Sofocure is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adults (see sections 4.2, 4.4 and 5.1).
For hepatitis C virus (HCV) genotype specific activity, see sections 4.4 and 5.1.

Sofocure treatment should be initiated and monitored by a physician experienced in the management of patients with CHC. Posology
The recommended dose is one 400 mg tablet, taken orally, once daily with food (see section 5.2).

Sofocure should be used in combination with other medicinal products. Monotherapy of Sofocure 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 Sofocure. The recommended co-administered medicinal product(s) and treatment duration for Sofocure combination therapy are provided in Table 1.
Table 1: Recommended co-administered medicinal product(s) and treatment duration for Sofocure combination therapy
Patient population*
Treatment
Duration Patients with genotype 1, 4, 5 or 6 CHC Sofocure + ribavirin + peginterferon alfa
12 weeksa,b

24 weeks Patients with genotype 2 CHC Sofocure + ribavirin
Sofocure + ribavirin
Only for use in patients ineligible or intolerant to peginterferon alfa (see section 4.4)
12 weeksb

Patients with genotype 3 CHC Sofocure + ribavirin + peginterferon alfa
12 weeksb
Sofocure + ribavirin
24 weeks

Patients with CHC awaiting liver transplantation
Sofocure + ribavirin
Until liver transplantationc
* 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 Sofocure, 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. See Special patient populations – Patients awaiting liver transplantation below.
The dose of ribavirin, when used in combination with Sofocure is weight-based (<75 kg = 1,000 mg and ≥75 kg = 1,200 mg) and administered orally in two divided doses with food.
Concerning co-administration with other direct-acting antivirals against HCV, see section 4.4.

Dose modification
Dose reduction of Sofocure is not recommended.
If Sofosbuvir is used in combination with peginterferon alfa, and a patient has a serious adverse reaction potentially related to this drug, 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 2 provides guidelines for dose modifications and discontinuation based on the patient's haemoglobin concentration and cardiac status.

Table 2: Ribavirin dose modification guideline for co-administration with Sofocure
Laboratory values
Reduce ribavirin dose to 600 mg/day if:
Discontinue ribavirin if:
Haemoglobin in subjects with no cardiac disease
Reduce ribavirin dose to 600 mg/day if:<10 g/dL
Discontinue ribavirin if:<8.5 g/dL

Haemoglobin in subjects with history of stable cardiac disease
Reduce ribavirin dose to 600 mg/day if:≥2 g/dL decrease in haemoglobin during any 4 week treatment period
Discontinue ribavirin if:<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).
Discontinuation of dosing
If the other medicinal products used in combination with Sofocure are permanently discontinued, Sofocure should also be discontinued (see section 4.4). Special patient populations
Elderly.
No dose adjustment is warranted for elderly patients (see section 5.2).

Renal impairment
No dose adjustment of Sofocure is required for patients with mild or moderate renal impairment. The safety and appropriate dose of Sofocure have not been established in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) or end stage renal disease (ESRD) requiring haemodialysis (see section 5.2).
Hepatic impairment
No dose adjustment of Sofocure 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 Sofocure have not been established in patients with decompensated cirrhosis.
Patients awaiting liver transplantation
The duration of administration of Sofocure 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).
Paediatric population
The safety and efficacy of Sofocure in children and adolescents aged <18 years have not yet been established. No data are available.

Method of administration
The film-coated tablet is for oral use. Patients should be instructed to swallow the tablet whole. The film-coated tablet should not be chewed or crushed, due to the bitter taste of the active substance. The tablet should be taken with food (see section 5.2).
Patients should be instructed that if vomiting occurs within 2 hours of dosing an additional tablet 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.
If a dose is missed and it is within 18 hours of the normal time, patients should be instructed to take the tablet as soon as possible and then patients should take the next dose at the usual time. If it is after 18 hours then patients should be instructed to wait and take the next dose at the usual time. Patients should be instructed not to take a double dose.

General
Sofocure 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 Sofocure are permanently discontinued, Sofocure should also be discontinued (see section 4.2). Consult the Summary of Product Characteristics for co-prescribed medicinal products before starting therapy with Sofocure. Severe bradycardia and heart block
Cases of severe bradycardia and heart block have been observed when sofosbuvir is used in combination with daclatasvir and concomitant amiodarone with or without other drugs that lower heart rate. The mechanism is not established. The concomitant use of amiodarone was limited through the clinical development of sofosbuvir plus direct-acting antivirals (DAAs). Cases are potentially life threatening, therefore amiodarone should only be used in patients on sofosbuvir + daclatasvir 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 are closely monitored when initiating sofosbuvir + daclatasvir. Patients who are identified as being high risk of bradyarrhythmia should be continuously monitored for 48 hours in an appropriate clinical setting. Due to the long half-life of amiodarone, appropriate monitoring should also be carried out for patients who have discontinued amiodarone within the past few months and are to be initiated on sofosbuvir in combination with daclatasvir. All patients receiving sofosbuvir + daclatasvir in combination with amiodarone with or without other drugs that lower heart rate should also be warned of the symptoms of bradycardia and heart block and should be advised to seek medical advice urgently should they experience them.

