LIPANTHYL Penta Film-coated tablet Ref.[50342] Active ingredients: Fenofibrate

Secondary causes of hyperlipidemia: Secondary cause of hypercholesterolemia, 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.

For hyperlipidaemic patients taking estrogens 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).

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 and thereafter periodically. Attention should be paid to patients who develop increase in transaminase levels and therapy should be discontinued if ASAT and ALAT (SGPT) levels increase to more than 3 times the upper limit of the normal range. When symptoms indicative of hepatitis occur (e.g. jaundice, pruritus), laboratory tests are to be conducted for verification and diagnosis is confirmed by laboratory testing, discontinuation of fenofibrate therapy should be considered.

Pancreatitis: Pancreatitis has been reported in patients taking fenofibrate (see sections Contraindications and Undesirable effects). This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with 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 case of hypoalbuminemia and previous renal insufficiency.

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.

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 upper 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 (statins), especially in cases of pre-existing muscular disease. Consequently, the co-prescription of fenofibrate with a statin or another fibrate should be reserved to patients with severe combined dyslipidaemia and high cardiovascular risk withoutany 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: Treatment should be interrupted in case of an increase in creatinine levels >50% and ULN (upper limit of normal). It is recommended that creatinine is measured during the first three months after initiation of treatment and thereafter periodically (for dose recommendations, see section 4.2 Posology and method of administration).

Excipients: This medicinal product contains lactose, therefore patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicinal product contains sucrose, therefore patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

LIPANTHYL PENTA 145, film-coated tablet should not be taken in patients allergic to soybean lecithin or related products due to the risk of hypersensitivity reactions.

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.

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.

HMG-CoA reductase inhibitors and other fibrates: The risk of serious muscle toxicity is increased if a fibrate is used concomitantly with HMG-CoA reductase inhibitors or other fibrates.

Combination therapy with HMG-CoA reductase inhibitors should be used with caution and patients monitored closely for signs of muscle toxicity (See section 4.4 Special warnings and precautions for use).

Glitazones: Some cases of reversible paradoxical reduction of HDL-cholesterol have been reported during concomitant administration of fenofibrate and glitazones. Therefore, it is recommended to monitor HDL-cholesterol if one of these components is added to the other and stopping of either therapy if HDL-cholesterol is too low.

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-tomoderate 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.

Fertility

Reversible effects on fertility have been observed in animals (see section 5.3). There are no clinical data on fertility from the use of LIPANTHYL PENTA 145.

Pregnancy

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 Preclinical safety data). The potential risk for humans is unknown. Therefore, fenofibrate should only be used during pregnancy after a careful benefit/risk assessment.

Lactation

It is unknown whether fenofibrate and/or its metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. Therefore fenofibrate should not be used during breast-feeding.

LIPANTHYL PENTA 145, film-coated tablet has no influence on the ability to drive and use machines.

The most commonly reported ADRs during LIPANTHYL PENTA 145 therapy are digestive, gastric or intestinal disorders.

The following undesirable effects have been observed during placebo-controlled clinical trials (n=2344) with the below indicated frequencies:

^* 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).
^** 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 nonsignificant increase in deep vein thrombosis (placebo: 1.0% [48/4900 patients] versus fenofibrate 1.4% [67/4895 patients]; p = 0.074).
^*** the average increase in blood homocysteine level in patients treated with fenofibrate was 6.5 μmol/L, and was reversible on discontinuation of fenofibrate treatment. The increased risk of venous thrombotic events may be related to the increased homocysteine level. The clinical significance of this is not clear.

In addition to those events reporting during clinical trials, the following side effects have been reported spontaneously during postmarketing use of LIPANTHYL PENTA 145. A precise frequency cannot be estimated from the available data and is therefore classified as “not known”.

Respiratory, thoracic and mediastinal disorders: Interstitial lung disease

Musculoskeletal, connective tissue and bone disorders: Rhabdomyolysis

Hepatobiliary disorders: jaundice, complications of cholelithiasis (e.g. cholecystitis, cholangitis, biliary colic).

Skin and Subcutaneous Tissue Disorders: severe cutaneous reactions (e.g. erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis).

Nervous system disorders: Fatigue.

Not applicable.