4.1. Therapeutic indications

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.

4.2. Posology and method of administration

Dietary measures initiated before therapy should be continued. Response to therapy should be monitored by determination of serum lipid values. If an adequate response has not been achieved after several months (e.g. 3 months), complementary or different therapeutic measures should be considered.

Posology:

Adults:

The recommended dose is 200 mg daily administered as one capsule of Lipantil® Micro 200mg.

The dose can be titrated up to 267 mg daily administered as one capsule of Lipantil® Micro 267 mg or 4 capsules of Lipantil® Micro 67 mg, if required. This maximum dose is not recommended in addition to a statin.

Special populations

Elderly patients (≥ 65 years old):

No dose adjustment is necessary. The usual dose is recommended, except for decreased renal function with estimated glomerular filtration rate < 60 mL/min/1.73 (see Patients with renal impairment).

Patients with renal impairment:

Fenofibrate should not be used if severe renal impairment, defined as eGFR <30 mL/min per 1.73 m2, is present. If eGFR is between 30 and 59 mL/min per 1.73 m2, the dose of fenofibrate should not exceed 100 mg standard or 67 mg micronized once daily. If, during follow-up, the eGFR decreases persistently to <30 mL/min per 1.73 m2, fenofibrate should be discontinued.

Hepatic impairment:

Lipantil® Micro 200 mg is not recommended for use in patients with hepatic impairment due to the lack of data.

Paediatric population:

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.

Method of administration:

Capsules should be swallowed whole during a meal.

4.3. Contraindications

- Hepatic insufficiency (including biliary cirrhosis and unexplained persistent liver function abnormality),

- Known gallbladder disease,

- Severe renal insufficiency (estimated glomerular filtration rate < 30 mL/min/1.73 m2),

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

- Known photoallergy or phototoxic reaction during treatment with fibrates or ketoprofen,

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Secondary causes of hyperlipidemia:

Secondary causes of hyperlipidemia, 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 considered. Secondary cause of hypercholesterolemia related to pharmacological treatment can be seen with diuretics, β-blocking agents, estrogens, progestogens, combined oral contraceptives, immunosuppressive agents and protease inhibitors. In these cases it should be ascertained whether the hyperlipidaemia is of primary or secondary nature (possible elevation of lipid values caused by these therapeutic agents).

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 are 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 AST (SGOT) and ALT (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), and diagnosis is confirmed by laboratory testing, fenofibrate therapy should be discontinued.

Pancreas:

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 with obstruction of the common bile duct.

Muscle:

Muscle toxicity, including rare cases of rhabdomyolysis, with or without renal failure 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 HMG-CoA reductase inhibitor or another fibrate should be reserved to patients with severe combined dyslipidaemia and high cardiovascular risk without any history of muscular disease and a close monitoring of potential muscle toxicity.

Renal function:

Lipantil Micro 200 mg is contraindicated in severe renal impairment (see section 4.3).

Lipantil Micro 200 mg 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 co-administered with statins. Elevations in serum creatinine were generally stable over time with no evidence for continued increases in serum creatinine with long term 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 co-administered fenofibrate and simvastatin versus 4.4% with statin monotherapy. 0.3% of patients receiving co-administration 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.

Excipients:

As this medicinal product 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 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

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.

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 or Other Fibrates

The risk of serious muscle toxicity is increased if a fibrate 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.

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-to-moderate 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.

Other

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.

4.6. Fertility, pregnancy and lactation

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). The potential risk for humans is unknown.

Therefore, Lipantil® Micro 200 mg 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.

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 Lipantil® Micro 200 mg.

4.7. Effects on ability to drive and use machines

Lipantil® Micro 200mg has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

The most commonly reported ADRs during Lipantil 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:

MedDRA system organ class

Common

≥1/100, <1/10

Uncommon

≥1/1,000, <1/100

Rare

≥1/10,000, <1/1,000

Very rare

<1/10,000 incl. isolated reports

Blood and lymphatic system disorders

Haemoglobin decreased

White blood cell count decreased

Immune system disorders

Hypersensitivity

Nervous system disorders

Headache

Vascular disorders

Thromboembolism (pulmonary embolism, deep vein thrombosis)*

Gastrointestinal disorders

Gastrointestinal signs and symptoms (abdominal pain, nausea, vomiting, diarrhoea, flatulence)

Pancreatitis*

Hepatobiliary disorders

Transaminases increased (see section 4.4)

Cholelithiasis (see section 4.4)

Hepatitis

Skin and subcutaneous tissue disorders

Cutaneous hypersensitivity (e.g. Rashes, pruritus, urticaria)

Alopecia

Photosensitivity reactions

Musculoskeletal, connective tissue and bone disorders

Muscle disorder (e.g. myalgia, myositis, muscular spasms and weakness)

Reproductive system and breast disorders

Sexual dysfunction

Investigations

Blood homocysteine level increased**

Blood creatinine increased

Blood urea increased

* 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).

** In the FIELD study 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 reported during clinical trials, the following side effects have been reported spontaneously during postmarketing use of Lipantil. 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)

- General disorders and administration site conditions: Fatigue

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 directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Only anecdotal cases of fenofibrate overdosage have been received. In the majority of cases no overdose symptoms were 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.