Bezalip (Bezafibrate)

BEZALIP®

Roche

Bezafibrate

Lipid Metabolism Regulator

Action And Clinical Pharmacology: The fibrates, including 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 bezafibrate) increase the high density lipoprotein (HDL) cholesterol fraction.

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 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. Changes by bezafibrate 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.

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: VLDL catabolism by increased lipoprotein and hepatic triglyceride lipase activities; attenuation of triglyceride biosynthesis by acetyl-CoA carboxylase enzyme inhibition; attenuation of cholesterol biosynthesis by inhibition of the rate-limiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase).

Bezafibrate is rapidly and almost completely absorbed from the standard 200 mg immediate release. The relative bioavailability of bezafibrate 400 mg sustained-release tablet compared to the standard 200 mg form is about 70%. A peak plasma concentration of about 8 mg/L is reached after 1 to 2 hours following a single 200 mg dose in healthy volunteers. With the 400 mg sustained-release tablet, a peak concentration of about 6 mg/L is reached after 3 to 4 hours. In human serum, 94 to 96% of bezafibrate is bound to protein. The apparent volume of distribution is about 17 L. The elimination is rapid, with excretion almost exclusively renal. Within 48 hours, 95% of the activity of the 4-labeled drug is recovered in the urine and 3% in the feces. Fifty percent of the applied dose is recovered in the urine as unchanged drug and 20% in the form of glucuronides. The rate of renal clearance ranges from 3.4 to 6 L/hour. The elimination half-life of bezafibrate is 1 to 2 hours.

In patients with severe renal failure, important accumulation of fibrates are observed with large increases in the half-life. Therefore, the dose of bezafibrate may need to be reduced in such instances, depending on the rate of creatinine clearance (see Dosage).

Indications And Clinical Uses: As an adjunct to diet and other therapeutic measures for: 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); 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.

Bezafibrate 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.

Contra-Indications: Hepatic or renal dysfunction, including primary biliary cirrhosis. Pre-existing gallbladder disease (see Precautions). Hypersensitivity to fibrates. Pregnancy or lactation.

Bezafibrate is not indicated for the treatment of Type I hyperlipoproteinemia.

Manufacturers’ Warnings In Clinical States: Drug Interactions : Concomitant Anticoagulants: Caution should be exercised when oral anticoagulants are given with 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.

Statins and Cyclosporine: Severe myositis and rhabdomyolysis have occurred when a statin or cyclosporine were administered with a fibrate. Therefore, the benefits and risks of using bezafibrate concomitantly with statins or cyclosporine should be carefully considered.

MAO inhibitors (with hepatotoxic potential) must not be administered together with bezafibrate.

Children: Limited experience is available in children at a dose of 10 to 20 mg/kg/day. Therefore, in the absence of adequate information concerning the long-term safety, bezafibrate should be used with caution in treating children.

Pregnancy: Strict birth control procedures must be exercised by women of childbearing potential. If pregnancy occurs despite birth control procedures, bezafibrate should be discontinued. Women planning a pregnancy should discontinue bezafibrate several months prior to conception.

Lactation: In the absence of data concerning the presence of bezafibrate in human breast milk, it should not be used by nursing mothers.

Cholelithiasis: Bezafibrate may increase cholesterol excretion into the bile, and may lead to cholelithiasis. If such is suspected, gallbladder studies are indicated. Bezafibrate therapy should be discontinued if gallstones are found.

Bezafibrate clinically, pharmacologically and chemically shows similarities with clofibrate. Physicians prescribing bezafibrate should also be familiar with the risks and benefits of clofibrate.

In long-term animal toxicity and carcinogenicity studies, bezafibrate has been shown to be hepatotoxic and possibly tumorigenic for the liver of rats. A drug-related dose-dependent increase in Leydig cell tumors was also observed in male rats. Administration of lipid-lowering agents of the fibrate class may cause peroxisome proliferation in animals. The phenomenon is species related and is more pronounced in small rodents.

Since a reduction of mortality from coronary artery disease and total mortality have not been established, bezafibrate should be administered only to those patients described in Indications. If a significant serum lipid response is not obtained in 3 months, bezafibrate should be discontinued. If bezafibrate 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 Precautions).

Precautions: Initial Therapy: Before instituting bezafibrate 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 bezafibrate is recommended, the potential risks and benefits should be carefully weighed. 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 bezafibrate treatment, particularly during the first months of therapy.

Reproduction Studies: 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.

