4.1. Therapeutic indications

Primary Hypercholesterolaemia

Ezetrol co-administered with an HMG-CoA reductase inhibitor (statin) is indicated as adjunctive therapy to diet for use in patients with primary (heterozygous familial and non-familial) hypercholesterolaemia who are not appropriately controlled with a statin alone.

Ezetrol monotherapy is indicated as adjunctive therapy to diet for use in patients with primary (heterozygous familial and non-familial) hypercholesterolaemia in whom a statin is considered inappropriate or is not tolerated.

Prevention of Cardiovascular Events

Ezetrol is indicated to reduce the risk of cardiovascular events (see section 5.1) in patients with coronary heart disease (CHD) and a history of acute coronary syndrome (ACS) when added to ongoing statin therapy or initiated concomitantly with a statin.

Homozygous Familial Hypercholesterolaemia (HoFH)

Ezetrol co-administered with a statin, is indicated as adjunctive therapy to diet for use in patients with HoFH. Patients may also receive adjunctive treatments (e.g. LDL apheresis).

Homozygous Sitosterolaemia (Phytosterolaemia)

Ezetrol is indicated as adjunctive therapy to diet for use in patients with homozygous familial sitosterolaemia.

4.2. Posology and method of administration

Posology

The patient should be on an appropriate lipid-lowering diet and should continue on this diet during treatment with Ezetrol.

Route of administration is oral. The recommended dose is one Ezetrol 10 mg tablet daily. Ezetrol can be administered at any time of the day, with or without food.

When Ezetrol is added to a statin, either the indicated usual initial dose of that particular statin or the already established higher statin dose should be continued. In this setting, the dosage instructions for that particular statin should be consulted.

Use in Patients with Coronary Heart Disease and ACS Event History

For incremental cardiovascular event reduction in patients with coronary heart disease and ACS event history, Ezetrol 10 mg may be administered with a statin with proven cardiovascular benefit.

Co-administration with bile acid sequestrants

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

Elderly

No dosage adjustment is required for elderly patients (see section 5.2).

Paediatric population

Initiation of treatment must be performed under review of a specialist.

Children and adolescents ≥ 6 : The safety and efficacy of ezetimibe in children aged 6 to 17 years has not been established. Current available data are described in sections 4.4, 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

When Ezetrol is administered with a statin, the dosage instructions for the statin in children should be consulted.

Children <6 years: The safety and efficacy of Ezetimibe in children aged < 6 years has not been established. No data are available.

Hepatic impairment

No dosage adjustment is required in patients with mild hepatic impairment (Child-Pugh score 5 to 6). Treatment with Ezetrol is not recommended in patients with moderate (Child-Pugh score 7 to 9) or severe (Child-Pugh score > 9) liver dysfunction (see sections 4.4 and 5.2).

Renal impairment

No dosage adjustment is required for renally impaired patients (see section 5.2).

4.3. Contraindications

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

When Ezetrol is co-administered with a statin, please refer to the SPC for that particular medicinal product.

Therapy with Ezetrol co-administered with a statin is contraindicated during pregnancy and lactation.

Ezetrol co-administered with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases.

4.4. Special warnings and precautions for use

When Ezetrol is co-administered with a statin, please refer to the SPC for that particular medicinal product.

Liver Enzymes

In controlled co-administration trials in patients receiving Ezetrol with a statin, consecutive transaminase elevations (≥ 3 X the upper limit of normal [ULN]) have been observed. When Ezetrol 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).

In the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), 18,144 patients with coronary heart disease and ACS event history were randomised to receive ezetimibe/simvastatin 10/40 mg daily (n = 9067) or simvastatin 40 mg daily (n = 9077). During a median follow-up of 6.0 years, the incidence of consecutive elevations of transaminases (≥3 X ULN) was 2.5% for ezetimibe/simvastatin and 2.3% for simvastatin (see section 4.8).

In a controlled clinical study in which over 9000 patients with chronic kidney disease were randomised to receive Ezetrol 10 mg combined with simvastatin 20 mg daily (n = 4650) or placebo (n = 4620) (median follow-up period of 4.9 years), the incidence of consecutive elevations of transaminases (> 3 X ULN) was 0.7% for Ezetrol combined with simvastatin and 0.6% for placebo (see section 4.8).

