AGIBEZA 200

Composition: Each film-coated tablet contains:
Bezafibrate . . . . . . . . . . . . . . . . . . . . . . 200 mg
Presentation:
Box of 3 blisters, 5 blisters, 10 blisters x 10 film-coated tablets.
Indications:
AGIBEZA 200 is indicated for the treatment of primary hyperlipidaemia types IIa, IIb, III, IV and V in patients who do not respond adequately to diet and other appropriate measures.

Additional information

Dosage and administration

Dosage
Usual dose for adults:
The recommended dosage is one tablet (200 mg), 3 times daily, taken with meals or after meals. A single dose of 400 mg, once daily may be taken with or immediately after main meal (dose of 400 mg once daily are not suitable for patient with kidney failure).
Treatment with bezafibrate must be combined with monitoring cholesterol and triglyceride. Treatment should be withdrawn if an adequate response has not been achieved within 3 to 4 months.
Dosage adjustment according to renal function (serum creatinine):
Serum creatinine (micromol/l) ~ Dosage
– Up to 135 200 mg ~ 3 times daily
– 136 – 225 200 mg ~ two times daily
– 226 – 530 200 mg ~ once daily
When bezafibrate is given in combination with cholestyramine, the two drugs should be taken at least 3 hours apart.
Administration:
Bezafibrate is taken orally, with meals or after meals that dietary fat restriction is required.

Contraindications

Hypersensitivity to bezafibrate and any of the excipients of this medicine.
Severe impaired hepatic function
Hypoalbuminemia
Primary biliary cirrhosis
Severe renal impairment
Nephrotic syndrome

Warnings and precautions for use

Bezafibrate should be used with caution in patients with renal impairment. When serum creatinine concentration increases gradually or the recommended dose of bezafibrate is not follwed, it may lead to rhabdomyolysis.
When bezafibrate is given in combination with cholestyramine, the two drugs should be taken at least 3 hours apart.
Patients are taking anticoagulants, if need to use bezafibrate, dose of anticoagulant should be reduced about 1/3.
Do not combine bezafibrate with drugs which are hepatotoxic such as MAO inhibitors, perhexiline.

Recommendation for pregnancy and breastfeeding

Pregnancy:
Clinical experience of treatment for pregnant women is very limited. So far there are no data that demonstrate the risk of teratogenicity. However, the drug is not recommended for use in pregnant women because of lack of safe evidence.
Breastfeeding
It is not known whether the drug is excreted in human milk. This drug is not recommended during breastfeeding.

Effects on ability to drive and use machines

AGIBEZA 200 may cause headache, dizziness. If affected, you should avoid driving or operating machinery.

Interactions, incompatibilities of medicine

Benzafibrate is strongly bound to serum proteins, displaces other drugs from plasma protein binding sites, and simultaneously changes the activity of P450, especially CYP3A4.
Coadministration of fibrates with HMG CoA reductase inhibitors (e.g. Pravastatin, fluvastatin) increases the risk of muscle injury and acute pancreatitis.
The combination of bezafibrate with cyclosporine increases the risk of myopathy.
Bezafibrate increases the effect of oral anticoagulants, thereby the risk of bleeding is increased.
Bezafibrate increases the effect of tolbutamide, phenytoin and sulfonylurea diuretics.
Bezafibrate interacts with bile acid-binding medicines such as cholestyramine, colestipol, and the absorption of bezafibrate is reduced.

Undesirable effects (ADRs)

The undesirable effects of bezafibrate are similar to those of fibrates, which are usually mild or not observed in the short-term treatment. Undesirable effects in the digestive system are predominant.
Common, ADR >1/100
Gastrointestinal: Gastrointestinal disorders, indigestion, nausea and mild diarrhea.
Uncommon, 1/1000 < ADR < 1/100
Central nervous system: Headache, dizziness.
Hepatic: Transaminases increased, biliary obstruction.
Skin: Urticaria.
Musculoskeletal: Myalgia.
Mild increase in serum creatinine is not associated with renal function.
Rarely, ADR < 1/1000
Hematologic: Decrease in hemoglobin, thrombocytopenia, leukopenia.
Reproductive system and breast disorders: Decreased libido and impotence
Stevens-Johnson syndrome (SJS).
Guidelines for ADR manangement:
In case of unexplained muscle pain, discontinue the treatment with bezafibrate and measure creatinine clearance (CK) levels to monitor.

Overdose and management

Overdose: Overdose of bezafibrate may cause severe, but reversible, renal failure.
Management: If overdose of drugs used for dyslipidemia occur, symptomatic and supportive treatment is usually recommended
There is no specific antidote.

Pharmacodynamic properties

Bezafibrate is a fibric acid derivative that is effective against lipid disorders. Bezafibrate inhibits biosynthesis of cholesterol in the liver, inhibits the synthesis of bile acids, enhances the excretion of cholesterol into the bile, the main effect is to reduce very low density lipoprotein and low density lipoprotein (VLDL and LDL) and increases high density lipoprotein (HDL), therefore, the drug significantly improves the distribution of cholesterol in plasma.
Bezafibrate lowers elevated blood lipids (triglycerides and cholesterol), thus, it it is used for the treatment of hyperlipoproteinemia types IIa, IIb, III, IV and V as an adjunct to a diet restricted in saturated fat and cholesterol.
The effect of bezafibrate is due to its agonist activity for PPARα, which is a receptor that plays an important role in lipid metabolism.

Pharmacokinetic properties

Absorption: Bezafibrate is absorbed from the gastrointestinal tract when taken with food, but poor absorption may be impaired under fasting condition and it is significantly reduced if taken after an overnight fast. Peak plasma concentrations occur within 2 to 4 hours after oral administration.
Distribution: The drug is highly bound to plasma albumin, therefore, it displaces antivitamin K compounds from the protein binding sites. Bezafibrate is over 95% bound to serum proteins, primarily albumin. The apparent volume of distribution is about 0.2 litre/kg.
The drug is widely distributed and concentrated in the liver, kidneys and intestine.
Metabolism: Bezafibrate is easily hydrolyzed to active metabolites.
Elimination: The elimination half-life is 2.1 hours.
60 – 90% of oral dose is excreted in the urine, 50% is recovered in the urine as unchanged drug and 20% in the form of glucuronides, the remainder is in the form of other metabolites. About 3% of dose is excreted in faeces.
The elimination of bezafibrate is not enhanced by diuretics and is not removed by hemodialysis.

Storage conditions, shelf-life, quality specification of the medicine

Storage conditions: Protect from humidity and light, below 30 degrees C.
Shelf – life: 36 months from the manufacture date.
Quality specification: BP 2016.