Fenofibrate

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Fenofibrate
Systematic (IUPAC) name
propan-2-yl 2-{4-[(4-chlorophenyl)carbonyl]phenoxy}-2-methylpropanoate
Clinical data
Trade namesFenoglide, Lipofen
AHFS/Drugs.commonograph
MedlinePlusa601052
Pregnancy cat.C (US)
Legal status ?
RoutesOral
Pharmacokinetic data
Protein binding99%
Metabolismglucuronidation
Half-life20 hours
Excretionurine (60%), feces (25%)
Identifiers
CAS number49562-28-9 YesY
ATC codeC10AB05
PubChemCID 3339
DrugBankDB01039
ChemSpider3222 YesY
UNIIU202363UOS YesY
KEGGD00565 YesY
ChEBICHEBI:5001 YesY
ChEMBLCHEMBL672 YesY
Chemical data
FormulaC20H21ClO4 
Mol. mass360.831 g/mol
 YesY (what is this?)  (verify)
 
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Fenofibrate
Systematic (IUPAC) name
propan-2-yl 2-{4-[(4-chlorophenyl)carbonyl]phenoxy}-2-methylpropanoate
Clinical data
Trade namesFenoglide, Lipofen
AHFS/Drugs.commonograph
MedlinePlusa601052
Pregnancy cat.C (US)
Legal status ?
RoutesOral
Pharmacokinetic data
Protein binding99%
Metabolismglucuronidation
Half-life20 hours
Excretionurine (60%), feces (25%)
Identifiers
CAS number49562-28-9 YesY
ATC codeC10AB05
PubChemCID 3339
DrugBankDB01039
ChemSpider3222 YesY
UNIIU202363UOS YesY
KEGGD00565 YesY
ChEBICHEBI:5001 YesY
ChEMBLCHEMBL672 YesY
Chemical data
FormulaC20H21ClO4 
Mol. mass360.831 g/mol
 YesY (what is this?)  (verify)

Fenofibrate (Abbott's Tricor) is a drug of the fibrate class. It is mainly used to reduce cholesterol levels in patients 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 triglycerides level. It is used alone or in conjunction with statins in the treatment of hypercholesterolemia and hypertriglyceridemia. Fenofibrate was developed by Groupe Fournier SA, before it was acquired in 2005 by Solvay Pharmaceutical, a business unit owned by the Belgian corporation, Solvay S.A.. In 2009 Solvay Pharmaceutical was in turn acquired by Abbott Laboratories, which now markets the drug.

Contents

Dosage

The pharmaceutical form and the strength may change from one country to another, and from one brand to another. In the United States, Tricor was reformulated in 2005 and is available in tablets of 48 and 145 mg. This reformulation is controversial, as it is seen as an attempt to stifle competition from generic equivalents of the drug,[1] and is the subject of antitrust litigation by generic drug manufacturer Teva.[1] 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.[2] 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).

Fenofibrate increases the serum level of statins. Therefore, a lower dose of statin is generally necessary. Dose of fenofibrate must also be lowered in moderate to severe renal failure and most experts recommend that fenofibrate be given in the morning and the statin at night.[citation needed]

Mechanism of action

Fenofibrate is a fibric acid derivative. 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.

PPARα also increases apoproteins AI and AII, which reduces very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) containing apoprotein B, and increases high-density lipoprotein (HDL) containing apoprotein AI and AII.

In addition, by reducing the synthesis and increasing the catabolism of VLDL, fenofibrate increases LDL clearance and reduces small and dense LDL, which are associated with coronary heart disease.[3]Better citation needed

Indications

Fenofibrate is primary therapy for hypercholesterolaemia and hypertriglyceridaemia alone or combined (types IIa, IIb, III, IV and V dyslipidaemias)[4], in situations in which first line therapy is insufficient or has unacceptable side-effects.

Fenofibrate is contraindicated in children, during pregnancy or lactation, in patients with liver insufficiency, presence of gallstones, renal insufficiency, in patients hypersensitive to fenofibrate and/or its excipients, known photoallergy or phototoxic reaction during treatment with fibrates or ketoprofen.

