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An overview of LOPID (gemfibrozil), a lipid-regulating agent used to decrease triglycerides and total cholesterol, and increase HDL cholesterol. It covers the pharmacological classification, actions, indications and clinical use, precautions, drug interactions, and adverse reactions of gemfibrozil. Animal and human studies are discussed, including the Helsinki Heart Study.
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Pr (^) LOPID ®
Gemfibrozil Capsules USP Gemfibrozil Tablets USP 300 mg Capsules & 600 mg Tablets
® (^) Warner-Lambert Company DATE OF REVISION:
Pfizer Canada Inc. Licensee January 22, 2010 17 300 Trans-Canada Highway Kirkland, Quebec H9J 2M
Pfizer Canada Inc. 2009
Control# 131842
Gemfibrozil Capsules USP Gemfibrozil Tablets USP 300 mg Capsules & 600 mg Tablets
Antihyperlipidemic Agent
LOPID (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 (Sf20-400) rich in triglycerides and to a lesser extent in the low density lipoprotein (LDL) fraction (Sf 0-20) rich in cholesterol. LOPID treatment of patients with elevated triglycerides due to Type IV hyperlipoproteinemia may cause a rise in LDL-cholesterol. In addition, LOPID increases the high density lipoprotein (HDL) cholesterol subfractions, HDL 2 and HDL 3 , as well as apolipoproteins AI and AII.
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 LOPID 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 (N. Engl. J. Med. 317:1237-1245, 1987).
The mechanism of action has not been definitely established. In man, LOPID has been shown to inhibit peripheral lipolysis and to decrease the hepatic extraction of free fatty acids, thus reducing hepatic triglyceride production. LOPID also inhibits the synthesis and increases clearance of VLDL carrier apolipoprotein B, leading to a decrease in VLDL.
Muscle Effects: There have been reports of severe myalgia myositis and rhabdomyolysis accompanied by markedly elevated creatinine kinase when gemfibrozil and HMG CoA reductase inhibitors were used concomitantly. (see PRECAUTIONS Drug Interactions). When rhabdomyolysis is severe the ensuing myoglobinuria can lead to acute renal failure. Therefore HMG CoA reductase inhibitors should not be used concomitantly with LOPID
Myopathy, defined as muscle aching or muscle weakness, associated with increases in plasma creatine phopsphokinase (CPK) values to greater than 10 times the Upper Limit of Normal (ULN), should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. The risk of myopathy and rhabdomyolosis during treatment with HMG CoA reductase inhibitors in combination with fibric acid derivatives is increased. The benefits and risks of combined therapy should be carefully considered (see PRECAUTIONS, Drug Interactions).
Rhabdomyolysis with renal dysfunction secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors. Gemfibrozil therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Gemfibrozil should be temporarily withheld in any patient experiencing an acute or serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine or electrolyte disorders; or uncontrolled epilepsy.
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.
If LOPID is chosen for treatment, the prescribing physician 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 )
Anticoagulants: Caution should be exercised when anticoagulants are given in conjunction with LOPID. 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.
Bile Acid-Binding Resins: Reduced bioavailability of LOPID may result when given simultaneously with resin-granule drugs such as colestipol. Administration of the drugs two hours or more apart is recommended.
HMG-CoA reductase inhibitors: There have been reports of severe myalgia, myositis and rhabdomyolysis accompanied by markedly elevated creatine kinase (CK) when gemfibrozil and HMG-CoA reductase inhibitors, were used concomitantly. When rhabdomyolysis is severe the ensuing myoglobinuria can lead to acute renal failure. Therefore, HMG-CoA reductase inhibitors should not be used concomitantly with LOPID (see WARNINGS, Muscle Effects).
Repaglinide: Serious cases of hypoglycemia have been reported following the concomitant use of repaglinide and gemfibrozil. This is likely due to inhibition of CYP 2C8 by gemfibrozil as evidenced by decreases in blood glucose that were proportional to the dose of gemfibrozil. In healthy volunteers, the levels of repaglinide were significantly increased when co-
administered with gemfibrozil. The averaged area under the curve (AUC) was increased 8- fold (range 6- to 15 fold) and the half-life increased 3 fold. When itraconazole, an inhibitor of CYP 3A4, was also given with gemfibrozil and repaglinide, even greater effects were observed: AUC for repaglinide was increased 19-fold and the half-life increased from 1.3 to 6 hours. (see CONTRAINDICATIONS ).
CYP2C8 inhibition by gemfibrozil can affect the metabolism of several major cardiovascular drugs such as amiodarone, verapamil, warfarin but also other drugs such as tolbutamide.
Gemfibrozil is also known to potently inhibit CYP2C9 activity. Therefore, CYP2C inhibition by gemfibrozil can affect the metabolism of several major cardiovascular drugs such as carvedilol and losartan but also other drugs such as phenytoin and diazepam (see CLINICAL PHARMACOLOGY AND PHARMACOKINETICS ).
