Cholib · 4.5 Interaction with other medicinal products and other forms of interaction · 2

HOS-096368 · has-adverse-reaction-information · PDF-Seite 33

Summary of the safety profile The most commonly reported adverse drug reactions (ADRs) during Cholib therapy are increased blood creatinine, upper respiratory tract infection, increased platelet count, gastroenteritis and increased alanine- aminotransferase. Tabulated list of adverse reactions During four double blind clinical trials of 24-week duration 1,237 patients have received treatment with co-administered fenofibrate and simvastatin. In a pooled analysis of these four trials, the rate of discontinuation due to treatment emergent adverse reactions was 5.0% (51 subjects on 1012) after 12 weeks of treatment with fenofibrate and simvastatin 145 mg/20 mg per day and 1.8% (4 subjects on 225) after 12 weeks of treatment with fenofibrate and simvastatin 145 mg/40 mg per day. Treatment emergent adverse reactions reported in patients receiving co-administration of fenofibrate and simvastatin occurring are listed below by system organ class and frequency. The adverse reactions of Cholib are in line with what is known from its two active substances: fenofibrate and simvastatin. 33 The frequencies of adverse reactions are ranked according to the following: 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) and not known (cannot be estimated from the available data). Adverse reactions observed with the co-administration of fenofibrate and simvastatin (Cholib) System Organ Class Adverse reactions Frequency Upper respiratory tract Infections and infestations Common infection, Gastroenteritis Blood and lymphatic Platelet count increased Common disorders Alanine- aminotransferase Hepatobiliary disorders Common increased Skin and subcutaneous tissue Dermatitis and eczema Uncommon disorders Blood creatinine increased Investigations very common (see sections 4.3 and 4.4) Description of selected adverse reactions Blood creatinine increased:

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HOS-096362 · has-adverse-reaction-information · PDF-Seite 11

Summary of the safety profile The most commonly reported adverse drug reactions (ADRs) during Cholib therapy are increased blood creatinine, upper respiratory tract infection, increased platelet count, gastroenteritis and increased alanine- aminotransferase. 11 Tabulated list of adverse reactions During four double blind clinical trials of 24-week duration 1,237 patients have received treatment with co-administered fenofibrate and simvastatin. In a pooled analysis of these four trials, the rate of discontinuation due to treatment emergent adverse reactions was 5.0% (51 subjects on 1012) after 12 weeks of treatment with fenofibrate and simvastatin 145 mg/20 mg per day and 1.8% (4 subjects on 225) after 12 weeks of treatment with fenofibrate and simvastatin 145 mg/40 mg per day. Treatment emergent adverse reactions reported in patients receiving co-administration of fenofibrate and simvastatin occurring are listed below by system organ class and frequency. The adverse reactions of Cholib are in line with what is known from its two active substances: fenofibrate and simvastatin. The frequencies of adverse reactions are ranked according to the following: 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) and not known (cannot be estimated from the available data). Adverse reactions observed with the co-administration of fenofibrate and simvastatin (Cholib) System Organ Class Adverse reactions Frequency Upper respiratory tract Infections and infestations Common infection, Gastroenteritis Blood and lymphatic Platelet count increased Common disorders Alanine- aminotransferase Hepatobiliary disorders Common increased Skin and subcutaneous tissue Dermatitis and eczema Uncommon disorders Blood creatinine increased (see Investigations very common sections 4.3 and 4.4) Description of selected adverse reactions Blood creatin

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HOS-096364 · has-contraindication-information · PDF-Seite 25

