Fenofibrate by Amneal Pharmaceuticals of New York LLC / BORA PHARMACEUTICAL LABORATORIES INC. FENOFIBRATE capsule

Fenofibrate by

Drug Labeling and Warnings

Fenofibrate by is a Prescription medication manufactured, distributed, or labeled by Amneal Pharmaceuticals of New York LLC, BORA PHARMACEUTICAL LABORATORIES INC.. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

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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 molecular formula is C20H21O4Cl and the molecular weight is 360.83; fenofibrate is insoluble in water. The melting point is 79° to 82°C. Fenofibrate is a white solid which is stable under ordinary conditions.

Inactive Ingredients: The inactive ingredients in fenofibrate capsules include croscarmellose sodium, hypromellose type 2910/6 cP, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The capsule shells contain gelatin and titanium dioxide. The 67 mg capsule shells also contain D&C Yellow No. 10 and FD&C Yellow No. 6. The 200 mg capsule shells also contain D&C Red No. 28, D&C Yellow No. 10, and FD&C Red No. 40.

Additionally, the capsule imprint ink contains shellac glaze, ferrosoferric oxide, propylene glycol, FD&C Blue No. 2, FD&C Red No. 40, D&C Yellow No. 10 Aluminum Lake, and FD&C Blue No. 1.

CLINICAL PHARMACOLOGY

A variety of clinical studies have demonstrated that elevated levels of total cholesterol (total-C), low density lipoprotein cholesterol (LDL-C), and apolipoprotein B (apo B), an LDL membrane complex, are associated with human atherosclerosis. Similarly, decreased levels of high density lipoprotein cholesterol (HDL-C) and its transport complex, apolipoprotein A (apo AI and apo AII) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C, LDL-C, and triglycerides, and inversely with the level of HDL-C. The independent effect of raising HDL-C or lowering triglycerides (TG) on the risk of cardiovascular morbidity and mortality has not been determined.

Fenofibric acid, the active metabolite of fenofibrate, produces reductions in total cholesterol, LDL cholesterol, apolipoprotein B, total triglycerides and triglyceride rich lipoprotein (VLDL) in treated patients. In addition, treatment with fenofibrate results in increases in high density lipoprotein (HDL) and apoproteins apo AI and apo AII).

The effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor α (PPARα). Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting fall in triglycerides produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPARα also induces an increase in the synthesis of apoproteins A-I, A-II and HDL-cholesterol.

Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid.

Pharmacokinetics/Metabolism

Clinical experience has been obtained with two different formulations of fenofibrate: a "micronized" and "non- micronized" formulation, which have been demonstrated to be bioequivalent. Comparisons of blood levels following oral administration of both formulations in healthy volunteers demonstrate that a single capsule containing 67 mg of the "micronized" formulation is bioequivalent to 100 mg of the "non-micronized" formulation. Three capsules containing 67 mg fenofibrate are bioequivalent to a single 200 mg fenofibrate capsule.

Absorption

The absolute bioavailability of fenofibrate cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However, fenofibrate is well absorbed from the gastrointestinal tract. Following oral administration in healthy volunteers, approximately 60% of a single-dose of radio-labelled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma levels of fenofibric acid occur within 6 to 8 hours after administration.

The absorption of fenofibrate is increased when administered with food. With micronized fenofibrate, the absorption is increased by approximately 35% under fed as compared to fasting conditions.

Distribution

In healthy volunteers, steady-state plasma levels of fenofibric acid were shown to be achieved within 5 days of dosing with single oral doses equivalent to 67 mg of fenofibrate capsules and did not demonstrate accumulation across time following multiple-dose administration. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects.

Metabolism

Following oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; no unchanged fenofibrate is detected in plasma.

Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to a benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine.

In vivo metabolism data indicate that neither fenofibrate nor fenofibric acid undergo oxidative metabolism (e.g., cytochrome P450) to a significant extent.

Excretion

After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabelled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces.

Fenofibric acid is eliminated with a half-life of 20 hours, allowing once daily administration in a clinical setting.

