Fenofibrate - Fenofibrate tablet, Film Coated
(Fenofibrate)Fenofibrate - Fenofibrate tablet, Film Coated Prescribing Information
- Primary hypercholesterolemia or mixed dyslipidemia: Initial dose of 145 mg once daily ().
2.2 Primary Hypercholesterolemia or Mixed DyslipidemiaThe initial dose of fenofibrate tablets is 145 mg once daily.
- Severe hypertriglyceridemia: Initial dose of 48 to 145 mg once daily. Maximum dose is 145 mg ().
2.3 Severe HypertriglyceridemiaThe 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.
- Renally impaired patients: Initial dose of 48 mg once daily ().
2.4 Impaired Renal FunctionTreatment 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 (8.6)and Clinical Pharmacology (12.3)]. - Geriatric patients: Select the dose on the basis of renal function ().
2.5 Geriatric PatientsDose selection for the elderly should be made on the basis of renal function
[see Use in Specific Populations (8.5)]. - Maybe taken without regard to meals ().
2.1 General ConsiderationsPatients 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 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 fenofibrate 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 145 mg once daily.
- 48 mg yellow, film coated, oval tablets, debossed “V3650” on one side and plain on the reverse side.
- 145 mg white, film coated, modified capsule shaped tablets, debossed “V3651” on one side and plain on the reverse side.
- Geriatric Use: Determine dose selection based on renal function ().
8.5 Geriatric UseFenofibric 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 (2.5)and Clinical Pharmacology (12.3)]. Elderly patients with normal renal function should require no dose modifications. Consider monitoring renal function in elderly patients taking fenofibrate. - Renal Impairment: Avoid use in severe renal impairment patients. Dose reduction is required in mild to moderate renal impairment patients ().
8.6 Renal ImpairmentThe use of fenofibrate should be avoided in patients who have severe renal impairment
[see Contraindications (4)]. 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.
Fenofibrate tablets are contraindicated in:
- patients with severe renal impairment, including those receiving dialysis[see.]
12.3 PharmacokineticsPlasma 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.
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.
AbsorptionThe absolute bioavailability of fenofibrate cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However, fenofibrate is well absorbed from the gastrointestinal tract. Following oral administration in healthy volunteers, approximately 60% of a single dose of radiolabelled fenofibrate 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.
Exposure to fenofibric acid in plasma, as measured by Cmaxand AUC, is not significantly different when a single 145 mg dose of fenofibrate is administered under fasting or nonfasting conditions.
DistributionUpon multiple dosing of fenofibrate, fenofibric acid steady state is achieved within 9 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.
MetabolismFollowing oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; no unchanged fenofibrate 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.
In vivometabolism data indicate that neither fenofibrate nor fenofibric acid undergo oxidative metabolism (e.g., cytochrome P450) to a significant extent.EliminationAfter absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabelled fenofibrate, 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.
Special PopulationsGeriatricsIn elderly volunteers 77 to 87 years of age, the oral clearance of fenofibric acid following a single oral dose of fenofibrate 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
[see Dosage and Administration (2.5)and Use in Specific Populations (8.5)].PediatricsThe pharmacokinetics of fenofibrate has not been studied in pediatric populations.
GenderNo pharmacokinetic difference between males and females has been observed for fenofibrate.
RaceThe influence of race on the pharmacokinetics of fenofibrate has not been studied, however fenofibrate is not metabolized by enzymes known for exhibiting inter-ethnic variability.
Renal ImpairmentThe 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 30-59 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 fenofibrate should be avoided in patients who have severe renal impairment and dose reduction is required in patients having mild to moderate renal impairment
[see Dosage and Administration (2.4)].Hepatic ImpairmentNo pharmacokinetic studies have been conducted in patients with hepatic impairment.
Drug-drug InteractionsIn vitrostudies using human liver microsomes indicate that fenofibrate 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 fenofibrate or fenofibric acid on other drugs.
