 
medicinal products that are substrates of these transporters. 
 
The intracellular metabolic activation pathway of sofosbuvir is mediated by generally low affinity and 
high capacity hydrolase and nucleotide phosphorylation pathways that are unlikely to be affected by 
concomitant medicinal products (see section 5.2). 
 
Patients treated with vitamin K antagonists 
 
As liver function may change during treatment with Sovaldi, a close monitoring of International 
Normalised Ratio (INR) values is recommended. 
 
Impact of DAA therapy on drugs metabolized by the liver 
 
The pharmacokinetics of drugs that are metabolized by the liver (e.g. immunosuppressive agents such 
as calcineurin inhibitors) may be impacted by changes in liver function during DAA therapy, related to 
clearance of HCV. 
 
Other interactions 
 
Drug interaction information for Sovaldi with potential concomitant medicinal products is summarised 
in Table 5 below (where 90% confidence interval (CI) of the geometric least-squares mean (GLSM) 



39 

ratio were within “↔”, extended above “↑”, or extended below “↓” the predetermined equivalence 
boundaries).  The table is not all-inclusive. 
 
Table 5: Interactions between Sovaldi and other medicinal products 
Medicinal product by 
therapeutic areas 

Effects on drug levels. 
Mean ratio (90% 
confidence interval) for 
AUC, Cmax, Cmina,b 

Recommendation concerning co-administration 
with Sovaldi 

ANALEPTICS 
Modafinil Interaction not studied. 

Expected: 
↓ Sofosbuvir 
↔ GS-331007 
 
(Induction of P-gp) 

Co-administration of Sovaldi with modafinil is 
expected to decrease the concentration of 
sofosbuvir, leading to reduced therapeutic effect of 
Sovaldi.  Such co-administration is not 
recommended. 

ANTIARRHYTHMICS 
Amiodarone Effect on amiodarone 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 Sovaldi (see 
sections 4.4 and 4.8). 

ANTICOAGULANTS 
Vitamin K antagonists Interaction not studied Close monitoring of INR is recommended with all 

vitamin K antagonists. This is due to liver function 
changes during treatment with Sovaldi. 

ANTICONVULSANTS 
Phenobarbital 
Phenytoin 

Interaction not studied. 
Expected: 
↓ Sofosbuvir 
↔ GS-331007 
 
(Induction of P-gp) 

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

Carbamazepine Sofosbuvir 
↓ Cmax 0.52 (0.43, 0.62) 
↓ AUC 0.52 (0.46, 0.59) 
Cmin (NA) 
 
GS 331007 
↔ Cmax 1.04 (0.97, 1.11) 
↔ AUC 0.99 (0.94, 1.04) 
Cmin (NA) 
 
(Induction of P-gp) 

Sovaldi is contraindicated with carbamazepine (see 
section 4.3). 

Oxcarbazepine Interaction not studied. 
Expected: 
↓ Sofosbuvir 
↔ GS-331007 
 
(Induction of P-gp) 

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



40 

Medicinal product by 
therapeutic areas 

Effects on drug levels. 
Mean ratio (90% 
confidence interval) for 
AUC, Cmax, Cmina,b 

Recommendation concerning co-administration 
with Sovaldi 

ANTIMYCOBACTERIALS 
Rifampicinf 
(600 mg single dose) 

Sofosbuvir 
↓ Cmax 0.23 (0.19, 0.29) 
↓ AUC 0.28 (0.24, 0.32) 
Cmin (NA) 
 
GS-331007 
↔ Cmax 1.23 (1.14, 1.34) 
↔ AUC 0.95 (0.88, 1.03) 
Cmin (NA) 
 
(Induction of P-gp) 

Sovaldi is contraindicated with rifampicin (see 
section 4.3). 

Rifabutin Sofosbuvir 
↓ Cmax 0.64 (0.53, 0.77) 
↓ AUC 0.76 (0.63, 0.91) 
Cmin (NA) 
 
GS 331007 
↔ Cmax 1.15 (1.03, 1.27) 
↔ AUC 1.03 (0.95, 1.12) 
Cmin (NA) 
 
(Induction of P-gp) 

No dose adjustment of Sovaldi is required when 
concomitantly used with rifabutin. 

Rifapentine Interaction not studied. 
Expected: 
↓ Sofosbuvir 
↔ GS-331007 
 
(Induction of P-gp) 

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

HERBAL SUPPLEMENTS 
St. John’s wort 
 

Interaction not studied. 
Expected: 
↓ Sofosbuvir 
↔ GS-331007 
 
(Induction of P-gp) 

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

HCV ANITIVIRAL AGENTS: HCV PROTEASE INHIBITORS 
Boceprevir (BOC) 
Telaprevir (TPV) 

Interaction not studied. 
Expected: 
↑ Sofosbuvir (TPV) 
↔ Sofosbuvir (BOC) 
↔ GS-331007 (TPV or 
BOC) 

No drug-drug interaction data exists regarding the 
co-administration of Sovaldi with boceprevir or 
telaprevir. 



41 

Medicinal product by 
therapeutic areas 

Effects on drug levels. 
Mean ratio (90% 
confidence interval) for 
AUC, Cmax, Cmina,b 

Recommendation concerning co-administration 
with Sovaldi 

NARCOTIC ANALGESICS 
Methadonef 
(Methadone maintenance 
therapy [30 to 
130 mg/daily]) 

R-methadone 
↔ Cmax 0.99 (0.85, 1.16) 
↔ AUC 1.01 (0.85, 1.21) 
↔ Cmin 0.94 (0.77, 1.14) 
 
S-methadone 
↔ Cmax 0.95 (0.79, 1.13) 
↔ AUC 0.95 (0.77, 1.17) 
↔ Cmin 0.95 (0.74, 1.22) 
 
Sofosbuvir 
↓ Cmax 0.95c (0.68, 1.33) 
↑ AUC 1.30c (1.00, 1.69) 
Cmin (NA) 
 
GS-331007 
↓ Cmax 0.73c (0.65, 0.83) 
↔ AUC 1.04c (0.89, 1.22) 
Cmin (NA) 

No dose adjustment of sofosbuvir or methadone is 
required when sofosbuvir and methadone are used 
concomitantly. 

IMMUNOSUPPRESSANTS 
Ciclosporine 
(600 mg single dose) 

Ciclosporin 
↔ Cmax 1.06 (0.94, 1.18) 
↔ AUC 0.98 (0.85, 1.14) 
Cmin (NA) 
 
Sofosbuvir 
↑ Cmax 2.54 (1.87, 3.45) 
↑ AUC 4.53 (3.26, 6.30) 
Cmin (NA) 
 
GS-331007 
↓ Cmax 0.60 (0.53, 0.69) 
↔ AUC 1.04 (0.90, 1.20) 
Cmin (NA) 

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

Tacrolimuse 
(5 mg single dose) 

Tacrolimus 
↓ Cmax 0.73 (0.59, 0.90) 
↔ AUC 1.09 (0.84, 1.40) 
Cmin  (NA) 
 
Sofosbuvir 
↓ Cmax 0.97 (0.65, 1.43) 
↑ AUC 1.13 (0.81, 1.57) 
Cmin (NA) 
 
GS-331007 
↔ Cmax 0.97 (0.83, 1.14) 
↔ AUC 1.00 (0.87, 1.13) 
Cmin (NA) 

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



42 

Medicinal product by 
therapeutic areas 

Effects on drug levels. 
Mean ratio (90% 
confidence interval) for 
AUC, Cmax, Cmina,b 

Recommendation concerning co-administration 
with Sovaldi 

HIV ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS 
Efavirenzf 
(600 mg once daily)d 

Efavirenz 
↔ Cmax 0.95 (0.85, 1.06) 
↔ AUC 0.96 (0.91, 1.03) 
↔ Cmin 0.96 (0.93, 0.98) 
 
Sofosbuvir 
↓ Cmax 0.81 (0.60, 1.10) 
↔ AUC 0.94 (0.76, 1.16) 
Cmin (NA) 
 
GS-331007 
↓ Cmax 0.77 (0.70, 0.84) 
↔ AUC 0.84 (0.76, 0.92) 
Cmin (NA) 

No dose adjustment of sofosbuvir or efavirenz is 
required when sofosbuvir and efavirenz are used 
concomitantly. 

Emtricitabinef 
(200 mg once daily)d 

Emtricitabine 
↔ Cmax 0.97 (0.88, 1.07) 
↔ AUC 0.99 (0.94, 1.05) 
↔ Cmin 1.04 (0.98, 1.11) 
 
Sofosbuvir 
↓ Cmax 0.81 (0.60, 1.10) 
↔ AUC 0.94 (0.76, 1.16) 
Cmin (NA) 
 
GS-331007 
↓ Cmax 0.77 (0.70, 0.84) 
↔ AUC 0.84 (0.76, 0.92) 
Cmin (NA) 

No dose adjustment of sofosbuvir or emtricitabine 
is required when sofosbuvir and emtricitabine are 
used concomitantly. 

Tenofovir disoproxilf 
(245 mg once daily)d 

Tenofovir 
↑ Cmax 1.25 (1.08, 1.45) 
↔ AUC 0.98 (0.91, 1.05) 
↔ Cmin 0.99 (0.91, 1.07) 
 
Sofosbuvir 
↓ Cmax 0.81 (0.60, 1.10) 
↔ AUC 0.94 (0.76, 1.16) 
Cmin (NA) 
 
GS-331007 
↓ Cmax 0.77 (0.70, 0.84) 
↔ AUC 0.84 (0.76, 0.92) 
Cmin (NA) 

No dose adjustment of sofosbuvir or tenofovir 
disoproxil is required when sofosbuvir and 
tenofovir disoproxil are used concomitantly. 

Rilpivirinef 
(25 mg once daily) 

Rilpivirine 
↔ Cmax 1.05 (0.97, 1.15) 
↔ AUC 1.06 (1.02, 1.09) 
↔ Cmin 0.99 (0.94, 1.04) 
 
Sofosbuvir 
↑ Cmax 1.21 (0.90, 1.62) 
↔ AUC 1.09 (0.94, 1.27) 
Cmin (NA) 
 
GS-331007 
↔ Cmax 1.06 (0.99, 1.14) 
↔ AUC 1.01 (0.97, 1.04) 
Cmin (NA) 

No dose adjustment of sofosbuvir or rilpivirine is 
required when sofosbuvir and rilpivirine are used 
concomitantly. 



43 

Medicinal product by 
therapeutic areas 

Effects on drug levels. 
Mean ratio (90% 
confidence interval) for 
AUC, Cmax, Cmina,b 

Recommendation concerning co-administration 
with Sovaldi 

HIV ANTIVIRAL AGENTS: HIV PROTEASE INHIBITORS 
Darunavir boosted with 
ritonavirf 
(800/100 mg once daily) 

Darunavir 
↔ Cmax 0.97 (0.94, 1.01) 
↔ AUC 0.97 (0.94, 1.00) 
↔ Cmin 0.86 (0.78, 0.96) 
 
Sofosbuvir 
↑ Cmax 1.45 (1.10, 1.92) 
↑ AUC 1.34 (1.12, 1.59) 
Cmin (NA) 
 
GS-331007 
↔ Cmax 0.97 (0.90, 1.05) 
↔ AUC 1.24 (1.18, 1.30) 
Cmin (NA) 

No dose adjustment of sofosbuvir or darunavir 
(ritonavir boosted) is required when sofosbuvir and 
darunavir are used concomitantly. 

