Fenofibrate 134 MG Oral Capsule
WARNINGS
Liver Function Fenofibrate at doses equivalent to 134 mg to 200 mg fenofibrate capsules per day has been associated with increases in serum transaminases [AST (SGOT) or ALT (SGPT)].
In a pooled analysis of 10 placebo-controlled trials, increases to >3 times the upper limit of normal occurred in 5.3% of patients taking fenofibrate versus 1.1% of patients treated with placebo.
When transaminase determinations were followed either after discontinuation of treatment or during continued treatment, a return to normal limits was usually observed.
The incidence of increases in transaminase related to fenofibrate therapy appear to be dose-related.
In an 8-week dose-ranging study, the incidence of ALT or AST elevations to at least three times the upper limit of normal was 13% in patients receiving dosages equivalent to 134 mg to 200 mg fenofibrate capsules per day and was 0% in those receiving dosages equivalent to 34 mg to 67 mg fenofibrate capsules per day, or placebo.
Hepatocellular, chronic active and cholestatic hepatitis associated with fenofibrate therapy have been reported after exposures of weeks to several years.
In extremely rare cases, cirrhosis has been reported in association with chronic active hepatitis.
Regular periodic monitoring of liver function, including serum ALT (SGPT) should be performed for the duration of therapy with fenofibrate capsules, and therapy discontinued if enzyme levels persist above three times the normal limit.
Cholelithiasis Fenofibrate, like clofibrate and gemfibrozil, may increase cholesterol excretion into the bile, leading to cholelithiasis.
If cholelithiasis is suspected, gallbladder studies are indicated.
Fenofibrate capsules therapy should be discontinued if gallstones are found.
Concomitant Oral Anticoagulants Caution should be exercised when anticoagulants are given in conjunction with fenofibrate capsules because of the potentiation of coumarin-type anticoagulants in prolonging the prothrombin time/INR.
The dosage of the anticoagulant should be reduced to maintain the prothrombin time/INR at the desired level to prevent bleeding complications.
Frequent prothrombin time/INR determinations are advisable until it has been definitely determined that the prothrombin time/INR has stabilized.
Concomitant HMG-CoA reductase inhibitors The combined use of fenofibrate capsules and HMG-CoA reductase inhibitors should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination.
In a single-dose drug interaction study in 23 healthy adults the concomitant administration of fenofibrate capsules and pravastatin resulted in no clinically important difference in the pharmacokinetics of fenofibric acid, pravastatin or its active metabolite 3a-hydroxy iso-pravastatin when compared to either drug given alone.
The combined use of fibric acid derivatives and HMG-CoA reductase inhibitors has been associated, in the absences of a marked pharmacokinetic interaction, in numerous case reports, with rhabdomyolysis, markedly elevated creatine kinase (CK) levels and myoglobinuria, leading in a high proportion of cases to acute renal failure.
The use of fibrates alone, including fenofibrate capsules, may occasionally be associated with myositis, myopathy, or rhabdomyolysis.
Patients receiving fenofibrate capsules and complaining of muscle pain, tenderness, or weakness should have prompt medical evaluation for myopathy, including serum creatine kinase level determination.
If myopathy/myositis is suspected or diagnosed, fenofibrate capsules therapy should be stopped.
Mortality The effect of fenofibrate capsules on coronary heart disease morbidity and mortality and non-cardiovascular mortality has not been established.
Other Considerations In the Coronary Drug Project, a large study of post myocardial infarction of patients treated for 5 years with clofibrate, there was no difference in mortality seen between the clofibrate group and the placebo group.
There was however, a difference in the rate of cholelithiasis and cholecystitis requiring surgery between the two groups (3.0% vs.
1.8%).
Because of chemical, pharmacological, and clinical similarities between fenofibrate capsules, clofibrate, and gemfibrozil, the adverse findings in 4 large randomized, placebo-controlled clinical studies with these other fibrate drugs may also apply to fenofibrate capsules.