Treatment-experienced patients with genotype 1, 4, 5 and 6 HCV infection
Sofocure 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 Sofocure 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 Sofocure 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
Sofocure 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 Sofocure and telaprevir or boceprevir. Such co-administration is not recommended (see also section 4.5). Pregnancy and concomitant use with ribavirin
When Sofocure 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 potent P-gp inducers
Medicinal products that are potent P-glycoprotein (P-gp) inducers in the intestine (e.g. rifampicin, St. John's wort [Hypericum perforatum], carbamazepine and phenytoin) may significantly decrease Sofosbuvir plasma concentration leading to reduced therapeutic effect of Sofocure. Such medicinal products should not be used with Sofocure (see section 4.5). Renal impairment
The safety of Sofocure has not been assessed in subjects with severe renal impairment (eGFR <30 mL/min/1.73 m2) or ESRD requiring haemodialysis. Furthermore, the appropriate dose has not been established. When Sofocure 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). HCV/HBV (hepatitis B virus) co-infection
There are no data on the use of Sofocure in patients with HCV/HBV co-infection.

Paediatric population
Sofocure is not recommended for use in children and adolescents under 18 years of age because the safety and efficacy have not been established in this population.

Sofosbuvir is a nucleotide prodrug. After oral administration of Sofocure, 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 potent P-gp inducers in the intestine (e.g. rifampicin, St. John's wort, carbamazepine and phenytoin) may decrease Sofosbuvir plasma concentration leading to reduced therapeutic effect of Sofocure and thus should not be used with Sofocure (see section 4.4). Co-administration of Sofocure with medicinal products that inhibit P-gp and/or BCRP may increase Sofosbuvir plasma concentration without increasing GS-331007 plasma concentration, thus Sofocure 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). Other interactions
Drug interaction information for Sofocure with potential concomitant medicinal products is summarized in Table 3 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.

Medicinal products that are potent P-gp inducers in the intestine (rifampicin, St. John's wort, carbamazepine and phenytoin) may significantly decrease sofosbuvir plasma concentration leading to reduced therapeutic effect. For this reason, sofosbuvir should not be co-administered with known inducers of P-gp.

Women of childbearing potential / contraception in males and females
When Sofocure 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 Sofocure 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 has shown excretion of metabolites in milk (for details see section 5.3).
A risk to newborns/infants cannot be excluded. Therefore, Sofocure should not be used during breast-feeding. Fertility
No human data on the effect of Sofocure on fertility are available. Animal studies do not indicate harmful effects on fertility.

Sofocure 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)..

Summary of the safety profile
During treatment with sofosbuvir in combination with ribavirin or with peginterferon alfa and ribavirin, the most frequently reported adverse drug reactions were consistent with the expected safety profile of ribavirin and peginterferon alfa treatment, without increasing the frequency or severity of the expected adverse drug reactions.
Assessment of adverse reactions is based on pooled data from five Phase 3 clinical studies (both controlled and uncontrolled).
The proportion of subjects who permanently discontinued treatment due to adverse reactions was 1.4% for subjects receiving placebo, 0.5% for subjects receiving sofosbuvir + ribavirin for 12 weeks, 0% for subjects receiving sofosbuvir + ribavirin for 16 weeks, 11.1% for subjects receiving peginterferon alfa + ribavirin for 24 weeks and 2.4% for subjects receiving sofosbuvir + peginterferon alfa + ribavirin for 12 weeks.

Tabulated summary of adverse reactions
Sofosbuvir has mainly 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 subjects receiving sofosbuvir and ribavirin or sofosbuvir, ribavirin and peginterferon alfa were fatigue, headache, nausea and insomnia.
The following adverse drug reactions have been identified with sofosbuvir in combination with ribavirin or in combination with peginterferon alfa and ribavirin (Table 4). 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)

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 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

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.

Other special population(s)
HIV/HCV co-infection
The safety profile of sofosbuvir and ribavirin in HCV/HIV co-infected subjects was similar to that observed in mono-infected HCV subjects 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 subjects prior to liver transplantation was similar to that observed in subjects treated with sofosbuvir and ribavirin in Phase 3 clinical studies (see section 5.1). Description of selected adverse reactions
Cardiac arrhythmias
Cases of severe bradycardia and heart block have been observed when sofosbuvir is used in combination with daclatasvir and concomitant amiodarone and/or other drugs that lower heart rate (see sections 4.4 and 4.5).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization 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:
Saudi Arabia:

The National Pharmacovigilance and Drug Safety Centre (NPC)
• Fax: +966-11-205-7662
• Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
• Toll free phone: 8002490000
• E-mail: npc.drug@sfda.gov.sa
• Website: www.sfda.gov.sa/npc

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 Sofocure. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Sofocure 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.

