Antara: Package Insert and Label Information (Page 2 of 4)

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect rates observed in clinical practice.

Adverse events reported by 2% or more of patients treated with fenofibrate and greater than placebo during double-blind, placebo-controlled trials, regardless of causality, are listed in Table 1. Adverse reactions 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.

*
Dosage equivalent to 90 mg fenofibrate
Significantly different from placebo
Body System Adverse Reaction 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%
Digestive
Abnormal Liver Function Tests 7.5% 1.4%
Nausea 2.3% 1.9%
Constipation 2.1% 1.4%
Metabolic and Nutritional Disorders
Increased AST 3.4% 0.5%
Increased ALT 3.0% 1.6%
Increased Creatine Phosphokinase 3.0% 1.4%
Respiratory
Respiratory Disorder 6.2% 5.5%
Rhinitis 2.3% 1.1%

Urticaria was seen in 1.1 vs. 0%, and rash in 1.4 vs. 0.8% of fenofibrate and placebo patients, respectively, in controlled trials.

Increases in Liver Enzymes

In a pooled analysis of 10 placebo-controlled trials, increases to >3 times the upper limit of normal in ALT occurred in 5.3% of patients taking fenofibrate at doses equivalent to 90 mg Antara daily versus 1.1% of patients treated with placebo.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of fenofibrate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: myalgia, rhabdomyolysis, pancreatitis, renal failure, muscle spasms, acute renal failure, hepatitis, cirrhosis, increased total bilirubin, anemia, arthralgia, asthenia, severely depressed HDL-cholesterol levels, and interstitial lung disease. Photosensitivity reactions have occurred days to months after initiation; in some of these cases, patients reported a prior photosensitivity reaction to ketoprofen.

7 DRUG INTERACTIONS

7.1 Coumarin Anticoagulants

Potentiation of coumarin-type anticoagulant effects has been observed with prolongation of the PT/INR.

Caution should be exercised when coumarin anticoagulants are given in conjunction with Antara. The dosage of the anticoagulants should be reduced to maintain the PT/INR at the desired level to prevent bleeding complications. Frequent PT/INR determinations are advisable until it has been definitely determined that the PT/INR has stabilized [see Warnings and Precautions (5.6) ].

7.2 Immunosuppressants

Immunosuppressants such as cyclosporine and tacrolimus can produce nephrotoxicity with decrease in creatinine clearance and because renal excretion is the primary elimination route of fibrate drugs including Antara, there is a risk that an interaction will lead to deterioration of renal function. The benefits and risks of using Antara with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed.

7.3 Bile-Acid Binding Resins

Since bile acid binding resins may bind other drugs given concurrently, patients should take Antara at least 1 hour before or 4 to 6 hours after a bile acid binding resin to avoid impeding its absorption.

7.4 Colchicine

Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co-administered with colchicine, and caution should be exercised when prescribing fenofibrate with colchicine.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

Safety in pregnant women has not been established. There are no adequate and well controlled studies of fenofibrate in pregnant women. Fenofibrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In female rats given oral dietary doses of 15, 75, and 300 mg/kg/day of fenofibrate from 15 days prior to mating through weaning, maternal toxicity was observed at 0.3 times the maximum recommended human dose (MRHD), based on body surface area comparisons; mg/m2.

In pregnant rats given oral dietary doses of 14, 127, and 361 mg/kg/day from gestation day 6-15 during the period of organogenesis, adverse developmental findings were not observed at 14 mg/kg/day (less than 1 times the MRHD, based on body surface area comparisons; mg/m2). At higher multiples of human doses, evidence of maternal toxicity was observed.

In pregnant rabbits given oral gavage doses of 15, 150, and 300 mg/kg/day from gestation day 6 to 18 during the period of organogenesis and allowed to deliver, aborted litters were observed at 150 mg/kg/day (10 times the MRHD, based on body surface area comparisons: mg/m2). No developmental findings were observed at 15 mg/kg/day (at less than 1 times the MRHD, based on body surface area comparisons; mg/m2).

In pregnant rats given oral dietary doses of 15, 75, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), maternal toxicity was observed at less than 1 times the MRHD, based on body surface area comparisons; mg/m2.

8.3 Nursing Mothers

Fenofibrate should not be used in nursing mothers. 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.

8.4 Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

8.5 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. Fenofibric acid exposure is not influenced by age. Since elderly patients have a higher incidence of renal impairment, dose selection for the elderly should be made on the basis of renal function [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ]. Elderly patients with normal renal function should require no dose modifications. Consider monitoring renal function in elderly patients taking Antara.

8.6 Renal Impairment

Fenofibrate should be avoided in patients with severe renal impairment [see Contraindications (4) ]. Dose reduction is required in patients with mild to moderate renal impairment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ]. Monitoring renal function in patients with renal impairment is recommended.

8.7 Hepatic Impairment

The use of Antara has not been evaluated in subjects with hepatic impairment [see Contraindications (4) and Clinical Pharmacology (12.3) ].

10 OVERDOSAGE

There is no specific treatment for overdose with Antara. 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.

11 DESCRIPTION

Antara (fenofibrate) Capsules, is a lipid regulating agent available as capsules for oral administration. Each capsule contains 30 mg or 90 mg of micronized fenofibrate. The chemical name for fenofibrate is 2-[4-(4-chlorobenzoyl) phenoxy] 2-methyl-propanoic acid, l-methylethyl ester with the following structural formula:

Fenofibrate
(click image for full-size original)

Fenofibrate

The empirical formula is C20 H21 O4 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 gelatin capsule contains hypromellose, simethicone emulsion, sodium lauryl sulphate, sugar spheres and talc. The capsule shell contains the following inactive ingredients: black iron oxide, D & C Yellow 10, potassium hydroxide, propylene glycol, gelatin, shellac, sodium lauryl sulphate, titanium dioxide. The 30 mg capsule shell contains following additional inactive ingredients: FD & C Blue 2, yellow iron oxide. The 90 mg capsule shell contains following additional inactive ingredients: FD & C Blue 1, FD & C Yellow 6.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The active moiety of Antara is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been extensively studied through oral administration of fenofibrate.

