FENOTIVO

Indications

• Mixed hyperlipidaemia
• Severe hypertriglyceridaemia
• Familial hypercholesterolaemia (under expert advice)

Dosage

Children: For children aged 4–14 years, the dosage is one 67 mg capsule per 20 kg body weight daily, with a maximum of four 67 mg capsules per day

Adults: Initially 200 mg daily, increased if necessary to a maximum of 267 mg daily, or 100 mg to 160 mg daily depending on the formulation and patient needs.

Mechanism of action

Fenofibrate activates PPARα, a nuclear receptor that regulates gene transcription involved in lipid metabolism. This activation increases lipolysis, enhances the activity of lipoprotein lipase, and reduces apoprotein C-III levels. The resultant effect is an alteration in lipid homeostasis, leading to decreased triglyceride levels and improved lipid profiles. Fenofibrate also exhibits anti-inflammatory properties by suppressing the production of inflammatory cytokines.

Pharmacodynamics

Fenofibrate is effective in treating primary hypercholesterolemia, mixed dyslipidemia, and severe hypertriglyceridemia. Its long half-life of 19-27 hours allows for once-daily dosing, making it convenient for patients. The therapeutic index is wide, but caution is advised due to the risks of rhabdomyolysis and myopathy, especially when used with statins.

Pharmacokinetics

Fenofibrate is absorbed after oral administration, with peak plasma concentrations occurring approximately 4-5 hours post-dose. It is extensively protein-bound and undergoes metabolism in the liver, converting to its active form. The elimination half-life is between 19 to 27 hours, and it is primarily excreted via urine. Dose adjustments may be necessary in cases of renal impairment.

Contra-indications

• Gall bladder disease
• Severe hepatic impairment
• Concurrent use of a statin in patients with risk factors for myopathy
• Hypoalbuminaemia
• Nephrotic syndrome
• Photosensitivity to fibrates

Adverse effects

• Alopecia
• Diarrhoea
• Dizziness
• Drowsiness
• Fatigue
• Gastrointestinal discomfort
• Headache
• Myalgia
• Nausea
• Skin reactions
• Vertigo
• Rhabdomyolysis
• Pancreatitis
• Hepatic disorders
• Sexual dysfunction
• Fatigue
• Interstitial lung disease

Interactions

• Fenofibrate + statins (increased risk of rhabdomyolysis)
• Fenofibrate + pravastatin (severe interaction, increases risk of rhabdomyolysis)
• Fenofibrate + fluvastatin (moderate interaction, increases risk of rhabdomyolysis)
• Fenofibrate + ketoprofen (photosensitivity)

Precautions

• Correct hypothyroidism before initiating treatment
• Monitor liver function and creatine kinase when fibrates are used in combination with a statin
• Use caution in patients with risk factors for myopathy or severe hypertriglyceridaemia

Pregnancy

Manufacturers advise avoiding use due to potential toxicity based on animal studies.

Breast-feeding

Manufacturer advises avoiding use as fenofibrate is present in milk in animal studies.

Storage

Store in a cool, dry place, away from direct sunlight.

Formulations

• Modified-release tablets (200 mg)
• Tablets (100 mg)
• Micronised capsules (67 mg)
• Micronised capsules (200 mg)
• Micronised capsules (267 mg)

Mechanism of action

Fenofibrate activates peroxisome proliferator activated receptor alpha (PPARα), increasing lipolysis, activating lipoprotein lipase, and reducing apoprotein C-III. PPARα is a nuclear receptor and its activation alters lipid, glucose, and amino acid homeostasis. Activation of PPARα activates transcription of gene transcription and translation that generates peroxisomes filled with hydrogen peroxide, reactive oxygen species, and hydroxyl radicals that also participate in lipolysis. This mechanism of increased lipid metabolism is also associated with increased oxidative stress on the liver. In rare cases this stress can lead to cirrhosis and chronic active hepatitis. Fenofibrate is a synthetic ligand for the nuclear receptor peroxisome proliferator-activated receptor (PPAR) alpha and has been widely used in the treatment of metabolic disorders, especially hyperlipemia, due to its lipid-lowering effect. The molecular mechanism of lipid-lowering is relatively well defined: an activated PPARalpha forms a PPAR-RXR heterodimer and this regulates the transcription of genes involved in energy metabolism by binding to PPAR response elements in their promoter regions, so-called "trans-activation". In addition, fenofibrate also has anti-inflammatory and anti-athrogenic effects in vascular endothelial and smooth muscle cells. /There is/ limited information about the anti-inflammatory mechanism of fenofibrate; however, "trans-repression" which suppresses production of inflammatory cytokines and adhesion molecules probably contributes to this mechanism. Furthermore, there are reports that fenofibrate affects endothelial cells in a PPARalpha-independent manner. In order to identify PPARalpha-dependently and PPARalpha-independently regulated transcripts, ... microarray data from human endothelial cells treated with fenofibrate, and with and without siRNA-mediated knock-down of PPARalpha /were obtained/. ... Dynamic Bayesian transcriptome networks /were used/ to reveal PPARalpha-dependent and -independent pathways. Transcriptome network analysis identified growth differentiation factor 15 (GDF15) as a hub gene having PPARalpha-independently regulated transcripts as its direct downstream children. This result suggests that GDF15 may be PPARalpha-independent master-regulator of fenofibrate action in human endothelial cells. The effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor a (PPARa). Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting fall in triglycerides produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPARa also induces an increase in the synthesis of apoproteins A-I, A-II and HDL-cholesterol. ... /This study/ investigated whether fenofibrate affects serum levels of retinol-binding protein-4 (RBP4), an adipocytokine that has recently been shown to link obesity and insulin resistance. Fenofibrate treatment significantly decreased serum RBP4 levels of dyslipidemic patients, which correlated with reduced body weight and increased insulin sensitivity. ... the effect of fenofibrate on RBP4 expression in obese rats /were also examined/. Fenofibrate greatly decreased RBP4 mRNA levels in adipose tissue but not in the liver, which correlated with decreased serum RBP4 levels and increased insulin sensitivity in obese rats. Consistent with a direct effect on RBP4 expression, fenofibrate treatment significantly reduced the mRNA expression levels

Pharmacodynamics

Fenofibrate is a fibrate that activates peroxisome proliferator activated receptor alpha (PPARα) to alter lipid metabolism and treat primary hypercholesterolemia, mixed dyslipidemia, and severe hypertriglyceridemia. Fenofibrate requires once daily dosing and has a half life of 19-27 hours so its duration of action is long. Fenofibrate capsules are given at a dose of 50-150mg daily so the therapeutic index is wide. Patients should be counselled about the risk of rhabdomyolysis, myopathy, and cholelithiasis when taking fibrates.