Ezetrol 10mg Tablet

Primary Hypercholesterolaemia

EZETROL, 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.

Reduction in Risk of Cardiovascular Events

EZETROL is indicated to reduce the risk of cardiovascular events 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, administered with a statin, is indicated for the reduction of elevated total-C and LDL-C levels in patients with HoFH.

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 EZETROL.

Posology

Use in Patients with Primary Hypercholesterolaemia

The recommended dose of EZETROL is 10 mg once daily, used alone, with a statin or with fenofibrate. EZETROL can be administered at any time of the day, with or without food.

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.

Special populations

Use in Patients with Renal Impairment/Chronic Kidney Disease

In patients with renal impairment, no dosage adjustment of EZETROL is necessary (see section 5.2).

Combination Therapy with Simvastatin

In patients with mild renal impairment (estimated GFR u2265 60 mL/min/1,73 mu00b2), no dosage adjustment of EZETROL or simvastatin is necessary. In patients with chronic kidney disease and estimated glomerular filtration rate < 60 mL/min/1,73 mu00b2, the dose of EZETROL is 10 mg and the dose of simvastatin is 20 mg once a day in the evening. In such patients, the use of higher doses of simvastatin should be closely monitored (see section 4.4).

Use in the Elderly

No dosage adjustment is required for elderly patients (see section 5).

Paediatric population

Children 6 years of age or older and adolescents: No dosage adjustment is required (see section 5). Children under 6 years of age: No clinical data on safety and efficacy are available, therefore treatment with EZETROL is contraindicated.

Use in Hepatic Impairment

No dosage adjustment is required in patients with mild hepatic insufficiency (Child Pugh score 5 to 6). Treatment with EZETROL is contraindicated in patients with moderate (Child Pugh score 7 to 9) or severe (Child Pugh score > 9) liver dysfunction due to unknown effects (see section 4.3 and section 5.2).

Co-administration with bile acid sequestrants

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

• Hypersensitivity to any component of this medication.
• Pregnancy, as no clinical data on exposed pregnancies is available.
• Lactation, as it is not known whether ezetimibe is excreted in human breast milk.
• Children below the age of 6 years.
• Moderate to severe hepatic impairment (Child Pugh score 7 or more). (When EZETROL is to be administered with a statin, please refer to the Package Insert for that particular medication.)

When EZETROL is to be administered with a statin, please refer to the Package Insert for that particular medication.

Liver Enzymes

In controlled co-administration trials in patients receiving EZETROL with a statin, consecutive transaminase elevations (u2265 3 x 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).

Skeletal Muscle

In clinical trials, the incidence of CPK >10 x ULN was 0,2 % for EZETROL vs. 0,1 % for placebo and 0,1 % for EZETROL co-administered with a statin vs. 0,4 % for statins alone. In post-marketing experience with EZETROL, cases of myopathy and rhabdomyolysis have been reported. 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. EZETROL and any statin that the patient is taking concomitantly should be immediately discontinued if myopathy is diagnosed or suspected. The presence of these symptoms and a creatine phosphokinase (CPK) level > 10 times the ULN indicates myopathy.

Fibrates

The safety and efficacy of EZETROL administered with fibrates have not been established. The co-administration of EZETROL with fibrates other than fenofibrate has not been studied.

Fenofibrate

If cholelithiasis is suspected in a patient receiving EZETROL and fenofibrate, gallbladder studies are indicated, and alternative lipid-lowering therapy should be considered (see section 4.8) and the Package Insert for fenofibrate.

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).

Statins

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

In preclinical studies, it has been shown that EZETROL does not induce cytochrome P450 medicine metabolising enzymes. No clinically significant pharmacokinetic interactions have been observed between EZETROL and medicines known to be metabolised by cytochromes P450 1A2, 2D6, 2C8, 2C9, and 3A4 or N-acetyltransferase. EZETROL had no significant effect on the pharmacokinetics of dapsone, dextromethorphan, digoxin, oral contraceptives (ethinylestradiol and levonorgestrel), glipizide, tolbutamide or midazolam (see section 4.4). Cimetidine, co-administered with EZETROL, had no effect on the bioavailability of EZETROL.

Antacids

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

Cholestyramine

Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe by approximately 55 %. The incremental LDL-C reduction due to adding EZETROL to cholestyramine may be lessened by this interaction.

Fibrates

Concomitant fenofibrate or gemfibrozil administration increased total EZETROL concentrations by approximately 1,5- and 1,7-fold respectively, however these increases are not considered clinically significant. The safety and effectiveness of EZETROL administered with fibrates have not been established. The safety and effectiveness of EZETROL co-administered with fenofibrate have been evaluated in a clinical study (see section 4.8); co-administration of EZETROL with other fibrates has not been studied. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, EZETROL increased cholesterol in the gallbladder bile. Although the relevance of this preclinical finding to humans is unknown, co-administration of EZETROL with fibrates (other than fenofibrate) is not recommended until use in patients is studied.

Statins

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

Pregnancy

The use of EZETROL is not recommended in pregnancy, as no clinical data on exposed pregnancies are available (see section 4.3).

