Prescription Drug Information: Fenofibrate (Page 2 of 5)

5.4 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. Monitor renal function in patients with renal impairment taking fenofibrate. Renal monitoring should also be considered for patients taking fenofibrate at risk for renal insufficiency such as the elderly and patients with diabetes.

5.5 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 therapy should be discontinued if gallstones are found.

5.6 Coumarin Anticoagulants


Caution should be exercised when coumarin anticoagulants are given in conjunction with fenofibrate because of the potentiation of coumarin-type anticoagulant effects in prolonging the Prothrombin Time/International Normalized Ratio (PT/INR). To prevent bleeding complications, frequent monitoring of PT/INR and dose adjustment of the anticoagulant are recommended until PT/INR has stabilized [see Drug Interactions (7.1)].

5.7 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.

5.8 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. Thrombocytopenia and agranulocytosis have been reported in individuals treated with fenofibrate. Periodic monitoring of red and white blood cell counts are recommended during the first 12 months of fenofibrate administration.

5.9 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.

5.10 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).

5.11 Paradoxical Decreases in HDL Cholesterol Levels

There have been postmarketing and clinical trial reports of severe decreases in HDL cholesterol levels (as low as 2 mg/dL) occurring in diabetic and non-diabetic patients initiated on fibrate therapy. The decrease in HDL-C is mirrored by a decrease in apolipoprotein A1. This decrease has been reported to occur within 2 weeks to years after initiation of fibrate therapy. The HDL-C levels remain depressed until fibrate therapy has been withdrawn; the response to withdrawal of fibrate therapy is rapid and sustained. The clinical significance of this decrease in HDL-C is unknown. It is recommended that HDL-C levels be checked within the first few months after initiation of fibrate therapy. If a severely depressed HDL-C level is detected, fibrate therapy should be withdrawn, and the HDL-C level monitored until it has returned to baseline, and fibrate therapy should not be re-initiated.

6 ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in the labeling:

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 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 1 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.

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.
* Dosage equivalent to 145 mg fenofibrate. ** Significantly different from Placebo.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.
BODY SYSTEM Fenofibrate* Placebo
Adverse Reaction (N=439) (N=365)
BODY AS A WHOLE
Abdominal Pain 4.6% 4.4%
Back Pain 3.4% 2.5%
Headache 3.2% 2.7%
DIGESTIVE
Nausea 2.3% 1.9%
Constipation 2.1% 1.4%
METABOLIC AND NUTRITIONAL DISORDERS
Abnormal Liver Function Tests 7.5%** 1.4%
Increased ALT 3.0% 1.6%
Increased CPK 3.0% 1.4%
Increased AST 3.4%** 0.5%
RESPIRATORY
Respiratory Disorder 6.2% 5.5%
Rhinitis 2.3% 1.1%

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 96 mg to 145 mg fenofibrate daily versus 1.1% of patients treated with placebo [see Warnings and Precautions (5.2)]. 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 96 mg to 145 mg fenofibrate daily and was 0% in those receiving dosages equivalent to 48 mg or less fenofibrate daily or placebo.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval 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, acute renal failure, muscle spasm, hepatitis, cirrhosis, increased total bilirubin, anemia, arthralgia, decreases in hemoglobin, decreases in hematocrit, white blood cell decreases, 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 fenofibrate. 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 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 of renal function. The benefits and risks of using fenofibrate tablets with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed and renal function monitored.

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