Gemfibrozil

Gemfibrozil
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];

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Overview

Gemfibrozil is a lipid regulating agent that is FDA approved for the {{{indicationType}}} of Types IV and V hyperlipidemia at risk of pancreatitis and who do not respond adequately to a determined dietary effort to control them, and 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) and who have the following triad of lipid abnormalities: low HDL-cholesterol levels in addition to elevated LDL-cholesterol and elevated triglycerides. Common adverse reactions include dyspepsia, abdominal pain, acute appendicitis, atrial fibrillation, diarrhea, fatigue, eczema, rash, vertigo, constipation, headache.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Types IV and V hyperlipidemia

• Dosing Information

• 1200 mg administered in two divided doses 30 minutes before the morning and evening meals

Condition 2

• Dosing Information

• (Dosage)

Off-Label Use and Dosage (Adult)

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Gemfibrozil FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information about Off-Label Guideline-Supported Use of Gemfibrozil in pediatric patients.

Non–Guideline-Supported Use

There is limited information about Off-Label Non–Guideline-Supported Use of Gemfibrozil in pediatric patients.

Contraindications

• Hepatic or severe renal dysfunction, including primary biliary cirrhosis.
• Preexisting gallbladder disease.
• Hypersensitivity to gemfibrozil.
• Combination therapy of gemfibrozil with repaglinide
• Combination therapy of gemfibrozil with simvastatin

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, 1000 subjects with previous myocardial infarction were treated for five years with clofibrate. There was no difference in mortality between the clofibrate-treated subjects and 3000 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), 5000 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 LOPID 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 LOPID 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 LOPID 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 LOPID 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 LOPID 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 LOPID at the 8.5 year follow-up (65 LOPID 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 LOPID and 9 in the group originally randomized to placebo (p=0.22). There were 30 (1.5%) deaths attributed to cancer in the group originally randomized to LOPID 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 neoplastic nodules were increased in males and females treated with clofibrate; hepatic neoplastic nodules were increased in males and females treated with gemfibrozil while testicular interstitial cell (Leydig cell) tumors were increased in males on all three drugs.

2. A gallstone prevalence substudy of 450 Helsinki Heart Study participants showed a trend toward a greater prevalence of gallstones during the study within the LOPID treatment group (7.5% versus 4.9% for the placebo group, a 55% excess for the gemfibrozil group). A trend toward a greater incidence of gallbladder surgery was observed for the LOPID group (17 versus 11 subjects, a 54% excess). This result did not differ statistically from the increased incidence of cholecystectomy observed in the WHO study in the group treated with clofibrate. Both clofibrate and gemfibrozil may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. LOPID therapy should be discontinued if gallstones are found. Cases of cholelithiasis have been reported with gemfibrozil therapy.

3. Since a reduction of mortality from coronary heart disease has not been demonstrated and because liver and interstitial cell testicular tumors were increased in rats, LOPID should be administered only to those patients described in the INDICATIONS AND USAGE section. If a significant serum lipid response is not obtained, LOPID should be discontinued.

4. Concomitant Anticoagulants – Caution should be exercised when anticoagulants are given in conjunction with LOPID. The dosage of the anticoagulant should be reduced to maintain the prothrombin time at the desired level to prevent bleeding complications. Frequent prothrombin determinations are advisable until it has been definitely determined that the prothrombin level has stabilized.

5. The concomitant administration of LOPID with simvastatin is contraindicated (see CONTRAINDICATIONS and PRECAUTIONS). Concomitant therapy with LOPID and an HMG-CoA reductase inhibitor is associated with an increased risk of skeletal muscle toxicity manifested as rhabdomyolysis, markedly elevated creatine kinase (CPK) levels, and myoglobinuria, leading in a high proportion of cases to acute renal failure and death. IN PATIENTS WHO HAVE HAD AN UNSATISFACTORY LIPID RESPONSE TO EITHER DRUG ALONE, THE BENEFIT OF COMBINED THERAPY WITH LOPID AND an HMG-CoA REDUCTASE INHIBITOR DOES NOT OUTWEIGH THE RISKS OF SEVERE MYOPATHY, rhabdomyolysis, AND ACUTE RENAL FAILURE (seePRECAUTIONS, Drug Interactions). The use of fibrates alone, including LOPID, may occasionally be associated with myositis. Patients receiving LOPID and complaining of muscle pain, tenderness, or weakness should have prompt medical evaluation for myositis, including serum creatine–kinase level determination. If myositis is suspected or diagnosed, LOPID therapy should be withdrawn.

6. Cataracts – Subcapsular bilateral cataracts occurred in 10%, and unilateral in 6.3%, of male rats treated with gemfibrozil at 10 times the human dose.