HIV ANTIVIRAL AGENTS: INTEGRASE INHIBITORS 
Raltegravirf 
(400 mg twice daily) 

Raltegravir 
↓ Cmax 0.57 (0.44, 0.75) 
↓ AUC 0.73 (0.59, 0.91) 
↔ Cmin 0.95 (0.81, 1.12) 
 
Sofosbuvir 
↔ Cmax 0.87 (0.71, 1.08) 
↔ AUC 0.95 (0.82, 1.09) 
Cmin (NA) 
 
GS-331007 
↔ Cmax 1.09 (0.99, 1.20) 
↔ AUC 1.03 (0.97, 1.08) 
Cmin (NA) 

No dose adjustment of sofosbuvir or raltegravir is 
required when sofosbuvir and raltegravir are used 
concomitantly. 

ORAL CONTRACEPTIVES 
Norgestimate/ethinyl 
estradiol 

Norgestromin 
↔ Cmax 1.06 (0.93, 1.22) 
↔ AUC 1.05 (0.92, 1.20) 
Cmin (NA) 
 
Norgestrel 
↔ Cmax 1.18 (0.99, 1.41) 
↔ AUC 1.19 (0.98, 1.44) 
Cmin (NA) 
 
Ethinyl estradiol 
↔ Cmax 1.14 (0.96, 1.36) 
↔ AUC 1.08 (0.93, 1.25) 
Cmin (NA) 

No dose adjustment of norgestimate/ethinyl 
estradiol is required when sofosbuvir and 
norgestimate/ethinyl estradiol are used 
concomitantly. 

NA = not available/not applicable 
a. Mean ratio (90% CI) of co-administered drug pharmacokinetics with/without sofosbuvir and mean ratio of sofosbuvir and 
GS-331007 with/without co-administered drug.  No effect = 1.00 
b. All interaction studies conducted in healthy volunteers 
c. Comparison based on historical control 
d. Administered as Atripla 
e. Bioequivalence boundary 80%-125% 
f. Equivalence boundary 70%-143% 
 



44 

4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential / contraception in males and females 
 
When Sovaldi is used in combination with ribavirin or peginterferon alfa/ribavirin, extreme care must 
be taken to avoid pregnancy in female patients and in female partners of male patients. Significant 
teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to 
ribavirin (see section 4.4). Women of childbearing potential or their male partners must use an 
effective form of contraception during treatment and for a period of time after the treatment has 
concluded as recommended in the Summary of Product Characteristics for ribavirin. Refer to the 
Summary of Product Characteristics for ribavirin for additional information. 
 
Pregnancy 
 
There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of sofosbuvir 
in pregnant women. 
 
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. 
No effects on foetal development have been observed in rats and rabbits at the highest doses tested. 
However, 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). 
 
As a precautionary measure, it is preferable to avoid the use of Sovaldi during pregnancy. 
 
However, if ribavirin is co-administered with sofosbuvir, the contraindications regarding use of 
ribavirin during pregnancy apply (see also the Summary of Product Characteristics for ribavirin). 
 
Breast-feeding 
 
It is unknown whether sofosbuvir and its metabolites are excreted in human milk. 
 
Available pharmacokinetic data in animals have shown excretion of metabolites in milk (for details 
see section 5.3). 
 
A risk to newborns/infants cannot be excluded.  Therefore, Sovaldi should not be used during 
breast-feeding. 
 
Fertility 
 
No human data on the effect of Sovaldi on fertility are available.  Animal studies do not indicate 
harmful effects on fertility. 
 
4.7 Effects on ability to drive and use machines 
 
Sovaldi has moderate influence on the ability to drive and use machines. Patients should be informed 
that fatigue and disturbance in attention, dizziness and blurred vision have been reported during 
treatment with sofosbuvir in combination with peginterferon alfa and ribavirin (see section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile in adults 
 
Assessment of adverse reactions is based on pooled data from five Phase 3 clinical studies (both 
controlled and uncontrolled). 
 
Sovaldi has been studied in combination with ribavirin, with or without peginterferon alfa. In this 
context, no adverse drug reactions specific to sofosbuvir have been identified. The most common 



45 

adverse drug reactions occurring in patients receiving sofosbuvir and ribavirin or sofosbuvir, ribavirin 
and peginterferon alfa were fatigue, headache, nausea and insomnia. 
 
Tabulated summary of adverse reactions 
 
The following adverse drug reactions have been identified with sofosbuvir in combination with 
ribavirin or in combination with peginterferon alfa and ribavirin (Table 6). The adverse reactions are 
listed below by body system organ class and frequency.  Frequencies are defined as follows: very 
common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to 
<1/1,000) or very rare (<1/10,000). 
 
Table 6: Adverse drug reactions identified with sofosbuvir in combination with ribavirin or 
peginterferon alfa and ribavirin 
Frequency SOFa + RBVb SOF + PEGc + RBV 
Infections and infestations: 
Common nasopharyngitis  
Blood and lymphatic system disorders: 

Very common haemoglobin decreased anaemia, neutropenia, lymphocyte count decreased, platelet count decreased 
Common anaemia  
Metabolism and nutrition disorders: 
Very common decreased appetited decreased appetite 
Common  weight decreased 
Psychiatric disorders: 
Very common insomnia insomnia 
Common depression depression, anxiety, agitation 
Nervous system disorders: 
Very common headache dizziness, headache 

Common disturbance in attention migraine, memory impairment, disturbance in attention 
Eye disorders: 
Common  vision blurred 
Respiratory, thoracic and mediastinal disorders: 
Very common  dyspnoea, cough 
Common dyspnoea, dyspnoea exertional, cough dyspnoea exertional 
Gastrointestinal disorders: 
Very common nausea diarrhoea, nausea, vomiting 

Common abdominal discomfort, constipation, dyspepsia 
constipation, dry mouth, gastroesophageal 
reflux 

Hepatobiliary disorders: 
Very common blood bilirubin increased blood bilirubin increased 
Skin and subcutaneous tissue disorders: 
Very common  rash, pruritus 
Common alopecia, dry skin, pruritus alopecia, dry skin 
Musculoskeletal and connective tissue disorders: 
Very common  arthralgia, myalgia 

Common arthralgia, back pain, muscle spasms, myalgia back pain, muscle spasms 

General disorders and administration site conditions: 

Very common fatigue, irritability chills, fatigue, influenza-like illness, irritability, pain, pyrexia 
Common pyrexia, asthenia chest pain, asthenia 
a. SOF = sofosbuvir; b. RBV = ribavirin; c. PEG = peginterferon alfa; d. Decreased appetite was identified as an adverse drug 
reaction to Sovaldi in combination with ribavirin oral solution in paediatric patients aged 3 to < 12 years 
 



46 

Description of selected adverse reactions 
 
Cardiac arrhythmias 
Cases of severe bradycardia and heart block have been observed when sofosbuvir containing-regimes 
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 
 
Other special population(s) 
 
HIV/HCV co-infection 
The safety profile of sofosbuvir and ribavirin in HCV/HIV co-infected adult patients was similar to 
that observed in mono-infected HCV patients treated with sofosbuvir and ribavirin in Phase 3 clinical 
studies (see section 5.1). 
 
Patients awaiting liver transplantation 
The safety profile of sofosbuvir and ribavirin in HCV infected adult patients prior to liver 
transplantation was similar to that observed in patients treated with sofosbuvir and ribavirin in Phase 3 
clinical studies (see section 5.1). 
 
Patients with Renal Impairment  
Sofosbuvir in a fixed dose combination with ledipasvir was administered for 12 weeks to 18 patients 
with genotype 1 CHC and severe renal impairment in an open-label study (Study 0154). 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. 
 
Adult liver transplant recipients 
The safety profile of sofosbuvir and ribavirin in liver transplant adult recipients with chronic 
hepatitis C was similar to that observed in patients treated with sofosbuvir and ribavirin in Phase 3 
clinical studies (see section 5.1). In study 0126, decreases in haemoglobin during treatment were very 
common with 32.5% (13/40 patients) experiencing a decline in haemoglobin to <10 g/dL, 1 of whom 
also had a decline to <8.5 g/dL. Eight patients (20%) received epoetin and/or a blood product.  In 
5 patients (12.5%), study drugs were discontinued, modified or interrupted due to adverse events. 
 
Paediatric population 
The safety and efficacy of Sovaldi in paediatric patients aged 3 years and above are based on data 
from 106 patients who were treated with Sovaldi and ribavirin for 12 weeks (genotype 2 patients) and 
for 24 weeks (genotype 3 patients) in a Phase 2, open-label clinical trial. No adverse drug reactions 
specific to Sovaldi have been identified. The adverse reactions observed were generally consistent 
with those observed in clinical studies of Sovaldi plus ribavirin in adults (see Table 6). Decreased 
appetite was observed as a very common adverse drug reaction to Sovaldi when given in combination 
with ribavirin oral solution in paediatric patients 3 to < 12 years. 
 
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. 
 

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


47 

4.9 Overdose 
 
The highest documented dose of sofosbuvir was a single supratherapeutic dose of sofosbuvir 1,200 mg 
administered to 59 healthy subjects. In that study, there were no untoward effects observed at this dose 
level, and adverse reactions were similar in frequency and severity to those reported in the placebo and 
sofosbuvir 400 mg treatment groups. The effects of higher doses are unknown. 
 
No specific antidote is available for overdose with Sovaldi.  If overdose occurs the patient must be 
monitored for evidence of toxicity. Treatment of overdose with Sovaldi 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 (53% extraction ratio) the predominant circulating metabolite 
GS-331007. A 4-hour haemodialysis session removed 18% of the administered dose. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antivirals for systemic use, direct-acting antiviral; ATC code: J05AP08 
 
Mechanism of action 
 
Sofosbuvir is a pan-genotypic inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is 
essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular 
metabolism to form the pharmacologically active uridine analog 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 with a 50% inhibitory concentration (IC50) value ranging from 0.7 to 
2.6 μM.  GS-461203 (the active metabolite of sofosbuvir) is not an inhibitor of human DNA and 
RNA polymerases nor an inhibitor of mitochondrial RNA polymerase. 
 
Antiviral activity 
 
In HCV replicon assays, the effective concentration (EC50) values of sofosbuvir against full-length 
replicons from genotype 1a, 1b, 2a, 3a and 4a were 0.04, 0.11, 0.05, 0.05 and 0.04 μM, respectively, 
and EC50 values of sofosbuvir against chimeric 1b replicons encoding NS5B from genotype 2b, 5a or 
6a were 0.014 to 0.015 μM. The mean ± SD EC50 of sofosbuvir against chimeric replicons encoding 
NS5B sequences from clinical isolates was 0.068 ± 0.024 μM for genotype 1a (n = 67), 
0.11 ± 0.029 μM for genotype 1b (n = 29), 0.035 ± 0.018 μM for genotype 2 (n = 15) and 
0.085 ± 0.034 μM for genotype 3a (n = 106). In these assays, the in vitro antiviral activity of 
sofosbuvir against the less common genotypes 4, 5 and 6 was similar to that observed for genotypes 1, 
2 and 3. 
 
The presence of 40% human serum had no effect on the anti-HCV activity of sofosbuvir. 
 
Resistance 
 
In cell culture 
HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple 
genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced susceptibility to sofosbuvir was associated 
with the primary NS5B substitution S282T in all replicon genotypes examined.  Site-directed 
mutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2- to 18-fold reduced 
susceptibility to sofosbuvir and reduced the replication viral capacity by 89% to 99% compared to the 
corresponding wild-type. In biochemical assays, recombinant NS5B polymerase from genotypes 1b, 
2a, 3a and 4a expressing the S282T substitution showed reduced susceptibility to GS-461203 
compared to respective wild-types. 
 



