Fenofibrate Capsules

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).

Initial Therapy

Laboratory studies should be done to ascertain that the lipid levels are consistently abnormal before instituting fenofibrate 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-loweringdrug 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 Therapy should be withdrawn in patients who do not have an adequate response after two months of treatment with the maximum recommended dose of 200 mg per day.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 reactions including severe skin rashes requiring patient hospitalization and treatment with steroids have occurred very rarely during treatment with fenofibrate, including rare spontaneous reports of Stevens-Johnson syndrome, and toxic epidermal necrolysis. 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.

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 postmarketing surveillance outside of the U.S. Periodic blood counts are recommended during the first 12 months of fenofibrate administration.

Skeletal Muscle

The use of fibrates alone, including fenofibrate, 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.

Venothromboembolic Disease

In the FIELD trial, pulmonary embolus (PE) and deep vein thrombosis (DVT) were observed at higher rates in the fenofibrate- than the placebo-treated group. Of 9,795 patients enrolled in FIELD, there were 4,900 in the placebo group and 4,895 in the fenofibrate group. For DVT, there were 48 events (1%) in the placebo group and 67 (1%) in the fenofibrate group (p = 0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (1%) in the fenofibrate group (p = 0.022).

In the Coronary Drug Project, a higher proportion of the clofibrate group experienced definite or suspected fatal or nonfatal pulmonary embolism or thrombophlebitis than the placebo group (5.2% vs. 3.3% at five years; p < 0.01).

Serum Creatinine

Elevations in serum creatinine have been reported in patients on fenofibrate. These elevations tend to return to baseline following discontinuation of fenofibrate. The clinical significance of these observations is unknown.

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 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, there is a risk that an interaction will lead to deterioration. The benefits and risks of using fenofibrate with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Two dietary carcinogenicity studies have been conducted in rats with fenofibrate. In the first 24 month study, rats were dosed with fenofibrate at 10, 45, and 200 mg/kg/day, approximately 0.3, 1, and 6 times the maximum recommended human dose (MRHD), based on body surface area comparisons (mg/m2). At a dose of 200 mg/kg/day (at 6 times the MRHD), the incidence of liver carcinomas was significantly increased in both sexes. A statistically significant increase in pancreatic carcinomas was observed in males at 1 and 6 times the MRHD; an increase in pancreatic adenomas and benign testicular interstitial cell tumors was observed at 6 times the MRHD in males. In a second 24 month rat carcinogenicity study in a different strain of rats, doses of 10 and 60 mg/kg/day (0.3 and 2 times the MRHD) produced significant increases in the incidence of pancreatic acinar adenomas in both sexes and increases in testicular interstitial cell tumors in males at 2 times the MRHD.

A 117 week carcinogenicity study was conducted in rats comparing three drugs: fenofibrate 10 and 60 mg/kg/day (0.3 and 2 times the MRHD), clofibrate (400 mg/kg/day; 2 times the human dose), and gemfibrozil (250 mg/kg/day; 2 times the human dose, based on mg/m2 surface area). Fenofibrate increased pancreatic acinar adenomas in both sexes. Clofibrate increased hepatocellular carcinoma and pancreatic acinar adenomas in males and hepatic neoplastic nodules in females. Gemfibrozil increased hepatic neoplastic nodules in males and females, while all three drugs increased testicular interstitial cell tumors in males.

In a 21 month study in mice, fenofibrate 10, 45, and 200 mg/kg/day (approximately 0.2, 1, and 3 times the MRHD on the basis of mg/m2 surface area) significantly increased the liver carcinomas in both sexes at 3 times the MRHD. In a second 18 month study at 10, 60, and 200 mg/kg/day, fenofibrate significantly increased the liver carcinomas in male mice and liver adenomas in female mice at 3 times the MRHD.

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 in primary rat hepatocytes.

In fertility studies rats were given oral dietary doses of fenofibrate, males received 61 days prior to mating and females 15 days prior to mating through weaning which resulted in no adverse effect on fertility at doses up to 300 mg/kg/day (~ 10 times the MRHD, based on mg/m2 surface area comparisons).

Pregnancy

Teratogenic Effects

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 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 to 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 lactaction day 21 (weaning), maternal toxicity was observed at less than 1 times the MRHD, based on body surface area comparisons: mg/m2.

Nursing Mothers

It is not known whether fenofibrate is excreted into milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from fenofibrate, a decision should be made whether to discontinue nursing or administration of fenofibrate taking into account the importance of the drug to the lactating woman.

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. Fenofibric acid exposure is not influenced by age. However, elderly patients have a higher incidence of renal impairment, such that dose selection for the elderly should be made on the basis of renal function (see CLINICAL PHARMACOLOGY, Special Populations, Renal Insufficiency). Elderly patients with normal renal function should require no dose modifications.

The following adverse reactions have been identified during post-approval use of fenofibrate:myalgia, rhabdomyolysis, pancreatitis, acute renal failure, muscle spasm, hepatitis, cirrhosis, anemia, arthralgia, decreases in hemoglobin, decreases in hematocrit, white blood cell decreases and asthenia. 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.

There is no specific treatment for overdose with fenofibrate. 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.