Hematologic Changes: Mild hemoglobin, leukocyte and platelet decreases have occurred occasionally following initiation of bezafibrate therapy. However, these levels stabilize during long-term administration. Periodic blood counts are recommended during the first 12 months of administration.

Liver Function: Abnormal liver function tests have been observed occasionally during bezafibrate 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. Bezafibrate therapy should be terminated if drug-related abnormalities persist.

Hepatobiliary Disease: In patients with a past history of jaundice or hepatic disorder, bezafibrate should be used with caution.

Skeletal Muscle: 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. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness/weakness, or marked elevations in creatinine 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 bezafibrate therapy should be discontinued if markedly elevated CPK levels (10 times the upper limit of normal) occur or myopathy is diagnosed.

Drug Interactions (see also Warnings): Resins: When bezafibrate is used concurrently with cholestyramine or any other resin, an interval of at least 2 hours should be maintained between the 2 drugs, since the absorption of bezafibrate is impaired by cholestyramine.

Estrogens: Since estrogens may lead to a rise in lipid levels, the prescribing of bezafibrate in patients taking estrogens or estrogen-containing contraceptives must be critically considered on an individual basis.

Renal Function: In patients with hypoalbuminemia, e.g., nephrotic syndrome, and in patients with renal insufficiency, the dosage of bezafibrate must be reduced and renal function should be monitored regularly (see Precautions, Skeletal Muscle). In dialysis patients, the dosage must be reduced to one 200 mg tablet every third day (see Dosage).

Adverse Reactions: In two separate double-blind placebo-controlled trials, a total of 88 patients on 200 mg bezafibrate t.i.d. and 87 patients on placebo were evaluated for adverse events. Listed in Table I are those adverse events with a positive induced risk occurring during the first 2 months of bezafibrate treatment.

The most common adverse reactions observed in clinical trial patients treated for up to 2 years with bezafibrate and from surveillance studies in countries where bezafibrate has been marketed for up to 14 years include: gastrointestinal: epigastric distress, flatulence, nausea, diarrhea, constipation; dermatologic: pruritus, urticaria or erythema.

Less common adverse reactions observed include: musculoskeletal: muscular weakness, pain and muscle cramps; CNS: headache, dizziness, alopecia.

In isolated cases, the occurrence of gallstones and potency disorders have been reported.

Abnormal liver function tests have been observed occasionally during bezafibrate therapy including elevated transaminases and decreased or rarely increased alkaline phosphatase.

Mild decreases in hemoglobin, leukocytes and platelets have been observed occasionally in patients receiving bezafibrate therapy.

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 Precautions).

Bezafibrate also has the potential to provoke CPK elevations which generally subsides when the drug is discontinued (see Precautions).

Symptoms And Treatment Of Overdose: Symptoms and Treatment: 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 bezafibrate must be stopped immediately and renal function must be carefully monitored (see Precautions).

Dosage And Administration: Recommended Dosage: 200 mg: The standard dosage is one 200 mg immediate-release tablet 3 times daily. In cases of good therapeutic response, especially in hypertriglyceridemia, the dosage can be reduced to one 200 mg tablet twice daily. For patients with a history of gastric sensitivity, the dosage may be gradually increased to the maintenance level.

The dosage in patients with renal insufficiency/dialysis must be adjusted according to serum creatinine levels or creatinine clearance.

It should be taken into account that creatinine clearance is a more reliable parameter than serum creatinine (especially in the elderly). The creatinine clearance can be estimated using the following equation (Cockroft and Gault equation) which is applicable to adults only.

Availability And Storage: 200 mg: Each round, white, immediate-release film-coated tablet, printed on both sides: above BM, below G6, contains: bezafibrate 200 mg. Nonmedicinal ingredients: colloidal silicon dioxide, kaolin, lactose, macrogol 10 000, magnesium stearate, maize starch, microcrystalline cellulose, poly (ethylacrylate, methylmethacrylate), polysorbate 80, sodium citrate, sodium starch glycolate, talc and titanium dioxide. Blister packs of 90.

400 mg: 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, lactose, macrogol 10 000, magnesium stearate, poly (ethylacrylate, methylmethacrylate), polysorbate 80, poly-02-hydroxypropyl, 0-methyl cellulose, polyvidone K25, sodium citrate, sodium lauryl sulfate, talc and titanium dioxide. Blister packs of 30.

Store at room temperature (15 to 30°C). Protect from high humidity.

BEZALIP® Roche Bezafibrate Lipid Metabolism Regulator

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