"The U.S. Food and Drug Administration today notified Ranbaxy Laboratories, Ltd., that it is prohibited from manufacturing and distributing active pharmaceutical ingredients (APIs) from its facility in Toansa, India, for FDA-regulated drug product"...
(Generic versions may still be available.)
- Patient Information:
Details with Side Effects
In a large study involving 5,000 patients in a clofibrate-treated group and 5,000 in a placebo-treated group followed for an average of five years on drug or placebo and one year beyond (the WHO study), there was a statistically significant 44% higher age-adjusted total mortality in the clofibrate-treated group than in a comparable placebo group. The excess deaths were due to noncardiovascular causes; half of this difference was due to malignancy; other causes of death included postcholecystectomy complications and pancreatitis. 3 In another prospective study involving 1,000 clofibrate- and 3,000 placebo-treated patients followed for an average of six years on drug or placebo (the Coronary Drug Project study), the noncardiovascular mortality rate, including that of malignancy, was not significantly different in the clofibrate- and placebo-treated groups. 4 This should not be interpreted to mean that clofibrate is not associated with an increased risk of noncardiovascular death, because the patients in the Coronary Drug Project were much older than those in the WHO study and they all had had a previous myocardial infarction, so that the deaths in the Coronary Drug Project were overwhelmingly due to cardiovascular causes, and it would have been very difficult to discern a clofibrate-associated risk of death due to noncardiovascular causes if it existed. Both studies demonstrated that clofibrate users have twice the risk of developing cholelithiasis and cholecystitis requiring surgery as do nonusers.
A potential benefit of clofibrate was, however, reported in the WHO study which involved patients with hypercholesterolemia and no history of myocardial infarction or angina pectoris. In this study, there was a statistically significant 25% decrease in subsequent nonfatal myocardial infarctions in the clofibrate-treated group when compared with the placebo group. There was no difference in incidence of fatal myocardial infarction in the two groups. In the Coronary Drug Project study, which involved patients with or without hypercholesterolemia and/or hypertriglyceridemia and with a history of previous myocardial infarction, there was no significant difference in incidence of either nonfatal or fatal myocardial infarction between the clofibrate- and placebo-treated groups. 3
As a result of these and other studies, the following can be stated:
BECAUSE OF THE TUMORIGENICITY OF CLOFIBRATE IN RODENTS AND THE POSSIBLE INCREASED RISK OF MALIGNANCY ASSOCIATED WITH CLOFIBRATE IN THE HUMAN, AS WELL AS THE INCREASED RISK OF CHOLELITHIASIS, AND BECAUSE THERE IS NOT, TO DATE, SUBSTANTIAL EVIDENCE OF A BENEFICIAL EFFECT ON CARDIOVASCULAR MORTALITY FROM CLOFIBRATE, THIS DRUG SHOULD BE UTILIZED ONLY FOR THOSE PATIENTS DESCRIBED IN THE INDICATIONS AND USAGE SECTION, AND SHOULD BE DISCONTINUED IF SIGNIFICANT LIPID RESPONSE IS NOT OBTAINED.
CAUTION SHOULD BE EXERCISED WHEN ANTICOAGULANTS ARE GIVEN IN CONJUNCTION WITH ATROMID-S (clofibrate) ®. THE DOSAGE OF THE ANTICOAGULANT SHOULD BE REDUCED USUALLY BY ONE-HALF (DEPENDING ON THE INDIVIDUAL CASE) 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 BEEN STABILIZED.
Myalgia, myositis, myopathy, and rhabdomyolysis with or without elevation of CPK have been associated with Atromid-S (clofibrate) therapy. Consideration should be given to withholding or discontinuing drug therapy in any patient with a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis, including: severe acute infection; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; and uncontrolled seizures.
Atromid-S (clofibrate) therapy should be discontinued if markedly elevated CPK levels occur or myositis is diagnosed.
Avoidance of Pregnancy
Strict birth-control procedures must be exercised by women of child-bearing potential. In patients who plan to become pregnant, clofibrate should be withdrawn several months before conception. Because of the possibility of pregnancy occurring despite birth-control precautions in patients taking clofibrate, the possible benefits of the drug to the patient must be weighed against possible hazards to the fetus. (See Pregnancy section.)
