Fenofibrate 67mg Capsules
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Fenofibrate 67 mg Capsules
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 67 mg fenofibrate. For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Hard-gelatin capsule
Hard-gelatin capsule with opaque yellow cap and body, filled with white to off-white powder, with small agglomerates, imprinted FM67 on both cap and body
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.
4.2 Posology and method of administration
For oral administration
Adults
In adults, the recommended initial dose is three 67 mg capsules taken daily in divided doses.
Fenofibrate should always be taken with food, because it is less well absorbed from an empty stomach. Dietary measures instituted before therapy should be continued.
The response to therapy should be monitored by determination of serum lipid values. The dosage may be altered within the range of two to four 67 mg capsules daily. Rapid reduction of serum lipid levels usually follows fenofibrate treatment, but treatment should be discontinued if an adequate response has not been achieved within three months.
Children
In children, the recommended dose is one capsule (67 mg) micronised fenofibrate/day/20 kg body weight (see section 4.4).
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 |
Two 67 mg capsules |
|
<20 |
One 67 mg capsule |
Hepatic disease
Patients with hepatic disease have not been studied.
4.3 Contraindications
- Hypersensitivity to fenofibrate or to any of the excipients
- Severe liver or renal dysfunction
- Gallbladder disease
- Biliary cirrhosis
- Known photoallergy or phototoxic reaction during treatment with fibrates or ketoprofen
- Chronic or acute pancreatitis with the exception of acute pancreatitis due to severe hypertriglyceridaemia
4.4 Special warnings and precautions for use
In renal impairment
In renal dysfunction the dose of fenofibrate may need to be reduced, depending on the rate of creatinine clearance (see section 4.2). Dose reduction should be considered in elderly patients with impaired renal function.
Liver _ function
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 be monitored every 3 months during the first 12 months of treatment. Attention should be paid to patients who develop increases in transaminase levels and therapy should be discontinued if ASAT and ALAT levels increase to more than 3 times the upper limit of the normal range or 100 IU.
Pancreatitis
Pancreatitis has been reported in patients taking fenofibrate (see sections 4.3 and 4.8). This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridaemia, a direct effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation, resulting in the obstruction of the common bile duct.
Myopathy
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.
Patients with pre disposing factors for myopathy and/or rhabdomyolysis, including age above 70 years, personal or familial history of hereditary muscular disorders, renal impairment, hypothyroidism and high alcohol intake, may be at increased risk of developing rhabdomyolysis. For these patients, the putative benefits and risks of fenofibrate therapy should be carefully weighed up.
The risk of muscle toxicity may be increased if fenofibrate 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 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).
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 measurement be considered during the first three months after initiation of treatment.
In children
Only an hereditary disease (familial hyperlipidaemia) justifies early treatment, and the precise nature of the hyperlipidaemia must be determined by genetic and laboratory investigations. It is recommended to begin treatment with controlled dietary restrictions for a period of at least 3 months. Proceeding to medicinal treatment should only be considered after specialist advice and only in severe forms with clinical signs of atherosclerosis and/or xanthomata and/or in cases where patients suffer from atherosclerotic cardiovascular disease before the age of 40.
4.5 Interaction with other medicinal products and other forms of interaction
Oral anti-coagulants
Fenofibrate enhances oral anti-coagulant effect and may increase the risk of bleeding. In patients receiving oral anti-coagulant therapy, the dose of anti-coagulant 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).
Ciclosporin
Some severe cases of reversible renal function impairment have been reported during concomitant administration of fenofibrate and ciclosporin. 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.
4.6 Fertility, 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. Therefore, fenofibrate should only be used during pregnancy after a careful benefit/risk assessment.
There are no data on the excretion of fenofibrate and/or its metabolites into breast milk. Consequently it should not be used in nursing mothers.
4.7 Effects on ability to drive and use machines
Fenofibrate has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
Estimated frequencies of events are ranked according to the following convention: common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).
Investigations
Rare: Increases in serum creatinine and urea, which are generally slight
Blood and lymphatic system disorders
Rare: Slight decrease in haemoglobin and leukocytes
Nervous system disorders
Rare: Headache, sexual asthenia
Ear and labyrinth disorders Rare: Vertigo
Respiratory, thoracic and mediastinal disorders Very rare: Interstitial pneumopathies
Gastrointestinal disorders
Common: Digestive, gastric or intestinal disorders (abdominal pain, nausea,
vomiting, diarrhoea, and flatulence) moderate in severity Uncommon: Pancreatitis*
Skin and subcutaneous tissue disorders
Uncommon: Reactions such as rashes, pruritus, urticaria or photosensitivity
reactions
Rare: Alopecia
Very rare: Cutaneous photosensitivity with erythema, vesiculation or nodulation
on parts of the skin exposed to sunlight or artificial UV light (e.g. sun lamp) in individual cases (even after many months of uncomplicated use)
Musculoskeletal and connective tissue disorders
Rare: Muscle toxicity (diffuse myalgia, myositis, muscular cramps and
weakness)
Very rare: Rhabdomyolysis.
