DRUGS & SUPPLEMENTS
Mylan-Fenofibrate Micro uses
1 INDICATIONS AND USAGE
Mylan-Fenofibrate Micro tablets are a peroxisome proliferator receptor alpha activator indicated as an adjunct to diet:
Important Limitations of Use: Mylan-Fenofibrate Micro was not shown to reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus (5.1).
1.1 PrimaryHypercholesterolemiaor Mixed Dyslipidemia
Mylan-Fenofibrate Micro tablets are 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.
1.2 Severe Hypertriglyceridemia
Mylan-Fenofibrate Micro tablets are 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 may increase the risk of developing pancreatitis. The effect of Mylan-Fenofibrate Micro therapy on reducing this risk has not been adequately studied.
1.3 Important Limitations of Use
Mylan-Fenofibrate Micro at a dose equivalent to 160 mg of Mylan-Fenofibrate Micro tablets was not shown to reduce coronary heart disease morbidity and mortality in a large, randomized controlled trial of patients with type 2 diabetes mellitus .
2 DOSAGE AND ADMINISTRATION
2.1 General Considerations
Patients should be placed on an appropriate lipid-lowering diet before receiving Mylan-Fenofibrate Micro tablets, and should continue this diet during treatment with Mylan-Fenofibrate Micro tablets. Mylan-Fenofibrate Micro tablets should be given with meals, thereby optimizing the bioavailability of the medication.
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 Mylan-Fenofibrate Micro tablets 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 160 mg once daily.
2.2 PrimaryHypercholesterolemiaor Mixed Dyslipidemia
The initial dose of Mylan-Fenofibrate Micro tablet is 160 mg once daily.
2.3 Severe Hypertriglyceridemia
The initial dose is 54 to 160 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 160 mg once daily.
2.4 Impaired RenalFunction
Treatment with Mylan-Fenofibrate Micro tablets should be initiated at a dose of 54 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 Mylan-Fenofibrate Micro tablets should be avoided in patients with severe renal impairment .
2.5 Geriatric Patients
Dose selection for the elderly should be made on the basis of renal function [see Use in Specific Populations (8.5) ].
3 DOSAGE FORMS AND STRENGTHS
Oral Tablets: 54 mg and 160 mg (3).
Mylan-Fenofibrate Micro tablets are contraindicated in:
- 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 .
- patients with preexisting gallbladder disease .
- nursing mothers
- patients with known hypersensitivity to Mylan-Fenofibrate Micro or fenofibric acid [see Warnings and Precautions (5.9) ].
5 WARNINGS AND PRECAUTIONS
5.1 MortalityandCoronary Heart Disease Morbidity
The effect of Mylan-Fenofibrate Micro tablets on coronary heart disease morbidity and mortality and non-cardiovascular mortality has 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 Mylan-Fenofibrate Micro. The mean duration of follow-up was 4.7 years. Mylan-Fenofibrate Micro plus statin combination therapy showed a non-significant 8% relative risk reduction in the primary outcome of major adverse cardiovascular events (MACE), a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular disease death (hazard ratio [HR] 0.92, 95% CI 0.79 to 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 to 0.99), and the hazard ratio for MACE in women receiving combination therapy versus statin monotherapy was 1.38 (95% CI 0.98 to 1.94) (interaction p=0.01). The clinical significance of this subgroup finding is unclear.
The Mylan-Fenofibrate Micro 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 Mylan-Fenofibrate Micro. Mylan-Fenofibrate Micro 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 to 1.05, p=0.16) and a significant 11% reduction in the secondary outcome of total cardiovascular disease events (HR 0.89 [0.80 to 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 Mylan-Fenofibrate Micro as compared to placebo.
Because of chemical, pharmacological, and clinical similarities between Mylan-Fenofibrate Micro tablets, clofibrate, and gemfibrozil, the adverse findings in 4 large randomized, placebo- controlled clinical studies with these other fibrate drugs may also apply to Mylan-Fenofibrate Micro tablets.
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 =.91 to 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 World Health Organization 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 to 5.05). The rate of gallbladder surgery was not statistically significant between study groups, but did trend higher in the gemfibrozil group, (1.9% vs. 0.3%, 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 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 Mylan-Fenofibrate Micro tablets therapy should be discontinued if markedly elevated CPK levels occur or myopathy/myositis is suspected or 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 .
Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co administered with colchicine, and caution should be exercised when prescribing Mylan-Fenofibrate Micro with colchicine .