• Hypersensitivity to the active substances, peanut, soya or to any of the excipients listed in section 6.1 (see also section 4.4) • Known photoallergy or phototoxic reaction during treatment with fibrates or ketoprofen • Active liver disease or unexplained persistent elevations of serum transaminases • Known gallbladder disease • Chronic or acute pancreatitis with the exception of acute pancreatitis due to severe hypertriglyceridaemia • Moderate to severe renal insufficiency (estimated glomerular filtration rate < 60 mL/min/1.73 m2) • Concomitant administration of potent CYP3A4 inhibitors (agents that increase AUC approximately 5 fold or greater) (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and medicinal products containing cobicistat) (see sections 4.4 and 4.5) • Concomitant administration of gemfibrozil, ciclosporin, or danazol (see sections 4.4 and 4.5) • Concomitant administration of glecaprevir, pibrentasvir, elbasvir or grazoprevir (see section 4.5) • Paediatric population (age below 18 years) • Pregnancy and breast-feeding (see section 4.6) • Personal history of myopathy and/or rhabdomyolysis with statins and/or fibrates or confirmed creatine phosphokinase elevation above 5 times the upper limit of normal (ULN) under previous statin treatment (see section 4.4) Concomitant administration of amiodarone, verapamil, amlodipine or diltiazem (see section 4.5)

HOS-096358 · has-contraindication-information · PDF-Seite 3

• Hypersensitivity to the active substances, peanut, soya or to any of the excipients listed in section 6.1 (see also section 4.4) • Known photoallergy or phototoxic reaction during treatment with fibrates or ketoprofen • Active liver disease or unexplained persistent elevations of serum transaminases • Known gallbladder disease • Chronic or acute pancreatitis with the exception of acute pancreatitis due to severe hypertriglyceridaemia • Moderate to severe renal insufficiency (estimated glomerular filtration rate < 60 mL/min/1.73 m2) • Concomitant administration of potent CYP3A4 inhibitors (agents that increase AUC approximately 5 fold or greater) (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and medicinal products containing cobicistat) (see sections 4.4 and 4.5) • Concomitant administration of gemfibrozil, ciclosporin, or danazol (see sections 4.4 and 4.5) • Concomitant administration of glecaprevir/ pibrentasvir (see section 4.5) • Paediatric population (age below 18 years) • Pregnancy and breast-feeding (see section 4.6) • Personal history of myopathy and/or rhabdomyolysis with statins and/or fibrates or confirmed creatine phosphokinase elevation above 5 times the upper limit of normal (ULN) under previous statin treatment (see section 4.4)

HOS-096357 · has-indication-information · PDF-Seite 2

Cholib is indicated as adjunctive therapy to diet and exercise in high cardiovascular risk adult patients with mixed dyslipidaemia to reduce triglycerides and increase HDL-C levels when LDL-C levels are adequately controlled with the corresponding dose of simvastatin monotherapy.

HOS-096363 · has-indication-information · PDF-Seite 24

Cholib is indicated as adjunctive therapy to diet and exercise in high cardiovascular risk adult patients with mixed dyslipidaemia to reduce triglycerides and increase HDL-C levels when LDL-C levels are adequately controlled with the corresponding dose of simvastatin monotherapy.

HOS-096366 · has-interaction-information · PDF-Seite 29

No interaction studies have been performed with Cholib. Interactions relevant to monotherapies Inhibitors of CYP 3A4 Simvastatin is a substrate of cytochrome P450 3A4. Multiple mechanisms may contribute to potential interactions with HMG Co-A reductase inhibitors. Drugs or herbal products that inhibit certain enzymes (e.g. CYP3A4) and/or transporter (e.g. OATP1B) pathways may increase simvastatin and simvastatin acid plasma concentrations and may lead to an increased risk of myopathy/rhabdomyolysis. Potent inhibitors of cytochrome P450 3A4 increase the risk of myopathy and rhabdomyolysis by increasing the concentration of HMG-CoA reductase inhibitory activity in plasma during simvastatin therapy. Such inhibitors include itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), cobicistat and nefazodone. Combination with itraconazole, ketoconazole, posaconazole, HIV protease inhibitors (e.g. nelfinavir), cobicistat, erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated (see section 4.3). If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with Cholib must be suspended during the course of treatment. Caution should be exercised when combining Cholib with certain other less potent CYP 3A4 inhibitors: fluconazole, verapamil, or diltiazem (see sections 4.3 and 4.4). Consult the prescribing information of all concomitantly used drugs to obtain further information about their potential interactions with simvastatin and/or the potential for enzyme or transporter alterations and possible adjustments to dose and regimens. Danazol The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with simvastatin. The dose of simvastatin should not exceed 10 mg daily in patients taking danazol. Therefore, the co-administration of Cholib with danazol is contraindicated (see section 4.3). Ciclosporin The risk of myopathy/rhabdomyolysis is increased by concomitant administration of ciclosporin with simvastatin. Although the mechanism is not fully understood, ciclosporin has been shown to increase the plasma exposure (AUC) to simvastatin acid, presumably due in part to inhibition of CYP 3A4 and OATP-1B1 transporter. Because the dose of simvastatin should not exceed 10 mg daily in patients 29 taking ciclosporin, the

