Sovaldi

Sovaldi 400 mg film-coated tablets

Each film-coated tablet contains 400 mg of sofosbuvir.

Film-coated tablet.

Yellow, capsule-shaped, film-coated tablet of dimensions 20 mm x 9 mm, debossed on one side with “GSI” and “7977” on the other side.

Sovaldi is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adults and in adolescents aged 12 to <18 years.

1.

Sovaldi treatment should be initiated and monitored by a physician experienced in the management of patients with CHC.

Posology

Adults

The recommended dose is one 400 mg tablet, taken orally, once daily with food.

Sovaldi should be used in combination with other medicinal products. Monotherapy of Sovaldi is not recommended. 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 treated with Sovaldi combination therapy

* 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.

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 Sovaldi 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

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 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 Sovaldi in adults

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).

Paediatric population

In adolescents aged 12 to < 18 years, the recommended dose of Sovaldi is one tablet once daily with food.

Sovaldi should be used in combination with other medicinal products. Monotherapy of Sovaldi is not recommended. The recommended treatment regimen and durations for Sovaldi combination therapy are provided in Table 3 and Table 4.

Table 3: Recommended treatment regimen and durations for adolescents aged 12 to < 18 years treated with Sovaldi

* Includes patients co infected with human immunodeficiency virus (HIV).

a. See Table 4 for weight based ribavirin dosing recommendations

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).

Table 4: Recommended dosing for ribavirin in combination therapy with Sovaldi in adolescents aged 12 to < 18 years

* The daily dosage of ribavirin is weight-based and is administered orally in two divided doses with food.

Dose modification in the paediatric population

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 in adults and adolescents

If the other medicinal products used in combination with Sovaldi are permanently discontinued, Sovaldi should also be discontinued.

Special patient populations

Elderly

No dose adjustment is warranted for elderly patients.

Renal impairment

No dose adjustment of Sovaldi is required for patients with mild or moderate renal impairment. The safety and appropriate dose of Sovaldi 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.

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). 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.

Liver transplant recipients

Sovaldi in combination with ribavirin is recommended for 24 weeks in liver transplant recipients. 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.

Paediatric population

The safety and efficacy of Sovaldi in children and adolescents aged <12 years have not yet been established. No data on paediatric patients < 12 years 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.

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.

Use with potent P-gp inducers

Medicinal products that are potent P-glycoprotein (P-gp) inducers in the intestine (rifampicin, rifabutin, St. John's wort [Hypericum perforatum], carbamazepine, phenobarbital and phenytoin). Co-administration will significantly decrease sofosbuvir plasma concentration and could result in loss of efficacy of Sovaldi.

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. Consult the Summary of Product Characteristics for co-prescribed medicinal products before starting therapy with Sovaldi.

Severe bradycardia and heart block

Cases of severe bradycardia and heart block have been observed when sofosbuvir is used in combination with another direct-acting antiviral (DAAs, including daclatasvir, simeprevir and ledipasvir) 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 DAAs. Cases are potentially life threatening, therefore amiodarone should only be used in patients on Sovaldi and another DAA when other alternative anti-arrhythmic treatments are not tolerated or are contraindicated. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone.

Should concomitant use of amiodarone be considered necessary it is recommended that patients are closely monitored when initiating Sovaldi and another DAA. Patients who are identified as being at 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 Sovaldi in combination with another DAA.

All patients receiving Sovaldi and another DAA 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

Sovaldi has not been studied in a Phase 3 study in treatment-experienced patients with genotype 1, 4, 5 and 6 HCV infection. 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.

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. 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. oxcarbazepine and modafinil) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of Sovaldi. Co-administration of such medicinal products is not recommended with Sovaldi.

Renal impairment

The safety of Sovaldi has not been assessed in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) or ESRD requiring haemodialysis. Furthermore, the appropriate dose has not been established. 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).

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.

Paediatric population

Sovaldi is not recommended for use in paediatric patients < 12 years because the safety and efficacy have not been established in this population.

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. 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 (rifampicin, rifabutin, St. John's wort, carbamazepine, phenobarbital and phenytoin) may significantly decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of Sovaldi and thus are contraindicated with Sovaldi. Medicinal products that are moderate P-gp inducers in the intestine (e.g. oxcarbazepine and modafinil) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of Sovaldi. Co-administration with such medicinal products is not recommended with Sovaldi. 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.