5.3 Liver Function
Mylan-Fenofibrate Micro at doses equivalent to 107 mg to 160 mg Mylan-Fenofibrate Micro tablets per day has been associated with increases in 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 Mylan-Fenofibrate Micro 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 Mylan-Fenofibrate Micro 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 107 mg to 160 mg Mylan-Fenofibrate Micro tablets per day and was 0% in those receiving dosages equivalent to 54 mg or less Mylan-Fenofibrate Micro tablets per day, or placebo. Hepatocellular, chronic active and cholestatic hepatitis associated with Mylan-Fenofibrate Micro 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.
Baseline and regular periodic monitoring of liver function, including serum ALT (SGPT) should be performed for the duration of therapy with Mylan-Fenofibrate Micro tablets, and therapy discontinued if enzyme levels persist above three times the normal limit.
5.4 Serum Creatinine
Elevations in serum creatinine have been reported in patients on Mylan-Fenofibrate Micro. These elevations tend to return to baseline following discontinuation of Mylan-Fenofibrate Micro. The clinical significance of these observations is unknown. Monitor renal function in patients with renal impairment taking Mylan-Fenofibrate Micro tablets. Renal monitoring should also be considered for patients taking Mylan-Fenofibrate Micro tablets at risk for renal insufficiency such as the elderly and patients with diabetes.
Mylan-Fenofibrate Micro, like clofibrate and gemfibrozil, may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Mylan-Fenofibrate Micro tablets therapy should be discontinued if gallstones are found.
5.6 Coumarin Anticoagulants
Caution should be exercised when coumarin anticoagulants are given in conjunction with Mylan-Fenofibrate Micro tablets because of the potentiation of coumarin-type anticoagulant effects in prolonging the Prothrombin Time/International Normalized Ratio. To prevent bleeding complications, frequent monitoring of PT/INR and dose adjustment of the anticoagulant are recommended until PT/INR has stabilized .
Pancreatitis has been reported in patients taking Mylan-Fenofibrate Micro, gemfibrozil, and clofibrate. This occurrence may represent a 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 initiation of Mylan-Fenofibrate Micro therapy. However, these levels stabilize during long- term administration. Thrombocytopenia and agranulocytosis have been reported in individuals treated with Mylan-Fenofibrate Micro. Periodic monitoring of red and white blood cell counts are recommended during the first 12 months of Mylan-Fenofibrate Micro tablets administration.
5.9 Hypersensitivity Reactions
Acute hypersensitivity reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis requiring patient hospitalization and treatment with steroids have been reported in individuals treated with fenofibrates. Urticaria was seen in 1.1 vs. 0%, and rash in 1.4 vs. 0.8% of Mylan-Fenofibrate Micro and placebo patients respectively in controlled trials.
5.10 Venothromboembolic Disease
In the FIELD trial, pulmonary embolus 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, there were 4,900 in the placebo group and 4,895 in the Mylan-Fenofibrate Micro group. For DVT,there were 48 events (1%) in the placebo group and 67 (1%) in the Mylan-Fenofibrate Micro group (p = 0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (1%) in the Mylan-Fenofibrate Micro 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 five years; p < 0.01).
5.11 Paradoxical Decreasesin HDL CholesterolLevels
There have been postmarketing and clinical trial reports of severe decreases in HDL cholesterol levels (as low as 2 mg/dL) occurring in diabetic and non-diabetic patients initiated on fibrate therapy. The decrease in HDL-C is mirrored by a decrease in apolipoprotein A1. This decrease has 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 rapid and sustained. The clinical significance of this decrease in HDL-C is unknown. It is recommended that HDL-C levels be checked within the first few months after initiation of fibrate therapy. If a severely depressed HDL-C level is detected, fibrate therapy should be withdrawn, and the HDL-C level monitored until it has returned to baseline, and fibrate therapy should not be re-initiated.
6 ADVERSE REACTIONS
The most common adverse reactions are abnormal liver tests, increased AST, increased ALT, increased CPK, and rhinitis (6).
To report SUSPECTED ADVERSE REACTIONS, contact Impax Laboratories, Inc. at 1-800-934-6729 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1 Clinical Trials Experience
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 events reported by 2% or more of patients treated with Mylan-Fenofibrate Micro (and greater than placebo) during the double-blind, placebo-controlled trials, regardless of causality, are listed in Table 1 below. Adverse events led to discontinuation of treatment in 5.0% of patients treated with Mylan-Fenofibrate Micro and in 3.0% treated with placebo. Increases in liver function tests were the most frequent events, causing discontinuation of Mylan-Fenofibrate Micro treatment in 1.6% of patients in double- blind trials.
