Fenofibrate Explained

Watchedfields:changed
Verifiedrevid:459443965
Width:182
Tradename:Fenoglide, Lipofen, others
Dailymedid:Fenofibrate
Pregnancy Au:B3
Routes Of Administration:By mouth
Atc Prefix:C10
Atc Suffix:AB05
Legal Au:S4
Legal Au Comment:[1]
Legal Uk:POM
Legal Uk Comment:[2]
Legal Us:Rx-only
Legal Status:Rx-only
Protein Bound:99%
Metabolism:glucuronidation
Elimination Half-Life:20 h
Excretion:urine (60%), feces (25%)
Cas Number:49562-28-9
Pubchem:3339
Iuphar Ligand:7186
Drugbank:DB01039
Chemspiderid:3222
Unii:U202363UOS
Kegg:D00565
Kegg2:C07586
Chebi:5001
Chembl:672
Iupac Name:propan-2-yl 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoate
C:20
H:21
Cl:1
O:4
Smiles:O=C(c1ccc(Cl)cc1)c2ccc(OC(C(=O)OC(C)C)(C)C)cc2
Stdinchi:1S/C20H21ClO4/c1-13(2)24-19(23)20(3,4)25-17-11-7-15(8-12-17)18(22)14-5-9-16(21)10-6-14/h5-13H,1-4H3
Stdinchikey:YMTINGFKWWXKFG-UHFFFAOYSA-N
Melting Point:80
Melting High:81

Fenofibrate (sold under the brand names Tricor, Fenobrat etc.), is an oral medication of the fibrate class used to treat abnormal blood lipid levels. It is less commonly used compared than statins because it treats a different type of cholesterol abnormality to statins. While statins have strong evidence for reducing heart disease and death, there is evidence to suggest that fenofibrate also reduces the risk of heart disease and death. However, this seems only to apply to specific populations of people with elevated triglyceride levels and reduced high-density lipoprotein (HDL) cholesterol.[3] [4] Its use is recommended together with dietary changes.

Common side effects include liver problems, breathing problems, abdominal pain, muscle problems, and nausea. Serious side effects may include toxic epidermal necrolysis, rhabdomyolysis, gallstones, and pancreatitis. Use during pregnancy and breastfeeding is not recommended.[5] [6] It works by multiple mechanisms.[7]

It was patented in 1969, and came into medical use in 1975.[8] It is available as a generic medication.[5] In 2021, it was the 81st most commonly prescribed medication in the United States, with more than 8million prescriptions.[9] [10]

Medical uses

Fenofibrate is mainly used for primary hypercholesterolemia or mixed dyslipidemia. Fenofibrate may slow the progression of diabetic retinopathy and the need for invasive treatment such as laser therapy in patients with type 2 diabetes with pre-existing retinopathy.[11] [12] [13] It was initially indicated for diabetic retinopathy in patients with type 2 diabetes and diabetic retinopathy in Australia.[14] The large scale, international FIELD and ACCORD-Eye trials found that fenofibrate therapy reduced required laser treatment for diabetic retinopathy by 1.5% over 5 years, as well as reducing progression by 3.7% over 4 years. [15] Further studies looking at the role of fenofibrate in the progression of diabetic retinopathy as the primary outcome is warranted to understand its role in this condition. Although no statistically significant cardiovascular risk benefits were identified in these trials, benefits may accrue to add on therapy to patients with high triglyceride dyslipidaemia currently taking statin medications.[16] [17]

Fenofibrate appears to reduce the risk of below ankle amputations in patients with Type 2 diabetes without microvascular disease.[18] The FIELD study reported that fenofibrate at doses of 200 mg daily, reduced the risk for any amputation by 37% independent of glycaemic control, presence or absence of dyslipidaemia and its lipid-lowering mechanism of action.[19] However, the cohort of participants who underwent amputations were more likely to have had previous cardiovascular disease (e.g. angina, myocardial infarction), longer duration of diabetes and had baseline neuropathy.

Fenofibrate has an off-label use as an added therapy of high blood uric acid levels in people who have gout.[20]

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.[21]

Severe hypertriglyceridemia type IV or V

It is used in tandem with diet for treatment of adults with severe hypertriglyceridemia. Improving glycemic control in diabetics showing fasting chylomicronemia usually reduces the need for pharmacologic intervention.

Statins remain the first line for treatment of blood cholesterol. AHA guidelines from 2013 did not find evidence for routine use of additional medications.[22]

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."[23]

Contraindications

Fenofibrate is contraindicated in:[21]

Adverse effects

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

Precautions

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.[24]

Musculoskeletal

Hepatotoxicity

Nephrotoxicity

Biliary

Coagulation/Bleeding

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.

