FENOFIBRATE_- fenofibrate_tablet

The active moiety of fenofibrate is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been extensively studied through oral administration of fenofibrate. in vivo in vitro A variety of clinical studies have demonstrated that elevated levels of total-C, LDL-C, and apo B, an LDL membrane complex, are associated with human atherosclerosis. Similarly, decreased levels of HDL-C and its transport complex, apolipoprotein A (apo AI and apo AII) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C, LDL-C, and TG, 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. Plasma concentrations of fenofibric acid after administration of three 48 mg or one 145 mg tablets are equivalent under fed conditions to one 200 mg micronized fenofibrate capsule. Absorption max Distribution Metabolism In vivo Elimination Special Populations Geriatrics [see Dosage and Administration ( 2. 5 Pediatrics Gender Race Renal Impairment 2 2 [see Dosage and Administration ( 2. 4 Hepatic Impairment Drug-drug Interactions In vitro Table 2. Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from Fenofibrate Administration Co-Administered Drug Dosage Regimen of Co-Administered Drug Dosage Regimen of Fenofibrate Changes in Fenofibric Acid Exposure AUC C max Lipid-lowering agents Atorvastatin 20 mg once daily for 10 days Fenofibrate 160 mg 1 down arrow2% down arrow4% Pravastatin 40 mg as a single dose Fenofibrate 3 x 67 mg 2 down arrow1% down arrow2% Fluvastatin 40 mg as a single dose Fenofibrate 160 mg 1 down arrow2% down arrow10% Anti-diabetic agents Glimepiride 1 mg as a single dose Fenofibrate 145 mg 1 up arrow1% down arrow1% Metformin 850 mg three times daily for 10 days Fenofibrate 54 mg 1 down arrow9% down arrow6% Rosiglitazone 8 mg once daily for 5 days Fenofibrate 145 mg 1 up arrow10% up arrow3% 1 2 Table 3. Effects of Fenofibrate Co-Administration on Systemic Exposure of Other Drugs Dosage Regimen of Fenofibrate Dosage Regimen of Co-Administered Drug Change in Co-Administered Drug Exposure Analyte AUC C max Lipid-lowering agents Fenofibrate 160 mg 1 Atorvastatin, 20 mg once daily for 10 days Atorvastatin down arrow17% 0% Fenofibrate 3 x 67 mg 2 Pravastatin, 40 mg as a single dose Pravastatin up arrow13% up arrow13% 3alpha-Hydroxyl-iso-pravastatin up arrow26% up arrow29% Fenofibrate 160 mg 1 Fluvastatin, 40 mg as a single dose (+)-3R, 5S-Fluvastatin up arrow15% up arrow16% Anti-diabetic agents Fenofibrate 145 mg 1 Glimepiride, 1 mg as a single dose Glimepiride up arrow35% up arrow18% Fenofibrate 54 mg 1 Metformin, 850 mg three times daily for 10 days Metformin up arrow3% up arrow6% Fenofibrate 145 mg 1 Rosiglitazone, 8 mg once daily for 5 days Rosiglitazone up arrow6% down arrow1% 1 2.

Fenofibrate is a peroxisome proliferator-activated receptor (PPAR) alpha agonist indicated as an adjunct to diet: To reduce elevated LDL-C, Total-C, TG and Apo B, and to increase HDL-C in adult patients with primary hypercholesterolemia or mixed dyslipidemia ( 1. 1 For treatment of adult patients with severe hypertriglyceridemia ( 1. 2 Limitations of Use: Fenofibrate was not shown to reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus ( 5. 1 Fenofibrate is indicated as adjunctive therapy to diet to reduce elevated low-density lipoprotein cholesterol (LDL-C), total cholesterol (Total-C), Triglycerides and apolipoprotein B (Apo B), and to increase high-density lipoprotein cholesterol (HDL-C) in adult patients with primary hypercholesterolemia or mixed dyslipidemia. Fenofibrate 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. Fenofibrate at a dose equivalent to 145 mg of 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.

