Gemfibrozil

INDICATIONS AND USAGE Gemfibrozil Tablets are indicated as adjunctive therapy to diet for: 1. Treatment of adult patients with very high elevations of serum triglyceride levels (Types IV and V hyperlipidemia) who present a risk of pancreatitis and who do not respond adequately to a determined dietary effort to control them. Patients who present such risk typically have serum triglycerides over 2,000 mg/dL and have elevations of VLDL-cholesterol as well as fasting chylomicrons (Type V hyperlipidemia). Subjects who consistently have total serum or plasma triglycerides below 1,000 mg/dL are unlikely to present a risk of pancreatitis. Gemfibrozil therapy may be considered for those subjects with triglyceride elevations between 1,000 and 2,000 mg/dL who have a history of pancreatitis or of recurrent abdominal pain typical of pancreatitis. It is recognized that some Type IV patients with triglycerides under 1,000 mg/dL may, through dietary or alcoholic indiscretion, convert to a Type V pattern with massive triglyceride elevations accompanying fasting chylomicronemia, but the influence of gemfibrozil therapy on the risk of pancreatitis in such situations has not been adequately studied. Drug therapy is not indicated for patients with Type I hyperlipoproteinemia, who have elevations of chylomicrons and plasma triglycerides, but who have normal levels of very low density lipoprotein (VLDL). Inspection of plasma refrigerated for 14 hours is helpful in distinguishing Types I, IV, and V hyperlipoproteinemia. 2. Reducing the risk of developing coronary heart disease only in Type IIb patients without history of or symptoms of existing coronary heart disease who have had an inadequate response to weight loss, dietary therapy, exercise, and other pharmacologic agents (such as bile acid sequestrants and nicotinic acid, known to reduce LDL- and raise HDL-cholesterol) and who have the following triad of lipid abnormalities: low HDL-cholesterol levels in addition to elevated LDL-cholesterol and elevated triglycerides (see WARNINGS , PRECAUTIONS , and CLINICAL PHARMACOLOGY ). The National Cholesterol Education Program has defined a serum HDL-cholesterol value that is consistently below 35 mg/dL as constituting an independent risk factor for coronary heart disease. Patients with significantly elevated triglycerides should be closely observed when treated with gemfibrozil. In some patients with high triglyceride levels, treatment with gemfibrozil is associated with a significant increase in LDL-cholesterol. BECAUSE OF POTENTIAL TOXICITY SUCH AS MALIGNANCY, GALLBLADDER DISEASE, ABDOMINAL PAIN LEADING TO APPENDECTOMY AND OTHER ABDOMINAL SURGERIES, AN INCREASED INCIDENCE IN NON-CORONARY MORTALITY, AND THE 44% RELATIVE INCREASE DURING THE TRIAL PERIOD IN AGE-ADJUSTED ALL-CAUSE MORTALITY SEEN WITH THE CHEMICALLY AND PHARMACOLOGICALLY RELATED DRUG, CLOFIBRATE, THE POTENTIAL BENEFIT OF GEMFIBROZIL IN TREATING TYPE IIA PATIENTS WITH ELEVATIONS OF LDL-CHOLESTEROL ONLY IS NOT LIKELY TO OUTWEIGH THE RISKS. GEMFIBROZIL IS ALSO NOT INDICATED FOR THE TREATMENT OF PATIENTS WITH LOW HDL-CHOLESTEROL AS THEIR ONLY LIPID ABNORMALITY. In a subgroup analysis of patients in the Helsinki Heart Study with above-median HDL-cholesterol values at baseline (greater than 46.4 mg/dL), the incidence of serious coronary events was similar for gemfibrozil and placebo subgroups (see Table I). The initial treatment for dyslipidemia is dietary therapy specific for the type of lipoprotein abnormality. Excess body weight and excess alcohol intake may be important factors in hypertriglyceridemia and should be managed prior to any drug therapy. Physical exercise can be an important ancillary measure, and has been associated with rises in HDL-cholesterol. Diseases contributory to hyperlipidemia such as hypothyroidism or diabetes mellitus should be looked for and adequately treated. Estrogen therapy is sometimes associated with massive rises in plasma triglycerides, especially in subjects w