Special Populations

Geriatrics

In elderly volunteers 77 to 87 years of age, the oral clearance of fenofibric acid following a single oral dose of fenofibrate was 1.2 L/h, which compares to 1.1 L/h in young adults. This indicates that a similar dosage regimen can be used in the elderly, without increasing accumulation of the drug or metabolites.

Pediatrics

Fenofibrate capsules have not been investigated in adequate and well-controlled trials in pediatric patients.

Gender

No pharmacokinetic difference between males and females has been observed for fenofibrate.

Race

The influence of race on the pharmacokinetics of fenofibrate has not been studied, however fenofibrate is not metabolized by enzymes known for exhibiting inter-ethnic variability. Therefore, inter-ethnic pharmacokinetic differences are very unlikely.

Renal insufficiency

In a study in patients with severe renal impairment (creatinine clearance < 50 mL/min), the rate of clearance of fenofibric acid was greatly reduced, and the compound accumulated during chronic dosage. However, in patients having moderate renal impairment (creatinine clearance of 50 mL/min to 90 mL/min), the oral clearance and the oral volume of distribution of fenofibric acid are increased compared to healthy adults (2.1 L/h and 95 L versus 1.1 L/h and 30 L, respectively). Therefore, the dosage of fenofibrate capsules should be minimized in patients who have severe renal impairment, while no modification of dosage is required in patients having moderate renal impairment.

Hepatic insufficiency

No pharmacokinetic studies have been conducted in patients having hepatic insufficiency.

Drug-drug interactions

In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations.

Potentiation of coumarin-type anti-coagulants has been observed with prolongation of the prothrombin time/INR.

Bile acid sequestrants have been shown to bind other drugs given concurrently. Therefore, fenofibrate should be taken at least 1 hour before or 4 to 6 hours after a bile acid binding resin to avoid impeding its absorption (see WARNINGS and PRECAUTIONS).

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+

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%*	-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 < 150 mg/dL (Type IIa)
Mean baseline lipid values (n=334)	307.7 mg/dL	227.7 mg/dL	58.1 mg/dL	101.7 mg/dL
All FEN (n=193)	-22.4%*	-31.4%*	+9.8%*	-23.5%*
Placebo (n=141)	0.2%	-2.2%	+2.6%	+11.7%
Baseline LDL-C > 160 mg/dL and TG < 150 mg/dL (Type IIb)
Mean baseline lipid values (n=242)	312.8 mg/dL	219.8 mg/dL	46.7 mg/dL	231.9 mg/dL
All FEN (n=126)	-16.8%*	-20.1%*	+14.6%*	-35.9%*
Placebo (n=116)	-3.0%	-6.6%	+2.3%	+0.9%
+ Duration of study treatment was 3 to 6 months * p = <0.05 vs. Placebo

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 trials1 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 1,500 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 Fredricks on 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*
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	18.7	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*
* = p < 0.05 vs. Placebo

The effect of fenofibrate capsules on cardiovascular morbidity and mortality has not been determined.

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 hyperlipoproteinemia2.

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
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	↑↔
C = cholesterol TG = triglycerides LDL = low density lipoprotein VLDL = very low density lipoprotein IDL = intermediate density lipoprotein

The NCEP Treatment Guidelines

Definite Athlerosclerotic Diseasea	Two or More Other Risk Factorsb	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*c (≥ 3.4)	< 100 (< 2.6)
aCoronary heart disease or peripheral vascular disease (including symptomatic carotid artery disease). b 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) CIn CHD patients with LDL-C levels 100 to 129 mg/dL, the physician should exercise clinical judgment in deciding whether to initiate drug treatment.

CONTRAINDICATIONS

Fenofibrate capsules are contraindicated in patients who exhibit hypersensitivity to fenofibrate.

Fenofibrate capsules are contraindicated in patients with hepatic or severe renal dysfunction, including primary biliary cirrhosis, and patients with unexplained persistent liver function abnormality.

Fenofibrate capsules are contraindicated in patients with preexisting gallbladder disease (see WARNINGS).

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 transaminases related to fenofibrate therapy appears 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 or 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 absence 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=4,081) 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 to 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 to 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).

