Drug Interactions
The rate and degree of absorption of bezafibrate is reduced by approximately 50% in the presence of cholestyramine but is only slightly reduced in the presence of food.
When bezafibrate is used concurrently with cholestyramine or any other resin, an interval of at least 2 h should be maintained between the two drugs, since the absorption of bezafibrate is impaired by cholestyramine.
Severe myositis and rhabdomyolysis have occurred when a cyclosporine was administered with a fibrate. Therefore, the benefits and risks of using BEZALIP SR concomitantly with cyclosporine should be carefully considered.
In isolated cases, reversible impairment of renal function (accompanied by a corresponding increase in the serum creatinine level) has been reported in organ transplant patients receiving immuno-suppressant therapy and concomitant bezafibrate. Renal function should be closely monitored in these patients and in the event of relevant significant changes in laboratory parameters, bezafibrate should be discontinued.
Caution should be exercised when oral anticoagulants are given with BEZALIP SR (bezafibrate). The dosage of anticoagulants should be reduced up to 50% to maintain the prothrombin time at the desired level to prevent bleeding complications. Careful frequent (perhaps weekly) monitoring of prothrombin time is therefore recommended until it has been definitely determined that the prothrombin level has been stabilized.
Serious hypoglycaemia may result in the combinatory use of bezafibrate and hypoglycaemic agents.
Interaction between fibrates and HMG-Co A reductase inhibitors (statins) may vary in nature and intensity depending on the combination of the administered drugs.
Due to the risk of rhabdomyolysis, bezafibrate should only be administered together with HMG-CoA reductase inhibitors in exceptional cases when strictly indicated. Patients receiving this combination therapy must be informed carefully of the symptoms of myopathy and monitored closely. Combination therapy must be discontinued immediately at the first signs of myopathy. This combination therapy must not be used in patients with predisposing factors for myopathy (impaired renal function, severe infection, trauma, surgery, disturbances of the hormonal or electrolyte balance and a high alcohol intake).
MAO-inhibitors (with hepatotoxic potential) must not be administered together with BEZALIP.
Since estrogens may lead to a rise in lipid levels, the prescribing of BEZALIP SR in patients taking estrogens or estrogen-containing contraceptives must be critically considered on an individual basis.
Information for the Patient
Bezalip SR
Dosage and Administration
Since a reduction of total mortality has not been established, BEZALIP SR (bezafibrate) should be administered only to those patients described in Indications and Clinical Use. If a significant serum lipid response is not obtained in three months, BEZALIP SR should be discontinued.
In patients with impaired renal function (serum creatinine >1.5 mg/100 mL, i.e. >135 µmol/L or creatinine clearance <60 mL/min), the BEZALIP SR 400 mg sustained release tablet should not be used.
Initial Therapy: Before instituting BEZALIP SR therapy, attempts should be made to control serum lipids with appropriate diet, exercise and weight loss in obese patients, as well as other medical problems, such as diabetes mellitus and hypothyroidism. In patients at high risk, consideration should be given to the control of other risk factors such as smoking, excessive alcohol intake, hormonal contraceptive use, and inadequately controlled hypertension.
Long-Term Therapy: Since long-term administration of BEZALIP SR is recommended, the potential risks and benefits should be carefully weighed.
The dosage is one BEZALIP SR 400 mg sustained release tablet once daily.
The 400 mg sustained-release tablet should be taken in the morning or evening with or after meals. The sustained release tablet should be swallowed without chewing with sufficient fluid. When BEZALIP SR 400 mg tablets are administered concurrently with resins, an interval of 2 hours should be maintained between the two drugs (see Warnings and Precautions).
Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take 2 doses at the same time.
Adverse Reactions
epigastric distress, flatulence, nausea, diarrhea, constipation.
Less common adverse reactions observed include:
muscular weakness, myalgia and muscle cramps.
The most common adverse reactions observed in clinical trial patients treated for up to 5 years with bezafibrate and from surveillance studies in countries where bezafibrate has been marketed since as early as 1978, also include:
alopecia, Stevens-Johnson syndrome, toxic epidermal necrolysis.
