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PURACAP LABORAT
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gemfibrozil 600 mg tablet

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Uses

Prevention of Cardiovascular Events

Primary Prevention

Gemfibrozil is used to reduce the risk of developing coronary heart disease (CHD) in patients with type IIb hyperlipoproteinemia without clinical evidence of CHD (primary prevention) who have an inadequate response to dietary management, weight loss, exercise, and drugs known to reduce low-density lipoprotein (LDL)-cholesterol and increase high-density lipoprotein (HDL)-cholesterol (e.g., bile acid sequestrants) and who have low HDL-cholesterol concentrations in addition to elevated LDL-cholesterol and triglyceride concentrations. Although gemfibrozil has been used effectively in patients with types IIa and IIb hyperlipoproteinemia to decrease elevated total or LDL-cholesterol concentrations, the drug appears to be more effective in reducing the incidence of serious coronary events in patients with type IIb hyperlipoproteinemia who have elevations of both LDL-cholesterol and triglyceride concentrations. Therefore, the manufacturers state that because of potential toxicity, including malignancy, gallbladder disease, abdominal pain leading to appendectomy and other abdominal surgeries, and an increased incidence of noncardiovascular and all-cause mortality associated with the chemically and pharmacologically similar drug, clofibrate (no longer commercially available in the US), the potential benefit of gemfibrozil in treating patients with type IIa hyperlipoproteinemia and elevations of LDL-cholesterol only is unlikely to outweigh the risks of such therapy.(See Cautions: Precautions and Contraindications.) Gemfibrozil is not indicated for use in the management of patients with low HDL-cholesterol as their only lipid abnormality (isolated low HDL-cholesterol).

The American College of Cardiology (ACC)/American Heart Association (AHA) guideline for management of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults states that nondrug therapies (i.e., lifestyle modifications), which include adherence to a heart-healthy diet, regular exercise, avoidance of tobacco products, and maintenance of a healthy weight, are the foundation of atherosclerotic cardiovascular disease (ASCVD) prevention. For additional details on lifestyle modifications, consult the most recent AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk (available at http://www.cardiosource.org or http://my.americanheart.org).

The ACC/AHA cholesterol management guideline states that nonstatin therapies (e.g., fibric acid derivatives) do not provide acceptable ASCVD risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD. The guideline states that nonstatin drugs may be useful as adjuncts to statin therapy in certain high-risk patients (e.g., patients with ASCVD, patients with LDL-cholesterol concentrations of 190 mg/dL or higher, patients with diabetes mellitus) who have a less-than-anticipated response to statins, are unable to tolerate even a less-than-recommended intensity of a statin, or are completely intolerant to statin therapy. When combination therapy with a fibric acid derivative and statin is required, fenofibrate is considered the drug of choice; gemfibrozil should not be used in combination with statin therapy because of an increased risk of adverse muscle effects and rhabdomyolysis. However, it should be noted that the addition of fenofibrate to simvastatin therapy in patients with diabetes mellitus has not been shown to substantially reduce the rate of major adverse cardiovascular events compared with statin monotherapy. For additional details on prevention of ASCVD, and also consult the most recent ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (available at http://www.cardiosource.org or http://my.americanheart.org).

In the Helsinki Heart Study (a large, multicenter, placebo-controlled study), long-term (up to 5 years) gemfibrozil (1200 mg daily) therapy in asymptomatic males with elevated pretreatment LDL- and/or VLDL-cholesterol concentrations (primary dyslipidemia, including types IIa, IIb, and IV hyperlipoproteinemia) who received dietary management was shown to reduce the risk of CHD. Average serum concentrations of total, LDL-, and non-HDL-cholesterol and triglycerides were decreased and HDL-cholesterol was increased in patients in this study and such changes were associated with a 34% reduction in CHD-associated end points (mainly fatal or nonfatal myocardial infarction and other death attributable to CHD), a 37% reduction in nonfatal myocardial infarction, and a 26% reduction in definite coronary death; however, overall mortality rate was similar for the gemfibrozil-treated and placebo groups. Subsequent analysis revealed that gemfibrozil therapy was associated with a substantial reduction in Q-wave but not non-Q-wave myocardial infarction. Subsequent detailed analyses of the serum lipid alterations in patients in the Helsinki Heart Study also indicated that reductions in LDL-cholesterol or increases in HDL-cholesterol were independently associated with reductions in coronary heart disease risk, while reductions in triglyceride concentrations had relatively little effect on CHD incidence. In a proportional hazards analysis in which risk factors such as age, blood pressure, smoking and drinking habits, baseline lipid concentrations, exercise, and relative weight were controlled, estimated reductions in CHD incidence of 23% or 15% were associated with mean HDL-cholesterol increases of 8% or mean LDL-cholesterol reductions of 7%, respectively, for the 2-year period immediately preceding a CHD end point. Reductions in the incidence of CHD-associated end points compared with placebo were observed among gemfibrozil-treated patients of all 3 lipoprotein types. However, reductions were greatest in patients with type IIb hyperlipoproteinemia and smallest in those with type IIa hyperlipoproteinemia; the number of CHD end points in patients with type IV hyperlipoproteinemia was insufficient for analysis. Substantial changes in triglyceride concentrations (mean reduction: 35%) in patients receiving gemfibrozil in this study had only a small effect (not statistically significant) on CHD incidence. While there is epidemiologic evidence to suggest that each 1-mg/dL increase in HDL-cholesterol may be associated with a 2-4% reduction in the incidence of CHD, it remains to be established whether HDL or one of its subfractions is responsible for protection against CHD or whether such protection is indirectly related to the relationship of HDL to other CHD risk factors such as obesity, smoking, exercise, or alcohol consumption.

