Lipofen Information
Lipofen () Indications And Usage
Lipofen () 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 obviate 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
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Lipofen () Dosage And Administration
Lipofen () capsules should be given with meals thereby optimizing the absorption of the medication.
Patients should be placed on an appropriate lipid-lowering diet before receiving Lipofen () , and should continue this diet during treatment with Lipofen () .
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.
Periodic determination of serum lipids should be obtained during initial therapy in order to establish the lowest effective dose of Lipofen () . Therapy should be withdrawn in patients who do not have an adequate response after two months of treatment with the maximum recommended dose of 150 mg per day.
Consideration should be given to reducing the dosage of Lipofen () if lipid levels fall significantly below the targeted range.
The initial dose is 50 to 150 mg per day. Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determination at 4 to 8 week intervals.
The maximum dose of Lipofen () is 150 mg once daily.
Lipofen () Contraindications
Lipofen () is contraindicated in:
Lipofen () Warnings And Precautions
The effect of Lipofen () on coronary heart disease morbidity and mortality and non-cardiovascular mortality has not been established.
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 fenofibrate, clofibrate, and gemfibrozil, the adverse findings in 4 large randomized, placebo-controlled clinical studies with these other fibrate drugs may also apply to Lipofen () .
In the Coronary Drug Project, a large study of post myocardial infarction 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=
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 second 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). The rate of gallbladder surgery was 1.9% in the gemfibrozil group compared to 0.3% in the placebo group, p=0.07).
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 insufficiency, or hypothyroidism.
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. Creatine phosphokinase (CPK) levels should be assessed in patients reporting these symptoms, and Lipofen () therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed.
Data from observational studies indicate that the risk for rhabdomyolysis is increased when fibrates, in particular gemfibrozil, are co-administered with an HMG-CoA reductase inhibitor (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
Fenofibrate at doses equivalent to 100 mg to 150 mg Lipofen () per day has been associated with increases in serum transaminases [AST (SGOT) or ALT (SGPT)]. In a pooled analysis of 10 placebo-controlled trials of fenofibrate, increases to > 3 times the upper limit of normal of ALT occurred in 5.3% of patients taking fenofibrate versus 1.1% of patients treated with placebo. The incidence of increases in transaminases observed with fenofibrate therapy may be dose related. When transaminase determinations were followed either after discontinuation of treatment or during continued treatment, a return to normal limits was usually observed.
Chronic active hepatocellular and cholestatic hepatitis associated with fenofibrate therapy have been reported after exposures of weeks to several years. In extremely rare cases, cirrhosis has been reported in association with chronic active hepatitis.
Periodic monitoring of liver tests (e.g. ALT) should be performed for the duration of therapy with Lipofen () , and therapy discontinued if enzyme levels persist above three times the normal limit.
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, 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 5 years; p
Lipofen () Adverse Reactions
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rate observed in clinical practice.
Adverse reactions 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 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.
Lipofen () Drug Interactions
Potentiation of coumarin-type anticoagulant effect has been observed with prolongation of the PT/INR.
Caution should be exercised when Lipofen () is given in conjunction with coumarin anticoagulants. Lipofen () may potentiate the anticoagulant effect of these agents resulting in prolongation of the PT/INR. To prevent bleeding complications, frequent monitoring of PT/INR and dose adjustment of the oral anticoagulant as recommended until the PT/INR has stabilized .
Lipofen () Overdosage
There is no specific treatment for overdose with Lipofen () . 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. The usual precautions should be observed to maintain the airway. Because fenofibrate is highly bound to plasma proteins, hemodialysis should not be considered.
Lipofen () Description
Lipofen () ® (fenofibrate capsules, USP), is a lipid regulating agent available as hard gelatin capsules for oral administration. Each hard gelatin capsule contains 50 or 150 mg of fenofibrate, USP. The chemical name for fenofibrate is 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester with the following structural formula:
The empirical formula is CHOC1 and the molecular weight is 360.83; fenofibrate is insoluble in water. The melting point is 79-82C. Fenofibrate is a white solid which is stable under ordinary conditions.
Lipofen () (fenofibrate capsules, USP) meets USP Dissolution Test 2.
Inactive Ingredients: Each hard gelatin capsule contains Gelucire 44/14 (lauroyl macrogol glyceride type 1500), polyethylene glycol 20,000, polyethylene glycol 8000, hydroxypropylcellulose, sodium starch glycolate, gelatin, titanium dioxide, shellac, propylene glycol, may also contain black iron oxide, FD&C Blue #1, FD&C Blue #2, FD&C Red #40, D&C Yellow #10.