In isolated cases, the occurrence of gallstones, cholestasis, cholelithiasis, thrombocytopenia (i.e., purpura), pancytopenia and erectile dysfunction have been reported.
Abnormal liver function test have been observed occasionally during bezafibrate therapy including elevated transaminases and decreased or rarely increased alkaline phosphatase. However, after five years of placebo-controlled double-blind therapy, the cumulative event rates for elevations in ALT and AST were similar between the placebo and bezafibrate groups (see Table 2).
Mild decreases in hemoglobin, leukocytes and erythrocytes, and slight increase in platelets have been observed occasionally in patients receiving bezafibrate therapy. A decline of alkaline phosphatase has been shown so consistently that it could be used as an indicator of patient compliance. A parallel decrease of gamma-glutamyl transferase has also been noted.
Slight increase in serum creatinine may occur. In patients with existing renal failure, if dosage recommendations are not followed, myositis and rhabdomyolysis may develop (see Warnings and Precautions).
Bezafibrate also has the potential to provoke CPK elevations which generally subsides when the drug is discontinued (see Warnings and Precautions).
pruritus, urticaria or erythema and isolated cases of photosensitivity.
Indications and Clinical Use
BEZALIP SR (bezafibrate) is indicated as an adjunct to diet and other therapeutic measures for:
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Treatment of patients with hypercholesterolemia Type IIa and IIb mixed hyperlipidemia, to regulate lipid and apoprotein levels (reduce serum TG, LDL cholesterol and apolipoprotein B, increase HDL cholesterol and apolipoprotein A).
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Treatment of adult patients with high to very high triglyceride levels, Fredrickson classification Type IV and V hyperlipidemias, who are at a high risk of sequelae and complications (i.e. pancreatitis) from their dyslipidemia.
BEZALIP SR may not be adequate therapy in some patients with familial combined hyperlipidemia with type IIb and type IV hyperlipoproteinemia. Initial therapy for dyslipidemia should include at least an equivalent of the American Heart Association (AHA) step 1 diet.
There is evidence from coronary angiographic studies to show that triglyceride-rich lipoproteins are an important factor in the progression of coronary artery disease. A 5-year double-blind, placebo-controlled intervention trial (bezafibrate coronary atherosclerosis intervention trial (BECAIT)) has demonstrated that bezafibrate retards or prevents the progression of atheroma in young post-infarction patients (<45 years). The results show that long-term treatment with bezafibrate, can retard the progression of focal atheroma resulting in a reduced cardiac morbidity. Analysis of treatment effect at each patient's last assessment showed that the change in minimum lumen diameter (MLD) was 0.13 mm less in the bezafibrate group than the placebo group (p=0.049). The 5-year cumulative coronary event rate (defined as sudden coronary death, fatal or non-fatal reinfarction, CABG or PTCA) was significantly lower for bezafibrate (3/47; 6.4%) versus placebo (11/45; 24.4%) treated patients (p=0.02).
Overdosage
For management of a suspected drug overdose, CPhA recommends that you contact your regional Poison Control Centre. See the eCPS Directories section for a list of Poison Control Centres.
While there has been no reported case of overdosage, symptomatic and supportive measures should be taken. Because bezafibrate is highly bound to plasma proteins, hemodialysis should not be considered.
In patients with existing impaired renal function, if dosage recommendations are not followed, overdosage may occur and severe rhabdomyolysis may develop. Administration of BEZALIP SR (bezafibrate) must be stopped immediately and renal function must be carefully monitored (see Warnings and Precautions).
Dosage Forms, Composition and Packaging
Each round, white, sustained-release film-coated tablet, printed on both sides: above BM, below D9, contains: bezafibrate 400 mg. Nonmedicinal ingredients: colloidal silicon dioxide, hydroxypropyl methylcellulose 2208 & 2910, lactose, magnesium stearate, methyl methacrylate, polyethyl acrylate, polyethylene glycol 10 000, polysorbate 80, povidone K25, sodium citrate, sodium lauryl sulfate, talc and titanium dioxide. Blister packs of 30.
