Fibricor

Uses

Fibricor is a fibrate used to treat severe hypertriglyceridemia, primary hypercholesterolemia, or mixed dyslipidemia.

For use as an adjunctive therapy to diet to: (a) reduce triglyceride levels in adult patients with severe hypertriglyceridemia, and (b) reduce elevated total cholesterol, low-density-lipoprotein (LDL-C), triglycerides, and apolipoprotein B, and to increase high-density-lipoprotein (HDL-C) in adult patients with primary hypercholesterolemia or mixed dyslipidemia (Fredrickson Types IIa and IIb).

Fibricor is also used to associated treatment for these conditions: Hypertriglyceridemias, Mixed Dyslipidemias, Primary Hypercholesterolemia

How Fibricor works

Having performed clinical studies with in vivo transgenic mice and in vitro human hepatocyte cultures, it is believed that the principal mechanism of action of fenofibric acid is demonstrated through its capability to activate peroxisome proliferator receptor alpha (PPAR-alpha) .

By activating PPAR-alpha, fenofibric acid increases lipolysis and the elimination of triglyceride-rich particles from plasma by actuating lipoprotein lipase and reducing production of apoprotein C-III, which acts as an inhibitor of lipoprotein lipase activity . The resultant decrease in triglycerides causes an alteration in the size and composition of low-density-lipoprotein from small, dense particles to large, buoyant ones . The size of these larger low-density-lipoprotein particles have a greater affinity for cholesterol receptors and are therefore catabolized more rapidly . Additionally, fenofibric acid's activation of PPAR-alpha also induces an increase in the synthesis of apoproteins apo A-I, apo A-II, and high-density-lipoprotein .

Moreover, the use of fenofibric acid can also act to reduce serum uric acid levels in ordinary or hyperuricemic individuals by increasing the urinary excretion of uric acid .

Toxicity

Oral LD50 (rat): 1242 mg/kg, Oral LD50 (mouse): 100 mg/kg, lntraperitoneal LD50 (mouse): 500 mg/kg

Fibricor is contraindicated for: (a) patients with severe renal impairment, including those receiving dialysis, (b) patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities, (c) patients with preexisting gallbladder disease, (d) patients with known hypersensitivity to fenofibric acid or Fenofibrate, and (e) nursing mothers .

The relationship between the use of fenofibric acid and risk of mortality and coronary heart disease morbidity has not been formally established . However, a number of studies involving fenofibrate and agents that are chemically and pharmacologically similar to fenofibrate demonstrate inconclusive results. In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, 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 . For the Coronary Drug Project, a large study of post myocardial infarction of patients treated for 5 years with clofibrate, there was a difference in the rate of cholelithiasis and cholecystitis requiring surgery between the clofibrate and placebo groups of 3.0% vs. 1.8%, respectively . The World Health Organization (WHO) also conducted a study in which 5000 subjects without known coronary artery disease were treated with placebo or clofibrate for 5 years and followed for an additional year . The results involved a statistically significant, higher age-adjusted all-cause mortality in the clofibrate group compared with the placebo group (5.70% vs. 3.96%, pLabel. With the Helsinki Heart Study, 4081 middle aged men without a history of coronary artery disease were given either placebo or gemfibrozil for 5 years, with a 3.5 year open extension afterward . Although total mortality was numerically higher in the gemfibrozil arm, it was statistically significant (p=0.19, 95% confidence interval for relative risk = 0.91-1.64). Finally, a secondary prevention component of the Helsinki Heart Study observed middle aged men not included in the primary prevention study because they had known or suspected coronary heart disease . When these subjects were administered gemfibrozil or placebo therapy for 5 years, cardiac deaths trended higher in the gemfibrozil group but was ultimately not statistically significant (HR 2.2, 95% confidence interval: 0.94-5.05) .

Fibrates facilitate 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 . Myopathy should be considered in any patient with diffuse myalgia, muscle tenderness or weakness, and/or marked elevations of creatine phosphokinase levels .

Fenofibrate administered across a range of doses with the higher dose equivalent to 105 mg fenofibric acid has been associated with increases in serum transaminases like AST (SGOT) and ALT (SGPT) . In a pooled analysis of 10 placebo-controlled trials, increases to more than 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 . If enzyme levels persist above three times the normal limit, therapy is to be discontinued . After discontinuing fenofibrate treatment or during continued treatment a return to normal transaminase limits was usually observed . The incidence of increases in transaminases observed with fenofibrate therapy appear to be dose related . From 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 35 mg to 105 mg fenofibric acid per day and was comparatively 0% in those receiving placebo or doses equivalent to 35 mg or less fenofibric acid per day . Hepatocellular, chronic active 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 associated with chronic active hepatitis .

