Zepatier

ZEPATIER treatment should be initiated and monitored by a physician experienced in the management of patients with CHC. Posology The recommended dose is one tablet once daily. 1). 1). A In the adult clinical studies, the dose of ribavirin was weight-based (< 66 kg = 800 mg/day, 66 to 80 kg = 1,000 mg/day, 81 to 105 kg = 1,200 mg/day, > 105 kg = 1,400 mg/day) administered in two divided doses with food.

For specific dosage instructions for ribavirin, including dose modification, refer to the ribavirin Summary of Product Characteristics. Patients should be instructed that if vomiting occurs within 4 hours of dosing, an additional tablet can be taken up to 8 hours before the next dose.

If vomiting occurs more than 4 hours after dosing, no further dose is needed. In case a dose of ZEPATIER is missed and it is within 16 hours of the time ZEPATIER is usually taken, the patient should be instructed to take ZEPATIER as soon as possible and then take the next dose of ZEPATIER at the usual time.

If more than 16 hours have passed since ZEPATIER is usually taken, then the patient should be instructed that the missed dose should NOT be taken and to take the next dose per the usual dosing schedule. Patients should be instructed not to take a double dose.

2). 2). Hepatic impairment No dose adjustment of ZEPATIER is required in patients with mild hepatic impairment (Child-Pugh A). 2). The safety and efficacy of ZEPATIER have not been established in liver transplant recipients. 2). The safety and efficacy of ZEPATIER in children aged less than 12 years have not been established.

4 Method of administration For oral use. 2).

Summary of the safety profile The safety of ZEPATIER was assessed based on 3 placebo-controlled studies and 7 uncontrolled Phase 2 and 3 clinical studies in approximately 2,000 subjects with chronic hepatitis C infection with compensated liver disease (with or without cirrhosis).

In clinical studies, the most commonly reported adverse reactions (greater than 10%) were fatigue and headache. Less than 1 % of subjects treated with ZEPATIER with or without ribavirin had serious adverse reactions (abdominal pain, transient ischaemic attack and anaemia).

Less than 1 % of subjects treated with ZEPATIER with or without ribavirin permanently discontinued treatment due to adverse reactions. The frequency of serious adverse reactions and discontinuations due to adverse reactions in subjects with compensated cirrhosis were comparable to those seen in subjects without cirrhosis.

When elbasvir/grazoprevir was studied with ribavirin, the most frequent adverse reactions to elbasvir/grazoprevir + ribavirin combination therapy were consistent with the known safety profile of ribavirin. Tabulated summary of adverse reactions The following adverse reactions were identified in patients taking ZEPATIER without ribavirin for 12 weeks.

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).

21 Table 3: Adverse reactions identified with ZEPATIER* Frequency Adverse reactions Metabolism and nutrition disorders: Common decreased appetite Psychiatric disorders: Common insomnia, anxiety, depression Nervous system disorders: Very common headache Common dizziness Gastrointestinal disorders: Common nausea, diarrhoea, constipation, upper abdominal pain, abdominal pain, dry mouth, vomiting Skin and subcutaneous tissue disorders: Common pruritus, alopecia Musculoskeletal and connective tissue disorders: Common arthralgia, myalgia General disorders and administration site conditions: Very common fatigue Common asthenia, irritability *Based on pooled data from patients treated with ZEPATIER for 12 weeks without ribavirin Description of selected adverse reactions Laboratory abnormalities Changes in selected laboratory parameters are described in Table 4.

ALT elevations The rate of late ALT elevations during treatment is directly related to the plasma exposure to grazoprevir. 8). 2). These late ALT elevations generally occurred at or after treatment week 8. Hepatic laboratory testing should be performed prior to therapy, at treatment week 8, and as clinically indicated.

For patients receiving 16 weeks of therapy, additional hepatic laboratory testing should be performed at treatment week 12. • Patients should be instructed to consult their healthcare professional without delay if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discoloured faeces.

• Discontinuation of ZEPATIER should be considered if ALT levels are confirmed to be greater than 10 times the ULN. • ZEPATIER should be discontinued if ALT elevation is accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or international normalised ratio (INR).

Genotype-specific activity The efficacy of ZEPATIER has not been demonstrated in HCV genotypes 2, 3, 5 and 6. ZEPATIER is not recommended in patients infected with these genotypes. 1). 5 Interactions with medicinal products Co-administration of ZEPATIER and OATP1B inhibitors is contraindicated because it may significantly increase grazoprevir plasma concentrations.

2). 5). 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. Use in diabetic patients Diabetics may experience improved glucose control potentially resulting in symptomatic hypoglycaemia, after initiating HCV direct acting antiviral (DAA) treatment.

1. 2). 5). Co-administration with inducers of cytochrome P450 3A (CYP3A) or P-glycoprotein (P-gp), such as efavirenz, phenytoin, carbamazepine, bosentan, etravirine, modafinil or St. 5).