Secondary Prevention

Gemfibrozil has been used in men with clinical evidence of CHD who have low HDL-cholesterol and moderately elevated LDL-cholesterol concentrations to reduce the risk of recurrent coronary events (secondary prevention), including death from coronary causes, myocardial infarction, and stroke. In the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) in men with a history of CHD (e.g., myocardial infarction), low HDL-cholesterol concentrations (40 mg/dL or less), and moderately elevated LDL-cholesterol concentrations (140 mg/dL or less), therapy with gemfibrozil (1200 mg daily) was associated with a 22% reduction in CHD mortality or nonfatal myocardial infarction compared with placebo. Therapy with gemfibrozil also reduced the risk of stroke by 25%.

Hyperlipoproteinemia

Gemfibrozil is used as an adjunct to dietary therapy for the management of severe hypertriglyceridemia in patients at risk of developing pancreatitis (typically those with serum triglyceride concentrations exceeding 2000 mg/dL and elevated concentrations of VLDL and fasting chylomicrons) who do not respond adequately to dietary management. Gemfibrozil also may be used in patients with triglyceride concentrations of 1000-2000 mg/dL who have a history of pancreatitis or of recurrent abdominal pain typical of pancreatitis; however, efficacy of the drug in patients with type IV hyperlipoproteinemia and triglyceride concentrations less than 1000 mg/dL who exhibit type V patterns subsequent to dietary or alcoholic indiscretion has not been adequately studied. The manufacturer states that gemfibrozil is not indicated for use in patients with type I hyperlipoproteinemia who have elevated triglyceride and chylomicron concentrations but normal VLDL-cholesterol concentrations.

The Third Report of the National Cholesterol Education Program (NCEP) (Adult Treatment Panel [ATP] III) stated that initiation of therapy and target goals in the management of hypertriglyceridemia depend on initial risk status and preexisting triglyceride concentrations. As in primary or secondary prevention of CHD, LDL-cholesterol is considered the primary target of therapy in most patients with borderline high (150-199 mg/dL) or high (200-499 mg/dL) triglyceride concentrations; in those with high triglyceride concentrations, non-HDL-cholesterol (sum of VLDL-cholesterol plus LDL-cholesterol, calculated as total cholesterol minus HDL-cholesterol) becomes a secondary target of therapy. The principal aim of therapy in patients with very high triglyceride concentrations (500 mg/dL or greater) is to prevent acute pancreatitis through triglyceride lowering; principal and secondary targets similar to those used in patients with borderline high or high triglycerides may be considered in these patients when triglyceride levels are reduced to less than 500 mg/dL.