The following adverse reactions have been identified during postapproval use of Mylan-Fenofibrate Micro: myalgia, rhabdomyolysis, pancreatitis, acute renal failure, muscle spasm, hepatitis, cirrhosis, anemia, arthralgia, decreases in hemoglobin, decreases in hematocrit, white blood cell decreases, asthenia, and severely depressed HDL-cholesterol levels. 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.
7 DRUG INTERACTIONS
7.1 Coumarin Anticoagulants
Potentiation of coumarin-type anticoagulant effects has been observed with prolongation of the PT/INR.
Caution should be exercised when coumarin anticoagulants are given in conjunction with Mylan-Fenofibrate Micro tablets. The dosage of the anticoagulants should be reduced to maintain the PT/INR at the desired level to prevent bleeding complications. Frequent PT/INR determinations are advisable until it has been definitely determined that the PT/INR has stabilized .
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 Mylan-Fenofibrate Micro tablets, there is a risk that an interaction will lead to deterioration of renal function. The benefits and risks of using Mylan-Fenofibrate Micro tablets with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed and renal function monitored.
7.3 Bile Acid BindingResins
Since bile acid binding resins may bind other drugs given concurrently, patients should take Mylan-Fenofibrate Micro 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 Mylan-Fenofibrate Micro with colchicine.
8 USE IN SPECIFIC POPULATIONS
P r e gnancy Category C
Safety in pregnant women has not been established. There are no adequate and well controlled studies of Mylan-Fenofibrate Micro in pregnant women. Mylan-Fenofibrate Micro should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In female rats given oral dietary doses of 15, 75, and 300 mg/kg/day of Mylan-Fenofibrate Micro from 15 days prior to mating through weaning, maternal toxicity was observed at 0.3 times the MRHD, based on body surface area comparisons; mg/m2.
In pregnant rats given oral dietary doses of 14, 127, and 361 mg/kg/day from gestation day 6 to 15 during the period of organogenesis, adverse developmental findings were not observed at 14 mg/kg/day (less than 1 times the MRHD, based on body surface area comparisons; mg/m2). At higher multiples of human doses evidence of maternal toxicity was observed.
In pregnant rabbits given oral gavage doses of 15, 150, and 300 mg/kg/day from gestation day 6-18 during the period of organogenesis and allowed to deliver, aborted litters were observed at 150 mg/kg/day (10 times the MRHD, based on body surface area comparisons: mg/m2). No developmental findings were observed at 15 mg/kg/day (at less than 1 times the MRHD, based on body surface area comparisons; mg/m2).
In pregnant rats given oral dietary doses of 15, 75, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), maternal toxicity was observed at less than 1 times the maximum recommended human dose (MRHD), based on body surface area comparisons; mg/m2.
Mylan-Fenofibrate Micro should not be used in nursing mothers. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
Safety and effectiveness have not been established in pediatric patients.
8.5 Geriatric Use
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 . Elderly patients with normal renal function should require no dose modifications. Consider monitoring renal function in elderly patients taking Mylan-Fenofibrate Micro tablets.
8.6 Renal Impairment
The use of Mylan-Fenofibrate Micro tablets should be avoided in patients who have severe renal impairment . Dose reduction is required in patients with mild to moderate renal impairment [ see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. Monitoring renal function in patients with renal impairment is recommended.
8.7 Hepatic Impairment
The use of Mylan-Fenofibrate Micro tablets has not been evaluated in subjects with hepatic impairment [ see C ontraindications (4) and Clinical Pharmacology (12.3)].
There is no specific treatment for overdose with Mylan-Fenofibrate Micro 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.
Mylan-Fenofibrate Micro tablets are a lipid regulating agent available as tablets for oral administration. Each tablet contains 54 mg or 160 mg of Mylan-Fenofibrate Micro. The chemical name for Mylan-Fenofibrate Micro is 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester with the following structural formula:
The empirical formula is C20H21O4Cl and the molecular weight is 360.83; Mylan-Fenofibrate Micro is insoluble in water. The melting point is 79 to 82°C. Mylan-Fenofibrate Micro is a white solid which is stable under ordinary conditions.
Each tablet contains croscarmellose sodium, NF; hypromellose type 2208/100,000 cP, USP; magnesium stearate, NF; and microcrystalline cellulose, NF. The film-coating material contains hypromellose type 2910/ 3 cP, 6 cP and 50 cP, macrogol, polydextrose, titanium dioxide and triacetin. In addition, the 54 mg strength film-coating material also contains D&C Yellow No. 10 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The active moiety of Mylan-Fenofibrate Micro tablets is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been extensively studied through oral administration of Mylan-Fenofibrate Micro.
