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4.2. Posology and method of administration
Renal impairment
Fibrazate® XL 400mg Tablets is contraindicated in dialysis patients.
4.3. Contraindications
• Known hypersensitivity to bezafibrate or any of the excipient in this tablet
• Known hypersensitivity to any other fibrates
• Bezafibrate is also contra-indicated in patients with advanced liver disease (except fatty infiltration of the liver which is linked to high triglyceride values)
• Gall-bladder disease with or without cholelithiasis
• Nephrotic syndrome or renal impairment with serum creatinine >135 micromol/l or creatinine clearance < 60 ml/min
• Patients who are undergoing dialysis
• Any other hypoalbuminaemic states
• Known photoallergic or phototoxic reactions to fibrate
• Concomitant use of HMG CoA reductase inhibitors (statins) in patients with or at risk of myopathy (see sections 4.4 and 4.5)
4.4. Special warnings and precautions for use
Bezafibrate along with other fibrates can cause myopathy, causing muscle weakness and pain, accompanied by an increase in creatine kinase (CPK). Rarely rhabdomyolysis can occur, but may be more likely to occur when fibrates are given in high doses in patients with renal impairment and in patients at risk of myopathy e.g. hypothyroidism, hormone or electrolyte imbalances, severe infections, surgery, trauma, and consumption of a lot of alcohol.
Due to the risk of rhabdomyolysis, bezafibrate and statins should not be used concomitantly, unless its unavoidable. Patients should be made aware of the signs of myopathy and increased CPK and advised to stop their therapy should they occur.
Bezafibrate alters the composition of bile, if cholelithiasis occurs, appropriate diagnostic procedures should be performed if cholelithic symptoms and signs appear (see section 4.8 Undesirable effects).
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. Interactions with other medicinal products and other forms of interaction
In isolated cases a marked though reversible impairment of renal function along with
the increased serum creatinine level has been seen in organ transplanted patients receiving ciclosporin and concomitant bezafibrate. These patients should be monitored closely and if laboratory tests show significant changes then the bezafibrate should be discontinued.
Patients treated with bezafibrate in combination HMG CoA reductase inhibitors, due to the pharmacodynamic interaction between these two classes of drugs, in some cases may cause an increased risk of myopathy (see section 3. Contraindications). For the dosages of the stains that can be used refer to the SPC of the relevant medicinal product
4.6. Fertility, pregnancy and lactation
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.
4.9. Overdose
There is no specific antidote. Therefore, appropriate symptomatic therapy is recommended in case of overdose. In patients with normal renal function, forced diuresis can be attempted to accelerate elimination.
No specific effects of acute overdose are known with the exception of rhabdomyolysis. In cases of rhabdomyolysis bezafibrate must be stopped immediately and renal function carefully monitored.
5.1. Pharmacodynamic properties
ATC Code: C10AB02
Bezafibrate lowers the raised levels of serum cholesterol and triglycerides (lowers low density lipoproteins (LDL) and very low lipoprotein (VLDL) levels, and raises the lowered high density lipoproteins (HDL) levels), this is achieved by stimulating the lipoprotein lipase and hepatic lipase, and by suppressing the 3 HMGCo-A reductase activity, and thereby simulating the LDL receptors on the cell plasma membranes.
Thus enabling the LDL levels to be reduced to a more normal level.
5.2. Pharmacokinetic properties
With Fibrazate® XL 400mg Tablets, 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 around 70%.
Distribution
Bezafibrate is highly protein bound (94-96%) and the apparent volume of distribution
is 17L.
Metabolism
50% of the administered bezafibrate dose is found in the urine as unchanged drug, and 20% in the metabolised form of glucuronides.
Elimination
Elimination is rapid and excretion almost entirely renally. 95% of the activity of 14Clabelled
drug is recovered in the urine, with 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 around 1-2 hours although elimination is markedly slowed in patients with limited renal function.
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