Lopid (Gemfibrozil)

LOPID®

Parke-Davis

Gemfibrozil

Antihyperlipidemic Agent

Action And Clinical Pharmacology: Gemfibrozil is a lipid regulating agent which decreases serum triglycerides and total cholesterol, and increases high density lipoprotein cholesterol. The lipid-lowering changes occur primarily in the very low density lipoprotein (VLDL) fraction (Sf 20 to 400) rich in triglycerides and to a lesser extent in the low density lipoprotein (LDL) fraction (Sf0 to 20) rich in cholesterol. Gemfibrozil treatment of patients with elevated triglycerides due to Type IV hyperlipoproteinemia may cause a rise in LDL-cholesterol. In addition, gemfibrozil increases the high density lipoprotein (HDL) cholesterol subfractions, HDL2 and HDL3, as well as apolipoproteins Al and All.

Epidemiological studies have shown that both low HDL-cholesterol and high LDL-cholesterol are independent risk factors for coronary heart disease. Depending on the type of hyperlipidemia, pharmacological intervention with gemfibrozil raises HDL-cholesterol and may lower LDL-cholesterol, and may be associated with reduced morbidity due to coronary heart disease as reported in the Helsinki Heart Study, a 5 year primary prevention Phase IV clinical trial.

The mechanism of action has not been definitely established. In man, gemfibrozil has been shown to inhibit peripheral lipolysis and to decrease the hepatic extraction of free fatty acids, thus reducing hepatic triglyceride production. Gemfibrozil also inhibits the synthesis and increases clearance of VLDL carrier apolipoprotein B, leading to a decrease in VLDL.

Animal studies suggest that gemfibrozil may, in addition to elevating HDL cholesterol (HDL-C), reduce incorporation of long-chain fatty acids into newly formed triglycerides, accelerate turnover and removal of cholesterol from the liver, and increase excretion of cholesterol in the feces.

Indications And Clinical Uses: An adjunct to diet and other therapeutic measures for treatment of adult patients with very high serum triglyceride levels, Fredrickson classification Type IV and V hyperlipidemias, who are at high risk of sequelae and complications (i.e. pancreatitis) from their hyperlipidemia.

Treatment of patients with hypercholesterolemia, Type lla and llb mixed dyslipidemias, to regulate lipid levels (reduce serum triglycerides and LDL cholesterol levels and increase HDL cholesterol).

Gemfibrozil alone may not be adequate therapy in some patients with familial combined hyperlipidemia with Type llb and IV hyperlipoproteinemia.

Initial therapy for hyperlipidemia should include a specific diet, weight reduction, and an exercise program and for patients with diabetes mellitus, a good diabetic control.

Contra-Indications: Hepatic and renal dysfunction, including primary biliary cirrhosis; pre-existing gallbladder disease (see Precautions); hypersensitivity to gemfibrozil; the drug should not be used in pregnant or lactating patients; treatment of Type I hyperlipoproteinemia.

Manufacturers’ Warnings In Clinical States: Drug Interactions : When gemfibrozil and lovastatin were used concomitantly, there have been reports of severe myositis with markedly elevated creatine kinase (CK) and myoglobinuria (rhabdomyolysis). When myoglobinuria is severe, acute renal failure may ensue. Therefore, lovastatin should not be used concomitantly with gemfibrozil.

Caution should be exercised when anticoagulants are given in conjunction with gemfibrozil. The dosage of the anticoagulant should be reduced to maintain the prothrombin time at the desired level to prevent bleeding complications. Frequent prothrombin determinations are advisable until it has been definitely determined that the prothrombin level has stabilized.

Reduced bioavailability of gemfibrozil may result when given simultaneously with resin-granule drugs such as colestipol. Administration of the drugs 2 hours or more apart is recommended.

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

Long-term studies with gemfibrozil have been conducted in rats and mice at 1 and 10 times the human dose. The incidence of benign liver nodules and liver carcinomas was significantly increased in high dose male rats. The incidence of liver carcinomas was increased also in low dose males, but the increase was not statistically significant (p>0.05). In high dose female rats, there was a significant increase in the combined incidence of benign and malignant liver neoplasms. There were no statistically significant differences from controls in the incidence of liver tumors in male and female mice, but the doses tested were lower than those shown to be carcinogenic with other fibrates. Liver and testicular cell tumors were increased in male rats.

Electron microscopy studies have demonstrated a florid hepatic peroxisome proliferation following gemfibrozil administration to male rats. Such changes have not been found in the liver of patients treated with this drug.

Toxicology studies in male rats revealed a dose-related increase of benign Leydig cell tumors. Subcapsular bilateral cataracts occurred in 10% and unilateral in 6.3% of the high dose males.

Cholelithiasis: Gemfibrozil may increase cholesterol excretion into the bile leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Drug therapy should be discontinued if gallstones are found.

Since a reduction of total mortality has not been demonstrated, gemfibrozil should be administered only in those patients described in the Indications section. If a significant serum lipid response is not obtained in 3 months, gemfibrozil should be discontinued.

If gemfibrozil is chosen for treatment, the prescribing physicians should discuss the proposed therapy and inform the patient of the expected benefits and potential risks which may be associated with long-term administration (see Precautions).

Children: Safety and efficacy in children have not been established.

Pregnancy: Strict birth control procedures must be exercised by women of childbearing potential. If pregnancy occurs despite birth control procedures, gemfibrozil should be discontinued.