The lipid-modifying effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor α. Through this mechanism, Mylan-Fenofibrate Micro 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 TG 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.
Mylan-Fenofibrate Micro also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid.
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.
Fenofibric acid, the active metabolite of Mylan-Fenofibrate Micro, produces reductions in total cholesterol, LDL cholesterol, apolipoprotein B, total triglycerides and triglyceride rich lipoprotein (VLDL) in treated patients. In addition, treatment with Mylan-Fenofibrate Micro results in increases in high density lipoprotein (HDL) and apolipoproteins apoAI and apoAII.
Mylan-Fenofibrate Micro is a pro-drug of the active chemical moiety fenofibric acid. Mylan-Fenofibrate Micro is converted by ester hydrolysis in the body to fenofibric acid which is the active constituent measurable in the circulation.
The absolute bioavailability of Mylan-Fenofibrate Micro cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However, Mylan-Fenofibrate Micro is well absorbed from the gastrointestinal tract. Following oral administration in healthy volunteers, approximately 60% of a single dose of radiolabelled Mylan-Fenofibrate Micro appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma levels of fenofibric acid occur within 6 to 8 hours after administration.
The absorption of Mylan-Fenofibrate Micro is increased when administered with food. With Mylan-Fenofibrate Micro tablets, the extent of absorption is increased by approximately 35% under fed as compared to fasting conditions.
Upon multiple dosing of Mylan-Fenofibrate Micro, fenofibric acid steady state is achieved within 5 days. Plasma concentrations of fenofibric acid at steady state are approximately double of those following a single dose. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects.
Following oral administration, Mylan-Fenofibrate Micro is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; no unchanged Mylan-Fenofibrate Micro is detected in plasma.
Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to a benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine.
I n vivo metabolism data indicate that neither Mylan-Fenofibrate Micro nor fenofibric acid undergo oxidative metabolism (e.g., cytochrome P450) to a significant extent.
After absorption, Mylan-Fenofibrate Micro is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabelled Mylan-Fenofibrate Micro, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces.
Fenofibric acid is eliminated with a half-life of 20 hours, allowing once daily dosing.
In elderly volunteers 77 to 87 years of age, the oral clearance of fenofibric acid following a single oral dose of Mylan-Fenofibrate Micro was 1.2 L/h, which compares to 1.1 L/h in young adults. This indicates that a similar dosage regimen can be used in elderly with normal renal function, without increasing accumulation of the drug or metabolites .
P e diatrics
The pharmacokinetics of Mylan-Fenofibrate Micro tablets has not been studied in pediatric populations.
No pharmacokinetic difference between males and females has been observed for Mylan-Fenofibrate Micro.
The influence of race on the pharmacokinetics of Mylan-Fenofibrate Micro has not been studied, however Mylan-Fenofibrate Micro is not metabolized by enzymes known for exhibiting inter-ethnic variability.
R e nal Impairment
The pharmacokinetics of fenofibric acid was examined in patients with mild, moderate, and severe renal impairment. Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73m2) showed 2.7-fold increase in exposure for fenofibric acid and increased accumulation of fenofibric acid during chronic dosing compared to that of healthy subjects. Patients with mild to moderate renal impairment (eGFR 30 to 59 mL/min/1.73m2) had similar exposure but an increase in the half-life for fenofibric acid compared to that of healthy subjects. Based on these findings, the use of Mylan-Fenofibrate Micro tablets should be avoided in patients who have severe renal impairment and dose reduction is required in patients having mild to moderate renal impairment .
No pharmacokinetic studies have been conducted in patients with hepatic impairment.
I n vitro studies using human liver microsomes indicate that Mylan-Fenofibrate Micro and fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of CYP2C8, CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations.
Table 2 describes the effects of co-administered drugs on fenofibric acid systemic exposure.
Table 3 describes the effects of co-administered Mylan-Fenofibrate Micro or fenofibric acid on other drugs.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility
Two dietary carcinogenicity studies have been conducted in rats with Mylan-Fenofibrate Micro. In the first 24 month study, Wistar rats were dosed with Mylan-Fenofibrate Micro at 10, 45, and 200 mg/kg/day, approximately 0.3, 1, and 6 times the maximum recommended human dose (MRHD), based on body surface area comparisons (mg/m2). 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.