ATP III stated that nondrug therapies and measures (i.e., weight reduction, increased physical activity, smoking cessation, restriction of excessive alcohol use, avoidance of high-carbohydrate [more than 60% of calories] diets) are considered the initial treatments of choice in the management of patients with borderline high or high triglyceride concentrations. Drug therapy, in addition to nonpharmacologic measures, also may be considered (after LDL-lowering therapy) in patients with high triglyceride concentrations to achieve the non-HDL-cholesterol goal. In these patients, ATP III recommended one of several options: intensifying therapy with an LDL-lowering drug (i.e., statin), initiating therapy with a triglyceride-lowering drug (i.e., fibric acid derivative or, preferably, niacin), or combining moderate doses of statins and triglyceride-lowering drugs. AHA states that although statins have consistently shown benefit in subgroups with or without high triglyceride concentrations, fibric acid derivatives have more commonly been shown to provide greater benefit in subgroups with increased triglyceride concentrations. Concomitant use with a fibric acid derivative (i.e., fenofibrate) requires reduction in the daily dosage of the statin and should be used with extreme caution to minimize the potential risk of myopathy and/or rhabdomyolysis. In addition, such combined regimens generally should be avoided in geriatric patients, in patients with acute or serious chronic illnesses (especially chronic renal disease), in those undergoing surgery, and in patients receiving certain interacting medications. (See Cautions: Precautions and Contraindications and see Drug Interactions: HMG-CoA Reductase Inhibitors [Statins].)

Patients with very high triglyceride concentrations should be treated more intensively to prevent development of acute pancreatitis. However, before initiating antilipemic therapy, patients with triglyceride concentrations of 500 mg/dL or greater should be evaluated to rule out secondary causes of hyperlipidemia. ATP III recommended elimination of alcohol from diet and identification and, preferably, discontinuance of drugs that increase triglyceride concentrations. In addition, insulin or oral antidiabetic therapy may be initiated (or dosage increased) in patients with hyperglycemia. In patients with triglyceride concentrations exceeding 1000 mg/dL, a very low-fat diet (less than 15% of total daily calories as fat) should be initiated immediately to improve chylomicronemia that contributes to hypertriglyceridemia. Weight reduction and increased physical activity as components of lifestyle modifications should be emphasized. Pharmacologic therapy with triglyceride-lowering drugs (i.e., niacin or, preferably, a fibric acid derivative) usually is required in patients with very high triglyceride concentrations and often can prevent acute pancreatitis. Because niacin may worsen hyperglycemia (and thus increase triglyceride concentrations), high doses (greater than 2 g daily) of the drug generally should be used with caution in patients with elevated serum glucose concentrations. For most patients with very high triglyceride concentrations, therapy is considered successful if triglyceride concentrations are reduced to less than 500 mg/dL; triglyceride concentrations often cannot be normalized in these patients. The principal aim of therapy is to prevent acute pancreatitis; efforts to modify CHD risk (by lowering LDL- and/or non-HDL-cholesterol concentrations) may be considered once triglyceride concentrations have been reduced to less than 500 mg/dL.

The AHA and some clinicians recommend that therapy with a fibric acid derivative or niacin be considered in patients with type III hyperlipoproteinemia in whom hyperlipidemia persists despite weight control; restricted intake of total fats, saturated fatty acids, and cholesterol; and an appropriate program of physical activity.

Patients with very high triglyceride and chylomicron concentrations usually have a genetic form of the disease and generally are unresponsive to triglyceride-lowering drugs. Treatment for these patients includes very low-fat diets, which may be supplemented with medium-chain triglycerides to minimize production of chylomicrons.

Several studies have compared the efficacy of gemfibrozil and clofibrate in hyperlipoproteinemia. Studies in patients with type IIa, IIb, or IV hyperlipoproteinemia comparing 400 mg of gemfibrozil twice daily (200-mg capsules were used in initial drug trials) with 750 mg of clofibrate twice daily showed that these drugs were equally effective in decreasing serum cholesterol and triglyceride concentrations. Other studies in healthy males and patients with types IIa, IIb, and IV hyperlipoproteinemia indicate that 600 mg of gemfibrozil twice daily or 1 g of clofibrate twice daily produces similar decreases in serum cholesterol and triglycerides. A gemfibrozil dosage of 1.6 g daily produces a greater decrease in total serum triglyceride and VLDL-triglyceride concentrations and a greater increase in HDL-cholesterol than does 2 g of clofibrate daily. Some patients who do not have an adequate therapeutic response to gemfibrozil may respond to clofibrate and vice versa. However, some patients with type IIa, IIb, or IV hyperlipoproteinemia may not respond adequately to either drug even when dosage is increased. Studies that adequately compare gemfibrozil with niacin, probucol (no longer commercially available in the US), or bile acid sequestrants such as cholestyramine are limited.

Other Uses

Gemfibrozil has been used effectively in a very limited number of patients with type III hyperlipoproteinemia to decrease elevated triglyceride and cholesterol concentrations associated with this disorder.

