Each tablet contains 160 mg Fenofibrate.
Pharmacology: Pharmacodynamics: Fenofibrate is a fibric acid derivative whose lipid modifying effects reported in humans are mediated via activation of Peroxisome Proliferator Activated Receptor mtype alpha (PPARa).
Through activation of PPARa, 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 PPARa, also induces an increase in the synthesis of apoproteins AII and AII.
Previously stated effects of fenofibrate on lipoproteins lead to a reduction in very low and low density fractions (VLDL and LDL) containing apoprotein Band 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 dense LDL, the levels of which are elevated in the atherogenic lipoprotein phenotype, a common disorder in patients at risk for coronary heart disease.
During clinical trials with fenofibrate, total cholesterol was reduced by 20 to 25%, triglycerides by 40 to 55% and HDL cholesterol was increased by 10 to 30%.
In hypercholesterolaemic patients, where LDL cholesterol levels are reduced by 20 to 35%, the overall effect on cholesterol results in a decrease in the ratios of total cholesterol to HDL cholesterol, LDL cholesterol to LDL cholesterol, or Apo B to Apo AI, all of which are markers of atherogenic risk.
There is evidence that treatment with fibrates may reduce coronary heart disease events but they have not been shown to decrease all- cause mortality in the primary or secondary prevention of cardiovascular disease.
Pharmacokinetics: Fenofibrate is a film-coated tablet containing 160 mg of micronized fenofibrate.
Absorption: Maximum plasma concentrations max) occur within 4 to 5 hours after oral administration.
Plasma concentrations are stable during continuous treatment min any given individual.
The absorption of fenofibrate is increased when administered with food.
Distribution: Fenofibric acid is strongly bound to plasma albumin (more than 99%).
Metabolism and Excretion: After oral administration, fenofibrate is rapidly hydrolysed by esterases to the active metabolite fenofibric acid. No unchanged fenofibrate can be detected in the plasma. Fenofibrate is not a substrate for CYP3A4. No hepatic microsomal metabolism is involved.
The drug is excreted mainly in the urine. Practically all the drug is eliminated within 6 days.
Fenofibrate is mainly excreted in the form of fenofibric acid and its glucuronide conjugate. In elderly patients, the fenofibric acid apparent total plasma clearance is not modified.
Kinetic studies following the administration of a single dose and continuous treatment have demonstrated that the drug does not accumulate. Fenofibric acid is not eliminated by hemodialysis.
The plasma elimination half-life of fenofibric is approximately 20 hours.
Toxicology: Preclinical safety data: Chronic toxicity studies have yielded no relevant information about specific toxicity of fenofibrate. Studies on mutagenicity of fenofibrate have been negative.
In rats and mice, liver tumours have been found at high dosages, which are attributable to peroxisome proliferation. These changes are specific to small rodents and have not been observed in other animal species. This is of no relevance to therapeutic use in man. Studies in mice, rats and rabbits did not reveal any teratogenic effect. Embryotoxic effects were observed at doses in the range of maternal toxicity. Prolongation of the gestation period and difficulties during delivery were observed at high doses. No sign of any effect on fertility has been detected.
Fenofibrate is used for the treatment of mixed hypercholesterolemia, hypertriglyceridemia, correction of low HDL in adults and treatment of dyslipidemia associated with metabolic syndrome and diabetes when the response to diet and lifestyle modification is inadequate.
Dietary measures initiated before therapy be continued. Response to therapy should be monitored by determination of serum lipid values. If an adequate response has not been achieved after several months (e.g. 3 months) complementary or different therapeutic measures should be considered.
Posology: Adults: The recommended dose of fenofibrate is one tablet (160 mg) to be taken once daily.
Elderly Patients: in elderly, without renal impairment, the usual adult dose is recommended.
Patient and Renal Impairment: Dosage reduction is required in patients with renal impairment. The use of dosage forms containing a lower dose of active ingredients (67 mg micronized fenofibrate capsule or 100 mg standard fenofibrate capsule) is recommended in these patients once daily.
In patients with severe chronic kidney disease, fenofibrate is not recommended.
Children: The safety and efficacy of fenofibrate in children and adolescents younger than 18 years has not been established. No data are available. Therefore, use of fenofibrate is not recommended in pediatric subjects under 18 years.
Hepatic Impairment: Fenofibrate 160 mg is not recommended for use in patients with hepatic impairment due to lack of data.
Method of Administration: Fenofibrate tablet should be swallowed whole during meal.
Only anecdotal cases of fenofibrate overdosage have been received. In the majority of cases no overdose symptoms were reported.
No specific antidote is known. If an overdose is suspected, treat symptomatically and institute appropriate supportive measures as required. Fenofibrate cannot be eliminated by hemodialysis.
Fenofibrate is contraindicated in patients with Hypersensitivity to fenofibrate or any component of this medication; Hepatic insufficiency (including biliary cirrhosis and unexplained persistent liver function abnormality); Severe chronic kidney disease; Chronic or acute pancreatitis with the exception of acute pancreatitis due to severe hypertriglyceridemia; Known proto allergy or phototoxic reaction during treatment with fibrates or ketoprofen; Pre-existing gallbladder disease.
