Fenofibrate

Fenofibrate

Systematic (IUPAC) name
propan-2-yl 2-{4-[(4-chlorophenyl)carbonyl]phenoxy}-2-methylpropanoate
Identifiers
CAS number	49562-28-9
ATC code	C10AB05
PubChem	3339
DrugBank	APRD00405
ChemSpider	3222
Chemical data
Formula	C20H21ClO4
Mol. mass	360.831 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	?
Protein binding	99%
Metabolism	urine
Half life	20 hours
Excretion	?
Therapeutic considerations
Pregnancy cat.	C(US)
Legal status
Routes	Oral
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Fenofibrate is a drug of the fibrate class. Fenofibrate was discovered by Groupe Fournier SA, before it was acquired in 2005 by Solvay Pharmaceutical, a business unit owned by the Belgian corporation, Solvay S.A. 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 tryglycerides level. It also appears to have a beneficial effect on the insulin resistance featured by the metabolic syndrome.^[1] It is used alone or in conjunction with statins in the treatment of hypercholesterolemia and hypertriglyceridemia. Fenofibrate is sold under the brand name Tricor and Trilipix by Abbott Labs, Lipofen by Kowa Pharmaceuticals America Inc, Lofibra by Teva, Lipanthyl and Lipidil by Solvay Pharmaceutical, Fenocor-67 by Ordain Health Care Pvt Ltd, Fenogal by SMB Laboratories, and Antara by Oscient Pharmaceuticals.

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 and is the subject of antitrust litigation by generic drug manufacturer Teva.^[2] 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^[3]. 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 appeared in 2005-2006 which also replaces 200 or 160 mg as the fenofibrate is nanonised (ie 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.

Mode of Action

Fenofibrate is a fibric acid, derivative whose lipid modifying effects reported in humans are mediated via activation of Peroxisome Proliferator Activated Receptor type alpha (PPARα). Through activation of PPARα fenofibrate increases the lipolysis and elimination of atherogenic Triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein CIII. Activation of PPARα also induces an increase in the synthesis of apoproteins AI and AII, which leads to a reduction in very low - and low density fractions (VLDL and LDL) containing apoprotein B and an increase in the high density lipoprotein fraction (HDL) containing apoprotein AI and AII. In addition, through modulation of the synthesis and catabolism of VLDL fractions, fenofibrate increases the LDL clearance and reduces small and dense LDL, the levels of which are elevated in the atherogenic lipoprotein phenotype, a common disorder in patients at risk for coronary heart disease.^[4].

Indication

Fenofibrate is indicated for hypercholesterolaemia and hypertriglyceridaemia alone or combined (types IIa, IIb, III, IV and V dyslipidaemias).

Contra-Indications

Fenofibrate is contra-indicated in children, during pregnancy or lactation, in patients with liver insufficiency, presence of gallstones, renal insufficiency, in patients hypersensitive to fenofibrate and/or 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]

Side Effects

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

Recent updates

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, which is the largest fibrate trial involving 9795 patients with type 2 diabetes mellitus published in 2005 did not show significantly lowering the risk for primary end point (non-fatal MI and CHD death). But, it does show a relative risk reduction of 11% for Non-Fatal MI & CHD, although statistically insignificant. While, the secondary end-point (total CVD events) is statistically significant with a relative risk reduction of 11% for total CVD events. However, the FIELD study involve a large percentage of drop in statin use for the patients especially in the placebo group, which in turn might affect the study itself. After the adjustment was done, it shows that a relative risk reduction of 19% for Non-Fatal MI & CHD Death, and 15% a relative risk reduction in total CVD events. ^[6]

In the FIELD study, it also shows the benefit of reducing the risk of microvascular complications in type 2 diabetes patients. Fenofibrate treatment led to reduction in the progression albuminuria (14% less progression and 15% more regression compared with placebo). In addition, there is a 30% reduction of the needs for laser treatment for retinopathy. ^[7]

The FIELD sub-analysis study, shows that fenofibrate reduces the first laser treatment by 31%. In addition, for macular oedema by 31% and for proliferative retinopathy by 30%. ^[8] In the ophtalmology sub-study, fenofibrate reduces the development or progression of retinopathy by reducing 22% in all patients and 79% in patients with pre-existing retinopathy. ^[9]

The FIELD study also showed that fenofibrate reduced the number of non-traumatic amputations by 38%.^[10]

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>2.3mmol/L & low HDL-C) in whom a 27% relative reduction risk of total CVD event was observed. Therefore, the absolute benefits of fenofibrate are likely to be greater when metabolic syndrome feature are present. The highest risk and greatest benefits of fenofibrate are seen among those with marked hypertriglyceridemia. ^[11]

Other uses

Fenofibrate has a uricosuric effect, making it of use in the management of gout.^[12]

Notes

External links

• MedlinePlus article on Fenofibrate