Maviret · 4.3 Contraindications · 1

HOS-098281 · has-adverse-reaction-information · PDF-Seite 37

Summary of the safety profile In pooled Phase 2 and 3 clinical studies of adult subjects receiving Maviret with genotype 1, 2, 3, 4, 5 or 6 chronic HCV infection the most commonly reported adverse reactions (incidence ≥ 10%) were headache and fatigue. Less than 0.1% of subjects treated with Maviret had serious adverse reactions (transient ischaemic attack). The proportion of subjects treated with Maviret who permanently discontinued treatment due to adverse reactions was 0.1%. In a Phase 3b clinical study of adult subjects receiving Maviret with genotype 1, 2, 3, or 4 acute HCV infection the most commonly reported adverse reactions (incidence ≥ 2%) were fatigue, asthenia, and headache, each reported in < 4% of subjects. No subject treated with Maviret had a serious adverse reaction; no subject discontinued treatment due to an adverse reaction. Tabulated list of adverse reactions The following adverse reactions were identified in registrational Phase 2 and 3 studies in adults with chronic HCV infection with or without cirrhosis treated with Maviret for 8, 12 or 16 weeks, or during post-marketing experience (Table 5). The adverse reactions are listed below by body system organ class and frequency. Frequencies are defined as follows: very common (≥ 1/10), common 37 (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000) or not known (cannot be estimated from the available data). Table 5: Adverse reactions identified with Maviret System Organ Class Frequency Adverse reactions Immune system disorders Uncommon Angioedema Nervous system disorders Very common Headache Gastrointestinal disorders Common Diarrhoea, nausea Skin and subcutaneous tissue Not known Pruritus disorders General disorders and Very common Fatigue administration site conditions Common Asthenia Investigations Common Elevation in total bilirubin Description of selected adverse reactions Chronic HCV infection Adverse reactions in subjects with severe renal impairment including subjects on dialysis The safety of Maviret in subjects with chronic kidney disease (including subjects on dialysis) and genotypes 1, 2, 3, 4, 5 or 6 chronic HCV infec

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HOS-098275 · has-adverse-reaction-information · PDF-Seite 11

Summary of the safety profile In pooled Phase 2 and 3 clinical studies of adult subjects receiving Maviret with genotype 1, 2, 3, 4, 5 or 6 chronic HCV infection the most commonly reported adverse reactions (incidence ≥ 10%) were headache and fatigue. Less than 0.1% of subjects treated with Maviret had serious adverse reactions (transient ischaemic attack). The proportion of subjects treated with Maviret who permanently discontinued treatment due to adverse reactions was 0.1%. In a Phase 3b clinical study of adult subjects receiving Maviret with genotype 1, 2, 3, or 4 acute HCV infection the most commonly reported adverse reactions (incidence ≥ 2%) were fatigue, asthenia, and headache, each reported in < 4% of subjects. No subject treated with Maviret had a serious adverse reaction; no subject discontinued treatment due to an adverse reaction. Tabulated list of adverse reactions The following adverse reactions were identified in registrational Phase 2 and 3 studies in adults with chronic HCV infection with or without cirrhosis treated with Maviret for 8, 12 or 16 weeks, or during post-marketing experience (Table 4). 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), very rare (< 1/10 000) or not known (cannot be estimated from the available data). Table 4: Adverse reactions identified with Maviret System Organ Class Frequency Adverse reactions Immune system disorders Uncommon Angioedema Nervous system disorders Very common Headache Gastrointestinal disorders Common Diarrhoea, nausea Skin and subcutaneous tissue Not known Pruritus disorders General disorders and Very common Fatigue administration site conditions Common Asthenia Investigations Common Elevation in total bilirubin 11 Description of selected adverse reactions Chronic HCV infection Adverse reactions in subjects with severe renal impairment including subjects on dialysis The safety of Maviret in subjects with chronic kidney disease (including subjects on dialysis) and genotypes 1, 2, 3, 4, 5 or 6 chronic HCV infe

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HOS-098277 · has-contraindication-information · PDF-Seite 30

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Patients with severe hepatic impairment (Child-Pugh C) (see sections 4.2, 4.4, and 5.2). Concomitant use with atazanavir containing products, atorvastatin, simvastatin, dabigatran etexilate, ethinyl oestradiol-containing products, strong P-gp and CYP3A inducers (e.g., rifampicin, carbamazepine, St. John’s wort (Hypericum perforatum), phenobarbital, phenytoin, and primidone) (see section 4.5).

HOS-098271 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Patients with severe hepatic impairment (Child-Pugh C) (see sections 4.2, 4.4, and 5.2). Concomitant use with atazanavir containing products, atorvastatin, simvastatin, dabigatran etexilate, ethinyl oestradiol-containing products, strong P-gp and CYP3A inducers (e.g., rifampicin, carbamazepine, St. John’s wort (Hypericum perforatum), phenobarbital, phenytoin, and primidone) (see section 4.5).

HOS-098276 · has-indication-information · PDF-Seite 28

Maviret coated granules is indicated for the treatment of acute and chronic hepatitis C virus (HCV) infection in children 3 years and older (see sections 4.2, 4.4. and 5.1).

