VA Class:CV350
Gemfibrozil, a fibric acid derivative, is a antilipemic agent.2
Prevention of Cardiovascular Events
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.1, 67, 68, 104, 105, 110, 127 Although gemfibrozil has been used effectively in patients with types IIa and IIb hyperlipoproteinemia16, 17, 21, 22, 24, 25, 28, 29, 37, 38, 43, 44, 45, 46, 47, 48, 49, 51, 53, 104 to decrease elevated total or LDL-cholesterol concentrations,21, 24, 25, 28, 37, 104 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.1 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.1 (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).1
The 2018 American Heart Association (AHA)/American College of Cardiology (ACC) cholesterol management guideline emphasizes lifestyle modification as the foundation of cardiovascular risk reduction.400 If pharmacologic therapy is needed, hydroxymethyl-glutaryl-CoA (HMG-CoA) reductase inhibitor (statin) therapy is recommended.400 Statins are considered the first-line drugs of choice for reducing low-density lipoprotein (LDL) cholesterol, the lipoprotein fraction found to be a major cause of clinical atherosclerotic cardiovascular disease (ASCVD).400 Nonstatin drugs may be considered as adjunctive therapy in certain high-risk patients who do not achieve adequate reductions in LDL-cholesterol concentrations with maximally tolerated statin therapy; however, other drugs (e.g., ezetimibe) are generally recommended for this use.400 Although fibrates can produce mild LDL-lowering effects, randomized controlled studies do not support their use as add-on therapy to statins.400 If a fibrate is necessary in a patient treated with a statin, AHA/ACC states that it is safer to use fenofibrate than gemfibrozil because of lower risk of severe myopathy.400 For additional details on prevention of ASCVD, see the HMG-CoA Reductase Inhibitors General Statement 24:06.08.
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.104, 105, 106, 110 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.104, 105, 106, 110 Subsequent analysis revealed that gemfibrozil therapy was associated with a substantial reduction in Q-wave but not non-Q-wave myocardial infarction.122 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.110 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.110 Reductions in the incidence of CHD-associated end points compared with placebo were observed among gemfibrozil-treated patients of all 3 lipoprotein types.110 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.110, 111 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.110, 111 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,105, 107 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.110, 112, 113, 114
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.137 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.137 Therapy with gemfibrozil also reduced the risk of stroke by 25%.137
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.1 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;1 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.1 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.1
The 2018 AHA/ACC cholesterol management guideline recommends nonpharmacologic therapy (e.g., lifestyle modification) and management of underlying factors whenever possible in adults with moderate hypertriglyceridemia (fasting or nonfasting triglyceride concentrations of 175-499 mg/dL).400 Because most patients with severe hypertriglyceridemia (fasting triglyceride concentrations of 500 mg/dL or greater) have multiple risk factors for ASCVD and are at increased risk of developing atherosclerotic disease, the guidelines state that it is reasonable to initiate statin therapy in selected patients with severe hypertriglyceridemia.400 Fibrates may be useful as adjunctive therapy in some patients with severe hypertriglyceridemia because of their triglyceride-lowering effects.400
Gemfibrozil has been used effectively in a very limited number of patients with type III hyperlipoproteinemia†17, 18, 37, 38, 43, 45, 49 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,129, 130, 131, 132 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.129 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.129
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.
Gemfibrozil is administered orally, 30 minutes before the morning and evening meals.1
Dosage of gemfibrozil must be carefully adjusted according to individual requirements and response.1, 17 Serum lipoprotein concentrations should be determined regularly during gemfibrozil therapy.1, 64, 67, 103, 106 (See Cautions: Precautions and Contraindications.)
For the management of hypertriglyceridemia or other hyperlipoproteinemias†, the usual adult dosage of gemfibrozil is 600 mg twice daily.1, 16, 17, 18, 21, 22, 24, 25, 26, 27, 30, 31, 91, 104, 106 The drug should be discontinued after 3 months if serum lipoprotein concentrations do not improve substantially.1
Adverse effects of gemfibrozil are infrequent and generally mild;16, 17, 18, 21, 24, 38, 43, 49, 104, 105, 106 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.1, 64, 73, 87 (See Cautions: Precautions and Contraindications.)
