Fenofibrate

Fenofibrate is a Peroxisome proliferator receptor alpha activator belonging to Antilipemic Agent.

Fenofibrate is a peroxisome proliferator receptor alpha activator used to lower LDL-C, total-C, triglycerides, and Apo B while increasing HDL-C in hypercholesterolemia, dyslipidemia, and hypertriglyceridemia.

Fenofibrate is well absorbed from the gastrointestinal tract. The bioavailability of Fenofibrate is approximately 81%. The peak plasma concentration of Fenofibrate is found to be 2-8 hours. Fenofibrate is widely distributed to most tissues. The plasma protein binding is approximately 99%. Fenofibrate is rapidly hydrolyzed in the tissue and plasma by esterases to its active metabolite, fenofibric acid, then undergoes hepatic or renal inactivation via glucuronidation. Fenofibrate is excreted mainly via urine (approximately 60% as metabolites); feces (25%). The Elimination half-life was found to be approximately 20 hours.

Fenofibrate shows common side effects like Headache, dizziness, diarrhea, sore throat, runny nose, sneezing, joint pain, etc.

Fenofibrate is available in the form of an Oral Tablet and Oral Capsule.

Fenofibrate is available in India, the US, the UK, Singapore, Canada, Spain, Japan, France, China, and Australia.

Fenofibrate belongs to the Antilipemic Agent and acts as a Peroxisome proliferator receptor alpha activator.

Fenofibrate activates peroxisome proliferator-activated receptor alpha (PPARα), increasing lipolysis, activating lipoprotein lipase, and reducing apoprotein C-III. PPARα is a nuclear receptor, and its activation alters lipid, glucose, and amino acid homeostasis. Activation of PPARα activates transcription of gene transcription and translation that generates peroxisomes filled with hydrogen peroxide, reactive oxygen species, and hydroxyl radicals that also participate in lipolysis. This mechanism of increased lipid metabolism is also associated with increased oxidative stress on the liver. In rare cases, this stress can lead to cirrhosis and chronic active hepatitis.

The Data on the onset and duration of action of Fenofibrate is not available.

The Tmax of Fenofibrate is approximately 2-8 hours.

Fenofibrate is available in the form of Oral Tablets and Oral capsules.

Fenofibrate tablets and capsules are taken orally, usually once daily.

Fenofibrate is a lipid (fat) lowering medicine. It is used to treat high blood cholesterol and triglycerides (fats) levels. This medicine reduces the levels of bad cholesterol and triglycerides and increases the levels of good cholesterol in your blood. This may further reduce the risk of heart attack or stroke (a condition that causes reduced oxygen supply to the brain).

Fenofibrate is a Peroxisome proliferator receptor alpha activator belonging to Antilipemic Agent.

Fenofibrate, a fibric acid derivative, elicits its lipid-modifying effect by activating the peroxisome proliferator-activated receptor-α (PPAR-α) which induces the synthesis of apoproteins A-I and A-II. It also increases VLDL catabolism, fatty acid oxidation, and elimination of atherogenic triglyceride-rich particles by activating lipoprotein lipase and reducing the production of apoprotein CIII (an inhibitor of lipoprotein lipase).

Fenofibrate is approved for use in the following clinical indications

• Primary Hypercholesterolemia or Mixed Dyslipidemia

Fenofibrate capsules are indicated as adjunctive therapy to diet to reduce elevated low-density lipoprotein cholesterol (LDL-C), total cholesterol (total-c), Triglycerides (TG), and apolipoprotein B (Apo B), and to increase high-density lipoprotein cholesterol (HDL-C) in adult patients with primary hypercholesterolemia or mixed dyslipidemia.

• Severe Hypertriglyceridemia

Fenofibrate capsules are also indicated as adjunctive therapy to diet for the 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 (e.g. > 2,000 mg/dL) may increase the risk of developing pancreatitis. The effect of fenofibrate therapy on reducing this risk has not been adequately studied.

• Primary Hypercholesterolemia or Mixed Dyslipidemia

The dose of fenofibrate capsules is 150 mg once daily.

• Severe Hypertriglyceridemia

The initial dose is 50 to 150 mg per day. Dosage should be individualized according to patient response and should be adjusted if necessary following repeat lipid determination at 4-to-8-week intervals.

