Each hard gelatin capsule contains: Fenofibrate BP 200 mg.
Pharmacology: Pharmacodynamics: Fenofibrate 200 mg capsule is a formulation containing 200 mg of micronised fenofibrate: the administration of this product results in effective plasma concentrations identical to those obtained with 3 capsules of Fenofibrate 67 mg capsules containing 67 mg of micronised fenofibrate.
The lipid-lowering properties of fenofibrate seen in clinical practice have been explained in vivo in transgenic mice and in human hepatocyte cultures by activation of Peroxisome Proliferator Activated Receptor α (PPARα). 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. Activation of PPARα also induces an increase in the synthesis of Apoprotein A-I, A-II and of HDL cholesterol.
Epidemiological studies have demonstrated a positive correlation between abnormally increased serum lipid levels and an increased risk of coronary heart disease. The control of such dyslipidaemias forms the rationale for treatment with fenofibrate. However, the possible beneficial and adverse long-term consequences of drugs used in the management of dyslipidaemia are still the subject of scientific discussion. Therefore, the presumptive beneficial effect of Fenofibrate 200 mg capsules on cardiovascular morbidity and mortality is as yet unproven.
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.
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial was a randomized placebo-controlled study of 5518 patients with type 2 diabetes mellitus treated with fenofibrate in addition to simvastatin. Fenofibrate plus simvastatin therapy did not show any significant differences compared to simvastatin monotherapy in the composite primary outcome of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death (hazard ratio [HR] 0.92, 95% CI 0.79-1.08, p = 0.32; absolute risk reduction: 0.74%). In the pre-specified subgroup of dyslipidaemic patients, defined as those in the lowest tertile of HDL-C (≤ 34 mg/dL or 0.88 mmol/L) and highest tertile of TG (≥ 204 mg/dL or 2.3 mmol/L) at baseline, fenofibrate plus simvastatin therapy demonstrated a 31% relative reduction compared to simvastatin monotherapy for the composite primary outcome (hazard ratio [HR] 0.69, 95% CI 0.49-0.97, p = 0.03; absolute risk reduction: 4.95%). Another prespecified subgroup analysis identified a statistically significant treatment-by-gender interaction (p = 0.01) indicating a possible treatment benefit of combination therapy in men (p=0.037) but a potentially higher risk for the primary outcome in women treated with combination therapy compared to simvastatin monotherapy (p=0.069). This was not observed in the aforementioned subgroup of patients with dyslipidaemia but there was also no clear evidence of benefit in dyslipidaemic women treated with fenofibrate plus simvastatin, and a possible harmful effect in this subgroup could not be excluded.
Studies with fenofibrate on lipoprotein fractions show decreases in levels of LDL and VLDL cholesterol. HDL cholesterol levels are frequently increased. LDL and VLDL triglycerides levels are also reduced. The overall effect is a decrease in the ratio of low and very low density lipoproteins to high density lipoproteins, which epidemiological studies have correlated with a decrease in atherogenic risk. Apolipoprotein-A and apolipoprotein-B levels are altered in parallel with HDL and LDL and VLDL levels respectively. Regression of xanthomata has been observed during fenofibrate therapy.
Plasma uric acid levels are increased in approximately 20% of hyperlipidaemic patients, particularly in those with type IV phenotype. Fenofibrate 200 mg capsules have a uricosuric effect and is therefore of additional benefit in such patients.
Patients with raised levels of fibrinogen and Lp(a) have shown significant reductions in these measurements during clinical trials with fenofibrate.
Pharmacokinetics: Fenofibrate is readily absorbed from the gastrointestinal tract when taken with food; absorption may be reduced if Fenofibrate is given on an empty stomach, although this depends on the formulation. It is rapidly hydrolysed to its active metabolite fenofibric acid which is about 99% bound to plasma albumin. The plasma elimination half-life is about 20 hours. Fenofibric acid is excreted mainly in the urine, mainly as the glucuronide conjugate, but also as a reduced form of fenofibric acid and its glucuronide. It is not removed by haemodialysis.
It is used to reduce low-density lipoprotein (LDL) cholesterol, total cholesterol, triglycerides, and apolipoprotein B, and to increase high-density lipoprotein (HDL) cholesterol, in the management of hyperlipidaemias.
200 mg once daily during a main meal.
Since it is less well-absorbed from an empty stomach, Fenofibrate 200 mg capsules should always be taken with food. Or as prescribed by the physician.
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 overdose is suspected, treat symptomatically and institute appropriate supportive measures as required. Fenofibrate cannot be eliminated by haemodialysis.