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HOS-096360 · has-interaction-information · PDF-Seite 7

No interaction studies have been performed with Cholib. Interactions relevant to monotherapies Inhibitors of CYP 3A4 Simvastatin is a substrate of cytochrome P450 3A4. Multiple mechanisms may contribute to potential interactions with HMG Co-A reductase inhibitors. Drugs or herbal products that inhibit certain enzymes (e.g. CYP3A4) and/or transporter (e.g. OATP1B) pathways may increase simvastatin and simvastatin acid plasma concentrations and may lead to an increased risk of myopathy/rhabdomyolysis. Potent inhibitors of cytochrome P450 3A4 increase the risk of myopathy and rhabdomyolysis by increasing the concentration of HMG-CoA reductase inhibitory activity in plasma during simvastatin therapy. Such inhibitors include itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), cobicistat and nefazodone. Combination with itraconazole, ketoconazole, posaconazole, HIV protease inhibitors (e.g. nelfinavir), cobicistat, erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated (see section 4.3). If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with Cholib must be suspended during the course of treatment. Caution should be exercised when combining Cholib with certain other less potent CYP 3A4 inhibitors: fluconazole, verapamil, or diltiazem (see sections 4.3 and 4.4). Consult the prescribing information of all concomitantly used drugs to obtain further information about their potential interactions with simvastatin and/or the potential for enzyme or transporter alterations and possible adjustments to dose and regimens. 7 Danazol The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with simvastatin. The dose of simvastatin should not exceed 10 mg daily in patients taking danazol. Therefore, the co-administration of Cholib with danazol is contraindicated (see section 4.3). Ciclosporin The risk of myopathy/rhabdomyolysis is increased by concomitant administration of ciclosporin with simvastatin. Although the mechanism is not fully understood, ciclosporin has been shown to increase the plasma exposure (AUC) to simvastatin acid, presumably due in part to inhibition of CYP 3A4 and OATP-1B1 transporter. Because the dose of simvastatin should not exceed 10 mg daily in patients taking ciclosporin, th

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HOS-096367 · has-pregnancy-information · PDF-Seite 33

Pregnancy Cholib As simvastatin is contraindicated during pregnancy (see hereafter), Cholib is contraindicated during pregnancy (see section 4.3). Fenofibrate There are no adequate data from the use of fenofibrate in pregnant women. Animal studies have shown embryo-toxic effects at doses in the range of maternal toxicity (see section 5.3). The potential risk for humans is unknown. Therefore, fenofibrate should only be used during pregnancy after a careful benefit/risk assessment. Simvastatin Simvastatin is contraindicated during pregnancy. Safety in pregnant women has not been established. Maternal treatment with simvastatin may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. For these reasons, simvastatin must not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with simvastatin must be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant. Breast-feeding It is unknown whether fenofibrate, simvastatin and/or their metabolites are excreted in human milk. Therefore, Cholib is contraindicated during breast-feeding (see section 4.3). Fertility Reversible effects on fertility have been observed in animals (see section 5.3). There are no clinical data on fertility from the use of Cholib.

