fenofibrate;pravastatin

HOS-095742 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile The most commonly reported adverse reactions (ADRs) during Pravafenix therapy are increased transaminase and gastrointestinal disorders. Tabulated list of adverse reactions In clinical trials, over 1,566 patients received Pravafenix. Adverse reactions have usually been mild and transient. 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). System organ class Adverse reaction Frequency Immune system Hypersensitivity reactions Uncommon disorders Metabolism and Diabetes mellitus aggravated, Obesity Uncommon nutrition disorders Psychiatric disorders Sleep disturbance including insomnia and nightmares Uncommon Nervous system Dizziness, headache, paraesthesia Uncommon disorders Cardiac disorders Palpitations Uncommon Gastrointestinal Abdominal distension, abdominal pain, abdominal pain upper, Common disorders constipation, diarrhoea, dry mouth, dyspepsia, eructation, flatulence, nausea, abdominal discomfort, vomiting. Hepatobiliary disorders Transaminases increased. Common Hepatic pain, gammaglutamyl transferase increased. Uncommon Skin and subcutaneous Pruritus, urticaria Uncommon tissue disorders 8  Arthralgia, back pain, blood creatine phosphokinase increased, Uncommon Musculoskeletal, muscle spasms, musculoskeletal pain, myalgia, pain in extremity. connective tissue and bone disorders Renal and urinary Blood creatinine increased, creatinine renal clearance decreased, Uncommon disorders creatinine renal clearance increased, Renal failure General disorders and Asthenia, fatigue, influenza like illness Uncommon administration site conditions Investigation Blo

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HOS-095738 · has-contraindication-information · PDF-Seite 3

- Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. - Severe hepatic impairment including biliary cirrhosis or active liver disease including unexplained persistent elevations in liver function tests (including serum transaminase elevation) exceeding 3 fold the upper limit of normal (ULN) (see section 4.4). - Children and adolescents (age below 18 years). - Moderate to severe renal impairment (defined as an estimated creatinine clearance < 60 ml/min). - Known photo allergy or photo toxic reaction during treatment with fibrates or ketoprofen. - Gallbladder disease (see section 4.4). - Chronic or acute pancreatitis with the exception of acute pancreatitis due to severe hypertriglyceridaemia (see section 4.4). - Pregnancy and breast-feeding (see section 4.6). - Personal history of myopathy and/or rhabdomyolysis with statins and/or fibrates or confirmed creatine phosphokinase (CK) elevation above 5 times the ULN under previous statin treatment (see section 4.4).

HOS-095737 · has-indication-information · PDF-Seite 2

Pravafenix is indicated as an adjunct to diet and other non-pharmacological treatment (e.g. exercise, weight reduction) for the treatment of mixed hyperlipidaemia in adult patients at high cardiovascular risk to reduce triglycerides and increase HDL-C when LDL-C levels are adequately controlled while on a treatment with pravastatin 40 mg monotherapy or on another moderate-intensity statin regimen.

HOS-095740 · has-interaction-information · PDF-Seite 6

There have been no formal interaction studies for Pravafenix; however the concomitant use of the active substances in patients in clinical studies has not resulted in any unexpected interactions. The following statements reflect the information available on the individual active substances (fenofibrate and pravastatin). Interactions relevant to pravastatin Colestyramine/Colestipol Concomitant administration resulted in approximately 40 to 50% decrease in the bioavailability of pravastatin. There was no clinically significant decrease in bioavailability or therapeutic effect when pravastatin was administered one hour before or four hours after colestyramine or one hour before colestipol. Ciclosporin Concomitant administration of pravastatin and ciclosporin leads to an approximately 4 fold increase in pravastatin systemic exposure. In some patients, however, the increase in pravastatin exposure may be larger. Clinical and biochemical monitoring of patients receiving this combination is recommended. Medicinal products metabolised by cytochrome P450 Pravastatin is not metabolised to a clinically significant extent by the cytochrome P450 system. This is why medicinal products that are metabolised by, or are inhibitors of, the cytochrome P450 system can be added to a stable regimen of pravastatin without causing significant changes in the plasma levels of pravastatin, as have been seen with other statins. The absence of a significant pharmacokinetic interaction with pravastatin has been specifically demonstrated for several medicinal products, particularly those that are substrates/inhibitors of CYP3A4 e.g. diltiazem, verapamil, itraconazole, ketoconazole, protease inhibitors, grapefruit juice and CYP2C9 inhibitors (e.g. fluconazole). In one of two interaction studies with pravastatin and erythromycin a statistically significant increase in the area under the curve (AUC) (70%) and Cmax (121%) of pravastatin was observed. In a similar study with clarithromycin a statistically significant increase in AUC (110%) and Cmax (127%) was observed. Although these changes were minor, caution should be exercised when associating pravastatin with erythromycin or clarithromycin. Fusidic acid The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyoly

