Mibezit 10,0 mg TABLET

Primary hypercholesterolaemia

MIBEZIT, administered with an HMG-CoA reductase inhibitor (statin) or alone, is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol (total-C) and low-density lipoprotein cholesterol (LDL-C), in patients with primary (heterozygous familial and non-familial) hypercholesterolaemia.

Homozygous Familial Hypercholesterolaemia (HoFH)

MIBEZIT administered with a statin, is indicated for the reduction of elevated total-C and LDL-C levels in patients with HoFH.

Posology

The patient should be on an appropriate lipid-lowering diet and weight loss program where indicated and should continue on this diet during treatment with MIBEZIT. The recommended dose is 10 mg once daily, used alone, with a statin, or with fenofibrate. MIBEZIT can be administered at any time of the day, with or without food.

Special populations

Elderly population

No dosage adjustment is required for elderly patients (see section 5.1)

Hepatic impairment

No dosage adjustment is required in patients with mild hepatic insufficiency (Child Pugh score 5 to 6). Treatment with ezetimibe is contra-indicated in patients with moderate (Child Pugh score 7 to 9) or severe (Child Pugh score greater than 9) liver dysfunction due to unknown effects (See section 4.3).

Co-administration with bile acid sequestrants

Dosing should occur either 2 or more hours before or 4 or more hours after administration of a bile acid sequestrant.

Paediatric population

Children 10 years of age or older: No dosage adjustment is required (see section 5.1)

Children under 10 years of age: No clinical data on safety and efficacy are available, therefore treatment is contra-indicated.

Method of administration

MIBEZIT is for oral use and can be administered at any time of the day, with or without food.

• Hypersensitivity to any ezetimibe or component of MIBEZIT.
• Pregnancy, as no clinical data on exposed pregnancies is available. Lactation, as it is not known whether ezetimibe is excreted into human breast milk.
• Children below the age of 10 years.
• Moderate to severe hepatic impairment (Child Pugh score 7 or more). (When MIBEZIT is to be administered with a statin, please refer to the Professional Information for that particular medication.)

Liver enzymes

In controlled co-administration trials in patients receiving 10 mg tablet with a statin, consecutive transaminase elevations (u2265 3 X the upper limit of normal [ULN]) have been observed. When MIBEZIT is co-administered with a statin, liver function tests should be performed at initiation of therapy and according to the recommendations of the statin (see section 4.8).

Skeletal muscle

In post-marketing experience with MIBEZIT cases of myopathy and rhabdomyolysis have been reported. If myopathy is suspected based on muscle symptoms or is confirmed by a creatine phosphokinase (CPK) level > 10 times the ULN, MIBEZIT, any statin, and any of these other medicines that the patient is taking concomitantly should be immediately discontinued. All patients starting therapy with MIBEZIT should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness (see section 4.8).

Hepatic impairment

Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic impairment, MIBEZIT is not recommended (see section 5.2).

Paediatric population

Efficacy and safety of MIBEZIT co-administered with simvastatin in patients 10 to 17 years of age with heterozygous familial hypercholesterolaemia have been evaluated in a controlled clinical trial in adolescent boys (Tanner Stage II or above) and in girls who were at least one year post-menarche. In this limited controlled study, there was generally no detectable effect on growth or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls. However, the effects of ezetimibe for a treatment period > 33 weeks on growth and sexual maturation have not been studied (see sections 4.2 and 4.8). The safety and efficacy of MIBEZIT 10 mg co-administered with doses of simvastatin above 40 mg daily have not been studied in paediatric patients 10 to 17 years of age. The safety and efficacy of MIBEZIT co-administered with simvastatin have not been studied in paediatric patients < 10 years of age (see sections 4.2 and 4.8). The long-term efficacy of therapy with MIBEZIT in patients below 17 years of age to reduce morbidity and mortality in adulthood has not been studied.

Fibrates

The safety and efficacy of MIBEZIT administered with fibrates have not been established. If cholelithiasis is suspected in a patient receiving MIBEZIT and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued and alternative lipid-lowering therapy should be considered (see sections 4.5 and 4.8).

Anticoagulants

If MIBEZIT is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalised Ratio (INR) should be appropriately monitored (see section 4.5).

Excipients: lactose intolerance

This medicine contains lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take MIBEZIT.

Antacids

Concomitant antacid administration decreased the rate of absorption of ezetimibe but had no effect on the bioavailability of ezetimibe. This decreased rate of absorption is not considered clinically significant.

