DailyMed Label: Gemfibrozil

DailyMed Label: Gemfibrozil

2010

DailyMed Prescription

Gemfibrozil

Gemfibrozil

State of Florida DOH Central Pharmacy

NDC: 53808-0251

NDC: 53808-0251

Gemfibrozil is a lipid regulating agent. It is available as tablets for oral administration. Each tablet contains 600 mg gemfibrozil. In addition, each tablet contains the following inactive ingredients: calcium stearate, colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polydextrose K, polyethylene glycol 4000, polysorbate 80, pregelatinized starch and titanium dioxide. The chemical name is 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, with the following structural formula: C 15 H 22 O 3 M.W. 250.35 The solubility in water and acid is 0.0019% and in dilute base it is greater than 1%. The melting point is 58 o to 61 o C. Gemfibrozil is a white solid which is stable under ordinary conditions. Structural formula for gemfibrozil

Gemfibrozil tablets are indicated as adjunctive therapy to diet for: 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 2000 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 1000 mg/dL are unlikely to present a risk of pancreatitis. Gemfibrozil therapy may be considered for those subjects with triglyceride elevations between 1000 and 2000 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 1000 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. 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 with familial hypertriglyceridemia. In such cases, discontinuation of estrogen therapy may obviate the need for specific drug therapy of hypertriglyceridemia. The use of drugs should be considered only when reasonable attempts have been made to obtain satisfactory results with nondrug methods. If the decision is made to use drugs, the patient should be instructed that this does not reduce the importance of adhering to diet.

The recommended dose for adults is 1200 mg administered in two divided doses 30 minutes before the morning and evening meal (see CLINICAL PHARMACOLOGY ).

1. Hepatic or severe renal dysfunction, including primary biliary cirrhosis. 2. Preexisiting gallbladder disease (see WARNINGS ). 3. Hypersensitivity to gemfibrozil. 4. Combination therapy of gemfibrozil with repaglinide (see PRECAUTIONS ).

