Bezafibrate 400 SR

/ Medison

Bezafibrate 400 retard film-coated tablets: 1 film-coated tablet to be taken once daily (morning or evening).
Note: Patients with renal insufficiency (serum creatinine values > 1.5 mg/dl or creatinine clearance < 60 ml/min) must not use Bezafibrate400 mg retard film-coated tablets. The coated tablets must not be chewed and must be taken with sufficient water either at mealtimes or after meals.
Elderly patients: In order to establish the right dosage, creatinine clearance should be determined, particularly in elderly patients.
Adults: In adults creatinine clearance is calculated using the following equation (Cockroft and Gault) by taking serum creatinine, body weight and age into account: Creatinine clearance (ml/min) = (140 – age [years] x body weight [kg] 72 x serum creatinine [mg/dl] To calculate creatinine clearance in women, the value obtained using the Cockroft and Gault formula is multiplied by a factor of 0.85. In patients with manifest hypalbuminaemia (as in patients with nephrotic syndrome), the dose should be further reduced. To prevent overdosing and overdose-induced rhabdomyolysis, bezafibrate plasma level determination is recommended to establish the correct dosage. Due to its high active substance content, Bezafibrate 400 mg retard film-coated tablets are contraindicated in these patients. Bezafibrate400 mg retard film-coated tablets are contraindicated in dialysis patients.
Patients with liver diseases: Except for fatty liver, which is the most common concomitant symptom in patients with hypertriglyceridaemia, Bezafibrate 400 mg retard film-coated tablets are contraindicated in all cases of liver diseases.
Children: Bezafibrate dosage has not been adequately investigated in children. For full details see prescribing information.

Hyperlipidemia in types 11a, 11b, III, IV, V where diet alone is insufficient.

Gallbladder disease. Known hypersensitivity, patients with severe liver dysfunction or primary biliary cirrhosis, and in those patients with severe renal disorders (serum creatinine values above 530 uMol/liter). Patients with the nephrotic syndrome, pregnant women or nursing mothers.

Besides hypertension and nicotine abuse, raised lipid blood levels are considered one of the most significant risk factors for incipient and progressive arteriosclerosis and its sequellae (coronary heart disease, impaired cerebral and peripheral blood circulation). Before starting treatment for hyperlipidaemia, patients should always be given dietary recommendations and have their risk factors identified and corrected. In many cases, disorders of fat metabolism can be improved by a change in diet, weight reduction, increased physical activity, and the adequate treatment of other concurrent metabolic disorders. Such measures, if instituted before drug therapy, should be kept up during treatment with Bezafibrate400 mg retard film-coated tablets. When establishing the diagnosis, it should be taken into account that blood lipid levels depend on different factors such as the time of day, the hour and nature of the last meal, alcohol intake, and stress. Since oestrogens can lead to increased lipid levels, Bezafibrate400 mg retard film-coated tablets should be prescribed on an individual basis and only after careful consideration to patients on oestrogen or oestrogen-containing contraceptives.
Kidneys: In patients with hypalbuminaemia, e.g. nephrotic syndrome, and those with renal insufficiency, Bezafibrate400 mg retard film-coated tablets should be replaced with lower-dose bezafibrate and kidney function monitored on a regular basis. Patients with pre-existing kidney insufficiency may suffer acute kidney failure if they do not strictly follow the prescribed dosage regimens based on determinations of their serum creatinine levels or their creatinine clearance. Since drug treatment for hyperlipidaemia signifies long-term treatment in most cases, careful individual consideration should be given before instituting such a treatment in these patients.
Muscles: Myotoxic effects and very rarely cases of rhabdomyolysis have been reported with the use of fibrates
and other lipid-lowering agents. The incidence of myotoxicity is increased in patients with hypalbuminaemia and renal insufficiency in their medical history. Diffuse myalgia, myositis, muscle spasms, muscular weakness and/or significant increases in creatine phosphokinase (CPK) (more than a ten-fold increase above the norm) point to myotoxicity, in which case treatment with the drug must be ceased. The risk of myotoxicity is increased if the drug is combined with another fibrate or a HMG-CoA reductase inhibitor (statin). This applies particularly if myopathy is already present. For this reason, the combination of bezafibrate with a statin should be limited to patients with severe combined hyperlipidaemia and increased cardiovascular risk who have not yet suffered from myopathy. This combination treatment should be instituted with care, and patients should be closely monitored for myotoxicity.
Liver: As with other lipid-lowering drugs, elevated transaminase levels have been reported in some patients treated with bezafibrate. In the majority of cases observed the elevations were transient, slight and asymptomatic. It is recommended that patients’ transaminase levels be checked every 3 months during the first year of treatment. Patients who have been diagnosed with raised transaminase blood levels should be carefully monitored. Treatment should be ceased if SGOT and SGPT levels increase by more than three- fold the upper limit of the norm.
Pancreas: Cases of pancreatitis have been reported during treatment with bezafibrate. In patients with severe hypertriglyceridaemia, this may be due to the lack of efficacy, direct side effect or cholelithiasis-mediated secondary effect of the drug with obstruction of the common bile duct.
Children: Children should only be treated with bezafibrate following accurate diagnosis, since little is known regarding long-term tolerability in children. Prescription of the drug during lactation is not recommended Patients with a rare hereditary intolerance to galactose, lactase deficiency or glucose-galactose malabsorption must not take Bezafibrate400 mg retard film-coated tablets.LDL and HDL levels should be monitored during treatment. Periodic blood counts and liver function tests are recommended.