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 Cmax Lipid-lowering agentsAtorvastatin 20 mg once daily for 10 days Fenofibrate 160 mg1once daily for 10 days ↓2% ↓4% Pravastatin 40 mg as a single dose Fenofibrate 3 x 67 mg2as a single dose ↓1% ↓2% Fluvastatin 40 mg as a single dose Fenofibrate 160 mg1as a single dose ↓2% ↓10% Anti-diabetic agentsGlimepiride 1 mg as a single dose Fenofibrate 145 mg1once daily for 10 days ↑1% ↓1% Metformin 850 mg three times daily for 10 days Fenofibrate 54 mg1three times daily for 10 days ↓9% ↓6% Rosiglitazone 8 mg once daily for 5 days Fenofibrate 145 mg1once daily for 14 days ↑10% ↑3% 1Fenofibrate oral tablet
2Fenofibrate oral micronized capsuleTable 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 Cmax Lipid-lowering agentsFenofibrate 160 mg1once
daily for 10 daysAtorvastatin, 20 mg once daily for 10 days Atorvastatin ↓17% 0% Fenofibrate 3 x 67 mg2as a single dose Pravastatin, 40 mg as a single dose Pravastatin ↑13% ↑13% 3α-Hydroxyl-iso-pravastatin ↑26% ↑29% Fenofibrate 160 mg1as a single dose Fluvastatin, 40 mg as a single dose (+)-3R, 5S-Fluvastatin ↑15% ↑16% Anti-diabetic agentsFenofibrate 145 mg1once daily for 10 days Glimepiride, 1 mg as a single dose Glimepiride ↑35% ↑18% Fenofibrate 54 mg1three times daily for 10 days Metformin, 850 mg three times daily for 10 days Metformin ↑3% ↑6% Fenofibrate 145 mg1once daily for 14 days Rosiglitazone, 8 mg once daily for 5 days Rosiglitazone ↑6% ↓1% 1Fenofibrate oral tablet
2Fenofibrate oral micronized capsule - patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities[see.]
5.3 Myopathy and RhabdomyolysisFibrates 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. CPK levels should be assessed in patients reporting these symptoms, and fenofibrate 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 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)].
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)]. - patients with preexisting gallbladder disease[see.]
5.5 CholelithiasisFenofibrate, like clofibrate and gemfibrozil, may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Fenofibrate therapy should be discontinued if gallstones are found.
- nursing mothers[see]
8.2 LactationRisk SummaryThere is no available information on the presence of fenofibrate in human milk, effects of the drug on the breastfed infant, or the effects on milk production. Fenofibrate is present in the milk of rats, and is therefore likely to be present in human milk. Because of the potential for serious adverse reactions in breastfed infants, such as disruption of infant lipid metabolism, women should not breastfeed during treatment with fenofibrate and for 5 days after the final dose
[see Contraindications (4)]. - patients with known hypersensitivity to fenofibrate or fenofibric acid[see].
5.9 Hypersensitivity ReactionsAcute HypersensitivityAnaphylaxis and angioedema have been reported postmarketing with fenofibrate. In some cases, reactions were life-threatening and required emergency treatment. If a patient develops signs or symptoms of an acute hypersensitivity reaction, advise them to seek immediate medical attention and discontinue fenofibrate.
Delayed HypersensitivitySevere cutaneous adverse drug reactions (SCAR), including Stevens-Johnson syndrome, toxic epidermal necrolysis, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported postmarketing, occurring days to weeks after initiation of fenofibrate. The cases of DRESS were associated with cutaneous reactions (such as rash or exfoliative dermatitis) and a combination of eosinophilia, fever, systemic organ involvement (renal, hepatic, or respiratory). Discontinue fenofibrate and treat patients appropriately if SCAR is suspected.
- Hepatotoxicity: Serious drug-induce liver injury, including liver transplantation and death, has been reported with fenofibrate. Monitor patient’s liver function, including serum ALT, AST, and total bilirubin, at baseline and periodically for the duration of therapy. Discontinue if signs or symptoms of liver injury develop or if elevated enzyme levels persist ()
5.2 HepatotoxicitySerious drug-induced liver injury (DILI), including liver transplantation and death, have been reported postmarketing with fenofibrate. 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 fenofibrate 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 cholestatice hepatitis, and cirrhosis has occurred in association with chronic active hepatitis.
In clinical trials, fenofibrate at doses equivalent to 96 mg to 145 mg fenofibrate daily has been associated with increase in serum AST or SLT. The incidence of increases in transaminases may be dose related [see Adverse Reaction (6.1)].