The most frequent adverse effects of gemfibrozil involve the GI tract1, 19, 24, 28, 37, 39, 104, 106 and occasionally may be severe enough to require discontinuance of the drug.19, 24, 37, 39 Abdominal pain1, 2, 17, 21, 24, 25, 28, 37, 39 (and, in some instances, acute appendicitis)1 and epigastric pain or dyspepsia1, 2, 21, 25, 32, 53 are common adverse GI effects reported with gemfibrozil.1 Nausea,1, 2, 25, 37, 39, 47 vomiting,1, 2, 25, 47, 48 diarrhea,1, 2, 16, 25, 32, 53 constipation,1, 2, 17 and flatulence2, 25 occur less frequently; cholestatic jaundice also has been reported.1 Dry mouth,2, 17 anorexia and/or weight loss,1, 16, 17, 48 gas pain,17 pancreatitis,1 colitis,1 and heartburn53 have also been reported in patients receiving gemfibrozil but have not been directly attributed to the drug.1
Headache,1, 2, 16 dizziness,1, 2, 25 drowsiness or somnolence,1, 17, 53 blurred vision,1, 2 paresthesia,1, 2 hypesthesia,1 taste perversion,1 peripheral neuritis,1 mental depression,1, 2 and impotence123, 125 and decreased libido1, 123, 125 have been reported in patients receiving gemfibrozil. Although a causal relationship has not been established, vertigo,1, 2 syncope,1, 2 insomnia,2 asthenia,2 chills,2 psychic problems,16 fatigue,1, 2 confusion,1 and seizures1 have also occurred in patients receiving the drug.
Slight decreases in hemoglobin1, 2 and hematocrit1, 2, 38 and in leukocyte count1, 2 have occurred in a few patients receiving gemfibrozil; these levels stabilize during long-term administration.1 Eosinophilia has also been reported.1, 2, 25, 45, 46 The drug may also affect blood coagulation.58 (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.1 Therefore, the manufacturer recommends that blood cell counts be monitored periodically during the first 12 months of therapy.1
Gemfibrozil may increase cholesterol excretion in bile,1, 34, 61 resulting in cholelithiasis.1, 26, 34 Cholecystitis and cholelithiasis have been reported with gemfibrozil therapy.1 If gallbladder studies indicate gallstones are present, gemfibrozil should be discontinued.1 (See Cautions: Precautions and Contraindications.) In one study, gallstones developed in about 1% of hyperlipoproteinemic patients receiving gemfibrozil for 1 year.25 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,104, 105 and the number of all GI operations (including hemorrhoidectomies) was substantially higher in patients receiving the drug.104 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.34, 94 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.34, 94
Atrial fibrillation1 has been reported infrequently with gemfibrozil therapy. Rash1, 2, 17, 25, 32, 45 (occasionally with eosinophilia),25, 45 dermatitis1, 2 (including exfoliative dermatitis)1 circumscribed exanthema,53 eczema,24 exacerbation of psoriasis,109 pruritus,1, 2, 17 urticaria,1, 2 angioedema,1 laryngeal edema,1 myasthenia,1 and painful extremities1, 2 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.21, 25, 26 Other studies, however, indicated there was no change in fasting blood glucose concentration or glucose tolerance.38, 45 Blood glucose concentrations should be monitored periodically during gemfibrozil therapy since they may increase slightly in some patients.21, 25, 26 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.17, 46
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.1 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 syndrome42, 98 and in uremic patients with chronic renal failure;97 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).1, 108, 116 (See Cautions: Precautions and Contraindications.) Back2 and neck pain,2 arthralgia,1 bursitis,2 muscle cramps,2 myalgia,1 swollen joints or synovitis,1, 48 myositis,1 and gout2 also have occurred in patients receiving gemfibrozil. Impotence,1, 53 chest pain,2 and liver function test abnormalities such as increased AST,1, 2, 24, 25, 47 ALT,1, 2, 24, 25 LDH,1, 2 creatine kinase (CK, creatine phosphokinase, CPK),1, 45, 47, 53 bilirubin,1 and alkaline phosphatase1, 2, 15, 25, 47 also have occurred in patients receiving the drug.1 Liver function test abnormalities usually return to baseline when the drug is discontinued.1 Positive antinuclear antibody reactions have been associated with gemfibrozil therapy but have not been directly attributed to the drug.1
In male rats receiving high-dose gemfibrozil, subcapsular bilateral cataracts occurred in 10% and unilateral cataracts occurred in 6.3%,1, 62 but the relevance of these findings to humans is not known. Although a causal relationship has not been established,1 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;1, 104 peripheral vascular disease and intracranial hemorrhage also were more common in gemfibrozil-treated patients in this study.1
