Fenoglide

FENOGLIDE- fenofibrate tablet
Sciele Pharma, Inc.

1.1 Hyperlipidemia and Mixed Dyslipidemia

Fenoglide is indicated as adjunctive therapy to diet to reduce elevated LDL-C, Total-C, Triglycerides, and Apo B, and to increase HDL-C in adult patients with primary hyperlipidemia or mixed dyslipidemia. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and non-pharmacological interventions alone has been inadequate.

1.2 Hypertriglyceridemia

Fenoglide is also indicated as adjunctive therapy to diet for treatment of adult patients with hypertriglyceridemia. Improving glycemic control in diabetic patients showing fasting chylomicronemia will usually reduce fasting triglycerides and eliminate chylomicronemia thereby obviating the need for pharmacologic intervention.

1.3 General Guidelines

Fenofibrate was not shown to reduce coronary heart disease morbidity and mortality in a large, randomized controlled trial of patients with type 2 diabetes mellitus. [see Warnings and Precautions(5.6).]

Markedly elevated levels of serum triglycerides (e.g. >2,000 mg/dL) may increase the risk of developing pancreatitis. The effect of Fenoglide therapy on reducing this risk has not been adequately studied.

Drug therapy is not indicated for patients who have elevations of chylomicrons and plasma triglycerides, but who have normal levels of very low density lipoprotein (VLDL). Inspection of plasma refrigerated for 14 hours is helpful in distinguishing these patients from those with elevated VLDL.2

2 DOSAGE AND ADMINISTRATION

2.1 Hyperlipidemia and Mixed Dyslipidemia

The initial dose of Fenoglide is 120 mg per day.

2.2 Hypertriglyceridemia

The initial dose is 40 to 120 mg per day. Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determinations at 4 to 8 week intervals. The maximum dose is 120 mg per day.

2.3 Renally Impaired Patients

Treatment with Fenoglide should be initiated at a dose of 40 mg/day in patients with mild to moderately impaired renal function, and increased only after evaluation of the effects on renal function and lipid levels at this dose. The use of Fenoglide should be avoided in patients with severely impaired renal function.

2.4 Elderly Patients

Dose selection for the elderly should be made on the basis of renal function. [See Use in Specific Populations (8.5). ]

2.5 General Dosing Information

To increase absorption of Fenoglide, take with food.

3 DOSAGE FORMS AND STRENGTHS

  • 40 mg: White to off-white oval tablets. Debossed “FLO”.
  • 120 mg: White to off-white oval tablets. Debossed “FHI”.

4 CONTRAINDICATIONS

  • Fenoglide is contraindicated in patients with severe renal dysfunction, including those receiving dialysis [see Clinical Pharmacology (12.3)]
  • Fenoglide is contraindicated in patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities [see Warnings and Precautions(5.1)]
  • Fenoglide is contraindicated in patients with gallbladder disease [see Warnings and Precautions (5.2)]
  • Fenoglide is contraindicated in nursing mothers [see Use in Specific Populations (8.3)]
  • Fenoglide is contraindicated in patients who have a known hypersensitivity to fenofibrate, such as severe skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis. [see Warnings and Precautions (5.9)]

5 WARNINGS AND PRECAUTIONS

5.1 Liver Tests

Fenofibrate at doses equivalent to 87 mg to 130 mg fenofibrate per day [at the highest dose, comparable to Fenoglide, 120 mg] can increase serum transaminases [AST (SGOT) or ALT (SGPT)].

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

When transaminase determinations were followed either after discontinuation of treatment or during continued treatment, a return to normal limits was usually observed. The incidence of increases in transaminases related to fenofibrate therapy appear to be dose related. In an 8-week dose-ranging study, the incidence of ALT or AST elevations to at least three times the upper limit of normal was 13% in patients receiving dosages equivalent to 87 mg to 130 mg fenofibrate per day and was 0% in those receiving dosages equivalent to 43 mg or less fenofibrate per day, or placebo. Hepatocellular, chronic active and cholestatic hepatitis have been reported after exposures of weeks to several years. In extremely rare cases, cirrhosis has been reported in association with chronic active hepatitis.

Regular periodic monitoring of liver tests, including serum ALT (SGPT) should be performed for the duration of therapy with Fenoglide, and therapy discontinued if enzyme levels persist above three times the normal limit.

5.2 Cholelithiasis

Fenofibrate increases cholesterol excretion into the bile, leading to risk of cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Fenoglide therapy should be discontinued if gallstones are found.

5.3 Concomitant Coumarin Anticoagulants

Caution should be exercised when anticoagulants are given in conjunction with Fenoglide because of the potentiation of coumarin-type anti-coagulants 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. [See Drug Interactions (7.1). ]

5.4 Skeletal Muscle

Treatment with fenofibrate increases risk of myopathy. Treatment with fenofibrate increases risk of 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 (CPK) 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.

5.5 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.

5.6 Mortality and Coronary Heart Disease Morbidity

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a 5-year randomized, placebo-controlled study of 9,795 patients with type 2 diabetes mellitus treated with fenofibrate. Fenofibrate demonstrated a non-significant 11% relative reduction in the primary outcome of coronary heart disease events (hazard ratio [HR] 0.89, 95% CI 0.75-1.05, p=0.16) and a significant 11% reduction in the secondary outcome of total cardiovascular disease events (HR 0.89 [0.80-0.99], p=0.04). There was a non-significant 11% (HR 1.11 [0.95, 1.29], p=0.18) and 19% (HR 1.19 [0.90, 1.57], p=0.22) increase in total and coronary heart disease mortality, respectively, with fenofibrate as compared to placebo.

In the Coronary Drug Project, a large study of post myocardial infarction of patients treated for 5 years with clofibrate, there was no difference in mortality seen between the clofibrate group and the placebo group.

In a study conducted by the World Health Organization (WHO), 5000 subjects without known coronary artery disease were treated with placebo or clofibrate for 5 years and followed for an additional one 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. This appeared to confirm the higher risk of gallbladder disease seen in clofibrate-treated patients studied in the Coronary Drug Project.

The Helsinki Heart Study was a large (n=4,081) study 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 higher in the gemfibrozil randomization group but did not achieve statistical significance (p=0.19, 95% confidence interval for relative risk G:P=0.91-1.64). Although cancer deaths trended higher in the gemfibrozil group (p=0.11), cancers (excluding basal cell carcinoma) were diagnosed with equal frequency in both study groups. Due to the limited size of the study, the relative risk of death from any cause was not shown to be different than that seen in the 9 year follow-up data from the WHO study (RR=1.29).

A secondary prevention component of the Helsinki Heart Study enrolled middle-aged men excluded from the primary prevention study because of known or suspected coronary heart disease. Subjects received gemfibrozil or placebo for 5 years. Although cardiac deaths trended higher in the gemfibrozil group, this was not statistically significant (hazard ratio 2.2, 95% confidence interval: 0.94-5.05).

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