PRECAUTIONS

Initial Therapy

Laboratory studies should be done to ascertain that the lipid levels are consistently abnormal before instituting fenofibrate capsules 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. Medications known to exacerbate hypertriglyceridemia (beta-blockers, thiazides, estrogens) should be discontinued or changed if possible prior to consideration of triglyceride-lowering drug therapy.

Continued therapy

Periodic determination of serum lipids should be obtained during initial therapy in order to establish the lowest effective dose of fenofibrate capsules. Therapy should be withdrawn in patients who do not have an adequate response after two months of treatment with the maximum recommended dose of 200 mg per day.

Pancreatitis

Pancreatitis has been reported in patients taking fenofibrate, gemfibrozil, and clofibrate. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct.

Hypersensitivity Reactions

Acute Hypersensitivity

Anaphylaxis and angioedema have been reported postmarketing with fenofibrate. In some cases, reactions were life-threatening and required emergency treatment. If a patient develops signs or symptoms of an acute hypersensitivity reaction, advise them to seek immediate medical attention and discontinue fenofibrate.

Delayed Hypersensitivity

Severe cutaneous adverse drug reactions (SCAR), including Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported postmarketing, occurring days to weeks after initiation of fenofibrate. The cases of DRESS were associated with cutaneous reactions (such as rash or exfoliative dermatitis) and a combination of eosinophilia, fever, system organ involvement (renal, hepatic, or respiratory).

Discontinue fenofibrate and treat patients appropriately if SCAR is suspected.

Hematologic Changes

Mild to moderate hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following initiation of fenofibrate therapy. However, these levels stabilize during long-term administration. Extremely rare spontaneous reports of thrombocytopenia and agranulocytosis have been received during post-marketing surveillance outside of the U.S. Periodic blood counts are recommended during the first 12 months of fenofibrate capsules administration.

Skeletal muscle

The use of fibrates alone, including fenofibrate capsules may occasionally be associated with myopathy. Treatment with drugs of the fibrate class has been associated on rare occasions with rhabdomyolysis, usually in patients with impaired renal function. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevations of creatine phosphokinase levels.

Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. CPK levels should be assessed in patients reporting these symptoms, and fenofibrate therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed.

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 24-month study in rats (10 mg/kg, 45 mg/kg, and 200 mg/kg; 0.3, 1, and 6 times the maximum recommended human dose on the basis of mg/meter2 of surface area), the incidence of liver carcinoma was significantly increased at 6 times the maximum recommended human dose in males and females. A statistically significant increase in pancreatic carcinomas occurred in males at 1 and 6 times the maximum recommended human dose; there were also increases in pancreatic adenomas and benign testicular interstitial cell tumors at 6 times the maximum recommended human dose in males. In a second 24-month study in a different strain of rats (doses of 10 mg/kg and 60 mg/kg; 0.3 and 2 times the maximum recommended human dose based on mg/meter2 surface area), there were significant increases in the incidence of pancreatic acinar adenomas in both sexes and increases in interstitial cell tumors of the testes at 2 times the maximum recommended human dose.

A comparative carcinogenicity study was done in rats comparing three drugs: fenofibrate (10 mg/kg and 70 mg/kg; 0.3 and 1.6 times the maximum recommended human dose), clofibrate (400 mg/kg; 1.6 times the human dose), and gemfibrozil (250 mg/kg; 1.7 times the human dose) (multiples based on mg/meter2 surface area). 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 gemfibrozil while testicular interstitial cell tumors were increased in males on all three drugs.

In a 21-month study in mice at doses of 10 mg/kg, 45 mg/kg, and 200 mg/kg (approximately 0.2, 0.7 and 3 times the maximum recommended human dose on the basis of mg/meter2 surface area), there were statistically significant increases in liver carcinoma at 3 times the maximum recommended human dose in both males and females. In a second 18-month study at the same doses, there was a significant increase in liver carcinoma in male mice and liver adenoma in female mice at 3 times the maximum recommended human dose.

Electron microscopy studies have demonstrated peroxisomal proliferation following fenofibrate administration to the rat. An adequate study to test for peroxisome proliferation in humans has not been done, but changes in peroxisome morphology and numbers have been observed in humans after treatment with other members of the fibrate class when liver biopsies were compared before and after treatment in the same individual.