The following undesirable effects may occur during treatment with Bezafibrate400 mg retard film- coated tablets:
Skin and skin appendages :Occasionally, allergic skin reactions such as pruritus, urticaria and other skin manifestations may occur. In isolated cases, generally reversible photoallergic or phototoxic reactions may occur, even after several months of complication-free treatment, in association with erythema, pruritus, blister formation and lichenoid changes. Very rarely, erythema multiforme, Stevens- Johnson syndrome and toxic epidermal necrolysis may occur. In this case, treatment with Bezafibrate400 mg retard film-coated tablets must be stopped immediately and appropriate treatment measures instituted.
Gastrointestinal tract : Occasionally, gastrointestinal disorders, such as sensation of fullness, nausea and loss of appetite, can occur.
Nervous system : Occasionally, headaches and dizziness may occur. The above side effects are generally transient and do not require cessation of treatment.
Liver : In isolated cases, impaired liver function (e.g. increase in transaminases, cholestasis) has been observed.
Blood :In isolated cases a slight drop in haemoglobin and leukocyte count has been observed. A drop in platelet count with haemorrhage in some cases (e.g. purpura) has also been observed in isolated cases. Isolated cases have also been reported of a simultaneous drop in all three blood-cell elements (pancytopenia).
Miscellaneous : In rare cases, hair loss, and in isolated cases, impaired potency have occurred. Most of the above-mentioned side effects generally rapidly subsided following cessation of treatment with Bezafibrate400 mg retard film-coated tablets.
Hypersensitivity : In isolated cases, generalised hypersensitivity reactions associated with tightness in the chest, dyspnoea, tachycardia, skin manifestations, hypotension, oedema, cardiovascular collapse, shivering and syncope have been observed. These allergic reactions require appropriate emergency treatment measures as well as the immediate cessation of treatment.
Kidneys : Long-term treatment frequently leads to slight elevations of serum creatinine.
Muscles :An important but rare side effect is myotoxicity associated with muscular pains, muscle weakness and muscle spasms. Creatine phosphokinase (CPK) must be determined in such cases. Rarely, significant CPK elevations can occur along with clinical symptoms of drug-related rhabdomyolysis. This is often due to excessively high doses, due for example to accumulation of the drug in patients with renal insufficiency. In case of suspected rhabdomyolysis, treatment with bezafibrate should be suspended immediately and kidney function monitored carefully.
Gallbladder : Bezafibrate alters the composition of bile. Whether, as has been observed with other drugs with similar action, long-term treatment with bezafibrate leads to an increase in gallstones, or whether the gallstones present during treatment with bezafibrate increase in size, is disputed. Gallstone formation has been reported in isolated cases. Abnormal laboratory findings The following abnormal laboratory findings have been reported during clinical studies and in the postmarketing phase Elevation of transaminase levels (occasionally).

As with other fibrates, bezafibrate must not be combined with HMG-CoA reductase inhibitors due to the risk of rhabdomyolysis. The product should not be administered together with perhexiline hydrogenmaleate or MAO- inhibitors. Patients taking cholestyramine and Bezafibrate400 mg retard film-coated tablets concurrently should wait for at least 2 hours between taking both drugs, since cholestyramine affects the absorption of bezafibrate.A significant but reversible reduction of kidney function (with a corresponding increase in serum creatinine) following the concurrent use of fibrate-containing drugs has been reported in some patients who had undergone an organ transplant and had been on immunosuppressant treatment. For this reason, kidney function should be carefully monitored in these patients and treatment with Bezafibrate400 mg retard film-coated tablets should be ceased where appropriate in case of significant changes in laboratory findings. Bezafibrate can potentiate the action of coumarin-type anticoagulants. For this reason, the anticoagulant dose should be reduced by 30 – 50% at the beginning of treatment with bezafibrate andthe beginning of treatment with bezafibrate and adjusted once blood coagulation is under control. Re-adjustment of the anticoagulant dose is also required following cessation of bezafibrate treatment.
Bezafibrate can potentiate the action of oral blood sugar-lowering drugs (e.g. sulphonyl ureas) and insulin. Bezafibrate influences the effects of phenytoin.

Pregnancy: No data are available on Bezafibrate 400 mg retard film-coated tablets in exposed pregnant women. For this reason, the drug should only be prescribed during pregnancy following a careful benefit/risk assessment, for example to female patients exposed to the risk of acute pancreatitis because of severe hypertriglyceridaemia (> 10 g/l). Animal experiment studies have given no indications of any teratogenic effect for Bezafibrate400 mg retard film-coated tablets.
Lactation: No information is available on the excretion of Bezafibrate 400 mg retard film-coated tablets in maternal milk. In principle, it is not recommended that the drug be prescribed during lactation.

There are no known symptoms of poisoning. Where appropriate, symptomatic treatment should be instituted. There is no known specific antidote. In case of suspected overdosing and rhabdomyolysis, treatment must be stopped. In patients with healthy kidneys, accelerated elimination may be attempted through forced diuresis. In case of rhabdomyolysis, patients should be given adequate liquids to prevent the development of a crush syndrome. It is not possible to dialyse bezafibrate.