Table 1. Incidence of Symptoms Reported in Controlled Pre-Marketing Studies
Symptom Gemfibrozil (n = 529)
Placebo (n = 236)
BODY AS A WHOLE Dizziness Chest pain Fatigue
Rash Pruritis Dermatitis Urticaria
Pain in extremities 1.5% 1.7% GASTROINTESTINAL Abdominal pain Diarrhea Nausea Epigastric pain Vomiting Flatulence
Gout 0.9% 0.8% CENTRAL NERVOUS SYSTEM Headache Paresthesia
Blurred vision 1.1% 0.8%
Number of Patients Withdrawn for Clinical Symptoms
Additional adverse reactions that have been reported, where a causal relationship to treatment with gemfibrozil is probable, are:
Hepatobiliary disorders Cholestatic jaundice Gastrointestinal disorders: Pancreatitis Nervous System disorders Dizziness, somnolence, paresthesia, peripheral neuritis, headache Psychiatric disorders: Decreased libido, depression Eye disorder: Blurred vision Reproductive system and Breast disorders: Impotence Musculoskeletal and connective tissue disorders Arthralgia, synovitis, myalgia, myopathy, myasthenia, painful extremities, rhabdomyolysis (See WARNINGS : Drug Interactions) Skin and subcutaneous tissue disorders: Exfoliative dermatitis, rash, dermatitis, pruritus, angioedema, urticaria, photosensitivity Respiratory, thoracic and mediastinal disorders Laryngeal edema Blood and lymphatic system disorders: Severe anemia, leukopenia, thrombocytopenia, eosinophilia, bone marrow hypoplasia (see PRECAUTIONS - Hematologic Changes )
Additional adverse reactions that have been reported included photosensitivity, alopecia, cholecystitis and cholelithiasis (see WARNINGS ).
(ii) Post-Marketing Study (Helsinki Heart Study):
The long-term safety of LOPID (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 LOPID for up to 5 years. Table 2 lists the most frequently reported adverse events and includes those occurring in at least 1% of all subjects treated with gemfibrozil. Dyspepsia (19.6% versus 11.9%), abdominal pain (9.8% versus 5.6%), acute appendicitis (1.2% versus 0.6%) and atrial fibrillation (0.7% versus 0.1%) occurred more often in the gemfibrozil group than the placebo group, while all other adverse events were similar in frequency between the two groups.
Table 2. Incidence of Adverse Events in Controlled Phase of Helsinki Heart Study Gemfibrozil Placebo
Overdosage has been reported with gemfibrozil. Symptoms reported with overdosage were abdominal cramps, abnormal liver function tests, diarrhea, increased CPK, joint and muscle pain, nausea and vomiting. In one case of accidental overdosage, where a child ingested 9 g of gemfibrozil, non-specific symptoms of nausea and vomiting were reported. The patient fully recovered.
Symptomatic supportive measures should be taken should overdosage occur.
For management of a suspected drug overdose, contact your regional Poison Control Centre.
The recommended dose for adults is 1200 mg administered in two 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 1500 mg.
Drug Substance
PROPER NAME : Gemfibrozil CHEMICAL NAME : 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid STRUCTURAL FORMULA:
DESCRIPTION: Gemfibrozil is a nonhalogenated phenoxypentanoic acid. It is a white, waxy powder which is stable under ordinary conditions.
The melting point is 58-61o^ C. Its solubility is 0.0019% (w/v) in water and in acid and over 1% in dilute base.
The mechanism by which these actions occur has not been firmly established. Additional studies in rats suggest that gemfibrozil inhibits the incorporation of long-chain fatty acids into newly formed triglycerides and inhibits basal adipose tissue lipolysis. Gemfibrozil also inhibits the production and increases the turnover rate of the beta-apolipoprotein moiety of VLDL, the resulting decrease in VLDL production providing the basis for the drug's ability to reduce lipid levels.
Gemfibrozil has no significant cardiovascular or central nervous system activity.
Gemfibrozil (LOPID) is well absorbed from the gastrointestinal tract following oral administration to laboratory animals and humans.
In animals, gemfibrozil is excreted in both urine and feces. In rats and dogs, the major route of excretion is fecal, accounting for 47% and 62% of a given dose in the two species, respectively. In monkeys, urinary excretion predominates, 62% of an administered dose being excreted by that route in four days; fecal excretion accounted for only 2% of the dose.
In human subjects, approximately 70% of a given dose is excreted in the urine, primarily as the glucuronide conjugate, with less than 2% excreted as unchanged gemfibrozil; 6% of the dose is accounted for in the feces. Peak plasma levels occur in one to two hours following single doses. The mean half-life was approximately 1.5 hours following single doses and 1.3 hours following multiple doses. Plasma levels appear proportional to dose and do not demonstrate accumulation across time following multiple doses.
Three metabolic pathways have been identified. The first metabolic pathway is that of conjugation of gemfibrozil and its metabolites. The second, and presumably the principal route, involves hydroxylation of the meta-methyl group of gemfibrozil, yielding a benzyl alcohol (Metabolite II) that undergoes rapid oxidation to a benzoic acid metabolite (Metabolite III, the major metabolite). The third pathway involves hydroxylation of the aromatic ring to a phenol (Metabolite I) which is further converted to a compound (Metabolite IV) with no intact carboxylic acid function, but which is phenolic in nature.