Hepatoma,1 retinal edema,1 extrasystoles,1 decreased fertility in males,1 alopecia,1 anaphylaxis,1 lupus-like syndrome,1 and vasculitis1 have been reported in patients receiving gemfibrozil, but a causal relationship has not been established.1
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.1
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.1 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.1, 84, 85 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;1, 81, 82, 83, 86 the association between clofibrate use and gallbladder disease was also apparent in this study.1, 82 The reason for increased mortality in these clofibrate-treated men is not known,81, 82, 83, 86 but the difference in mortality was most marked during the treatment period81, 82, 83 (although not related to duration of treatment)81 and was not apparent when only the period of observation following discontinuance of the drug was considered.83 In primary and secondary prevention studies, gallbladder surgery and appendectomy were performed more frequently in patients receiving gemfibrozil than in those who received placebo;1 the possibility that other findings associated with clofibrate therapy may also apply to use of gemfibrozil should be considered.1
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.1, 108, 118, 119, 120, 121, 134, 135 (See Cautions: Precautions and Contraindications and see Drug Interactions: Antilipemic Agents, in the HMG-CoA Reductase Inhibitors General Statement 24:06.08.) Evidence of this myopathy may be seen as early as 3 weeks after initiation of combined therapy or after several months.1, 116 The use of fibric acid derivatives alone, including gemfibrozil, occasionally has been associated with myositis.1, 97, 98, 115, 117 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.1 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.1, 108, 116 If myositis is suspected or diagnosed, gemfibrozil therapy should be discontinued.1
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,1, 64, 66, 67, 70, 106 weight reduction in overweight patients,1, 64, 66, 70, 106 exercise,1, 64, 106 restriction of alcohol intake)1, 60, 64, 66, 69, 106 the treatment of any underlying disorder that might be the cause of the lipid abnormality.1, 64, 69, 106 Response to gemfibrozil is variable, and it is not always possible to predict which patients will have a favorable response.1, 23, 24 Fasting serum triglyceride and cholesterol concentrations should be determined prior to73, 103 and regularly (e.g., every 3-6 months) during gemfibrozil therapy.1, 64, 67, 103, 106 If possible, the LDL and HDL fractions should also be determined.73, 94, 103, 106 Serum triglyceride and total cholesterol concentrations usually decrease maximally within 4-12 weeks.37, 38, 106 Treatment should be continued as long as a favorable response in serum triglyceride or cholesterol concentrations is present and the drug is well tolerated.64, 106 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.1, 105 When gemfibrozil is discontinued, serum lipids usually return to pretreatment levels within 6-8 weeks.38 If no appreciable triglyceride- or cholesterol-lowering effect occurs after 3 months, the drug should be discontinued.1, 24
Patients receiving gemfibrozil are at increased risk of developing cholelithiasis.1, 26, 34 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.1 Appropriate diagnostic tests should be performed if signs or symptoms referable to the biliary system occur.1 Liver function tests and complete blood cell counts should be performed periodically.1 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.106, 127 Gemfibrozil should be discontinued if abnormalities in liver function test results persist.1
Exacerbation of renal insufficiency has been reported in patients with baseline plasma creatinine concentrations exceeding 2 mg/dL.1 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.1
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.1
Safety and efficacy of gemfibrozil in pediatric patients have not been established.128
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.62
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.1, 62 Male rats receiving low dosage had an increased incidence of liver carcinoma, but this increase was not statistically significant.1 In addition, male rats had a dose-related and significant increase in benign Leydig cell tumors.1 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;1 however, the doses tested were lower than those shown to be carcinogenic with other fibric acid derivatives.1
