Fenofibrate

Fenofibrate
Clinical data
Trade names Fenoglide, Lipofen, other
AHFS/Drugs.com Monograph
MedlinePlus a601052
License data
Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    administration    		 by mouth
    ATC code
    Legal status
    Legal status
    • In general: ℞ (Prescription only)
    Pharmacokinetic data
    Protein binding 99%
    Metabolism glucuronidation
    Elimination half-life 20 h
    Excretion urine (60%), feces (25%)
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    ECHA InfoCard 100.051.234 Edit this at Wikidata
    Chemical and physical data
    Formula C20H21ClO4
    Molar mass 360.831 g/mol
    3D model (JSmol)
    Melting point 80 to 81 °C (176 to 178 °F)
      (verify)

    Fenofibrate, marketed as Tricor and under several other brand names, is a drug of the fibrate class. It is mainly used to reduce cholesterol levels in people at risk of cardiovascular disease. Like other fibrates, it reduces both low-density lipoprotein (LDL) and very low density lipoprotein (VLDL) levels, as well as increasing high-density lipoprotein (HDL) levels and reducing triglyceride levels.[1] It is used alone or along with statins in the treatment of hypercholesterolemia and hypertriglyceridemia. However, due to lack of cardiovascular benefit in several large trials and the risk of side effects such as muscle damage, the FDA withdrew approval for the use in high cholesterol treatment in combination with statins. [2]

    Fenofibrate has been used since 1975 and is one of the most commonly prescribed fibrates.[1]

    Medical uses

    Fenofibrate is mainly used for primary hypercholesterolemia or mixed dyslipidemia. Fenofibrate appears to decrease the risk of cardiovascular disease and possibly diabetic retinopathy in those with diabetes mellitus,[3][4] and firstly indicated for the reduction in the progression of diabetic retinopathy in patients with type 2 diabetes and existing diabetic retinopathy in Australia.[5] It also appears to be helpful in decreasing amputations of the lower legs in this same group of people.[6] Fenofibrate also has an off-label use as an added therapy of high blood uric acid levels in people who have gout.[7]

    It is used in addition to diet to reduce elevated low-density lipoprotein cholesterol (LDL), total cholesterol, triglycerides (TG), and apolipoprotein B (apo B), and to increase high-density lipoprotein cholesterol (HDL) in adults with primary hypercholesterolemia or mixed dyslipidemia.[8]

    It is used in addition to diet for treatment of adults with severe hypertriglyceridemia. Improving glycemic control in diabetics showing fasting chylomicronemia will usually decrease the need for pharmacologic intervention.[8]

    Statins remain the first line for treatment of blood cholesterol. AHA guidelines from 2013 did not find evidence for routine use of additional medications.[9]

    Additionally, in 2016, the FDA filed "Withdrawal of Approval of Indications Related to the Coadministration With Statins in Applications for Niacin Extended-Release Tablets and Fenofibric Acid Delayed Release Capsules" noting "the Agency has concluded that the totality of the scientific evidence no longer supports the conclusion that a drug-induced reduction in triglyceride levels and/or increase in HDL cholesterol levels in statin-treated patients results in a reduction in the risk of cardiovascular events. Consistent with this conclusion, FDA has determined that the benefits of niacin ER tablets and fenofibric acid DR capsules for coadministration with statins no longer outweigh the risks, and the approvals for this indication should be withdrawn."[10]

    Contraindications

    Fenofibrate is contraindicated in:[8]

    Adverse effects

    The most common adverse events (>3% of patients with coadministered statins) are[11]

    Precautions

    Musculoskeletal

    Hepatotoxicity

    Nephrotoxicity

    • Can increase serum creatinine levels; renal function should be monitored periodically in patients with renal insufficiency[11]

    Biliary

    Coagulation/Bleeding

    • Exercise caution in concomitant treatment with oral Coumadin anticoagulants (e.g. warfarin). Adjust the dosage of Coumadin to maintain the prothrombin time/INR at desired level to prevent bleeding complications.[11]

    Overdose

    “There is no specific treatment for overdose with fenofibric acid delayed-release capsules. General supportive care is indicated, including monitoring of vital signs and observation of clinical status”. Additionally, hemodialysis should not be considered as an overdose treatment option because fenofibrate heavily binds to plasma proteins and does not dialyze well.[11]

    Interactions

    These drug interactions with fenofibrate are considered major and may need therapy modifications:

    • Bile acid sequestrants (e.g. cholestyramine, colestipol, etc.): If taken together, bile acid resins may bind to fenofibrate, resulting in a decrease in fenofibrate absorption. To maximize absorption, patients need to separate administration by at least 1 h before or 4 h to 6 h after taking the bile acid sequestrant.[11][12]
    • Immunosuppressants (e.g. ciclosporin or tacrolimus): An increased risk of renal dysfunction exists with concomitant use of immunosuppressants and fenofibrate. Approach with caution when coadministering additional medications that decrease renal function.[13]
    • Vitamin K antagonists (e.g. warfarin): As previously mentioned, fenofibrate interacts with coumadin anticoagulants to increase the risk of bleeding. Dosage adjustment of vitamin K antagonist may be necessary.[11]
    • Statins: Combination of statins and fenofibrate may increase the risk of rhabdomyolysis or myopathy.[14]

    Mechanism of action

    "In summary, enhanced catabolism of triglyceride-rich particles and reduced secretion of VLDL underlie the hypotriglyceridemic effect of fibrates, whereas their effect on HDL metabolism is associated with changes in HDL apolipoprotein expression."[15]

    Fenofibrate is a fibric acid derivative, a prodrug comprising fenofibric acid linked to an isopropyl ester. It lowers lipid levels by activating peroxisome proliferator-activated receptor alpha (PPARα). PPARα activates lipoprotein lipase and reduces apoprotein CIII, which increases lipolysis and elimination of triglyceride-rich particles from plasma.[15]

    PPARα also increases apoproteins AI and AII, reduces VLDL- and LDL-containing apoprotein B, and increases HDL-containing apoprotein AI and AII.

    Formulations

    Fenofibrate is available in several formulations and is sold under several brand names, including Tricor by AbbVie, Lipofen by Kowa Pharmaceuticals America Inc, Lofibra by Teva, Lipanthyl, Lipidil, Lipantil micro and Supralip by Abbott Laboratories, Fenocor-67 by Ordain Health Care, Fibractiv 105/35 by Cogentrix Pharma( India), Fenogal by SMB Laboratories, Antara by Oscient Pharmaceuticals, Tricheck by Zydus (CND), Atorva TG by Zydus Medica, Golip by GolgiUSA and Stanlip by Ranbaxy (India). Different formulations may differ in terms of pharmacokinetic properties, particularly bioavailability; some must be taken with meals, whereas others may be taken without regard to food.[16]

    The active form of fenofibrate, fenofibric acid, is also available in the United States, sold as Trilipix. Fenofibric acid may be taken without regard to the timing of meals.[11][17]

    When fenofibrate and a statin are given as combination therapy, it is recommended that fenofibrate be given in the morning and the statin at night, so that the peak dosages do not overlap.[18]

    Controversy

    In the United States, Tricor was reformulated in 2005. This reformulation is controversial, as it is seen as an attempt to stifle competition from generic equivalents of the drug,[19] and is the subject of antitrust litigation by generic drug manufacturer Teva.[19] Also available in the United States, Lofibra is available in 54 and 160 mg tablets, as well as 67, 134, and 200;mg micronized capsules.[20] Generic equivalents of Lofibra capsules are currently available in all three strengths in the United States. In Europe, it is available in either coated tablet or capsule; the strength range includes 67, 145, 160 and 200 mg. The differences among strengths are a result of altered bioavailability (the fraction absorbed by the body) due to particle size. For example, 200 mg can be replaced by 160 mg micronized fenofibrate. The 145 mg strength is a new strength that appeared in 2005-2006 which also replaces 200 or 160 mg as the fenofibrate is nanonised (i.e. the particle size is below 400 nm).

    History

    Fenofibrate was first synthesized in 1974 as a derivative of clofibrate, and was launched on the French market shortly thereafter. It was initially known as procetofen, and was later renamed fenofibrate' to comply with World Health Organization International Nonproprietary Name guidelines.[21]

    Fenofibrate was developed by Groupe Fournier SA of France, which was acquired in 2005 by Solvay Pharmaceuticals, a business unit of the Belgian corporation Solvay S.A.. In 2009, Solvay was, in turn, acquired by Abbott Laboratories (now AbbVie).

