Fenofibrate

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Fenofibrate
Fenofibrate structure.svg
Systematic (IUPAC) name
propan-2-yl 2-{4-[(4-chlorophenyl)carbonyl]phenoxy}-2-methylpropanoate
Clinical data
Trade names Fenoglide, Lipofen
AHFS/Drugs.com monograph
MedlinePlus a601052
Pregnancy cat. C (US)
Legal status Legend
Routes Oral
Pharmacokinetic data
Protein binding 99%
Metabolism glucuronidation
Half-life 20 hours
Excretion urine (60%), feces (25%)
Identifiers
CAS number 49562-28-9 YesY
ATC code C10AB05
PubChem CID 3339
DrugBank DB01039
ChemSpider 3222 YesY
UNII U202363UOS YesY
KEGG D00565 YesY
ChEBI CHEBI:5001 YesY
ChEMBL CHEMBL672 YesY
Chemical data
Formula C20H21ClO4 
Mol. mass 360.831 g/mol
 YesY (what is this?)  (verify)

Fenofibrate (Abbott's Tricor) (lipanthyl) is a drug of the fibrate class. It is a prodrug comprising fenofibric acid linked to an isopropyl ester. 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. On Feb 26, 2013, Mylan Pharmaceuticals, a subsidiary of global pharmaceutical company Mylan, launched Fenofibrate Capsules USP, 43 mg and 130 mg.

Dosage[edit]

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).

The combination of fenofibrate and statins may increase risk of myopathy and/or rhabdomyolysis. The mechanism of action is unknown. The dose of fenofibrate must also be lowered in moderate to severe renal failure.[citation needed] It is recommended that fenofibrate be given in the morning and the statin at night.[3]

Mechanism of action[edit]

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, 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.[4]Better citation needed

Indications[edit]

Fenofibrate is primary therapy for hypercholesterolaemia and hypertriglyceridaemia alone or combined (types IIa, IIb, III, IV and V dyslipidaemias),[5] and/or in situations in which first line therapy is insufficient or has unacceptable side-effects.

Additionally, in Europe, fenofibrate is indicated in mixed hyperlipidemia in patients with high cardiovascular risk in addition to a statin when triglycerides and HDL are not adequately controlled.

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[edit]

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.[6]

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.[7]

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.[7]

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%.[8] 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.[8]

The FIELD study also showed that fenofibrate reduced the number of non-traumatic amputations by 38%.[9]

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 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,[10] 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.[11]

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.[12] 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 (>200 mg/dll) and low high-density lipoprotein cholesterol levels (<35–40 mg/dl).[13]

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.[14]

It also appears to have a beneficial effect on the insulin resistance featured by the metabolic syndrome.[15]

Side effects[edit]

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

Scientific[edit]

Fenofibrate exhibits anticonvulsant properties comparable to the ketogenic diet in adult rats, using pentylenetetrazol and lithium-pilocarpine models [16]

Brand names[edit]

Fenofibrate is sold under the brand name Tricor and Trilipix by Abbvie, Lipofen by Kowa Pharmaceuticals America Inc, Lofibra by Teva, Lipanthyl, Lipidil, 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 and Storfib by Ranbaxy Laboratories (India).[citation needed]

Notes[edit]

  1. ^ a b Abbott's request to dismiss the antitrust charge over Tricor was rejected. FDANews, Drug Daily Bulletin, (June 1, 2006) [1]
  2. ^ TEVA Pharmartsau6i8mkst7oceutical Lofibra Product Site
  3. ^ "In combined therapy, fibrates should be given in the morning and statins at night so that the peak dosages do not overlap." Rohit Seth Loomba; Rohit Arora (2009). "Fibrates: Where Are We Now?". Therapeutic Advances in Cardiovascular Disease 3 (1): 91–96. 
  4. ^ Package Insert: Laboratories Fournier SA, (September 2003)
  5. ^ Package Insert: Abbot Laboratories (October 2010)
  6. ^ 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.
  7. ^ 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. 
  8. ^ 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
  9. ^ 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].
  10. ^ 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.
  11. ^ 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.
  12. ^ 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. 
  13. ^ 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
  14. ^ 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
  15. ^ 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. 
  16. ^ 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.  edit

External links[edit]