In electron microscopic studies in male rats receiving gemfibrozil, florid hepatic peroxisome proliferation was observed;1, 11, 57 this effect is related to increased liver cell proliferation and, ultimately, liver cell tumors in these animals.1, 57 Hepatocellular enlargement has been observed in toxicologic studies in animals.2, 8 (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.1, 12, 50 Studies in male rats receiving high dosages of the drug indicated that interstitial cell tumors of the testes were increased.1, 62 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.62
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,104, 105 although the incidence of basal-cell carcinoma was increased slightly in gemfibrozil-treated patients.104 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.104
Pregnancy, Fertility, and Lactation
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).1 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.1 Currently, most experts recommend that hyperlipoproteinemias in pregnant women generally be managed with dietary measures;73, 94, 106 consultation with a lipid specialist may be indicated for pregnant women with severe forms of hyperlipidemia.106
The effect of gemfibrozil on fertility is not known.1 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.1, 2 This effect on fertility was reversible after the drug had been discontinued for about 8 weeks, and decreased fertility was not transmitted to offspring.1
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 rate102 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.1 Dose-related skeletal variations and, rarely, anophthalmia also have been reported.1 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.1
It is not known if gemfibrozil is distributed into milk.1, 102 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.1
Like clofibrate (no longer commercially available in the US),79 gemfibrozil may potentiate the anticoagulant effects of oral anticoagulants (e.g., warfarin).1, 102, 124 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.1, 124 Dosage adjustment of the oral anticoagulant may be required to maintain the prothrombin time at the desired level and to prevent bleeding complications.1, 124
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.1, 108, 116 (See Cautions: Precautions and Contraindications, and see Drug Interactions: Antilipemic Agents, in the HMG-CoA Reductase Inhibitors General Statement 24:06.08.)
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.138, 139 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.138, 139 Plasma repaglinide concentration at 7 hours increased 28.6-fold with concomitant gemfibrozil administration and 70.4-fold with concomitant gemfibrozil-itraconazole therapy.138, 139 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.138 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.138
Although formal drug interaction studies have not been performed to date, clinically important interactions have not been reported94 in patients receiving gemfibrozil concurrently with cardiac glycosides,17, 24 diuretics,16, 17, 24 nitroglycerin,17 hypotensive agents,17 benzodiazepines,24 or salicylates.24β-adrenergic blocking agents have been used in patients receiving gemfibrozil,16, 22, 24, 30 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.30, 74 Other drugs, such as thiazide diuretics, which may increase total cholesterol and triglyceride concentrations and LDL concentration;74 methyldopa, which may decrease HDL and LDL;74 and estrogens, which may increase serum triglycerides,73 could also blunt the response to gemfibrozil.
Limited information is available on the acute toxicity of gemfibrozil.1
The acute lethal dose of gemfibrozil in humans is not known.1 The oral LD50 of gemfibrozil is 3.16 and 4.79 g/kg in mice and rats, respectively.2, 8 In animals, lethal doses produced incoordination, depression, flaccid prostration, and dyspnea; slight hepatocellular enlargement was noted in animal survivors who were sacrificed and examined 14 days after the dose.2, 8 In monkeys, a gemfibrozil dosage of 300 mg/kg daily for 3 months produced sporadic anorexia, salivation, and vomiting in some animals.10 A 7-year-old child has recovered after ingesting up to 9 g of the drug.126
Treatment of gemfibrozil overdosage involves symptomatic and supportive care.1 In acute gemfibrozil overdosage, the stomach should be emptied immediately (e.g., by gastric lavage).94 If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents.94, 104
