"The U.S. Food and Drug Administration today approved Kynamro (mipomersen sodium) injection as an addition to lipid-lowering medications and diet to treat patients with a rare type of high cholesterol called homozygous familial hypercholesterolemi"...
- 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.
- 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.
- 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.
- Concomitant Anticoagulants – Caution should be exercised when warfarin is given in conjunction with LOPID. The dosage of 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.
- 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 (see PRECAUTIONS: 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.
- Cataracts – Subcapsular bilateral cataracts occurred in 10%, and unilateral in 6.3%, of male rats treated with gemfibrozil at 10 times the human dose.
- CYP2C8 substrates -Gemfibrozil, an inhibitor of CYP2C8, may increase exposure of CYP2C8 substrates when administered concomitantly (see PRECAUTIONS: DRUG INTERACTIONS).
- OATP1B1 substrates – Gemfibrozil is an inhibitor of organic anion-transporter polyprotein (OATP) 1B1 and may increase exposure of drugs that are substrates of OATP1B1 (e.g., atrasentan, atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, SN38 [active metabolite of irinotecan], rosuvastatin, pitavastatin, pravastatin, rifampin, valsartan, olmesartan). Therefore, dosing reductions of drugs that are substrates of OATP1B1 may be required when gemfibrozil is used concomitantly (see PRECAUTIONS: DRUG INTERACTIONS). Combination therapy of gemfibrozil with simvastatin or with repaglinide, which are OATP1B1 substrates, is contraindicated (see CONTRAINDICATIONS).
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.
Periodic determination of serum lipids should be obtained, and the drug withdrawn if lipid response is inadequate after three months of therapy.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
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 LOPID 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.
Pregnancy Category C
LOPID 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. LOPID should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Administration of LOPID 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, 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 LOPID 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 LOPID 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 LOPID 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 LOPID 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 LOPID administration.
Abnormal liver function tests have been observed occasionally during LOPID administration, including elevations of AST, ALT, LDH, bilirubin, and alkaline phosphatase. These are usually reversible when LOPID is discontinued. Therefore, periodic liver function studies are recommended and LOPID therapy should be terminated if abnormalities persist.
There have been reports of worsening renal insufficiency upon the addition of LOPID 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 LOPID.
Safety and efficacy in pediatric patients have not been established.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 4/19/2016
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