48 

In clinical studies - Adults 
In a pooled analysis of 991 patients who received sofosbuvir in Phase 3 studies, 226 patients qualified 
for resistance analysis due to virologic failure or early study drug discontinuation and having 
HCV RNA >1,000 IU/mL. Post-baseline NS5B sequences were available for 225 of the 226 patients, 
with deep sequencing data (assay cutoff of 1%) from 221 of these patients. The sofosbuvir-associated 
resistance substitution S282T was not detected in any of these patients by deep sequencing or 
population sequencing. The S282T substitution in NS5B was detected in a single subject receiving 
Sovaldi monotherapy in a Phase 2 study. This subject harboured <1% HCV S282T at baseline and 
developed S282T (>99%) at 4 weeks post-treatment which resulted in a 13.5-fold change in sofosbuvir 
EC50 and reduced viral replication capacity. The S282T substitution reverted to wild-type over the next 
8 weeks and was no longer detectable by deep sequencing at 12 weeks post-treatment. 
 
Two NS5B substitutions, L159F and V321A, were detected in post-treatment relapse samples from 
multiple genotype 3 HCV infected patients in the Phase 3 clinical studies. No shift in the phenotypic 
susceptibility to sofosbuvir or ribavirin of subject isolates with these substitutions was detected.  In 
addition, S282R and L320F substitutions were detected on treatment by deep sequencing in a 
pre-transplant subject with a partial treatment response. The clinical significance of these findings is 
unknown. 
 
Effect of baseline HCV polymorphisms on treatment outcome 
 
Adult population 
Baseline NS5B sequences were obtained for 1,292 patients from Phase 3 studies by population 
sequencing and the S282T substitution was not detected in any subject with available baseline 
sequence. In an analysis evaluating the effect of baseline polymorphisms on treatment outcome, no 
statistically significant association was observed between the presence of any HCV NS5B variant at 
baseline and treatment outcome. 
 
Paediatric population 
The presence of NS5B RAVs did not impact treatment outcome; all patients with baseline NS5B 
nucleoside inhibitor RAVs achieved SVR following treatment with sofosbuvir.  
 
Cross-resistance 
 
HCV replicons expressing the sofosbuvir-associated resistance substitution S282T were fully 
susceptible to other classes of anti-HCV agents. Sofosbuvir retained activity against the 
NS5B substitutions L159F and L320F associated with resistance to other nucleoside inhibitors.  
Sofosbuvir was fully active against substitutions associated with resistance to other direct-acting 
antivirals with different mechanisms of actions, such as NS5B non-nucleoside inhibitors, NS3 protease 
inhibitors and NS5A inhibitors. 
 
Clinical efficacy and safety 
 
The efficacy of sofosbuvir was evaluated in five Phase 3 studies in a total of 1,568 adult patients with 
genotypes 1 to 6 chronic hepatitis C.  One study was conducted in treatment-naïve patients with 
genotype 1, 4, 5 or 6 chronic hepatitis C in combination with peginterferon alfa 2a and ribavirin and 
the other four studies were conducted in patients with genotype 2 or 3 chronic hepatitis C in 
combination with ribavirin including one in treatment-naïve patients, one in interferon intolerant, 
ineligible or unwilling patients, one in patients previously treated with an interferon-based regimen, 
and one in all patients irrespective of prior treatment history or ability to receive treatment with 
interferon. Patients in these studies had compensated liver disease including cirrhosis. Sofosbuvir was 
administered at a dose of 400 mg once daily. The ribavirin dose was weight-based at 1,000-1,200 mg 
daily administered in two divided doses, and the peginterferon alfa 2a dose, where applicable, was 
180 μg per week. Treatment duration was fixed in each study and was not guided by patients’ 
HCV RNA levels (no response guided algorithm). 
 



49 

Plasma HCV RNA values were measured during the clinical studies using the COBAS TaqMan 
HCV test (version 2.0), for use with the High Pure System. The assay had a lower limit of 
quantification (LLOQ) of 25 IU/mL. Sustained virologic response (SVR) was the primary endpoint to 
determine the HCV cure rate for all studies which was defined as HCV RNA less than LLOQ at 
12 weeks after the end of treatment (SVR12). 
 
Clinical studies in patients with genotype 1, 4, 5 and 6 chronic hepatitis C 
Treatment-naïve adult patients - NEUTRINO (study 110) 
NEUTRINO was an open-label, single-arm study that evaluated 12 weeks of treatment with sofosbuvir 
in combination with peginterferon alfa 2a and ribavirin in treatment-naïve patients with genotype 1, 4, 
5 or 6 HCV infection. 
 
Treated patients (n = 327) had a median age of 54 years (range: 19 to 70); 64% of the patients were 
male; 79% were White; 17% were Black; 14% were Hispanic or Latino; mean body mass index was 
29 kg/m2 (range: 18 to 56 kg/m2); 78% had baseline HCV RNA greater than 6 log10 IU/mL; 17% had 
cirrhosis; 89% had HCV genotype 1 and 11% had HCV genotype 4, 5 or 6.  Table 7 presents the 
response rates for the treatment group of sofosbuvir + peginterferon alfa + ribavirin. 
 
Table 7: Response rates in study NEUTRINO 
 SOF+PEG+RBV 

12 weeks 
(n = 327) 

Overall SVR12 91% (296/327) 
Outcome for patients without 
SVR12 

 

 On-treatment virologic failure 0/327 
 Relapsea 9% (28/326) 
 Otherb 1% (3/327) 
a. The denominator for relapse is the number of patients with HCV RNA <LLOQ at their last on-treatment assessment. 
b. Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up). 
 
Response rates for selected subgroups are presented in Table 8. 
 
Table 8: SVR12 rates for selected subgroups in NEUTRINO 
 SOF+PEG+RBV 

12 weeks 
(n = 327) 

Genotype  
 Genotype 1 90% (262/292) 
 Genotype 4, 5 or 6 97% (34/35) 
Cirrhosis  
 No 93% (253/273) 
 Yes 80% (43/54) 
Race  
 Black 87% (47/54) 
 Non-Black 91% (249/273) 
 
SVR12 rates were similarly high in patients with baseline IL28B C/C allele [94/95 (99%)] and 
non-C/C (C/T or T/T) allele [202/232 (87%)]. 
 
27/28 patients with genotype 4 HCV achieved SVR12.  A single subject with genotype 5 and all 
6 patients with genotype 6 HCV infection in this study achieved SVR12. 
 
Clinical studies in patients with genotype 2 and 3 chronic hepatitis C 
Treatment-naïve adults - FISSION (study 1231) 
FISSION was a randomised, open-label, active-controlled study that evaluated 12 weeks of treatment 
with sofosbuvir and ribavirin compared to 24 weeks of treatment with peginterferon alfa 2a and 
ribavirin in treatment-naïve patients with genotype 2 or 3 HCV infection. The ribavirin doses used in 
the sofosbuvir + ribavirin and peginterferon alfa 2a + ribavirin arms were weight-based 



50 

1,000-1,200 mg/day and 800 mg/day regardless of weight, respectively. Patients were randomised in a 
1:1 ratio and stratified by cirrhosis (presence versus absence), HCV genotype (2 versus 3) and baseline 
HCV RNA level (<6 log10 IU/mL versus ≥6 log10 IU/mL).  Patients with genotype 2 or 3 HCV were 
enrolled in an approximately 1:3 ratio. 
 
Treated patients (n = 499) had a median age of 50 years (range: 19 to 77); 66% of the patients were 
male; 87% were White; 3% were Black; 14% were Hispanic or Latino; mean body mass index was 
28 kg/m2 (range: 17 to 52 kg/m2); 57% had baseline HCV RNA levels greater than 6 log10 IU/mL; 
20% had cirrhosis; 72% had HCV genotype 3. Table 9 presents the response rates for the treatment 
groups of sofosbuvir + ribavirin and peginterferon alfa + ribavirin. 
 
Table 9: Response rates in study FISSION 
 SOF+RBV 

12 weeks 
(n = 256)a 

PEG+RBV 
24 weeks 
(n = 243) 

Overall SVR12 67% (171/256) 67% (162/243) 
 Genotype 2 95% (69/73) 78% (52/67) 
 Genotype 3 56% (102/183) 63% (110/176) 
Outcome for patients without 
SVR12 

  

 On-treatment virologic failure < 1% (1/256) 7% (18/243) 
 Relapseb 30% (76/252) 21% (46/217) 
 Otherc 3% (8/256) 7% (17/243) 
a. The efficacy analysis includes 3 patients with recombinant genotype 2/1 HCV infection. 
b. The denominator for relapse is the number of patients with HCV RNA <LLOQ at their last on-treatment assessment. 
c. Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up). 
 
The difference in the overall SVR12 rates between sofosbuvir + ribavirin and peginterferon alfa + 
ribavirin treatment groups was 0.3% (95% confidence interval: -7.5% to 8.0%) and the study met the 
predefined non-inferiority criterion. 
 
Response rates for patients with cirrhosis at baseline are presented in Table 10 by HCV genotype. 
 
Table 10: SVR12 rates by cirrhosis and genotype in study FISSION 

 Genotype 2 Genotype 3 
 SOF+RBV 

12 weeks 
(n = 73)a 

PEG+RBV 
24 weeks 
(n = 67) 

SOF+RBV 
12 weeks 
(n = 183) 

PEG+RBV 
24 weeks 
(n = 176) 

Cirrhosis     
 No 97% (59/61) 81% (44/54) 61% (89/145) 71% (99/139) 
 Yes 83% (10/12) 62% (8/13) 34% (13/38) 30% (11/37) 
a. The efficacy analysis includes 3 patients with recombinant genotype 2/1 HCV infection. 
 
Interferon intolerant, ineligible or unwilling adults - POSITRON (study 107) 
POSITRON was a randomised, double-blinded, placebo-controlled study that evaluated 12 weeks of 
treatment with sofosbuvir and ribavirin (n = 207) compared to placebo (n = 71) in patients who are 
interferon intolerant, ineligible or unwilling. Patients were randomised in 3:1 ratio and stratified by 
cirrhosis (presence versus absence). 
 
Treated patients (n = 278) had a median age of 54 years (range: 21 to 75); 54% of the patients were 
male; 91% were White; 5% were Black; 11% were Hispanic or Latino; mean body mass index was 
28 kg/m2 (range: 18 to 53 kg/m2); 70% had baseline HCV RNA levels greater than 6 log10 IU/mL; 
16% had cirrhosis; 49% had HCV genotype 3.  The proportions of patients who were interferon 
intolerant, ineligible, or unwilling were 9%, 44%, and 47%, respectively. Most patients had no prior 
HCV treatment (81.3%). Table 11 presents the response rates for the treatment groups of sofosbuvir + 
ribavirin and placebo. 
 



51 

Table 11: Response rates in study POSITRON 
 SOF+RBV 

12 weeks 
(n = 207) 

Placebo 
12 weeks 
(n = 71) 

Overall SVR12 78% (161/207) 0/71 
 Genotype 2 93% (101/109) 0/34 
 Genotype 3 61% (60/98) 0/37 
Outcome for patients without 
SVR12 

  

 On-treatment virologic failure 0/207 97% (69/71) 
 Relapsea 20% (42/205) 0/0 
 Otherb 2% (4/207) 3% (2/71) 
a. The denominator for relapse is the number of patients with HCV RNA <LLOQ at their last on-treatment assessment. 
b. Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up). 
 
The SVR12 rate in the sofosbuvir + ribavirin treatment group was statistically significant when 
compared to placebo (p <0.001). 
 
Table 12 presents the subgroup analysis by genotype for cirrhosis and interferon classification. 
 