The exact mechanism(s) of action of gemfibrozil has not been fully elucidated.1, 34, 36, 75, 76, 91 Many of the pharmacologic effects of gemfibrozil are similar to those of clofibrate (no longer commercially available in the US),1, 64, 73, 76 but in patients with hyperlipoproteinemia, gemfibrozil decreases triglyceride15, 19, 30, 64, 73, 76, 95, 104 and increases high-density lipoprotein (HDL)-cholesterol concentrations1, 15, 16, 19, 21, 22, 24, 25, 26, 31, 32, 33, 34, 36, 38, 45, 61, 67, 88, 91, 94, 95, 96, 104 to a greater extent than clofibrate.15, 19, 67, 94 Like clofibrate, gemfibrozil increases low-density lipoprotein (LDL)-cholesterol in patients with hypertriglyceridemia15, 30, 68 and decreases LDL-cholesterol in some patients with hypercholesterolemia or combined hypercholesterolemia and hypertriglyceridemia.15, 19, 68, 76
Gemfibrozil decreases serum triglycerides in healthy individuals34, 61 and in patients with hypertriglyceridemia.1, 15, 16, 17, 18, 19, 21, 22, 23, 24, 26, 27, 28, 29, 30, 32, 33, 37, 38, 45, 48, 76, 91, 104 The drug principally decreases serum very low-density lipoprotein (VLDL)-triglyceride concentration1, 15, 17, 18, 19, 25, 33, 37, 38, 45, 48, 76 and, to a lesser extent, LDL-triglyceride concentration.1, 15, 33, 37, 38, 45, 76 HDL-triglyceride is usually decreased23, 33, 37 slightly.15, 45 Gemfibrozil usually increases the HDL-cholesterol fraction in healthy individuals34, 61, 88 and in patients with hyperlipoproteinemia,1, 15, 16, 19, 21, 22, 24, 25, 26, 31, 32, 33, 36, 38, 45, 88, 91 an action that may be beneficial in slowing the progression of atherosclerosis and in reducing the risk of coronary heart disease (CHD).1, 36, 73, 88, 104, 105, 110 Gemfibrozil causes a variable reduction in serum total cholesterol,1, 15, 16, 17, 18, 19, 21, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 37, 38, 48, 68, 105, 106 because the decrease in serum cholesterol is a net result of a decrease in VLDL-cholesterol,18, 19, 21, 25, 26, 28, 32, 33, 38, 45 an increase in HDL-cholesterol,37, 68 and an increase15, 21, 30, 33, 37, 45, 91 or decrease in LDL-cholesterol.21, 24, 26, 32, 37, 38, 45 Generally, gemfibrozil increases LDL-cholesterol in patients with type IV or V hyperlipoproteinemia and decreases LDL-cholesterol in type IIa or IIb disorder.21, 25, 28, 45, 91 Gemfibrozil decreases serum concentrations of phospholipids.33
In one large multicenter study in patients with type IIa, IIb, or IV hyperlipoproteinemia who received 800 mg of gemfibrozil daily for 6 weeks and then 1200 mg for an additional 6 weeks, serum triglyceride concentrations decreased by 44, 45, or 40%, respectively; serum total cholesterol concentration decreased by 4.2, 8.6, or 1.8%, respectively; VLDL-cholesterol decreased by 44.3, 45, or 40.8%, respectively; and HDL-cholesterol increased by 24.6, 19.5, or 17.4%, respectively.1, 21 LDL-cholesterol concentration decreased by 5.8 and 6.4% in patients with types IIa and IIb disorder, respectively, and increased by 14.6% in patients with type IV disorder.1, 21 The ratio of HDL-cholesterol to total cholesterol, one indicator of the degree of cardiovascular risk associated with hyperlipoproteinemia, increased toward normal by 33, 34, and 23%, respectively.1, 21 With long-term follow-up, decreases in serum triglyceride concentrations were maintained or concentrations decreased further; serum total cholesterol and VLDL-cholesterol concentrations decreased further; LDL-cholesterol concentration decreased further in types IIa and IIb hyperlipoproteinemia and was less increased in type IV disorder; and the ratio of HDL-cholesterol to total cholesterol increased further in types IIa and IV disorder and was maintained in type IIb.28 In one study in patients with type V hyperlipoproteinemia who received 1200 mg of gemfibrozil daily for 8 weeks, serum triglyceride concentrations decreased by 58%, total serum cholesterol decreased by 6%, LDL-cholesterol increased by 32%, and HDL-cholesterol increased by 33%.91 In the Helsinki Heart Study (a large, multicenter, placebo-controlled study) in patients with elevated pretreatment LDL- and/or VLDL-cholesterol concentrations (primary dyslipidemia, including types IIa, IIb, and IV disorder) who received 1200 mg of gemfibrozil daily for up to 5 years, detailed analyses of serum lipid alterations indicated that serum triglyceride concentrations decreased on average by about 35%, total serum cholesterol decreased by 10%, LDL-cholesterol decreased by 11%, and HDL-cholesterol increased by 11% during the entire intervention period.