Adverse Reactions

Clinical Trials Experience

Central Nervous System

(list/description of adverse reactions)

Cardiovascular

• Atrial fibrillation:

• Incidence: 0.7%
• In the double-blind, placebo-controlled phase of the Helsinki study the incidence of atrial fibrillation was 0.7% with gemfibrozil (n=2046) compared with 0.1% with placebo (n=2035). The difference was statistically significant

• Hyperhomocysteinemia

• Hyperhomocystinemia was associated with fenofibrate therapy, but not gemfibrozil therapy, based on a randomized, crossover trial (n=22, all males). Homocysteine plasma concentrations are thought to be related to renal function, and elevated levels are considered a risk factor for adverse cardiovascular effects. Enrollees underwent a 6-week medication period, followed by a 6-week washout period and another 6- week treatment period. Micronized fenofibrate doses were 200 milligrams/day (mg/day) and gemfibrozil doses were 900 mg/day. Plasma homocysteine levels increased significantly during fenofibrate therapy (baseline 10.7 to 14.4 micromols/Liter) while decreasing slightly during gemfibrozil treatment (12.9 to 12.4) (p=0.007; gemfibrozil versus fenofibrate). Also, creatinine and cystatin C increased significantly only during fenofibrate dosing (p=0.006 and p=0.04, respectively, gemfibrozil vs fenofibrate). Overall, 9 of 22 patients had abnormally high homocysteine concentrations after use of fenofibrate. Both medications produced positive effects on triglyceride levels. The authors postulate that the increases in homocysteine resulted from degradation of renal function caused by fenofibrate therapy

• Raynaud's phenomenon

• A case of Raynaud's phenomenon in 3 digits of both hands, which progressed to digital pulp infarction, vasculitis, and polyarthritis occurred in a 34-year-old male. The patient had received gemfibrozil for 3 years prior to this event. Following drug discontinuation and symptomatic therapy, symptoms resolved

Dermatologic

• Eczema

• Incidence: 1.9%
• In the double-blind, placebo-controlled phase of the Helsinki study, the incidence of eczema was 1.9% with gemfibrozil treatment (n=2046) compared with 1.2% with placebo (n=2035).

• Polymyositis

• Exacerbation of dermatomyositis/polymyositis was reported in a 64-year-old female following the administration of gemfibrozil 600 mg twice daily for 2 months. The patient developed a scaly, pruritic, purple rash, increasing weakness, and a CPK of 828 units (normal up to 300). The patient responded to discontinuation of gemfibrozil along with steroid therapy.

• Rash

• Incidence: 1.7%
• In the double-blind, placebo-controlled phase of the Helsinki study, the incidence of rash was 1.7% with gemfibrozil treatment (n=2046) compared with 1.3% with placebo (n=2035). The difference was not statistically significant

Endocrine

• Abnormal glucose level

• Gemfibrozil does not appear to affect plasma glucose or insulin concentrations in nondiabetic patients. However, data regarding gemfibrozil's effect on glucose metabolism in noninsulin dependent diabetics has been conflicting.
• During a 3-month study involving 24 nondiabetic patients with endogenous hypertriglyceridemia, treatment with gemfibrozil (600 milligrams (mg) twice daily) did not affect plasma glucose or insulin concentrations [59].
• One study reported significant decreases in mean hourly plasma glucose concentrations in sulfonylurea-treated non-insulin-dependent diabetes mellitus patients with fasting plasma glucose levels above 9 millimoles/liter (mmol/L) (fair control; n=6) receiving gemfibrozil 600 to 1200 milligrams/day (mg/day). However, in patients with fasting plasma glucose levels below 9 mmol/L (good control; n=6) there was a mean modest increase in glucose concentration from 9.2 to 11.7 mmol/L.
• One study [61] reported that gemfibrozil decreases fasting and OGTT (oral glucose tolerance test)-stimulated glucose in hypertriglyceridemic patients with glucose intolerance, but does not have a significant effect in subjects with normal glucose metabolism. Patients and controls received gemfibrozil 1200 milligrams (mg)/day.
• Gemfibrozil 600 milligrams (mg) orally twice daily for 15 days was reported to produce no relevant effect on glucose metabolism in noninsulin dependent diabetic outpatients in a controlled study. However, more studies involving longer periods of treatment are required to determine effects of the drug on glucose metabolism.

• Hyperkalemia

• Life-threatening hyperkalemia and rhabdomyolysis developed in a 72- year-old diabetic woman treated with cerivastatin and gemfibrozil. She was taking metformin 850 mg, hydrochlorothiazide 12.5 mg, and cerivastatin 0.2 mg (all once daily) for diabetes (NIDDM) and hypercholesterolemia. Serum creatinine was 66 micromol/L. Because of ongoing hyperlipidemia, gemfibrozil 600 mg was added to therapy. Three days later she was admitted with complaints of chest pain and severe muscle pain. Laboratory tests showed serum potassium 10.3 mmol/L, blood urea nitrogen 42.3 mmol/L, serum creatinine 550 micromoles/L, and creatine kinase 58,886 units/L. Glucose and insulin were given immediately and hemodialysis was started. Potassium concentrations decreased to 4.7 mmol/L, and electrocardiographic abnormalities resolved. She required dialysis for 7 weeks. Her creatinine concentration stabilized at 190 micromol/L (creatinine clearance 55 mL/min). The authors suspected the life-threatening events were caused by concomitant cerivastatin and gemfibrozil due to the temporal relationship

Gastrointestinal

• Abdominal pain

• Incidence: 9.8%
• In the double-blind, placebo-controlled phase of the Helsinki study, the incidence of abdominal pain was 9.8% with gemfibrozil (n=2046) compared with 5.6% with placebo (n=2035). The difference was statistically significant.