Lipofen () Clinical Pharmacology
The active moiety of Lipofen () is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been extensively studied through oral administration of fenofibrate.
The lipid-modifying effects of fenofibric acid seen in clinical practice have been explained in transgenic mice and in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor α (PPARα). Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting decrease in triglycerides produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPARα also induces an increase in the synthesis of apolipoproteins A-I, A-II and HDL-cholesterol.
Elevated levels of total-C, LDL-C, and apo B and decreased levels of HDL-C and its transport complex, Apo AI and Apo AII, are risk factors for atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C, LDL-C, and triglycerides, and inversely with the level of HDL-C. The independent effect of raising HDL-C or lowering triglycerides (TG) on the risk of cardiovascular morbidity and mortality has not been determined.
Fenofibric acid, the active metabolite of fenofibrate, produces reductions in total cholesterol, LDL cholesterol, apolipoprotein B, total triglycerides and triglyceride rich lipoprotein (VLDL) in treated patients. In addition, treatment with fenofibrate results in increases in high density lipoprotein (HDL) and apolipoproteins apo AI and apo AII.
The extent and rate of absorption of fenofibric acid after administration of 150 mg Lipofen () capsules are equivalent under low-fat and high-fat fed conditions to 160 mg Tricor® tablets.
Fenofibrate is a pro-drug of the active chemical moiety fenofibric acid. Fenofibrate is converted by ester hydrolysis in the body to fenofibric acid which is the active constituent measurable in the circulation. In a bioavailability study with Lipofen () capsules 200 mg, following single-dose administration, the plasma concentration (AUC) for the parent compound fenofibrate was approximately 40 μg/mL compared to 204 μg/mL for the metabolite, fenofibric acid. In the same study, the half-life was observed to be 0.91 hrs for the parent compound versus 16.76 hrs for the metabolite.
Lipofen () Clinical Studies
Clinical trials have not been conducted with Lipofen () .
The effects of fenofibrate at a dose equivalent to 150 mg per day of Lipofen () were assessed from four randomized, placebo-controlled, double-blind, parallel-group studies including patients with the following mean baseline lipid values: total-C 306.9 mg/dL; LDL-C 213.8 mg/dL; HDL-C 52.3 mg/dL; and triglycerides 191.0 mg/dL. Fenofibrate therapy lowered LDL-C, Total-C, and the LDL-C/HDL-C ratio. Fenofibrate therapy also lowered triglycerides and raised HDL-C (see ).
In a subset of the subjects, measurements of apo B were conducted. Fenofibrate treatment significantly reduced apo B from baseline to endpoint as compared with placebo (-25.1% vs. 2.4%, p
The effects of fenofibrate on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trials of 147 hypertriglyceridemic patients. Patients were treated for eight weeks under protocols that differed only in that one entered patients with baseline TG levels of 500 to 1500 mg/dL, and the other TG levels of 350 to 500 mg/dL. In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia, treatment with fenofibrate at dosages equivalent to 150 mg Lipofen () per day decreased primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol. Treatment of some with elevated triglycerides often results in an increase of LDL-C (see ).
The effect of Lipofen () on cardiovascular morbidity and mortality has not been determined.
Lipofen () How Supplied/storage And Handling
Lipofen () ® (fenofibrate capsules, USP) is available in two strengths:
50 mg: Size 3 white opaque/white opaque gelatin capsule, imprinted in black ink with “50” between lines on the body, “G 246” on the cap and containing a white to almost white paste, available in bottles of 30 (NDC 66869-137-20) and 90 (NDC 66869-137-30).
150 mg: Size 1 white opaque/white opaque gelatin capsule, imprinted in green ink with “150” between lines on the body, “G 248” on the cap and containing a white to almost white paste, available in bottles of 30 (NDC 66869-147-20) and 90 (NDC 66869-147-30).
Store at Controlled Room Temperature, 15ºC - 30ºC (59ºF - 86ºF). Keep out of the reach of children. Protect from moisture and light.
Lipofen () Patient Counseling Information
Patients should be advised:
Manufactured by:Galephar Pharmaceutical Research Inc. Juncos, PR 00777-3873
Manufactured for:Kowa Pharmaceuticals America, Inc.Montgomery, AL 36117
Lipofen ()
Lipofen ()
