Fenofibrate 267mg Capsules

Each capsule contains 267mg fenofibrate.

For excipients, see 6.1

Capsules, hard

Green and caramel, hard gelatin capsules

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.

Fenofibrate should only be used in patients in whom a full investigation has been performed to define their abnormality. Other risk factors, such as hypertension and smoking, may also require management.

Adults

The initial recommended dose is one capsule of fenofibrate 200mg taken daily with food. However, in patients with severe dyslipidaemia, an increased dose of 267 mg, is recommended. 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.

Children

This dosage is not recommended in children.

Elderly

In elderly patients without renal impairment, the normal adult dose is recommended.

Renal Impairment

In patients with renal impairment, the dosage may need to be reduced depending on rate of creatinine clearance.

Fenofibrate 267mg Capsules is therapeutically equivalent to LIPANTIL^®267 Capsules (micronised fenofibrate) or 400 mg of the standard formulation (non-micronised).

Fenofibrate 267mg is contraindicated in children, 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.

Use during pregnancy and lactation (see section 4.6).

Chronic or acute pancreatitis with the exception of acute pancreatitis due to severe hypertriglyceridemia

Secondary causes of dyslipidaemia, 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.

Response to therapy should be monitored by determination of serum lipid values (total cholesterol, LDL-C, triglycerides). If an adequate response has not been achieved after several months (e.g. 3 months) complementary or different therapeutic measures should be considered.

Renal function

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.

It is recommended that creatinine is measured during the first three months after initiation of treatment and thereafter periodically. Treatment should be interrupted in case of an increase in creatinine levels> 50% of (upper limit of normal).

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 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. 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 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 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).

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 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 he 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.

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.

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.

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.

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.

No effect noted to date.

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.

Uncommon: Pancreatitis*

Cardiovascular system

Uncommon: Thromboembolism (pulmonary embolism, deep vein thrombosis)*

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.

* In the FIELD-study, a randomized placebo-controlled trial performed in 9795 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 % [48/4900 patients] versus fenofibrate 1.4% [67/4895 patients]; p = 0.074).

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.

Pharrmacotherapeutic group: Serum Lipid Reducing Agents/Cholesterol and Triglyceride Reducers/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 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 Apoproteins A-I A-Il 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 dyslipidaemias forms the rationale for treatment with fenofibrate. However, the possible beneficial and adverse long–term consequences of drugs used in the management of dyslipidaemias 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. 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.

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 15 µg / ml for a daily dosage of 200 mg 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 anticoagulant 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.

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.

Lauroyl macrogolglycerides

Hydroxypropylcellulose

Macrogol

Sodium starch glycolate

Composition of the capsule shell:

Gelatin

Titanium dioxide (E 171)

Yellow iron oxide (E172)

Red iron oxide (E172)

Black iron oxide (E172)

Indigo carmine (E132)

Not applicable

3 years

There are no special storage instructions.

PVC aluminium foil blisters

Packs of 28 and 30 capsules. Not all pack sizes may be marketed

Not applicable

Winthrop Pharmaceuticals (UK) Limited

One Onlsow Street

Guildford

Surrey

GU1 4YS

United Kingdom

PL 17780/0137

07-07-2010

27-05-11