Lofibra

Fenofibrate is a prescription medication used to lower cholesterol and triglycerides (a type of fat), and to increase "good" cholesterol in the blood. It may be used alone or with other cholesterol-lowering medications. Fenofibrate belongs to a group of drugs called fibrates which work by increasing the activity of an enzyme involved in removing triglycerides and cholesterols from the body.

This medication comes in capsule and tablet form and is taken once a day, with or without food.

Common side effects of fenofibrate include headaches, heartburn, nausea, and muscle aches.

Lofibra is part of the drug class:

• Fibrates

Tell your healthcare provider if you are breastfeeding or plan to breastfeed. It is not known if fenofibrate passes into your breast milk. You and your healthcare provider should decide if you will take fenofibrate or breastfeed. You should not do both.

If you also take cholestyramine, colesevelam, or colestipol: Wait 4 to 6 hours after taking any of these other medicines before you take fenofibrate. Avoid taking fenofibrate within 1 hour before taking the other medicine.

Avoid drinking alcohol. It can raise triglyceride levels, and may also damage your liver while you are taking fenofibrate.

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 Lofibra®. 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 [see Warnings and Precautions (5.6)].

Immunosuppressants

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 Lofibra®, there is a risk that an interaction will lead to deterioration of renal function. The benefits and risks of using Lofibra® (fenofibrate tablets) with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed and renal function monitored.

Bile Acid Binding Resins

Since bile acid binding resins may bind other drugs given concurrently, patients should take Lofibra® at least 1 hour before or 4 to 6 hours after a bile acid binding resin to avoid impeding its absorption.

Colchicine

Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co-administered with colchicine, and caution should be exercised when prescribing fenofibrate with colchicine.

Mechanism of Action

The active moiety of Lofibra® is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been extensively studied through oral administration of fenofibrate.

The lipid-modifying effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor α (PPARα). Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity).

The resulting decrease in 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.

Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid.

Pharmacodynamics

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 fenofibrate, produces reductions in total cholesterol, LDL cholesterol, apolipoprotein B, total triglycerides and triglyceride rich lipoprotein (VLDL) in treated patients. In addition, treatment with fenofibrate results in increases in high density lipoprotein (HDL) and apolipoproteins apoAI and apoAII.

Pharmacokinetics

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.

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.

Absorption

The 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 Cmax and AUC, is not significantly different when a single 145 mg dose of fenofibrate is administered under fasting or nonfasting conditions.

Distribution

Upon 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.

Metabolism

Following 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 vivo metabolism data indicate that neither fenofibrate nor fenofibric acid undergo oxidative metabolism (e.g., cytochrome P450) to a significant extent.

Elimination

After 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 Populations

Geriatrics

In 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)].

Pediatrics

The pharmacokinetics of Lofibra® has not been studied in pediatric populations.

Gender

No pharmacokinetic difference between males and females has been observed for fenofibrate.

Race

The 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 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 30-59 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 Lofibra® 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 Impairment

No pharmacokinetic studies have been conducted in patients with hepatic impairment.

Drug-drug Interactions

In vitro studies 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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), 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: fenofibrate 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). Fenofibrate 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, fenofibrate 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, fenofibrate 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 fenofibrate 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.

Mutagenesis: Fenofibrate 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 fenofibrate, 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).

Lofibra® (fenofibrate tablets USP) 54 mg 90s Label Text

NDC 57844-691-98

Lofibra®
(fenofibrate
tablets USP)
54 mg

TEVA

Rx only

90 TABLETS

Applies to fenofibrate: oral capsule, oral tablet

Along with its needed effects, fenofibrate (the active ingredient contained in Lofibra) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking fenofibrate:

• Chills or fever
• hives, itching, or skin rash
• muscle aches and pains
• nausea or vomiting

• Chronic indigestion
• dark urine
• muscle cramps, pain, stiffness, swelling, or weakness
• troubled breathing
• unusual bleeding or bruising
• unusual tiredness
• yellow eyes or skin

• Agitation
• bloating
• bloody urine
• decreased frequency or amount of urine
• lower back or side pain
• pains in the stomach, side, or abdomen, possibly radiating to the back
• swelling of the face, fingers, or lower legs
• swollen joints
• upper right abdominal or stomach pain

Some side effects of fenofibrate may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Runny nose
• sneezing
• stuffy nose

• Back pain
• diarrhea
• eye irritation
• gas
• increased sensitivity of the skin to sunlight

• Lack or loss of strength

Applies to fenofibrate: oral capsule, oral tablet

General

The most frequently reported side effects were abnormal liver tests, AST increased, ALT increased, creatine phosphokinase (CPK) increased, and rhinitis.[Ref]