Laboratory studies should be done to ascertain that the lipid levels are consistently abnormal. Before instituting gemfibrozil therapy, every attempt should be made to control serum lipids with appropriate diet, exercise, weight loss in obese patients, and control of any medical problems such as diabetes mellitus and hypothyroidism that are contributing to the lipid abnormalities. Periodic determination of serum lipids should be obtained, and the drug withdrawn if lipid response is inadequate after three months of therapy. The risk of myopathy and rhabdomyolysis is increased with combined gemfibrozil and HMG-CoA reductase inhibitor therapy. Myopathy or rhabdomyolysis with or without acute renal failure have been reported as early as three weeks after initiation of combined therapy or after several months (see WARNINGS ). There is no assurance that periodic monitoring of creatine kinase will prevent the occurrence of severe myopathy and kidney damage. CAUTION SHOULD BE EXERCISED WHEN ANTICOAGULANTS ARE GIVEN IN CONJUNCTION WITH GEMFIBROZIL. THE DOSAGE OF THE ANTICOAGULANT SHOULD BE REDUCED TO MAINTAIN THE PROTHROMBIN TIME AT THE DESIRED LEVEL TO PREVENT BLEEDING COMPLICATIONS. FREQUENT PROTHROMBIN DETERMINATIONS ARE ADVISABLE UNTIL IT HAS BEEN DEFINITELY DETERMINED THAT THE PROTHROMBIN LEVEL HAS STABILIZED. In healthy volunteers, coadministration with gemfibrozil increased the plasma concentration of repaglinide and prolonged its hypoglycemic effects. Coadministration of gemfibrozil and repaglinide increases the risk for severe hypoglycemia and is contraindicated (see CONTRAINDICATIONS ). Long-term studies have been conducted in rats at 0.2 and 1.3 times the human exposure (based on AUC). The incidence of benign liver nodules and liver carcinomas was significantly increased in high dose male rats. The incidence of liver carcinomas increased also in low dose males, but this increase was not statistically significant (p = 0.1). Male rats had a dose-related and statistically significant increase of benign Leydig cell tumors. The higher dose female rats had a significant increase in the combined incidence of benign and malignant liver neoplasms. Long-term studies have been conducted in mice at 0.1 and 0.7 times the human exposure (based on AUC). There were no statistically significant differences from controls in the incidence of liver tumors, but the doses tested were lower than those shown to be carcinogenic with other fibrates. Electron microscopy studies have demonstrated a florid hepatic peroxisome proliferation following gemfibrozil administration to the male rat. An adequate study to test for peroxisome proliferation has not been done in humans but changes in peroxisome morphology have been observed. Peroxisome proliferation has been shown to occur in humans with either of two other drugs of the fibrate class when liver biopsies were compared before and after treatment in the same individual. Administration of approximately 2 times the human dose (based on surface area) to male rats for 10 weeks resulted in a dose-related decrease of fertility. Subsequent studies demonstrated that this effect was reversed after a drug-free period of about eight weeks, and it was not transmitted to the offspring. Gemfibrozil has been shown to produce adverse effects in rats and rabbits at doses between 0.5 and 3 times the human dose (based on surface area). There are no adequate and well-controlled studies in pregnant women. Gemfibrozil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Administration of gemfibrozil to female rats at 2 times the human dose (based on surface area) before and throughout gestation caused a dose-related decrease in conception rate and an increase in stillborns and a slight reduction in pup weight during lactation. There were also dose-related increased skeletal variations. Anophthalmia occurred, but rarely. Administration of 0.6 and 2 times the human dose (based on surface area) of gemfibrozil to female rats from gestation day 15 through weaning caused dose-related decreases in birth weight and suppressions of pup growth during lactation. Administration of 1 and 3 times the human dose (based on surface area) of gemfibrozil to female rabbits during organogenesis caused a dose-related decrease in litter size and, at the high dose, an increased incidence of parietal bone variations. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for gemfibrozil in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Mild hemoglobin, hematocrit and white blood cell decreases have been observed in occasional patients following initiation of gemfibrozil therapy. However, these levels stabilize during long-term administration. Rarely, severe anemia, leukopenia, thrombocytopenia, and bone marrow hypoplasia have been reported. Therefore, periodic blood counts are recommended during the first 12 months of gemfibrozil administration. Abnormal liver function tests have been observed occasionally during gemfibrozil administration, including elevations of AST (SGOT), ALT (SGPT), LDH, bilirubin, and alkaline phosphatase. These are usually reversible when gemfibrozil is discontinued. Therefore, periodic liver function studies are recommended and gemfibrozil therapy should be terminated if abnormalities persist. There have been reports of worsening renal insufficiency upon the addition of gemfibrozil therapy in individuals with baseline plasma creatinine > 2.0 mg/dL. In such patients, the use of alternative therapy should be considered against the risks and benefits of a lower dose of gemfibrozil. Safety and efficacy in pediatric patients have not been established.

In the double-blind controlled phase of the primary prevention component of the Helsinki Heart Study, 2046 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 tablets USP, 600 mg are available as white to off-white, oval, film-coated tablets scored on one side, debossed "93"-"670" on the scored side. They are supplied by State of Florida DOH Central Pharmacy as follows: NDC Strength Quantity/Form Color Source Prod. Code 53808-0251-1 600 mg 30 Tablets in a Blister Pack white to off-white 0093-0670 Store at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature]. Protect from light and humidity. Dispense contents in a tight container as defined in the USP, with a child-resistant closure (as required). Manufactured In Israel By: TEVA PHARMACEUTICAL IND. LTD. Jerusalem, 91010, Israel Manufactured For: TEVA PHARMACEUTICALS USA Sellersville, PA 18960 This Product was Repackaged By: State of Florida DOH Central Pharmacy 104-2 Hamilton Park Drive Tallahassee, FL 32304 United States