    Research

    In adult rat studies using pentylenetetrazol and lithium-pilocarpine models, fenofibrate exhibits anticonvulsant properties comparable to the ketogenic diet potentially via agonism of PPAR-a. These findings may be useful for future ketogenic diet study protocols.[22]

    References

    1. 1 2 Yang LP, Keating GM (2009). "Fenofibric acid: in combination therapy in the treatment of mixed dyslipidemia". Am J Cardiovasc Drugs. 9 (6): 401–9. doi:10.2165/11203920-000000000-00000. PMID 19929038.
    2. ↑ "Medscape Log In". www.medscape.com. Retrieved 2017-02-09.
    3. ↑ Wong TY, Simó R, Mitchell P (Jul 2012). "Fenofibrate - a potential systemic treatment for diabetic retinopathy?". Am J Ophthalmol. 154 (1): 6–12. doi:10.1016/j.ajo.2012.03.013. PMID 22709833.
    4. ↑ Fazio S (2009). "More clinical lessons from the FIELD study". Cardiovasc Drugs Ther. 23 (3): 235–41. doi:10.1007/s10557-008-6160-5. PMID 19160032.
    5. ↑ "Australian Public Assessment Report for fenofibrate". TGA. TGA. Retrieved 27 June 2015.
    6. ↑ Steiner G (2009). "How can we improve the management of vascular risk in type 2 diabetes: insights from FIELD". Cardiovasc Drugs Ther. 23 (5): 403–8. doi:10.1007/s10557-009-6190-7. PMID 19757004.
    7. ↑ Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, Pillinger MH, Merill J, Lee S, Prakash S, Kaldas M, Gogia M, Perez-Ruiz F, Taylor W, Lioté F, Choi H, Singh JA, Dalbeth N, Kaplan S, Niyyar V, Jones D, Yarows SA, Roessler B, Kerr G, King C, Levy G, Furst DE, Edwards NL, Mandell B, Schumacher HR, Robbins M, Wenger N, Terkeltaub R (2012). "2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia". Arthritis Care Res (Hoboken). 64 (10): 1431–46. doi:10.1002/acr.21772. PMC 3683400. PMID 23024028.
    8. 1 2 3 Package Insert: Abbot Laboratories (October 2010)
    9. ↑ Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC, Watson K, Wilson PW, Eddleman KM, Jarrett NM, LaBresh K, Nevo L, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC, Tomaselli GF (2014). "2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines". Circulation. 129 (25 Suppl 2): S1–45. doi:10.1161/01.cir.0000437738.63853.7a. PMID 24222016.
    10. ↑ https://s3.amazonaws.com/public-inspection.federalregister.gov/2016-08887.pdf
    11. 1 2 3 4 5 6 7 8 9 10 Fenofibric Acid FDA Label Prescribing Information"FDA Label Information" (PDF). FDA.
    12. ↑ Product Information: TriCor(TM), fenofibrate. Abbott Laboratories, North Chicago, IL, 1998.
    13. ↑ Product Information: Sandimmune(R) oral capsules, oral solution, intravenous injection, cyclosporine oral capsules, oral solution, intravenous injection. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2010.
    14. ↑ Product Information: TRICOR(R) oral tablets, fenofibrate oral tablets. Abbott Laboratories, North Chicago, IL, 2007.
    15. 1 2 Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC (1998). "Mechanism of action of fibrates on lipid and lipoprotein metabolism". Circulation. 98 (19): 2088–93. doi:10.1161/01.cir.98.19.2088. PMID 9808609.
    16. ↑ Ling H, Luoma JT, Hilleman D (2013). "A review of currently available fenofibrate and fenofibric acid formulations". Cardiol Res. 4 (2): 47–55. doi:10.4021/cr270w. PMC 5358213.
    17. ↑ Alagona P (2010). "Fenofibric acid: a new fibrate approved for use in combination with statin for the treatment of mixed dyslipidemia". Vasc Health Risk Manag. 6: 351–62. doi:10.2147/vhrm.s6714. PMC 2879297. PMID 20531954.
    18. ↑ Wierzbicki AS, Mikhailidis DP, Wray R, Schacter M, Cramb R, Simpson WG, Byrne CB (2003). "Statin-fibrate combination: therapy for hyperlipidemia: a review". Curr Med Res Opin. 19 (3): 155–68. doi:10.1185/030079903125001668. PMID 12814127.
    19. 1 2 Abbott's request to dismiss the antitrust charge over Tricor was rejected. FDANews, Drug Daily Bulletin, (June 1, 2006)
    20. ↑ TEVA Pharmartsau6i8mkst7oceutical Lofibra Product Site
    21. ↑ Lalloyer F, Staels B (2010). "Fibrates, glitazones, and peroxisome proliferator-activated receptors". Arterioscler. Thromb. Vasc. Biol. 30 (5): 894–9. doi:10.1161/ATVBAHA.108.179689. PMC 2997800. PMID 20393155.
    22. ↑ Porta N, Vallée L, Lecointe C, Bouchaert E, Staels B, Bordet R, Auvin S (2009). "Fenofibrate, a peroxisome proliferator-activated receptor-alpha agonist, exerts anticonvulsive properties". Epilepsia. 50 (4): 943–8. doi:10.1111/j.1528-1167.2008.01901.x. PMID 19054409.
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