Cholestyramine

Concomitant cholestyramine administration decreased the mean area under the curve (AUC) of total ezetimibe (ezetimibe + ezetimibe-glucuronide) approximately 55 %. The incremental low-density lipoprotein cholesterol (LDL-C) reduction due to adding MIBEZIT to cholestyramine may be lessened by this interaction (see section 4.2).

Fibrates

In patients receiving fenofibrate and MIBEZIT, medical practitioners should be aware of the possible risk of cholelithiasis and gallbladder disease (see sections 4.4 and 4.8). If cholelithiasis is suspected in a patient receiving MIBEZIT and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued (see section 4.8).

Concomitant fenofibrate or gemfibrozil administration modestly increased total ezetimibe concentrations (approximately 1,5- and 1,7-fold respectively). Co-administration of MIBEZIT with other fibrates has not been studied. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. A lithogenic risk associated with the therapeutic use of this medicine cannot be ruled out.

Statins

No clinically significant pharmacokinetic interactions were seen when MIBEZIT was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, or rosuvastatin.

Ciclosporin

In a study of post-renal transplant patients with creatinine clearance of > 50 mL/min on a stable dose of ciclosporin, a single 10 mg dose of MIBEZIT resulted in a 3,4 fold (range 2,3 to 7,9 fold) increase in the mean AUC for total ezetimibe compared to a healthy control population, receiving ezetimibe alone, from another study. In a different study, a renal transplant patient with severe renal impairment who was receiving ciclosporin and multiple other medications demonstrated a 12-fold greater exposure to total ezetimibe compared to concurrent controls receiving ezetimibe alone. In a two-period crossover study in healthy subjects, daily administration of 20 mg ezetimibe for 8 days with a single 100 mg dose of ciclosporin on Day 7 resulted in a mean 15 % increase in ciclosporin AUC (range 10 % decrease to 51 % increase) compared to a single 100 mg dose of ciclosporin alone. A controlled study on the effect of co-administered ezetimibe on ciclosporin exposure in renal transplant patients has not been conducted. Caution should be exercised when initiating MIBEZIT in the setting of ciclosporin. Ciclosporin concentrations should be monitored in patients receiving MIBEZIT and ciclosporin (see section 4.4).

Anticoagulants

Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of healthy adult males. However, there have been post-marketing reports of increased International Normalised Ratio (INR) in patients who had MIBEZIT added to warfarin or fluindione. If MIBEZIT is added to warfarin, another coumarin anticoagulant, or fluindione, INR should be appropriately monitored (see section 4.4).

Paediatric population

Interaction studies have only been performed in adults.

MIBEZIT co-administered with a statin is contraindicated during pregnancy and lactation (see section 4.3), please refer to the Professional Information for that particular statin.

Pregnancy

MIBEZIT is contraindicated in pregnancy (see section 4.3). No clinical data are available on the use of MIBEZIT during pregnancy.

Lactation

MIBEZIT should not be used during lactation. Studies on rats have shown that ezetimibe is secreted into breast milk. It is not known if ezetimibe is secreted into human breast milk.

Fertility

No clinical trial data are available on the effects of ezetimibe on human fertility. Ezetimibe had no effect on the fertility of male or female rats.

No studies on the effects on the ability to drive and use machines have been performed. However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported.

The most frequently observed adverse reactions are headache, abdominal pain, diarrhoea, flatulence, myalgia, fatigue and increased liver enzymes (ALT and/or AST).

In post-marketing experience with MIBEZIT cases of myopathy and rhabdomyolysis have been reported (see section 4.4).

Tabulated list of adverse reactions

Adverse reactions observed in clinical studies of MIBEZIT (as a monotherapy or co-administered with a statin) or MIBEZIT reported from post-marketing use either administered alone or with a statin are listed in the table below. These reactions are presented by system organ class and by frequency.