Table 12: SVR12 rates for selected subgroups by genotype in POSITRON 

 SOF+RBV 
12 weeks 

 Genotype 2 
(n = 109) 

Genotype 3 
(n = 98) 

Cirrhosis   
 No 92% (85/92) 68% (57/84) 
 Yes 94% (16/17) 21% (3/14) 
Interferon classification   
 Ineligible 88% (36/41) 70% (33/47) 
 Intolerant 100% (9/9) 50% (4/8) 
 Unwilling 95% (56/59) 53% (23/43) 
 
Previously treated adults - FUSION (study 108) 
FUSION was a randomised, double-blinded study that evaluated 12 or 16 weeks of treatment with 
sofosbuvir and ribavirin in patients who did not achieve SVR with prior interferon-based treatment 
(relapsers and nonresponders).  Patients were randomised in a 1:1 ratio and stratified by cirrhosis 
(presence versus absence) and HCV genotype (2 versus 3). 
 
Treated patients (n = 201) had a median age of 56 years (range: 24 to 70); 70% of the patients were 
male; 87% were White; 3% were Black; 9% were Hispanic or Latino; mean body mass index was 
29 kg/m2 (range: 19 to 44 kg/m2); 73% had baseline HCV RNA levels greater than 6 log10 IU/mL; 
34% had cirrhosis; 63% had HCV genotype 3; 75% were prior relapsers.  Table 13 presents the 
response rates for the treatment groups of sofosbuvir + ribavirin for 12 weeks and 16 weeks. 
 
Table 13: Response rates in study FUSION 
 SOF+RBV 

12 weeks 
(n = 103)a 

SOF+RBV 
16 weeks 
(n = 98)a 

Overall SVR12 50% (51/103) 71% (70/98) 
 Genotype 2 82% (32/39) 89% (31/35) 
 Genotype 3 30% (19/64) 62% (39/63) 
Outcome for patients without SVR12   
 On-treatment virologic failure 0/103 0/98 
 Relapseb 48% (49/103) 29% (28/98) 
 Otherc 3% (3/103) 0/98 
a. The efficacy analysis includes 6 patients with recombinant genotype 2/1 HCV infection. 
b. The denominator for relapse is the number of patients with HCV RNA <LLOQ at their last on-treatment assessment. 
c. Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up). 
 



52 

Table 14 presents the subgroup analysis by genotype for cirrhosis and response to prior 
HCV treatment. 
 
Table 14: SVR12 rates for selected subgroups by genotype in study FUSION 

 Genotype 2 Genotype 3 
 SOF+RBV 

12 weeks 
(n = 39) 

SOF+RBV 
16 weeks 
(n = 35) 

SOF+RBV 
12 weeks 
(n = 64) 

SOF+RBV 
16 weeks 
(n = 63) 

Cirrhosis     
 No 90% (26/29) 92% (24/26) 37% (14/38) 63% (25/40) 
 Yes 60% (6/10) 78% (7/9) 19% (5/26) 61% (14/23) 
Response to prior 
HCV treatment 

    

 Relapser 86% (25/29) 89% (24/27) 31% (15/49) 65% (30/46) 
 Nonresponder 70% (7/10) 88% (7/8) 27% (4/15) 53% (9/17) 
 
Treatment-naïve and previously treated adults - VALENCE (study 133) 
VALENCE was a Phase 3 study that evaluated sofosbuvir in combination with weight-based ribavirin 
for the treatment of genotype 2 or 3 HCV infection in treatment-naïve patients or patients who did not 
achieve SVR with prior interferon-based treatment, including patients with compensated cirrhosis. The 
study was designed as a direct comparison of sofosbuvir and ribavirin versus placebo for 12 weeks. 
However, based on emerging data, the study was unblinded and all HCV genotype 2 patients 
continued to receive sofosbuvir and ribavirin for 12 weeks, whilst treatment for HCV genotype 3 
patients was extended to 24 weeks. Eleven HCV genotype 3 patients had already completed treatment 
with sofosbuvir and ribavirin for 12 weeks at the time of the amendment. 
 
Treated patients (n = 419) had a median age of 51 years (range: 19 to 74); 60% of the patients were 
male; median body mass index was 25 kg/m2 (range: 17 to 44 kg/m2); the mean baseline HCV RNA 
level was 6.4 log10 IU/mL; 21% had cirrhosis; 78% had HCV genotype 3; 65% were prior relapsers.  
Table 15 presents the response rates for the treatment groups of sofosbuvir + ribavirin for 12 weeks 
and 24 weeks. 
 
Placebo recipients are not included in the tables since none achieved SVR12. 
 
Table 15: Response rates in study VALENCE 

 
Genotype 2 
SOF+RBV 12 weeks 
(n = 73) 

Genotype 3 
SOF+RBV 12 weeks 
(n = 11) 

Genotype 3 
SOF+RBV 24 weeks 
(n = 250) 

Overall SVR12 93% (68/73) 27% (3/11) 84% (210/250) 
Outcome for patients 
without SVR12    

 On-treatment virologic failure 
0% (0/73) 0% (0/11) 0.4% (1/250) 

 Relapsea 7% (5/73) 55% (6/11) 14% (34/249) 
 Otherb 0% (0/73) 18% (2/11) 2% (5/250) 
a. The denominator for relapse is the number of patients with HCV RNA <LLOQ at their last on-treatment assessment. 
b. Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up). 
 
Table 16 presents the subgroup analysis by genotype for cirrhosis and exposure to prior 
HCV treatment. 
 



53 

Table 16: SVR12 rates for selected subgroups by genotype in study VALENCE 
 Genotype 2 

SOF+RBV 12 weeks 
(n = 73) 

Genotype 3 
SOF+RBV 24 weeks 
(n = 250) 

Treatment-naïve 97% (31/32) 93% (98/105) 
 Non-cirrhotic 97% (29/30) 93% (86/92) 
 Cirrhotic 100% (2/2) 92% (12/13) 
Treatment-experienced 90% (37/41) 77% (112/145) 
 Non-cirrhotic 91% (30/33) 85% (85/100) 
 Cirrhotic 88% (7/8) 60% (27/45) 
 
SVR12 to SVR24 concordance 
The concordance between SVR12 and SVR24 (SVR 24 weeks after the end of the treatment) 
following treatment with sofosbuvir in combination with ribavirin or ribavirin and pegylated interferon 
demonstrates a positive predictive value of 99% and a negative predictive value of 99%. 
 
Clinical efficacy and safety in special populations 
HCV/HIV co-infected adult patients - PHOTON-1 (study 123) 
Sofosbuvir was studied in an open-label clinical study evaluating the safety and efficacy of 12 or 
24 weeks of treatment with sofosbuvir and ribavirin in patients with genotype 1, 2 or 3 chronic 
hepatitis C co-infected with HIV-1.  Genotype 2 and 3 patients were either treatment-naïve or 
experienced, whereas genotype 1 patients were naïve to prior treatment. Treatment duration was 
12 weeks in treatment-naïve patients with genotype 2 or 3 HCV infection, and 24 weeks in 
treatment-experienced patients with genotype 3 HCV infection, as well as patients with genotype 1 
HCV infection. Patients received 400 mg sofosbuvir and weight-based ribavirin (1,000 mg for patients 
weighing <75 kg or 1,200 mg for patients weighing ≥75 kg). Patients were either not on antiretroviral 
therapy with a CD4+ cell count >500 cells/mm3 or had virologically suppressed HIV-1 with a CD4+ 
cell count >200 cells/mm3.  95% of patients received antiretroviral therapy at the time of enrolment.  
Preliminary SVR12 data are available for 210 patients. 
 
Table 17 presents the response rates by genotype and exposure to prior HCV treatment. 
 
Table 17: Response rates in study PHOTON-1 

 

Genotype 2/3 
treatment-naïve  
SOF+RBV 
12 weeks 
(n = 68) 

Genotype 2/3 
treatment-experienced  
SOF+RBV 
24 weeks 
(n = 28) 

Genotype 1 
treatment-naïve  
SOF+RBV 
24 weeks 
(n = 114) 

Overall SVR12 75% (51/68) 93% (26/28) 76% (87/114) 
Outcome for patients 
without SVR12    

 On-treatment virologic failure 1% (1/68) 0/28 1% (1/114) 

 Relapsea 18% (12/67) 7% (2/28) 22% (25/113) 
 Otherb 6% (4/68) 0/28 1% (1/114) 
a. The denominator for relapse is the number of patients with HCV RNA <LLOQ at their last on-treatment assessment. 
b. Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up). 
 
Table 18 presents the subgroup analysis by genotype for cirrhosis. 
 
Table 18: SVR12 rates for selected subgroups by genotype in study PHOTON-1 

 HCV genotype 2 HCV genotype 3 

 
SOF+RBV 
12 weeks 
TN (n = 26) 

SOF+RBV 
24 weeks 
TE (n = 15) 

SOF+RBV 
12 weeks 
TN (n = 42) 

SOF+RBV 
24 weeks 
TE (n = 13) 

Overall 88% (23/26) 93% (14/15) 67% (28/42) 92% (12/13) 
 No cirrhosis 88% (22/25) 92% (12/13) 67% (24/36) 100% (8/8) 
 Cirrhosis 100% (1/1) 100% (2/2) 67% (4/6) 80% (4/5) 
TN = treatment-naïve; TE = treatment-experienced. 



54 

 
Adult patients awaiting liver transplantation - Study 2025 
Sofosbuvir was studied in HCV infected patients prior to undergoing liver transplantation in an 
open-label clinical study evaluating the safety and efficacy of sofosbuvir and ribavirin administered 
pre-transplant to prevent post-transplant HCV reinfection. The primary endpoint of the study was 
post-transplant virologic response (pTVR, HCV RNA <LLOQ at 12 weeks post-transplant). 
HCV infected patients, regardless of genotype, with hepatocellular carcinoma (HCC) meeting the 
MILAN criteria received 400 mg sofosbuvir and 1,000-1,200 mg ribavirin daily for a maximum of 
24 weeks, subsequently amended to 48 weeks, or until the time of liver transplantation, whichever 
occurred first. An interim analysis was conducted on 61 patients who received sofosbuvir and 
ribavirin; the majority of patients had HCV genotype 1, 44 patients were CPT class A and 17 patients 
were CPT class B. Of these 61 patients, 44 patients underwent liver transplantation following up to 
48 weeks of treatment with sofosbuvir and ribavirin; 41 had HCV RNA <LLOQ at the time of 
transplantation.  The virologic response rates of the 41 patients transplanted with HCV RNA <LLOQ 
is described in Table 19. Duration of viral suppression prior to transplantation was the most predictive 
factor for pTVR in those who were HCV RNA <LLOQ at the time of transplantation. 
 
Table 19: Virologic response post-transplant in patients with HCV RNA <LLOQ at the time of 
liver transplantation 
 Week 12 

post-transplant 
(pTVR)b 

Virologic response in 
evaluable patientsa 23/37 (62%) 

a. Evaluable patients are defined as those who have reached the specified time point at the time of the interim analysis. 
b. pTVR: post-transplant virologic response (HCV RNA <LLOQ at 12 weeks post-procedure). 
 
In patients that discontinued therapy at 24 weeks, according to protocol, the relapse rate was 11/15. 
 
Adult liver transplant recipients - Study 0126 
Sofosbuvir was studied in an open-label clinical study evaluating the safety and efficacy of 24 weeks 
of treatment with sofosbuvir and ribavirin in liver transplant recipients with chronic hepatitis C.  
Eligible patients were ≥18 years old and had undergone liver transplantation 6 to 150 months prior to 
screening.  Patients had HCV RNA ≥104 IU/mL at screening and documented evidence of chronic 
HCV infection pre-transplantation. The starting dose of ribavirin was 400 mg given in a divided daily 
dose. If patients maintained haemoglobin levels ≥12 g/dL, ribavirin dose was increased at weeks 2, 4, 
and up to every 4 weeks until the appropriate weight-based dose was reached (1,000 mg daily in 
patients <75 kg, 1,200 mg daily in patients ≥75 kg). The median ribavirin dose was 600 mg-800 mg 
daily at weeks 4-24. 
 
