Sovaldi 400 mg film-coated tablets

Each film-coated tablet contains 400 mg of sofosbuvir.

For the full list of excipients, see section 6.1.

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 (see sections 4.2, 4.4 and 5.1).

For hepatitis C virus (HCV) genotype specific activity, see sections 4.4 and 5.1.

Sovaldi 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).

Sovaldi should be used in combination with other medicinal products. Monotherapy of Sovaldi is not recommended (see section 5.1). Refer also to the Summary of Product Characteristics of the medicinal products that are used in combination with Sovaldi. The recommended co-administered medicinal product(s) and treatment duration for Sovaldi combination therapy are provided in Table 1.

Table 1: Recommended co-administered medicinal product(s) and treatment duration for 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 (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 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 HCV, see section 4.4.

Dose modification

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

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 Sovaldi are permanently discontinued, Sovaldi 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 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 (see section 5.2).

Hepatic impairment

No dose adjustment of Sovaldi is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh-Turcotte [CPT] class A, B or C) (see section 5.2). The safety and efficacy of Sovaldi have not been established in patients with decompensated cirrhosis.

Patients awaiting liver transplantation

The duration of administration of Sovaldi in patients awaiting liver transplantation should be guided by an assessment of the potential benefits and risks for the individual patient (see section 5.1).

Paediatric population

The safety and efficacy of Sovaldi 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.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

General

Sovaldi is not recommended for administration as monotherapy and should be prescribed in combination with other medicinal products for the treatment of hepatitis C infection. If the other medicinal products used in combination with Sovaldi are permanently discontinued, Sovaldi should also be discontinued (see section 4.2). Consult the Summary of Product Characteristics for co-prescribed medicinal products before starting therapy with Sovaldi.

Treatment-experienced patients with genotype 1, 4, 5 and 6 HCV infection

Sovaldi has not been studied in a Phase 3 study in treatment-experienced patients with genotype 1, 4, 5 and 6 HCV infection. Thus, the optimal treatment duration in this population has not been established (see also sections 4.2 and 5.1).

Consideration should be given to treating these patients, and potentially extending the duration of therapy with sofosbuvir, peginterferon alfa and ribavirin beyond 12 weeks and up to 24 weeks; especially for those subgroups who have one or more factors historically associated with lower response rates to interferon-based therapies (advanced fibrosis/cirrhosis, high baseline viral concentrations, black race, IL28B non CC genotype).

Treatment of patients with genotype 5 or 6 HCV infection

The clinical data to support the use of Sovaldi in patients with genotype 5 and 6 HCV infection is very limited (see section 5.1).

Interferon-free therapy for genotype 1, 4, 5 and 6 HCV infection

Interferon-free regimens for patients with genotype 1, 4, 5 and 6 HCV infection with Sovaldi have not been investigated in Phase 3 studies (see section 5.1). The optimal regimen and treatment duration have not been established. Such regimens should only be used for patients that are intolerant to or ineligible for interferon therapy, and are in urgent need of treatment.

Co-administration with other direct-acting antivirals against HCV

Sovaldi should only be co-administered with other direct-acting antiviral medicinal products if the benefit is considered to outweigh the risks based upon available data. There are no data to support the co-administration of Sovaldi and telaprevir or boceprevir. Such co-administration is not recommended (see also section 4.5).

Pregnancy and concomitant use with ribavirin

When Sovaldi is used in combination with ribavirin or peginterferon alfa/ribavirin, women of childbearing potential or their male partners must use an effective form of contraception during the treatment and for a period of time after the treatment as recommended in the Summary of Product Characteristics for ribavirin. Refer to the Summary of Product Characteristics for ribavirin for additional information.

Use with 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 Sovaldi. Such medicinal products should not be used with Sovaldi (see section 4.5).

Renal impairment

The safety of Sovaldi 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 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

There are no data on the use of Sovaldi in patients with HCV/HBV co-infection.

Paediatric population

Sovaldi 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 Sovaldi, sofosbuvir is rapidly absorbed and subject to extensive first-pass hepatic and intestinal metabolism. Intracellular hydrolytic prodrug cleavage catalysed by enzymes including carboxylesterase 1 and sequential phosphorylation steps catalysed by nucleotide kinases result in formation of the pharmacologically active uridine nucleoside analogue triphosphate. The predominant inactive circulating metabolite GS-331007 that accounts for greater than 90% of drug-related material systemic exposure is formed through pathways sequential and parallel to formation of active metabolite. The parent sofosbuvir accounts for approximately 4% of drug-related material systemic exposure (see section 5.2). In clinical pharmacology studies, both sofosbuvir and GS-331007 were monitored for purposes of pharmacokinetic analyses.

Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while GS-331007 is not. Medicinal products that are 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 Sovaldi and thus should not be used with Sovaldi (see section 4.4). Co-administration of Sovaldi with medicinal products that inhibit P-gp and/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasma concentration, thus Sovaldi may be co-administered with P-gp and/or BCRP inhibitors. Sofosbuvir and GS-331007 are not inhibitors of P-gp and BCRP and thus are not expected to increase exposures of medicinal products that are substrates of these transporters.

The intracellular metabolic activation pathway of sofosbuvir is mediated by generally low affinity and high capacity hydrolase and nucleotide phosphorylation pathways that are unlikely to be affected by concomitant medicinal products (see section 5.2).

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