Fenofibric Acid 135 mg Capsule, Delayed Release, 90-count

5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Serious drug-induced liver injury, including liver transplantation and death, has been reported with fenofibrates, including fenofibric acid delayed-release capsules. Monitor patient’s liver function, including serum ALT, AST, and total bilirubin, at baseline and periodically for the duration of therapy. Discontinue if signs or symptoms of liver injury develop or if elevated enzyme levels persist ( 5.2 ).

Myopathy and R habdomyolysis: Have been reported in patients taking fenofibrates. Risks are increased during co-administration with a statin, in geriatric patients, and in patients with renal impairment or hypothyroidism. Discontinue fenofibric acid delayed-release capsules if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected.

Temporarily discontinue fenofibric acid delayed-release capsules in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the fenofibric acid delayed-release capsules dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever ( 5.3 ).

Increases in Serum Creatinine: Monitor renal function in patients with renal impairment taking Trilipix. Consider monitoring renal function in patients at risk for renal impairment ( 5.4 ). Cholelithiasis: Fenofibrate may increase cholesterol excretion into the bile, leading to cholelithiasis.

If cholelithiasis is suspected, gallbladder studies are indicated ( 5.5 ). Hypersensitivity Reactions: Acute hypersensitivity reactions, including anaphylaxis and angioedema, and delayed hypersensitivity reactions, including severe cutaneous adverse drug reactions have been reported postmarketing. Some cases were life-threatening and required emergency treatment.

Discontinue fenofibric acid delayed-release capsules and treat appropriately if reactions occur ( 5.9 ).

5.1Mortality and Coronary Heart Disease Morbidity Fenofibrate did not reduce cardiovascular disease morbidity or mortality in two large, randomized controlled trials of patients with type 2 diabetes mellitus [see Clinical Studies ( 14.4 )] . Because of chemical, pharmacological, and clinical similarities between fenofibrates, including fenofibric acid delayed-release capsules; pemafibrate; clofibrate; and gemfibrozil; the findings in 5 large randomized, placebo-controlled clinical trials with these other fibrate drugs may also apply to fenofibric acid delayed-release capsules.

Pemafibrate did not reduce cardiovascular disease morbidity or mortality in a large, randomized, placebo-controlled trial of patients with type 2 diabetes mellitus on background statin therapy [see Clinical Studies ( 14.4 )] . In the Coronary Drug Project, a large trial conducted from 1965 to 1985 in men post myocardial infarction, there was no difference in mortality or nonfatal myocardial infarction between the clofibrate group and the placebo group after 5 years of treatment (NCT00000482). In a trial conducted by the World Health Organization (WHO) from 1965 to 1976, men without known coronary artery disease were treated with placebo or clofibrate for 5 years and followed for an additional 1 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.

The Helsinki Heart Study, conducted from 1982 to 1987, was a large (N = 4,081) trial 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 but not statistically higher in the gemfibrozil ra…

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Mortality and coronary heart disease morbidity [see Warnings and Precautions ( 5.1 ) ] Hepatoxicity [see Warnings and Precautions ( 5.2 ) ] Myopathy and Rhabdomyolysis [see Warnings and Precautions ( 5.3 )] Increases in Serum Creatinine [see Warnings and Precautions ( 5.4 )] Cholelithiasis [see Warnings and Precautions ( 5.5 )] Increased Bleeding Risk with Coumarin Anticoagulants [see Warnings and Precautions ( 5.6 )] Pancreatitis [see Warnings and Precautions ( 5.7 ) ] Hematologic Changes [see Warnings and Precautions ( 5.8 )] Hypersensitivity reactions [see Warnings and Precautions ( 5.9 ) ] Venothromboembolic disease [see Warnings and Precautions ( 5.10 ) ] Paradoxical Decreases in HDL Cholesterol Levels [see Warnings and Precautions ( 5.11 )] Adverse reactions (≥ 2% and greater than placebo): abnormal liver tests, increased AST, increased ALT, increased CPK, and rhinitis ( 6.1 ).