Skeletal Muscle

In post-marketing experience with Ezetrol, cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin concomitantly with Ezetrol. However, rhabdomyolysis has been reported very rarely with Ezetrol monotherapy and very rarely with the addition of Ezetrol to other agents known to be associated with increased risk of rhabdomyolysis. If myopathy is suspected based on muscle symptoms or is confirmed by a creatine phosphokinase (CPK) level > 10 times the ULN, Ezetrol, any statin, and any of these other agents that the patient is taking concomitantly should be immediately discontinued. All patients starting therapy with Ezetrol should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness (see section 4.8).

In IMPROVE-IT, 18,144 patients with coronary heart disease and ACS event history were randomised to receive ezetimibe/simvastatin 10/40 mg daily (n = 9067) or simvastatin 40 mg daily (n = 9077). During a median follow-up of 6.0 years, the incidence of myopathy was 0.2% for ezetimibe/simvastatin and 0.1% for simvastatin, where myopathy was defined as unexplained muscle weakness or pain with a serum CK ≥ 10 times ULN or two consecutive observations of CK ≥ 5 and < 10 times ULN. The incidence of rhabdomyolysis was 0.1% for ezetimibe/simvastatin and 0.2% for simvastatin, where rhabdomyolysis was defined as unexplained muscle weakness or pain with a serum CK ≥ 10 times ULN with evidence of renal injury, ≥ 5 times ULN and < 10 times ULN on two consecutive occasions with evidence of renal injury or CK ≥ 10,000 IU/L without evidence of renal injury (see section 4.8).

In a clinical trial in which over 9000 patients with chronic kidney disease were randomised to receive Ezetrol 10 mg combined with simvastatin 20 mg daily (n = 4650) or placebo (n = 4620) (median follow-up 4.9 years), the incidence of myopathy/rhabdomyolysis was 0.2% for Ezetrol combined with simvastatin and 0.1% for placebo (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, Ezetrol is not recommended (see section 5.2).

Paediatric population

Efficacy and safety of Ezetrol in patients 6 to10 years of age with heterozygous familial or non-familial hypercholesterolaemia have been evaluated in a 12-week placebo-controlled clinical trial. Effects of ezetimibe for treatment periods > 12 weeks have not been studied in this age group (see sections 4.2, 4.8, 5.1 and 5.2).

Ezetrol has not been studied in patients younger than 6 years of age (see sections 4.2 and 4.8).

Efficacy and safety of Ezetrol 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 Ezetrol co-administered with doses of simvastatin above 40mg daily have not been studied in paediatric patients 10 to 17 years of age.

The safety and efficacy of Ezetrol 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 Ezetrol in patients below 17 years of age to reduce morbidity and mortality in adulthood has not been studied.

Fibrates

The safety and efficacy of Ezetrol administered with fibrates have not been established.

If cholelithiasis is suspected in a patient receiving Ezetrol and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued (see sections 4.5 and 4.8).

Ciclosporin

Caution should be exercised when initiating Ezetrol in the setting of ciclosporin. Ciclosporin concentrations should be monitored in patients receiving Ezetrol and ciclosporin (see section 4.5).

Anticoagulants

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

Excipient

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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

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

In preclinical studies, it has been shown that ezetimibe does not induce cytochrome P450 drug metabolising enzymes. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and drugs known to be metabolised by cytochromes P450 1A2, 2D6, 2C8, 2C9, and 3A4, or N-acetyltransferase.

In clinical interaction studies, ezetimibe had no effect on the pharmacokinetics of dapsone, dextromethorphan, digoxin, oral contraceptives (ethinyl estradiol and levonorgestrel), glipizide, tolbutamide, or midazolam during co-administration. Cimetidine, co-administered with ezetimibe, had no effect on the bioavailability of ezetimibe.

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 Ezetrol to cholestyramine may be lessened by this interaction (see section 4.2).

Fibrates

In patients receiving fenofibrate and Ezetrol, physicians 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 Ezetrol 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 Ezetrol with other fibrates has not been studied.

Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In animal studies, ezetimibe sometimes increased cholesterol in the gallbladder bile but not in all species (see section 5.3). A lithogenic risk associated with the therapeutic use of Ezetrol cannot be ruled out.

Statins

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

Ciclosporin

In a study of eight post-renal transplant patients with creatinine clearance of > 50 mL/min on a stable dose of ciclosporin, a single 10-mg dose of Ezetrol 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 (n = 17). 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 twelve 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 Ezetrol in the setting of ciclosporin. Ciclosporin concentrations should be monitored in patients receiving Ezetrol 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 twelve healthy adult males. However, there have been post-marketing reports of increased International Normalised Ratio (INR) in patients who had Ezetrol added to warfarin or fluindione. If Ezetrol 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.