Primary hypercholesterolemia or mixed dyslipidemia: Initial dose of 145 mg once daily ( 2. 1 Patients should be placed on an appropriate lipid-lowering diet before receiving fenofibrate tablets, and should continue this diet during treatment with fenofibrate tablets. Fenofibrate tablets can be given without regard to meals. The initial dose of fenofibrate tablets is 145 mg once daily. The initial dose is 48 to 145 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 145 mg once daily. Treatment with fenofibrate tablets should be initiated at a dose of 48 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 fenofibrate tablets should be avoided in patients with severe renal impairment [see Use in Specific Populations ( 8. 3 Dose selection for the elderly should be made on the basis of renal function [see Use in Specific Populations ( 8.

The following serious adverse reactions are described below and elsewhere in the labeling: [see Warnings and Precautions ( 5. 1 [see Warnings and Precautions ( 5. 2 [see Warnings and Precautions ( 5. 7 [see Warnings and Precautions ( 5. 9 [see Warnings and Precautions ( 5. 10 Adverse reactions > 2% and at least 1% greater than placebo: Abnormal liver tests, increased AST, increased ALT, increased CPK, and rhinitis ( 6 To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc. at 1-888-943-3210 or 1-855-926-3384 or FDA at 1-800-FDA-1088 or www. gov/medwatch 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 Reactions Reported by 2% or More of Patients Treated with Fenofibrate and Greater than Placebo During the Double-Blind, Placebo-Controlled Trials Fenofibrate* Adverse Reaction (N=439) (N=365) BODY AS A WHOLE Abdominal Pain 4. 4% Back Pain 3. 5% Headache 3. 7% DIGESTIVE Nausea 2. 9% Constipation 2. 4% METABOLIC AND NUTRITIONAL DISORDERS Abnormal Liver Increased ALT 3. 6% Increased CPK 3. 4% Increased AST 3. 5% RESPIRATORY Respiratory Disorder 6. 5% Rhinitis 2. 1% * Dosage equivalent to 145 mg fenofibrate. Urticaria was seen in 1. 0%, and rash in 1. 8% of fenofibrate and placebo patients respectively in controlled trials. Increases in Liver Enzymes [see Warnings and Precautions ( 5. 2 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.

Fenofibrate tablets are contraindicated in: [see Clinical Pharmacology ( 12. 3 [see Warnings and Precautions ( 5. 2 [see Warnings and Precautions ( 5. 5 [see Use in Specific Populations ( 8. 9 Severe renal dysfunction, including dialysis patients ( 4 8.

Geriatric Use: Determine dose selection based on renal function ( 8. 6 Risk Summary 2 Data Animal Data In pregnant rats given oral dietary doses of 15, 75, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), no adverse developmental effects were observed at 15 mg/kg/day (less than the clinical exposure at the MRHD, based on body surface area comparisons), despite maternal toxicity (decreased weight gain). Post-implantation loss was observed at >= 75 mg/kg/day (>= 2 times the clinical exposure at the MRHD) in the presence of maternal toxicity (decreased weight gain). Decreased pup survival was noted at 300 mg/kg/day (10 times the clinical exposure at the MRHD), which was associated with decreased maternal body weight gain/maternal neglect. Risk Summary [see Contraindications ( 4 Safety and effectiveness have not been established in pediatric patients. Fenofibric acid is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Fenofibric acid exposure is not influenced by age. Since elderly patients have a higher incidence of renal impairment, dose selection for the elderly should be made on the basis of renal function [see Dosage and Administration ( 2. 3 The use of fenofibrate tablets should be avoided in patients who have severe renal impairment [see Contraindications ( 4 [see Dosage and Administration ( 2. 3 The use of fenofibrate tablets has not been evaluated in subjects with hepatic impairment [see Contraindications ( 4 12.

Coumarin anticoagulants: ( 7. 3 Potentiation of coumarin-type anticoagulant effects has been observed with prolongation of the PT/INR. [see Warnings and Precautions ( 5. 6 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 with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed and renal function monitored. Since bile acid binding resins may bind other drugs given concurrently, patients should take fenofibrate tablets at least 1 hour before or 4 to 6 hours after a bile acid binding resin to avoid impeding its absorption. Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co-administered with colchicine, and caution should be exercised when prescribing fenofibrate with colchicine.