HOS-098270 · has-indication-information · PDF-Seite 2

Maviret is indicated for the treatment of acute and chronic hepatitis C virus (HCV) infection in adults and children aged 3 years and older (see sections 4.2, 4.4. and 5.1).

HOS-098279 · has-interaction-information · PDF-Seite 31

Potential for Maviret to affect other medicinal products Glecaprevir and pibrentasvir are inhibitors of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide (OATP) 1B1/3. Co-administration with Maviret may increase plasma concentrations of medicinal products that are substrates of P-gp (e.g. dabigatran etexilate, digoxin), BCRP (e.g. rosuvastatin), or OATP1B1/3 (e.g. atorvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin). See Table 4 for specific recommendations on interactions with sensitive substrates of P-gp, BCRP, and OATP1B1/3. For other P-gp, BCRP, or OATP1B1/3 substrates, dose adjustment may be needed. Glecaprevir and pibrentasvir are weak inhibitors of cytochrome P450 (CYP) 3A and uridine glucuronosyltransferase (UGT) 1A1 in vivo. Clinically significant increases in exposure were not observed for sensitive substrates of CYP3A (midazolam, felodipine) or UGT1A1 (raltegravir) when administered with Maviret. Both glecaprevir and pibrentasvir inhibit the bile salt export pump (BSEP) in vitro. Significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, UGT1A6, UGT1A9, UGT1A4, UGT2B7, OCT1, OCT2, OAT1, OAT3, MATE1 or MATE2K are not expected. Patients treated with vitamin K antagonists As liver function may change during treatment with Maviret, a close monitoring of International Normalised Ratio (INR) values is recommended. 31 Potential for other medicinal products to affect Maviret Use with strong P-gp/CYP3A inducers Medicinal products that are strong P-gp and CYP3A inducers (e.g., rifampicin, carbamazepine, St. John’s wort (Hypericum perforatum), phenobarbital, phenytoin, and primidone) could significantly decrease glecaprevir or pibrentasvir plasma concentrations and may lead to reduced therapeutic effect of Maviret or loss of virologic response. Co-administration of such medicinal products with Maviret is contraindicated (see section 4.3). Co-administration of Maviret with medicinal products that are moderate inducers P-gp/CYP3A may decrease glecaprevir and pibrentasvir plasma concentrations (e.g. oxcarbazepine, eslicarbazepine, lumacaftor, crizotinib). Co-administration of moderate inducers is not recommended (see section 4.4). Glecaprevir and pibrentasvir are substrates of the efflux transporters P-gp and/or BCRP. Glecaprevir is also a substrate of the hepatic uptake transporters OATP1B1/3. Co-administration of Maviret wi

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HOS-098273 · has-interaction-information · PDF-Seite 5

Potential for Maviret to affect other medicinal products Glecaprevir and pibrentasvir are inhibitors of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide (OATP) 1B1/3. Co-administration with Maviret may increase plasma concentrations of medicinal products that are substrates of P-gp (e.g. dabigatran etexilate, digoxin), BCRP (e.g. rosuvastatin), or OATP1B1/3 (e.g. atorvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin). See Table 3 for specific recommendations on interactions with sensitive substrates of P-gp, BCRP, and OATP1B1/3. For other P-gp, BCRP, or OATP1B1/3 substrates, dose adjustment may be needed. Glecaprevir and pibrentasvir are weak inhibitors of cytochrome P450 (CYP) 3A and uridine glucuronosyltransferase (UGT) 1A1 in vivo. Clinically significant increases in exposure were not observed for sensitive substrates of CYP3A (midazolam, felodipine) or UGT1A1 (raltegravir) when administered with Maviret. Both glecaprevir and pibrentasvir inhibit the bile salt export pump (BSEP) in vitro. Significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, UGT1A6, UGT1A9, UGT1A4, UGT2B7, OCT1, OCT2, OAT1, OAT3, MATE1 or MATE2K are not expected. Patients treated with vitamin K antagonists As liver function may change during treatment with Maviret, a close monitoring of International Normalised Ratio (INR) values is recommended. Potential for other medicinal products to affect Maviret Use with strong P-gp/CYP3A inducers Medicinal products that are strong P-gp and CYP3A inducers (e.g., rifampicin, carbamazepine, St. John’s wort (Hypericum perforatum), phenobarbital, phenytoin, and primidone) could significantly decrease glecaprevir or pibrentasvir plasma concentrations and may lead to reduced therapeutic effect of Maviret or loss of virologic response. Co-administration of such medicinal products with Maviret is contraindicated (see section 4.3). Co-administration of Maviret with medicinal products that are moderate inducers P-gp/CYP3A may decrease glecaprevir and pibrentasvir plasma concentrations (e.g. oxcarbazepine, eslicarbazepine, lumacaftor, crizotinib). Co-administration of moderate inducers is not recommended (see section 4.4). Glecaprevir and pibrentasvir are substrates of the efflux transporters P-gp and/or BCRP. Glecaprevir is also a substrate of the hepatic uptake transporters OATP1B1/3. Co-administration of Maviret with medicinal products that inhibit P-gp and BCRP (e.g. cicl