Fenofibrate has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and unscheduled DNA synthesis.

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/meter2 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.

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.

Pediatric Use

Safety and efficacy in pediatric patients have not been established.

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.

ADVERSE REACTIONS

Photosensitivity reactions have occurred days to months after initiation; in some of these cases, patients reported a prior photosensitivity reaction to ketoprofen.

CLINICAL

Adverse events reported by 2% or more of patients treated with fenofibrate during the double-blind, placebo-controlled trials, regardless of causality, are listed in the table below. Adverse events led to discontinuation of treatment in 5.0% of patients treated with fenofibrate and in 3.0% treated with placebo. Increases in liver function tests were the most frequent events, causing discontinuation of fenofibrate treatment in 1.6% of patients in double-blind trials.

BODY SYSTEM; Adverse Event	Fenofibrate*; (N=439)	PLACEBO; (N=365)
BODY AS A WHOLE
Abdominal Pain	4.6%	4.4%
Back Pain	3.4%	2.5%
Headache	3.2%	2.7%
Asthenia	2.1%	3.0%
Flu Syndrome	2.1%	2.7%
DIGESTIVE
Liver Function Tests Abnormal	7.5%†	1.4%
Diarrhea	2.3%	4.1%
Nausea	2.3%	1.9%
Constipation	2.1%	1.4%
METABOLIC AND NUTRITIONAL DISORDERS
SGPT Increased	3.0%	1.6%
Creatine Phosphokinase Increased	3.0%	1.4%
SGOT Increased	3.4%†	0.5%
RESPIRATORY
Respiratory Disorder	6.2%	5.5%
Rhinitis	2.3%	1.1%
* Dosage equivalent to 200 mg fenofibrate capsules † Significantly different from Placebo

Additional adverse events reported by three or more patients in placebo-controlled trials or reported in other controlled or open trials, regardless of causality are listed below.

BODY AS A WHOLE: Chest pain, pain (unspecified), infection, malaise, allergic reaction, cyst, hernia, fever, photosensitivity reaction, and accidental injury.

CARDIOVASCULAR SYSTEM: Angina pectoris, hypertension, vasodilatation, coronary artery disorder, electrocardiogram abnormal, ventricular extrasystoles, myocardial infarct, peripheral vascular disorder, migraine, varicose vein, cardiovascular disorder, hypotension, palpitation, vascular disorder, arrhythmia, phlebitis, tachycardia, extrasystoles, and atrial fibrillation.

DIGESTIVE SYSTEM: Dyspepsia, flatulence, nausea, increased appetite, gastroenteritis, cholelithiasis, rectal disorder, esophagitis, gastritis, colitis, tooth disorder, vomiting, anorexia, gastrointestinal disorder, duodenal ulcer, nausea and vomiting, peptic ulcer, rectal hemorrhage, liver fatty deposit, cholecystitis, eructation, gamma glutamyl transpeptidase, and diarrhea.

ENDOCRINE SYSTEM: Diabetes mellitus

HEMIC AND LYMPHATIC SYSTEM: Anemia, leukopenia, ecchymosis, eosinophilia, lymphadenopathy, and thrombocytopenia.

METABOLIC AND NUTRITIONAL DISORDERS: Creatinine increased, weight gain, hypoglycemia, gout, weight loss, edema, hyperuricemia, and peripheral edema.

MUSCULOSKELETAL SYSTEM: Myositis, myalgia, arthralgia, arthritis, tenosynovitis, joint disorder, arthrosis, leg cramps, bursitis, and myasthenia.

NERVOUS SYSTEM: Dizziness, insomnia, depression, vertigo, libido decreased, anxiety, paresthesia, dry mouth, hypertonia, nervousness, neuralgia, and somnolence.

RESPIRATORY SYSTEM: Pharyngitis, bronchitis, cough increased, dyspnea, asthma, pneumonia, laryngitis, and sinusitis.

SKIN AND APPENDAGES: Rash, pruritus, eczema, herpes zoster, urticaria, acne, sweating, fungal dermatitis, skin disorder, alopecia, contact dermatitis, herpes simplex, maculopapular rash, nail disorder, and skin ulcer.