Secondary causes of hyperlipidemia, such as uncontrolled type 2 diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemia, obstructive liver disease or alcoholism should be adequately treated before fenofibrate therapy is considered. Secondary caused of hypercholesterolemia related to pharmacological treatment can be seen with diuretics, β-blocking agents, estrogens, progestogens, combined oral contraceptives, immunosuppressive agents and protease inhibitors. In this cases it should be ascertained whether the hyperlipidaemia is of primary or secondary nature (possible elevation of lipid values caused by theses therapeutic agents).
Liver function: as with other lipid lowering agents, increases have been reported in transaminase levels are monitored every 3 months during the first 12 months of treatment and thereafter periodically. attention should be paid to patients who develop increase in transaminase levels and therapy should be discontinued is AST (SGOT) and ALT {SGPT) levels increase to more than 3 times the upper limit of the normal range. When symptoms indicative of hepatitis occurs (e.g. jaundice, pruritus), and diagnosis is confirmed by laboratory testing, fenofibrate therapy should be discontinued.
Pancreas: Pancreatitis has been reported in patients taking fenofibrate (see Contraindications and Adverse Reactions). This occurrence may present a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect. or a secondary phenomenon mediated through biliary tract stone or sludge formation, resulting in the obstruction of the common bile duct.
Muscle: Muscle toxicity, including rare cases of rhabdomyolysis, with or without renal failure, has been reported with administration of fibrates and other lipid - lowering agents. The incidence of this disorder increases in cases of hypoalbuminaemia and previous renal insufficiency.
Patients with pre-disposing factors for myopathy and/or rhabdomyolysis, including age above 70 years old, personal or familial history of hereditary muscular disorders, renal impairment, hypothyroidism and high alcohol intake, may be at an increased risk of developing rhabdomyolysis. For these patients, the putative benefits and risks of fenofibrate therapy should be carefully weighed up.
Muscle toxicity should be suspected in patients presenting diffuse myalgia, myositis, muscular cramps and weakness and/or mark increases in CPK (levels exceeding 5 times the normal range). In such cases treatment with fenofibrate should be stopped.
The risk of muscle toxicity may be increased if the drug is administered with another fibrate or an HMG-CoA reductase inhibitor, especially in cases of pre-existing muscular disease. Consequently, the coprescription of fenofibrate with a HMG-CoA reductase inhibitor or another fibrate should be reserved to patients with severe combined dyslipidaemia and high cardiovascular risk without any history of muscular disease and with a close monitoring of potential muscle toxicity.
Renal function: Treatment should be interrupted in case of an increase in creatinine levels .50% ULN (upper limit of normal). it is recommended that creatinine is measured during the first 3 months after initiation of treatment and thereafter periodically (see Dosage & Administration).
Effects on Ability to Drive and Use Machines: Fenofibrate 160 mg, film-coated tablet has no or negligible influence on the ability to drive and use machines.
Pregnancy: There are no adequate data from the use of fenofibrate in pregnant women. Animal studies have not demonstrated any teratogenic effects. Embryotoxic effects have been shown at doses in the range of maternal toxicity (see Pharmacology: Toxicology Preclinical safety data under Actions). The potential risk for humans is unknown. Therefore, Fenofibrate 160 mg film-coated tablets should only be used during pregnancy after a careful benefit/risk assessment.
Lactation: It is unknown whether fenofibrate and/or its metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. Therefore fenofibrate should not be used during breast-feeding.
The most commonly reported ADRs during fenofibrate therapy digestive, gastric or intestinal disorders.
The following undesirable effects have been observed during placebo controlled clinical trials (n=2344) and post-marketing with the below indicated frequencies: (See Table.)
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Oral anticoagulants: Fenofibrate enhances oral anticoagulant effect and may increase risk of bleeding. It is recommended that the dose of anticoagulants is reduced by about one third at the start of treatment and then gradually adjusted if necessary according to INR (International Normalised Ratio) monitoring.
Cyclosporin: Some severe cases of reversible renal function impairment have been reported during concomitant administration of fenofibrate and cyclosporin. The renal function of this patients must therefore be closely monitored and the treatment with fenofibrate stopped in the case of severe alteration of laboratory parameters.
HMG-CoA reductase inhibitors and other fibrates: The risk of serious muscle toxicity is increased if a fibrate is used concomitantly with HMG CoA reductase inhibitor or other fibrates. Such combination therapy should be used with caution and patients monitored closely for signs of muscle toxicity (See Precautions).
Glitazones: Some cases of reversible paradoxical reduction of HDL-cholesterol have been reported during concomitant administration of fenofibrate and glitazones. Therefore, it is recommended to monitor HDL-cholesterol if one of these components is added to the other and stopping either therapy if HDL-cholesterol is too low.
Cytochrome P450 enzymes: In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of CYP2C19 and CYP2A6, and mild to- moderate inhibitors of CYP2C9 at therapeutic concentrations.
Patients co-administered fenofibrate and CYP2C19, CYP2A6, and especially CYP2C9 metabolised drugs with a narrow therapeutic index should be carefully monitored and, If necessary, dose adjustment of these drugs is recommended.
Store at temperature not exceeding 25°C.
C10AB05 - fenofibrate ; Belongs to the class of fibrates. Used in the treatment of hyperlipidemia.
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