Forty patients (33 with HCV genotype 1 infection, 6 with HCV genotype 3 infection, and 1 with HCV 
genotype 4 infection) were enrolled, 35 of whom had previously failed interferon-based treatment, and 
16 of whom had cirrhosis. 28 out of 40 (70%) patients achieved SVR12: 22/33 (73%) with HCV 
genotype 1 infection, 6/6 (100%) with HCV genotype 3 infection, and 0/1 (0%) with HCV genotype 4 
infection. All patients who achieved SVR12 achieved SVR24 and SVR48. 
 
Overview of outcomes by therapeutic regimen and treatment duration, a comparison across studies 
The following tables (Table 20 to Table 23) present data from Phase 2 and Phase 3 studies relevant to 
the dosing to help clinicians determine the best regimen for individual patients. 
 



55 

Table 20: Outcomes by therapeutic regimen and treatment duration, a comparison across 
studies in genotype 1 HCV infection 
Patient population 
(Study number/name) 

Regimen/Duration Subgroup SVR12 rate % (n/N) 

Treatment-naïvea 
(NEUTRINO) SOF+PEG+RBV 12 weeks

 

Overall 90% (262/292) 
Genotype 1a 92% (206/225) 
Genotype 1b 83% (55/66) 
No cirrhosis 93% (253/273) 
Cirrhosis 80% (43/54) 

Treatment-naïve and 
co-infected with HIV  
(PHOTON-1) 

SOF+RBV 24 weeks 

Overall 76% (87/114) 
Genotype 1a 82% (74/90) 
Genotype 1b 54% (13/24) 
No cirrhosis 77% (84/109) 
Cirrhosis 60% (3/5) 

Treatment-naïve 
(QUANTUMb and 11-1-0258b)   SOF+RBV 24 weeks 

Overallc 65% (104/159) 
Genotype 1ac 69% (84/121) 
Genotype 1bc 53% (20/38) 
No cirrhosisc 68% (100/148) 
Cirrhosisc 36% (4/11) 

n = number of patients with SVR12 response; N = total number of patients per group. 
a. For previously treated patients with genotype 1 HCV infection, no data exists with the combination of sofosbuvir, 
peginterferon alfa and ribavirin.  Consideration should be given to treating these patients, and potentially extending the 
duration of therapy with sofosbuvir, peginterferon alfa and ribavirin beyond 12 weeks and up to 24 weeks; especially for 
those subgroups who have one or more factors historically associated with lower response rates to interferon-based therapies 
(prior null response to peginterferon alfa and ribavirin therapy, advanced fibrosis/cirrhosis, high baseline viral concentrations, 
black race, IL28B non CC genotype). 
b. These are exploratory or Phase 2 studies.  The outcomes should be interpreted with caution, as subject numbers are small 
and SVR rates may be impacted by the selection of patients. 
c. Summary data from both studies. 
 
Table 21: Outcomes by therapeutic regimen and treatment duration, a comparison across 
studies in genotype 2 HCV infection 
Patient population 
(Study number/name) 

Regimen/Duration Subgroup SVR12 rate % (n/N) 

Treatment-naïve 
(FISSION) SOF+RBV 12 weeks

 
Overall 95% (69/73) 
No cirrhosis 97% (59/61) 
Cirrhosis 83% (10/12) 

Interferon intolerant, ineligible 
or unwilling 
(POSITRON) 

SOF+RBV 12 weeks 
Overall 93% (101/109) 
No cirrhosis 92% (85/92) 
Cirrhosis 94% (16/17) 

Treatment-experienced 
(FUSION) SOF+RBV 12 weeks 

Overall 82% (32/39) 
No cirrhosis 90% (26/29) 
Cirrhosis 60% (6/10) 

Treatment-naïve 
(VALENCE) SOF+RBV 12 weeks 

Overall 97% (31/32) 
No cirrhosis 97% (29/30) 
Cirrhosis 100% (2/2) 

Treatment-experienced 
(VALENCE) SOF+RBV 12 weeks 

Overall 90% (37/41) 
No cirrhosis 91% (30/33) 
Cirrhosis 88% (7/8) 

Treatment-experienced 
(FUSION) SOF+RBV 16 weeks 

Overall 89% (31/35) 
No cirrhosis 92% (24/26) 
Cirrhosis 78% (7/9) 

Treatment-naïve  
co-infected with HIV 
(PHOTON-1) 

SOF+RBV 12 weeks 
Overall 88% (23/26) 
No cirrhosis 88% (22/25) 
Cirrhosis 100% (1/1) 

Treatment-experienced 
co-infected with HIV 
(PHOTON-1) 

SOF+RBV 24 weeks 
Overalla 93% (14/15) 
No cirrhosisa 92% (12/13) 
Cirrhosisa 100% (2/2) 

Treatment-naïve 
(ELECTRONb and PROTONb) SOF+PEG+RBV 12 weeks

 Overallc 96% (25/26) 



56 

Patient population 
(Study number/name) 

Regimen/Duration Subgroup SVR12 rate % (n/N) 

Treatment-experienced 
(LONESTAR-2b) SOF+PEG+RBV 12 weeks 

Overall 96% (22/23) 
No cirrhosis 100% (9/9) 
Cirrhosis 93% (13/14) 

n = number of patients with SVR12 response; N = total number of patients per group. 
a. These data are preliminary. 
b. These are exploratory or Phase 2 studies.  The outcomes should be interpreted with caution, as subject numbers are small 
and SVR rates may be impacted by the selection of patients.  In the ELECTRON study (N = 11), the duration of 
peginterferon alfa ranged from 4-12 weeks in combination with sofosbuvir + ribavirin. 
c. All patients were non-cirrhotic in these two studies. 
 
Table 22: Outcomes by therapeutic regimen and treatment duration, a comparison across 
studies in genotype 3 HCV infection 
Patient population 
(Study number/name) 

Regimen/Duration Subgroup SVR12 rate % (n/N) 

Treatment-naïve 
(FISSION) SOF+RBV 12 weeks

 
Overall 56% (102/183) 
No cirrhosis 61% (89/145) 
Cirrhosis 34% (13/38) 

Interferon intolerant, ineligible 
or unwilling 
(POSITRON) 

SOF+RBV 12 weeks 
Overall 61% (60/98) 
No cirrhosis 68% (57/84) 
Cirrhosis 21% (3/14) 

Treatment-experienced 
(FUSION) SOF+RBV 12 weeks 

Overall 30% (19/64) 
No cirrhosis 37% (14/38) 
Cirrhosis 19% (5/26) 

Treatment-experienced 
(FUSION) SOF+RBV 16 weeks 

Overall 62% (39/63) 
No cirrhosis 63% (25/40) 
Cirrhosis 61% (14/23) 

Treatment-naïve  
(VALENCE) SOF+RBV 24 weeks 

Overall 93% (98/105) 
No cirrhosis 94% (86/92) 
Cirrhosis 92% (12/13) 

Treatment-experienced 
(VALENCE) SOF+RBV 24 weeks

 
Overall 77% (112/145) 
No cirrhosis 85% (85/100) 
Cirrhosis 60% (27/45) 

Treatment-naïve  
co-infected with HIV 
(PHOTON-1) 

SOF+RBV 12 weeks 
Overall 67% (28/42) 
No cirrhosis 67% (24/36) 
Cirrhosis 67% (4/6) 

Treatment-experienced 
co-infected with HIV 
(PHOTON-1) 

SOF+RBV 24 weeks 
Overalla 92% (12/13) 
No cirrhosisa 100% (8/8) 
Cirrhosisa 80% (4/5) 

Treatment-naïve 
(ELECTRONb and PROTONb) SOF+PEG+RBV 12 weeks

 Overallc 97% (38/39) 

Treatment-experienced 
(LONESTAR-2b) SOF+PEG+RBV 12 weeks 

Overall 83% (20/24) 
No cirrhosis 83% (10/12) 
Cirrhosis 83% (10/12) 

n = number of patients with SVR12 response; N = total number of patients per group. 
a. These data are preliminary. 
b. These are exploratory or Phase 2 studies.  The outcomes should be interpreted with caution, as subject numbers are small 
and SVR rates may be impacted by the selection of patients.  In the ELECTRON study (N = 11), the duration of 
peginterferon alfa ranged from 4-12 weeks in combination with sofosbuvir + ribavirin. 
c. All patients were non-cirrhotic in these two studies. 
 
Table 23: Outcomes by therapeutic regimen and treatment duration, a comparison across 
studies in genotype 4, 5 and 6 HCV infection 
Patient population 
(Study number/name) 

Regimen/Duration Subgroup SVR12 rate % (n/N) 

Treatment-naïve 
(NEUTRINO) SOF+PEG+RBV 12 weeks

 
Overall 97% (34/35) 
No cirrhosis 100% (33/33) 
Cirrhosis 50% (1/2) 

n = number of patients with SVR12 response; N = total number of patients per group. 
 



57 

Patients with renal impairment 
Study 0154 was an open-label clinical study that evaluated the safety and efficacy of 24 weeks of 
treatment with sofosbuvir in combination with ribavirin in 20 genotype 1 or 3 HCV-infected patients 
with severe renal impairment not requiring dialysis. Following treatment with sofosbuvir 200 mg or 
400 mg in combination with ribavirin the SVR12 rate in patients with ESRD was 40% and 60%, 
respectively. The safety and efficacy of 12 weeks of treatment with ledipasvir/sofosbuvir in 18 
genotype 1 HCV-infected patients with severe renal impairment not requiring dialysis was also studied 
in Study 0154. At baseline, two patients had cirrhosis and the mean eGFR was 24.9 mL/min (range: 
9.0-39.6).  SVR12 was achieved in 100 % (18/18) of patients treated with ledipasvir/sofosbuvir.  
 
Study 4063 was an open-label study that evaluated a fixed dose combination of sofosbuvir and 
ledipasvir in 95 patients with HCV-infection and ESRD requiring dialysis. The SVR rates for the 8, 
12, and 24 week ledipasvir/sofosbuvir treatment groups were 93% (42/45), 100% (31/31), and 79% 
(15/19), respectively. Of the seven patients who did not achieve SVR12, none experienced virologic 
failure or relapsed. 
 
Study 4062 was an open-label study that evaluated a fixed dose combination of sofosbuvir and 
velpatasvir in 59 HCV-infected patients with ESRD requiring dialysis. The SVR rate was 95% 
(56/59); of the three patients that did not achieve SVR12, one had completed sofosbuvir with 
velpatasvir treatment and relapsed.  
 
Paediatric population 
The efficacy of sofosbuvir in HCV-infected patients aged 3years and above was evaluated in a 
Phase 2, open label clinical trial that enrolled 106 patients with genotype 2 (n = 31) or genotype 3 
(n = 75) chronic HCV infection.  Patients with HCV genotype 2 or 3 infection in the trial were treated 
with sofosbuvir with ribavirin for 12 or 24 weeks, respectively. 
 
Patients aged 12 to < 18 Years: 
Sofosbuvir was evaluated in 52 patients 12 to < 18 years with genotype 2 (n = 13) or genotype 3 (n = 
39) HCV infection. The median age was 15 years (range: 12 to 17); 40% of the patients were female; 
90% were White, 4% were Black, and 2% were Asian; 4% were Hispanic/Latino; mean weight was 
60.4 kg (range: 29.6 to 75.6 kg); 17% were treatment experienced; 65% had baseline HCV RNA 
levels greater than or equal to 800,000 IU/mL; and no patients had known cirrhosis.  The majority of 
patients (69%) had been infected through vertical transmission. 
 
