Bezalip Mono

Bezafibrate 400mg.

For excipients see section 6.1.

Modified release tablet for oral use.

Bezalip Mono is a round film-coated tablet with a white core and is imprinted D9.

Bezalip Mono is indicated for use in hyperlipidaemias of Type IIa, IIb, III, IV and V (Fredrickson classification).

Bezalip Mono 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 Mono 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 dosage for Bezalip Mono is one tablet daily, equivalent to 400mg bezafibrate. The tablets should be swallowed whole with sufficient fluid after a meal either at night or in the morning.

Elderly

Bezalip Mono should not be used in elderly patients if the creatinine clearance is below 60 ml/min (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 contraindicated.

Bezalip Mono is contra-indicated in patients with renal impairment with serum creatinine> 135 micromol/l or creatinine clearance < 60ml/min. Such patients may be treated with conventional Bezalip tablets (200mg bezafibrate) using an appropriately reduced daily dosage.

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 Treatment should be withdrawn if an adequate response has not been achieved within 3 to 4 months.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

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 or creatinine clearance are not strictly followed.

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, hypothyroidism, severe infection, trauma, surgery, disturbances of hormone or electrolyte imbalance and a high alcohol intake).

Because of the risk of rhabdomyolysis, bezafibrate should be used in combination with HMG CoA reductase inhibitors only in exceptional cases when strictly indicated. Patients should be informed of and monitored for signs of myopathy and increased CPK activity and combination therapy discontinued immediately if signs of myopathy develop.

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).

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

Care is required in administering Bezalip Mono 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 Mono.

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 Mono 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 Contraindications). For specific dose restrictions of statins refer 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 Bezalip Mono in patients receiving oestrogens or oestrogen containing preparations should be considered on an individual basis.

Animal studies are insuffcient with respect to effects on pregnancy, embryonal/foetal development, parturition or postnatal development. The potential risk for humans is unknown.

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

Bezalip Mono should not be used during pregnancy or lacation unless clearly indicated.

Bezalip 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.

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 according to MedDRA System Organ Class is displayed below:

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

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.

Absorption

With 400 mg Bezalip Mono, 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%.

Distribution

The protein-binding of bezafibrate in serum is approximately 95% and 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 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.

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.

Lactose

Povidone

Sodium laurilsulfate

Hypromellose

Silica, colloidal hydrated

Magnesium stearate (E572)

Polymethacrylic acid esters

Macrogol 10,000

Talc (E553b)

Titanium dioxide (E171)

Polysorbate 80

Sodium citrate (E331).

Not applicable.

5 years.

Bezalip Mono requires no special storage conditions.

Packs of 28 or 30 tablets in PVC/Aluminium blister strips. HDPE containers of 28 tablets.

Not applicable.

Actavis Group PTC ehf

Reykjavíkurvegi 76-78

220 Hafnarfjordur

Iceland.

PL 30306/0126

1 April 1999

03/04/09