Because therapy with gemfibrozil or other antilipemic agents (i.e., bile acid sequestrants, statins, niacin) has been shown to reduce mortality and nonfatal coronary events (e.g., myocardial infarction) in patients with or without CHD who have normal or elevated cholesterol concentrations, ACC and AHA currently recommend initiation of antilipemic therapy in combination with aspirin, nitrates, and β-adrenergic blockers for the management of chronic stable angina in patients with documented or suspected CHD who have LDL-cholesterol concentrations greater than 130 mg/dL. The ACC and AHA state that the decision to initiate antilipemic therapy in patients with CHD and LDL-cholesterol concentrations of 100-129 mg/dL must be individualized based on clinical judgment of the risks and benefit of such therapy.

For further information on the role of antilipemic therapy in the treatment of lipoprotein disorders, the prevention of cardiovascular events, and other conditions, see General Principles of Antilipemic Therapy in the HMG-CoA Reductase Inhibitors General Statement 24:06.08.

Dosage and Administration

Administration

Gemfibrozil is administered orally, 30 minutes before the morning and evening meals.

Dosage

Dosage of gemfibrozil must be carefully adjusted according to individual requirements and response. Serum lipoprotein concentrations should be determined regularly during gemfibrozil therapy.(See Cautions: Precautions and Contraindications.)

For the management of hypertriglyceridemia or other hyperlipoproteinemias, the usual adult dosage of gemfibrozil is 600 mg twice daily. The drug should be discontinued after 3 months if serum lipoprotein concentrations do not improve substantially.

Cautions

Adverse effects of gemfibrozil are infrequent and generally mild; however, because of the chemical, pharmacologic, and clinical similarities between clofibrate (no longer commercially available in the US) and gemfibrozil, the possibility that gemfibrozil may share the toxic potentials of clofibrate should be considered.(See Cautions: Precautions and Contraindications.)

GI Effects

The most frequent adverse effects of gemfibrozil involve the GI tract and occasionally may be severe enough to require discontinuance of the drug. Abdominal pain (and, in some instances, acute appendicitis) and epigastric pain or dyspepsia are common adverse GI effects reported with gemfibrozil. Nausea, vomiting, diarrhea, constipation, and flatulence occur less frequently; cholestatic jaundice also has been reported. Dry mouth, anorexia and/or weight loss, gas pain, pancreatitis, colitis, and heartburn have also been reported in patients receiving gemfibrozil but have not been directly attributed to the drug.

Nervous System Effects

Headache, dizziness, drowsiness or somnolence, blurred vision, paresthesia, hypesthesia, taste perversion, peripheral neuritis, mental depression, and impotence and decreased libido have been reported in patients receiving gemfibrozil. Although a causal relationship has not been established, vertigo, syncope, insomnia, asthenia, chills, psychic problems, fatigue, confusion, and seizures have also occurred in patients receiving the drug.

Hematologic Effects

Slight decreases in hemoglobin and hematocrit and in leukocyte count have occurred in a few patients receiving gemfibrozil; these levels stabilize during long-term administration. Eosinophilia has also been reported. The drug may also affect blood coagulation.(See Pharmacology: Blood Coagulation and see Drug Interactions: Oral Anticoagulants.) Severe anemia, leukopenia, thrombocytopenia, and bone marrow hypoplasia reportedly have occurred rarely in patients receiving gemfibrozil. Therefore, the manufacturer recommends that blood cell counts be monitored periodically during the first 12 months of therapy.

Cholelithiasis

Gemfibrozil may increase cholesterol excretion in bile, resulting in cholelithiasis. Cholecystitis and cholelithiasis have been reported with gemfibrozil therapy. If gallbladder studies indicate gallstones are present, gemfibrozil should be discontinued.(See Cautions: Precautions and Contraindications.) In one study, gallstones developed in about 1% of hyperlipoproteinemic patients receiving gemfibrozil for 1 year. In a large, long-term (up to 5 years), placebo-controlled study, the number of gallstone operations was slightly (but not statistically significantly) higher in patients receiving gemfibrozil compared with placebo, and the number of all GI operations (including hemorrhoidectomies) was substantially higher in patients receiving the drug. Further prospective clinical studies in patients with hyperlipoproteinemia are required to determine whether gemfibrozil, like clofibrate, is associated with an increased incidence of gallstones and whether the risk of developing cholelithiasis is similar to that associated with clofibrate use. It should be kept in mind that any drug that reduces serum cholesterol by promoting biliary cholesterol excretion may increase (in varying degrees) biliary cholesterol saturation, which is one factor in the formation of gallstones.