Women who are planning pregnancy should discontinue gemfibrozil several months prior to conception.

Lactation: Because of the potential for tumorigenicity shown for gemfibrozil in rats, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Precautions: Initial Therapy: Before instituting gemfibrozil therapy, attempts should be made to control serum lipids and lipoproteins with appropriate diet, exercise, weight loss in obese patients, and control of diabetes mellitus.

Long-term Therapy: Because long-term administration of gemfibrozil is recommended, pretreatment clinical chemistry studies should be performed to ensure that the patient has elevated serum lipid or low HDL cholesterol levels. Periodic determinations of serum lipids should be done during gemfibrozil administration, including measurement of LDL-cholesterol/HDL-cholesterol ratio, particularly in Type IV hyperlipoproteinemic patients.

Impairment of Fertility: Administration of approximately 3 and 10 times the human dose to male rats for 10 weeks resulted in a dose-related decrease of fertility. Subsequent studies demonstrated that this effect was reversed after a drug-free period of about 8 weeks, and it was not transmitted to their offspring.

Hematologic Changes: Mild hemoglobin, hematocrit and white cell decreases have been observed in occasional patients following initiation of gemfibrozil therapy. The levels then stabilize during long-term administration. Rarely, severe anemia, leukopenia, thrombocytopenia, eosinophilia and bone marrow hypoplasia have been reported. Therefore, periodic blood count determinations are recommended during the first 12 months of gemfibrozil administration.

Liver Function: Abnormal liver function tests have been observed occasionally during gemfibrozil administration, including elevations of AST, ALT, LDH, creatine kinase, bilirubin and alkaline phosphatase. These are usually reversible when the drug is discontinued. Therefore periodic liver function studies are recommended and gemfibrozil therapy should be terminated if abnormalities persist.

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

Cardiac Arrhythmias: Although no clinically significant abnormalities occurred that could be attributed to gemfibrozil, the possibility exists that such abnormalities may occur.

Adverse Reactions: Premarketing Studies: Gemfibrozil has been carefully evaluated in over 3 000 patients having received the drug in monitored clinical studies prior to marketing. Symptoms reporting during the controlled phase in studies of 805 subjects were considered for safety. The principal symptoms for which incidence was greater with gemfibrozil than with placebo involved the gastrointestinal system. Nausea and vomiting, and abdominal and epigastric pain occurred more often in the gemfibrozil group than in the placebo group. However, the incidence was low: nausea, 4.3% with gemfibrozil versus 3.8% with placebo; vomiting, 2.3% versus 0.8%; abdominal pain, 6.4% versus 4.2%; and epigastric pain, 3.4% versus 1.7%.

Additional adverse reactions that have been reported, where a causal relationship to treatment with gemfibrozil is probable, are:

Gastrointestinal: cholestatic jaundice, pancreatitis. CNS: somnolence, peripheral neuritis, depression, decreased libido. Genitourinary: impotence. Musculoskeletal: arthralgia, synovitis, myalgia, myopathy, myasthenia, rhabdomyolysis (see Warnings, Drug Interactions). Integumentary: exfoliative dermatitis, photosensitivity. Immune: angioedema, laryngeal edema.

Postmarketing Study (Helsinki Heart Study): The long-term safety of gemfibrozil was established in the Helsinki Heart Study, a 5-year primary prevention Phase IV clinical trial. In the double-blind phase of the Helsinki Heart Study, 2 046 patients received gemfibrozil for up to 5 years. Dyspepsia, abdominal pain, acute appendicitis and atrial fibrillation occurred more often in the gemfibrozil group than the placebo group, while all other adverse events were similar in frequency between the two groups.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Overdosage has been reported with gemfibrozil. In 1 case of accidental overdosage, where a child ingested 9 g of gemfibrozil, nonspecific symptoms of nausea and vomitting were reported. The patient fully recovered.

Symptomatic supportive measures should be taken should overdosage occur.

Dosage: Adults: The recommended dose is 1 200 mg administered in 2 divided doses (two 300 mg capsules or one 600 mg tablet twice a day) 30 minutes before the morning and evening meal. The maximum recommended daily dose is 1 500 mg.

Availability And Storage: 300 mg: Each maroon and white capsule contains: gemfibrozil 300 mg. Nonmedicinal ingredients: Capsule: cornstarch, polysorbate 80 and silica gel. Capsule shell: contains: colloidal silicon dioxide, FD&C Blue No. 1, FD&C Red No. 3, gelatin, sodium lauryl sulfate and titanium dioxide. Energy: 3.4 kJ (0.8 kcal). Gluten-, lactose-, paraben-, sodium-, sulfite- and tartrazine-free. Bottles of 100 and 250.

600 mg: Each white, ellipsoidal, film-coated tablet, imprinted “Lopid 600 mg” on one side and “Parke-Davis” on the other, contains: gemfibrozil 600 mg. Nonmedicinal ingredients: calcium stearate, candelilla wax, colloidal silicon dioxide, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylparaben, microcrystalline cellulose, Opacode Black, polyethylene glycol, polysorbate 80, pregelatinized starch, propylparaben and titanium dioxide. Energy: 2.0 kJ (0.47 kcal). Gluten-, lactose-, paraben-, sodium-, sulfite- and tartrazine-free. Bottles of 100 and 250.

Store below 30°C. (Shown in Product Recognition Section)

LOPID® Parke-Davis Gemfibrozil Antihyperlipidemic Agent

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