Interactions

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

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."

Fenofibrate is a fibrate 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.[29]

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:

The 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.[30]

The choline salt of fenofibrate is available in the United States, sold as Trilipix, and may be taken without regard to meals.[31]

Environmental presence

Fenofibric acid was one of the 12 compounds identified in sludge samples taken from 12 wastewater treatment plants in California that were associated with estrogenic activity in in vitro.[32]

History

Fenofibrate was first synthesized in 1974, as a derivative of clofibrate, and was initially offered in France. It was initially known as procetofen, and was later renamed fenofibrate to comply with World Health Organization International Nonproprietary Name guidelines.[33]

Fenofibrate was developed by Groupe Fournier SA of France.

Society and culture

In the United States, Tricor was reformulated in 2005. This reformulation was controversial, seen as an attempt to stifle competition from generic equivalents,[34] and was the subject of antitrust litigation by Teva.

Notes and References

  1. Web site: Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017 . Therapeutic Goods Administration (TGA) . 21 June 2022 . 30 March 2024.
  2. Web site: Fenofibrate 267mg Capsules - Summary of Product Characteristics (SmPC) . (emc) . 12 February 2020 . 13 April 2020.
  3. Ginsberg HN, Elam MB, Lovato LC, Crouse JR, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm RH, Ismail-Beigi F, Bigger JT, Goff DC, Cushman WC, Simons-Morton DG, Byington RP . 6 . Effects of combination lipid therapy in type 2 diabetes mellitus . The New England Journal of Medicine . 362 . 17 . 1563–1574 . April 2010 . 20228404 . 2879499 . 10.1056/NEJMoa1001282 .
  4. Kim NH, Han KH, Choi J, Lee J, Kim SG . Use of fenofibrate on cardiovascular outcomes in statin users with metabolic syndrome: propensity matched cohort study . BMJ . 366 . l5125 . September 2019 . 31562117 . 10.1136/bmj.l5125 . 6763755 . 203580658 .
  5. Book: British national formulary : BNF 76 . 2018 . Pharmaceutical Press . 9780857113382 . 76 . 198.
  6. Web site: Fenofibrate Pregnancy and Breastfeeding Warnings . Drugs.com . 3 March 2019 . en.
  7. Web site: Fenofibric Acid/Fenofibrate Monograph for Professionals . Drugs.com . American Society of Health-System Pharmacists . 3 March 2019 .
  8. Book: Fischer J, Ganellin CR . Analogue-based Drug Discovery . 2006 . John Wiley & Sons . 9783527607495 . 474 .
  9. Web site: The Top 300 of 2021 . ClinCalc . 14 January 2024 . 15 January 2024 . https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx . live .
  10. Web site: Fenofibrate - Drug Usage Statistics . ClinCalc . 14 January 2024.
  11. Wong TY, Simó R, Mitchell P . Fenofibrate - a potential systemic treatment for diabetic retinopathy? . American Journal of Ophthalmology . 154 . 1 . 6–12 . July 2012 . 22709833 . 10.1016/j.ajo.2012.03.013 .
  12. Keech AC, Mitchell P, Summanen PA, O'Day J, Davis TM, Moffitt MS, Taskinen MR, Simes RJ, Tse D, Williamson E, Merrifield A, Laatikainen LT, d'Emden MC, Crimet DC, O'Connell RL, Colman PG . 6 . Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial . English . Lancet . 370 . 9600 . 1687–1697 . November 2007 . 17988728 . 10.1016/S0140-6736(07)61607-9 . 30479730 .
  13. Chew EY, Davis MD, Danis RP, Lovato JF, Perdue LH, Greven C, Genuth S, Goff DC, Leiter LA, Ismail-Beigi F, Ambrosius WT . 6 . The effects of medical management on the progression of diabetic retinopathy in persons with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study . English . Ophthalmology . 121 . 12 . 2443–2451 . December 2014 . 25172198 . 4252767 . 10.1016/j.ophtha.2014.07.019 .
  14. Web site: Australian Public Assessment Report for fenofibrate. TGA. 27 June 2015. 29 June 2015. https://web.archive.org/web/20150629223527/https://www.tga.gov.au/file/6794/download. dead.
  15. Fazio S . More clinical lessons from the FIELD study . Cardiovascular Drugs and Therapy . 23 . 3 . 235–241 . June 2009 . 19160032 . 10.1007/s10557-008-6160-5 . 7987660 .
