NEPALM APPENDIX I SUMMARY OF PRODUCT CHARACTERISTICS. Fenofibrate mg Per single capsule

Transcription

1 NEPALM APPENDIX I SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT FEGENOR 140 mg, capsule 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Fenofibrate mg Per single capsule For the complete list of excipients, see section PHARMACEUTICAL FORM Capsule 4. CLINICAL PARTICULARS 4.1. Therapeutic indications In the adult Hypercholesterolemia (type IIa) and endogenous hypertriglyceridemia in adults, isolated (type IV) or in association (types IIb and III): - when a suitable and diligently followed diet is found to be insufficient, - all the more so when the cholesterolemia after dieting remains high and/or there are associated risk factors Adherence to diet remains essential. At the present time, there are no controlled long-term trials available showing the efficacy of fenofibrate in the primary or secondary prevention of complications of atherosclerosis. In children: see sections 4.2 and Posology and method of administration In combination with a diet, this medicine constitutes a long term symptomatic treatment the efficacy of which must be periodically monitored. In adults: This dosage is exclusively reserved for maintenance treatment when the cholesterol level is stabilised. A dosage of 1 capsule per day of FEGENOR 140 mg or 2 capsules per day of FEGENOR 67 mg can be recommended provided the serum cholesterol is monitored every 3 months. Go back to a dosage of 3 capsules of FEGENOR 67 mg per day in the event of a further increase in lipid parameter levels. 1

2 In children: No comprehensive paediatric experience with fenofibrate is available yet. The precise nature of the hyperlipidemia must be established through the genetic and laboratory study of the disorder the hereditary nature of which (familial hyperlipidemia) alone justifies an early therapeutic approach. It is recommended that treatment commences with a strictly controlled diet over a period of at least 3 months. If medicinal treatment is found to be essential, for example in severe forms accompanied by clinical signs of atherosclerosis and/or xanthomatous deposits and/or in cases where the parents are suffering from atheromatous cardiovascular manifestations before the age of 40 years, the prescription of fenofibrate is then reserved for the specialist. The maximum recommended dosage is 67 mg of micronised fenofibrate per 20 kg and per day from the age of 10 years, or one capsule of FEGENOR 140 mg for a child weighing over 40 kg Contraindications This medicine must never be prescribed in the following situations: - hepatic failure, - renal failure (see section 4.4), - in children weighing less than 40 kg, - known phototoxicity reactions or photo-allergy during treatment with fenofibrate or with a substance with a related structure, and in particular, ketoprofen, - in combination with another fibrate (See heading 4.5) In general, this medicine is not recommended in combination with HMG CoA reductase inhibitors (see section 4.5), or during breast feeding (see section 4.6) Special warnings and precautions for use Warnings Muscular involvement, including rare cases of rhabdomyolysis, have been reported with the fibrates. They can occur with a greater frequency in cases of hypoalbuminemia. Muscular involvement must be considered in any patient presenting with diffuse myalgia, a painful muscular sensitivity and/or a marked elevation in the CPK, which is muscular in origin (level greater than 5 times normal): in these circumstances treatment must be withheld. Furthermore, the risk of muscular involvement may be increased in the event of combination with another fibrate or with a HMG CoA reductase inhibitor (cf. Medicinal Interactions). Due to the presence of lactose, this medicine is contraindicated in cases of congenital galactosemia, the glucose and galactose malabsorption syndrome and in lactase deficiency. Precautions for use - In children, as long term safety has not been demonstrated and as the effects specific to the development of a growing person are unknown, its use should only be considered when faced with severe lipid disorders and when responsive to treatment. - If after a several month period of administration (3 to 6 months), a satisfactory reduction in the serum concentrations of lipids has not been obtained, then supplementary or different therapeutic approaches must be contemplated. - In some patients, usually transient increases in transaminases have been observed. In the current state of knowledge the following appears justified:. a systematic monitoring of transaminases every 3 months during the 12 first months of treatment, 2

3 . a cessation of treatment in cases of an increase in ASAT and ALAT to more than 3 times the upper limit of normal. - In cases of concomitant treatment with the oral anti-coagulants, an increased monitoring of the prothrombin level, expressed by the INR is called for (cf. heading Medicinal Interactions ) Interaction with other medicinal products and other forms of interaction Contraindicated combinations + Other fibrates: Increased risk of undesirable effects of the rhabdomyolysis type and pharmacodynamic antagonism between the two compounds. Inadvisable combinations + HMG CoA reductase inhibitors: Increased risk of undesirable effects of the rhabdomyolysis type. Combinations the subject of precautions for use + Oral anticoagulants: Increase in the oral anticoagulant effect and of the haemorrhagic risk (by displacement of its plasma protein binding). More frequent monitoring of the INR level. Dosage adjustment of the oral anticoagulant during treatment with fenofibrate and 8 days after its cessation Pregnancy and lactation Pregnancy The results of studies undertaken in animals has not revealed any evidence of a teratogenic effect. In clinical practice, no malformative or foetotoxic effect has been seen up to now. However, the follow-up of pregnancies exposed to fenofibrate is insufficient to exclude all risk. There is no indication for the prescription of fibrates during pregnancy, with the exception of major hypertriglyceridemia (> 10g/l) which are inadequately corrected by diet and which expose the expectant mother to the risk of an acute pancreatitis. Lactation There is no information on the excretion of fenofibrate into maternal milk. As a result, its prescription is inadvisable during breast feeding Effects on the ability to drive and use machines 4.8. Undesirable effects Cases of muscular involvement (diffuse myalgias, painful sensitivity, weakness) as well as rare cases of rhabdomyolysis, sometimes severe, have been reported as with other fibrates. They are usually reversible on cessation of treatment (see section 4.4). Other undesirable effects, less frequent and of moderate severity, have also been reported: - gastric or intestinal GI tract disorders of the dyspepsic type, - increase in transaminases (see section 4.4), - allergic skin reactions such as eruptions, itching, urticaria or photosensitivity reactions have rarely been reported. In certain cases, even after several months of use without complication, a cutaneous photosensitisation can appear with erythema, papules, vesicles or eczematiform eruptions commencing in areas exposed to sunlight or to artificial UV light (UV lamps). There are currently no controlled studies enabling a general assessment of the long term undesirable effects, especially the risk of biliary lithiasis. 3