The maximum dose of fenofibrate capsules is 150 mg once daily.

Fenofibrate is available in various strengths as 48 mg; 145 mg; 54 mg; 160 mg; 67 mg; micronized 200 mg; 134 mg; 40 mg; 120 mg; 43 mg; 130 mg; 30 mg; 90 mg; 50 mg; 150 mg.

Fenofibrate is available in the form of Oral Tablets and Oral Capsules.

• Dosage Adjustment in Kidney Patient

CrCl >80 mL/minute: No dosage adjustment is necessary.

CrCl >30 to 80 mL/minute: Use the lowest available tablet strength (if a formulation is not available in a strength that is ≤67 mg, then an alternate formulation should be used); do not titrate.

CrCl ≤30 mL/minute: Use contraindicated.

Fenofibrate is contraindicated in patients with

• Patients with severe renal impairment, including those receiving dialysis.
• Patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities.
• Patients with preexisting gall bladder disease.
• Patients with known hypersensitivity to Fenofibrate or fenofibric acid.
• Nursing mothers

• HDL Cholesterol

A paradoxical, severe, and reversible decrease in HDL-C (as low as 2 mg/dL) with a simultaneous decrease in apolipoprotein A1 has been reported within 2 weeks to years after initiation of fibrate therapy; clinical significance is unknown.

• Venous thromboembolism

Use has been associated with pulmonary embolism and deep vein thrombosis. Use with caution in patients with risk factors for venous thromboembolism.

• Serum Creatinine

Elevations in serum creatinine have been reported in patients on Fenofibrate. These elevations tend to return to baseline following discontinuation of Fenofibrate. The clinical significance of these observations is unknown. Monitor renal function in patients with renal impairment by taking Fenofibrate. Renal monitoring should also be considered for patients taking Fenofibrate who are at risk for renal insufficiencies, such as the elderly and patients with diabetes.

• Cholelithiasis

Fenofibrate, 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

Caution should be exercised when Fenofibrate is given in conjunction with coumarin anticoagulants. Fenofibrate may potentiate the anticoagulant effects of these agents resulting in prolongation of the Prothrombin Time/International Normalized Ratio (PT/INR). To prevent bleeding complications, frequent monitoring of PT/INR and dose adjustment of the anticoagulant are recommended until PT/INR has stabilized.

• Pancreatitis

Pancreatitis has been reported in patients taking Fenofibrate, 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.

• Hematologic Changes

Mild to moderate decreases in hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following the initiation of fenofibrate therapy. However, these levels stabilize during long-term administration. Thrombocytopenia and agranulocytosis have been reported in individuals treated with Fenofibrate. Periodic monitoring of red and white blood cell counts is recommended during the first 12 months of fenofibrate administration.

• Hypersensitivity Reactions

Acute hypersensitivity reactions including severe skin rashes such as Steven-Johnson syndrome and toxic epidermal necrolysis requiring patient hospitalization and treatment with steroids have been reported in individuals treated with Fenofibrate. 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.

There is no available information on the presence of Fenofibrate in human milk, the 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.

Triglyceride and lipid concentrations increase during pregnancy as required for normal fetal development. When increases are greater than expected, supervised dietary intervention should be initiated. In patients who are pregnant develop severe hypertriglyceridemia and are at risk for pancreatitis, the use of Fenofibrate beginning in the second trimester is one intervention that may be considered. Agents other than Fenofibrate should be used for hypercholesterolemia.

Common Adverse effects

• Increased serum alanine aminotransferase, increased serum aspartate aminotransferase, pulmonary embolism, skin rash, urticaria, abdominal pain, constipation, diarrhea, dyspepsia, dizziness, pain, arthralgia, increased creatine phosphokinase in blood specimen, limb pain, myalgia, nasopharyngitis, rhinitis, sinusitis, upper respiratory tract infection.

Rare Adverse effects

• Acute generalized exanthematous pustulosis, skin photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, decreased HDL cholesterol (can be severe), Pancreatitis, agranulocytosis, anemia, thrombocytopenia, cholestatic hepatitis, hepatic cirrhosis, hepatocellular hepatitis, hepatotoxicity (including acute and severe), increased serum bilirubin, anaphylaxis, angioedema, drug reaction with eosinophilia and systemic symptoms, Headache, asthenia, muscle spasm, myopathy, rhabdomyolysis, acute kidney injury, interstitial pulmonary disease.