In a study conducted by the World Health Organization (WHO), 5000 subjects without known coronary artery disease were treated with placebo or clofibrate for 5 years and followed for an additional one year.
There was a statistically significant, higher age-adjusted all-cause mortality in the clofibrate group compared with the placebo group (5.70% vs.
3.96%, p=<0.01).
Excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis.
This appeared to confirm the higher risk of gallbladder disease seen in clofibrate-treated patients studied in the Coronary Drug Project.
The Helsinki Heart Study was a large (n=4081) study of middle-aged men without a history of coronary artery disease.
Subjects received either placebo or gemfibrozil for 5 years, with a 3.5 year open extension afterward.
Total mortality was numerically higher in the gemfibrozil randomization group but did not achieve statistical significance (p=0.19, 95% confidence interval for relative risk G:P=0.91-1.64).
Although cancer deaths trended higher in the gemfibrozil group (p=0.11), cancers (excluding basal cell carcinoma) were diagnosed with equal frequency in both study groups.
Due to the limited size of the study, the relative risk of death from any cause was not shown to be different than that seen in the 9 year follow-up data from World Health Organization study (RR=1.29).
Similarly, the numerical excess of gallbladder surgeries in the gemfibrozil group did not differ statistically from that observed in the WHO study.
A secondary prevention component of the Helsinki Heart Study enrolled middle-aged men excluded from the primary prevention study because of known or suspected coronary heart disease.
Subjects received gemfibrozil or placebo for 5 years.
Although cardiac deaths trended higher in the gemfibrozil group, this was not statistically significant (hazard ratio 2.2, 95% confidence interval: 0.94-5.05).
The rate of gallbladder surgery was not statistically significant between study groups, but did trend higher in the gemfibrozil group, (1.9% vs.
0.3%, p=0.07).
There was a statistically significant difference in the number of appendectomies in the gemfibrozil group (6/311 vs.
0/317, p=0.029).
DRUG INTERACTIONS
Drug Interactions Oral Anticoagulants CAUTION SHOULD BE EXERCISED WHEN COUMARIN ANTICOAGULANTS ARE GIVEN IN CONJUNCTION WITH FENOFIBRATE CAPSULES.
THE DOSAGE OF THE ANTICOAGULANTS SHOULD BE REDUCED TO MAINTAIN THE PROTHROMBIN TIME/INR AT THE DESIRED LEVEL TO PREVENT BLEEDING COMPLICATIONS.
FREQUENT PROTHROMBIN TIME/INR DETERMINATIONS ARE ADVISABLE UNTIL IT HAS BEEN DEFINITELY DETERMINED THAT THE PROTHROMBIN TIME/INR HAS STABILIZED.
HMG-CoA reductase inhibitors The combined use of fenofibrate capsules and HMG-CoA reductase inhibitors should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination (see WARNINGS ).
Resins Since bile acid sequestrants may bind other drugs given concurrently, patients should take fenofibrate capsules at least 1 hour before or 4 to 6 hours after a bile acid binding resin to avoid impeding its absorption.
Cyclosporine Because cyclosporine can produce nephrotoxicity with decreases in creatinine clearance and rises in serum creatinine, and because renal excretion is the primary elimination route of fibrate drugs including fenofibrate capsules, there is a risk that an interaction will lead to deterioration.
The benefits and risks of using fenofibrate capsules with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed.
OVERDOSAGE
There is no specific treatment for overdose with fenofibrate capsules.
General supportive care of the patient is indicated, including monitoring of vital signs and observation of clinical status, should an overdose occur.
If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway.
Because fenofibrate is highly bound to plasma proteins, hemodialysis should not be considered.
DESCRIPTION
Fenofibrate Capsules (micronized), is a lipid regulating agent available as capsules for oral administration.
Each capsule contains 67 mg, 134 mg or 200 mg of micronized fenofibrate.
