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| __NOTOC__
| | #REDIRECT [[Gemfibrozil#Warnings]] |
| {{Gemfibrozil}}
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| {{CMG}}; {{AE}} {{SS}}
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| ==Warnings and Precautions==
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| ===WARNINGS===
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| 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.
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| 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.
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| 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).
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| 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 carcinoma]]s 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).
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| 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.
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| 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.
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| 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.
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| 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.
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| 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.
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| 6. [[Cataract]]s – Subcapsular bilateral [[cataract]]s occurred in 10%, and unilateral in 6.3%, of male rats treated with gemfibrozil at 10 times the human dose.
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| ===PRECAUTIONS===
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| ====Initial Therapy====
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| Laboratory studies should be done to ascertain that the lipid levels are consistently abnormal. Before instituting LOPID 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.
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| ====Continued Therapy====
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| Periodic determination of serum lipids should be obtained, and the drug withdrawn if lipid response is inadequate after three months of therapy.
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| ====Drug Interactions====
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| =====HMG-CoA Reductase Inhibitors=====
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| The concomitant administration of LOPID with [[simvastatin]] is contraindicated (see CONTRAINDICATIONS and WARNINGS). 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.
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| =====Anticoagulants=====
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| CAUTION SHOULD BE EXERCISED WHEN ANTI-COAGULANTS 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.
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| =====Repaglinide=====
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| 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).
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| =====Bile Acid-Binding Resins=====
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| 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. | |
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| =====Colchicine=====
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| [[Myopathy]], including [[rhabdomyolysis]], has been reported with chronic administration of colchicine at therapeutic doses. Concomitant use of LOPID may potentiate the development of [[myopathy]]. Patients with renal dysfunction and elderly patients are at increased risk. Caution should be exercised when prescribing LOPID with colchicine, especially in elderly patients or patients with [[renal dysfunction]].<ref>{{Cite web | last = | first = | title = DailyMed: Search | url = http://dailymed.nlm.nih.gov/dailymed/search.cfm?startswith=+Lopid&x=11&y=10 | publisher = | date = | accessdate = 13 February 2014 }}</ref>
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| ==References==
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| {{Reflist|2}}
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| {{Lipid modifying agents}}
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| | [[Category: Cardiovascular Drugs]] |
| | [[Category: Drug]] |
| [[Category:Fibrates]] | | [[Category:Fibrates]] |
| [[Category:Phenol ethers]]
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| [[Category:Cardiovascular Drug]]
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| [[Category:Drug]]
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