• Coumarin Anticoagulants

Potentiation of coumarin-type anticoagulant effect has been observed with prolongation of the PT/INR. Caution should be exercised when Fenofibrate is given in conjunction with coumarin anticoagulants. Fenofibrate may potentiate the anticoagulant effect of these agents resulting in the prolongation of the PT/INR. To prevent bleeding complications, frequent monitoring of PT/INR and dose adjustment of the oral anticoagulant as recommended until the PT/INR has stabilized.

• Immunosuppressants

Immunosuppressant agents such as cyclosporine and tacrolimus can impair renal function and because renal excretion is the primary elimination route of fibrate drugs including fenofibrate capsules, there is a risk that an interaction will lead to deterioration of renal function. When immunosuppressants and other potentially nephrotoxic agents are co-administered with fenofibrate capsules, the lowest effective dose of fenofibrate capsules should be employed, and renal function should be monitored.

• Bile-Acid Binding Resins

Since bile-acid binding resins may bind other drugs given concurrently, patients should take Fenofibrate 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 Fenofibrate co-administered with colchicine, and caution should be exercised when prescribing Fenofibrate with colchicine.

The common side effects of Fenofibrate include the following

Common

● Constipation, diarrhea, Heartburn, pain in the back, arm, or legs, Headache, joint pain.

Rare

● Muscle pain, weakness, or tenderness, fever, blistering or peeling skin, Rash, trouble breathing, changes in urination, abdominal pain, hives, pain in the upper back between the shoulder blades or under the right shoulder, stomach pain, especially in the upper right part of the stomach, nausea, vomiting, redness, swelling, pain, tenderness, or warmth in one leg, shortness of breath, pain when breathing, coughing up blood, swelling of the face, throat, tongue, lips, and eyes, difficulty swallowing or breathing, hoarseness.

• Pregnancy

Pregnancy Category C

Limited available data on fenofibrate use in pregnant women are insufficient to determine a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, no evidence of embryo-fetal toxicity was observed with oral administration of Fenofibrate in rats and rabbits during organogenesis at doses less than or equivalent to the maximum recommended clinical dose of 145 mg daily, based on body surface area (mg/m2). Adverse reproductive outcomes occurred at higher doses in the presence of maternal toxicity. Fenofibrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Nursing Mothers

There is no available information on the presence of Fenofibrate in human milk, the 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.

• Pediatric Use

As per FDA, safety and effectiveness have not been established in pediatric patients.

• 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 based on renal function. Elderly patients with normal renal function should require no dose modifications. Consider monitoring renal function in elderly patients taking Fenofibrate.

There is no specific treatment for an overdose with Fenofibrate. 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 drugs 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.

Pharmacodynamic

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 apo A-II.

Pharmacokinetics

• 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 non-fasting conditions.

• Distribution

Upon multiple dosing of Fenofibrate, fenofibric acid steady state is achieved within 9 days. Plasma concentrations of fenofibric acid at a steady state are approximately double 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 the urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to a benzhydryl metabolite which is, in turn, conjugated with glucuronic acid and excreted in the urine. In vivo metabolism data indicate that neither Fenofibrate nor fenofibric acid undergoes oxidative metabolism (e.g., cytochrome P450) to a significant extent.

• Excretion

After absorption, Fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid, and fenofibric acid glucuronide. After administration of radio-labeled 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.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021656s029lbl.pdf
• https://www.rxlist.com/fenofibrate-drug.htm#indications
• https://reference.medscape.com/drug/tricor-lofibra-tablets-fenofibrate-342451
• https://medlineplus.gov/druginfo/meds/a601052.html#side-effects
• https://www.mims.com/india/drug/info/fenofibrate?type=full&mtype=generic
• https://go.drugbank.com/drugs/DB01039
• https://www.drugs.com/dosage/fenofibrate.html
• https://www.uptodate.com/contents/fenofibrate-drug-information#F22370318
• https://www.practo.com/medicine-info/fenofibrate-639-api