CLINICAL PHARMACOLOGY Gemfibrozil is a lipid regulating agent which decreases serum triglycerides and very low density lipoprotein (VLDL) cholesterol, and increases high density lipoprotein (HDL) cholesterol. While modest decreases in total and low density lipoprotein (LDL) cholesterol may be observed with gemfibrozil therapy, treatment of patients with elevated triglycerides due to Type IV hyperlipoproteinemia often results in a rise in LDL-cholesterol. LDL-cholesterol levels in Type IIb patients with elevations of both serum LDL-cholesterol and triglycerides are, in general, minimally affected by gemfibrozil treatment; however, gemfibrozil usually raises HDLcholesterol significantly in this group. Gemfibrozil increases levels of high density lipoprotein (HDL) subfractions HDL 2 and HDL 3 , as well as apolipoproteins AI and AII. Epidemiological studies have shown that both low HDL-cholesterol and high LDL-cholesterol are independent risk factors for coronary heart disease. In the primary prevention component of the Helsinki Heart Study, in which 4,081 male patients between the ages of 40 and 55 were studied in a randomized, double-blind, placebo-controlled fashion, gemfibrozil therapy was associated with significant reductions in total plasma triglycerides and a significant increase in high density lipoprotein cholesterol. Moderate reductions in total plasma cholesterol and low density lipoprotein cholesterol were observed for the gemfibrozil treatment group as a whole, but the lipid response was heterogeneous, especially among different Fredrickson types. The study involved subjects with serum non-HDL-cholesterol of over 200 mg/dL and no previous history of coronary heart disease. Over the five-year study period, the gemfibrozil group experienced a 1.4% absolute (34% relative) reduction in the rate of serious coronary events (sudden cardiac deaths plus fatal and nonfatal myocardial infarctions) compared to placebo, p=0.04 (see Table I). There was a 37% relative reduction in the rate of nonfatal myocardial infarction compared to placebo, equivalent to a treatment-related difference of 13.1 events per thousand persons. Deaths from any cause during the double-blind portion of the study totaled 44 (2.2%) in the gemfibrozil randomization group and 43 (2.1 %) in the placebo group. Table I Reduction in CHD Rates (events per 1,000 patients) by Baseline Lipids 1 in the Helsinki Heart Study, Years 0-5 2 All Patients LDL-C>175; HDL-C>46.4 LDL-C>175; TG>177 LDL-C>175; TG>200; HDL-C<35 P G Dif 3 P G Dif P G Dif P G Dif Incidence of Events 4 41 27 14 32 29 3 71 44 27 149 64 85 1 lipid values in mg/dL at baseline 2 p = placebo group; G = Gemfibrozil group 3 difference in rates between placebo and Gemfibrozil groups 4 fatal and nonfatal myocardial infarctions plus sudden cardiac deaths (events per 1,000 patients over 5 years) Among Fredrickson types, during the 5-year double-blind portion of the primary prevention component of the Helsinki Heart Study, the gre

DOSAGE AND ADMINISTRATION The recommended dose for adults is 1,200 mg administered in two divided doses 30 minutes before the morning and evening meals (see CLINICAL PHARMACOLOGY ).

ADVERSE REACTIONS In the double-blind controlled phase of the primary prevention component of the Helsinki Heart Study, 2,046 patients received gemfibrozil for up to five years. In that study, the following adverse reactions were statistically more frequent in subjects in the gemfibrozil group: GEMFIBROZIL ( N = 2,046 ) PLACEBO ( N = 2,035 ) Frequency in percent of subjects Gastrointestinal reactions 34.2 23.8 Dyspepsia 19.6 11.9 Abdominal pain 9.8 5.6 Acute appendicitis 1.2 0.6 (histologically confirmed in most cases where data were available) Atrial fibrillation 0.7 0.1 Adverse events reported by more than 1% of subjects, but without a significant difference between groups: Diarrhea 7.2 6.5 Fatigue 3.8 3.5 Nausea/Vomiting 2.5 2.1 Eczema 1.9 1.2 Rash 1.7 1.3 Vertigo 1.5 1.3 Constipation 1.4 1.3 Headache 1.2 1.1 Gallbladder surgery was performed in 0.9% of gemfibrozil and 0.5% of placebo subjects in the primary prevention component, a 64% excess, which is not statistically different from the excess of gallbladder surgery observed in the clofibrate group compared to the placebo group of the WHO study. Gallbladder surgery was also performed more frequently in the gemfibrozil group compared to the placebo group (1.9% versus 0.3%, p=0.07) in the secondary prevention component. A statistically significant increase in appendectomy in the gemfibrozil group was seen also in the secondary prevention component (6 on gemfibrozil versus 0 on placebo, p=0.014). Nervous system and special senses adverse reactions were more common in the gemfibrozil group. These included hypesthesia, paresthesias, and taste perversion. Other adverse reactions that were more common among gemfibrozil treatment group subjects but where a causal relationship was not established include cataracts, peripheral vascular disease, and intracerebral hemorrhage. From other studies it seems probable that gemfibrozil is causally related to the occurrence of MUSCULOSKELETAL SYMPTOMS (see WARNINGS ), and to ABNORMAL LIVER FUNCTION TESTS and HEMATOLOGIC CHANGES (see PRECAUTIONS ). Reports of viral and bacterial infections (common cold, cough, urinary tract infections) were more common in gemfibrozil treated patients in other controlled clinical trials of 805 patients. Additional adverse reactions that have been reported for gemfibrozil are listed below by system. These are categorized according to whether a causal relationship to treatment with gemfibrozil is probable or not established: CAUSAL RELATIONSHIP PROBABLE CAUSAL RELATIONSHIP NOT ESTABLISHED General: weight loss Cardiac: extrasystoles Gastrointestinal: cholestatic jaundice pancreatitis hepatoma colitis Central Nervous System: dizziness somnolence paresthesiaperipheral neuritisdecreased libidodepression headache confusion convulsions syncope Eye: blurred vision retinal edema Genitourinary: impotence decreased male fertility renal dysfunction Musculoskeletal: myopathy myasthenia myalgia painful extremities arthralgia synovitis rhabdomyolysis (see WARNINGS and Drug Interactions under PRECAUTIONS ) Clinical Laboratory: increased creatine phosphokinase increased bilirubin increased liver transaminases (AST, ALT) increased alkaline phosphatase positive antinuclear antibody Hematopoietic: anemia leukopenia bone marrow hypoplasia eosinophilia thrombocytopenia Immunologic: angicedema laryngeal edema urticaria anaphylaxis Lupus-like syndrome vasculitis Integumentary: exfoliative dermatitis rash dermatitis pruritus alopecia photosensitivity Additional adverse reactions that have been reported include cholecystitis and cholelithiasis ( see WARNINGS ).