Because of the long-term administration of a drug of this nature, adequate baseline studies should be performed to determine that the patient has significantly elevated serum lipid levels. Frequent determinations of serum lipids should be obtained during the first few months of Atromid-S (clofibrate) administration, and periodic determinations made thereafter. The drug should be withdrawn after three months if response is inadequate. However, in the case of xanthoma tuberosum, the drug should be employed for longer periods (even up to one year) provided that there is a reduction in the size and/or number of the xanthomata.
Since cholelithiasis is a possible side effect of clofibrate therapy, appropriate diagnostic procedures should be performed if signs and symptoms related to disease of the biliary system should occur.
Clofibrate may produce "flu-like" symptoms (muscular aching, soreness, cramping) associated with increased creatine kinase levels indicative of drug-induced myopathy. The physician should differentiate this from actual viral and/or bacterial disease.
Use with caution in patients with peptic ulcer, since reactivation has been reported. Whether this is drug related is unknown.
Various cardiac arrhythmias have been reported with the use of clofibrate.
Subsequent serum lipid determinations should be done to detect a paradoxical rise in serum cholesterol or triglyceride levels. Clofibrate will not alter the seasonal variations of serum cholesterol: peak elevations in midwinter and late summer and decreases in fall and spring. If the drug is discontinued, the patient should be continued on an appropriate hypolipidemic diet, and serum lipids should be monitored until stabilized, as a rise in these values to or above the original baseline may occur.
During clofibrate therapy, frequent serum-transaminase determinations and other liver-function tests should be performed, since the drug may produce abnormalities in these parameters. These effects are usually reversible when the drug is discontinued. Hepatic biopsies are usually within normal limits. If the hepatic-function tests steadily rise or show excessive abnormalities, the drug should be withdrawn. Therefore, use with caution in those patients with a past history of jaundice or hepatic disease.
Caution should be exercised when anticoagulants are given in conjunction with Atromid-S (clofibrate) . Usually, the dosage of the anticoagulant should be reduced by one-half (depending on the individual case) to maintain the prothrombin time at the desired level to prevent bleeding complications. Frequent prothrombin determinations are advisable until it has been determined definitely that the prothrombin level has been stabilized.
Atromid-S (clofibrate) may displace acidic drugs such as phenytoin or tolbutamide from their binding sites. Caution should be exercised when treating patients with either of these drugs or other highly protein-bound drugs and Atromid-S (clofibrate) . The hypoglycemic effect of tolbutamide has been reported to increase when Atromid-S (clofibrate) is given concurrently.
Fulminant rhabdomyolysis has been seen as early as three weeks after initiation of combined therapy with another fibrate and lovastatin but may be seen after several months. For these reasons, it is felt that, in most subjects who have had an unsatisfactory lipid response to either drug alone, the possible benefits of combined therapy with lovastatin and a fibrate do not outweigh the risks of severe myopathy, rhabdomyolysis, and acute renal failure. While it is not known whether this interaction occurs with fibrates other than gemfibrozil, myopathy and rhabdomyolysis have occasionally been associated with the use of fibrates alone, including clofibrate. Therefore, the combined use of lovastatin with fibrates should generally be avoided.
WARNINGS section for information on carcinogenesis and mutagenesis.
Arrest of spermatogenesis has been seen in both dogs and monkeys at doses approximately 2 times the maximum recommended human dose (based on surface area).
Electron microscopy studies have demonstrated peroxisomal proliferation following clofibrate administration to the rat. Changes in peroxisome morphology and numbers have been observed in humans after treatment with several members of the fibrate class, including clofibrate, when liver biopsies were compared before and after treatment in the same individual.
Pregnancy Category C. Animal reproduction studies have not been conducted with Atromid-S (clofibrate) . It is also not known whether Atromid-S (clofibrate) can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. However, animal reproduction studies with clofibrate plus androsterone showed increases in neonatal deaths and pup mortality during lactation.
Atromid-S (clofibrate) is contraindicated in lactating women, since an active metabolite (CPIB) has been measured in breast milk.
Safety and efficacy in pediatric patients have not been established.
Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.
Additional Atromid-S Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find out what women really need.