The SVR12 rate was 98% overall (100% [13/13] in genotype 2 patients and 97% [38/39]) in 
genotype 3 patients. No patient experienced on-treatment virologic failure or relapse; one patient with 
genotype 3 HCV infection achieved SVR4 but did not return for the SVR12 visit. 
 
Patients aged 6 to < 12 Years:  
Sofosbuvir was evaluated in 41 patients 6 to < 12 years of age with genotype 2 (n = 13), or genotype 3 
(n = 28) HCV infection. The median age was 9 years (range: 6 to 11); 73% of the patients were 
female; 71% were White and 20% were Asian; 15% were Hispanic/Latino; mean weight was 33.7 kg 
(range: 15.1 to 80.0 kg); 98% were treatment naive; 46% had baseline HCV RNA levels greater than 
or equal to 800,000 IU /mL; and no patients had known cirrhosis. The majority of patients (98%) had 
been infected through vertical transmission. 
 
The SVR12 rate was 100% (100% [13/13] in genotype 2 patients and 100% [28/28] in genotype 3 
patients). No patients experienced on-treatment virologic failure or relapse. 
 
Patients aged 3 to < 6 Years:  
Sofosbuvir was evaluated in 13 patients 3 to < 6 years with genotype 2 (n = 5) or genotype 3 (n = 8) 
HCV infection. The median age was 4 years (range: 3 to 5); 77% of the patients were female; 69% 
were White, 8% were Black, and 8% were Asian; 8% were Hispanic/Latino; mean weight was 16.8 kg 
(range: 13.0 to 19.2 kg); 100% were treatment naive; 23% had baseline HCV RNA levels greater than 
or equal to 800,000 IU/mL; and no patients had known cirrhosis. The majority of patients (85%) had 
been infected through vertical transmission. 



58 

 
The SVR12 rate was 92% overall (80% [4/5] in genotype 2 patients and 100% [8/8] in genotype 3 
patients). No patients experienced on-treatment virologic failure or relapse; one patient with 
genotype 2 HCV prematurely discontinued study treatment after three days due to abnormal taste of 
the medication and did not return for post-treatment Week 12. 
 
 
5.2 Pharmacokinetic properties 
 
Sofosbuvir is a nucleotide prodrug that is extensively metabolised.  The active metabolite is formed in 
hepatocytes and not observed in plasma. The predominant (>90%) metabolite, GS-331007, is inactive. 
It is formed through sequential and parallel pathways to the formation of active metabolite. 
 
Absorption 
 
The pharmacokinetic properties of sofosbuvir and the predominant circulating metabolite GS-331007 
have been evaluated in healthy adult subjects and in patients with chronic hepatitis C. Following oral 
administration, sofosbuvir was absorbed quickly and the peak plasma concentration was observed 
~0.5-2 hour post-dose, regardless of dose level. Peak plasma concentration of GS-331007 was 
observed between 2 to 4 hours post-dose. Based on population pharmacokinetic analysis in patients 
with genotypes 1 to 6 HCV infection (n = 986), steady-state AUC0-24 for sofosbuvir and GS-331007 
was 1,010 ng•h/mL and 7,200 ng•h/mL, respectively. Relative to healthy subjects (n = 284), the 
sofosbuvir and GS-331007 AUC0-24 was 57% higher and 39% lower, respectively in HCV infected 
patients. 
 
Effects of food 
Relative to fasting conditions, the administration of a single dose of sofosbuvir with a standardised 
high fat meal slowed the rate of absorption of sofosbuvir. The extent of absorption of sofosbuvir was 
increased approximately 1.8-fold, with little effect on peak concentration. The exposure to GS-331007 
was not altered in the presence of a high-fat meal. 
 
Distribution 
 
Sofosbuvir is not a substrate for hepatic uptake transporters, organic anion-transporting polypeptide 
(OATP) 1B1 or 1B3, and organic cation transporter (OCT) 1. While subject to active tubular secretion, 
GS-331007 is not a substrate for renal transporters including organic anion transporter (OAT) 1 or 3, 
OCT2, MRP2, P-gp, BCRP or MATE1.  Sofosbuvir and GS-331007 are not inhibitors of drug 
transporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3 and OCT1.  GS-331007 is not an 
inhibitor of OAT1, OCT2, and MATE1. 
 
Sofosbuvir is approximately 85% bound to human plasma proteins (ex vivo data) 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. 
 
Biotransformation 
 
Sofosbuvir is extensively metabolised in the liver to form the pharmacologically active nucleoside 
analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of 
the carboxyl ester moiety catalysed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and 
phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by 
phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the 
formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks 
anti-HCV activity in vitro.  Sofosbuvir and GS-331007 are not substrates or inhibitors of UGT1A1 or 
CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 enzymes. 
 



59 

After a single 400 mg oral dose of [14C]-sofosbuvir, sofosbuvir and GS-331007 accounted for 
approximately 4% and >90% of drug-related material (sum of molecular weight-adjusted AUC of 
sofosbuvir and its metabolites) systemic exposure, respectively. 
 
Elimination 
 
Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose 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. This data indicate that renal clearance is the major elimination 
pathway for GS-331007 with a large part actively secreted. The median terminal half-lives of 
sofosbuvir and GS-331007 were 0.4 and 27 hours respectively. 
 
Linearity/non-linearity 
 
The dose linearity of sofosbuvir and its primary metabolite, GS-331007, was evaluated in fasted 
healthy subjects. Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of 
200 mg to 400 mg. 
 
Pharmacokinetics in special populations 
 
Gender and race 
No clinically relevant pharmacokinetic differences due to gender or race have been identified for 
sofosbuvir and GS-331007. 
 
Elderly 
Population pharmacokinetic analysis in HCV infected patients showed that within the age range 
(19 to 75 years) analysed, age did not have a clinically relevant effect on the exposure to sofosbuvir 
and GS-331007. Clinical studies of sofosbuvir included 65 patients aged 65 and over.  The response 
rates observed for patients over 65 years of age were similar to that of younger patients across 
treatment groups. 
 
Renal impairment 
A summary of the effect of varying degrees of renal impairment (RI) on the exposures of sofosbuvir 
and GS-331007 compared to subjects with normal renal function, as described in the text below, are 
provided in Table 24.  
 
Table 24: Effect of varying degrees of renal impairment on exposures (AUC) of sofosbuvir and 
GS-331007 compared to subjects with normal renal function 

 HCV-Negative Subjects HCV-Infected 
Subjects 

Mild RI 
(eGFR ≥50 
and <80 
mL/min/1.73
m2) 

Moderate RI 
(eGFR ≥30 
and <50 
mL/min/1.73
m2) 

Severe RI 
(eGFR <30 
mL/min/1.7
3m2) 

ESRD Requiring 
Dialysis 

Severe RI 
(eGFR <30 
mL/min/1.
73m2) 

ESRD 
Requiring 
Dialysis Dosed 1 hr 

Before 
Dialysis 

Dosed 1 hr 
After 
Dialysis 

Sofosbuvir 1.6-fold↑ 2.1-fold↑ 2.7-fold↑ 1.3-fold↑ 1.6-fold↑ ~2-fold↑ 1.9-fold↑ 
GS-331007 1.6-fold↑ 1.9-fold↑ 5.5-fold↑ ≥10-fold↑ ≥20-fold↑ ~7-fold↑ 21-fold↑ 

 
The pharmacokinetics of sofosbuvir were studied in HCV negative adult 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 adult 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 sofosbuvir dose. 
 



60 

In HCV-infected adult 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 adult patients with severe renal impairment.  
 
The pharmacokinetics of sofosbuvir, and GS-331007 were studied in HCV-infected adult patients with 
ESRD requiring dialysis treated with ledipasvir/sofosbuvir (n = 94) for 8, 12, or 24 weeks or 
sofosbuvir/velpatasvir (n = 59) for 12 weeks, and compared to patients without renal impairment in the 
ledipasvir/sofosbuvir and sofosbuvir/velpatasvir Phase 2/3 trials (see section 4.4). 
 
Hepatic impairment 
The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in 
adult HCV-infected patients with moderate and severe hepatic impairment (CPT class B and C).  
Relative to patients with normal hepatic function, the sofosbuvir AUC0-24 was 126% and 143% higher 
in moderate and severe hepatic impairment, while the GS-331007 AUC0-24 was 18% and 9% higher, 
respectively. Population pharmacokinetics analysis in adult HCV-infected patients indicated that 
cirrhosis had no clinically relevant effect on the exposure to sofosbuvir and GS-331007. No dose 
adjustment of sofosbuvir is recommended for patients with mild, moderate and severe hepatic 
impairment (see section 4.2). 
 
Paediatric population 
Sofosbuvir and GS-331007 exposures in paediatric patients aged 3 years and above were similar to 
those in adults from Phase 2/3 studies following administration of sofosbuvir.   
 
The pharmacokinetics of sofosbuvir and GS-331007 have not been established in paediatric patients 
aged < 3 years (see section 4.2). 
 
Pharmacokinetic/pharmacodynamic relationship(s) 
 
Efficacy, in terms of rapid virologic response, has been shown to correlate with exposure to sofosbuvir 
as well as GS 331007. However, neither of these entities has been evidenced to be a general surrogate 
marker for efficacy (SVR12) at the therapeutic 400 mg dose. 
 
5.3 Preclinical safety data 
 
In repeat dose toxicology studies in rat and dog, high doses of the 1:1 diastereomeric mixture caused 
adverse liver (dog) and heart (rat) effects and gastrointestinal reactions (dog). Exposure to sofosbuvir 
in rodent studies could not be detected likely due to high esterase activity; however, exposure to the 
major metabolite GS-331007 at the adverse dose was 29 times (rat) and 123 times (dog) higher than 
the clinical exposure at 400 mg sofosbuvir. No liver or heart findings were observed in chronic 
toxicity studies at exposures 9 times (rat) and 27 times (dog) higher than the clinical exposure. 
 
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. 
 
Carcinogenicity studies in mice and rats do not indicate any carcinogenicity potential of sofosbuvir 
administered at doses up to 600 mg/kg/day in mouse and 750 mg/kg/day in rat. Exposure to 
GS-331007 in these studies was up to 30 times (mouse) and 15 times (rat) higher than the clinical 
exposure at 400 mg sofosbuvir. 
 
Sofosbuvir had no effects on embryo-foetal viability or on fertility in rat and was not teratogenic in rat 
and rabbit development studies. No adverse effects on behaviour, reproduction or development of 
offspring in rat were reported. In rabbit studies exposure to sofosbuvir was 9 times the expected 
clinical exposure. In the rat studies, exposure to sofosbuvir could not be determined but exposure 
margins based on the major human metabolite ranged from 8 to 28 times higher than the clinical 
exposure at 400 mg sofosbuvir. 



61 

 
Sofosbuvir-derived material was transferred through the placenta in pregnant rats and into the milk of 
lactating rats. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Granule Cores 
Lactose monohydrate 
Microcrystalline cellulose 
Croscarmellose sodium 
Hydroxypropyl cellulose 
Colloidal anhydrous silica 
Sodium stearyl fumarate 
 
Film-coating 
Hypromellose 
Macrogol 400 
Amino methacrylate copolymer 
Talc 
Stearic acid 
Sodium lauryl sulfate 
Colloidal anhydrous silica 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Sovaldi oral granules,150 mg and 200 mg, are supplied in sachets consisting of 
polyester/aluminium/polyethylene film in cartons. Each carton contains 28 sachets. 
 