CYP2C8 inhibition by gemfibrozil can affect the metabolism of several major cardiovascular drugs such as amiodarone, verapamil, warfarin but also other drugs such as tolbutamide.
Gemfibrozil is also known to potently inhibit CYP2C9 activity. Therefore, CYP2C9 inhibition by gemfibrozil can affect the metabolism of several major cardiovascular drugs such as carvedilol and losartan but also other drugs such as phenytoin and diazepam (see PRECAUTIONS - Drug Interactions).
Gemfibrozil is completely absorbed after oral administration, reaching peak plasma concentrations one to two hours after dosing. Gemfibrozil pharmacokinetics are affected by the timing of meals relative to time of dosing. In one study, both the rate and extent of absorption of the drug were significantly increased when administered 0.5 hour before meals. Average Area Under the Curve (AUC) was reduced by 14 to 44% when gemfibrozil was administered after meals compared to 0. hour before meals. In a subsequent study, rate of absorption of gemfibrozil was maximum when administered 0.5 hour before meals with the Cmax 50-60% greater than when given either with meals or fasting. In this study, there were no significant effects on AUC of timing of dose relative to meals.
Gemfibrozil is highly bound to plasma proteins and there is potential for displacement interactions with other drugs.
Following the controlled phase of the multicentre trial, 349 subjects entered a long-term open treatment phase with gemfibrozil. Total cholesterol, triglycerides and total LDL-cholesterol levels consistently remained below the baseline placebo values throughout the long-term trial. HDL- cholesterol and the HDL-cholesterol to total cholesterol ratio both consistently remained above the placebo baseline values during the long-term trial. By the end of 12 lunar months of treatment, the improvement in lipid values had increased for nearly every parameter. The greatest changes during the long-term treatment were observed in total cholesterol, LDL-cholesterol, total LDL-cholesterol, and HDL-cholesterol to total cholesterol ratio. These results indicate that the improvement achieved during the control period was maintained or increased during the long-term trial.
Gemfibrozil versus Clofibrate
The lipid regulating effect of gemfibrozil was also studied against clofibrate. In a study of 32 patients with type IIa, IIb or type IV hyperlipidemia, 17 patients were treated with gemfibrozil, 1200 mg per day, and 15 patients with clofibrate, 2000 mg per day, for 18 weeks. The two drugs had similar effects on total plasma cholesterol, triglycerides and LDL-cholesterol levels, but gemfibrozil had significantly greater effect in elevating HDL-cholesterol and HDL/total cholesterol ratios. The mean percent increases in HDL-cholesterol levels were 22.4% with gemfibrozil and 8.6% with clofibrate, while the HDL/total cholesterol ratio increased 43.0% with gemfibrozil and 25.9% with clofibrate.
Primary-Prevention Trial (Helsinki Heart Study)
The Helsinki Heart Study investigated the effect of LOPID (gemfibrozil) on the incidence of coronary heart disease (CHD) in a randomized, double-blind, five-year trial in middle-aged men ( to 55 years of age) who were free of coronary heart symptoms on entry, but were at a high risk because of abnormal levels of blood lipids (i.e. non-HDL-cholesterol > 200 mg/dl). The study was aimed at testing the hypothesis that reducing serum total cholesterol and LDL-cholesterol, and increasing HDL-cholesterol with gemfibrozil would reduce the incidence of cardiac disease. One group of men (2,046) received 1200 mg (600 mg b.i.d.) of gemfibrozil per day and another group (2,035) received placebo. In terms of Fredrickson types, the subjects entered into the study were distributed as follows:
Treatment Group Fredrickson Type Total Number Type IIa Type IIb Type IV Type V
LOPID 1293 570 182 1 2046 Placebo 1297 561 177 0 2035
Serum lipids (i.e. total triglycerides, total cholesterol, LDL-cholesterol and HDL cholesterol) were measured periodically during the study. Efficacy of treatment was determined by comparing the incidence of cardiovascular endpoints (i.e. fatal and nonfatal myocardial infarction, sudden and unwitnessed cardiac death) on an intent-to-treat basis.
Gemfibrozil caused a marked change in the serum lipid levels of patients. The lipid changes occurred rapidly, being noted during the first 3-months of treatment and persisted over the 5-year treatment period. The percent changes in serum lipid levels of the gemfibrozil group by Fredrickson type averaged across the 5-year study period relative to baseline are shown in the following table:
% Change From Baseline in Gemfibrozil Group Over 5-Year Period
Serum Lipid Parameter Type IIa (n = 1293)
Type IIb (n = 570)
Type IV (n = 182)
All Subjects^1 (2046)
Triglycerides -26.3% -44.3% -49.9% -37.3% Total Cholesterol -9.2% -8.6% -5.0% -8.7%
LDL-Cholesterol (^) -11.4% -4.1% +4.8% -8.2%
HDL-Cholesterol +8.5% +11.7% +9.6% +9.0% Non-HDL-Cholesterol -13.5% -12.4% -7.8% -12.5% (^1) One subject was a Fredrickson Type V.