Fenofibrate is contraindicated in patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities [see Contraindication (4)]. Monitor patient’s liver function, including serum ALT, AST and total bilirubin, at baseline and periodically for the duration of therapy with fenofibrate. Discontinue fenofibrate 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 fenofibrate in these patients if there is no alternative explanation for the liver injury. - Myopathy and rhabdomyolysis: Have been reported in patients taking fenofibrate. Risk are increased during co-administered with a statin (with a significantly higher rate observed for gemfibrozil), particularly in elderly patients and patients with diabetes, renal failure, or hypothyroidism ().
5.3 Myopathy and RhabdomyolysisFibrates 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. CPK levels should be assessed in patients reporting these symptoms, and fenofibrate 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 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)].
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)]. - Serum creatinine: Fenofibrate can reversibly increase serum creatinine levels (
5.4). Monitor renal function periodically in patients with renal impairment ().8.6 Renal ImpairmentThe use of fenofibrate should be avoided in patients who have severe renal impairment
[see Contraindications (4)]. 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. - Cholelithiasis: Fenofibrate increases cholesterol excretion into the bile, leading to risk of cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated ().
5.5 CholelithiasisFenofibrate, like clofibrate and gemfibrozil, may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Fenofibrate therapy should be discontinued if gallstones are found.
- Coumarin anticoagulants: Use caution in concomitant treatment with oral coumarin anticoagulants. Adjust the dosage of coumarin anticoagulant to maintain the prothrombin time/INR at the desired level to prevent bleeding complications (
5.6). - Hypersensitivity Reactions: Acute hypersensitivity reactions, including anaphylaxis and angioedema, and delayed hypersensitivity reactions, including severe cutaneous adverse drug reactions have been reported postmarketing. Some cases were life-threatening and required emergency treatment. Discontinue fenofibrate and treat patients appropriately if reactions occur (
5.9).
Adverse reactions > 2% and at least 1% greater than placebo: Abnormal liver tests, increased AST, increased ALT, increased CPK, and rhinitis (
Adverse reactions > 2% and at least 1% greater than placebo: Abnormal liver tests, increased AST, increased ALT, increased CPK, and rhinitis .
The following serious adverse reactions are described below and elsewhere in the labeling:
• Mortality and coronary heart disease morbidity [see Warnings and Precautions (5.1)]
• Hepatoxicity [see Warnings and Precautions (5.2)]
• Pancreatitis [see Warnings and Precautions (5.7)]
• Hypersensitivity reactions [see Warnings and Precautions (5.9)]
• Venothromboembolic disease [see Warnings and Precautions (5.10)]
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 fenofibrate (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 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.
BODY SYSTEM Adverse Reaction | Fenofibrate* (N=439) | Placebo (N=365) |
BODY AS A WHOLE | ||
| Abdominal Pain | 4.6% | 4.4% |
| Back Pain | 3.4% | 2.5% |
| Headache | 3.2% | 2.7% |
DIGESTIVE | ||
| Nausea | 2.3% | 1.9% |
| Constipation | 2.1% | 1.4% |
METABOLIC AND NUTRITIONAL DISORDERS | ||
| Abnormal Liver Function Tests | 7.5%** | 1.4% |
| Increased ALT | 3.0% | 1.6% |
| Increased CPK | 3.0% | 1.4% |
| Increased AST | 3.4%** | 0.5% |
RESPIRATORY | ||
| Respiratory Disorder | 6.2% | 5.5% |
| Rhinitis | 2.3% | 1.1% |
| * Dosage equivalent to 145 mg fenofibrate tablets. ** Significantly different from Placebo. | ||
Urticaria was seen in 1.1% vs. 0%, and rash in 1.4% vs. 0.8% of fenofibrate and placebo patients respectively in controlled trials.
In a pooled analysis of 10 placebo-controlled trials, increases to > 3 times the upper limit of normal in ALT occurred in 5.3% of patients taking fenofibrate at doses equivalent to 96 mg to 145 mg fenofibrate tablets daily versus 1.1% of patients treated with placebo [see Warnings and Precautions (5.2)]. In an 8-week study, the incidence of ALT or AST elevations ≥ 3 times the upper limit of normal was 13% in patients receiving dosages equivalent to 96 mg to 145 mg fenofibrate tablets daily and was 0% in those receiving dosages equivalent to 48 mg or less fenofibrate tablets daily or placebo.
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.