4.6. Fertility, pregnancy and lactation

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

Pregnancy

Ezetrol should be given to pregnant women only if clearly necessary. No clinical data are available on the use of Ezetrol during pregnancy. Animal studies on the use of ezetimibe in monotherapy have shown no evidence of direct or indirect harmful effects on pregnancy, embryofoetal development, birth or postnatal development (see section 5.3).

Lactation

Ezetrol 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 (see section 5.3).

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

Tabulated list of adverse reactions (clinical studies and post-marketing experience)

In clinical studies of up to 112 weeks duration, Ezetrol 10 mg daily was administered alone in 2396 patients, with a statin in 11308 patients or with fenofibrate in 185 patients. Adverse reactions were usually mild and transient. The overall incidence of side effects was similar between Ezetrol and placebo. Similarly, the discontinuation rate due to adverse experiences was comparable between Ezetrol and placebo.

Ezetrol administered alone or co-administered with a statin:

The following adverse reactions were observed in patients treated with Ezetrol (n = 2396) and at a greater incidence than placebo (n = 1159) or in patients treated with Ezetrol coadministered with a statin (n = 11308) and at a greater incidence than statin administered alone (n = 9361). Post-marketing Adverse reactions were derived from reports containing Ezetrol either administered alone or with a statin. Adverse reactions observed in clinical studies of Ezetrol (as a monotherapy or co-administered with a statin) or Ezetrol reported from post-marketing use either administered alone or with a statin are listed in Table 1. These reactions are presented by system organ class and by frequency.

Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

Table 1

Adverse Reactions

System organ class

Frequency

Adverse reaction

Blood and lymphatic system disorders

Not known

thrombocytopaenia

Immune system disorders

Not known

hypersensitivity; including rash; urticaria; anaphylaxis and angio-oedema

Metabolism and nutrition disorders

Uncommon

decreased appetite

Psychiatric disorders

Not known

depression

Nervous system disorders

Common

headache

Uncommon

paraesthesia

Not known

dizziness

Vascular disorders

Uncommon

hot flush; hypertension

Respiratory, thoracic and mediastinal disorders

Uncommon

cough

Not known

dyspnoea

Gastrointestinal disorders

Common

abdominal pain; diarrhoea; flatulence

Uncommon

dyspepsia; gastrooesophageal reflux disease; nausea; dry mouth; gastritis

Not known

pancreatitis; constipation

Hepatobiliary disorders

Not known

hepatitis; cholelithiasis; cholecystitis

Skin and subcutaneous tissue disorders

Uncommon

pruritus; rash; urticaria

Not known

erythema multiforme

Musculoskeletal and connective tissue disorders

Common

myalgia

Uncommon

arthralgia; muscle spasms; neck pain; back pain; muscular weakness; pain in extremity

Not known

myopathy/rhabdomyolysis (see section 4.4)

General disorders and administration site conditions

Common

fatigue

Uncommon

chest pain; pain; asthenia; oedema peripheral

Investigations

Common

ALT and/or AST increased

Uncommon

blood CPK increased; gamma-glutamyltransferase increased; liver function test abnormal

Ezetrol co-administered with fenofibrate

Gastrointestinal disorders: abdominal pain (common)

In a multicentre, double-blind, placebo-controlled, clinical study in patients with mixed hyperlipidaemia, 625 patients were treated for up to 12 weeks and 576 patients for up to 1 year. In this study, 172 patients treated with Ezetrol and fenofibrate completed 12 weeks of therapy, and 230 patients treated with Ezetrol and fenofibrate (including 109 who received Ezetrol alone for the first 12 weeks) completed 1 year of therapy. This study was not designed to compare treatment groups for infrequent events. Incidence rates (95% CI) for clinically important elevations (> 3 X ULN, consecutive) in serum transaminases were 4.5% (1.9, 8.8) and 2.7% (1.2, 5.4) for fenofibrate monotherapy and Ezetrol co-administered with fenofibrate, respectively, adjusted for treatment exposure. Corresponding incidence rates for cholecystectomy were 0.6% (0.0, 3.1) and 1.7% (0.6, 4.0) for fenofibrate monotherapy and Ezetrol co-administered with fenofibrate, respectively (see sections 4.4 and 4.5).