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 HDL-cholesterol 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 4081 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 1000 patients) by Baseline Lipids lipid values in mg/dL at baseline in the Helsinki Heart Study, Years 0 to 5 P = placebo group; G = gemfibrozil group   All Patients LDL-C > 175; HDL-C > 46.4 LDL-C > 175; TG > 177 LDL-C > 175; TG > 200; HDL-C < 35 Incidents of Events fatal and nonfatal myocardial infarctions plus sudden cardiac deaths (events per 1000 patients over 5 years) P G Dif difference in rates between placebo and gemfibrozil groups P G Dif P G Dif P G Dif   41 27 14 32 29 3 71 44 27 149 64 85 Among Fredrickson types, during the 5 year double-blind portion of the primary prevention component of the Helsinki Heart Study, the greatest reduction in the incidence of serious coronary events occurred in Type IIb patients who had elevations of both LDL-cholesterol and total plasma triglycerides. This subgroup of Type IIb gemfibrozil group patients had a lower mean HDL-cholesterol level at baseline than the Type IIa subgroup that had elevations of LDL-cholesterol and normal plasma triglycerides. The mean increase in HDL-cholesterol among the Type IIb patients in this study was 12.6% compared to placebo. The mean change in LDL-cholesterol among Type IIb patients was -4.1% with gemfibrozil compared to a rise of 3.9% in the placebo subgroup. The Type IIb subjects in the Helsinki Heart Study had 26 fewer coronary events per thousand persons over five years in the gemfibrozil group compared to placebo. The difference in coronary events was substantially greater between gemfibrozil and placebo for that subgroup of patients with the triad of LDL-cholesterol > 175 mg/dL (> 4.5 mmol), triglycerides > 200 mg/dL (> 2.2 mmol), and HDL-cholesterol < 35 mg/dL (< 0.90 mmol) (see Table I ). Further information is available from a 3.5 year (8.5 year cumulative) follow-up of all subjects who had participated in the Helsinki Heart Study. At the completion of the Helsinki Heart Study, subjects could choose to start, stop, or continue to receive gemfibrozil; without knowledge of their own lipid values or double-blind treatment, 60% of patients originally randomized to placebo began therapy with gemfibrozil and 60% of patients originally randomized to gemfibrozil continued medication. After approximately 6.5 years following randomization, all patients were informed of their original treatment group and lipid values during the five years of the double-blind treatment. After further elective changes in gemfibrozil treatment status, 61% of patients in the group originally randomized to gemfibrozil were taking drug; in the group originally randomized to placebo, 65% were taking gemfibrozil. The event rate per 1000 occurring during the open-label follow-up period is detailed in Table II . Table II: Cardiac Events and All-Cause Mortality (events per 1000 patients) Occurring During the 3.5 Year Open-Label Follow-up to the Helsinki Heart Study The six open-label groups are designated first by the original randomization (P = placebo, G = gemfibrozil) and then by the drug taken in the follow-up period (N = Attend clinic but took no drug, G = gemfibrozil, Drop = No attendance at clinic during open-label). Group: PDrop PN PG GDrop GN GG N = 215 N = 494 N = 1283 N = 221 N = 574 N = 1207 Cardiac Events 38.8 22.9 22.5 37.2 28.3 25.4 All-Cause Mortality 41.9 22.3 15.6 72.3 19.2 24.9 Cumulative mortality through 8.5 years showed a 20% relative excess of deaths in the group originally randomized to gemfibrozil versus the originally randomized placebo group and a 20% relative decrease in cardiac events in the group originally randomized to gemfibrozil versus the originally randomized placebo group (see Table III ). This analysis of the originally randomized "intent-to-treat" population neglects the possible complicating effects of treatment switching during the open-label phase. Adjustment of hazard ratios taking into account open-label treatment status from years 6.5 to 8.5 could change the reported hazard ratios for mortality toward unity. Table III: Cardiac Events, Cardiac Deaths, Non-Cardiac Deaths and All-Cause Mortality in the Helsinki Heart Study, Years 0 to 8.5 Intention-to-Treat Analysis of originally randomized patients neglecting the open-label treatment switches and exposure to study conditions. Event Gemfibrozil at Study Start Placebo at Study Start Gemfibrozil: Placebo Hazard Ratio Hazard ratio for risk of event in the group originally randomized to gemfibrozil compared to the group originally randomized to placebo neglecting open-label treatment switch and exposure to study condition. CI Hazard Ratio 95% confidence intervals of gemfibrozil:placebo group hazard ratio Cardiac Events Fatal and non-fatal myocardial infarctions plus sudden cardiac deaths over the 8.5 year period. 