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 
 
 



62 

8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/13/894/004 
EU/1/13/894/005 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 16 January 2014 
Date of latest renewal: 17 September 2018 
 
 
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 



63 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 

 



64 

A. MANUFACTURER(S) 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 
 
The requirements for submission of periodic safety update reports 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 

In order to evaluate the recurrence of hepatocellular carcinoma associated with 
Sovaldi, 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 



65 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 



66 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



67 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
BOTTLE AND CARTON LABELLING 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Sovaldi 400 mg film-coated tablets 
sofosbuvir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 400 mg of sofosbuvir. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 film-coated tablets. 
84 (3 bottles of 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 
 
 



68 

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/1/13/894/001 28 film-coated tablets 
EU/1/13/894/002 84 (3 bottles of 28) film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Sovaldi 400 mg film-coated tablets [Outer packaging only] 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: {number} 
SN: {number} 
NN: {number} 
 



69 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
BOTTLE AND CARTON LABELLING 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Sovaldi 200 mg film-coated tablets 
sofosbuvir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 200 mg of sofosbuvir. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 film-coated tablets. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



70 

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/1/13/894/003 28 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Sovaldi 200 mg film-coated tablets [Outer packaging only] 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: {number} 
SN: {number} 
NN:{number} 



71 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
CARTON LABELLING 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Sovaldi 150 mg coated granules in sachet 
sofosbuvir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each sachet of coated granules contains 150 mg of sofosbuvir. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 sachets in carton. 
 
 
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 
 
 
 



72 

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/1/13/894/004 28 sachets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Sovaldi 150 mg coated granules in sachet [Outer packaging only] 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: {number} 
SN: {number} 
NN: {number} 



73 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNIT 
 
SACHET 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Sovaldi 150 mg coated granules in sachet 
sofosbuvir 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER < DONATION AND PRODUCT CODES> 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
GILEAD 
 
 



74 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
CARTON LABELLING 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Sovaldi 200 mg coated granules in sachet 
sofosbuvir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each sachet of coated granules contains 200 mg sofosbuvir. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose.  See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 sachets in carton. 
 
 
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 
 
 



75 

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/1/13/894/005 28 sachets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Sovaldi 200 mg coated granules in sachet [Outer packaging only] 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: {number} 
SN: {number} 
NN: {number} 



76 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNIT 
 
SACHET 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Sovaldi 200 mg coated granules in sachet 
sofosbuvir 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER < DONATION AND PRODUCT CODES> 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
GILEAD 
 



77 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
 



78 

Package leaflet: Information for the user 
 

Sovaldi 400 mg film-coated tablets 
Sovaldi 200 mg film-coated tablets 

sofosbuvir 
 

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 Sovaldi is and what it is used for 
2. What you need to know before you take Sovaldi 
3. How to take Sovaldi 
4. Possible side effects 
5. How to store Sovaldi 
6. Contents of the pack and other information 
 
If Sovaldi has been prescribed for your child, please note that all the information in this leaflet is 
applicable to your child (in this case please read “your child” instead of “you”). 
 
1. What Sovaldi is and what it is used for 
 
Sovaldi contains the active substance sofosbuvir which is given to treat hepatitis C virus infection in 
adults and children 3 years of age and older. 
 
Hepatitis C is a virus that infects the liver. This medicine works by lowering the amount of hepatitis C 
virus in your body and removing the virus from your blood over a period of time. 
 
Sovaldi is always taken with other medicines to treat hepatitis C. It will not work on its own. It is 
commonly taken with either: 
 
• Ribavirin (children and adult patients), or 
• Peginterferon alfa and ribavirin (adult patients) 
 
It is very important that you also read the leaflets for the other medicines that you will be taking with 
Sovaldi. If you have any questions about your medicines, please ask your doctor or pharmacist. 
 
 
2. What you need to know before you take Sovaldi 
 
Do not take Sovaldi 
• If you are allergic to sofosbuvir or any of the other ingredients of this medicine (listed in 

section 6 of this leaflet). 
 
• If you are currently taking any of the following medicines: 

• Rifampicin (antibiotic used to treat infections, including tuberculosis); 



79 

• St. John’s wort (herbal medicine used to treat depression); 
• Carbamazepine, phenobarbital and phenytoin (medicines used to treat epilepsy and 

prevent seizures). 
 
If any of these conditions apply to you, tell your doctor immediately. 
 
Warnings and precautions 
Sovaldi is always taken with other medicines to treat hepatitis C (see section 1 above). Talk to your 
doctor or pharmacist before taking this medicine 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 different treatments if you have taken this medicine. If treatment with Sovaldi is 
needed, you may require additional heart monitoring; 

• have liver problems other than hepatitis C, e.g. if you are awaiting a liver transplantation; 
• have a current or previous infection with the hepatitis B virus, since your doctor may want to 

monitor you more closely; 
• have diabetes. You may need closer monitoring of your blood glucose levels and/or adjustment 

of your diabetes medication after starting Sovaldi. Some diabetic patients have experienced low 
sugar levels in the blood (hypoglycaemia) after starting treatment with medicines like Sovaldi. 

 
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 Sovaldi. This is so your 
doctor can: 
• Decide what other medicines you should take with Sovaldi and for how long; 
• 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 under 3 years of age. The use of Sovaldi in children under 
3 years of age has not yet been studied. 
 
Other medicines and Sovaldi 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines.  
 
Warfarin and other similar medicines called vitamin K antagonists are 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 Sovaldi. 
 
Talk to your doctor about taking Sovaldi if you are taking any of the following medicines: 
• Oxcarbazepine (a medicine used to treat epilepsy and prevent seizures); 
• Modafinil (a medicine to treat people with narcolepsy to help them stay awake). 
• Rifapentine (a medicine used to treat infections, including tuberculosis); 
This is because they may make Sovaldi work less well. 



80 

 
Tell your doctor if you take any of the following medicines: 
• amiodarone, used to treat irregular heartbeats. 
 
If you are not sure of what medicines can be taken with Sovaldi, talk to your doctor or pharmacist. 
 
Pregnancy and contraception 
Pregnancy must be avoided due to the use of Sovaldi together with ribavirin. It is very important that 
you read the "Pregnancy" section in the ribavirin package leaflet very carefully. Ribavirin can be very 
damaging to an unborn baby. Therefore, special precautions in sexual activity must be taken if there is 
any chance for pregnancy to occur. 
 
• Sovaldi is commonly used together with ribavirin. Ribavirin can damage your unborn baby. It is 

therefore very important that you (or your partner) do not become pregnant during this 
therapy. 

• You or your partner must use an effective birth control method during treatment and 
afterwards. It is very important that you read the “Pregnancy” section in the ribavirin package 
leaflet very carefully. Ask your doctor for an effective contraceptive method suitable for you. 

• If you or your partner become pregnant during Sovaldi treatment or in the months that follow, 
you must contact your doctor immediately. 

 
Breast-feeding 
You should not breast-feed during treatment with Sovaldi. It is not known whether sofosbuvir, the 
active substance of Sovaldi, passes into human breast milk. 
 
Driving and using machines 
When taking Sovaldi together with other medicines for the treatment of hepatitis C infection, patients 
have reported tiredness, dizziness, blurred vision and reduced attention. If you feel tired, dizzy, have 
blurred vision or reduced attention after taking Sovaldi you should not take part in activities such as 
driving, riding a bike or operating machines. 
 
 
3. How to take Sovaldi 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
Recommended dose 
Sovaldi is to be taken as advised by your doctor. The recommended dose of Sovaldi in adults is 
one tablet (400 mg) once a day with food. Your doctor will tell you for how long you should take 
Sovaldi. 
 
The recommended dose of Sovaldi in children aged 3 years and above is based on weight. Take 
Sovaldi with food, as advised by your doctor. 
 
Swallow the tablet(s) whole. Do not chew, crush or split the tablet as it has a very bitter taste. Tell 
your doctor or pharmacist if you have problems swallowing tablets. 
 
Sovaldi should always be taken in combination with other medicinal products for use against 
hepatitis C as advised by your doctor. 
 
If you are sick (vomit) less than 2 hours after taking Sovaldi, take another dose. If you vomit more 
than 2 hours after taking Sovaldi you do not need to take another dose until your next regularly 
scheduled dose. 
 
Kidney problems 
Tell your doctor if you have kidney problems or if you are on kidney dialysis. 



81 

 
If you take more Sovaldi than you should 
If you accidentally take more than the recommended dose you should contact your doctor or nearest 
emergency department immediately for advice. Keep the tablet bottle with you so that you can easily 
describe what you have taken. 
 
If you forget to take Sovaldi 
It is important not to miss a dose of this medicine. 
 
If you do miss a dose: 
• and you notice within 18 hours of the time you usually take Sovaldi, you must take the dose as 

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

next dose at your usual time. Do not take a double dose (two doses close together). 
 
Do not stop taking Sovaldi 
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 medicines 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 can cause side effects, although not everybody gets them. 
 
When you take Sovaldi in combination with amiodarone (a medicine used for heart problems), you 
may get one or more of the side effects below: 
• slow or irregular heartbeat or heart rhythm problems 
• shortness of breath or worsening of any shortness of breath you already have 
Tell your doctor or your pharmacist if you notice any of the above side effects during therapy. 
 
When you take Sovaldi with ribavirin or both peginterferon alfa and ribavirin, you may get one or 
more of the side effects below: 
 
Very common side effects 
(may affect more than 1 in 10 people) 
• fever, chills, flu-like symptoms 
• diarrhoea, feeling sick (nausea), being sick (vomiting) 
• trouble sleeping (insomnia) 
• feeling tired and irritable 
• headache 
• rash, itchy skin 
• loss of appetite, decreased appetite 
• feeling dizzy 
• muscle aches and pains, pain in the joints 
• shortness of breath, cough 
 
Blood tests may also show: 
• low red blood cell count (anaemia); the signs may include feeling tired, headaches, shortness of 

breath when exercising 
• low white blood cell count (neutropenia); the signs may include getting more infections than 

usual, including fevers and chills, or sore throat or mouth ulcers 
• low blood platelet count 



82 

• changes in your liver (as shown by increased amounts of a substance called bilirubin in the 
blood) 

 
Common side effects 
(may affect up to 1 in 10 people) 
• changes in your mood, feeling depressed, feeling anxious and feeling agitated 
• blurred vision 
• severe headaches (migraine), memory loss, loss of concentration 
• weight loss 
• shortness of breath when exercising 
• stomach discomfort, constipation, dry mouth, indigestion, acid reflux 
• hair loss and thinning hair 
• dry skin 
• back pain, muscle spasms 
• chest pain, feeling weak 
• getting a cold (nasopharyngitis) 
 
Other effects that may be seen during treatment with sofosbuvir: 
The frequency of the following side effects is not known (frequency cannot be estimated from the 
available data). 
• a wide-spread severe rash with peeling skin which may be accompanied by fever, flu-like 

symptoms, blisters in the mouth, eyes, and/or genitals (Stevens-Johnson syndrome).  
 

If any of the side effects get serious tell your doctor. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report any side effects directly to 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 Sovaldi 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the bottle and carton after {EXP}. 
The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Sovaldi contains 
 
• The active substance is sofosbuvir. Each film-coated tablet contains 400 mg of sofosbuvir or 

200 mg of sofosbuvir. 
 
• The other ingredients are 

Tablet core: 
Mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silica, 
magnesium stearate. 

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


83 

 
Film-coating: 
Polyvinyl alcohol, titanium dioxide, macrogol 3350, talc, iron oxide yellow. 

 
What Sovaldi looks like and contents of the pack 
Sovaldi 400 mg film-coated tablets are yellow, capsule-shaped tablets, debossed on one side with 
“GSI” and “7977” on the other side. The tablet is approximately 20 mm long and 9 mm wide. 
 
Sovaldi 200 mg film-coated tablets are yellow, oval-shaped, film-coated tablets, debossed with “GSI” 
on one side and “200” on the other side. The tablet is approximately 15 mm long and 8 mm wide. 
 