Other Adverse Effects

Atrial fibrillation has been reported infrequently with gemfibrozil therapy. Rash (occasionally with eosinophilia), dermatitis (including exfoliative dermatitis) circumscribed exanthema, eczema, exacerbation of psoriasis, pruritus, urticaria, angioedema, laryngeal edema, myasthenia, and painful extremities also have occurred in patients receiving gemfibrozil.

When compared with placebo in some studies, gemfibrozil has caused slight increases in fasting blood glucose concentration and decreased glucose tolerance in patients without diabetes mellitus. Other studies, however, indicated there was no change in fasting blood glucose concentration or glucose tolerance. Blood glucose concentrations should be monitored periodically during gemfibrozil therapy since they may increase slightly in some patients. Patients with diabetes mellitus who are receiving insulin or oral antidiabetic agents (e.g., chlorpropamide, glyburide) may require some increase in insulin or oral antidiabetic agent dosage when gemfibrozil therapy is initiated.

Viral and bacterial infections (e.g., common cold, cough, and urinary tract infections) were more common in patients receiving gemfibrozil during clinical trials than in those receiving placebo, but these adverse effects have not been directly attributed to the drug. Gemfibrozil has not been reported to date to cause the acute flu-like muscular syndrome that has occurred with clofibrate mainly in patients with nephrotic syndrome and in uremic patients with chronic renal failure; however, myopathy and/or fatal or nonfatal rhabdomyolysis has occurred in patients receiving gemfibrozil concomitantly with certain statins (e.g., cerivastatin [no longer commercially available], lovastatin).(See Cautions: Precautions and Contraindications.) Back and neck pain, arthralgia, bursitis, muscle cramps, myalgia, swollen joints or synovitis, myositis, and gout also have occurred in patients receiving gemfibrozil. Impotence, chest pain, and liver function test abnormalities such as increased AST, ALT, LDH, creatine kinase (CK, creatine phosphokinase, CPK), bilirubin, and alkaline phosphatase also have occurred in patients receiving the drug. Liver function test abnormalities usually return to baseline when the drug is discontinued. Positive antinuclear antibody reactions have been associated with gemfibrozil therapy but have not been directly attributed to the drug.

In male rats receiving high-dose gemfibrozil, subcapsular bilateral cataracts occurred in 10% and unilateral cataracts occurred in 6.3%, but the relevance of these findings to humans is not known. Although a causal relationship has not been established, the number of ocular operations (mainly cataract surgery) in a large, long-term (up to 5 years), placebo-controlled study was slightly (but not statistically significantly) higher in patients receiving gemfibrozil compared with placebo; peripheral vascular disease and intracranial hemorrhage also were more common in gemfibrozil-treated patients in this study.

Hepatoma, retinal edema, extrasystoles, decreased fertility in males, alopecia, anaphylaxis, lupus-like syndrome, and vasculitis have been reported in patients receiving gemfibrozil, but a causal relationship has not been established.

Precautions and Contraindications

Because a reduction in mortality from coronary heart disease has not been demonstrated and because an increased incidence of liver and interstitial cell testicular tumors in rats has been associated with use of the drug, gemfibrozil should be used only in carefully selected patients (see Uses), and therapy with the drug should be discontinued if a substantial lipid response is not obtained.

Because gemfibrozil is chemically, pharmacologically, and clinically similar to clofibrate, some adverse effects of clofibrate such as an increased incidence of cholesterol gallstones, cholecystitis requiring surgery, postcholecystectomy complications, malignancy, and pancreatitis may also apply to gemfibrozil and the usual precautions associated with clofibrate therapy should be observed. During 6 years of observation in the Coronary Drug Project (a large, multicenter, placebo-controlled study) in men with previous myocardial infarction, patients who received 1.8 g of clofibrate daily had no greater mortality than those who received placebo, but about 1.6 times as many of those who received clofibrate developed cholecystographic or surgical evidence of cholelithiasis or cholecystitis. In the WHO Cooperative Trial on Ischaemic Heart Disease (another large, multicenter, placebo-controlled study), men without CHD but with increased serum cholesterol concentrations who received 1.6 g of clofibrate daily for an average of 5.3 years and were followed for an average of an additional 7.9 years had a higher overall mortality and a higher mortality for non-CHD causes than those receiving placebo; the association between clofibrate use and gallbladder disease was also apparent in this study. The reason for increased mortality in these clofibrate-treated men is not known, but the difference in mortality was most marked during the treatment period (although not related to duration of treatment) and was not apparent when only the period of observation following discontinuance of the drug was considered. In primary and secondary prevention studies, gallbladder surgery and appendectomy were performed more frequently in patients receiving gemfibrozil than in those who received placebo; the possibility that other findings associated with clofibrate therapy may also apply to use of gemfibrozil should be considered.