OVERDOSAGE
There is no specific treatment for overdose with fenofibrate tablets. 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; usual precautions should be observed to maintain the airway. Because fenofibric acid is highly bound to plasma proteins, hemodialysis should not be considered.
NONCLINICAL TOXICOLOGY
Two dietary carcinogenicity studies have been conducted in rats with fenofibrate. In the first 24- month study, Wistar rats were dosed with fenofibrate at 10, 45, and 200 mg/kg/day, approximately 0.3, 1, and 6 times the maximum recommended human dose (MRHD) of 300 mg fenofibrate daily, equivalent to 145 mg fenofibrate daily, based on body surface area comparisons. At a dose of 200 mg/kg/day (at 6 times the MRHD), the incidence of liver carcinomas was significantly increased in both sexes. A statistically significant increase in pancreatic carcinomas was observed in males at 1 and 6 times the MRHD; an increase in pancreatic adenomas and benign testicular interstitial cell tumors was observed at 6 times the MRHD in males. In a second 24-month rat carcinogenicity study in a different strain of rats (Sprague-Dawley), doses of 10 and 60 mg/kg/day (0.3 and 2 times the MRHD) produced significant increases in the incidence of pancreatic acinar adenomas in both sexes and increases in testicular interstitial cell tumors in males at 2 times the MRHD. 2
CLINICAL STUDIES
The effects of fenofibrate at a dose equivalent to 145 mg fenofibrate tablets per day 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. Fenofibrate therapy lowered LDL-C, Total-C, and the LDL-C/HDL-C ratio. Fenofibrate therapy also lowered triglycerides and raised HDL-C (see Table 4). Mean Percent Change in Lipid Parameters at End of Treatmentdagger Treatment Group Total-C LDL-C HDL-C TG Pooled Cohort 306. 9 mg/dL 213. 3 mg/dL 191. 0 mg/dL All FEN (n=361) -18. 9%* Placebo (n=285) -0. 7% Baseline LDL-C > 160 mg/dL and TG < 150 mg/dL Mean baseline lipid values (n=334) 307. 7 mg/dL 227. 1 mg/dL 101. 7 mg/dL All FEN (n=193) -22. 5%* Placebo (n=141) +0. 7% Baseline LDL-C >160 mg/dL and TG >= 150 mg/dL Mean baseline lipid values (n=242) 312. 8 mg/dL 219. 7 mg/dL 231. 9 mg/dL All FEN (n=126) -16. 9%* Placebo (n=116) -3. 9% dagger 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. 0001, n=213 and 143 respectively). 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 fenofibrate tablets 145 mg per day decreased primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol. Treatment of patients with elevated triglycerides often results in an increase of LDL-C (see Table 5). Effects of fenofibrate in Patients With Severe Hypertriglyceridemia Study 1 Placebo Fenofibrate Baseline TG levels 350 to 499 mg/dL N Baseline (Mean) Endpoint (Mean) % Change (Mean) N Baseline (Mean) Endpoint (Mean) % Change (Mean) Triglycerides 28 449 450 -0. 5 27 432 223 -46. 2* VLDL Triglycerides 19 367 350 2. 7 19 350 178 -44. 1* Total Cholesterol 28 255 261 2. 8 27 252 227 -9. 1* HDL Cholesterol 28 35 36 4 27 34 40 19. 6* LDL Cholesterol 120 129 12 27 128 137 14. 5 VLDL Cholesterol 27 99 99 5. 8 27 92 46 -44. 7* Study 2 Placebo Fenofibrate Baseline TG levels 500 to 1500 mg/dL N Baseline (Mean) Endpoint (Mean) % Change (Mean) N Baseline (Mean) Endpoint (Mean) % Change (Mean) Triglycerides 44 710 750 7. 2 48 726 308 -54. 5* VLDL Triglycerides 29 537 571 18. 7 33 543 205 -50. 6* Total Cholesterol 44 272 271 0. 4 48 261 223 -13. 8* HDL Cholesterol 44 27 28 5. 0 48 30 36 22. 9* LDL Cholesterol 42 100 90 -4. 2 45 103 131 45. 0* VLDL Cholesterol 42 137 142 11. 0 45 126 54 -49. 4* * The effect of fenofibrate on cardiovascular morbidity and mortality has not been determined.

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