The chemical name for fenofibrate is 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester with the following structural formula: The empirical formula is C 20 H 21 O 4 Cl and the molecular weight is 360.83; fenofibrate is insoluble in water.
The melting point is 79-82°C.
Fenofibrate is a white solid which is stable under ordinary conditions.
Inactive Ingredients: Each capsule also contains croscarmellose sodium, NF; hydroxypropyl methylcellulose, USP; magnesium sulfate, NF; microcrystalline cellulose, NF; and sodium lauryl sulfate, NF.
Chemical Structure
CLINICAL STUDIES
Clinical Trials Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb) The effects of fenofibrate at a dose equivalent to 200 mg fenofibrate capsules per day were assessed from four randomized, placebo-controlled, double-blind, parallel-group studies including patients with the following mean baseline lipid values: total-C 306.9 mg/dL; LDL-C 213.8 mg/dL; HDL-C 52.3 mg/dL; and triglycerides 191.0 mg/dL.
Fenofibrate capsules therapy lowered LDL-C, Total-C and the LDL-C/HDL-C ratio.
Fenofibrate capsules therapy also lowered triglycerides and raised HDL-C (see Table 1 ).
Table 1 Mean Percent Change in Lipid Parameters at End of Treatment Duration of study treatment was 3 to 6 months Treatment Group Total-C LDL-C HDL-C TG Pooled Cohort Mean baseline lipid values (n=646) 306.9 mg/dL 213.8 mg/dL 52.3 mg/dL 191.0 mg/dL All FEN (n=361) -18.7% p = <0.05 vs.
Placebo -20.6% +11.0% -28.9% Placebo (n=285) -0.4% -2.2% +0.7% +7.7% Baseline LDL-C > 160 mg/dL and TG 160 mg/dL and TG < 150 mg/dL (Type IIb) Mean baseline lipid values (n=646) 312.8 mg/dL 219.8 mg/dL 46.7 mg/dL 231.9 mg/dL All FEN (n=361) -16.8% -20.1% +14.6% -35.9% Placebo (n=285) -3.0% -6.6% +2.3% +0.9% In a subset of the subjects, measurements of apo B were conducted.
Fenofibrate capsules treatment significantly reduced apo B from baseline to endpoint as compared with placebo (-25.1% vs.
2.4%, p<0.0001, n=213 and 143 respectively).
Hypertriglyceridemia (Fredrickson Type IV and V) The effects of fenofibrate on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trials 1 of 147 hypertriglyceridemia patients (Fredrickson Types IV and V).
Patients were treated for eight weeks under protocols that differed only in that one entered patients with baseline triglyceride (TG) levels of 500 to 1500 mg/dL, and the other TG levels of 350 to 500 mg/dL.
In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia (Type IV/V hyperlipidemia), treatment with fenofibrate at dosages equivalent to 200 mg fenofibrate capsules per day decreased primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol.
Treatment of patients with Type IV hyperlipoproteinemia and elevated triglycerides often results in an increase of low density lipoprotein (LDL) cholesterol (see Table 2 ).
Table 2 Effects of Fenofibrate Capsules in Patients with Fredrickson Type IV/V Hyperlipidemia Study 1 Placebo Fenofibrate Capsules Baseline TG levels 350 to 499 mg/dL N Baseline (Mean) Endpoint (Mean) % Change (Mean) N Baseline (Mean) Endpoint (Mean) % Change (Mean) Triglycerides 28 449 450 -0.5 27 432 223 -46.2 = p<0.05 vs.