• Acute appendicitis

• Incidence: 1.2% [54]
• In the double-blind, placebo-controlled phase of the Helsinki study, the incidence of acute appendicitis was 1.2% with gemfibrozil (n=2046) compared with 0.6% with placebo (n=2035). The difference was statistically significant and histologically confirmed in cases where data was available .

• Cholecystitis

• In the Coronary Drug Project, a large study of postmyocardial infarction patients treated with clofibrate for 5 years, twice the number of patients treated with clofibrate experienced cholelithiasis and cholecystitis requiring surgery.

• Cholelithiasis

• In the Coronary Drug Project, a large study of postmyocardial infarction patients treated with clofibrate for 5 years, twice the number of patients treated with clofibrate experienced cholelithiasis and cholecystitis requiring surgery.

• Diarrhea

• Incidence: 7.2%
• In the double-blind, placebo-controlled phase of the Helsinki study, the incidence of diarrhea was 7.2% with gemfibrozil (n=2046) compared with 6.5% with placebo (n=2035).

• Indigestion

• Incidence: 19.6%.
• In the double-blind, placebo-controlled phase of the Helsinki study, the incidence of dyspepsia was 19.6% with gemfibrozil (n=2046) compared with 11.9% with placebo (n=2035). The difference was statistically significant

Hematologic

• Eosinophilic gastroenteritis

• An allergic reaction to gemfibrozil manifested as eosinophilic gastroenteritis in a 56-year-old woman being treated for hyperlipidemia. Two weeks after initiation of gemfibrozil therapy (dose unspecified), the patient experienced watery diarrhea and lower abdominal cramping, which was progressively worsening. She had a history of allergic rhinitis, asthma, gout, and diabetes mellitus. On admission, the patient was pale and dehydrated; her eosinophil count was 1820/cubic millimeter (mm(3)), later increasing to 4850/mm3 (normal, 0 to 440/mm3). Endoscopy showed prominent antral folds, a gastric polyp, and duodenal and jejunal mucosal granularity. Multiple biopsies of the upper and lower gastrointestinal (GI) tract revealed eosinophilic aggregation and infiltration most prominently in the mucosal layers of the stomach antrum, duodenum, ascending colon, transverse colon, and rectum. Gemfibrozil was withdrawn; methylprednisolone (125 milligrams (mg) twice a day) followed by prednisone (40 milligrams (mg)/day) brought gradual resolution of symptoms. Twice the patient was rechallenged with gemfibrozil and each time diarrhea and peripheral eosinophilia returned.

• Fibrinogen in blood above reference range

• A study enrolling 27 hyperlipidemic patients with stable peripheral arterial occlusive disease reported a 17.6% mean increase in plasma fibrinogen. This effect was the only adverse effect on blood components monitored; other parameters (e.g., antithrombin III, Factor VIIc, plasma lipid peroxides) suggested a beneficial effect in peripheral arterial disease.

• RBC count abnormal

• Long-term treatment with gemfibrozil (3 to 7 months) was not associated with any significant decreases in blood cell counts. However, reduced hemoglobin, reduced hematocrit, and reduced white cell blood count have rarely occurred with initiation of gemfibrozil therapy. The levels stabilized with continuation of therapy; however, the manufacturer suggests that periodic blood counts are warranted during the first year of treatment.

• White blood cell count abnormal

• Long-term treatment with gemfibrozil (3 to 7 months) was not associated with any significant decreases in blood cell counts. However, reduced hemoglobin, reduced hematocrit, and reduced white cell blood count have rarely occurred with initiation of gemfibrozil therapy. The levels stabilized with continuation of therapy; however, the manufacturer suggests that periodic blood counts are warranted during the first year of treatment

Postmarketing Experience

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Drug Interactions

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Use in Specific Populations

Pregnancy

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Labor and Delivery

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Nursing Mothers

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Geriatic Use

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Renal Impairment

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Females of Reproductive Potential and Males

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Immunocompromised Patients

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Others

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Administration and Monitoring

Administration

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Monitoring

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IV Compatibility

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Y-Site

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Overdosage

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Chronic Overdose

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Pharmacology

Gemfibrozil
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Storage

There is limited information regarding Gemfibrozil Storage in the drug label.

Images

Drug Images

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Patient Counseling Information

(Patient Counseling Information)

Precautions with Alcohol

Alcohol-Gemfibrozil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Gemfibrozil Brand Names in the drug label.

Look-Alike Drug Names

• (Paired Confused Name 1a) — (Paired Confused Name 1b)
• (Paired Confused Name 2a) — (Paired Confused Name 2b)
• (Paired Confused Name 3a) — (Paired Confused Name 3b)

Drug Shortage Status

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References

The contents of this FDA label are provided by the National Library of Medicine.