Breastfeeding

The use of EZETROL is not recommended during lactation, as it is not known whether ezetimibe is excreted into human breast milk (see section 4.3). Mothers on treatment with EZETROL should not breastfeed their infants.

Certain side effects that have been reported with EZETROL may affect some patients' ability to drive or operate machinery. Individual responses to EZETROL may vary (see section 4.8).

The following common (u2265 1 % to < 10 %) or uncommon (u2265 0,1 % to < 1,0 %) medicine related adverse experiences were reported in patients taking EZETROL alone or co-administered with a statin.

EZETROL administered alone:

Investigations

Uncommon: ALT and/or AST increased, blood CPK increased, gamma-glutamyltransferase increased, abnormal liver function test

Respiratory, Thoracic and Mediastinal Disorders

Uncommon: cough

Gastrointestinal Disorders

Common: abdominal pain, diarrhoea, flatulence

Uncommon: dyspepsia, gastroesophageal reflux disease, nausea

Musculoskeletal and Connective Tissue Disorders

Uncommon: arthralgia, muscle spasms, neck pain

Metabolism and Nutrition Disorders

Uncommon: decreased appetite

Vascular Disorders

Uncommon: hot flush, hypertension

General Disorders and Administration Site Conditions

Common: fatigue

Uncommon: chest pain, pain.

EZETROL co-administered with a statin:

Investigations

Common: increased ALT and/or AST

Nervous System Disorders

Common: headache

Uncommon: paraesthesia

Gastrointestinal Disorders

Uncommon: dry mouth, gastritis

Skin and Subcutaneous Tissue Disorders

Uncommon: pruritus, rash, urticaria

Musculoskeletal and Connective Tissue Disorders

Common: myalgia

Uncommon: back pain, muscular weakness, pain in extremity

General Disorders and Administration Site Condition

Uncommon: asthenia, oedema peripheral.

EZETROL co-administered with fenofibrate:

Gastrointestinal systems disorders

Common: abdominal pain.

Adverse reactions from clinical trials

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 for up to 1 year. 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 to 8,8) and 2,7 % (1,2 to 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 to 3,1) and 1,7 % (0,6 to 4,0) for fenofibrate monotherapy and EZETROL co-administered with fenofibrate, respectively (see section 4.4). There were no CPK elevations > 10 x ULN in either treatment group in this study.

Adverse experiences reported in more than or equal to 2 % of patients treated with EZETROL and at an incidence greater than placebo in placebo-controlled studies of EZETROL, regardless of causality assessment, are shown in Table 1.

TABLE 1: Clinical Adverse Reactions Occurring in u2265 2 % of Patients Treated with EZETROL and at an Incidence Greater than Placebo, Regardless of Causality

Body System/Organ Class Adverse Reaction EZETROL 10 mg (%) n=2 396 Placebo (%) n=1 159 Gastrointestinal disorders Diarrhoea 4,1 3,7 General disorders and administration site conditions Fatigue 2,4 1,5 Infections and infestations Influenza 2,0 1,5 Sinusitis 2,8 2,2 Upper respiratory tract infection 4,3 2,5 Musculoskeletal and connective tissue disorders Arthralgia 3,0 2,2 Pain in extremity 2,7 2,5

The frequency of less common adverse events was comparable between EZETROL and placebo.

Clinical adverse experiences reported in more than or equal to 2 % of patients and at an incidence greater than statin, regardless of causality assessment, are shown in Table 2.

TABLE 2: Clinical Adverse Reactions Occurring in u2265 2 % of Patients Treated with EZETROL Co-Administered with a Statin and at an Incidence Greater than Statin, Regardless of Causality

Body System/Organ Class Adverse Reaction All Statins * (%) n=9 361 EZETROL + All Statins * (%) n=11 308 Gastrointestinal disorders Diarrhoea 2,2 2,5 General disorders and administration site conditions Fatigue 1,6 2,0 Infections and infestations Influenza 2,1 2,2 Nasopharyngitis 3,3 3,7 Upper respiratory tract infection 2,8 2,9 Musculoskeletal and connective tissue disorders Arthralgia 2,4 2,6 Back pain 2,3 2,4 Myalgia 2,7 3,2 Pain in extremity 1,9 2,1 * All Statins = all doses of all statins

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, the safety and tolerability profile of the group treated with EZETROL was similar to that of adult patients treated with EZETROL (see section 5). In a study involving adolescent (10 to 17 years of age) patients with heterozygous familial hypercholesterolaemia, the safety and tolerability profile of the group co-administered EZETROL and simvastatin was similar to that of adult patients co-administered EZETROL and simvastatin (see section 5).

Laboratory values

In controlled clinical monotherapy trials, the incidence of clinically significant elevations in serum transaminases (ALT and/or AST u2265 3 x the upper limit of normal (ULN), consecutive) was not statistically different 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).

Clinically significant elevations of creatinine phosphokinase (CPK; u2265 10 x ULN) in patients treated with EZETROL administered alone or co-administered with a statin were similar to elevations seen with placebo or statin administered alone, respectively.

In the event of an overdose, symptomatic and supportive measures should be employed. 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, and 40 mg/day to 27 patients with homozygous sitosterolaemia for 26 weeks, was generally well tolerated.