110 In general, patients with type III,37 IV,32 or V91, 94 hyperlipoproteinemia who receive gemfibrozil have greater decreases in serum triglyceride concentrations than those with type IIa or IIb hyperlipoproteinemia.32 Serum total cholesterol concentration is generally decreased by the drug more in type IIa21, 25, 28, 29, 32, 37 and IIb disorder21, 25, 28, 29, 32, 37 than in type III37 or IV.21, 25, 28, 29, 32, 37 VLDL-cholesterol is generally decreased by 40-50%21, 25, 26, 28, 32, 38 in type IIa, IIb, or IV hyperlipoproteinemia. LDL-cholesterol decreases to a greater extent in types IIa and IIb disorder21, 25, 28, 37 than in patients with type IV whose pretreatment concentrations are elevated; in patients with type IV disorder whose pretreatment concentrations are reduced, LDL-cholesterol generally increases during gemfibrozil therapy.37 Gemfibrozil generally increases HDL-cholesterol by 10-35%15, 16, 21, 24, 25, 28, 31, 32, 33, 38, 91 in type IIa, IIb, IV, or V hyperlipoproteinemia.
The exact mechanism(s) of action of gemfibrozil has not been established.1, 6, 14, 76 In humans, gemfibrozil inhibits lipolysis of fat in adipose tissue1, 54, 56, 75, 76, 91 and decreases the hepatic uptake of plasma free fatty acids1, 54, 75, 76 (i.e., free fatty acid turnover is decreased),51, 54, 75 thereby reducing hepatic triglyceride production1, 54, 75, 76 (triglyceride turnover rate is decreased).51, 75 The drug also reportedly inhibits production1, 15, 54, 75, 91 and increases clearance1, 75, 102 of VLDL-apoprotein B (VLDL-apo B), leading to a decrease in VLDL-triglyceride production,1, 15, 45, 54, 75 enhanced clearance of VLDL-triglyceride,15 and, subsequently, a decrease in serum triglyceride concentrations.2, 54, 91 The increase in serum total LDL concentration that may occur with gemfibrozil may be caused by a decrease in the catabolic rate of LDL, possibly secondary to an effect(s) of the drug on hepatic metabolism of LDL,54 and/or by an increase in the catabolic rate of VLDL-cholesterol.91 In animals, gemfibrozil reduces incorporation of long-chain fatty acids into newly formed triglycerides1, 6 and inhibits basal,6, 55, 56 norepinephrine-induced,56 isoproterenol-stimulated,55, 56 and cyclic adenosine-3',5'-monophosphate (AMP)-stimulated55 lipolysis of adipose tissue. It has been proposed that this reduction in adipose tissue lipolysis may be a mechanism for decreased serum triglyceride concentrations;55, 56 however, it is unlikely that the drug's antilipemic effect in humans results from this mechanism of action.60
Gemfibrozil increases postheparin plasma lipoprotein lipase45, 51, 91 and hepatic lipoprotein lipase activities,45 but neither effect has been correlated with changes in serum lipid concentrations45 or in fatty acid flux,51 or with the rate of triglyceride turnover.51 In one study, adipose tissue lipoprotein lipase was unaffected by gemfibrozil.38 Gemfibrozil's effects on lipoprotein lipase appear to be less pronounced than those of clofibrate45, 76 and may not contribute substantially to gemfibrozil's effect on serum triglyceride concentrations.36, 45, 51 However, in one study in patients with type V hyperlipoproteinemia, gemfibrozil increased postheparin plasma lipoprotein lipase activity by 25%, and this effect was thought to contribute to the drug's overall effect on serum triglycerides.91
Animal studies indicate that gemfibrozil slightly increases the activities of carnitine acyltransferases and accelerates mitochondrial oxidation of fatty acids, but these effects are not the mechanisms by which the drug decreases serum triglyceride concentrations.14
