Fenofibrate 67 mg capsules.

Each capsule contains 67 mg of micronised fenofibrate.

For excipients, see 6.1.

Capsule, hard.

Yellow, hard gelatine capsule.

Fenofibrate 67 mg capsules are 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.

Adults

In adults, the recommended initial dose is 3 capsules taken daily taken in divided doses. Fenofibrate 67 mg 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.

The response to therapy should be monitored by determination of serum lipid values and the dosage may be altered within the range 2-4 capsules of Fenofibrate 67 mg daily.

Children

In children, the recommended dose is one capsule (67 mg) micronised fenofibrate/day/20 kg body weight.

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:

Fenofibrate 67 mg capsules are contraindicated 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.

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

Use during pregnancy and lactation (see section 4.6).

This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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 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.

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 (see section 4.8). 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

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 rabdomyolysis, including age above 70 years, personal or family history of hereditary muscular disorders, renal impairment, hypothyroidism and high alcohol intake, may also be at an increased risk of developing rabdomyolysis. 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).

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.

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 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.

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.

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 67 mg capsules should not be administered to women who are pregnant or are breast feeding.

No effect noted to date.

The adverse drug reactions are stated in the table below using the following convention:

Very common (>1/10); common (>1/100; <1/10); uncommon (>1/1,000); (<1/100); rare (>1/10,000); (<1/1,000); very rare (<1/10,000) including isolated reports.

* 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.

Serum Lipid Reducing Agents/Cholesterol and Triglyceride Reducers/Fibrates. ATC code: C10 AB 05.

Fenofibrate 67 mg capsule is a formulation containing 67 mg of micronized 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 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 hyperlipidaemias are still the subject of scientific discussion. Therefore the presumptive beneficial effect of Fenofibrate 67 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 placebocontrolled 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, nonfatal 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 2.3mmol/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 consistently show decreases in levels of LDL-cholesterol. HDL-cholesterol levels are frequently increased. Triglycerides 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 67 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.

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 15µg/ml for a daily dosage of 200 mg of micronised fenofibrate, equivalent to 3 capsules of 67 mg 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.

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.

Excipients: lactose monohydrate, pregelatinised starch, sodium lauryl sulphate, povidone, magnesium stearate.

Composition of the capsule shell: gelatin, titanium dioxide (E 171), quinoline yellow (E 104) and sunset yellow (E 110).

No effect noted to date.

30 months.

Do not store above 25°C.

Store in the original package.

Blister, PVC (250 μm)-PVDC (40 g/m²)/Alu (20 µm) and

Blister, PVC (250 μm)-PVDC (60 g/m²)/Alu (20 µm)

Pack sizes: 60, 90.

Not all pack sizes may be marketed.

Capsules should be swallowed whole with water.

Actavis UK Limited

(Trading style: Actavis)

Whiddon Valley

BARNSTAPLE

N Devon EX32 8NS

United Kingdom

PL 00142/0551

29 June 2004

Renewal – 03.08.2009

24.06.2011