  16. Elam MB, Ginsberg HN, Lovato LC, Corson M, Largay J, Leiter LA, Lopez C, O'Connor PJ, Sweeney ME, Weiss D, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm R, Ismail-Beigi F, Goff DC, Fleg JL, Rosenberg Y, Byington RP . 6 . Association of Fenofibrate Therapy With Long-term Cardiovascular Risk in Statin-Treated Patients With Type 2 Diabetes . JAMA Cardiology . 2 . 4 . 370–380 . April 2017 . 28030716 . 5470410 . 10.1001/jamacardio.2016.4828 .
  17. Kim NH, Han KH, Choi J, Lee J, Kim SG . Use of fenofibrate on cardiovascular outcomes in statin users with metabolic syndrome: propensity matched cohort study . BMJ . 366 . l5125 . September 2019 . 31562117 . 6763755 . 10.1136/bmj.l5125 .
  18. Rajamani K, Colman PG, Li LP, Best JD, Voysey M, D'Emden MC, Laakso M, Baker JR, Keech AC . 6 . Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial . Lancet . 373 . 9677 . 1780–1788 . May 2009 . 19465233 . 2687887 . 10.1016/S0140-6736(09)60698-X .
  19. Steiner G . How can we improve the management of vascular risk in type 2 diabetes: insights from FIELD . Cardiovascular Drugs and Therapy . 23 . 5 . 403–408 . October 2009 . 19757004 . 10.1007/s10557-009-6190-7 . 12747599 .
  20. 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 . 6 . 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia . Arthritis Care & Research . 64 . 10 . 1431–1446 . October 2012 . 23024028 . 3683400 . 10.1002/acr.21772 .
  21. Web site: TRICOR (fenofibrate) Package Insert . Abbot Laboratories . October 2010 .
  22. 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 . 6 . 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 . June 2014 . 24222016 . 10.1161/01.cir.0000437738.63853.7a . free .
  23. Web site: AbbVie Inc. et al; Withdrawal of Approval of Indications Related to the Coadministration With Statins in Applications for Niacin Extended-Release Tablets and Fenofibric Acid Delayed- Release Capsules . Food and Drug Administration . 18 April 2016 .
  24. Wierzbicki AS, Mikhailidis DP, Wray R, Schacter M, Cramb R, Simpson WG, Byrne CB . Statin-fibrate combination: therapy for hyperlipidemia: a review . Current Medical Research and Opinion . 19 . 3 . 155–168 . 2003 . 12814127 . 10.1185/030079903125001668 . 35948128 .
  25. Fenofibric Acid FDA Label Prescribing InformationWeb site: FDA Label Information. FDA.
  26. Product Information: TriCor(TM), fenofibrate. Abbott Laboratories, North Chicago, IL, 1998.
  27. Product Information: Sandimmune(R) oral capsules, oral solution, intravenous injection, cyclosporine oral capsules, oral solution, intravenous injection. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2010.
  28. Product Information: TRICOR(R) oral tablets, fenofibrate oral tablets. Abbott Laboratories, North Chicago, IL, 2007.
  29. Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC . Mechanism of action of fibrates on lipid and lipoprotein metabolism . Circulation . 98 . 19 . 2088–2093 . November 1998 . 9808609 . 10.1161/01.cir.98.19.2088 . 10.1.1.1004.321 . 5858864 .
  30. Ling H, Luoma JT, Hilleman D . A Review of Currently Available Fenofibrate and Fenofibric Acid Formulations . Cardiology Research . 4 . 2 . 47–55 . April 2013 . 28352420 . 5358213 . 10.4021/cr270w .
  31. Alagona P . Fenofibric acid: a new fibrate approved for use in combination with statin for the treatment of mixed dyslipidemia . Vascular Health and Risk Management . 6 . 351–362 . May 2010 . 20531954 . 2879297 . 10.2147/vhrm.s6714 . free .
  32. Black GP, He G, Denison MS, Young TM . Using Estrogenic Activity and Nontargeted Chemical Analysis to Identify Contaminants in Sewage Sludge . Environmental Science & Technology . 55 . 10 . 6729–6739 . May 2021 . 33909413 . 8378343 . 10.1021/acs.est.0c07846 . 2021EnST...55.6729B .
  33. Lalloyer F, Staels B . Fibrates, glitazones, and peroxisome proliferator-activated receptors . Arteriosclerosis, Thrombosis, and Vascular Biology . 30 . 5 . 894–899 . May 2010 . 20393155 . 2997800 . 10.1161/ATVBAHA.108.179689 .
  34. Web site: 1 June 2006. Abbott's request to dismiss the antitrust charge over Tricor was rejected.. FDANews, Drug Daily Bulletin.

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