Prescription Drug Information: ANTARA
ANTARA- fenofibrate capsule
Lupin Pharmaceuticals, Inc.
1 INDICATIONS AND USAGE
1.1 Primary Hypercholesterolemia and Mixed Dyslipidemia
Antara is indicated as adjunctive therapy to diet to reduce elevated low-density lipoprotein cholesterol (LDL-C), total cholesterol (Total-C), triglycerides (TG), and apolipoprotein B (Apo B), and to increase high-density lipoprotein cholesterol (HDL-C) in adult patients with primary hypercholesterolemia or mixed dyslipidemia.
1.2 Severe Hypertriglyceridemia
Antara is also indicated as adjunctive therapy to diet for treatment of adult patients with severe 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.
Markedly elevated levels of serum triglycerides (e.g, > 2,000 mg/dL) may increase the risk of developing pancreatitis. The effect of fenofibrate therapy on reducing this risk has not been adequately studied.
1.3 Important Limitations of Use
Fenofibrate was not shown to reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus. [see Warnings and Precautions (5.1)].
2 DOSAGE AND ADMINISTRATION
2.1 General Considerations
Patients should be placed on an appropriate lipid-lowering diet before receiving Antara, and should continue this diet during treatment with Antara. Antara capsules can be given without regard to meals.
Patients should be advised to swallow Antara capsules whole. Do not open, crush, dissolve or chew capsules.
The initial treatment for dyslipidemia is dietary therapy specific for the type of lipoprotein abnormality. Excess body weight and excess alcoholic intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy. Physical exercise can be an important ancillary measure. Diseases contributory to hyperlipidemia, such as hypothyroidism or diabetes mellitus should be looked for and adequately treated. Estrogen therapy, thiazide diuretics and beta-blockers, are sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia. In such cases, discontinuation of the specific etiologic agent may obviate the need for specific drug therapy of hypertriglyceridemia.
Lipid levels should be monitored periodically and consideration should be given to reducing the dosage of Antara if lipid levels fall significantly below the targeted range.
Therapy should be withdrawn in patients who do not have an adequate response after two months of treatment with the maximum recommended dose of 130 mg once daily.
2.2 Primary Hypercholesterolemia and Mixed Dyslipidemia
The initial dose of Antara is 130 mg per day.
2.3 Severe Hypertriglyceridemia
The initial dose is 43 to 130 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 130 mg per day.
2.4 Impaired Renal Function
Treatment with Antara should be initiated at a dose of 43 mg per day in patients having 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 Antara should be avoided in patients with severe renal impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
2.5 Geriatric Patients
Dose selection for the elderly should be made on the basis of renal function [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]
3 DOSAGE FORMS AND STRENGTHS
- 43 mg capsules, imprinted with “43” and a segmented band, on the light green cap and “ANTARA” and “LUPIN” on the white to off-white body.
- 130 mg capsules, imprinted with “130” and a segmented band, on the dark green cap and “ANTARA” and “LUPIN” on the white body.
4 CONTRAINDICATIONS
- patients with severe renal impairment, including those receiving dialysis [see Clinical Pharmacology (12.3)].
- patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities[see Warnings and Precautions (5.2)].
- patients with preexisting gallbladder disease [see Warnings and Precautions (5.5)].
- nursing mothers [see Use in Specific Populations (8.3)].
- patients with known hypersensitivity to fenofibric acid or fenofibrate[see Warnings and Precautions (5.9)].
5 WARNINGS AND PRECAUTIONS
5.1 Mortality and Coronary Heart Disease Morbidity
The effects of Antara on coronary heart disease morbidity and mortality and non-cardiovascular mortality have not been established.
The Action to Control Cardiovascular Risk in Diabetes Lipid (ACCORD Lipid) trial was a randomized placebo-controlled study of 5518 patients with type 2 diabetes mellitus on background statin therapy treated with fenofibrate. The mean duration of follow-up was 4.7 years. Fenofibrate plus statin combination therapy showed a nonsignificant 8% relative risk reduction in the primary outcome of major adverse cardiovascular events (MACE), a composite of non-fatal myocardial infarction, nonfatal stroke, and cardiovascular disease death (hazard ratio [HR] 0.92, 95% CI 0.79-1.08) (p=0.32) as compared to statin monotherapy. In a gender subgroup analysis, the hazard ratio for MACE in men receiving combination therapy versus statin monotherapy was 0.82 (95% CI 0.69-0.99), and the hazard ratio for MACE in women receiving combination therapy versus statin monotherapy was 1.38 (95% CI 0.98-1.94) (interaction p=0.01). The clinical significance of this subgroup finding is unclear.
The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a 5-year randomized, placebo-controlled study of 9795 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.
Because of chemical, pharmacological, and clinical similarities between TRICOR (fenofibrate tablets), clofibrate, and gemfibrozil, the adverse findings in 4 large randomized, placebo-controlled clinical studies with these other fibrate drugs may also apply to Antara.
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. There was however, a difference in the rate of cholelithiasis and cholecystitis requiring surgery between the two groups (3.0% vs. 1.8%).
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=4081) 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).
5.2 Hepatotoxicity
Serious drug-induced liver injury (DILI), including liver transplantation and death, have been reported postmarketing with Antara. 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 Antara 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 130 mg Antara daily has been associated with increases in serum AST or ALT. The incidence of increases in transaminases may be dose related [see Adverse Reactions (6.1)].
Antara 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 Antara. Discontinue Antara 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 Antara in these patients if there is no alternative explanation for the liver injury.
5.3 Myopathy and Rhabdomyolysis
Fibrates increase the risk for myopathy, and have been associated with rhabdomyolysis. The risk for serious muscle toxicity appears to be increased in elderly patients and in patients with diabetes, renal failure, or hypothyroidism.
Data from observational studies suggest that the risk for rhabdomyolysis is increased when fibrates, in particularly gemfibrozil, are co-administered with a statin. The combination should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination [(see Clinical Pharmacology (12.3) ].
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 Antara therapy should be discontinued if markedly elevated CPK levels occur or myopathy/myositis is suspected or diagnosed.
Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co-administered with colchicine, and caution should be exercised when prescribing fenofibrate with colchicine [see Drug Interactions (7.4) ].
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