Warnings and Precautions
Standard tests for teratology, fertility and peri- and post-natal effects in animals have shown a relative absence of risk, however, embryotoxicity has occurred in animals at toxic doses.
Abnormal liver function tests have been observed occasionally during BEZALIP SR administration, including elevated transaminases, and decreased or, rarely, increased alkaline phosphatase. However, these abnormalities are reversible upon discontinuation of the drug. Therefore, periodic liver function tests (AST, ALT, and GGT [if originally elevated]) in addition to other baseline tests are recommended after 3 to 6 months and at least yearly thereafter. BEZALIP SR therapy should be terminated if drug related abnormalities persist.
Mild hemoglobin, leucocyte and platelet decreases have occurred occasionally following initiation of BEZALIP SR therapy. However, these levels stabilize during long-term administration. Periodic blood counts are recommended during the first 12 months of BEZALIP SR administration.
Treatment with drugs of the fibrate class including bezafibrate has been associated on rare occasions with myositis or rhabdomyolysis, usually in patients with impaired renal function (see Contraindications). Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness/weakness, or marked elevations in creatine phosphokinase levels. Patients should be advised to report unexplained muscle pain, tenderness or weakness promptly, particularly if accompanied by malaise or fever. CPK levels should be assessed in patients reporting these symptoms, and BEZALIP SR therapy should be discontinued if markedly elevated CPK levels (10 times the upper limit of normal) occur or myopathy is diagnosed.
Bezafibrate clinically, pharmacologically and chemically shows similarities with clofibrate. Physicians prescribing BEZALIP SR (bezafibrate) should also be familiar with the risks and benefits of clofibrate.
If BEZALIP SR is chosen for treatment, the prescribing physician should discuss the proposed therapy and inform the patient of the expected benefits and potential risks associated with long-term administration (see Warnings and Precautions).
Adequate pretreatment laboratory studies should be performed to ensure patients have elevated serum cholesterol and/or triglycerides with or without low HDL levels. Periodic determinations of serum lipids, fasting glucose, creatinine, ALT, CGT and CPK should be considered during BEZALIP treatment, particularly during the first months of therapy.
In patients with a past history of jaundice or hepatic disorder, BEZALIP SR should be used with caution.
BEZALIP SR 400 mg sustained release tablets should not be used in elderly patients as the creatinine clearance after 70 years of age is normally lower than 60 mL/min (see Dosage and Administration).
Limited experience is available in children at a dose of 10-20 mg/kg/day. Therefore, in the absence of adequate information concerning the long-term safety, BEZALIP SR should be used with caution in treating children.
Strict birth control procedures must be exercised by women of childbearing potential. If pregnancy occurs despite birth control procedures, BEZALIP SR should be discontinued. Women planning a pregnancy should discontinue BEZALIP SR several months prior to conception (see Contraindications).
In the absence of data concerning the presence of bezafibrate in human breast milk, BEZALIP SR should not be used by nursing mothers (see Contraindications).
BEZALIP SR may increase cholesterol excretion into the bile, and may lead to cholelithiasis. Appropriate diagnostic procedures should be performed if cholelithiasis-related signs and symptoms should occur. BEZALIP SR therapy should be discontinued if gallstones are found.
Storage and Stability
BEZALIP SR (bezafibrate) tablets should be stored at room temperature (15-30°C). Protect from high humidity.
Action and Clinical Pharmacology
Liver disease (except fatty liver) is a contraindication.
Pharmacokinetic investigations in the elderly suggest that elimination may be delayed in cases of impaired liver function. Liver disease (except fatty liver) is a contraindication (see Hepatic Insufficiency below).
In human serum, 94-96% of bezafibrate is bound to protein. The apparent volume of distribution is about 17 L. There is no accumulation of the drug following repeated administration for periods of 28 days to 1 year.
A peak concentration of about 6 mg/L is reached after 3-4 h with the 400 mg sustained release tablet.
The fibrates, including BEZALIP SR (bezafibrate) , lower elevated serum lipids by decreasing the low density lipoprotein (LDL) fraction rich in cholesterol and the very low density lipoprotein (VLDL) fraction rich in triglycerides. In addition, fibrates (including BEZALIP SR) increase the high density lipoprotein (HDL) cholesterol fraction.
