POM: Prescription only medicine
This information is intended for use by health professionals
AdultsThe recommended daily dose for Fibrazate® XL 400mg Tablets is one tablet, equivalent to 400mg bezafibrate, after a meal either in the morning or at night.
Older peopleFibrazate® XL 400mg Tablets should not be prescribed/administered to older people whose creatinine clearance is below 60ml/min (see Renal impairment below).
Paediatric populationInformation available to date is not adequate for a dose recommendation in children.
Renal impairmentFibrazate® XL 400mg Tablets are contraindicated in dialysis patients. Bezafibrate should not be given to patients with renal impairment with serum creatinine > 135 micromol/l or creatinine clearance < 60 ml/min. Such patients may be treated with conventional tablets using an appropriately reduced daily dose.For patients with a history of gastric sensitivity, the dosage may be gradually increased over 5-7 days to the maintenance level.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 Treatment should be withdrawn if an adequate response has not been achieved within 3 to 4 months.
Method of administrationSwallow whole tablet with sufficient fluid.
PregnancyThere are limited data from the use of bezafibrate in pregnant women. Animal studies are insufficient with respect to reproductive toxicity. Fibrazate® XL 400mg Tablets are not recommended during pregnancy and in women of childbearing potential not using contraception.
BreastfeedingThere is insufficient information on the excretion of bezafibrate or its metabolites in human breast milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Fibrazate® XL 400mg Tablets therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Blood and lymphatic system disorders:Very rare: Pancytopenia, thrombocytopenic purpura.
Immune system disorders:Uncommon: Hypersensitivity reactions including anaphylactic reactions.
Metabolism and nutrition disorders:Common: Decreased appetite.
Nervous system disorders:Uncommon: Dizziness, headache.Rare: Peripheral neuropathy, paraesthesia.
Psychiatric disorders:Rare: Depression, insomnia.
Gastrointestinal disorders:Common: Gastrointestinal disorders.Uncommon: Abdominal pain, constipation, dyspepsia, abdominal distension, diarrhoea, nausea.Rare: Pancreatitis
Hepatobiliary disorders:Uncommon: Cholestasis. Very rare: Cholelithiasis.
Skin and subcutaneous tissue disorders:Uncommon: Pruritus, urticaria, photosensitivity reaction, alopecia, rash. Very rare: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders:Uncommon: Muscular weakness, myalgia, muscle cramp. Very rare: Rhabdomyolysis.
Renal and urinary disorders:Uncommon: Acute renal failure.
Reproductive system and breast disorders:Uncommon: Erectile dysfunction NOS.
Respiratory, thoracic and mediastinal disorders:Very rare: Interstitial lung disease.
Investigations:Uncommon: Increased blood creatinine phosphokinase, blood creatinine increased, decreased gamma-glutamyl transferase and in parallel alkaline phosphataseVery rare: Haemoglobin decreased, platelet increased, white blood cell count decreased, gamma-glutamyl transferase increased, transaminase increased.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme (www.mhra.gov.uk/yellowcard).
Mechanism of Action:Bezafibrate lowers elevated blood lipids (triglycerides and cholesterol). Elevated VLDL and LDL are reduced by treatment with bezafibrate, whilst HDL-levels are increased. The activity of triglyceride lipases (lipoprotein lipase and hepatic lipoprotein lipase) involved in the catabolism of triglyceride-rich lipoproteins is increased by bezafibrate. In the course of the intensified degradation of triglyceride-rich lipoproteins (chylomicrons, VLDL), precursors for the formation of HDL are formed which explains an increase in HDL. Furthermore, cholesterol biosynthesis is reduced by bezafibrate, which is accompanied by a stimulation of the LDL-receptor-mediated lipoprotein catabolism. 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.There is evidence that treatment with fibrates may reduce coronary heart disease events but they have not been shown to decrease all-cause mortality in the primary or secondary prevention of cardiovascular disease.
Clinical efficacy and safety:No data available.
AbsorptionBezafibrate is rapidly and almost completely absorbed from the standard tablet formulation. A peak plasma concentration of about 14mg/L is reached after 2 hours following ingestion of 2 x 200 mg standard tablets given as a single dose in healthy volunteers. With bezafibrate 400 mg modified release tablets, a peak concentration of about 8 mg is reached after about 4 hours. The relative bioavailability of bezafibrate retard compared to the standard form is about 70%.
DistributionThe protein-binding of bezafibrate in serum is approximately 95%. The apparent volume of distribution is 17 litres.
Biotransformation50% of the administered bezafibrate dose is recovered in the urine as unchanged drug and 20% in the form of glucuronides.
EliminationElimination is rapid with excretion almost exclusively renal. 95% of the activity of 14C-labelled drug is recovered in the urine and 3% in the faeces within 48 hours. Fifty percent of the applied dose is recovered in the urine as unchanged drug and 20% in form of glucuronides. The rate of renal clearance ranges from 3.4 to 6.0 l/h. The apparent half-life of bezafibrate prolonged-release tablets is about 2-4 hours.
Pharmacokinetics in Special PopulationsThe elimination of bezafibrate is reduced in patients with impaired renal function and dosage adjustments may be necessary to prevent drug accumulation and toxic effects (see section 4.2).Pharmacokinetic studies in the older people suggest that elimination may be delayed in cases of impaired liver function. Significant liver disease (except fatty liver) is a contraindication for the use of Bezafibrate (see section 4.3).In older people, there is a physiogical reduction of the renal function with age. Bezafibrate dosage should be adjusted based on the serum creatinine and creatinine clearance values) see section 4.2).Because of its high protein binding, bezafibrate cannot be dialysed (cuprophane filter). The use of bezafibrate is contraindicated in dialysis patients.
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