WARNINGS 1. Because of chemical, pharmacological, and clinical similarities between gemfibrozil and clofibrate, the adverse findings with clofibrate in two large clinical studies may also apply to gemfibrozil. In the first of those studies, the Coronary Drug Project, 1,000 subjects with previous myocardial infarction were treated for five years with clofibrate. There was no difference in mortality between the clofibrate-treated subjects and 3,000 placebo-treated subjects, but twice as many clofibrate-treated subjects developed cholelithiasis and cholecystitis requiring surgery. In the other study, conducted by the World Health Organization (WHO), 5,000 subjects without known coronary heart disease were treated with clofibrate for five years and followed one year beyond. There was a statistically significant (44%) higher age-adjusted total mortality in the clofibrate-treated group than in a comparable placebo-treated control group during the trial period. The excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis. The higher risk of clofibrate-treated subjects for gallbladder disease was confirmed. Because of the more limited size of the Helsinki Heart Study, the observed difference in mortality from any cause between the gemfibrozil and placebo groups is not statistically significantly different from the 29% excess mortality reported in the clofibrate group in the separate WHO study at the nine year follow-up (see CLINICAL PHARMACOLOGY ). Noncoronary heart disease related mortality showed an excess in the group originally randomized to gemfibrozil primarily due to cancer deaths observed during the open-label extension. During the five year primary prevention component of the Helsinki Heart Study, mortality from any cause was 44 (2.2%) in the gemfibrozil group and 43 (2.1%) in the placebo group; including the 3.5 year follow-up period since the trial was completed, cumulative mortality from any cause was 101 (4.9%) in the gemfibrozil group and 83 (4.1%) in the group originally randomized to placebo (hazard ratio 1:20 in favor of placebo). Because of the more limited size of the Helsinki Heart Study, the observed difference in mortality from any cause between the gemfibrozil and placebo groups at Year-5 or at Year-8.5 is not statistically significantly different from the 29% excess mortality reported in the clofibrate group in the separate WHO study at the nine year follow-up. Noncoronary heart disease related mortality showed an excess in the group originally randomized to gemfibrozil at the 8.5 year follow-up (65 gemfibrozil versus 45 placebo noncoronary deaths). The incidence of cancer (excluding basal cell carcinoma) discovered during the trial and in the 3.5 years after the trial was completed was 51 (2.5%) in both originally randomized groups. In addition, there were 16 basal cell carcinomas in the group originally randomized to gemfibrozil and 9 in the group randomized to placebo (p=0.22). There were 30 (1.5%) deaths attributed to cancer in the group originally randomized to gemfibrozil and 18 (0.9%) in the group originally randomized to placebo (p=0.11). Adverse outcomes, including coronary events, were higher in gemfibrozil patients in a corresponding study in men with a history of known or suspected coronary heart disease in the secondary prevention component of the Helsinki Heart Study (see CLINICAL PHARMACOLOGY ). A comparative carcinogenicity study was also done in rats comparing three drugs in this class: fenofibrate (10 and 60 mg/kg; 0.3 and 1.6 times the human dose, respectively), clofibrate (400 mg/kg; 1.6 times the human dose), and gemfibrozil (250 mg/kg; 1.7 times the human dose). Pancreatic acinar adenomas were increased in males and females on fenofibrate; hepatocellular carcinoma and pancreatic acinar adenomas were increased in males and hepatic neoplastic nodules in females treated with clofibrate; hepatic neoplast

CONTRAINDICATIONS Hepatic or severe renal dysfunction, including primary biliary cirrhosis. Preexisting gallbladder disease (see WARNINGS ). Hypersensitivity to gemfibrozil. Combination therapy of gemfibrozil with simvastatin (see WARNINGS and PRECAUTIONS ). Combination therapy of gemfibrozil with repaglinide (see PRECAUTIONS ). Combination therapy of gemfibrozil with dasabuvir (see PRECAUTIONS ). Combination therapy of gemfibrozil with selexipag (see PRECAUTIONS ).

OVERDOSAGE There have been reported cases of overdosage with gemfibrozil. In one case, a 7-year-old child recovered after ingesting up to 9 grams of gemfibrozil. Symptoms reported with overdosage were abdominal cramps, abnormal liver function tests, diarrhea, increased CPK, joint and muscle pain, nausea and vomiting. Symptomatic supportive measures should be taken, should an overdose occur.