Concomitant therapy with gemfibrozil and certain statins (e.g., cerivastatin [no longer commercially available], lovastatin) has been associated with markedly elevated CK concentrations, myoglobinuria, leading in a high proportion of cases to acute renal failure, and fatal or nonfatal rhabdomyolysis. (See and see .) Evidence of this myopathy may be seen as early as 3 weeks after initiation of combined therapy or after several months. The use of fibric acid derivatives alone, including gemfibrozil, occasionally has been associated with myositis. The manufacturers state that periodic monitoring of CK may not be adequate to prevent the occurrence of severe myopathy and kidney damage and, in most individuals who have had an unsatisfactory lipid response to gemfibrozil or lovastatin alone, the possible benefit of combined therapy with these drugs does not outweigh the risks of severe myopathy, rhabdomyolysis, and acute renal failure. Patients receiving gemfibrozil who complain of muscle pain, tenderness, or weakness should be evaluated promptly for myositis; such evaluation should include determination of CK concentrations. If myositis is suspected or diagnosed, gemfibrozil therapy should be discontinued.

Prior to institution of gemfibrozil therapy, a vigorous attempt should be made to control serum triglycerides and cholesterol by therapeutic lifestyle changes (i.e., appropriate dietary regimens for the type of hyperlipoproteinemia, weight reduction in overweight patients, exercise, restriction of alcohol intake) the treatment of any underlying disorder that might be the cause of the lipid abnormality. Response to gemfibrozil is variable, and it is not always possible to predict which patients will have a favorable response. Fasting serum triglyceride and cholesterol concentrations should be determined prior to and regularly (e.g., every 3-6 months) during gemfibrozil therapy. If possible, the LDL and HDL fractions should also be determined. Serum triglyceride and total cholesterol concentrations usually decrease maximally within 4-12 weeks. Treatment should be continued as long as a favorable response in serum triglyceride or cholesterol concentrations is present and the drug is well tolerated. Patients who have substantially elevated serum triglyceride concentrations should be closely monitored to detect possible marked increases in LDL-cholesterol that may occur with gemfibrozil therapy. When gemfibrozil is discontinued, serum lipids usually return to pretreatment levels within 6-8 weeks. If no appreciable triglyceride- or cholesterol-lowering effect occurs after 3 months, the drug should be discontinued.

Patients receiving gemfibrozil are at increased risk of developing cholelithiasis. An associated increase in morbidity associated with cholelithiasis and in mortality from cholecystectomy must be weighed against the anticipated benefit of therapy with the drug. Appropriate diagnostic tests should be performed if signs or symptoms referable to the biliary system occur. Liver function tests and complete blood cell counts should be performed periodically. Some clinicians suggest that patients be monitored every 4-6 months during long-term antilipemic therapy for clinical and potential adverse effects and for compliance with the prescribed regimen, and that additional monitoring may be necessary if abnormalities are noted or high-dose therapy is used. Gemfibrozil should be discontinued if abnormalities in liver function test results persist.

Exacerbation of renal insufficiency has been reported in patients with baseline plasma creatinine concentrations exceeding 2 mg/dL. Therefore, the manufacturers state that the use of alternative antilipemic therapy should be considered against the risks and benefits of a lower dose of gemfibrozil.

Gemfibrozil is contraindicated in patients who have a history of hypersensitivity to the drug, in patients with preexisting gallbladder disease, and in those with hepatic (including primary biliary cirrhosis) or severe renal dysfunction.

Pediatric Precautions

Safety and efficacy of gemfibrozil in pediatric patients have not been established.

Mutagenicity and Carcinogenicity

It is not known if gemfibrozil is mutagenic or carcinogenic in humans. No evidence of mutagenic potential was seen for gemfibrozil or its metabolites in the Ames microbial mutagen test with or without metabolic activation.