Efficacy

Three randomized, double-blind, multicenter, phase III trials have shown that treatment with fenofibric acid plus a statin (atorvastatin, rosuvastatin or simvastatin) improved HDL and triglyceride levels significantly better than statin monotherapy and improved LDL levels better than fenofibric acid monotherapy.[5]

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study (2005), the largest, with 9795 patients with type 2 diabetes mellitus did not show a lower risk for the primary end point (non-fatal myocardial infarction and coronary heart disease death). The secondary end-point (total cardiovascular disease events) showed a relative risk reduction of 11% for total CVD events. A large proportion of placebo patients took statins during the trial, which weakened the effect. After an adjustment for statin drop in, the relative risk reductions were 19% for Non-Fatal MI and CHD Death, and 15% for total CVD events.[6]

The FIELD study also showed a beneficial reduction in the risk of microvascular complications in type 2 diabetes patients. Fenofibrate treatment led to reduction in the progression of albuminuria (14% less progression and 15% more regression compared with placebo). In addition, there was a 30% reduction in the needs for laser treatment for retinopathy.[6]

A FIELD sub-study analysis found that fenofibrate reduces the first laser treatment by 31%, reduced macular oedema by 31% and proliferative retinopathy by 30%.[7] In the sub-study, fenofibrate reduced the development or progression of retinopathy by reducing 22% in all patients and 79% in patients with pre-existing retinopathy.[7]

The FIELD study also showed that fenofibrate reduced the number of non-traumatic amputations by 38%.[8]

Like most fibrates, fenofibrate can cause stomach upsets and myopathy (muscle pain) and very rarely rhabdomyolysis. This risk is increased when used together with statins. However, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study provides important information that long-term treatment with fenofibrate therapy appears to have a favorable safety profile in patients with type 2 diabetes, even when nonstudy lipid-lowering medications were added. In FIELD, there were no cases of rhabdomyolysis reported in patients on combination therapy with fenofibrate and a statin. Thus, there is an increasing body of evidence that fenofibrate/statin combination therapy is safe and effective at managing dyslipidemia in patients with type 2 diabetes who are at risk for cardiovascular events. The ACCORD study, however, does not support the above statement about effectiveness (see below).

The recent FIELD Sub-analysis study published in Diabetes Care 2009, showed that fenofibrate significantly reduced CVD events in those with low HDL cholesterol and hypertension. The largest effect of fenofibrate to reduce CVD risk was observed in subjects with marked dyslipidemia (TG>2.3 mmol/L & low HDL-C) in whom a 27% relative reduction risk of total CVD event was observed. Some have argued that the absolute benefits of fenofibrate are likely to be greater when metabolic syndrome features are present. The highest risk and greatest benefits of fenofibrate are seen among those with marked hypertriglyceridemia[9], however these conclusions are not based on the predetermined endpoints of the study in the full group.

Classic markers of macrovascular and microvascular risk were associated with lower extremity amputations in patients with type 2 diabetes. Treatment with fenofibrate was associated with a lower risk of amputations, particularly minor amputations without known large-vessel disease, probably through non-lipid mechanisms. These findings could lead to a change in standard treatment for the prevention of diabetes-related lower-limb amputations.[10]

In 2010, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed that fenofibrate plus statins in patients with type 2 diabetes does not reduce cardiovascular events more than use of statins alone.[11] The ACCORD enrolled 5518 patients and followed them up for 4.7 years, providing moderately strong evidence for lack of real life benefit for using fibrates in diabetic patients with high cholesterol.

Although ACCORD-Lipid trial did not provide support for the general addition of fenofibrate to statin-treated patients with type 2 diabetes mellitus (T2DM), it added significantly to the results from fibrate monotherapy trials indicative of benefit from such treatment in subgroups of patients who present with significant dyslipidemia. In particular, ACCORD-Lipid trial, in our view, supports the addition of fenofibrate to statin therapy in patients with T2DM and optimal low-density lipoprotein cholesterol levels but persistent, significant hypertriglyceridemia (>200mg/dll) and low high-density lipoprotein cholesterol levels (<35-40mg/dl).[12]

Fenofibrate reduced albuminuria and slowed estimated GFR loss over 5 years (FIELD), despite initially and reversibly increasing plasma creatinine. Fenofibrate may delay albuminuria and GFR impairment in type 2 diabetes patients. Confirmatory studies are merited.[13]

It also appears to have a beneficial effect on the insulin resistance featured by the metabolic syndrome.[14]

Side effects

Gastrointestinal: Digestive, gastric or intestinal disorders (abdominal pain, nausea, vomiting, diarrhea, and flatulence). Skin Reactions: Rashes, Pruritus, urticaria or photosensitivity reactions.