Increases in serum creatinine have been reported in patients on Fenofibrate . These elevations tend to return to baseline following discontinuation of the drug . Although the clinical significance of these observations is unknown, renal monitoring should be considered for patients with renal impairment and for patients at risk for renal insufficiency, perhaps like patients with diabetes or the elderly .

Fibricor may increase cholesterol excretion into the bile, leading to cholelithiasis . If gallstones are found, fenofibric acid should be discontinued .

Caution must be exercised over the ability of fenofibric acid to potentiate the anticoagulant effects of coumarin anticoagulants, resulting in prolongation of the prothrombin time/International Normalized Ratio (PT/INR) .

Pancreatitis has also been reported in patients taking Fenofibrate . This effect may be caused by the 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 .

Mild to moderate hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following the start of fenofibrate therapy . However, although these levels tend to stabilize during long-term administration of the medication , thrombocytopenia and agranulocytosis have been observed in patients treated with fenofibrates as well . Scheduled monitoring of red and white blood cell counts during the first 12 months of fenofibric acid administration is subsequently recommended .

Acute hypersensitivity reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis requiring patient hospitalization and treatment with steroids have been reported in patients treated with fenofibrates .

In the fenofibrate arm during the FIELD trial, occurrences of pulmonary embolus (PE) and deep vein thrombosis (DVT) were recorded at higher rates when compared to the placebo group . In particular, the placebo group had N=4900 and the fenofibrate group N=4895 . For DVT there were 48 events (1%) in the placebo group and 67 (1%) in the fenofibrate group with p=0.074 . While for PE, there were 32 (0.7%) events in the placebo group and 53 (1%) in the fenofibrate group with p=0.022 . Likewise, in the Coronary Drug Project, a higher proportion of the clofibrate group reported definite or suspected fatal or nonfatal PE or thrombophlebitis when compared to the placebo group (5.2% vs 3.3% at 5 years with pLabel.

Additionally there have been postmarketing and clinical trial reports of serious paradoxical decreases in HDL cholesterol levels to as low as 2 mg/dL happening in diabetic and non-diabetic patients initiated on fibrate therapy . This decrease in HDL-C is accompanied by a decrease in apolipoprotein A1. Such decreases have 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 in fact rapid and sustained . HDL-C levels are recommended to be checked within the first few months after initiation of fibrate therapy. In the case of severely depressed HDL-C levels being detected, fibrate therapy should be withdrawn and HDL-C levels monitored until it has returned to baseline with no intention or plan to re-initiate fibrate therapy .

Adverse effects associated with the use of fenofibrate and fenofibric acid include abdominal pain, back pain, headache, nausea, constipation, abnormal liver tests, increased AST, increased ALT, increased creatine phosphokinase, respiratory disorder, rhinitis, diarrhea, dyspepsia, nasopharyngitis, sinusitis, upper respiratory tract infection, arthralgia, myalgia, pain in extremity, and/or dizziness .

Adverse effects identified during the post-approval use period of fenofibrate include rhabdomyolysis, panrcreatitis, renal failure, muscle spasms, acute renal failure, hepatitis, cirrhosis, anemia, asthenia, and severely depressed HDL-cholesterol levels .

As Fibricor has the capability to potentiate the anticoagulant effect of coumarin anticoagulants (and subsequently prolong the PT/INR of patients), caution should be exercised when oral coumarin anticoagulants are given in conjunction with fenofibric acid. Frequent PT/INR determinations are therefore advisable until stabilized PT/INR readings are obtained .

Fibricor should be administered to patients at least 1 hour before or 4 to 6 hours after a bile acid resin is given as such drugs may bind other agents being given concurrently and impede their absorption .

Immunosuppressant medications like cyclosporine and tacrolimus can cause nephrotoxicity with decreases in creatinine clearance and rises in serum creatinine, and because renal excretion is the main elimination route for fenofibric acid, there exists a risk that an interaction could lead to deterioration of renal function . As a consequence, the benefits and risks of using fenofibric acid with any other potentially nephrotoxic agents should be carefully considered and the lowest effective dose employed .

Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co-administered with colchicine, and caution should be exercised when considering the combination use of fenofibrates with colchicine .

No well controlled studies regarding the use of fenofibric acid in pregnant women have been established . Since the safety of fenofibric acid in pregnant women has not been formally elucidated, fenofibric acid should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus .

