SOVALDI

Sovaldi treatment should be initiated and monitored by a physician experienced in the management of patients with CHC. Posology The recommended dose of Sovaldi in paediatric patients aged 3 years and above is based on weight (as detailed in Table 2).

2). Sovaldi should be used in combination with other medicinal products. 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.

4) 24 weeks Adult and paediatric patients aged 3 years and above with genotype 2 CHC Sovaldid + ribavirinc,e 12 weeksb Sovaldi + ribavirinc + peginterferon alfa 12 weeksb Adult patients with genotype 3 CHC Sovaldi + ribavirinc 24 weeks Paediatric patients aged 3 years and above with genotype 3 CHC Sovaldid + ribavirine 24 weeks Adult patients with CHC awaiting liver transplantation Sovaldi + ribavirinc Until liver transplantationf * Includes patients co-infected with human immunodeficiency virus (HIV).

a. 4). b. g. advanced fibrosis/cirrhosis, high baseline viral concentrations, black race, IL28B non CC genotype, prior null response to peginterferon alfa and ribavirin therapy). c. Adults: weight-based ribavirin (<75 kg = 1,000 mg and ≥75 kg = 1,200 mg); administered orally in two divided doses with food.

Paediatric Patients: for ribavirin dosing recommendations see Table 3 below. d. See Table 2 for weight-based Sovaldi dosing recommendations for paediatric patients aged 3 years and above. e. See Table 3 for weight-based ribavirin dosing recommendations for paediatric patients aged 3 years and above.

f. See Special patient populations – Patients awaiting liver transplantation below. 1). Please refer to the Summary of Product Characteristics for Sovaldi 200 mg or 400 mg tablets. In paediatric patients aged 3 years and above the following ribavirin dosing is recommended where ribavirin is divided into two daily doses and given with food: Table 3: Guidance for ribavirin dosing when administered in combination with Sovaldi to HCV-infected paediatric patients aged 3 years and above.

Body weight kg Ribavirin Dose* < 47 15 mg/kg/day 47-49 600 mg/day 50-65 800 mg/day 66-80 1000 mg/day > 81 1200 mg/day * The daily dosage of ribavirin is weight-based and is administered orally in two divided doses with food. Concerning co-administration with other direct-acting antivirals against HCV, see section

Summary of the safety profile in adults Assessment of adverse reactions is based on pooled data from five Phase 3 clinical studies (both controlled and uncontrolled). Sovaldi has been studied in combination with ribavirin, with or without peginterferon alfa.

In this context, no adverse drug reactions specific to sofosbuvir have been identified. The most common adverse drug reactions occurring in patients receiving sofosbuvir and ribavirin or sofosbuvir, ribavirin and peginterferon alfa were fatigue, headache, nausea and insomnia.

Tabulated summary of adverse reactions The following adverse drug reactions have been identified with sofosbuvir in combination with ribavirin or in combination with peginterferon alfa and ribavirin (Table 6). The adverse reactions are listed below by body system organ class and frequency.

Frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) or very rare (<1/10,000).

Table 6:

Adverse drug reactions identified with sofosbuvir in combination with ribavirin or peginterferon alfa and ribavirin Frequency SOFa + RBVb SOF + PEGc + RBV Infections and infestations: Common nasopharyngitis Blood and lymphatic system disorders: Very common haemoglobin decreased anaemia, neutropenia, lymphocyte count decreased, platelet count decreased Common anaemia Metabolism and nutrition disorders: Very common decreased appetited decreased appetite Common weight decreased Frequency SOFa + RBVb SOF + PEGc + RBV Psychiatric disorders: Very common insomnia insomnia Common depression depression, anxiety, agitation Nervous system disorders: Very common headache dizziness, headache Common disturbance in attention migraine, memory impairment, disturbance in attention Eye disorders: Common vision blurred Respiratory, thoracic and mediastinal disorders: Very common dyspnoea, cough Common dyspnoea, dyspnoea exertional, cough dyspnoea exertional Gastrointestinal disorders: Very common nausea diarrhoea, nausea, vomiting Common abdominal discomfort, constipation, dyspepsia constipation, dry mouth, gastroesophageal reflux Hepatobiliary disorders: Very common blood bilirubin increased blood bilirubin increased Skin and subcutaneous tissue disorders: Very common rash, pruritus Common alopecia, dry skin, pruritus alopecia, dry skin Musculoskeletal and connective tissue disorders: Very common arthralgia, myalgia Common arthralgia, back pain, muscle spasms, myalgia back pain, muscle spasms General disorders and administration site conditions: Very common fatigue, irritability chills, fatigue, influenza-like illness, irritability, pain, pyrexia Common pyrexia, asthenia chest pain, asthenia a.

4. Dose modification in adults Dose reduction of Sovaldi is not recommended. If sofosbuvir is used in combination with peginterferon alfa, and a patient has a serious adverse reaction potentially related to this medicinal product, the peginterferon alfa dose should be reduced or discontinued.

Refer to the peginterferon alfa Summary of Product Characteristics for additional information about how to reduce and/or discontinue the peginterferon alfa dose. If a patient has a serious adverse reaction potentially related to ribavirin, the ribavirin dose should be modified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity.

Table 4 provides guidelines for dose modifications and discontinuation based on the patient’s haemoglobin concentration and cardiac status. 5 g/dL Haemoglobin in patients with history of stable cardiac disease ≥2 g/dL decrease in haemoglobin during any 4 week treatment period <12 g/dL despite 4 weeks at reduced dose Once ribavirin has been withheld due to either a laboratory abnormality or clinical manifestation, an attempt may be made to restart ribavirin at 600 mg daily and further increase the dose to 800 mg daily.

However, it is not recommended that ribavirin be increased to the original assigned dose (1,000 mg to 1,200 mg daily). Dose modification in paediatric patients aged 3 years and above Dose reduction of Sovaldi is not recommended. If a patient has a serious adverse reaction potentially related to ribavirin, the ribavirin dose should be modified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity.

Refer to the ribavirin prescribing information for guidance on dose modification or discontinuation. 4). Vomiting and missed doses Patients should be instructed that if vomiting occurs within 2 hours of dosing an additional dose should be taken.

If vomiting occurs more than 2 hours after dosing, no further dose is needed. These recommendations are based on the absorption kinetics of sofosbuvir and GS-331007 suggesting that the majority of the dose is absorbed within 2 hours after dosing.

1. Medicinal products that are strong P-glycoprotein (P-gp) inducers in the intestine (carbamazepine, phenobarbital, phenytoin, rifampicin and St. John’s wort). 5).