System Organ Class Frequency Frequent Less Frequent Not known Blood and lymphatic system disorders Thrombocytopaenia Immune system disorders Hypersensitivity; including rash; Urticaria; Anaphylaxis and Angio-oedema Metabolism and nutrition disorders Decreased appetite Psychiatric disorders Depression Nervous system disorders Headache Paraesthesia Dizziness Vascular disorders Hot flush; Hypertension Respiratory, thoracic and mediastinal disorders Cough Dyspnoea Gastrointestinal disorders Abdominal pain; Diarrhoea; Flatulence Dyspepsia; Gastro oesophageal reflux disease; Nausea; Dry mouth; Gastritis Pancreatitis; Constipation Hepatobiliary disorders Hepatitis; Cholelithiasis; Cholecystitis Skin and subcutaneous tissue disorders Pruritus; Rash; Urticaria Erythema multiforme Musculoskeletal and connective tissue disorders Myalgia Arthralgia; Muscle Spasms; Neck pain; Back pain; Muscular weakness; Pain in extremity. Myopathy/Rhabdomyolysis (see section 4.4) General disorders and administration site conditions Fatigue Chest pain; Pain; Asthenia; Increased oedema peripheral Investigations Increased ALT and/or AST Blood CPK; increased Gamma-Glutamyl transferase; Abnormal liver function test MIBEZIT co-administered with fenofibrate Gastrointestinal disorders: abdominal pain (common)

Clinically important elevations (> 3 X ULN, consecutive) in serum transaminases have been observed when MIBEZIT was co-administered with fenofibrate (4,5 %) compared with fenofibrate monotherapy (2,7 %). Corresponding incidence rates for cholecystectomy were also higher MIBEZIT was co-administered with fenofibrate (1,7 %) compared with fenofibrate monotherapy (0,6 %).

Paediatric (6 to 17 years of age) patients In the paediatric patient group (6 - 10 years old), higher elevations of ALT and/or AST (u2265 3 X ULN, consecutive) were observed in ezetimibe administered patients (1,1 %) compared to the placebo group (0 %). There were no elevations of CPK (u2265 10 X ULN). No cases of myopathy were reported. When ezetimibe was administered with simvastatin in paediatric patients (10 - 17 years old), higher elevations of ALT and/or AST (u2265 3 X ULN, consecutive) were observed in ezetimibe/simvastatin patients (3 %) compared to the simvastatin monotherapy group (2 %); these figures were respectively 2 % and 0 % for elevation of CPK (u2265 10 X ULN). No cases of myopathy were reported. Patients with coronary heart disease and acute coronary syndrome (ACS) event history In patients treated with either ezetimibe/simvastatin 10/40 mg (some titrated up to ezetimibe/simvastatin 10/80 mg) or simvastatin 40 mg (some titrated up to simvastatin 80 mg), the incidence of myopathy was 0,2 % for ezetimibe/simvastatin and 0,1 % for simvastatin. The incidence of rhabdomyolysis was 0,1 % for ezetimibe/simvastatin and 0,2 % for simvastatin. The incidence of consecutive elevations of transaminases (u2265 3 X ULN) was 2,5 % for ezetimibe/simvastatin and 2,3 % for simvastatin (see section 4.4). Gallbladder-related adverse effects were reported in 3,1 % vs 3,5 % of patients allocated to ezetimibe/simvastatin and simvastatin, respectively. The incidence of cholecystectomy hospitalisations was 1,5 % in both treatment groups. Cancer (defined as any new malignancy) was diagnosed in 9,4 % vs 9,5 %, respectively. Patients with chronic kidney disease In this patient group, the incidence of myopathy/rhabdomyolysis was 0,2 % in patients treated with MIBEZIT combined with simvastatin and 0,1 % in patients treated with placebo. Consecutive elevations of transaminases (> 3X ULN) occurred in 0,7 % of patients treated with MIBEZIT combined with simvastatin compared with 0,6 % of patients treated with placebo (see section 4.4). Laboratory values The incidence of clinically important elevations in serum transaminases (ALT and/or AST u2265 3 X ULN, consecutive) was observed to be similar between ezetimibe (0,5 %) and placebo (0,3 %). In co-administration, the incidence was 1,3 % for patients treated with ezetimibe co-administered with a statin and 0,4 % for patients treated with a statin alone (see section 4.4). CPK > 10 X ULN was reported for 0,2 % patients administered ezetimibe alone vs 0,1 % patients administered placebo, and for 0,1 % patients co-administered ezetimibe and a statin vs 0,4 % patients administered a statin alone (see section 4.4).

In clinical studies, administration of ezetimibe, 50 mg /day to healthy subjects for up to 14 days, or 40 mg /day to patients with primary hypercholesterolaemia for up to 56 days, was generally well tolerated. In animals, no toxicity was observed after single oral doses of 5000 mg /kg of ezetimibe in rats and mice and 3000 mg /kg in dogs. A few cases of overdosage with ezetimibe have been reported; most have not been associated with adverse experiences. In the event of an overdose, symptomatic and supportive measures should be employed.