Long-term studies in mice and rats receiving gemfibrozil dosages resulting in 0.2-1.3 times the human exposure (based on AUC) indicated that the incidence of benign and malignant liver tumors was increased in male and female rats receiving high dosages of the drug. Male rats receiving low dosage had an increased incidence of liver carcinoma, but this increase was not statistically significant. In addition, male rats had a dose-related and significant increase in benign Leydig cell tumors. Long-term studies conducted in mice at 0.1-0.7 times the human exposure (based on AUC) indicated that the incidence of liver tumors in mice was similar to that in control animals; however, the doses tested were lower than those shown to be carcinogenic with other fibric acid derivatives.

In electron microscopic studies in male rats receiving gemfibrozil, florid hepatic peroxisome proliferation was observed; this effect is related to increased liver cell proliferation and, ultimately, liver cell tumors in these animals. Hepatocellular enlargement has been observed in toxicologic studies in animals.(See Acute Toxicity: Pathogenesis.) Liver biopsies in humans receiving long-term gemfibrozil therapy indicate that the drug does not appear to increase peroxisome proliferation, and there were no other adverse effects on the hepatocyte. Studies in male rats receiving high dosages of the drug indicated that interstitial cell tumors of the testes were increased. Male rats also had an increased incidence of tumors of the adrenal medulla with high and low dosages of gemfibrozil and pancreatic acinar cell adenomas with low dosages.

In a large, long-term (up to 5 years), placebo-controlled study in patients receiving 1200 mg of gemfibrozil daily, overall cancer risk was not increased in patients receiving the drug compared with placebo, although the incidence of basal-cell carcinoma was increased slightly in gemfibrozil-treated patients. However, the difference was not statistically significant and the frequency of this carcinoma was exceptionally low in the placebo group; additional evaluation of these findings is necessary.

Pregnancy, Fertility, and Lactation

Pregnancy

Gemfibrozil has been shown to produce adverse fetal and fertility effects in rats and rabbits at dosages 0.5-3 times the usual human dosage (based on surface area). There are no adequate and controlled studies using gemfibrozil in pregnant women; because the drug has been shown to be tumorigenic in some animals, gemfibrozil should be used during pregnancy only when the potential benefits clearly justify the possible risks to the woman and/or fetus. Currently, most experts recommend that hyperlipoproteinemias in pregnant women generally be managed with dietary measures; consultation with a lipid specialist may be indicated for pregnant women with severe forms of hyperlipidemia.

Fertility

The effect of gemfibrozil on fertility is not known. Reproduction studies in male rats using gemfibrozil dosages about 0.6 and 2 times the usual human dosage for 10 weeks indicated a dose-related decrease of fertility. This effect on fertility was reversible after the drug had been discontinued for about 8 weeks, and decreased fertility was not transmitted to offspring.

Administration of gemfibrozil dosages of 0.6 and 2 times the usual human dosage (based on surface area) to female rats before and throughout gestation resulted in a dose-related decrease in conception rate and, at the high dose, an increase in stillborns, a decrease in birth weight, and suppression of pup growth and a slight reduction in pup weight during lactation. Dose-related skeletal variations and, rarely, anophthalmia also have been reported. Administration of dosages of 1 and 3 times the usual human dosage (based on surface area) to female rabbits during organogenesis resulted in a dose-related decrease in litter size and, at the high dose, an increased incidence of parietal bone variations.

Lactation

It is not known if gemfibrozil is distributed into milk. Because of the potential for serious adverse reactions to gemfibrozil in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drug Interactions

Oral Anticoagulants

Like clofibrate (no longer commercially available in the US), gemfibrozil may potentiate the anticoagulant effects of oral anticoagulants (e.g., warfarin). When gemfibrozil is administered with oral anticoagulants, prothrombin time should be closely monitored during and for several days following initiation of concomitant therapy until it has been determined that prothrombin time has stabilized. Dosage adjustment of the oral anticoagulant may be required to maintain the prothrombin time at the desired level and to prevent bleeding complications.

HMG-CoA Reductase Inhibitors (Statins)

Myopathy and/or fatal or nonfatal rhabdomyolysis has occurred with combined gemfibrozil and statin (e.g., cerivastatin [no longer commercially available], lovastatin) therapy.(See Cautions: Precautions and Contraindications, and