Paediatric (6 to 17 years of age) Patients

In a study involving paediatric (6 to 10 years of age) patients with heterozygous familial or non-familial hypercholesterolaemia (n = 138), elevations of ALT and/or AST (≥ 3 X ULN, consecutive) were observed in 1.1% (1 patient) of the ezetimibe patients compared to 0% in the placebo group. There were no elevations of CPK (≥ 10 X ULN). No cases of myopathy were reported.

In a separate study involving adolescent (10 to 17 years of age) patients with heterozygous familial hypercholesterolaemia (n = 248), elevations of ALT and/or AST (≥ 3 X ULN, consecutive) were observed in 3% (4 patients) of the ezetimibe/simvastatin patients compared to 2% (2 patients) in the simvastatin monotherapy group; these figures were respectively 2% (2 patients) and 0% for elevation of CPK (≥ 10 X ULN). No cases of myopathy were reported.

These trials were not suited for comparison of rare adverse drug reactions.

Patients with Coronary Heart Disease and ACS Event History

In the IMPROVE-IT study (see section 5.1), involving 18144 patients treated with either ezetimibe/simvastatin 10/40 mg (n = 9067; of whom 6% were uptitrated to ezetimibe/simvastatin 10/80 mg) or simvastatin 40 mg (n = 9077; of whom 27% were uptitrated to simvastatin 80 mg), the safety profiles were similar during a median follow-up period of 6.0 years. Discontinuation rates due to adverse experiences were 10.6% for patients treated with ezetimibe/simvastatin and 10.1% for patients treated with simvastatin. The incidence of myopathy was 0.2% for ezetimibe/simvastatin and 0.1% for simvastatin, where myopathy was defined as unexplained muscle weakness or pain with a serum CK ≥ 10 times ULN or two consecutive observations of CK ≥ 5 and < 10 times ULN. The incidence of rhabdomyolysis was 0.1% for ezetimibe/simvastatin and 0.2% for simvastatin, where rhabdomyolysis was defined as unexplained muscle weakness or pain with a serum CK ≥ 10 times ULN with evidence of renal injury, ≥ 5 times ULN and < 10 times ULN on two consecutive occasions with evidence of renal injury or CK ≥ 10,000 IU/L without evidence of renal injury. The incidence of consecutive elevations of transaminases (≥ 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 during the trial in 9.4% vs 9.5%, respectively.

Patients with Chronic Kidney Disease

In the Study of Heart and Renal Protection (SHARP) (see section 5.1), involving over 9000 patients treated with a fixed dose combination of Ezetrol 10 mg with simvastatin 20 mg daily (n = 4650) or placebo (n = 4620), the safety profiles were comparable during a median follow-up period of 4.9 years. In this trial, only serious adverse events and discontinuations due to any adverse events were recorded. Discontinuation rates due to adverse events were comparable (10.4% in patients treated with Ezetrol combined with simvastatin, 9.8% in patients treated with placebo). The incidence of myopathy/rhabdomyolysis was 0.2% in patients treated with Ezetrol 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 Ezetrol combined with simvastatin compared with 0.6% of patients treated with placebo (see section 4.4). In this trial, there were no statistically significant increases in the incidence of pre-specified adverse events, including cancer (9.4% for Ezetrol combined with simvastatin, 9.5% for placebo), hepatitis, cholecystectomy or complications of gallstones or pancreatitis.

Laboratory values:

In controlled clinical monotherapy trials, the incidence of clinically important elevations in serum transaminases (ALT and/or AST ≥ 3 X ULN, consecutive) was similar between Ezetrol (0.5%) and placebo (0.3%). In co-administration trials, the incidence was 1.3% for patients treated with Ezetrol co-administered with a statin and 0.4% for patients treated with a statin alone. These elevations were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment (see section 4.4).

In clinical trials, CPK > 10 X ULN was reported for 4 of 1674 (0.2%) patients administered Ezetrol alone vs 1 of 786 (0.1%) patients administered placebo, and for 1 of 917 (0.1%) patients co-administered Ezetrol and a statin vs 4 of 929 (0.4%) patients administered a statin alone. There was no excess of myopathy or rhabdomyolysis associated with Ezetrol compared with the relevant control arm (placebo or statin alone) (see section 4.4).

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, or 40 mg/day to 18 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 Ezetrol have been reported; most have not been associated with adverse experiences. Reported adverse experiences have not been serious. In the event of an overdose, symptomatic and supportive measures should be employed.