Fenofibrate Capsules, USP (micronized), 67 mg are hard gelatin capsule shells with pink opaque cap and pink opaque body imprinted IG and 470 with black ink. They are supplied as follows:

NDC 16714-739-01 Bottles of 90 capsules
NDC 16714-739-02 Bottles of 100 capsules

Fenofibrate Capsules, USP (micronized), 134 mg are hard gelatin capsule shells with blue opaque cap and blue opaque body imprinted IG and 471 with black ink. They are supplied as follows:

NDC 16714-740-01 Bottles of 90 capsules
NDC 16714-740-02 Bottles of 100 capsules

Fenofibrate Capsules, USP (micronized), 200 mg are hard gelatin capsule shells with orange opaque cap and orange opaque body imprinted IG and 472 with black ink. They are supplied as follows:

NDC 16714-741-01 Bottles of 90 capsules
NDC 16714-741-02 Bottles of 100 capsules

STORAGE

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Keep out of the reach of children. Protect from moisture.

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.

Manufactured by:
InvaGen Pharmaceuticals, Inc.
(a subsidiary of Cipla Ltd.)
Hauppauge, NY 11788

Manufactured for:
Northstar Rx LLC
Memphis, TN 38141.

Iss. 6/2017

PRINCIPAL DISPLAY PANEL - 67 mg

NDC 16714-739-01

Rx only

Fenofibrate
Capsules, USP
67 mg
90 Capsules

♦NORTHSTARx™

PRINCIPAL DISPLAY PANEL - 134 mg

NDC 16714-740-01

Rx only

Fenofibrate
Capsules, USP
134 mg
90 Capsules

♦NORTHSTARx™

PRINCIPAL DISPLAY PANEL - 200 mg

NDC 16714-741-01

Rx only

Fenofibrate
Capsules, USP
200 mg
90 Capsules

♦NORTHSTARx™

FENOFIBRATE  fenofibrate capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:16714-739 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FENOFIBRATE (FENOFIBRIC ACID) FENOFIBRATE 67 mg

Inactive Ingredients Ingredient Name Strength LACTOSE MONOHYDRATE   CROSPOVIDONE, UNSPECIFIED   POVIDONE, UNSPECIFIED   SODIUM LAURYL SULFATE   SILICON DIOXIDE   MAGNESIUM STEARATE   FD&C BLUE NO. 1   FD&C RED NO. 3   D&C YELLOW NO. 10   TITANIUM DIOXIDE   GELATIN, UNSPECIFIED

Product Characteristics Color PINK (Pink opaque cap) , PINK (Pink opaque body) Score no score Shape CAPSULE Size 14mm Flavor Imprint Code IG;470 Contains

Packaging # Item Code Package Description 1 NDC:16714-739-01 90 CAPSULE in 1 BOTTLE, PLASTIC 2 NDC:16714-739-02 100 CAPSULE in 1 BOTTLE, PLASTIC

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA207378 08/21/2017

FENOFIBRATE  fenofibrate capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:16714-740 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FENOFIBRATE (FENOFIBRIC ACID) FENOFIBRATE 134 mg

Inactive Ingredients Ingredient Name Strength LACTOSE MONOHYDRATE   CROSPOVIDONE, UNSPECIFIED   POVIDONE, UNSPECIFIED   SODIUM LAURYL SULFATE   SILICON DIOXIDE   MAGNESIUM STEARATE   FD&C BLUE NO. 1   D&C RED NO. 28   TITANIUM DIOXIDE   GELATIN, UNSPECIFIED

Product Characteristics Color BLUE (Blue opaque cap) , BLUE (Blue opaque body) Score no score Shape CAPSULE Size 18mm Flavor Imprint Code IG;471 Contains

Packaging # Item Code Package Description 1 NDC:16714-740-01 90 CAPSULE in 1 BOTTLE, PLASTIC 2 NDC:16714-740-02 100 CAPSULE in 1 BOTTLE, PLASTIC

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA207378 08/21/2017

FENOFIBRATE  fenofibrate capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:16714-741 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FENOFIBRATE (FENOFIBRIC ACID) FENOFIBRATE 200 mg

Inactive Ingredients Ingredient Name Strength LACTOSE MONOHYDRATE   CROSPOVIDONE, UNSPECIFIED   POVIDONE, UNSPECIFIED   SODIUM LAURYL SULFATE   SILICON DIOXIDE   MAGNESIUM STEARATE   FD&C BLUE NO. 1   FD&C RED NO. 40   FD&C YELLOW NO. 6   TITANIUM DIOXIDE   GELATIN, UNSPECIFIED

Product Characteristics Color ORANGE (Orange opaque cap) , ORANGE (Orange opaque body) Score no score Shape CAPSULE Size 19mm Flavor Imprint Code IG;472 Contains

Packaging # Item Code Package Description 1 NDC:16714-741-01 90 CAPSULE in 1 BOTTLE, PLASTIC 2 NDC:16714-741-02 100 CAPSULE in 1 BOTTLE, PLASTIC

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA207378 08/21/2017

Labeler - Northstar Rx LLC (830546433)

Registrant - InvaGen Pharmaceuticals Inc. (165104469)

Establishment
Name	Address	ID/FEI	Operations
InvaGen Pharmaceuticals Inc.		165104469	manufacture(16714-739, 16714-740, 16714-741), analysis(16714-739, 16714-740, 16714-741)

Revised: 08/2017   Northstar Rx LLC