Placebo VLDL Triglycerides 19 367 350 2.7 19 350 178 -44.1 Total Cholesterol 28 255 261 2.8 27 252 227 -9.1 HDL Cholesterol 28 35 36 4 27 34 40 19.6 LDL Cholesterol 28 120 129 12 27 128 137 14.5 VLDL Cholesterol 27 99 99 5.8 27 92 46 -44.7 Study 2 Placebo Fenofibrate Capsules Baseline TG levels 500 to 1500 mg/dL N Baseline (Mean) Endpoint (Mean) % Change (Mean) N Baseline (Mean) Endpoint (Mean) % Change (Mean) Triglycerides 44 710 750 7.2 48 726 308 -54.5 VLDL Triglycerides 29 537 571 187 33 543 205 -50.6 Total Cholesterol 44 272 271 0.4 48 261 223 -13.8 HDL Cholesterol 44 27 28 5.0 48 30 36 22.9 LDL Cholesterol 42 100 90 -4.2 45 103 131 45.0 VLDL Cholesterol 42 137 142 11.0 45 126 54 -49.4 The effect of fenofibrate capsules on cardiovascular morbidity and mortality has not been determined.
HOW SUPPLIED
Fenofibrate Capsules – Each #1 gelatin capsules contains 134 mg of fenofibrate, micronized.
Each capsule is imprinted in black with “G 0522”.
NDC: 60760-0902-30 BOTTLE OF 30 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Protect from moisture.
Dispense in tightly-closed, light-resistant container (USP).
GERIATRIC USE
Geriatric Use Fenofibric acid is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection.
INDICATIONS AND USAGE
Treatment of Hypercholesterolemia Fenofibrate capsules are indicated as adjunctive therapy to diet for the reduction of LDL-C, Total-C, Triglycerides and apo B in adult patients with primary hypercholesterolemia or mixed dyslipidemia (Fredrickson Types IIa and IIb).
Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and non-pharmacological interventions alone has been inadequate (see National Cholesterol Education Program [NCEP] Treatment Guidelines , below).
Treatment of Hypertriglyceridemia Fenofibrate capsules are also indicated as adjunctive therapy to diet for treatment of adult patients with hypertriglyceridemia (Fredrickson Types IV and V hyperlipidemia).
Improving glycemic control in diabetic patients showing fasting chylomicronemia will usually reduce fasting triglycerides and eliminate chylomicronemia thereby obviating the need for pharmacologic intervention.
Markedly elevated levels of serum triglycerides (e.g.
> 2,000 mg/dL) may increase the risk of developing pancreatitis.
The effect of fenofibrate capsules therapy on reducing this risk has not been adequately studied.
Drug therapy is not indicated for patients with Type I hyperlipoproteinemia, who have elevations of chylomicrons and plasma triglycerides, but who have normal levels of very low density lipoprotein (VLDL).
Inspection of plasma refrigerated for 14 hours is helpful in distinguishing Types I, IV and V hyperlipoproteinemia 2 .
The initial treatment for dyslipidemia is dietary therapy specific for the type of lipoprotein abnormality.
Excess body weight and excess alcoholic intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy.
Physical exercise can be an important ancillary measure.
Diseases contributory to hyperlipidemia, such as hypothyroidism or diabetes mellitus should be looked for and adequately treated.
Estrogen therapy, like thiazide diuretics and beta-blockers, is sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia.
In such cases, discontinuation of the specific etiologic agent may obviate the need for specific drug therapy of hypertriglyceridemia.
The use of drugs should be considered only when reasonable attempts have been made to obtain satisfactory results with non-drug methods.
If the decision is made to use drugs, the patient should be instructed that this does not reduce the importance of adhering to diet (see WARNINGS and PRECAUTIONS ).
Fredrickson Classification of Hyperlipoproteinemias Type Lipoprotein Elevated Lipid Elevation Major Minor C = cholesterol TG = triglycerides LDL = low density lipoprotein VLDL = very low density lipoprotein IDL = intermediate density lipoprotein I (rare) Chylomicrons TG ↑↔C IIa LDL C — IIb LDL, VLDL C TG III (rare) IDL C, TG — IV VLDL TG ↑↔C V (rare) Chylomicrons, VLDL TG ↑↔ The NCEP Treatment Guidelines Definite Athlerosclerotic Disease Coronary heart disease or peripheral vascular disease (including symptomatic carotid artery disease).