4 4.9. Overdose Symptomatic treatment 5. PHARMACOLOGICAL PROPERTIES 5.1. Pharmacodynamic properties Pharmacotherapeutic class: HYPOLIPIDEMIA/HYPOCHOLESTEROLEMIA AND HYPOTRIGLYCERIDEMIA INDUCING AGENT / FIBRATE (C 10 AB05: cardiovascular system) Fenofibrate can lower cholesterolemia by 20 to 25 % and triglyceridemia by 40 to 50 %. - The reduction in cholesterolemia is due to the lowering of the low density atherogenic fractions (VLDL and LDL). It improves the distribution of plasma cholesterol by reducing the total cholesterol / HDL cholesterol ratio, which is increased in atherogenic hyperlipidemias. - The relationship between hypercholesterolemia and atherosclerosis is established, likewise the relationship between atherosclerosis and the coronary risk. Low levels of HDL are associated with an increased coronary risk. High levels of triglycerides are associated with an increase in the vascular risk, though it cannot be confirmed that this relationship is independent. The triglycerides moreover may be implicated in the process of atherogenesis and also thrombogenesis. - Deposits of extravascular cholesterol (tendinous and tuberous xanthomata) may undergo a major regression or even totally disappear under prolonged effective treatment (major reduction in cholesterolemia). - A uricosuric effect has been demonstrated in lyperlipidemic patients giving rise to a mean reduction in serum uric acid levels of the order of 25 %. - On fenofibrate, the increase in apoproteins A1 and the reduction in apoproteins B improves the apo A1/apo B ratio, which may be considered as an atherogenic risk marker. - A platelet antiaggregant effect of fenofibrate has been shown in animals, then in man during one clinical study. It is manifested by a reduction in ADP, arachidonic acid and epinephrine aggregation. In rats: treated with fenofibrate, an 80 % inhibition in the activity of microsomal hepatic HMG Coreductase has been observed. This phenomenon may play a role in the mechanism of action of fenofibrate. - By activation of the Peroxysome Proliferator Activated Receptor of the (PPAR α) type, fenofibrate increases lipolysis and the elimination from the plasma of particles rich in triglycerides by activating the lipase lipoprotein and by reducing the production of apoprotein C III Pharmacokinetic properties Absorption: The unchanged product is not found in the plasma. The major plasmatic metabolite is fenofibric acid. The maximum plasma concentration is reached on average 5 hours after ingestion of the medicine. The mean plasmatic concentration is of the order of 15 µg/ml at a dosage of 200 mg of micronised fenofibrate per day. In the same individual, plasma concentrations are stable on continuous treatment. Distribution: Fenofibric acid is strongly bound to plasma albumin and can displace antivitamin Ks from protein binding sites and potentiate their anticoagulant effect (cf. section medicinal interactions ). 4

5 Plasma half-life: The plasma half-life of fenofibric acid is of the order of 20 hours. Metabolism and excretion: Excretion is mainly via the urinary tract: almost all the product is excreted over 6 days. Fenofibrate is mainly excreted in the form of fenofibric acid and its glycoconjugated derivative. Kinetic studies after single dose and continuous treatment, suggests the absence of accumulation. Fenofibric acid is not removed during haemodialysis Preclinical safety data 6. PHARMACEUTICAL PARTICULARS 6.1. List of excipients Sodium lauryl sulphate, monohydrated lactose, povidone K 30, sodium croscarmellose, sodium carboxymethyl starch (type A), magnesium stearate. Composition of the capsule coating: gelatine, titanium dioxide (E 171) 6.2. Incompatibilities 6.3. Shelf life 3 years 6.4. Special precautions for storage Store at a temperature not exceeding +25 C Nature and contents of container 28 and 30 or 90 capsules in blister strips (PVC/Aluminium) Special precautions for disposal and other handling No special requirements. 7. MARKETING AUTHORISATION HOLDER NEPALM 837 bis Allée de Paris, ZAC des Playes LA SEYNE SUR MER 8. MARKETING AUTHORISATION NUMBERS or : 28 capsules in blister strips (PVC/Aluminium) or : 30 capsules in blister strips (PVC/Aluminium) or : 90 capsules in blister strips (PVC/Aluminium) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 13 September

6 10. DATE OF REVISION OF THE TEXT 02/06/ DOSIMETRY 12. INSTRUCTIONS FOR THE PREPARATION OF RADIOPHARMACEUTICALS List II PRESCRIPTION AND SUPPLY CONDITIONS 6