FENOFIBRATE Tablet Ref.[51352] Active ingredients: Fenofibrate

Liver function

As with other lipid lowering agents, 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 increase 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 hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through bilary tract stone or sludge formation, resulting in the obstruction of the common bile duct.

Muscle

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 old, 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.

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.

Renal function

Fenofibrate is contraindicated in severe renal impairment (see section 4.3).

Fenofibrate should be used with caution in patients with mild to moderate renal insufficiency. Dose should be adjusted in patients whose estimated glomerular filtration rate is 30 to 59 mL/min/1.73 m² (see section 4.2).

Reversible elevations in serum creatinine have been reported in patients receiving Fenofibrate monotherapy or coadministered with statins. Elevations in serum creatinine were generally stable over time with no evidence for continued increases in serum creatinine with long therapy and tended to return to baseline following discontinuation of treatment.

During clinical trials, 10% of patients had a creatinine increase from baseline greater than 30 µmol/L with coadministered Fenofibrate and simvastatin versus 4.4% with statin monotherapy. 0.3% of patients receiving coadministration had clinically relevant increases in creatinine to values >200 µmol/L.

Treatment should be interrupted when creatinine level is 50% above the upper limit of normal.

It is recommended that creatinine is measured during the first 3 months after initiation of treatment and periodically thereafter.

Other warnings

For hyperlipidaemic patients taking oestrogens or contraceptives containing oestrogens it should be ascertained whether the hyperlipidaemia is of primary or secondary nature (possible elevation of lipid values caused by oral oestrogen).

As fenofibrate 160 mg tablets contains lactose, patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicine contains less than 1mmol sodium (23mg) per tablet, that is to say essentially ‘sodium-free’.

Oral anticoagulants

Fenofibrate enhances oral anticoagulant effect and may increase risk of bleeding. It is recommended that the dose of anticoagulants is reduced by about one third at the start of treatment and then gradually adjusted if necessary according to INR (International Normalised Ratio) monitoring. Therefore, this combination is not recommended.

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.

HMG-CoA reductase inhibitors and other fibrates

The risk of serious muscle toxicity I 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)

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. Therefore, fenofibrate 160mg tablets should only be used after a careful benefit/risk assessment.

There are no data on the excretion of fenofibrate and/or its metabolites into breast milk. Consequently, fenofibrate 160mg tablets should not be used in nursing mothers.

No effect noted.

The frequencies of adverse events are ranked according top the following: 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

Gastrointestinal

Common: Digestive, gastric or intestinal disorders (abdominal pain, nausea, vomiting, diarrhoea, and flatulence) moderate in severity

Uncommon: Pancreatitis*

Hepato-biliary disorders

Common: Moderately elevated levels of serum transaminases (see Special Precautions for use).

Uncommon: Development of gallstones

Very rare: Episodes of hepatitis. 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).

Cardiovascular system

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

Skin and subcutaneous tissue disorder

Uncommon: rashes, pruritus, urticaria or photosensitivity reactions.

Rare: alopecia

Very rare: cutaneous photosensitivity with erythema, vesiculation or nodulation on parts of the skin expose to sunlight or artificial light (e.g. sunlamp) in individual cases (even after many months of uncomplicated use)

Musculoskeletal, connective tissue and bone disorders

Rare: diffuse myalgia, myositis, muscular cramps and weakness

Not known: rhabdomyolysis

Blood and lymphatic system disorders

Rare: decrease in haemoglobin and leukocytes

Nervous system disorder

Rare: sexual asthenia

Respiratory, thoracic and mediastinal disorders

Not known: interstitial pneumopathies

Investigation

Uncommon: increases in serum creatinine and urea

^* In the FIELD study, a randomised placebo controlled trial performed in 9795 patients with type II diabetes mellitus, a statistically significant increase in pancreatitis cases was observed in patients receiving fenofibrate verses patients receiving placebo. (0.8% versus 05% 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).

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.

Not applicable.