Fibrates.

Fenofibrate

Lipantil Micro 67 mg: yellow capsules. Lipantil Micro 200: orange capsules. Lipantil Micro 267: orange/ivory hard gelatin capsules.

Capsules, fenofibrate (micronised) 67mg , 200mg , 267mg .

Lipantil^® Micro 200mg 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.

- Mixed hyperlipidaemia in patients at high cardiovascular risk in addition to a statin when triglycerides and HDL cholesterol are not adequately controlled.

Adults

The recommended initial dose is one capsule taken daily during a main meal. In elderly patients without renal impairment, the normal adult dose is recommended. Since it is less well absorbed from an empty stomach, Lipantil Micro 200 should always be taken with food. Dietary restrictions instituted before therapy should be continued.

Adults

The recommended initial dose is one capsule taken daily during a main meal. In elderly patients without renal impairment, the normal adult dose is recommended. Since it is less well absorbed from an empty stomach, Lipantil Micro 200 should always be taken with food. Dietary restrictions instituted before therapy should be continued.

Adults

The recommended initial dose is one capsule taken daily during a main meal. In elderly patients without renal impairment, the normal adult dose is recommended. Since it is less well absorbed from an empty stomach, Lipantil Micro 200 should always be taken with food. Dietary restrictions instituted before therapy should be continued.

Lipantil Micro 200 is contra-indicated in children, in patients with severe liver dysfunction, gallbladder disease, biliary cirrhosis, severe renal disorders 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

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. In this case, Lipantil Micro 67 (micronised fenofibrate) should be used, e.g. 2 capsules of Lipantil Micro 67 daily for creatinine clearance levels of <60 ml/min and 1 capsule of Lipantil Micro 67 daily for creatinine clearance levels of <20 ml/min.

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)

Use of Lipantil Micro 67 is also to be preferred in elderly patients with renal impairment where dosage reduction may be required.

Liver function abnormalities

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 sections 4.3 and 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 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).

For patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption: although the amount of lactose contained in Lipantil Micro 200 mg is low, caution should be exercised in these patients (as no study has been formally conducted in this special population).

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.

There is currently no evidence to suggest that fenofibrate affects the pharmacokinetics of simvastatin.

Cyclosporin

Some severe cases of reversible renal function impairment have been reported during concomitant administration of fenofibrate and cyclosporin. 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.

Adverse reactions observed during Lipantil Micro 200 treatment are not very frequent (2 - 4 % of cases): 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).

Fournier

(POM)

23 November 2011