SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Bezafibrate 200 mg Tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Bezafibrate 200mg

For excipients, please refer to section 6.1.

3    PHARMACEUTICAL FORM

Tablets for oral use.

Bezafibrate tablets are white, round, biconvex, film coated tablets imprinted with “BZ” on one side and “200” on the other side.

4.    CLINICAL PARTICULARS

4.1. Therapeutic Indications

Bezafibrate is indicated for use in hyperlipidaemias of type IIa, IIb, III, IV and V

(Fredrickson classification).

Bezafibrate 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 bezafibrate is to control abnormalities of serum lipids and lipoproteins to reduce or prevent the long term adverse 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

Adult

The recommended dosage for bezafibrate 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 of bezafibrate should be adjusted according to serum creatinine levels or creatinine clearance as follows:

Serum Creatinine	Creatinine Clearance	Dosage
(micromol/l)	(ml/min)	(tablets/day)
Up to 135	Over 60	3
136 - 125	60 - 40	2
226 - 530	40 - 15	1 every 1 or 2 days
Over 530	Less than 15	Contraindicated
Dialysis Patients		1 every 3rd day

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 Treatment should be withdrawn if an adequate response has not been achieved within 3 to 4 months.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)

•    Gall bladder disease with or without cholelithiasis,

•    Patients with nephrotic syndrome and severe renal failure (serum creatinine > 530gmol/l; creatinine clearance <15ml/min ) and patients undergoing dialysis (see section 4.2).

•    Combination therapy of bezafibrate with HMG CoA reductase inhibitors in patients with predisposing factors for myopathy (see sections 4.4. and 4.5)

•    Patients with previous known hypersensitivity to bezafibrate, to any component of the product or to other fibrates.

•    Known photoallergic or phototoxic reactions to fibrates

4.4 Special warnings and precautions for use

•    Bezafibrate should be used as an adjunct to diet and measures such as physical activity, weight loss and adequate treatment of other metabolic disorders (e.g. diabetes, gout).

•    Secondary causes of dyslipidaemia, such as uncontrolled type 2 diabetes mellitus, hypothyroidism, nephritic syndrome, dysproteinemia, obstructive liver disease, pharmacological treatment, alcoholism should be adequately treated before Bezafibrate therapy is initiated.

•    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) has been observed. The risk of rhabdomyolysis may be increased when higher than recommended doses of bezafibrate are used, most frequently in the presence of impaired renal function and in patients with predisposing factors for myopathy, (including renal impairment, elderly (aged >65 years), personal of familial history of hereditary muscular disorders and previous history of muscular toxicity with a fibrate or other lipid lowering drugs, 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 informed of symptoms and 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 4.3 and 4.5).

•    Bezafibrate alters the composition of bile. There have been isolated reports of the development of gallstones.

•    As bezafibrate could cause cholelithiasis appropriate diagnostic procedures should be performed if cholelithic symptoms and signs occur (see section 4.8 Undesirable effects).

•    Since oestrogens may lead to a rise in lipid levels, the prescribing of bezafibrate in patients taking oestrogens or oestrogen-containing contraceptives must be critically considered on an individual basis.

•    When bezafibrate is given in combination with anion-exchange resins (e.g. colestyramine), the two drugs should be taken at least 2 hours apart.

• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Care should be taken when administering bezafibrate 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. Although hypoglycaemia has not been observed, increased monitoring of the glycaemic status may be warranted for a brief period after introduction of bezafibrate.

Should combined therapy with an ion-exchange resin be considered necessary, an interval of 2 hours should be allowed to elapse between the intake of the resin and bezafibrate as the absorption of bezafibrate otherwise may be impaired.

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.

MAO-inhibitors (with hepatotoxic potential) should not be administered together with bezafibrate.

Interaction between HMG CoA reductase inhibitors and fibrates may vary in nature and intensity depending on the combination of the administered drugs. A pharmacodynamic interaction between these two classes of drugs may, in some cases, also contribute to an increase in the risk of myopathy (see section 4.3 and 4.4) for specific dose recommendations of statins refer also to the SPC of the relevant product.

4.6 Pregnancy and lactation

There are limited data from the use of bezafibrate in pregnant women. Animal studies are insufficient with respect to reproductive toxicity. Bezafibrate is not recommended during pregnancy and in women of childbearing potential not using contraception.

There is insufficient information on the excretion of bezafibrate or its metabolites in human 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 bezafibrate therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

4.7    Effects on ability to drive and use machines

Bezafibrate has been shown to cause dizziness and can have a minor to moderate effect on the ability to drive or use machines. Patients should not drive or use machines if they are affected.

4.8    Undesirable effects

The overall safety profile of bezafibrate is based on a combination of clinical study data and post-marketing experience.

The frequency of adverse drug reactions (ADRs) according to MedDRA System Organ Class is displayed in the table below. Frequency of reporting: Common (> 1/100 and <1/10), Uncommon ( > 1/1,000 and <1/100), Rare ( > 1/10,000 and <1/1000), Very rare (<1/10,000), not known (Can not be estimated from the available data).

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.

Gastrointestinal disorders:

Uncommon: Gastrointestinal disorders such as 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 phosphatase

Very rare: Haemoglobin decreased, platelet increased, white blood cell count decreased, gamma-glutamyl transferase increased, transaminase increased.

Other reaction Not known: Fatigue

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 serum levels of cholesterol and triglycerides. This means specifically, that it lowers elevated low density lipoprotein and very low density lipoprotein levels. This action is brought about by the stimulation of lipoprotein lipase and hepatic lipase, and the suppression of the activity of 3 HMGCo-A reductase resulting in stimulation of low density lipoprotein receptors on the cell surface.

Studies have indicated that bezafibrate is effective in treating hyperlipidaemia in patients with diabetes mellitus. Some cases show 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 occur around 2 hours after ingestion of bezafibrate 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 significantly slower in the presence of limited renal function. Elimination may be increased by forced diuresis. The drug substance is non-dialysable (cuprophane filter).

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

Microcrystalline cellulose

Anhydrous lactose

Sodium starch glycollate

Calcium hydrogen phosphate dihydrate

Maize starch

Povidone

Magnesium stearate Talc

Colloidal anhydrous silica

Opadry White YS-1-7003 (tablet coat containing: titanium dioxide E171, hypromellose, macrogol 400 and polysorbate 80)

Tablets may be ink-coded with Opacode Black (black iron oxide, shellac, lecithin and antifoam).

6.2. Incompatibilities

None known.

6.3. Shelf Life

36 months.

6.4. Special Precautions for Storage

Do not store above 25°C. Store in the original container.

6.5. Nature and Contents of Container

PVC film blister covered on one side with an aluminium foil. Each pack contains 30 [or 28, 56, 84, 90, 100, 112 or 120] tablets

Instruction for Use/Handling

No special instructions are required.

7. MARKETING AUTHORISATION HOLDER

Pliva Pharma Limited Vision House Bedford Road Petersfield Hampshire GU32 3QB United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

PL 10622/0042

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF

AUTHORISATION

16 July 2001

10 DATE OF REVISION OF THE TEXT

26/03/2013