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HOS-098280 · has-pregnancy-information · PDF-Seite 37

Pregnancy There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of glecaprevir or pibrentasvir in pregnant women. Studies in rats/mice with glecaprevir or pibrentasvir do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Maternal toxicity associated with embryo-foetal loss has been observed in the rabbit with glecaprevir which precluded evaluation of glecaprevir at clinical exposures in this species (see section 5.3). As a precautionary measure, Maviret use is not recommended in pregnancy. Breast-feeding It is unknown whether glecaprevir or pibrentasvir are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of glecaprevir and pibrentasvir in milk (for details see section 5.3). A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Maviret 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 glecaprevir and/or pibrentasvir on fertility are available. Animal studies do not indicate harmful effects of glecaprevir or pibrentasvir on fertility at exposures higher than the exposures in humans at the recommended dose (see section 5.3).

HOS-098274 · has-pregnancy-information · PDF-Seite 10

Pregnancy There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of glecaprevir or pibrentasvir in pregnant women. Studies in rats/mice with glecaprevir or pibrentasvir do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Maternal toxicity associated with embryo-foetal loss has been observed in the rabbit with glecaprevir which precluded evaluation of glecaprevir at clinical exposures in this species (see section 5.3). As a precautionary measure, Maviret use is not recommended in pregnancy. 10 Breast-feeding It is unknown whether glecaprevir or pibrentasvir are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of glecaprevir and pibrentasvir in milk (for details see section 5.3). A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Maviret 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 glecaprevir and/or pibrentasvir on fertility are available. Animal studies do not indicate harmful effects of glecaprevir or pibrentasvir on fertility at exposures higher than the exposures in humans at the recommended dose (see section 5.3).

HOS-098278 · has-warning-information · PDF-Seite 30

Hepatitis B virus reactivation 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. Hepatic impairment Maviret is not recommended in patients with moderate hepatic impairment (Child-Pugh B) and is contraindicated in patients with severe hepatic impairment (Child-Pugh C) (see sections 4.2, 4.3, and 5.2). Patients who failed a prior regimen containing an NS5A- and/or an NS3/4A-inhibitor Genotype 1-infected (and a very limited number of genotype 4-infected) patients with prior failure on regimens that may confer resistance to glecaprevir/pibrentasvir were studied in studies MAGELLAN-1 and B16-439 (section 5.1). The risk of failure was, as expected, highest for those exposed to both classes. A resistance algorithm predictive of the risk for failure by baseline resistance has not been established. Accumulating double class resistance was a general finding for patients who failed re-treatment with glecaprevir/pibrentasvir in MAGELLAN-1. No re-treatment data is available for patients infected with genotypes 2, 3, 5 or 6. Maviret is not recommended for the re-treatment of patients with prior exposure to NS3/4A- and/or NS5A inhibitors. 30 Drug-drug interactions Co-administration is not recommended with several medicinal products as detailed in section 4.5. Use in diabetic patients Diabetics may experience improved glucose control, potentially resulting in symptomatic hypoglycaemia, after initiating HCV direct acting antiviral treatment. Glucose levels of diabetic patients initiating direct acting antiviral therapy should be closely monitored, particularly within the first 3 months, and their diabetic medicine modified when necessary. The physician in charge of the diabetic care of the patient should be informed when direct acting antiviral therapy is initiated. Lactose Maviret granules contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. Propylene glycol This medicinal product contains 4 mg propylene glycol in each sachet. Sodium This medicinal p

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HOS-098272 · has-warning-information · PDF-Seite 4

Hepatitis B virus reactivation 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. Hepatic impairment Maviret is not recommended in patients with moderate hepatic impairment (Child-Pugh B) and is contraindicated in patients with severe hepatic impairment (Child-Pugh C) (see sections 4.2, 4.3, and 5.2). Patients who failed a prior regimen containing an NS5A- and/or an NS3/4A-inhibitor Genotype 1-infected (and a very limited number of genotype 4-infected) patients with prior failure on regimens that may confer resistance to glecaprevir/pibrentasvir were studied in studies MAGELLAN-1 and B16-439 (section 5.1). The risk of failure was, as expected, highest for those exposed to both classes. A resistance algorithm predictive of the risk for failure by baseline resistance has not been established. Accumulating double class resistance was a general finding for patients who failed re-treatment with glecaprevir/pibrentasvir in MAGELLAN-1. No re-treatment data is available for patients infected with genotypes 2, 3, 5 or 6. Maviret is not recommended for the re-treatment of patients with prior exposure to NS3/4A- and/or NS5A inhibitors. Drug-drug interactions Co-administration is not recommended with several medicinal products as detailed in section 4.5. Use in diabetic patients Diabetics may experience improved glucose control, potentially resulting in symptomatic hypoglycaemia, after initiating HCV direct acting antiviral treatment. Glucose levels of diabetic patients initiating direct acting antiviral therapy should be closely monitored, particularly within the first 3 months, and their diabetic medicines modified when necessary. The physician in charge of the diabetic care of the patient should be informed when direct acting antiviral therapy is initiated. 4 Lactose Maviret contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. Sodium This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-fr

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