Fenofibrate 200 mg Capsule, 100-count — NDC 13668-438-01 (Billing 13668-0438-01)

WARNINGS Hepatotoxicity: Serious drug-induced liver injury (DILI), including liver transplantation and death, have been reported postmarketing with fenofibrate. DILI has been reported within the first few weeks of treatment or after several months of therapy and in some cases has reversed with discontinuation of fenofibrate treatment. Patients with DILI have experienced signs and symptoms including dark urine, abnormal stool, jaundice, malaise, abdominal pain, myalgia, weight loss, pruritus, and nausea.

Many patients had concurrent elevations of total bilirubin, serum alanine transaminase (ALT), and aspartate transaminase (AST). DILI has been characterized as hepatocellular, chronic active, and cholestatic hepatitis, and cirrhosis has occurred in association with chronic active hepatitis. In clinical trials, fenofibrate at doses equivalent to 134 mg to 200 mg fenofibrate daily has been associated with increases in serum AST or ALT The incidence of increases in transaminases may be dose-related.

Fenofibrate is contraindicated in patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities [see Contraindications ( 4 )]. Monitor patient’s liver function, including serum ALT, AST, and total bilirubin, at baseline and periodically for the duration of therapy with fenofibrate. Discontinue fenofibrate if signs or symptoms of liver injury develop or if elevated enzyme levels persist (ALT or AST > 3 times the upper limit of normal, or if accompanied by elevation of bilirubin).

Do not restart fenofibrate in these patients if there is no alternative explanation for the liver injury. 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 capsule 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. Concomitant administration of fenofibrate (equivalent to fenofibrate 200 mg) and pravastatin (40 mg) once daily for 10 days increased the mean C max and AUC values for pravastatin by 36% (range from 69% decrease to 321% increase) and 28% (range from 54% decrease to 128% increase), respectively, and for 3α-hydroxy-iso-pravastatin by 55% (range from 32% decrease to 314% increase) and 39% (range from 24% decrease to 261% increase), respectively.

(See also CLINICAL PHARMACOLOGY, Drug-drug Interactions). The combined use of fibric acid derivatives and HMG-CoA reductase inhibitors has been associated, in the absences of a marked pharmacokinetic interaction, in numerous case reports, with rhabdomyolysis, markedly elevated creatine kinase (CK) levels and myoglobinuria, leading in a high proportion of cases to acute renal failure. The use of fibrates alone, including fenofibrate capsules may occasionally be associated with myositis, myopathy, or rhabdomyolysis.

Patients receiving fenofibrate capsules and complaining of muscle pain, tenderness, or weakness should have prompt medical evaluation for myopathy, including serum creatine kinase level determination. If myopathy/myositis is suspected or diagnosed, fenofibrate capsule therapy should be stopped.… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS Clinical Studies 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 the rates observed in practice. Adverse events reported by 2% or more of patients treated with fenofibrate (and greater than placebo) during the double-blind, placebo-controlled trials, regardless of causality, are listed in Table 3 below.

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

Table 3. Adverse Reactions Reported by 2% or More of Patients Treated with Fenofibrate and Greater than Placebo During the Double-Blind, Placebo-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 versus 1.1% of patients treated with placebo. In an 8-week study, the incidence of ALT or AST elevations ≥ 3 times the upper limit of normal was 13% in patients receiving dosages equivalent to 134 mg to 200 mg fenofibrate daily and was 0% in those receiving dosages equivalent to 34 mg to 67 mg fenofibrate daily or placebo.

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

To report SUSPECTED ADVERSE REACTIONS, contact Torrent Pharma Inc. at 1-800-912-9561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Body System

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: 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/m 2 ).

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/m 2 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/m 2 surface area) significantly increased the liver 23 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, mou… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS Initial Therapy : Laboratory studies should be done to ascertain that the lipid levels are consistently abnormal before instituting fenofibrate capsule 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, systemic 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 capsule administration. Myopathy and Rhabdomyolysis: 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. 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… [Excerpted — this section continues on DailyMed.]