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Fenofibrate 200mg Capsules

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Fenofibrate 200 mg Capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 200 mg fenofibrate. For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Hard-gelatin capsule

Hard-gelatin capsule with opaque red-orange cap and body, filled with white to off-white powder, with small agglomerates, imprinted FM200 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

For doses not realisable/practicable with this strength, other strengths and pharmaceutical forms are available.

Adults

In adults, the recommended initial dose is one 200 mg capsule taken daily during a main meal.

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. 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

The safety and efficacy of fenofibrate 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

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.

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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.

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.

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.

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)

Allura red AC

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 blisters in the outer carton.

6.5    Nature and contents of container

Transparent PVC/PVdC - Aluminium blister packs:

Pack sizes of 1, 20, 28, 30, 50, 60, 90, 100 or 300 (10 x 30) 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 00289/1159

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

03/02/2010

10 DATE OF REVISION OF THE TEXT

16/06/2015