To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of fenofibric acid delayed-release capsules has been established in adults with hypertriglyceridemia or primary hyperlipidemia based on adequate and well-controlled trials of other formulations of fenofibrate, referenced below as “fenofibrate” [see Clinical Studies ( 14 )].

Dosages of fenofibrate used in these trials were comparable to fenofibric acid delayed-release capsules 135 mg per day [see Clinical Pharmacology ( 12.3 )]. Adverse reactions reported by 2% or more of patients treated with fenofibrate (and greater than placebo) during the double-blind, placebo-controlled trials are listed in Table 1 . Adverse reactions led to discontinuation of treatment in 5% of patients treated with fenofibrate and in 3% 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. Table 1. Adverse Reactions Reported by 2% or More of Patients Treated with Fenofibrate and Greater than Placebo During the Double-Blind, Placebo-Controlled Trials Adverse Reaction Placebo (N = 365) Fenofibrate (N = 439) Abnormal Liver Tests 1% 8% Abdominal Pain 4% 5% Increased ALT 2% 3% Increased AST 1% 3% Increased Creatine Phosphokinase 1% 3% Constipation 1% 2% Rhinitis 1% 2% Other Adverse Reactions Urticaria 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 three 12-week, double-blind, controlled studies of fenofibric acid delayed-release capsules, increases in ALT and AST > 3 times the upper limit of normal on two consecutive occasions occurred in 1.9% and 0.2%, respectively, of patients receiving fenofibric acid delayed-release capsules 135 mg daily and placebo, without other lipid-altering drugs .

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 either an intermediate or maximum recommended daily dosage of fenofibrate versus 1.1% of patients treated with placebo. In an 8-week trial, the incidence of ALT or AST elevations ≥ 3 times the upper limit of normal was 13% in patients receiving an intermediate daily dosage or the maximum recommended daily dosage of fenofibrate and was 0% in those receiving the lowest recommended daily dosage of fenofibrate or placebo [see Warnings and Precautions ( 5.2 )] .

Clinical trials with fenofibric acid delayed-release capsules did not include a plac…

7 DRUG INTERACTIONS Table 2 presents clinically important drug interactions with Trilipix. Table 2. Clinically Important Drug Interactions with Trilipix Statins Clinical Impact: Fibrates may cause myopathy when given alone.

The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with statins. Intervention: Consider if the benefit of using Trilipix concomitantly with statin therapy outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dosage titration of statin therapy.

Colchicine Clinical Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with fenofibrates. Intervention: Consider if the benefit of using colchicine concomitantly with Trilipix outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dosage titration of colchicine.

Coumarin Anticoagulants Clinical Impact: Fibrates may cause potentiation of coumarin-type anticoagulant effects with prolongation of the PT/INR. Intervention: Caution should be exercised when coumarin anticoagulants are given in conjunction with Trilipix. 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 Immunosuppressants Clinical Impact: Immunosuppressants such as cyclosporine and tacrolimus 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 Trilipix, there is a risk that an interaction will lead to deterioration of renal function. Intervention: The benefits and risks of using Trilipix with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dosage employed and renal function monitored.

Bile-Acid Binding Resins Clinical Impact: Bile-acid binding resins may bind other drugs given concurrently. Intervention: In patients taking a bile acid resin, administer Trilipix at least 1 hour before or 4 to 6 hours after the bile acid resin to avoid impeding its absorption. Consider if the benefit of concomitant use of statins or colchicine outweighs the increased risk of myopathy and rhabdomyolysis.

Monitor patients for signs and symptoms of myopathy ( 7 ). Exercise caution in concomitant treatment with coumarin anticoagulants. Reduce the dosage of coumarin to maintain the PT/INR at the desired level to prevent bleeding complications ( 7 ).

Consider the benefits and risks of concomitant use with immunosuppressants and other potentially nephrotoxic agents. Use the lowest effective dosage and monitor renal function ( 7 ). Administer Trilipix at least 1 hour before or 4 to 6 hours after a bile acid resin to avoid impeding its absorption ( 7 ).