Moreover, fenofibric acid should not be used in nursing mothers. Under the circumstances, a decision should be made between having to discontinue nursing or to discontinue the use of fenofibric acid, taking into perspective the importance of the drug therapy to the mother .

The safety and effectiveness of fenofibric acid in paediatric patients has not been formally established .

Fibricor is predominantly excreted by the kidney system unchanged or as fenofibric acid glucuronide . The risk of experiencing adverse reactions associated with exposure to fenofibric acid may consequently be greater in patients with impaired renal function . Subsequently, because elderly patients may have a higher incidence of renal impairment, the dosage of fenofibric acid for geriatric patients should be based upon renal function, with normal renal function requiring no dosage modifications . Renal function monitoring in elderly patients taking fenofibric acid is recommended .

In patients with severe renal impairment, the use of fenofibric acid is to be avoided while dose reductions is necessary in patients with mild to moderate renal impairment . Monitoring renal function in patients with renal impairment is recommended .

The use of fenofibric acid has not been evaluated in patients with hepatic impairment .

In a 24 month study, Wistar rats were dosed at various levels of fenofibrate. At a dose of 200mg/kg/day (6 times the maximum recommended human dose [MRHD] based on body surface area comparisons mg/m2), the incidence of liver carcinomas was significantly increased in both sexes of the rats . At doses of 10 (0.3 times the MRHD) and 200 mg/kg/day, a statistically significant increase in pancreatic carcinomas was observed in males, and an increase in pancreatic adenomas and benign testicular interstitial cell tumours were observed at 200 mg/kg/day in males . In a second 24 month study on the Sprague-Dawley strain of rats, doses of 10 and 60 mg/kg/day produced significant increases in the incidence of pancreatic acinar adenomas in both sexes of the rats and increases in interstitial cell tumours of the testes at 2 times the MRHD .

In addition, fenofibrate 10 and 60 mg/kg/day, clofibrate 400 mg/kg/day (2 times the MRHD), and gemfibrozil 250 mg/kg/day (2 times the MRHD) are studied in a 117 week study in rats. Fenofibrate increased pancreatic acing adenomas in both sexes of the rats . Clofibrate increased hepatocellular carcinoma and pancreatic acinar adenomas in males and hepatic neoplastic nodules in females . And finally, gemfibrozil increased hepatic neoplastic nodules in males and females, while all three drugs increased testicular interstitial cell tumours in males .

In a 21 month study with CF-1 mice, fenofibrate 10, 45, and 200 mg/kg/day (approximately 0.2, 1, and 3 times the MRHD) significantly increased the liver carcinomas in both sexes at 3 times the MRHD . With a second 18 month study at 10, 60, and 200 mg/kg/day, fenofibrate significantly increased the liver carcinomas in male and female mice 3 times the MRHD .

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 was shown to be devoid of mutagenic potential in the Ames and micronucleus tests in vivo/rat . In addition, fenofibric acid, has bee.n demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and sister chromatid exchange in human lymphocytes, and unscheduled DNA synthesis in primary rat hepatocytes .

In a fertility study, rats were given oral dietary doses of fenofibrate. Males received doses for 61 days prior to mating and females for 15 days prior to mating through weaning, which resulted in no adverse effect on fertility at doses up to 300 mg/kg/day (~10 times the MRHD, based on mg/m2 surface area comparisons) .

Food Interaction

• Take with or without food.

Volume of Distribution

The volume of distribution for fenofibric acid is demonstrated to be 70.9 +/- 27.5 L .

Elimination Route

Some studies have demonstrated that the bioavailability of fenofibric acid (a sample administration of 130 mg oral suspension to healthy volunteers about 4 hours after a light breakfast) is approximately 81% in the stomach, 88% in the proximal small bowel, 84% in the distal small bowel, and 78% in the colon . Nevertheless, following the oral administration of fenofibric acid in healthy volunteers, median peak plasma levels for the drug occurred about 2.5 hours after administration . Moreover, exposure after administration of three 35 mg fenofibric acid tablets is largely comparable to that of one 105 mg tablet .

Half Life

Following once daily dosing, fenofibric acid demonstrates an elimination associated with a half-life of about 20 hours after absorption .

Clearance

In five elderly volunteers aged 77 to 87, the oral clearance of fenofibric acid after a single oral dose of fenofibrate was 1.2 L/h, which compares to 1.1 L/h in young adults .

Elimination Route

Fibricor metabolites are largely excreted in the urine .

Innovators Monograph

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