Each bottle of Sovaldi 400 mg film-coated tablets 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 sizes are available:  

• outer cartons containing 1 bottle of 28 film-coated tablets for the 400 mg and 200 mg film-
coated tablets  

• and 84 (3 bottles of 28) film-coated tablets for the 400 mg film coated tablets only. Not all 
pack sizes may be marketed in your country. 

 
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 
 



84 

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 825999 
 

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 113700 
 

 
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/


85 

 
Package leaflet: Information for the user 

 
Sovaldi 150 mg coated granules in sachet 
Sovaldi 200 mg coated granules in sachet 

sofosbuvir 
 

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 Sovaldi is and what it is used for 
2. What you need to know before you take Sovaldi 
3. How to take Sovaldi 
4. Possible side effects 
5. How to store Sovaldi 
6. Contents of the pack and other information 
 
If Sovaldi has been prescribed for your child, please note that all the information in this leaflet is 
applicable to your child (in this case please read “your child” instead of “you”). 
 
1. What Sovaldi is and what it is used for 
 
Sovaldi granules contain the active substance sofosbuvir which is given in a granule formulation to 
treat hepatitis C virus infection in adults and children aged 3 years of age and older. 
 
Hepatitis C is a virus that infects the liver. This medicine works by lowering the amount of hepatitis C 
virus in your body and removing the virus from your blood over a period of time. 
 
Sovaldi is always taken with other medicines to treat hepatitis C.  It will not work on its own.  It is 
commonly taken with either: 
 
• Ribavirin (children and adult patients), or 
• Peginterferon alfa and ribavirin (adult patients) 
 
It is very important that you also read the leaflets for the other medicines that you will be taking with 
Sovaldi. If you have any questions about your medicines, please ask your doctor or pharmacist. 
 
 
2. What you need to know before you take Sovaldi 
 
Do not take Sovaldi 
• If you are allergic to sofosbuvir or any of the other ingredients of this medicine (listed in 

section 6 of this leaflet). 
 
 



86 

• If you are currently taking any of the following medicines: 
• Rifampicin (antibiotic used to treat infections, including tuberculosis); 
• St. John’s wort (herbal medicine used to treat depression); 
• Carbamazepine, phenobarbital and phenytoin (medicines used to treat epilepsy and 

prevent seizures). 
 
 If any of these conditions apply to you, tell your doctor immediately. 
 
Warnings and precautions 
Sovaldi is always taken with other medicines to treat hepatitis C (see section 1 above). Talk to your 
doctor or pharmacist before taking this medicine 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 different treatments if you have taken this medicine. If treatment with Sovaldi is 
needed, you may require additional heart monitoring; 

• have liver problems other than hepatitis C, e.g. if you are awaiting a liver transplantation; 
• have a current or previous infection with the hepatitis B virus, since your doctor may want to 

monitor you more closely; 
• have diabetes. You may need closer monitoring of your blood glucose levels and/or adjustment 

of your diabetes medication after starting Sovaldi. Some diabetic patients have experienced low 
sugar levels in the blood (hypoglycaemia) after starting treatment with medicines like Sovaldi. 

 
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 Sovaldi.  This is so your 
doctor can:  
• Decide what other medicines you should take with Sovaldi and for how long; 
• Confirm that your treatment has worked and you are free of the hepatitis C virus. 
 
Children  
Do not give this medicine to children under 3 years of age. The use of Sovaldi in children under 
3 years of age has not yet been studied. 
 
Other medicines and Sovaldi 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines.   
 
Warfarin and other similar medicines called vitamin K antagonists are 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 Sovaldi. 
 
Talk to your doctor about taking Sovaldi if you are taking any of the following medicines: 
• Oxcarbazepine (a medicine used to treat epilepsy and prevent seizures); 
• Modafinil (a medicine to treat people with narcolepsy to help you stay awake). 



87 

• Rifapentine (a medicine used to treat infections, including tuberculosis); 
This is because they may make Sovaldi work less well. 
 
Tell your doctor if you take any of the following medicines: 
• amiodarone, used to treat irregular heartbeats. 
 
If you are not sure of what medicines can be taken with Sovaldi, talk to your doctor or pharmacist. 
 
Pregnancy and contraception 
Pregnancy must be avoided due to the use of Sovaldi together with ribavirin. It is very important that 
you read the "Pregnancy" section in the ribavirin package leaflet very carefully. Ribavirin can be very 
damaging to an unborn baby. Therefore, special precautions in sexual activity must be taken if there is 
any chance for pregnancy to occur. 
 
• Sovaldi is commonly used together with ribavirin.  Ribavirin can damage your unborn baby.  It 

is therefore very important that you (or your partner) do not become pregnant during this 
therapy. 

• You or your partner must use an effective birth control method during treatment and 
afterwards.  It is very important that you read the “Pregnancy” section in the ribavirin package 
leaflet very carefully.  Ask your doctor for an effective contraceptive method suitable for you. 

• If you or your partner become pregnant during Sovaldi treatment or in the months that follow, 
you must contact your doctor immediately. 

 
Breast-feeding 
Do not breast-feed during treatment with Sovaldi.  It is not known whether sofosbuvir, the active 
substance of Sovaldi, passes into human breast milk. 
 
Driving and using machines 
When taking Sovaldi together with other medicines for the treatment of hepatitis C infection, patients 
have reported tiredness, dizziness, blurred vision and reduced attention. If you feel tired, dizzy, have 
blurred vision or reduced attention after taking Sovaldi you should not take part in activities such as 
driving, riding a bike or operating machines. 
 
Sovaldi granules contain lactose 

• If you have been told by your doctor that you have an intolerance to some sugars, 
contact your doctor before taking this medicinal product. 

 
 
3. How to take Sovaldi 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
Recommended dose 
Sovaldi is to be taken as advised by your doctor. Your doctor will tell you for how long you should 
take Sovaldi and how many sachets you should take. 
 
The recommended dose is the entire contents of the sachet(s), taken once daily shortly before food, 
shortly after food, or with food.  
 
To help with swallowing of the Sovaldi oral granules you can use food or water as detailed below. 
Alternatively, Sovaldi can be swallowed without food or water. 
 
Sovaldi should always be taken in combination with other medicinal products for use against 
hepatitis C as advised by your doctor. 
 



88 

Giving Sovaldi granules with food to aid swallowing: 
1. Hold sachet with cut line on top 
2. Shake sachet gently to settle contents 
3. Tear sachet open along cut line, or use scissors to cut across line 
4. Carefully pour entire contents of sachet onto one or more spoonfuls of non-acidic soft food such as, 
chocolate syrup, mashed potato or ice-cream at or below room temperature 
5. Make sure that no granules remain in the sachet 
6. Take all the granules within 30 minutes of gently mixing with food 
7. Swallow combination of food and granules without chewing to avoid a bitter taste. Make sure that 
all the food is eaten. 
 
Giving Sovaldi granules without food or water or with water to aid swallowing: 
1. Hold sachet with cut line on top 
2. Shake sachet gently to settle contents 
3. Tear sachet open along cut line, or use scissors to cut across line 
4. The granules can be taken directly in the mouth and swallowed without chewing to avoid a bitter 
taste or with or without non-acidic liquids such as water. Do not use fruit juices, for example apple, 
cranberry, grape, orange, pineapple as these are acidic and should not be used. 
5. Make sure no granules remain in the sachet 
6. Swallow all the granules. 
 
If you are sick (vomit) less than 2 hours after taking Sovaldi, take another sachet(s). If you vomit 
more than 2 hours after taking Sovaldi, you do not need to take another dose until your next regularly 
scheduled dose 
 
Kidney problems 
Tell your doctor if you have kidney problems or if you are on kidney dialysis. 
 
If you take more Sovaldi than you should 
If you accidentally take more than the recommended dose you should contact your doctor or nearest 
emergency department immediately for advice. Keep the sachet carton with you so that you can easily 
describe what you have taken. 
 
If you forget to take Sovaldi 
It is important not to miss a dose of this medicine. 
 
If you do miss a dose: 
• and you notice within 18 hours of the time you usually take Sovaldi, you must take the dose as 

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

next dose at your usual time. Do not take a double dose (two doses close together). 
 
Do not stop taking Sovaldi 
You should not stop taking this medicine unless your doctor tells you. It is very important that you 
complete the full course of treatment to give the medicines 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 can cause side effects, although not everybody gets them. 
 
When you take Sovaldi in combination with amiodarone (a medicine used for heart problems), you 
may get one or more of the side effects below: 
• slow or irregular heartbeat or heart rhythm problems 



89 

• shortness of breath or worsening of any shortness of breath you already have 
Tell your doctor or your pharmacist if you notice any of the above side effects during therapy. 
 
When you take Sovaldi with ribavirin or both peginterferon alfa and ribavirin, you may get one or 
more of the side effects below: 
 
Very common side effects 
(may affect more than 1 in 10 people) 
• fever, chills, flu-like symptoms 
• diarrhoea, feeling sick (nausea), being sick (vomiting) 
• trouble sleeping (insomnia) 
• feeling tired and irritable 
• headache 
• rash, itchy skin 
• loss of appetite, decreased appetite 
• feeling dizzy 
• muscle aches and pains, pain in the joints 
• shortness of breath, cough 
 
Blood tests may also show: 
• low red blood cell count (anaemia); the signs may include feeling tired, headaches, shortness of 

breath when exercising 
• low white blood cell count (neutropenia); the signs may include getting more infections than 

usual, including fevers and chills, or sore throat or mouth ulcers 
• low blood platelet count 
• changes in your liver (as shown by increased amounts of a substance called bilirubin in the 

blood) 
 
Common side effects 
(may affect up to 1 in 10 people) 
• changes in your mood, feeling depressed, feeling anxious and feeling agitated 
• blurred vision 
• severe headaches (migraine), memory loss, loss of concentration 
• weight loss 
• shortness of breath when exercising 
• stomach discomfort, constipation, dry mouth, indigestion, acid reflux 
• hair loss and thinning hair 
• dry skin 
• back pain, muscle spasms 
• chest pain, feeling weak 
• getting a cold (nasopharyngitis) 
 
Other effects that may be seen during treatment with sofosbuvir: 
The frequency of the following side effects is not known (frequency cannot be estimated from the 
available data). 

• a wide-spread severe rash with peeling skin which may be accompanied by fever, flu-like 
symptoms, blisters in the mouth, eyes, and/or genitals (Stevens-Johnson syndrome). 

 
If any of the side effects get serious tell your doctor. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report any side effects directly to the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 

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


90 

 
 
5. How to store Sovaldi 
 
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 sachet and carton after {EXP}. 
The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Sovaldi contains 
 
The active substance is sofosbuvir.  

• Sovaldi 150 mg coated granules in sachet contains 150 mg sofosbuvir.  
• Sovaldi 200 mg coated granules in sachet contains 200 mg sofosbuvir. 
• The other ingredients are lactose monohydrate, microcrystalline cellulose, croscarmellose 

sodium, hydroxypropyl cellulose, colloidal anhydrous silica, sodium stearyl fumarate, 
hypromellose, macrogol 400, amino methacrylate copolymer, talc, stearic acid, sodium lauryl 
sulfate. 

 
What Sovaldi looks like and contents of the pack 
The granules are white to off-white and contained in a sachet.  
 
The following pack size is available:  

• outer carton containing 28 sachets. 
 
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 
 



91 

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

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

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

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

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

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

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

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

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

Österreich 
Gilead Sciences GesmbH 
Tel: + 43 1 260 830 
 

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

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

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

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

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 


	SUMMARY OF PRODUCT CHARACTERISTICS
	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
	A. LABELLING
	B. PACKAGE LEAFLET