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.

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

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%

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. 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.

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 has shown excretion of metabolites in milk.

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.

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.

Summary of the safety profile in adults

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 patients who permanently discontinued treatment due to adverse reactions was 1.4% for patients receiving placebo, 0.5% for patients receiving sofosbuvir + ribavirin for 12 weeks, 0% for patients receiving sofosbuvir + ribavirin for 16 weeks, 11.1% for patients receiving peginterferon alfa + ribavirin for 24 weeks and 2.4% for patients receiving sofosbuvir + peginterferon alfa + ribavirin for 12 weeks.

Tabulated summary of adverse reactions

Sovaldi 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 patients 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 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

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 adult patients was similar to that observed in mono-infected HCV patients treated with sofosbuvir and ribavirin in Phase 3 clinical studies.

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.

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. 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 adolescents aged 12 to <18 years are based on data from 50 patients who were treated with Sovaldi and ribavirin for 12 weeks (genotype 2 patients) and 24 weeks (genotype 3 patients) in a Phase 2, open-label clinical trial. The adverse reactions observed were consistent with those observed in clinical studies of Sovaldi plus ribavirin in adults (see Table 6).

Description of selected adverse reactions

Cardiac arrhythmias

Cases of severe bradycardia and heart block have been observed when sofosbuvir is used in combination with another DAA (including daclatasvir, simeprevir and ledipasvir) and concomitant amiodarone and/or other drugs that lower heart rate.

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:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

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.

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 - 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

Baseline NS5B sequences were obtained for 47 patients in the Phase 2 study. Among these, one patient was found to have a NS5B RAV substitution (F289L). This patient achieved SVR12.

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).

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

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

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

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

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

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

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

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

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

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

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

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 AUC_0-24 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 AUC_0-24 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.

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

The pharmacokinetics of sofosbuvir were studied in HCV negative patients with mild (eGFR >50 and <80 mL/min/1.73 m²), moderate (eGFR >30 and <50 mL/min/1.73 m²), severe renal impairment (eGFR <30 mL/min/1.73 m²) and patients with ESRD requiring haemodialysis following a single 400 mg dose of sofosbuvir. Relative to patients with normal renal function (eGFR >80 mL/min/1.73 m²), the sofosbuvir AUC_0-inf was 61%, 107% and 171% higher in mild, moderate and severe renal impairment, while the GS-331007 AUC_0-inf was 55%, 88% and 451% higher, respectively. In patients with ESRD, relative to patients with normal renal function, sofosbuvir AUC_0-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 AUC_0-inf of GS-331007 in patients 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 patients when Sovaldi 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 Sovaldi has not been assessed in patients with severe renal impairment or ESRD.

Hepatic impairment

The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in HCV infected patients with moderate and severe hepatic impairment (CPT class B and C). Relative to patients with normal hepatic function, the sofosbuvir AUC_0-24 was 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC_0-24 was 18% and 9% higher, respectively. Population pharmacokinetics analysis in 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.

Paediatric population

Sofosbuvir and GS-331007 exposures in adolescents aged 12 to <18 years were similar to those in adults from Phase 2/3 studies following administration of sofosbuvir (400 mg). The pharmacokinetics of sofosbuvir and GS-331007 have not been established in paediatric patients < 12 years of age.

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 (E421)

Microcrystalline cellulose (E460(i))

Croscarmellose sodium

Colloidal anhydrous silica (E551)

Magnesium stearate (E470b)

Film-coating

Polyvinyl alcohol (E1203)

Titanium dioxide (E171)

Macrogol 3350 (E1521)

Talc (E553b)

Yellow iron oxide (E172)

Not applicable.

5 years.

This medicinal product does not require any special storage conditions.

Sovaldi 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.

The following pack sizes are available: outer cartons containing 1 bottle of 28 film-coated tablets and outer cartons containing 84 (3 bottles of 28) film-coated tablets.

Not all pack sizes may be marketed.

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

Gilead Sciences International Ltd.

Cambridge

CB21 6GT

United Kingdom

EU/1/13/894/001

EU/1/13/894/002

Date of first authorisation: 16 January 2014

09/2017