Chemistry:Fenofibrate

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Short description: Drug of the fibrate class, mainly used to reduce cholesterol levels
Fenofibrate
Fenofibrate structure.svg
Clinical data
Trade namesFenoglide, Lipofen, others
AHFS/Drugs.comMonograph
MedlinePlusa601052
License data
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • UK: POM (Prescription only) [1]
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding99%
Metabolismglucuronidation
Elimination half-life20 h
Excretionurine (60%), feces (25%)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC20H21ClO4
Molar mass360.83 g·mol−1
3D model (JSmol)
Melting point80 to 81 °C (176 to 178 °F)
  (verify)

Fenofibrate (sold under the brand names Tricor, Fenobrat etc.), is an oral medication of the fibrate class used to treat abnormal blood lipid levels.[2] 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.[2][3][4] Its use is recommended together with dietary changes.[2]

Common side effects include liver problems, breathing problems, abdominal pain, muscle problems, and nausea.[2] Serious side effects may include toxic epidermal necrolysis, rhabdomyolysis, gallstones, and pancreatitis.[2] Use during pregnancy and breastfeeding is not recommended.[5][6] It works by multiple mechanisms.[2]

It was patented in 1969, and came into medical use in 1975.[7] It is available as a generic medication.[5] In 2020, it was the 95th most commonly prescribed medication in the United States with more than 7 million prescriptions.[8][9]

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.[10][11][12] It was initially indicated for diabetic retinopathy in patients with type 2 diabetes and diabetic retinopathy in Australia.[13] 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. [10][11][12][14] 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.[15][16]

Fenofibrate appears to reduce the risk of below ankle amputations in patients with Type 2 diabetes without microvascular disease.[17] 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.[17][18] 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.[17][18]

Fenofibrate has an off-label use as an added therapy of high blood uric acid levels in people who have gout.[19]

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.[20]

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.[20]

Statins remain the first line for treatment of blood cholesterol. AHA guidelines from 2013 did not find evidence for routine use of additional medications.[21]

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."[22]

Contraindications

Fenofibrate is contraindicated in:[20]

  • Patients with severe renal impairment, including those receiving dialysis (2.7-fold increase in exposure, and increased accumulation during chronic dosing in patients with estimated glomerular filtration rate < 30 mL/min)
  • Patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function test abnormalities
  • Patients with preexisting gallbladder disease
  • Nursing mothers
  • Hypothyreosis
  • Patients with known hypersensitivity to fenofibrate or fenofibric acid

Adverse effects

The most common adverse events (>3% of patients with coadministered statins) are[23]

  • Headache
  • Back pain
  • Nasopharyngitis
  • Nausea
  • Myalgia
  • Joint pain or arthralgia
  • Diarrhea
  • Upper respiratory tract infection
  • Calculi (Kidney Stones)


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

  • Can increase serum transaminases; liver tests should be monitored periodically[23]

Nephrotoxicity

Biliary

  • Can increase cholesterol excretion into the bile, leading to risk of cholelithiasis; if suspected, gallbladder studies are indicated. See "Interaction" section under Bile acid sequestrant[23]

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.[23]

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.[23]

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.[23][25]
  • 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.[26]
  • 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.[23]
  • Statins: Combination of statins and fenofibrate may increase the risk of rhabdomyolysis or myopathy.[27]

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."[28]

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.[28]

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
  • Fenogal by SMB Laboratories
  • Antara by Oscient Pharmaceuticals
  • Tricheck by Zydus (CND)
  • Atorva TG by Zydus Medica
  • Golip by GolgiUSA
  • Stanlip by Sun Pharma (India)

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.[29]

The choline salt of fenofibrate is available in the United States, sold as Trilipix, and may be taken without regard to meals.[23][30]

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.[31]

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.[32]

Fenofibrate was developed by Groupe Fournier SA of France.

In the United States, Tricor was reformulated in 2005. This reformulation was controversial, seen as an attempt to stifle competition from generic equivalents,[33] and was the subject of antitrust litigation by Teva.[33]