SPECIAL SENSES: Conjunctivitis, eye disorder, amblyopia, ear pain, otitis media, abnormal vision, cataract specified, and refraction disorder.

UROGENITAL SYSTEM: Urinary frequency, prostatic disorder, dysuria, kidney function abnormal, urolithiasis, gynecomastia, unintended pregnancy, vaginal moniliasis, and cystitis.

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.

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 mg per day 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.

HOW SUPPLIED

Fenofibrate Capsules – Each #3 gelatin capsule contains 67 mg of fenofibrate, micronized. Each capsule is imprinted in black with "G 0511".
They are available as follows:

Bottles of 100:                                                NDC: 0115-0511-01

Fenofibrate Capsules – Each #1 gelatin capsules contains 134 mg of fenofibrate, micronized. Each capsule is imprinted in black with "G 0522".
They are available as follows:

Bottles of 100:                                                NDC: 0115-0522-01
Bottles of 500:                                                NDC: 0115-0522-02

Fenofibrate Capsules – Each #1 gelatin capsules contains 200 mg of fenofibrate, micronized. Each capsule is imprinted in black with "G 0533".
They are available as follows:

Bottles of 100:                                                NDC: 0115-0533-01
Bottles of 500:                                                NDC: 0115-0533-02

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).

REFERENCES

1. GOLDBERG AC, et al. Fenofibrate for the Treatment of Type IV and V Hyperlipoproteinemias: A Double-Blind, Placebo-Controlled Multicenter US Study. Clinical Therapeutics, 11, pp. 69 - 83, 1989.
2. NIKKILA EA, Familial Lipoprotein Lipase Deficiency and Related Disorders of Chylomicron Metabolism. In Stanbury J.B., et al. (eds.): The Metabolic Basis of Inherited Disease, 5th edition, McGraw-Hill, 1983, Chap. 30, pp. 622 - 642.
3. BROWN WV, et al. Effects of Fenofibrate on Plasma Lipids: Double-Blind, Multicenter Study in Patients with Type IIA or IIB Hyperlipidemia. Arteriosclerosis. 6, pp. 670 - 678, 1986.

SPL UNCLASSIFIED SECTION

Manufactured by:
Bora Pharmaceutical Laboratories Inc.
Jhunan, Taiwan

Distributed by:
Amneal Pharmaceuticals LLC
Bridgewater, NJ 08807

184-12

Rev. 11-2018-00

PRINCIPAL DISPLAY PANEL - 67 mg Capsule Bottle Label

PRINCIPAL DISPLAY PANEL - 134 mg Capsule Bottle Label

PRINCIPAL DISPLAY PANEL - 200 mg Capsule Bottle Label

INGREDIENTS AND APPEARANCE

FENOFIBRATE 
fenofibrate capsule

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	Item Code (Source)	NDC: 0115-0511
Route of Administration	ORAL

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
FENOFIBRATE (UNII: U202363UOS) (FENOFIBRIC ACID - UNII:BGF9MN2HU1)	FENOFIBRATE	67 mg

Inactive Ingredients
Ingredient Name	Strength
CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)
HYPROMELLOSE 2910 (6 MPA.S) (UNII: 0WZ8WG20P6)
MAGNESIUM STEARATE (UNII: 70097M6I30)
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)
SODIUM LAURYL SULFATE (UNII: 368GB5141J)
GELATIN (UNII: 2G86QN327L)
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)
FD&C YELLOW NO. 6 (UNII: H77VEI93A8)
SHELLAC (UNII: 46N107B71O)
FERROSOFERRIC OXIDE (UNII: XM0M87F357)
PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
FD&C BLUE NO. 2 (UNII: L06K8R7DQK)
FD&C RED NO. 40 (UNII: WZB9127XOA)
ALUMINUM OXIDE (UNII: LMI26O6933)
FD&C BLUE NO. 1 (UNII: H3R47K3TBD)

Product Characteristics
Color	YELLOW (pale yellow)	Score	no score
Shape	CAPSULE	Size	16mm
Flavor		Imprint Code	G;0511
Contains

