Fenofibrate 267mg Capsules
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Fenofibrate 267mg Capsules
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 267mg micronised fenofibrate.
For a full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Hard Capsule
Ivory yellow cap/green body, self locked hard gelatin capsules of size ‘0 elongated’ imprinted with ‘FB267’ on cap and body containing white to off white granular powder.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Fenofibrate is indicated as an adjunct to diet and other non-pharmacological treatment (e.g. exercise, weight reduction) for the following:
- Treatment of severe hypertriglyceridaemia with or without low HDL cholesterol.
- Mixed hyperlipidaemia when a statin is contraindicated or not tolerated.
- Mixed hyperlipidaemia in patients at high cardiovascular risk in addition to a statin when triglycerides and HDL cholesterol are not adequately controlled.
4.2 Posology and method of administration
Adults: The initial recommended dose is one capsule of Fenofibrate 267mg Capsules taken daily with food. However, in patients with severe dyslipidaemia, an increased dose of 267mg (Fenofibrate 267mg Capsules), is recommended. Fenofibrate 267mg Capsules should always be taken with food, because it is less well absorbed from an empty stomach. Dietary measures instituted before therapy should be continued.
Paediatric population:
The safety and efficacy of fenofibrate in children in children and adolescents younger than 18 years has not been established. No data are available. Therefore, the use of fenofibrate is not recommended in paediatric subjects under 18 years
Elderly: In elderly patients without renal impairment, the normal adult dose is recommended.
Renal impairment: In renal dysfunction, the dosage may need to be reduced depending on the rate of creatinine clearance, for example:
|
Creatinine clearance (ml/min) |
Dosage |
|
<60 |
One Fenofibrate Micro 140mg capsule |
|
<20 |
One Fenofibrate Micro 67mg capsule |
4.3 Contraindications
Fenofibrate is contra-indicated in patients with severe liver or renal dysfunction, gallbladder disease, biliary cirrhosis and in patients hypersensitive to fenofibrate or any component of this medication, known photoallergy or phototoxic reaction during treatment with fibrates or ketoprofen.
See also section 4.6 (Pregnancy and lactation)
4.4 Special warnings and precautions for use
Renal Impairment: In renal dysfunction the dose of fenofibrate may need to be reduced, depending on the rate of creatinine clearance. In this case, Fenofibrate 67mg Capsules (micronised fenofibrate) should be used, e.g. 2 Fenofibrate 67mg Capsules daily for creatinine clearance levels of <60ml/min and 1 Fenofibrate 67mg Capsule daily for creatinine clearance levels of <20ml/min.
Use of Fenofibrate 267mg Capsules is also to be preferred in elderly patients with renal impairment where dosage reduction may be required.
Serum Transaminases: Moderately elevated levels of serum transaminases may be found in some patients but rarely interfere with treatment. However, it is recommended that serum transaminases should be monitored every three months during the first twelve months of treatment. Treatment should be interrupted in the event of ALAT (SGPT) or ASAT (SGOT) elevations to more than 3 times the upper limit of the normal range or more than one hundred international units.
Pancreatitis: 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.
Myopathy: Patients with pre-disposing factors for rhabdomyolysis, including renal impairment, hypothyroidism and high alcohol intake, may be at an increased risk of developing rhabdomyolysis.
Muscle toxicity, including very rare cases of rhabdomyolysis, 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. 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 preexisting muscular disease. Consequently, the co-prescription of fenofibrate with a statin should be reserved to patients with severe combined dyslipidaemia and high cardiovascular risk without any history of muscular disease. This combination therapy should be used with caution and patients should be monitored closely for signs of muscle toxicity.
For hyperlipidaemic patients taking oestrogens or contraceptives containing oestrogen it should be ascertained whether the hyperlipidaemia is of primary or secondary nature (possible elevation of lipid values caused by oral oestrogen).
4.5 Interaction with other medicinal products and other forms of interaction
Oral anti-coagulants
Fenofibrate enhances oral anti-coagulant effect and may increase risk of bleeding. In patients receiving oral anti-coagulant therapy, the dose of anticoagulant should be reduced by about one-third at the commencement of treatment and then gradually adjusted if necessary according to INR (International Normalised Ratio) monitoring.
HMG-CoA reductase inhibitors or Other Fibrates
The risk of serious muscle toxicity is increased if fenofibrate is used concomitantly with HMG-CoA reductase inhibitors or other fibrates. Such combination therapy should be used with caution and patients monitored closely for signs of muscle toxicity (see section 4.4).
There is currently no evidence to suggest that fenofibrate affects the pharmacokinetics of simvastatin.
Cyclosporin
Some severe cases of reversible renal function impairment have been reported during concomitant administration of fenofibrate and cyclosporin. The renal function of these patients must therefore be closely monitored and the treatment with fenofibrate stopped in the case of severe alteration of laboratory parameters.