Hepatic

Common (1% to 10%): Liver function tests abnormal, AST increased, ALT increased
Uncommon (0.1% to 1%): Cholelithiasis
Rare (less than 0.1%): Hepatitis
Postmarketing reports: Cirrhosis, liver fatty deposit, cholecystitis, jaundice, cholangitis, biliary colic[Ref]

Respiratory

Very common (10% or more): Rhinitis (up to 23.2%), bronchitis (16.4%)
Common (1% to 10%): Respiratory disorder, pharyngitis, sinusitis
Uncommon (0.1% to 1%): Pulmonary embolism
Very rare (less than 0.01%): Interstitial pneumopathy
Frequency not reported: Cough increased, dyspnea, asthma, pneumonia, laryngitis
Postmarketing reports: Interstitial lung disease[Ref]

Musculoskeletal

Very common (10% or more): Arthralgia (up to 25.1%), back pain (up to 15%)
Common (1% to 10%): Back pain, myalgia
Uncommon (0.1% to 1%): Diffuse myalgia, myositis, muscle cramp, muscle weakness
Very rare (less than 0.01%): Rhabdomyolysis
Frequency not reported: Arthritis, tenosynovitis, joint disorder, arthrosis, leg cramp, bursitis, myasthenia
Postmarketing reports: Muscle spasm[Ref]

Gastrointestinal

Very common (10% or more): Abdominal pain (up to 15.9%)
Common (1% to 10%): Nausea, constipation, diarrhea, vomiting, flatulence
Uncommon (0.1% to 1%): Pancreatitis
Frequency not reported: Dyspepsia, gastroenteritis, rectal disorder, esophagitis, gastritis, colitis, tooth disorder, gastrointestinal disorder, duodenal ulcer, peptic ulcer, rectal hemorrhage, eructation, gamma glutamyl transpeptidase, dry mouth[Ref]

Nervous system

Common (1% to 10%): Headache, dizziness
Rare (less than 0.1%): Peripheral neuropathy
Frequency not reported: Migraine, paresthesia, hypertonia, neuralgia, somnolence[Ref]

Dermatologic

Common (1% to 10%): Rash, pruritus, urticaria
Uncommon (0.1% to 1%): Photosensitivity reaction
Rare (0.01% to 0.1%): Alopecia
Very rare (less than 0.01%): Cutaneous photosensitivity with erythema, vesiculation, nodulation
Frequency not reported: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, eczema, acne, sweating, fungal dermatitis, skin disorder, contact dermatitis, maculopapular rash, nail disorder, skin ulcer
Postmarketing reports: Ecchymosis[Ref]

Cardiovascular

Uncommon (0.1% to 1%): Deep vein thrombosis
Frequency not reported: Angina pectoris, hypertension, vasodilatation, coronary artery disorder, electrocardiogram abnormal, extrasystole, myocardial infarct, peripheral vascular disorder, varicose vein, cardiovascular disorder, hypotension, palpitation, arrhythmia, phlebitis, tachycardia, atrial fibrillation[Ref]

Ocular

Common (1% to 10%): Conjunctivitis
Frequency not reported: Eye disorder, amblyopia, abnormal vision, cataract specified, refraction disorder[Ref]

Other

Very common (10% or more): Accidental injury (up to 18.4%), flu syndrome (up to 17.9%), chest pain (up to 10.1%)
Common (1% to 10%): Creatine phosphokinase increased, malaise, vertigo, fatigue
Uncommon (0.1% to 1%): Serum creatinine increased, urea increased
Rare (less than 0.1%): Sexual asthenia
Frequency not reported: Pain, infection, cyst, hernia, fever, peripheral edema, ear pain, otitis media, herpes zoster, herpes simplex, weight gain, weight loss, edema
Postmarketing reports: Asthenia[Ref]

Genitourinary

Uncommon (0.1% to 1%): Sexual dysfunction
Frequency not reported: Urinary frequency, prostatic disorder, dysuria, gynecomastia, vaginal moniliasis, cystitis[Ref]

Hematologic

Rare (less than 0.1%): Hemoglobin decreased, leukopenia
Frequency not reported: Eosinophilia, lymphadenopathy, thrombocytopenia, anemia
Postmarketing reports: Hematocrit decreased[Ref]

Metabolic

Frequency not reported: Appetite increased, anorexia, diabetes mellitus, hypoglycemia, gout, hyperuricemia
Postmarketing reports: High-density lipoprotein cholesterol levels severely depressed[Ref]

Renal

Frequency not reported: Kidney function abnormal, urolithiasis
Postmarketing reports: Renal failure, acute renal failure[Ref]

Psychiatric

Common (1% to 10%): Insomnia
Frequency not reported: Depression, libido decreased, anxiety, nervousness[Ref]

Endocrine

Frequency not reported: Diabetes mellitus[Ref]

Hypersensitivity

Rare (less than 0.1%): Hypersensitivity reaction
Frequency not reported: Allergic reaction[Ref]

Some side effects of Lofibra may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.