Packaging
#	Item Code	Package Description	Marketing Start Date	Marketing End Date
1	NDC: 0115-0511-01	100 in 1 BOTTLE; Type 0: Not a Combination Product	02/01/2010

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA075868	02/01/2010

FENOFIBRATE 
fenofibrate capsule

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	Item Code (Source)	NDC: 0115-0522
Route of Administration	ORAL

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
FENOFIBRATE (UNII: U202363UOS) (FENOFIBRIC ACID - UNII:BGF9MN2HU1)	FENOFIBRATE	134 mg

Inactive Ingredients
Ingredient Name	Strength
CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)
HYPROMELLOSE 2910 (6 MPA.S) (UNII: 0WZ8WG20P6)
MAGNESIUM STEARATE (UNII: 70097M6I30)
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)
SODIUM LAURYL SULFATE (UNII: 368GB5141J)
GELATIN (UNII: 2G86QN327L)
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
SHELLAC (UNII: 46N107B71O)
FERROSOFERRIC OXIDE (UNII: XM0M87F357)
PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
FD&C BLUE NO. 2 (UNII: L06K8R7DQK)
FD&C RED NO. 40 (UNII: WZB9127XOA)
D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)
ALUMINUM OXIDE (UNII: LMI26O6933)
FD&C BLUE NO. 1 (UNII: H3R47K3TBD)

Product Characteristics
Color	WHITE	Score	no score
Shape	CAPSULE	Size	19mm
Flavor		Imprint Code	G;0522
Contains

Packaging
#	Item Code	Package Description	Marketing Start Date	Marketing End Date
1	NDC: 0115-0522-01	100 in 1 BOTTLE; Type 0: Not a Combination Product	02/01/2010
2	NDC: 0115-0522-02	500 in 1 BOTTLE; Type 0: Not a Combination Product	02/01/2010

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA075868	02/01/2010

FENOFIBRATE 
fenofibrate capsule

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	Item Code (Source)	NDC: 0115-0533
Route of Administration	ORAL

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
FENOFIBRATE (UNII: U202363UOS) (FENOFIBRIC ACID - UNII:BGF9MN2HU1)	FENOFIBRATE	200 mg

Inactive Ingredients
Ingredient Name	Strength
CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)
HYPROMELLOSE 2910 (6 MPA.S) (UNII: 0WZ8WG20P6)
MAGNESIUM STEARATE (UNII: 70097M6I30)
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)
SODIUM LAURYL SULFATE (UNII: 368GB5141J)
GELATIN (UNII: 2G86QN327L)
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
D&C RED NO. 28 (UNII: 767IP0Y5NH)
D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)
FD&C RED NO. 40 (UNII: WZB9127XOA)
SHELLAC (UNII: 46N107B71O)
FERROSOFERRIC OXIDE (UNII: XM0M87F357)
PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
FD&C BLUE NO. 2 (UNII: L06K8R7DQK)
ALUMINUM OXIDE (UNII: LMI26O6933)
FD&C BLUE NO. 1 (UNII: H3R47K3TBD)

Product Characteristics
Color	ORANGE	Score	no score
Shape	CAPSULE	Size	19mm
Flavor		Imprint Code	G;0533
Contains

Packaging
#	Item Code	Package Description	Marketing Start Date	Marketing End Date
1	NDC: 0115-0533-01	100 in 1 BOTTLE; Type 0: Not a Combination Product	02/01/2010
2	NDC: 0115-0533-02	500 in 1 BOTTLE; Type 0: Not a Combination Product	02/01/2010

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA075868	02/01/2010

Labeler - Amneal Pharmaceuticals of New York LLC (123797875)

Establishment
Name	Address	ID/FEI	Business Operations
BORA PHARMACEUTICAL LABORATORIES INC.		656139511	ANALYSIS(0115-0511, 0115-0522, 0115-0533) , LABEL(0115-0511, 0115-0522, 0115-0533) , MANUFACTURE(0115-0511, 0115-0522, 0115-0533) , PACK(0115-0511, 0115-0522, 0115-0533)

Establishment
Name	Address	ID/FEI	Business Operations
Reed-Lane		001819879	PACK(0115-0511, 0115-0522, 0115-0533)