The mechanisms of action of the fibrates have not been definitely established. Work carried out to date, including the information derived from animal studies, suggests that the major modes of action of the fibrates likely encompass the following:
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VLDL catabolism by increased lipoprotein and hepatic triglyceride lipase activities
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attenuation of triglyceride biosynthesis by acetyl-CoA carboxylase enzyme inhibition
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attenuation of cholesterol biosynthesis by inhibition of the rate-limiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase).
The elimination is rapid, with excretion almost exclusively renal. Within 48 h, 95% of the activity of the 14C-labelled drug is recovered in the urine and 3% in the feces. The rate of renal clearance ranges from 3.4 to 6.0 L/h. The elimination half-life of bezafibrate is 1-2 h. The elimination of bezafibrate is reduced in patients with renal insufficiency. BEZALIP SR 400 mg tablets are contraindicated in patients with renal impairment (see Contraindications).
In patients with severe renal failure, important accumulation of fibrates are observed with large increases in the half-life. There is a correlation between creatinine clearance and the elimination half-life of bezafibrate. Because bezafibrate is highly bound to plasma proteins, hemodialysis should not be considered. Bezafibrate is contraindicated in patients with renal impairment (serum creatinine levels >1.5 mg /100 mL, i.e. >135 µmol/L, or creatinine clearance <60 mL/min) including in patients undergoing dialysis (see Contraindications and Warnings and Precautions).
After administration of 14C-labelled bezafibrate, 95% of the administered dose was excreted within 48 hours in the urine and the remainder was found in the feces. In the urine, about 50% was present as unchanged bezafibrate, about 25% as bezafibrate glucuronide and the remainder as metabolites, one of which was identified as hydroxy-bezafibrate, which does not have any lipid-lowering properties in animals. Clofibric acid was not found as a metabolite.
Due to their major action on lipoprotein and hepatic triglyceride lipase, the fibrates appear to produce a greater reduction on the VLDL than on the LDL fraction. Therapeutic doses of BEZALIP SR (bezafibrate) produce variable elevations of HDL cholesterol, a reduction in the content of LDL cholesterol, and a substantial reduction in the triglyceride content of the VLDL fraction. 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. Changes by BEZALIP SR in the lipid components (VLDL-triglycerides, VLDL-cholesterol, LDL-cholesterol, HDL-cholesterol) are usually paralleled by changes in the corresponding apolipoproteins: apolipoprotein B is reduced, while apolipoprotein A1 and A2 may be increased.
Bezafibrate also exerts an effect on thrombogenic factors: in addition to an inhibition of platelet aggregation, a significant decrease in elevated plasma fibrinogen levels as well as a reduction of blood viscosity can be achieved.
Some data may indicate that a reduction in blood glucose concentration due to an increase in glucose tolerance may be observed in diabetic patients. In the same patients, the concentration of fasting and postprandial free fatty acids may be reduced by bezafibrate.
Limited experience is available in children.
Contraindications
Hepatic impairment, including primary biliary cirrhosis.
Renal impairment (serum creatinine levels >1.5 mg/100 mL, i.e., >135 μmol/L, or creatinine clearance <60 mL/min or in patients undergoing dialysis) (see Warnings and Precautions, Musculoskeletal and Action and Clinical Pharmacology, Pharmacokinetics, Renal Insufficiency).
Pre-existing gallbladder disease (see Warnings and Precautions).
Hypersensitivity to bezafibrate, to any component of the product or to other fibrates.
Photoallergic or phototoxic reactions to fibrates.
Pregnancy or lactation.
BEZALIP SR (bezafibrate) is not indicated for the treatment of Type I hyperlipoproteinemia.
Combination therapy of BEZALIP SR 400 mg with HMG-CoA reductase inhibitors in patients with predisposing factors for myopathy e.g. preexisting renal impairment, severe infection, trauma, surgery, disturbances of the hormonal or electrolyte balance (see Drug Interactions).
