1. Name Of The Medicinal Product
Bezalip
Bezafibrate 200mg Tablets
2. Qualitative And Quantitative Composition
Bezafibrate 200mg
3. Pharmaceutical Form
Tablet for oral use.
Bezalip is a round film-coated tablet with a white core and is imprinted G6.
4. Clinical Particulars
4.1 Therapeutic Indications
Bezalip is indicated for use in hyperlipidaemias of Type IIa, IIb, III, IV and V (Fredrickson classification).
Bezalip should be employed only in patients with a fully defined and diagnosed lipid abnormality which is inadequately controlled by dietary means, or by other changes in life-style such as physical exercise and weight reduction, and in whom the long-term risks associated with the condition warrant treatment.
The rationale for the use of Bezalip is to control abnormalities of serum lipids and lipoproteins to reduce or prevent the long term effects which have been shown by many epidemiological studies to be positively and strongly correlated with such hyperlipidaemias.
4.2 Posology And Method Of Administration
Adults
The recommended dosage for Bezalip tablets is three tablets daily, equivalent to 600mg bezafibrate. The tablets should be swallowed whole with a little fluid after each meal.
Elderly
No specific dosage reduction is necessary in elderly patients.
Children
At present there is inadequate information regarding an appropriate dosage in children.
Renal impairment
In patients with renal insufficiency the dose should be adjusted according to serum creatinine levels or creatinine clearance as shown in the following table;
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In dialysis patients the dosage must be further reduced. As a general rule a dosage of one Bezalip tablet every third day is recommended, to avoid overdosage. The patient should be carefully monitored.
The response to therapy is normally rapid, although a progressive improvement may occur over a number of weeks. Treatment should be withdrawn if an adequate response has not been achieved within 3 to 4 months.
4.3 Contraindications
Significant hepatic disease (other than fatty infiltration of the liver associated with raised triglyceride values), severe renal insufficiency (serum creatinine> 530μmol/l; creatinine clearance <15ml/min), gall bladder disease with or without cholelithiasis, nephrotic syndrome, known photoallergic or phototoxic reactions to fibrates and hypersensitivity to bezafibrate or any component of the product or to other fibrates.
4.4 Special Warnings And Precautions For Use
See Preclinical safety data.
Bezafibrate could cause cholelithiasis, although there is no evidence of an increased frequency of gallstones in patients treated with Bezalip. Appropriate diagnostic procedures should be performed if cholelithic symptoms and signs occur (see section 4.8 Undesirable effects).
Muscle effects: Bezafibrate and other fibrates may cause myopathy, manifested as muscle weakness or pain, often accompanied by a considerable increase in creatine kinase (CPK). In isolated cases severe muscle damage (rhabdomyolysis) may occur. The risk of rhabdomyolysis may be increased in patients with predisposing factors for myopathy, (including renal impairment, hypothyroidism, severe infection, trauma, surgery, disturbances of hormone or electrolyte imbalance and a high alcohol intake).
Bezafibrate should be used with caution in combination with HMG CoA reductase inhibitors as the combination of HMG CoA inhibitors and fibrates has been shown to increase the incidence and severity of myopathy. Patients should be monitored for signs of myopathy and increased CPK activity and combination therapy discontinued if signs of myopathy develop. Combination therapy should not be used in patients with predisposing factors for myopathy (see section 4.5 Interaction with other medicaments and other forms of interaction).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Care is required in administering Bezalip to patients taking coumarin-type anti-coagulants, the action of which may be potentiated. The dosage of anti-coagulant should be reduced by up to 50% and readjusted by monitoring blood coagulation.
As bezafibrate improves glucose utilisation the action of antidiabetic medication, including insulin, may be potentiated. Hypoglycaemia has not been observed although increased monitoring of the glycaemic status may be warranted for a brief period after introduction of Bezalip.
In isolated cases, a pronounced though reversible impairment of renal function (accompanied by a corresponding increase in serum creatinine level) has been reported in organ transplant patients receiving cyclosporin therapy and concomitant bezafibrate. Accordingly, renal function should be closely monitored in these patients and, in the event of relevant significant changes in laboratory parameters, bezafibrate, should if necessary, be discontinued.
Should combined therapy with an ion-exchange resin be considered necessary, there should be an interval of 2 hours between the intake of the resin and Bezalip as the absorption of bezafibrate otherwise may be impaired.
Concomitant therapy with HMG CoA reductase inhibitors and fibrates has been reported to increase the risk of myopathy (see section 4.4 Special warnings and precautions). The underlying mechanism for this remains unclear; the available data do not suggest a pharmacokinetic interaction between bezafibrate and HMG CoA reductase inhibitors.
