Zepatier · 4.6 Fertility, pregnancy and lactation · 1

HOS-217283 · has-adverse-reaction-information · PDF-Seite 20

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). 20 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

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HOS-217279 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Patients with moderate or severe hepatic impairment (Child-Pugh B or C) (see sections 4.2 and 5.2). Co-administration with inhibitors of organic anion transporting polypeptide 1B (OATP1B), such as rifampicin, atazanavir, darunavir, lopinavir, saquinavir, tipranavir, cobicistat or ciclosporin (see sections 4.4 and 4.5). Co-administration with inducers of cytochrome P450 3A (CYP3A) or P-glycoprotein (P-gp), such as efavirenz, phenytoin, carbamazepine, bosentan, etravirine, modafinil or St. John’s wort (Hypericum perforatum) (see sections 4.4 and 4.5).

HOS-217278 · has-indication-information · PDF-Seite 2

ZEPATIER is indicated for the treatment of chronic hepatitis C (CHC) in adult and paediatric patients 12 years of age and older who weigh at least 30 kg (see sections 4.2, 4.4 and 5.1). For hepatitis C virus (HCV) genotype-specific activity see sections 4.4 and 5.1.

HOS-217281 · has-interaction-information · PDF-Seite 5

Potential for other medicinal products to affect ZEPATIER Grazoprevir is a substrate of OATP1B drug transporters. Co-administration of ZEPATIER with medicinal products that inhibit OATP1B transporters is contraindicated because it may result in a significant increase in the plasma concentration of grazoprevir (see sections 4.3 and 4.4). Elbasvir and grazoprevir are substrates of CYP3A and P-gp. Co-administration of inducers of CYP3A or P-gp with ZEPATIER is contraindicated because it may decrease elbasvir and grazoprevir plasma concentrations, which may lead to reduced therapeutic effect of ZEPATIER (see sections 4.3 and 4.4). Co-administration of ZEPATIER with strong CYP3A inhibitors increases elbasvir and grazoprevir plasma concentrations, and co-administration is not recommended (see Table 2 and section 4.4). 5 Co-administration of ZEPATIER with P-gp inhibitors is expected to have a minimal effect on the plasma concentrations of ZEPATIER. The potential for grazoprevir to be a breast cancer resistance protein (BCRP) substrate cannot be excluded. Potential for ZEPATIER to affect other medicinal products Elbasvir and grazoprevir are inhibitors of the drug transporter BCRP at the intestinal level in humans and may increase plasma concentrations of co-administered BCRP substrates. Elbasvir is not a CYP3A inhibitor in vitro and grazoprevir is a weak CYP3A inhibitor in humans. Co-administration with grazoprevir did not result in clinically relevant increases in exposures of CYP3A substrates. Therefore, no dose adjustment is required for CYP3A substrates when co-administered with ZEPATIER. Elbasvir has minimal intestinal P-gp inhibition in humans, and does not result in clinically relevant increases in concentrations of digoxin (a P-gp substrate), with an 11% increase in plasma AUC. Grazoprevir is not a P-gp inhibitor based on in vitro data. Elbasvir and grazoprevir are not OATP1B inhibitors in humans. Based on in vitro data, clinically significant interactions with ZEPATIER as an inhibitor of other CYP enzymes, UGT1A1, esterases (CES1, CES2, and CatA), OAT1, OAT3, and OCT2 are not expected. Based on in vitro data, a potential for GZR to inhibit BSEP cannot be excluded. Multiple-dose administration of elbasvir or grazoprevir is unlikely to induce the metabolism of medicinal products metabolised by CYP isoforms based on in vitro data. Patients treated with vitamin K antagonists As liver function m

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HOS-217282 · has-pregnancy-information · PDF-Seite 19

If ZEPATIER is co-administered with ribavirin, the information for ribavirin with regard to contraception, pregnancy testing, pregnancy, breast-feeding, and fertility also applies to this combination regimen (refer to the Summary of Product Characteristics for the co-administered medicinal product for additional information). Women of childbearing potential / contraception in males and females When ZEPATIER is used in combination with 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. Pregnancy There are no adequate and well-controlled studies with ZEPATIER in pregnant women. Animal studies do not indicate harmful effects with respect to reproductive toxicity. Because reproduction 19 animal studies are not always predictive of human response, ZEPATIER should be used only if the potential benefit justifies the potential risk to the fetus. Breast-feeding It is unknown whether elbasvir or grazoprevir and their metabolites are excreted in human milk. Available pharmacokinetic data in animals has shown excretion of elbasvir and grazoprevir in milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ZEPATIER therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility No human data on the effect of elbasvir and grazoprevir on fertility are available. Animal studies do not indicate harmful effects of elbasvir or grazoprevir on fertility at elbasvir and grazoprevir exposures higher than the exposure in humans at the recommended clinical dose (see section 5.3).

HOS-217280 · has-warning-information · PDF-Seite 4

ALT elevations The rate of late ALT elevations during treatment is directly related to the plasma exposure to grazoprevir. During clinical studies with ZEPATIER with or without ribavirin, < 1 % of subjects experienced elevations of ALT from normal levels to greater than 5 times the upper limit of normal (ULN), (see section 4.8). Higher rates of late ALT elevations occurred in females (2 % [11/652]), Asians (2 % [4/165]), and subjects aged ≥ 65 years (2 % [3/187]) (see sections 4.8 and 5.2). 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. Retreatment The efficacy of ZEPATIER in patients previously exposed to ZEPATIER, or to medicinal products of the same classes as those of ZEPATIER (NS5A inhibitors or NS3/4A inhibitors other than telaprevir, simeprevir, boceprevir), has not been demonstrated (see section 5.1). 4 Interactions with medicinal products Co-administration of ZEPATIER and OATP1B inhibitors is contraindicated because it may significantly increase grazoprevir plasma concentrations. Co-administration of ZEPATIER and CYP3A or P-gp inducers is contraindicated because it may significantly decrease elbasvir and grazoprevir plasma concentrations and may lead to a reduced therapeutic effect of ZEPATIER (see sections 4.3, 4.5 and 5.2). The concomitant use of ZEPATIER and strong CYP3A inhibitors increases elbasvir and grazoprevir concentrations, and co-administration is not recommended (see section 4

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