1. -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. Initial Therapy
2. -Periodic determination of serum lipids should be obtained, and the drug withdrawn if lipid response is inadequate after three months of therapy. Continued Therapy
3. (A) 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 .) There is no assurance that periodic monitoring of creatine kinase will prevent the occurrence of severe myopathy and kidney damage. Drug Interactions- HMG-CoA reductase inhibitors: WARNINGS
(B) CAUTION SHOULD BE EXERCISED WHEN WARFARIN IS GIVEN IN CONJUNCTION WITH GEMFIBROZIL. THE DOSAGE OF THE WARFARIN 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. Anticoagulants:
(C) In healthy volunteers, co-administration with gemfibrozil (600 mg twice daily for 3 days) resulted in an 8.1-fold (range 5.5-to 15.0-fold) higher repaglinide AUC and a 28.6-fold (range 18.5- to 80.1-fold) higher repaglinide plasma concentration 7 hours after the dose. In the same study, gemfibrozil (600 mg twice daily for 3 days) + itraconazole (200 mg in the morning and 100 mg in the evening at Day 1, then 100 mg twice daily at Day 2-3) resulted in a 19.4- (range 12.9- to 24.7-fold) higher repaglinide AUC and a 70.4-fold (range 42.9- to 119.2-fold) higher repaglinide plasma concentration 7 hours after the dose. In addition, gemfibrozil alone or gemfibrozil + itraconazole prolonged the hypoglycemic effects of repaglinide. Co-administration of gemfibrozil and repaglinide increases the risk of severe hypoglycemia and is contraindicated (see CONTRAINDICATIONS). Repaglinide:
(D) Gemfibrozil AUC was reduced by 30% when gemfibrozil was given (600 mg) simultaneously with resin-granule drugs such as colestipol (5 g). Administration of the drugs two hours or more apart is recommended because gemfibrozil exposure was not significantly affected when it was administered two hours apart from colestipol. (E) Myopathy, including rhabdomyolysis, has been reported with chronic administration of colchicine at therapeutic doses. Concomitant use of gemfibrozil may potentiate the development of myopathy. Patients with renal dysfunction and elderly patients are at increased risk. Caution should be exercised when prescribing gemfibrozil with colchicine, especially in elderly patients or patients with renal dysfunction.
Bile Acid-Binding Resins:
4. –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. Carcinogenesis, Mutagenesis, Impairment of Fertility
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.
5. 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. Pregnancy Category C-
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.
6. 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. Nursing Mothers-
7. 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. Hematologic Changes-
8. 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 Liver Function-
9. 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. Kidney Function-
10. Safety and efficacy in pediatric patients have not been established. Pediatric Use-
Adverse Reactions to Gemfibrozil
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 (N = 2046)||PLACEBO (N = 2035)|
|Frequency in percent of subjects|
|(histologically confirmed in most cases where data were available)|
|Adverse events reported by more than 1% of subjects, but without a significant difference between groups:|
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 compared to the placebo group of the WHO study. Gallbladder surgery
Gallbladder surgery was also performed more frequently in the gemfibrozil group compared to placebo (1.9% vs 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 vs 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 ), and to ABNORMAL LIVER FUNCTION TESTS and HEMATOLOGIC CHANGES (see ). WARNINGSPRECAUTIONS
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 PROBALE||CAUSAL RELATIONSHIP NOT ESTABLISHED|
|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 and under ) WARINGSDrug InteractionsPRECUATIONS|
|Clinical Laboratory:||increased creatine phosphokinase increased bilirubin increased liver transaminases (AST [SGOT],ALT [SGPT]) increased alkaline phosphatase||positive antinuclear antibody|
|Hematopoietic:||anemia leukopenia bone marrow hypoplasiaeosinophilia||thrombocytopenia|
|Immunologic:||angicedema laryngeal edema urticaria||anaphylaxis lupus like syndrome vasculitis|
|Integumentary:||exfoliative dermatitisrash dermatitis pruritus||alopeciaphotosensitivity|
Additional adverse reactions that have been reported include cholecystitis and cholelithiasis (see WARNINGS ).
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