In animals, gemfibrozil accelerates turnover and removal of cholesterol from the liver,1, 13 stimulates sterol biosynthesis,13 and increases fecal excretion of cholesterol.1, 15 In humans, gemfibrozil increases biliary cholesterol excretion.1, 34, 61 (See Pharmacology: Other Metabolic Effects.) Fecal bile acid excretion decreases15, 35 simultaneously with an increase in fecal excretion of neutral steroids, and there is no net change in total steroid excretion or in cholesterol balance (cholesterol biosynthesis).15 It has been postulated that gemfibrozil also decreases cholesterol synthesis.61 In patients with hypertriglyceridemia, gemfibrozil may decrease production and fractional clearance of LDL-cholesterol toward normal.30
The mechanism(s) by which gemfibrozil increases serum HDL-cholesterol concentration has not been fully elucidated.36, 76, 80, 88, 91 After 2-4 months of gemfibrozil therapy in patients with type IIa, IIb, IV, or V hyperlipoproteinemia, HDL-apoprotein A-I (HDL-apo A-I) may be either unchanged16 or increased1, 23, 31, 91 and HDL-apoprotein A-II (HDL-apo A-II) is increased.1, 16, 23, 31, 91 Unlike niacin, gemfibrozil has not been shown to reduce HDL2 catabolism.88, 91 Gemfibrozil has been reported to increase the synthetic rates of HDL-apo A-I and HDL-apo A-II in patients with type V hyperlipoproteinemia.91 The HDL2 subfraction is increased to a greater degree than the HDL3 subfraction during gemfibrozil therapy.23, 80, 91 Low HDL2 concentrations have been reported to correlate with increased coronary heart disease.23, 80 Gemfibrozil increases serum reserve cholesterol binding capacity (SRCBC), the capacity of serum to solubilize additional cholesterol, by about 60%.31 SRCBC exists in a subclass of HDL.31 In patients with types IIa, IIb, or IV hyperlipoproteinemia, serum concentrations of apoprotein B usually decrease during gemfibrozil therapy;31, 32 decreases in apoprotein B follow changes in LDL-cholesterol.32 However, in another study in patients with primary hypertriglyceridemia associated with CHD, LDL-apoprotein B increased in a few patients.30 In patients with type V hyperlipoproteinemia, apoprotein B concentration has been reported to increase during gemfibrozil therapy.91
Gemfibrozil does not substantially change Lp(a) lipoprotein concentration,31 a lipoprotein that may be strongly correlated with atherosclerosis.32 In one study in patients with type IIa, IIb, or IV hyperlipoproteinemia who received gemfibrozil, those with or without Lp(a) lipoprotein concentration had similar decreases in triglyceride and total cholesterol concentrations and in the ratio of LDL-cholesterol and HDL-cholesterol (i.e., the ratio decreased by about 22% in both),32 but those with Lp(a) lipoprotein had slightly greater decreases in LDL-cholesterol (17 vs 11%) and less marked increases in HDL-cholesterol (10 vs 21%).32
In animals, gemfibrozil does not increase or has very minimal effect on activity of hepatic α-glycerophosphate dehydrogenase6, 14 or liver catalase.6 Hepatic acetyl-CoA carboxylase activity is either unchanged or inhibited.6 Gemfibrozil substantially increases peroxisome proliferation (peroxidative functions are related to catalase and fatty acid oxidases) in rats,1, 11, 57 an action that is related to increased liver cell proliferation and ultimately liver cell tumors in these animals.1, 57 However, in humans, gemfibrozil does not appear to increase peroxisome proliferation.1, 12, 50 (See Cautions: Mutagenicity and Carcinogenicity.)