Pharmacotherapeutic group: Direct-acting antiviral; ATC code: J05AX15. 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.
In clinical studies
In a pooled analysis of 991 subjects who received sofosbuvir in Phase 3 studies, 226 subjects 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 subjects, with deep sequencing data (assay cutoff of 1%) from 221 of these subjects. The sofosbuvir-associated resistance substitution S282T was not detected in any of these subjects by deep sequencing or population sequencing. The S282T substitution in NS5B was detected in a single subject receiving Sofosbuvir 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 subjects 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
Baseline NS5B sequences were obtained for 1,292 subjects 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. 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 subjects with genotypes 1 to 6 chronic hepatitis C. One study was conducted in treatment-naïve subjects 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 subjects with genotype 2 or 3 chronic hepatitis C in combination with ribavirin including one in treatment-naïve subjects, one in interferon intolerant, ineligible or unwilling subjects, one in subjects previously treated with an interferon-based regimen, and one in all subjects irrespective of prior treatment history or ability to receive treatment with interferon. Subjects 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 subjects' 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 subjects with genotype 1, 4, 5 and 6 chronic hepatitis C
Treatment-naïve subjects - 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 subjects with genotype 1, 4, 5 or 6 HCV infection.
Treated subjects (n = 327) had a median age of 54 years (range: 19 to 70); 64% of the subjects 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 5 presents the response rates for the treatment group of sofosbuvir + peginterferon alfa + ribavirin.

SVR12 rates were similarly high in subjects 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 subjects with genotype 6 HCV infection in this study achieved SVR12. Clinical studies in subjects with genotype 2 and 3 chronic hepatitis C
Treatment-naïve adults - FISSION (study 1231)
FISSION was a randomized, 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 subjects 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. Subjects were randomized 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). Subjects with genotype 2 or 3 HCV were enrolled in an approximately 1:3 ratio.
Treated subjects (n = 499) had a median age of 50 years (range: 19 to 77); 66% of the subjects 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 7 presents the response rates for the treatment groups of sofosbuvir + ribavirin and peginterferon alfa + ribavirin.

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 subjects with cirrhosis at baseline are presented in Table 8 by HCV genotype.

Interferon intolerant, ineligible or unwilling adults - POSITRON (study 107)
POSITRON was a randomized, double-blinded, placebo-controlled study that evaluated 12 weeks of treatment with sofosbuvir and ribavirin (n = 207) compared to placebo (n = 71) in subjects who are interferon intolerant, ineligible or unwilling. Subjects were randomized in 3:1 ratio and stratified by cirrhosis (presence versus absence).
Treated subjects (n = 278) had a median age of 54 years (range: 21 to 75); 54% of the subjects 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 subjects who were interferon intolerant, ineligible, or unwilling were 9%, 44%, and 47%, respectively. Most subjects had no prior HCV treatment (81.3%). Table 9 presents the response rates for the treatment groups of sofosbuvir + ribavirin and placebo.

The SVR12 rate in the sofosbuvir + ribavirin treatment group was statistically significant when compared to placebo (p <0.001).
Table 10 presents the subgroup analysis by genotype for cirrhosis and interferon classification.

FUSION was a randomized, double-blinded study that evaluated 12 or 16 weeks of treatment with sofosbuvir and ribavirin in subjects who did not achieve SVR with prior interferon-based treatment (relapsers and nonresponders). Subjects were randomized in a 1:1 ratio and stratified by cirrhosis (presence versus absence) and HCV genotype (2 versus 3).
Treated subjects (n = 201) had a median age of 56 years (range: 24 to 70); 70% of the subjects 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 11 presents the response rates for the treatment groups of sofosbuvir + ribavirin for 12 weeks and 16 weeks.

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 subjects or subjects who did not achieve SVR with prior interferon-based treatment, including subjects 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 subjects continued to receive sofosbuvir and ribavirin for 12 weeks, whilst treatment for HCV genotype 3 subjects was extended to 24 weeks. Eleven HCV genotype 3 subjects had already completed treatment with sofosbuvir and ribavirin for 12 weeks at the time of the amendment.

Treated subjects (n = 419) had a median age of 51 years (range: 19 to 74); 60% of the subjects 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 13 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.

