Document: spc-doc_PL 15773-0061 change

• spc-doc_PL 15773-0061
• spc-doc_PL 30306-0125

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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Bezafibrate 200mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains bezafibrate 200mg.

For excipients see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet

White, round, biconvex, film-coated tablet.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Bezafibrate 200mg Tablets are indicated for use in hyperlipidaemias of Type IIa, IIb, III, IV and V (Fredrickson classification).

Bezafibrate 200mg Tablets 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 200mg Tablets 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 Bezafibrate 200mg Tablets is one tablet three times a day, equivalent to 600 mg bezafibrate. The tablets should be swallowed whole with sufficient fluid after a meal. Occasionally gastrointestinal symptoms may occur. In susceptible patients a slowly increasing dosage over 5 to 7 days may help avoid such symptoms.

Elderly:

In elderly patients there is a physiological reduction of the renal function with age. Bezafibrate dosage should be adjusted based on serum creatine clearance values (see Renal impairment below).

Children:

At present there is inadequate information regarding an appropriate dosage in children.

Renal impairment:

In dialysis patients the use of bezafibrate is contractindicated.

In patients with renal insufficiency the dose should be adjusted according to serum creatinine levels or creatinine clearance as shown in the following table.

Serum creatinine (pmol/l)	Creatinine clearance (ml/min)	Dosage (tablets/day)
Up to 135	Over 60	3
136-225	60-40	2
226-530	40-15	1 every 1 or 2 days
Over 530	Less than 15	Contraindicated

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 (statins) in patients with predisposing factors for myopathy (see sections 4.4 and 4.5)

•    known hypersensitivity to bezafibrate or any component of the product or to other fibrates

•    known photoallergic or phototoxic reactions to fibrates.

4.4 Special warnings and precautions for use

Patients with impaired renal function should be monitored regularly. In these patients acute renal failure may develop if dosage recommendations according to the presenting serum creatinine clearance are not strictly followed.

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).

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 necessity for treatment with bezafibrate in patients receiving oestrogens or oestrogen containing preparations should be considered on an individual basis.

When Bezafibrate is given in combination with anion-exchange resins (e.g. cholestyramine) the two drugs should always be taken at least 2 hours apart.

4.5 Interaction with other medicinal products and other forms of interaction

Care is required in administering bezafibrate to patients taking coumarin-type anti-coagulants, the action of which may be potentiated. The dosage of the anti-coagulant should be reduced by up to 50 % and readjusted by monitoring blood coagulation.

As bezafibrate improves glucose utilisation the action of antidiabetic medicinal products, 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 bezafibrate therapy.

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 bezafibrate as the absorption of bezafibrate otherwise may be impaired.

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.

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 bezafibrate in patients receiving oestrogens or oestrogen containing preparations should be considered on an individual basis.

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 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 data from Boehringer Mannheim 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).

Blood and Lymphatic System

Very rare:    Pancytopenia

Thrombocytopenia 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

Gastro-intestinal Disorders

Uncommon:    Gastrointestinal disorders such as abdominal distension, diarrhoea,

nausea

Rare:    Pancreatitis

Hepato-biliary Disorders:

Uncommon:    Cholestasis

Very rare:    Cholelithiasis (see section 4.4 Special warnings and special

precautions for

use)

Skin and subcutaneous tissue Disorders

Uncommon:    Pruritis

Urticaria

Photosensitivity reactions

Alopecia

Rash

Very rare:    Erythema multiforme

Stevens-Johnson Syndrome Toxic epidermal necrolysis

Musculoskeletal and Connective Tissue Disorders

Uncommon:    Muscular weakness,

Myalgia Muscle cramps

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.

4.9 Overdose

No specific effects of acute overdose are known apart from rhabdomyolysis. There is no specific antidote. Thus appropriate symptomatic therapy is recommended in cases of overdose. In cases of rhabdomyolysis, bezafibrate must be stopped immediately and renal function carefully monitored.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC Code: C10AB02

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

Absorption:

Bezafibrate is rapidly and almost completely absorbed from the standard tablet formulation. A peak plasma concentration of about 14mg/L I sreached after 2 hours following ingestion of 2 x 200mg standard tablets given as a single dose in healthy volunteers.

Distribution:

The protein-binding of bezafibrate in serum is approximately 95 %. The apparent volume of distribution (Vd) is 17 l.

Metabolism:

50% of the administered bezafibrate dose is recovered in the urine as unchanged drug and 20% in the form of glucuronides.

Elimination:

Elimination 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. The rate of renal clearance ranges from 3.4 to 6.0 l/h. The elimination half-life is in the order of 1 - 2 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. The 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.

6.1 List of excipients

Povidone, microcrystalline cellulose, maize starch, magnesium stearate, colloidal anhydrous silica, croscarmellose sodium, talc, hypromellose, titanium dioxide (E 171), macrogol 6000.

6.2 Incompatibilities

None known

6.3 Shelf life

60 months

6.4 Special precautions for storage

None

6.5 Nature and contents of container

Blisters made of PVC 250pm/aluminium 20pm containing 10 tablets each.

Packs with 30, 50, 100, 500 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

None

7    MARKETING AUTHORISATION HOLDER

Ratiopharm GmbH Graf-Arco-Str.3