Repaglinide

Concomitant administration of gemfibrozil 600 mg and a single 0.25-mg dose of repaglinide (dosage strength not commercially available in the US) in healthy individuals receiving gemfibrozil 600 mg twice daily for 3 days increased repaglinide AUC by 8.1-fold and prolonged the half-life of repaglinide from 1.3 to 3.7 hours. When both gemfibrozil and itraconazole were co-administered with repaglinide, the AUC of repaglinide was increased 19-fold and repaglinide half-life was prolonged to 6.1 hours. Plasma repaglinide concentration at 7 hours increased 28.6-fold with concomitant gemfibrozil administration and 70.4-fold with concomitant gemfibrozil-itraconazole therapy. Gemfibrozil therapy should not be initiated in patients taking repaglinide, and those taking gemfibrozil should not begin therapy with repaglinide, since such concomitant use may enhance and prolong the hypoglycemic effects of repaglinide. In addition, because of the apparent synergistic inhibitory effect of gemfibrozil and itraconazole on repaglinide metabolism, patients already receiving concomitant therapy with repaglinide and gemfibrozil should not receive itraconazole.

Other Drugs

Although formal drug interaction studies have not been performed to date, clinically important interactions have not been reported in patients receiving gemfibrozil concurrently with cardiac glycosides, diuretics, nitroglycerin, hypotensive agents, benzodiazepines, or salicylates. β-adrenergic blocking agents have been used in patients receiving gemfibrozil, but it should be kept in mind that some β-adrenergic blocking agents can cause modest increases in serum triglycerides and decreases in HDL-cholesterol that may blunt the response to gemfibrozil. Other drugs, such as thiazide diuretics, which may increase total cholesterol and triglyceride concentrations and LDL concentration; methyldopa, which may decrease HDL and LDL; and estrogens, which may increase serum triglycerides, could also blunt the response to gemfibrozil.

Pharmacokinetics

Absorption

Gemfibrozil is rapidly and completely absorbed from the GI tract. The relative bioavailability of gemfibrozil capsules compared with an oral solution of the drug is 97%. The drug undergoes enterohepatic circulation. Plasma gemfibrozil concentrations show marked interindividual variability but tend to increase proportionally with increasing dose. Plasma concentrations of the drug do not appear to correlate with therapeutic response. Following single or multiple oral doses of gemfibrozil, peak plasma concentrations of the drug occur within 1-2 hours. Following oral administration of a single 800-mg dose in healthy adults in one study, mean peak plasma gemfibrozil concentrations of 33 mcg/mL occurred 1-2 hours after ingestion. Following oral administration of multiple doses of the drug (600 mg twice daily) in healthy adults in another study, mean peak plasma concentrations of the drug were 16-23 mcg/mL about 1-2 hours after a dose.

Distribution

In animals, maximum tissue concentrations of gemfibrozil were reached 1 hour after administration of a single dose, and highest concentrations occurred in liver and kidneys.

About 95% of gemfibrozil is protein bound. In vitro at concentrations of 0.1-12 mcg/mL, 97% of gemfibrozil is bound to 4% human serum albumin; the major metabolite of gemfibrozil (metabolite III) has no effect on the binding capacity of gemfibrozil.

Studies in monkeys indicate that gemfibrozil crosses the placenta.

Elimination

The elimination half-life of gemfibrozil is about 1.5 hours after a single dose and 1.3-1.5 hours after multiple doses in individuals with normal renal function. Gemfibrozil does not accumulate in plasma following administration of multiple oral doses in individuals with normal renal function.

The exact metabolic fate of gemfibrozil has not been fully elucidated, but the drug appears to be metabolized in the liver to 4 major metabolites produced via 3 metabolic pathways. Gemfibrozil undergoes hydroxylation of the m-methyl group to the corresponding benzyl alcohol derivative (metabolite II), which is rapidly oxidized to a benzoic acid metabolite (metabolite III, 3-[(4-carboxy-4-methylpentyl)oxy]-4-methylbenzoic acid), the major metabolite. The drug also undergoes hydroxylation of the aromatic ring to produce a phenol derivative (metabolite I) which is probably further metabolized to a compound that is phenolic but has no intact carboxylic acid function (metabolite IV). Metabolite I is pharmacologically active. The drug and its metabolites also undergo conjugation.

Gemfibrozil and its metabolites are excreted mainly in urine. In one study, 65.6% of an oral dose of radiolabeled gemfibrozil was excreted in urine, principally as unconjugated and conjugated drug, in 5 days; less than 2% of the dose was excreted in urine as unchanged drug and 6% of the dose was excreted in feces. In another study, 48% of the drug was excreted in urine as conjugated and unconjugated gemfibrozil and 18.8, 13.3, and 2.3% as conjugated and unconjugated forms of metabolite III, metabolites II and IV, and metabolite I, respectively; about 56% of the drug and metabolites in urine were present as glucuronide conjugates.

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