HOS-096361 · has-pregnancy-information · PDF-Seite 11

Pregnancy Cholib As simvastatin is contraindicated during pregnancy (see hereafter), Cholib is contraindicated during pregnancy (see section 4.3). Fenofibrate There are no adequate data from the use of fenofibrate in pregnant women. Animal studies have shown embryo-toxic effects at doses in the range of maternal toxicity (see section 5.3). The potential risk for humans is unknown. Therefore, fenofibrate should only be used during pregnancy after a careful benefit/risk assessment. Simvastatin Simvastatin is contraindicated during pregnancy. Safety in pregnant women has not been established. Maternal treatment with simvastatin may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. For these reasons, simvastatin must not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with simvastatin must be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant. Breast-feeding It is unknown whether fenofibrate, simvastatin and/or their metabolites are excreted in human milk. Therefore, Cholib is contraindicated during breast-feeding (see section 4.3). Fertility Reversible effects on fertility have been observed in animals (see section 5.3). There are no clinical data on fertility from the use of Cholib.

HOS-096365 · has-warning-information · PDF-Seite 25

Muscle Skeletal muscle toxicity, including rare cases of rhabdomyolysis with or without renal failure, has been reported with administration of lipid-lowering substances like fibrates and statins. The risk of myopathy with statins and fibrates is known to be related to the dose of each component and to the nature of the fibrate. Reduced function of transport proteins Reduced function of hepatic OATP transport proteins can increase the systemic exposure of simvastatin and increase the risk of myopathy and rhabdomyolysis. Reduced function can occur as the result of inhibition by interacting medicines (eg ciclosporin) or in patients who are carriers of the SLCO1B1 c.521T>C genotype. 25 Patients carrying the SLCO1B1 gene allele (c.521T>C) coding for a less active OATP1B1 protein have an increased systemic exposure of simvastatin and increased risk of myopathy. The risk of high dose (80 mg) simvastatin related myopathy is about 1 % in general, without genetic testing. Based on the results of the SEARCH trial, homozygote C allele carriers (also called CC) treated with 80 mg have a 15% risk of myopathy within one year, while the risk in heterozygote C allele carriers (CT) is 1.5%. The corresponding risk is 0.3% in patients having the most common genotype (TT) (See section 5.2). Immune-mediated necrotizing myopathy (IMNM) There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti- HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Consider risk of IMNM carefully prior to initiation of another statin. If therapy is initiated with another statin, monitor for signs and symptoms of IMNM. Measures to reduce the risk of myopathy caused by medicinal product interactions The risk of muscle toxicity may be increased if Cholib is administered with another fibrate, statin, niacin, fusidic acid or other specific concomitant substances (for specific interactions see section 4.5). Physicians contemplating combined therapy with Cholib and lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid) or medici

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HOS-096359 · has-warning-information · PDF-Seite 3

Muscle Skeletal muscle toxicity, including rare cases of rhabdomyolysis with or without renal failure, has been reported with administration of lipid-lowering substances like fibrates and statins. The risk of myopathy with statins and fibrates is known to be related to the dose of each component and to the nature of the fibrate. 3 Reduced function of transport proteins Reduced function of hepatic OATP transport proteins can increase the systemic exposure of simvastatin and increase the risk of myopathy and rhabdomyolysis. Reduced function can occur as the result of inhibition by interacting medicines (eg ciclosporin) or in patients who are carriers of the SLCO1B1 c.521T>C genotype. Patients carrying the SLCO1B1 gene allele (c.521T>C) coding for a less active OATP1B1 protein have an increased systemic exposure of simvastatin and increased risk of myopathy. The risk of high dose (80 mg) simvastatin related myopathy is about 1 % in general, without genetic testing. Based on the results of the SEARCH trial, homozygote C allele carriers (also called CC) treated with 80 mg have a 15% risk of myopathy within one year, while the risk in heterozygote C allele carriers (CT) is 1.5%. The corresponding risk is 0.3% in patients having the most common genotype (TT) (See section 5.2). Immune-mediated necrotizing myopathy (IMNM) There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti- HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Consider risk of IMNM carefully prior to initiation of another statin. If therapy is initiated with another statin, monitor for signs and symptoms of IMNM. Measures to reduce the risk of myopathy caused by medicinal product interactions The risk of muscle toxicity may be increased if Cholib is administered with another fibrate, statin, niacin, fusidic acid or other specific concomitant substances (for specific interactions see section 4.5). Physicians contemplating combined therapy with Cholib and lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid) or medi

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