Gemfibrozil increases cholesterol saturation of gallbladder and hepatic bile.61 One study in healthy normolipemic men receiving 1200 mg94 of gemfibrozil daily for 3 months showed that biliary cholesterol secretion increased, biliary phospholipid concentration increased, and biliary secretion of bile acids decreased (as a result of decreased chenodeoxycholic acid secretion), causing a marked increase in the lithogenicity of gallbladder bile.61 In addition, the lithogenicity of hepatic bile was increased secondary to increased hepatic secretion of cholesterol and decreased hepatic bile acid secretion.61 However, a short-term study indicated that the biliary cholesterol saturation was not appreciably increased.34 Gemfibrozil-induced changes in bile acid composition include increased cholic acid, slightly decreased chenodeoxycholic and deoxycholic acid, and unchanged lithocholic and ursodeoxycholic acid concentrations.61 However, the hepatic secretion rates of chenodeoxycholic and deoxycholic acids are decreased and cholic acid secretion is unchanged.61
Gemfibrozil decreases platelet adhesiveness, but platelet aggregation induced by adenosine diphosphate, epinephrine, or collagen is not markedly changed and bleeding time is not affected.59 Plasma fibrinogen concentrations are unchanged38, 58 or slightly decreased53 during gemfibrozil therapy, whereas plasma fibrinogen is markedly decreased with clofibrate.58 Antithrombin III is slightly increased with gemfibrozil but is decreased with clofibrate.58 In patients with increased plasma heparin neutralizing activity secondary to atherosclerosis, administration of gemfibrozil decreased the heparin neutralizing capacity.58
In one study in adult men with type IIa or IIb hyperlipoproteinemia who received gemfibrozil, both plasma prekallikrein and kininogen increased and kallikrein increased very slightly.22 It has been postulated that these changes may indicate a correction of impaired blood coagulation and/or fibrinolysis that occurs in some patients with type II hyperlipoproteinemias.22
Gemfibrozil is rapidly and completely absorbed from the GI tract.2, 7, 76 The relative bioavailability of gemfibrozil capsules compared with an oral solution of the drug is 97%.10 The drug undergoes enterohepatic circulation.2 Plasma gemfibrozil concentrations show marked interindividual variability29 but tend to increase proportionally with increasing dose.1, 2, 29 Plasma concentrations of the drug do not appear to correlate with therapeutic response.29, 102 Following single or multiple oral doses of gemfibrozil, peak plasma concentrations of the drug occur within 1-2 hours.1, 2, 7, 9 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.2 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.2, 7
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.2
About 95% of gemfibrozil is protein bound.2 In vitro at concentrations of 0.1-12 mcg/mL,2 97% of gemfibrozil is bound to 4% human serum albumin;2, 40 the major metabolite of gemfibrozil (metabolite III) has no effect on the binding capacity of gemfibrozil.2
Studies in monkeys indicate that gemfibrozil crosses the placenta.2
The elimination half-life of gemfibrozil is about 1.5 hours after a single dose9, 10 and 1.3-1.5 hours after multiple doses1, 7 in individuals with normal renal function. Gemfibrozil does not accumulate in plasma following administration of multiple oral doses1, 2, 7, 9 in individuals with normal renal function.7, 9
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.2, 7, 102 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.2, 7 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).2, 7 Metabolite I is pharmacologically active.102 The drug and its metabolites also undergo conjugation.2, 7
Gemfibrozil and its metabolites are excreted mainly in urine.1, 2, 7, 9 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;1, 2, 7 less than 2% of the dose was excreted in urine as unchanged drug1, 7 and 6% of the dose was excreted in feces.1, 2, 7 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;2, 102 about 56% of the drug and metabolites in urine were present as glucuronide conjugates.2
Gemfibrozil, a nonhalogenated phenoxypentanoic acid, is an antilipemic agent.2 The drug is structurally related to clofibrate (no longer commercially available in the US) and clofibric acid (the active metabolite of clofibrate).4, 5, 7, 76 Gemfibrozil and clofibrate have been referred to as fibric acid derivatives.15, 30, 73, 90
Gemfibrozil occurs as a white solid.1, 2 The drug has solubilities of 19 mcg/mL in water1, 2 and 100 mg/mL in alcohol at room temperature.102
Commercially available gemfibrozil tablets should be stored in tight containers3 at a temperature less than 30°C.1
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 600 mg* | ||
Lopid® (scored) |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Parke Davis. Lopid® (gemfibrozil tablets) prescribing information. New York, NY; 2003 Oct.
2. Parke-Davis. Lopid® (gemfibrozil) compendium of pharmacological and clinical studies. Morris Plains, NJ; 1982 Feb.
3. The United States pharmacopeia, 21st rev, and The national formulary, 16th ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1985: 457.
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