Other uses

Fenofibrate has a uricosuric effect, making it of use in the management of gout.[15] It also acts as a blood thinner by lowering the amount of fibrinogen in the blood.[16]

Scientific

Fenofibrate exhibits anticonvulsant properties comparable to the ketogenic diet in adult rats, using pentylenetetrazol and lithium-pilocarpine models [17]

Brand names

Fenofibrate is sold under the brand name Tricor and Trilipix by Abbott Labs, Lipofen by Kowa Pharmaceuticals America Inc, Lofibra by Teva, Lipanthyl, Lipidil, and Supralip by Solvay Pharmaceutical, Fenocor-67 by Ordain Health Care, Fenogal by SMB Laboratories, Antara by Oscient Pharmaceuticals,Tricheck by Zydus (CND) and Golip by GolgiUSA.[citation needed]

Notes

  1. ^ a b Abbott's request to dismiss antitrust charge over Tricor rejected. FDANews, Drug Daily Bulletin, (June 1, 2006) [1]
  2. ^ TEVA Pharmaceutical Lofibra Product Site
  3. ^ Package Insert: Laboratories Fournier SA, (September 2003)
  4. ^ Package Insert: Abbot Laboratories (October 2010)
  5. ^ Yang L, Keating GM.Fenofibric Acid: In Combination therapy in the Treatment of Mixed Dyslipidemia. American Journal of Cardiovascular Drugs 2009; 9(6): 401-409. doi:10.2165/11203920-000000000-00000.
  6. ^ a b FIELD study investigators; Simes, RJ; Barter, P; Best, J; Scott, R; Taskinen, MR; Forder, P; Pillai, A et al. (2005). "Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial". Lancet 366 (9500): 1849–61. doi:10.1016/S0140-6736(05)67667-2. PMID 16310551.
  7. ^ a b FIELD study investigators. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD Study): a randomised controlled trial Lancet. 370. 1687-97. 2007
  8. ^ Burgess D, et al., on behalf of the field investigators. Effect of fenofibrate on silent myocardial infarction, hospitalization for acute coronary syndromes and amputation in type 2 diabetes: the FIELD study. Circulation 2007; 116: II_838 [abstract].
  9. ^ Russell Scott, et al., On behalf of the field investigators. Effects of fenofibrate treatment on cardiovascular disease risk in 9,795 individuals with type 2 diabetes and various components of the metabolic synndrome: the FIELD study. Diabetes Care 2009; 32: 493-498.
  10. ^ Kushwin Rajamani , et al., On behalf of the field investigators. Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD Study): a prespecified analysis of a randomised controlled trial. Lancet 2009; 373: 1780-88.
  11. ^ ACCORD Study, Group; Ginsberg, HN, Elam, MB, Lovato, LC, Crouse JR, 3rd, Leiter, LA, Linz, P, Friedewald, WT, Buse, JB, Gerstein, HC, Probstfield, J, Grimm, RH, Ismail-Beigi, F, Bigger, JT, Goff DC, Jr, Cushman, WC, Simons-Morton, DG, Byington, RP (2010-04-29). "Effects of combination lipid therapy in type 2 diabetes mellitus.". The New England Journal of Medicine 362 (17): 1563–74. doi:10.1056/NEJMoa1001282. PMC 2879499. PMID 20228404. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2879499/.
  12. ^ Marshall Elam, Laura C. Lovato and Henry Ginsberg. Role of fibrates in cardiovascular disease prevention, the ACCORD-Lipid perspective.Current Opinion in Lipidology 2011; 22: 55–61
  13. ^ Davis TM, & et al. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Diabetologica 2011 Feb; 54(2): 280-90
  14. ^ Wysocki J, Belowski D, Kalina M, Kochanski L, Okopien B, Kalina Z (2004). "Effects of micronized fenofibrate on insulin resistance in patients with metabolic syndrome". Int J Clin Pharmacol Ther 42 (4): 212–7. PMID 15124979.
  15. ^ Bardin T (June 2003). "Fenofibrate and losartan". Ann. Rheum. Dis. 62 (6): 497–8. doi:10.1136/ard.62.6.497. PMC 1754575. PMID 12759281. http://ard.bmjjournals.com/cgi/content/full/62/6/497.
  16. ^ de la Serna G. "Fenofibrate decreases plasma fibrinogen, improves lipid profile, and reduces uricemia". Clinical Pharmacology & Therapeutics 66 (2). doi:10.1053/cp.1999.v66.99709. http://www.nature.com/clpt/journal/v66/n2/abs/clpt1999438a.html.
  17. ^ 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. PMID 19054409. edit

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