MAO-inhibitors (with hepatotoxic potential) should not be administered together with bezafibrate.
Since oestrogens may lead to a rise in lipid levels, the necessity for treatment with Bezalip in patients receiving oestrogens or oestrogen containing preparations should be considered on an individual basis.
4.6 Pregnancy And Lactation
Although the drug substance has not been shown in animal studies to have any adverse effects on the foetus, it is recommended that Bezalip should not be administered to either pregnant women or to those who are breast feeding.
4.7 Effects On Ability To Drive And Use Machines
None known.
4.8 Undesirable Effects
Gastro-intestinal system:
− occasionally gastro-intestinal symptoms such as loss of appetite, feelings of fullness in the stomach and nausea may occur. These side-effects are usually transient and generally do not require withdrawal of the drug. In susceptible patients a slowly increasing dosage over 5 to 7 days may help to avoid such symptoms.
Hepato-biliary system:
− in isolated cases, increase of transaminases, cholestasis and gallstones (see section 4.4 Special warnings and special precautions for use).
Hypersensitivity:
− occasionally allergic skin reactions such as pruritus or urticaria.
− in isolated cases, photosensitivity or generalised hypersensitivity reactions may occur.
Haematology:
Isolated cases of:
− decreases in haemoglobin and leucocytes.
− thrombocytopenia, which may cause bleeding (e.g. purpura).
− pancytopenia.
Renal system:
− frequently slight increases in serum creatinine. In patients with existing impairment of renal function, if dosage recommendations are not followed, myopathy may develop (in extreme cases rhabdomyolysis).
Muscular system:
− Muscular weakness, myalgia and muscle cramps, often accompanied by a considerable increase in creatine kinase may occur. In isolated cases, severe muscular damage (rhabdomyolysis) has been observed. In cases of rhabdomyolysis, bezafibrate must be stopped immediately and renal function closely monitored.
Others:
− in rare cases, headache and dizziness, alopecia.
− isolated cases of potency disorders have been reported.
In general, most of the adverse drug reactions disappear after withdrawal of Bezalip.
4.9 Overdose
No specific effects of acute overdose are known. Rhabdomyolysis has occurred. In cases of rhabdomyolysis, bezafibrate must be stopped immediately and renal function carefully monitored.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Bezafibrate lowers elevated levels of serum cholesterol and triglycerides (i.e. lowers elevated low density lipoprotein and very low density lipoprotein levels, and raises lowered high density lipoprotein levels) by stimulating lipoprotein lipase and hepatic lipase, and by suppressing the activity of 3 HMGCo-A reductase resulting in stimulation of low density lipoprotein receptors on the cell surface.
Studies have shown bezafibrate to be effective in treating hyperlipidaemia in patients with diabetes mellitus. Some cases showed a beneficial reduction in fasting blood glucose.
Significant reductions in serum fibrinogen levels have been observed in hyperfibrinogenaemic patients treated with bezafibrate.
5.2 Pharmacokinetic Properties
Maximum concentrations of bezafibrate appear around 2 hours after ingestion of Bezalip tablets. The protein-binding of bezafibrate in serum is approximately 95%. The elimination half-life is in the order of 2.1 hours although elimination is markedly slowed in the presence of limited renal function. Elimination may be increased in forced diuresis. The drug substance is non-dialysable (cuprophane filter).
5.3 Preclinical Safety Data
The chronic administration of a high dose of bezafibrate to rats was associated with hepatic tumour formation in females. This dosage was in the order of 30 to 40 times the human dosage. No such effect was apparent at reduced intake levels approximating more closely to the lipid-lowering dosage in humans.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Table core:
maize starch,
microcrystalline cellulose,
colloidal silicon dioxide,
sodium starch glycollate,
magnesium stearate.
Film-coating:
polyvinyl alcohol,
titanium dioxide (E171),
macrogol,
talc.
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
5 years.
6.4 Special Precautions For Storage
Do not store above 25 °C.
6.5 Nature And Contents Of Container
Packs of 84 or 100 tablets in PVC/Aluminium blister strips.
6.6 Special Precautions For Disposal And Other Handling
Not applicable.
7. Marketing Authorisation Holder
Actavis Group PTC ehf
Reykjavíkurvegi 76-78
220 Hafnarfjordur
Iceland.
8. Marketing Authorisation Number(S)
PL 30306/0125
9. Date Of First Authorisation/Renewal Of The Authorisation
1 April 1999
10. Date Of Revision Of The Text
13/10/2009
11 DOSIMETRY (IF APPLICABLE)
12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)
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