Two or More Other Risk Factors Other risk factors for coronary heart disease (CHD) include: age (males: ≥ 45 years; females: ≥ 55 years or premature menopause without estrogen replacement therapy); family history of premature CHD; current cigarette smoking; hypertension; confirmed HDL-C <35 mg/dL (<0.91mmol/L); and diabetes mellitus.
Subtract 1 risk factor if HDL-C is ≥ 60 mg/dL (≥1.6 mmol/L) LDL-Cholesterol mg/dL (mmol/L) Initiation Level Goal No No ≥ 190 (≥ 4.9) < 160 (< 4.1) No Yes ≥ 160 (≥ 4.1) < 130 (< 3.4) Yes Yes or No ≥ 130* In CHD patients with LDL-C levels 100 to 129 mg/dL, the physician should exercise clinical judgment in deciding whether to initiate drug treatment.
(≥ 3.4) < 100 (< 2.6)
PEDIATRIC USE
Pediatric Use Safety and efficacy in pediatric patients have not been established.
PREGNANCY
Pregnancy Category C Fenofibrate has been shown to be embryocidal and teratogenic in rats when given in doses 7 to 10 times the maximum recommended human dose and embryocidal in rabbits when given at 9 times the maximum recommended human dose (on the basis of mg/meter 2 surface area).
There are no adequate and well-controlled studies in pregnant women.
Fenofibrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Administration of 9 times the maximum recommended human dose of fenofibrate to female rats before and throughout gestation caused 100% of dams to delay delivery and resulted in a 60% increase in post-implantation loss, a decrease in litter size, a decrease in birth weight, a 40% survival of pups at birth, a 4% survival of pups as neonates, and a 0% survival of pups to weaning, and an increase in spina bifida.
Administration of 10 times the maximum recommended human dose to female rats on days 6 to 15 of gestation caused an increase in gross, visceral and skeletal findings in fetuses (domed head/hunched shoulders/rounded body/abnormal chest, kyphosis, stunted fetuses, elongated sternal ribs, malformed sternebrae, extra foramen in palatine, misshapen vertebrae, supernumerary ribs).
Administration of 7 times the maximum recommended human dose to female rats from day 15 of gestation through weaning caused a delay in delivery, a 40% decrease in live births, a 75% decrease in neonatal survival, and decreases in pup weight, at birth as well as on days 4 and 21 post-partum.
Administration of 9 and 18 times the maximum recommended human dose to female rabbits caused abortions in 10% of dams at 9 times and 25% of dams at 18 times the maximum recommended human dose and death of 7% of fetuses at 18 times the maximum recommended human dose.
NUSRING MOTHERS
Nursing mothers Fenofibrate should not be used in nursing mothers.
Because of the potential for tumorigenicity seen in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug.
DOSAGE AND ADMINISTRATION
Patients should be placed on an appropriate lipid-lowering diet before receiving fenofibrate capsules, and should continue this diet during treatment with fenofibrate capsules.
Fenofibrate capsules should be given with meals, thereby optimizing the bioavailability of the medication.
For the treatment of adult patients with primary hypercholesterolemia or mixed hyperlipidemia, the initial dose of fenofibrate capsules is 200 mg per day.
For adult patients with hypertriglyceridemia, the initial dose is 67 to 200 mg per day.
Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determinations at 4 to 8 week intervals.
The maximum dose is 200 mg per day.
Treatment with fenofibrate capsules should be initiated at a dose of 67 mg/day in patients having impaired renal function, and increased only after evaluation of the effects on renal function and lipid levels at this dose.
In the elderly, the initial dose should likewise be limited to 67 mg/day.
Lipid levels should be monitored periodically and consideration should be given to reducing the dosage of fenofibrate capsules if lipid levels fall significantly below the targeted range.