Zimbacol XL tablets

1. Name Of The Medicinal Product

Zimbacol XL

2. Qualitative And Quantitative Composition

Each tablet contains 400mg bezafibrate

3. Pharmaceutical Form

Modified release tablets

4. Clinical Particulars

4.1 Therapeutic Indications

Zimbacol XL is indicated for use in hyperlipidaemia of Type IIa, IIb, III, IV and V under the Frederikson Classification.

Bezafibrate should be administered only to patients with a fully defined and diagnosed lipid abnormality where changes in diet or lifestyle (for example greater physical activity and weight reduction) cannot control the condition and in whom the long term risks associated with the condition warrant treatment. The rationale for use of bezafibrate is to control abnormal increases in serum lipid and lipoprotein levels or prevent long term adverse effects that have been shown by many epidemiological studies to be positively and strongly correlated with such hyperlipidaemias.

4.2 Posology And Method Of Administration

Adults

Zimbacol XL should be taken orally. The dosage is one 400mg tablet daily. Tablets should be swallowed whole with a little fluid after a meal, either morning or night.

Elderly

There are no specific dosage requirements for elderly patients.

Children

There is currently insufficient information available to recommend an appropriate dosage in children.

The response to therapy is normally rapid, but a gradual improvement may occur over several weeks. Treatment should be stopped if an adequate response has not been achieved within 3 to 4 months.

4.3 Contraindications

Bezafibrate is contra-indicated in patients with severe hepatic disease (other than fatty infiltration of the liver associated with raised triglyceride values), gall bladder disease with or without cholelithiasis, nephrotic syndrome and severe renal disorders (serum creatinine greater than 135 μmoles/l or creatinine clearance less than 60ml/min). Bezafibrate is contra-indicated in patients hypersensitive to bezafibrate.

4.4 Special Warnings And Precautions For Use

Zimbacol XL is contra-indicated in patients with renal impairment (serum creatinine greater than 135 μmoles/l or creatinine clearance less than 60ml/min). Such patients may be treated with conventional bezafibrate tablets (200mg bezafibrate) using a reduced daily dosage.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Care is required in administering bezafibrate to patients receiving coumarin-type anti-coagulant therapy. The dose of anti-coagulant should be reduced initially by 50% and adjusted according to prothrombin time.

As bezafibrate can improve glucose utilisation, the action of anti-diabetic medication might be potentiated. Caution must be taken as hypoglycaemia has been observed rarely and monitoring of glycaemic status is warranted especially during initiation of therapy with Zimbacol XL.

Bezafibrate should not be administered with MAO-inhibitors with hepatotoxic potential.

HMG CoA reductase inhibitors taken in combination with fibrates may increase the risk of myopathy and should therefore be used with caution. Patients predisposed to myopathy (impaired renal function, severe infection, trauma, surgery, disturbances of hormone or electrolyte balance) should not be given this combination therapy.

If combined therapy with an ion-exchange resin is necessary, to avoid impairment of bezafibrate absorption, there should be an interval of two hours between intake of the resin and Zimbacol XL.

Oestrogens may lead to a rise in lipid levels and therefore the necessity for treatment with Zimbacol XL in patients receiving oestrogens or oestrogen containing preparations should be considered on an individual basis.

4.6 Pregnancy And Lactation

Bezafibrate has not been shown to have any adverse effects on the foetus during animal studies, however, it is recommended that bezafibrate should not be administered to women either when they are pregnant or breast-feeding.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

The most frequent adverse effects during treatment with bezafibrate are gastrointestinal in nature, such as nausea, loss of appetite, vomiting, diarrhoea, dyspepsia, flatulence and abdominal discomfort. These symptoms are generally transient and resolve without drug withdrawal or dosage adjustment. Other less frequently occurring adverse effects include weight gain, headache, dizziness, fatigue or drowsiness, skin rashes, pruritus, alopecia, impotence, anaemia and leucopenia. Rarely, muscle cramps and weakness may occur, accompanied by increases in creatinine phosphokinase concentrations and serum myoglobin. These adverse effects are generally rapidly resolved following withdrawal of therapy.

Serum creatinine has been observed to increase in patients with normal renal function. For patients with renal dysfunction care should be taken as failure to follow dosage guidelines could result in rhabdomyolysis.

There have been isolated reports of cholecystitis, gallstones and sometimes pancreatitis in patients receiving fibrates. However, there is no evidence that the administration of bezafibrate is associated with these problems.

4.9 Overdose

In cases of acute overdosage, treatment, where necessary, should be symptomatic. There is no evidence of serious clinical or biochemical effects following bezafibrate overdosage.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Bezafibrate is a fibric acid derivative with hypolipidaemic activity. It has the isobutyric group in common with clofibrate, but it is 10 times more potent than clofibrate at reducing serum cholesterol and triglycerides. Bezafibrate has four separate metabolic effects: a limitation of substrate availability for triglyceride synthesis in the liver; promotion of the action of lipoprotein lipase; modulation of low density lipoprotein (LDL) receptor/ligand interaction; and stimulation of reverse cholesterol transport.

5.2 Pharmacokinetic Properties

Bezafibrate is rapidly and almost completely absorbed from the gastrointestinal tract and there is no presystemic metabolism. Maximum plasma concentrations occur at approximately 4 hours after administration of Zimbacol XL (average plasma half-life 3.4 hours). The protein-binding of bezafibrate in serum is approximately 95%. Elimination is mainly in urine (>90%) either as polar metabolites or unchanged bezafibrate. A small percentage of the dose is excreted in the faeces. Elimination may be increased in forced diuresis.

5.3 Preclinical Safety Data

Chronic administration of a high dose of bezafibrate to rats was associated with hepatic tumour formation in females. However, the dosage was in the order of 30 to 40 times the human dosage and no similar effect was observed at lower dose levels correlating more closely to the lipid lowering dose in humans.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Zimbacol XL contains the following excipients:

Maize starch, sodium starch glycollate, lactose, poly(ethyl acrylate-methyl methacrylate), magnesium stearate, polysorbate 80, hypromellose, talc, calcium carbonate, povidone, arabic gum, titanium dioxide (E171), glucose, sucrose, purified water, Macrogol 6000.

6.2 Incompatibilities

None stated.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Zimbacol XL is available in rigid PVC film / Aluminium foil blister strips packed in outer cardboard cartons.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

Archimedes Pharma UK Limited

250 South Oak Way, Green Park

Reading

Berkshire

RG2 6UG

UK

8. Marketing Authorisation Number(S)

PL 12406/0010

9. Date Of First Authorisation/Renewal Of The Authorisation

16 May 2000

10. Date Of Revision Of The Text

6 April 2009

ZIMT400-SPC07

® Zimbacol is a registered trade mark