Other
No proven clinical interactions of fenofibrate with other drugs have been reported, although in vitro interaction studies suggest displacement of phenylbutazone from plasma protein binding sites. In common with other fibrates, fenofibrate induces microsomal mixed-function oxidases involved in fatty acid metabolism in rodents and may interact with drugs metabolised by these enzymes.
4.6 Pregnancy and lactation
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 section 5.3). The potential risk for humans is unknown. 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 pregnant or are breast feeding.
4.7 Effects on ability to drive and use machines
No effect noted to date
4.8 Undesirable effects
Fenofibrate is generally well tolerated. Adverse reactions observed during fenofibrate treatment are not very frequent; they are generally minor, transient and do not interfere with treatment.
The most commonly reported adverse reactions include:
Gastrointestinal: Digestive, gastric or intestinal disorders (abdominal pain, nausea, vomiting, diarrhoea, and flatulence) moderate in severity.
Skin: Reactions such as rashes, pruritus, urticaria or photosensitivity reactions; in individual cases (even after many months of uncomplicated use) cutaneous photosensitivity may occur with erythema, vesiculation or nodulation on parts of the skin exposed to sunlight or artificial UV light (e.g. sun lamp). Neurological disorders: Headache General disorders: Fatigue Disorders of the ear: Vertigo Less frequently reported adverse reactions:
Liver: Moderately elevated levels of serum transaminases may be found in some patients but rarely interfere with treatment (see also section 4.4). Episodes of hepatitis have been reported very rarely. When symptoms (e.g. jaundice, pruritus) indicative of hepatitis occur, laboratory tests are to be conducted for verification and fenofibrate discontinued, if applicable (see Special Warnings). Development of gallstones has been reported.
Muscle: As with other lipid lowering agents, cases of muscle toxicity (diffuse myalgia, myositis, muscular cramps and weakness) and very rare cases of rhabdomyolysis have been reported. These effects are usually reversible when the drug is withdrawn (see Special Warnings).
In rare cases, the following effects are reported: Sexual asthenia and alopecia. Increases in serum creatinine and urea, which are generally slight, and also a slight decrease in haemoglobin and leukocytes may be observed. Very rare cases of interstitial pneumopathies have been reported.
4.9 Overdose
No case of overdosage has been 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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC code: C10 AB 05
Serum Lipid Reducing Agents/Cholesterol and Triglyceride Reducers/ Fibrates.
Fenofibrate 267mg Capsules is a formulation containing 267mg of micronised fenofibrate; the administration of this product results in effective plasma concentrations identical to those obtained with 3 capsules of 67mg 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 type 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. Activation of PPARa also induces an increase in the synthesis of Apoproteins 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 dyslipidaemia forms the rationale for treatment with Fenofibrate Micro 267. 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 Micro 267 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 (<34mg/dl or 0.88 mmol/L) and highest tertile of TG (>204mg/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 are 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 disease. Fenofibrate 267mg Capsules has 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.
5.2 Pharmacokinetic properties
Absorption
The unchanged compound is not recovered in the plasma. Fenofibric acid is the major plasma metabolite. Peak plasma concentration occurs after a mean period of 5 hours following dosing.
Mean plasma concentration is 15pg/ml for a daily dosage of 200mg of micronised fenofibrate.
Steady state levels are observed throughout continuous treatments.
Fenofibric acid is highly bound to plasma albumin: it can displace antivitamin K compounds from the protein binding sites and potentiate their anti-coagulant effect.
Plasma half-life
The plasma half-life of elimination of fenofibric acid is approximately 20 hours.
Metabolism and excretion
The product is mainly excreted in the urine: 70% in 24 hours and 88% in 6 days, at which time total excretion in urine and faeces reaches 93%. Fenofibrate is mainly excreted as fenofibric acid and its derived glucuroconjugate.
Kinetic studies after administration of repeated doses show the absence of accumulation of the product.
Fenofibric acid is not eliminated during haemodialysis.
5.3 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.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Intragranular
Sodium lauryl sulphate
Lactose
Pregelatinised starch Crospovidone
Extragranular Crospovidone Pregelatinised starch Talc
Colloidal anhydrous silica Magnesium stearate
Capsule
Gelatin
Titanium dioxide (E171)
FD & C blue No. 2 (E132)
Yellow iron oxide (E172)
Printing Ink Shellac glaze Iron oxide black Propylene glycol
6.2 Incompatibilities
Not applicable
6.3 Shelf life
2 years
6.4 Special precautions for storage
Store in the original package Do not store above 25°C
6.5 Nature and contents of container
Blister strip of clear transparent PVC film coated with PVdC on the inner side with a backing of aluminium foil
Pack size of 10, 14, 20, 28, 30, 56, 60 or 90 capsules. Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirement
7 MARKETING AUTHORISATION HOLDER
Ranbaxy (UK) Limited Building 4, Chiswick Park 566 Chiswick High Road London, W4 5YE United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 14894/0369
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
02/01/2007
10 DATE OF REVISION OF THE TEXT
13/07/2012