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HOS-095741 · has-pregnancy-information · PDF-Seite 7

Pregnancy Pravafenix There are no data from the combined use of pravastatin and fenofibrate in pregnant women. The combination has not been tested in reproductive toxicity studies. The potential risk for humans is unknown. Therefore, as far as pravastatin is contra indicated (see below), Pravafenix is contraindicated during pregnancy (see section 4.3). Pravastatin sodium Pravastatin is contraindicated during pregnancy and should be administered to women of childbearing potential only when such patients are unlikely to conceive and have been informed of the potential risk. Special caution is recommended in women of childbearing potential to ensure proper understanding of the potential risk associated with pravastatin therapy during pregnancy. If a patient plans to become pregnant or becomes pregnant, the physician has to be informed immediately and pravastatin should be discontinued because of the potential risk to the foetus. Fenofibrate There are no data from the use of fenofibrate in pregnant women. Animal studies have not demonstrated any teratogenic effects. Embryotoxic effects have been shown at doses in the range of maternal toxicity (see section 5.3). The potential risk for humans is unknown. Breastfeeding Pravafenix 7 No studies in lactating animals have been conducted with Pravafenix. Therefore, taking into account the contra indication of pravastatin during lactation, Pravafenix is contraindicated during breastfeeding (see section 4.3). Pravastatin sodium A small amount of pravastatin is excreted in human breast milk; therefore pravastatin is contraindicated during breastfeeding (see section 4.3). Fenofibrate Fenofibrate is excreted in milk of female rat. There are no data on the excretion of fenofibrate and/or its metabolites into human breast milk. Fertility No effect on fertility in reproductive toxicity studies have been observed with both fenofibrate and pravastatin (see section 5.3) There are no data on fertility from the combined use of fenofibrate and pravastatin

HOS-095739 · has-warning-information · PDF-Seite 3

The pharmacokinetics properties of Pravafenix are not completely identical to the co-administration of the existing monotherapies when taken with fat-meal or in fasting state. Patients should not be switched from a free co-administration of fenofibrate and pravastatin preparation to Pravafenix (see section 5.2.). Nervous system disorders In few cases, statins have been reported to induce de novo or aggravate pre-existing myasthenia gravis or ocular myasthenia (see section 4.8). Pravafenix should be discontinued in case of aggravation of symptoms. Recurrences when the same or a different statin was (re-) administered have been reported. Musculoskeletal and connective tissue disorders As with other lipid lowering substances, pravastatin or fenofibrate have been associated with the onset of myalgia, myopathy and very rarely rhabdomyolysis with or without secondary renal insufficiency. Rhabdomyolysis is an acute potentially fatal condition of skeletal muscle, which may develop at any time during treatment and is characterised by massive muscle destruction associated with major increase in CK (usually > 30 or 40 times the ULN) leading to myoglobinuria. The risk of muscle toxicity is increased when a fibrate and a 3-hydroxy-3-methyl-glutaryl- Coenzyme A (HMG-CoA) reductase inhibitor are administered together. Myopathy must be considered in any patient presenting with unexplained muscle symptoms such as pain or tenderness, muscle weakness, or muscle cramps. In such cases CK levels should be measured (see below). 3 Consequently, the potential benefit/risk ratio of Pravafenix should be closely assessed before treatment initiation and patients should be monitored for any signs of muscle toxicity. Certain predisposing factors such as age > 70, renal impairment, hepatic impairment, hypothyroidism, personal history of muscular toxicity with a statin or fibrate, personal or familial history of hereditary muscular disorders or alcohol abuse may increase the risk of muscular toxicity and therefore CK measurement is indicated before starting the combination therapy in these patients (see below). Statins including pravastatin must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. Th

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