In the double-blind controlled phase of the primary prevention component of the Helsinki Heart Study, 2046 patients received LOPID for up to five years. In that study, the following adverse reactions were statistically more frequent in subjects in the LOPID group:

Gallbladder surgery was performed in 0.9% of LOPID 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 was also performed more frequently in the LOPID 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 LOPID group. These included hypesthesia, paresthesias, and taste perversion. Other adverse reactions that were more common among LOPID 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 LOPID 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 LOPID is probable or not established:

Additional adverse reactions that have been reported include cholecystitis and cholelithiasis (ref. 12) (see WARNINGS).

(A) HMG-CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis is increased with combined gemfibrozil and HMG-CoA reductase inhibitor therapy (see CONTRAINDICATIONS). 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 (refs. 8, 9, 10, 11). (See WARNINGS.) There is no assurance that periodic monitoring of creatine kinase will prevent the occurrence of severe myopathy and kidney damage.

(B) 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.

(C) Repaglinide: In vivo data from a study that evaluated the co-administration of gemfibrozil with repaglinide in healthy subjects resulted in a significant increase in repaglinide blood levels. Patients taking repaglinide should not start taking gemfibrozil; patients taking gemfibrozil should not start taking repaglinide. Concomitant use may result in enhanced and prolonged blood glucose-lowering effects of repaglinide. Caution should be used in patients already on repaglinide and gemfibrozil – blood glucose levels should be monitored and repaglinide dose adjustment may be needed. Rare post marketing events of serious hypoglycemia have been reported in patients taking repaglinide and gemfibrozil together. In this same study, gemfibrozil and itraconazole had a synergistic metabolic inhibitory effect on repaglinide. Therefore, patients taking repaglinide and gemfibrozil should not take itraconazole.

REFERENCES

8. Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdomyolysis associated with lovastatin/gemfibrozil combination therapy. JAMA 1990;264:71–75.

9. Bermingham RP, Whitsitt TB, Smart ML et al. Rhabdomyolysis in a patient receiving the combination of cerivastatin and gemfibrozil. Am J Health-Syst Pharm 2000;57:461–464.

10. Duell PB, Connor WE, Illingworth DR. Rhabdomyolysis after taking atorvastatin with gemfibrozil. Am J Cardiol 1998;81:368–369.

11. Tal A, Rajeshawari M, Isley W. Rhabdomyolysis associated with simvastatin/gemfibrozil therapy. South Med J 1997;90:546–547.

12. Data on file. Pfizer; NY, NY.

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