110 131 0.80 0.62 to 1.03 Cardiac Deaths 36 38 0.98 0.63 to 1.54 Non-Cardiac Deaths 65 45 1.40 0.95 to 2.05 All-Cause Mortality 101 83 1.20 0.90 to 1.61 It is not clear to what extent the findings of the primary prevention component of the Helsinki Heart Study can be extrapolated to other segments of the dyslipidemic population not studied (such as women, younger or older males, or those with lipid abnormalities limited solely to HDL-cholesterol) or to other lipid-altering drugs. The secondary prevention component of the Helsinki Heart Study was conducted over five years in parallel and at the same centers in Finland in 628 middle-aged males excluded from the primary prevention component of the Helsinki Heart Study because of a history of angina, myocardial infarction or unexplained ECG changes. The primary efficacy endpoint of the study was cardiac events (the sum of fatal and non-fatal myocardial infarctions and sudden cardiac deaths). The hazard ratio (gemfibrozil:placebo) for cardiac events was 1.47 (95% confidence limits 0.88 to 2.48, p = 0.14). Of the 35 patients in the gemfibrozil group who experienced cardiac events, 12 patients suffered events after discontinuation from the study. Of the 24 patients in the placebo group with cardiac events, 4 patients suffered events after discontinuation from the study. There were 17 cardiac deaths in the gemfibrozil group and 8 in the placebo group (hazard ratio 2.18; 95% confidence limits 0.94 to 5.05, p = 0.06). Ten of these deaths in the gemfibrozil group and 3 in the placebo group occurred after discontinuation from therapy. In this study of patients with known or suspected coronary heart disease, no benefit from gemfibrozil treatment was observed in reducing cardiac events or cardiac deaths. Thus, gemfibrozil has shown benefit only in selected dyslipidemic patients without suspected or established coronary heart disease. Even in patients with coronary heart disease and the triad of elevated LDL-cholesterol, elevated triglycerides, plus low HDL-cholesterol, the possible effect of gemfibrozil on coronary events has not been adequately studied. No efficacy in the patients with established coronary heart disease was observed during the Coronary Drug Project with the chemically and pharmacologically related drug, clofibrate. The Coronary Drug Project was a 6 year randomized, double-blind study involving 1000 clofibrate, 1000 nicotinic acid, and 3000 placebo patients with known coronary heart disease. A clinically and statistically significant reduction in myocardial infarctions was seen in the concurrent nicotinic acid group compared to placebo; no reduction was seen with clofibrate. The mechanism of action of gemfibrozil has not been definitely established. In man, gemfibrozil has been shown to inhibit peripheral lipolysis and to decrease the hepatic extraction of free fatty acids, thus reducing hepatic triglyceride production. Gemfibrozil inhibits synthesis and increases clearance of VLDL carrier apolipoprotein B, leading to a decrease in VLDL production. Animal studies suggest that gemfibrozil may, in addition to elevating HDL-cholesterol, reduce incorporation of long-chain fatty acids into newly formed triglycerides, accelerate turnover and removal of cholesterol from the liver, and increase excretion of cholesterol in the feces. Gemfibrozil is well absorbed from the gastrointestinal tract after oral administration. Peak plasma levels occur in 1 to 2 hours with a plasma half-life of 1.5 hours following multiple doses. Gemfibrozil is completely absorbed after oral administration of gemfibrozil tablets, reaching peak plasma concentrations 1 to 2 hours after dosing. Gemfibrozil pharmacokinetics are affected by the timing of meals relative to time of dosing. In one study, both the rate and extent of absorption of the drug were significantly increased when administered 0.5 hour before meals. Average AUC was reduced by 14 to 44% when gemfibrozil was administered after meals compared to 0.5 hour before meals. In a subsequent study, rate of absorption of gemfibrozil was maximum when administered 0.5 hour before meals with the C max 50 to 60% greater than when given either with meals or fasting. In this study, there were no significant effects on AUC of timing of dose relative to meals (see DOSAGE AND ADMINISTRATION ). Gemfibrozil mainly undergoes oxidation of a ring methyl group to successively form a hydroxymethyl and a carboxyl metabolite. Approximately seventy percent of the administered human dose is excreted in the urine, mostly as the glucuronide conjugate, with less than 2% excreted as unchanged gemfibrozil. Six percent of the dose is accounted for in the feces. Gemfibrozil is highly bound to plasma proteins and there is potential for displacement interactions with other drugs (see PRECAUTIONS ).

NDC 53808- 0251 -1 GEMFIBROZIL Tablets USP 600 mg Each tablet contains: gemfibrozil, USP 600 mg Rx only 30 TABLETS TEVA Image of Bottle Label