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 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 subjects with genotype 1, 2 or 3 chronic hepatitis C co-infected with HIV-1. Genotype 2 and 3 subjects were either treatment-naïve or experienced, whereas genotype 1 subjects were naïve to prior treatment. Treatment duration was 12 weeks in treatment-naïve subjects with genotype 2 or 3 HCV infection, and 24 weeks in treatment-experienced subjects with genotype 3 HCV infection, as well as subjects with genotype 1 HCV infection. Subjects received 400 mg sofosbuvir and weight-based ribavirin (1,000 mg for subjects weighing <75 kg or 1,200 mg for subjects weighing ≥75 kg). Subjects 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 subjects.
 

Patients awaiting liver transplantation - Study 2025
Sofosbuvir was studied in HCV infected subjects 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 subjects, 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 subjects who received sofosbuvir and ribavirin; the majority of subjects had HCV genotype 1, 44 subjects were CPT class A and 17 subjects were CPT class B. Of these 61 subjects, 44 subjects 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 subjects transplanted with HCV RNA <LLOQ is described in Table 17. 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.

In patients that discontinued therapy at 24 weeks, according to protocol, the relapse rate was 11/15. Overview of outcomes by therapeutic regimen and treatment duration, a comparison across studies
The following tables (Table 18 to Table 21) present data from Phase 2 and Phase 3 studies relevant to the dosing to help clinicians determine the best regimen for individual patients.

Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with sofosbuvir in one or more subsets of the paediatric populations in the treatment of chronic hepatitis C (see section 4.2 for information on paediatric use).

Sofosbuvir is a nucleotide prodrug that is extensively metabolized. 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 subjects 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 subjects 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 AUC0-24was 57% higher and 39% lower, respectively in HCV infected subjects.
Effects of food
Relative to fasting conditions, the administration of a single dose of sofosbuvir with a standardized 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 transporters including the organic anion-transporting polypeptide (OATP) 1B1 or 1B3. While subject to active tubular secretion, GS-331007 is not a substrate or inhibitor for renal transporters including organic anion transporter (OAT) 1 or 3, or organic cation transporter (OCT) 2, MRP2, P-gp, BCRP or 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 metabolized 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 subjects showed that within the age range (19 to 75 years) analyzed, age did not have a clinically relevant effect on the exposure to sofosbuvir and GS-331007. Clinical studies of sofosbuvir included 65 subjects aged 65 and over. The response rates observed for subjects over 65 years of age were similar to that of younger subjects across treatment groups.
Renal impairment
The pharmacokinetics of sofosbuvir were studied in HCV negative subjects 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 subjects with ESRD requiring haemodialysis following a single 400 mg dose of sofosbuvir. Relative to subjects with normal renal function (eGFR >80 mL/min/1.73 m2),

the sofosbuvir AUC0-inf was 61%, 107% and 171% higher in mild, moderate and severe renal impairment, while the GS-331007 AUC0-inf was 55%, 88% and 451% higher, respectively. In subjects with ESRD, relative to subjects with normal renal function, sofosbuvir AUC0-inf was 28% higher when sofosbuvir was dosed 1 hour before haemodialysis compared with 60% higher when sofosbuvir was dosed 1 hour after haemodialysis. The AUC0-inf of GS-331007 in subjects with ESRD could not be reliably determined. However, data indicate at least 10-fold and 20-fold higher exposure to GS-331007 in ESRD compared to normal subjects when Sofosbuvir was administered 1 hour before or 1 hour after haemodialysis, respectively.
Haemodialysis can efficiently remove (53% extraction ratio) the predominant circulating metabolite GS-331007. A 4-hour haemodialysis session removed approximately 18% of administered dose. No dose adjustment is required for patients with mild or moderate renal impairment. The safety of Sofosbuvir has not been assessed in patients with severe renal impairment or ESRD (see section 4.4).

Hepatic impairment
The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in HCV infected subjects with moderate and severe hepatic impairment (CPT class B and C). Relative to subjects with normal hepatic function, the sofosbuvir AUC0-24 was 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC0-24was 18% and 9% higher, respectively. Population pharmacokinetics analysis in HCV infected subjects 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
The pharmacokinetics of sofosbuvir and GS-331007 in paediatric subjects have not been established (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.
 

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.
Sofosbuvir-derived material was transferred through the placenta in pregnant rats and into the milk of lactating rats.

Tablet core
Mannitol.
Microcrystalline cellulose.
Croscarmellose sodium.
Colloidal anhydrous silica.
Magnesium stearate. Film-coating
Opadry 85F 92259 Yellow.

Not applicable.

Store below 30ºC, in dry place.

Sofocure tablets are supplied in a carton box containing plastic HDPE bottle (containing 28 film-coated), desiccant and leaflet. The plastic bottle is aluminium sealed and closed with a plastic HDPE cap.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.