Fibrazate^® XL 400mg Modified Release Tablets.

Bezatard^® XL 400mg Modified Release Tablets.*

Each tablet contains 400mg of bezafibrate.

For a full list of excipients, see section 6.1.

Modified release tablet.

White, round, film-coated, biconvex tablet, embossed with '400' on one side, and plain on the other.

For the treatment of hyperlipoproteinaemia types IIa, IIb, III, IV and V of the Fredrickson classification.

Fibrazate^® XL 400mg Modified Release 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 Fibrazate^® XL 400mg Modified Release 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.

Adults

The recommended daily dose for Fibrazate^® XL 400mg Tablets is one tablet, equivalent to 400mg bezafibrate, to be swallowed whole with sufficient fluid, after a meal either in the morning or at night.

Elderly

Fibrazate^® XL 400mg Tablets should not be prescribed/administered to elderly patients whose creatinine clearance is below 60ml/min (see Renal impairment below).

Children:

Information available to date is not adequate for a dose recommendation in children.

Renal impairment

Fibrazate^® XL 400mg Tablets is 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.

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 Treatment should be withdrawn if an adequate response has not been achieved within 3 to 4 months

Significant hepatic disease (other than fatty infiltration of the liver associated with raised triglyceride values), gall bladder disease with or without cholelithiasis, nephrotic syndrome or renal impairment (serum creatinine > 135 micromol/l or creatinine clearance < 60ml/min.) Patients undergoing dialysis, known photoallergic or phototoxic reactions to fibrates. Hypersensitivity to bezafibrate or any component of the product or to other fibrates. Concomitant use of HMG CoA reductase inhibitors (statins) in patients with predisposing factors for myopathy (see sections 4.4 and 4.5).

- 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, nephrotic 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).

- 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

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.

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.

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 immuno-suppressant 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.

Pregnancy

Animal studies carried out have shown insufficient with respect to effects on pregnancy, embryonal/foetal development, parturition or postnatal development, therefore, the potential risk for humans is unknown.

Breastfeeding

There is insufficient information for the excretion of bezafibrate or its metabolites into breast milk.

Bezatard^®XL 400mg Tablets should not be used during pregnancy or lactation unless clearly indicated.

Fibrazate^® XL 400mg Tablets has been shown to cause dizziness and can have a minor to moderate effect on the ability to drive or operate machinery. Patients should not drive or use machines if affected.

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).

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.

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.

ATC Code: C10AB02

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.

Efficacy / Clinical Studies:

No data available.

Absorption

Bezalip 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.

Distribution

The protein-binding of bezafibrate in serum is approximately 95%. The apparent volume of distribution is 17 litres.

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).

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 human.

Core: Polyethylene oxide, magnesium stearate, purified siliceous earth

Film Coat: talc, hypromellose, macrogol 4000, titanium dioxide (E171).

Not Applicable

3 years

Do not store above 30°C.

Blister packs comprised of PVC/PVDC/aluminium strips enclosed in an outer carton containing 28 or 30 tablets.

Not applicable.

Sandoz Ltd

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

PL 4416/0325

18/02/2009

04/2011

*An individual name to be printed as appropriate for the intended recipient.