The lipid lowering 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 decrease 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.

12.2 Pharmacodynamics

A variety of clinical studies have demonstrated that elevated levels of total-C, DL-C, and Apo B, an LDL membrane complex, are associated with human atherosclerosis. Similarly, decreased levels of HDL-C and its transport complex, apolipoprotein A (Apo AI and Apo All) 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 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.

12.3 Pharmacokinetics

Fenofibrate is a pro-drug of the active chemical moiety fenofibric acid. Fenofibrate is converted by ester hydrolysis in the body to fenofibric acid which is the active constituent measurable in the circulation.

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 radiolabeled 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 from Antara capsules 90 mg occur within 2 to 6 hours after administration.

In the presence of a high-fat meal, there was a 26.7% increase in AUC and 15.35% increase in Cmax of fenofibric acid from Antara capsule 30mg relative to fasting state,

Distribution

In healthy volunteers, steady-state plasma levels of fenofibric acid were shown to be achieved within a week of dosing 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.

Elimination

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

Fenofibrate acid from Antara is eliminated with a half-life of 23 hours, allowing once daily dosing.

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 with normal renal function, without increasing accumulation of the drug or metabolites [see Dosage and Administration (2.4) and Use in Special Populations (8.5) ].

Pediatrics

The pharmacokinetics of Antara has not been studied in pediatric populations.

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.

Renal Impairment

The pharmacokinetics of fenofibric acid was examined in patients with mild, moderate, and severe renal impairment. Patients with severe renal impairment (creatinine clearance [CrCl] ≤ 30 mL/min or estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73m2) showed 2.7-fold increase in exposure for fenofibric acid and increased accumulation of fenofibric acid during chronic dosing compared to that of healthy subjects. Patients with mild to moderate (CrCl 30-80 mL/min or eGFR 30-59 mL/min/1.73m2) renal impairment had similar exposure but an increase in the half-life for fenofibric acid compared to that of healthy subjects. Based on these findings, the use of Antara should be avoided in patients who have severe renal impairment and dose reduction is required in patients having mild to moderate renal impairment [see Dosage and Administration (2.4) ].

Hepatic Impairment

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

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 inhibitor of CYP2C8, CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations.

Table 2 describes the effects of co-administered drugs on fenofibric acid systemic exposure.

Table 3 describes the effects of co-administered fenofibric acid on exposure to other drugs.

Table 2 Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from Antara or Fenofibrate Administration
*
TriCor (fenofibrate) oral tablet
TriCor (fenofibrate) oral micronized capsule
Co Administered Drug Dosage Regimen of Co Administered Drug Dosage Regimen of Fenofibrate Changes in Fenofibric Acid Exposure
AUC Cm a x
No dosing adjustments required for Antara with the following co administered drugs
Lipid lowing agents
Atorvastatin 20 mg once daily for 10 days Fenofibrate 160 mg * once daily for 10 days ↓2% ↓4%
Pravastatin 40 mg as a single dose Fenofibrate 3 x 67 mg as a single dose ↓1% ↓2%
Fluvastatin 40 mg as a single dose Fenofibrate 160 mg * as a single dose ↓2% ↓10%
Anti diabetic agents
Glimepiride 1 mg once daily as a single dose Fenofibrate 145 mg * once daily for 10 days ↑1% ↓1%
Metformin 850 mg three times daily for 10 days Fenofibrate 54 mg * three times daily for 10 days ↓9% ↓6%
Rosiglitazone 8 mg once daily for 5 days Fenofibrate 145 mg * once daily for 14 days ↑10% ↑3%
Table 3 Effects of Antara or Fenofibrate Co-Administration on Systemic Exposure of Other Drugs
*
TriCor (fenofibrate) oral tablet
TriCor (fenofibrate) oral micronized capsule
Dosage Regimen of Fenofibrate Dosage Regimen of Co Administered Drug Changes in Co Administered Drug Exposure
Analyte AUC Cm a x
No dosing adjustments required for these co administered drugs with Antara
Lipid lowing agents
Fenofibrate 160 mg * once daily for 10 days Atorvastatin, 20 mg once daily for 10 days Atorvastatin ↓17% 0%
Fenofibrate 3 x 67 mg as a single dose Pravastatin, 40 mg as a single dose Pravastatin ↑13% ↑13%
3α-Hydroxyl-isopravastatin ↑26% ↑29%
Fenofibrate 160 mg * once daily for 10 days Pravastatin, 40 mg once daily for 10 days Pravastatin ↑28% ↑36%
3α-Hydroxyl-isopravastatin ↑39% ↑55%
Fenofibrate 160 mg * as a single dose Fluvastatin, 40 mg as a single dose (+)-3R, 5S Fluvastatin ↑15% ↑16%
Anti diabetic agents
Fenofibrate 145 mg * once daily for 10 days Glimepiride, 1 mg once daily as a single dose Glimepiride ↑35% ↑18%
Fenofibrate 54 mg * three times daily for 10 days Metformin, 850 mg three times daily for 10 days Metformin ↑3% ↑6%
Fenofibrate 145 mg * once daily for 14 days Rosiglitazone, 8 mg once daily for 5 days Rosiglitazone ↑6% ↓1%

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