References

  1. ↑ "Fenofibrate 267mg Capsules - Summary of Product Characteristics (SmPC)". 12 February 2020. https://www.medicines.org.uk/emc/medicine/22425/SPC. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 "Fenofibric Acid/Fenofibrate Monograph for Professionals". American Society of Health-System Pharmacists. https://www.drugs.com/monograph/fenofibric-acid-fenofibrate.html. 
  3. ↑ "Effects of combination lipid therapy in type 2 diabetes mellitus". The New England Journal of Medicine 362 (17): 1563–1574. April 2010. doi:10.1056/NEJMoa1001282. PMID 20228404. 
  4. ↑ "Use of fenofibrate on cardiovascular outcomes in statin users with metabolic syndrome: propensity matched cohort study". BMJ 366: l5125. September 2019. doi:10.1136/bmj.l5125. PMID 31562117. 
  5. ↑ 5.0 5.1 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 198. ISBN 9780857113382. 
  6. ↑ "Fenofibrate Pregnancy and Breastfeeding Warnings" (in en). https://www.drugs.com/pregnancy/fenofibrate.html. 
  7. ↑ (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 474. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA474. 
  8. ↑ "The Top 300 of 2020". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  9. ↑ "Fenofibrate - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Fenofibrate. 
  10. ↑ 10.0 10.1 "Fenofibrate - a potential systemic treatment for diabetic retinopathy?". American Journal of Ophthalmology 154 (1): 6–12. July 2012. doi:10.1016/j.ajo.2012.03.013. PMID 22709833. 
  11. ↑ 11.0 11.1 "Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial" (in English). Lancet 370 (9600): 1687–1697. November 2007. doi:10.1016/S0140-6736(07)61607-9. PMID 17988728. 
  12. ↑ 12.0 12.1 "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" (in English). Ophthalmology 121 (12): 2443–2451. December 2014. doi:10.1016/j.ophtha.2014.07.019. PMID 25172198. 
  13. ↑ "Australian Public Assessment Report for fenofibrate". https://www.tga.gov.au/file/6794/download. 
  14. ↑ "More clinical lessons from the FIELD study". Cardiovascular Drugs and Therapy 23 (3): 235–241. June 2009. doi:10.1007/s10557-008-6160-5. PMID 19160032. 
  15. ↑ "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. doi:10.1001/jamacardio.2016.4828. PMID 28030716. 
  16. ↑ "Use of fenofibrate on cardiovascular outcomes in statin users with metabolic syndrome: propensity matched cohort study". BMJ 366: l5125. September 2019. doi:10.1136/bmj.l5125. PMID 31562117. 
  17. ↑ 17.0 17.1 17.2 "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. doi:10.1016/S0140-6736(09)60698-X. PMID 19465233. 
  18. ↑ 18.0 18.1 "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. doi:10.1007/s10557-009-6190-7. PMID 19757004. 
  19. ↑ "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. doi:10.1002/acr.21772. PMID 23024028. 
  20. ↑ 20.0 20.1 20.2 "TRICOR (fenofibrate) Package Insert". Abbot Laboratories. October 2010. http://www.rxabbott.com/pdf/tricorpi.pdf. 
  21. ↑ "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. doi:10.1161/01.cir.0000437738.63853.7a. PMID 24222016. 
  22. ↑ "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. https://s3.amazonaws.com/public-inspection.federalregister.gov/2016-08887.pdf. 
  23. ↑ 23.0 23.1 23.2 23.3 23.4 23.5 23.6 23.7 23.8 23.9 Fenofibric Acid FDA Label Prescribing Information"FDA Label Information". FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/201573Orig1s000lbl.pdf. 
  24. ↑ "Statin-fibrate combination: therapy for hyperlipidemia: a review". Current Medical Research and Opinion 19 (3): 155–168. 2003. doi:10.1185/030079903125001668. PMID 12814127. 
  25. ↑ Product Information: TriCor(TM), fenofibrate. Abbott Laboratories, North Chicago, IL, 1998.
  26. ↑ Product Information: Sandimmune(R) oral capsules, oral solution, intravenous injection, cyclosporine oral capsules, oral solution, intravenous injection. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2010.
  27. ↑ Product Information: TRICOR(R) oral tablets, fenofibrate oral tablets. Abbott Laboratories, North Chicago, IL, 2007.
  28. ↑ 28.0 28.1 "Mechanism of action of fibrates on lipid and lipoprotein metabolism". Circulation 98 (19): 2088–2093. November 1998. doi:10.1161/01.cir.98.19.2088. PMID 9808609. 
  29. ↑ "A Review of Currently Available Fenofibrate and Fenofibric Acid Formulations". Cardiology Research 4 (2): 47–55. April 2013. doi:10.4021/cr270w. PMID 28352420. 
  30. ↑ "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. doi:10.2147/vhrm.s6714. PMID 20531954. 
  31. ↑ "Using Estrogenic Activity and Nontargeted Chemical Analysis to Identify Contaminants in Sewage Sludge". Environmental Science & Technology 55 (10): 6729–6739. May 2021. doi:10.1021/acs.est.0c07846. PMID 33909413. Bibcode: 2021EnST...55.6729B. 
  32. ↑ "Fibrates, glitazones, and peroxisome proliferator-activated receptors". Arteriosclerosis, Thrombosis, and Vascular Biology 30 (5): 894–899. May 2010. doi:10.1161/ATVBAHA.108.179689. PMID 20393155. 
  33. ↑ 33.0 33.1 "Abbott's request to dismiss the antitrust charge over Tricor was rejected.". FDANews, Drug Daily Bulletin. 1 June 2006. http://www.fdanews.com/newsletter/article?issueId=9284&articleId=87219. 

External links



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