Vascular disorders
Uncommon: Thromboembolism (pulmonary embolism, deep vein thrombosis)*
General disorders Rare: Fatigue
Hepatobiliary disorders
Common: Moderately elevated levels of serum transaminases may be found in
some patients but rarely interfere with treatment (see section 4.4).
Uncommon: Development of gallstones has been reported.
Very rare: 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 section 4.4).
* In the FIELD-study, a randomised placebo-controlled trial performed in 9,795 patients with type 2 diabetes mellitus, a statistically significant increase in pancreatitis cases was observed in patients receiving fenofibrate versus patients receiving placebo (0.8% versus 0.5%; p = 0.031). In the same study, a statistically significant increase was reported in the incidence of pulmonary embolism (0.7% in the placebo group versus 1.1% in the fenofibrate group; p = 0.022) and a statistically non-significant increase in deep vein thromboses (placebo: 1.0 % [48/4,900 patients] versus fenofibrate 1.4% [67/4,895 patients]; p = 0.074).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
No case of overdose has been reported. No specific antidote is known. If overdose is suspected, symptomatic treatment and appropriate supportive measures should be insituted as required. Fenofibrate cannot be eliminated by haemodialysis.
Pharmacotherapeutic classification: Lipid-modifying agents, plain; fibrates
ATC code: C10A B05
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 increased serum lipid levels and an increased risk of coronary heart disease. The control of such dyslipidaemia forms the rationale for treatment with fenofibrate. However, the possible beneficial and adverse long-term consequences of agents used in the hyperlipidaemias are still the subject of scientific discussion. Therefore the presumptive beneficial effect of fenofibrate on cardiovascular morbidity and mortality is as yet unproven.
Studies with fenofibrate consistently show decreases in levels of LDL-cholesterol and VLDL-cholesterol. HDL-cholesterol levels are frequently increased. Triglyceride levels are also reduced. This results in a decrease in the ratio of low and very low density lipoproteins to high density lipoproteins, which has been correlated with a decrease in atherogenic risk in epidemiological studies. 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 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.
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.
Limited paediatric data are available. The effects of fenofibrate in dyslipidemic children have been studied in two small clinical trials and in an open long-term surveillance registry with 76 hypercholesterolemic children aged 3 to 18 years receiving fenofibrate for 1 to 11 years. However, due to limited data and methodological insufficiencies, no definitive conclusion can be drawn on the use of fenofibrate in dyslipidemic children.
Adverse events similar to those observed in adults have been reported in children: leucopenia, liver function test abnormal, rhabdomyolysis, renal failure, hepatitis, jaundice, myositis and rhabdomyolysis.
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.
The mean plasma concentration is 15 microgrammes/ml for a daily dosage of 200 mg of micronised fenofibrate, equivalent to three 67 mg capsules.
Steady state levels are observed throughout continuous treatments.
Fenofibric acid is highly bound to plasma albumin; it can displace antivitamin K compounds from protein binding sites and may 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
Capsule contents Sodium laurilsulfate Povidone (K-25)
Maize Starch, pregelatinised Crospovidone (Type A)
Croscarmellose sodium
Sodium starch glycolate (potato origin)
Colloidal silica anhydrous Sodium stearyl fumarate
Capsule shell Gelatin
Titanium dioxide (E171)
Quinoline yellow Iron oxide yellow (E172)
Edible Printing ink containing shellac, iron oxide black, propylene glycol.
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package in order to protect from light. Keep the blister in the outer carton.
6.5 Nature and contents of container
Transparent PVC/PVdC - Aluminium blister packs:
Pack sizes of 1, 28, 30, 50, 60, 84, 90 or 100 hard-gelatin capsules. Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Teva UK Limited,
Brampton Road,
Hampden Park,
Eastbourne,
East Sussex,
BN22 9AG
8 MARKETING AUTHORISATION NUMBER(S)
PL 00289/1158
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION 03/02/2010
10 DATE OF REVISION OF THE TEXT
16/06/2015