Hypersensitivity to active ingredients or any component of the formulation.
Fenofibrate should not be given to patients with severe hepatic impairment or significant liver disease, gallstones or gallbladder disorders or hypoalbuminaemic states such as nephrotic syndrome. It should be used with caution in renal impairment and is contraindicated if creatinine clearance is below 15 mL/minute unless the patient is on dialysis.
Secondary causes of hyperlipidemia: Secondary causes of hyperlipidemia, such as uncontrolled type 2 diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemia, obstructive liver disease, pharmacological treatment, alcoholism, should be adequately treated before fenofibrate therapy is initiated. Secondary cause 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 these cases, it should be ascertained whether the hyperlipidemia is of primary or secondary nature (possible elevation of lipid values caused by these therapeutic agents).
Renal function: Fenofibrate 200 mg capsules are contraindicated in severe renal impairment.
Fenofibrate 200 mg capsules should be used with caution in patients with mild to moderate renal insufficiency. Dose should be adjusted in patients whose estimated glomerular filtration rate is 30 to 59 mL/min/1.73 m2.
Reversible elevations in serum creatinine have been reported in patients receiving fenofibrate monotherapy or co-administered with statins. Elevations in serum creatinine were generally stable over time with no evidence for continued increases in serum creatinine with long term therapy and tended to return to baseline following discontinuation of treatment.
During clinical trials, 10% of patients had a creatinine increase from baseline greater than 30 μmol/L with co-administered fenofibrate and simvastatin versus 4.4% with statin monotherapy. 0.3% of patients receiving co-administration had clinically relevant increases in creatinine to values > 200 μmol/L.
Treatment should be interrupted when creatinine level is 50% above the upper limit of normal. It is recommended that creatinine is measured during the first 3 months after initiation of treatment and periodically thereafter.
Liver function: As with other lipid-lowering agents, increases have been reported in transaminase levels in some patients. In the majority of cases, these elevations were transient, minor and asymptomatic. It is recommended that 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 if AST (SGOT) and ALT (SGPT) levels increase to more than 3 times the upper limit of the normal range. When symptoms indicative of hepatitis occur (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. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridaemia, 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 very 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 ages above 70 years, personal or familial history of hereditary muscular disorders, renal impairment, hypothyroidism and high alcohol intake, may also 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 marked 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 co-prescription of fenofibrate with an 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 a close monitoring of potential muscle toxicity.
This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Pregnancy: Fenofibrate should not be administered to women who are pregnant.
Lactation: There are no data on the excretion of Fenofibrate and/or its metabolites into breast milk. It is therefore recommended that Fenofibrate should not be administered to women who are breast feeding.
The most common adverse effect of Fenofibrate therapy are gastrointestinal disturbances including anorexia, nausea, and gastric discomfort. Other adverse effects reported to occur less frequently include headache, dizziness, vertigo, fatigue, skin rashes, pruritus, photosensitivity, alopecia, impotence, anaemia, leukopenia, and thrombocytopenia. Raised serum-aminotransferase concentrations have occasionally been reported.
Fenofibrate is highly protein-bound and may displace other drugs from protein binding sites.
Interactions may also occur through changes in the activity of cytochrome P450 isoenzymes, particularly CYP3A4.
Fenofibrate may enhance the effects of oral anticoagulants; the dose of anticoagulant should be reduced when treatment with a fibrate is started, and then adjusted gradually if necessary. Recommendations vary; licensed product information for Fenofibrate suggests a reduction of upto 50% in the dosage of anticoagulant. The mechanism of the interaction is unclear; fibrates have been reported to displace warfarin from protein binding sites but other mechanisms are probably also involved.
Other drugs that may be displaced from plasma proteins by Fenofibrate include tolbutamide and other sulfonylurea antidiabetics, phenytoin, and in patients with hypoalbuminaemia, furosemide. The interaction with antidiabetics is complex since fibrates may alter glucose tolerance in diabetic patients. The dosage of antidiabetics may need adjusting during bezafibrate therapy.
There is an increased risk of myopathy if Fenofibrate are used with statins.
Fenofibrate may interact with ciclosporin, although reports have been conflicting.
However, nephrotoxicity associated with increased ciclosporin concentrations has been reported with bezafibrate and renal function should be monitored.
Cholestasis has been reported in a patient given Fenofibrate with raloxifene.
Store at temperatures not exceeding 30° C.
C10AB05 - fenofibrate ; Belongs to the class of fibrates. Used in the treatment of hyperlipidemia.
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