A 117-week carcinogenicity study was conducted in rats comparing three drugs: Mylan-Fenofibrate Micro 10 and 60 mg/kg/day (0.3 and 2 times the MRHD), clofibrate (400 mg/kg/day; 2 times the human dose), and gemfibrozil (250 mg/kg/day; 2 times the human dose, based on mg/m2 surface area). Mylan-Fenofibrate Micro increased pancreatic acinar adenomas in both sexes. Clofibrate increased hepatocellular carcinoma and pancreatic acinar adenomas in males and hepatic neoplastic nodules in females. Gemfibrozil increased hepatic neoplastic nodules in males and females, while all three drugs increased testicular interstitial cell tumors in males.
In a 21-month study in CF-1 mice, Mylan-Fenofibrate Micro 10, 45, and 200 mg/kg/day (approximately 0.2, 1, and 3 times the MRHD on the basis of mg/m2 surface area) significantly increased the liver carcinomas in both sexes at 3 times the MRHD. In a second 18-month study at 10, 60, and 200 mg/kg/day, Mylan-Fenofibrate Micro significantly increased the liver carcinomas in male mice and liver adenomas in female mice at 3 times the MRHD.
Electron microscopy studies have demonstrated peroxisomal proliferation following Mylan-Fenofibrate Micro administration to the rat. An adequate study to test for peroxisome proliferation in humans has not been done, but 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.
M u t agenesis: Mylan-Fenofibrate Micro has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and unscheduled DNA synthesis in primary rat hepatocytes.
Impairment of Fertility: In fertility studies rats were given oral dietary doses of Mylan-Fenofibrate Micro, males received 61 days prior to mating and females 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).
14 CLINICAL STUDIES
14.1 PrimaryHypercholesterolemia and MixedDyslipidemia
The effects of Mylan-Fenofibrate Micro at a dose equivalent to 160 mg Mylan-Fenofibrate Micro 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 191.0 mg/dL. Mylan-Fenofibrate Micro tablets therapy lowered LDL-C, Total-C, and the LDL-C/HDL-C ratio. Mylan-Fenofibrate Micro tablets therapy also lowered triglycerides and raised HDL-C.
In a subset of the subjects, measurements of apo B were conducted. Mylan-Fenofibrate Micro tablets treatment significantly reduced apo B from baseline to endpoint as compared with placebo (-25.1% vs. 2.4%, p < 0.0001, n=213 and 143 respectively).
14.2 Severe Hypertriglyceridemia
The effects of Mylan-Fenofibrate Micro 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 Mylan-Fenofibrate Micro at dosages equivalent to Mylan-Fenofibrate Micro tablets 160 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.
The effect of Mylan-Fenofibrate Micro tablets on cardiovascular morbidity and mortality has not been determined.
16 HOW SUPPLIED/STORAGE ANDHANDLING
Mylan-Fenofibrate Micro tablets, 54 mg are yellow, film-coated, oval shape tablets debossed with “G”on one side and “351” on the other side.
Bottles of 90 NDC 0115-5511-10
Bottles of 100 NDC 0115-5511-01
Bottles of 500 NDC 0115-5511-02
Bottles of 1000 NDC 0115-5511-03
Mylan-Fenofibrate Micro tablets, 160 mg are white to off-white, film-coated, modified capsule shaped tablets, debossed with “G352” on one side and plain on the other side.
Bottles of 90 NDC 0115-5522-10
Bottles of 100 NDC 0115-5522-01
Bottles of 500 NDC 0115-5522-02
Bottles of 1000 NDC 0115-5522-03
Store at 20° to 25°C (68° to 77°F). Keep out of reach of children. Protect from moisture.
Dispense in tightly-closed, light-resistant container as defined in the USP, with a child-resistant closure, as required.
17 PATIENT COUNSELING INFORMATION
Patients should be advised:
Hayward, CA 94544
Mylan-Fenofibrate Micro pharmaceutical active ingredients containing related brand and generic drugs:
Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.
Mylan-Fenofibrate Micro available forms, composition, doses:
Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.
Mylan-Fenofibrate Micro destination | category:
Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.
Mylan-Fenofibrate Micro Anatomical Therapeutic Chemical codes:
A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.
Mylan-Fenofibrate Micro pharmaceutical companies:
Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.
Frequently asked QuestionsCan i drive or operate heavy machine after consuming Mylan-Fenofibrate Micro?
Depending on the reaction of the Mylan-Fenofibrate Micro after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Mylan-Fenofibrate Micro not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Mylan-Fenofibrate Micro addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
ReviewsDrugs.com conducted a study on Mylan-Fenofibrate Micro, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Mylan-Fenofibrate Micro consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.
The information was verified by Dr. Arunabha Ray, MD Pharmacology