EZETIMIBE/SIMVASTATIN

Posology Hypercholesterolaemia The patient should be on an appropriate lipid-lowering diet and should continue on this diet during treatment with Ezetimibe/Simvastatin. Route of administration is oral. The dosage range of Ezetimibe/Simvastatin is 10/10 mg/day through 10/80 mg/day in the evening.

All dosages may not be available in all member states. The typical dose is 10/20 mg/day or 10/40 mg/day given as a single dose in the evening. 1). The patient's low-density lipoprotein cholesterol (LDL-C) level, coronary heart disease risk status, and response to current cholesterol- lowering therapy should be considered when starting therapy or adjusting the dose.

1, Table 2) and the response to the current cholesterol-lowering therapy. Adjustments of dosage, if required, should be made at intervals of not less than 4 weeks. Ezetimibe/Simvastatin can be administered with or without food. The tablet should not be split.

Patients with Coronary Heart Disease and ACS Event History In the cardiovascular events risk reduction study (IMPROVE-IT), the starting dose was 10/40 mg once a day in the evening. The 10/80mg dose is only recommended when the benefits are expected to outweigh the potential risks.

Homozygous Familial Hypercholesterolaemia The recommended starting dosage for patients with homozygous familial hypercholesterolaemia is Ezetimibe/Simvastatin 10/40 mg/day in the evening. 4). , LDL apheresis) in these patients or if such treatments are unavailable.

5). Co-administration with other medicines Dosing of Ezetimibe/Simvastatin should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant. 5). 5). 2). Paediatric population Initiation of treatment must be performed under review of a specialist.

Adolescents ≥ 10 years (pubertal status: boys Tanner Stage II and above and girls who are at least one year post-menarche): The clinical experience in paediatric and adolescent patients (aged 10-17 years old) is limited. The recommended usual starting dose is 10/10 mg once a day in the evening.

2). 2). The experience in pre- pubertal children is limited. Hepatic Impairment No dosage adjustment is required in patients with mild hepatic impairment (Child-Pugh score 5 to 6). Treatment with Ezetimibe/Simvastatin is not recommended in patients with moderate (Child-Pugh score 7 to 9) or severe (Child-Pugh score > 9) liver dysfunction.

Ezetimibe / simvastatin (or co-administration of ezetimibe and simvastatin equivalent to ezetimibe / simvastatin) has been evaluated for safety in approximately 12,000 patients in clinical trials. The following adverse reactions were observed in clinical studies of ezetimibe / simvastatin in patients treated with ezetimibe / simvastatin (n = 2,404) and at a greater incidence than placebo (n = 1,340), in patients treated with ezetimibe / simvastatin (n = 9,595) and at a greater incidence than statins administered alone (n = 8,883) in clinical studies of ezetimibe or simvastatin, and/or reported from post-marketing use with ezetimibe / simvastatin or ezetimibe or simvastatin.

These reactions are presented in Table 1 by system organ class and by frequency.

The frequencies of adverse events are ranked according to the following:

Very common (≥ 1/10), Common (≥ 1/100, < 1/10), Uncommon (≥ 1/1000, < 1/100), Rare (≥ 1/10,000, < 1/1000), Very Rare (< 1/10,000) including isolated reports, and Not Known (cannot be estimated from the available data). 5). ** There have been very rare reports of immune-mediated necrotising myopathy (IMNM), an autoimmune myopathy, during or after treatment with some statins.

4). Paediatric population In a study involving adolescent (10 to 17 years of age) patients with heterozygous familial hypercholesterolaemia (n=248), elevations of ALT and/or AST (≥3X 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 (≥ 10X ULN).

No cases of myopathy were reported. This trial was not suited for comparison of rare adverse drug reactions. 0 years. 1% for patients treated with simvastatin. 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.

Myopathy/Rhabdomyolysis In post-marketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin concomitantly with ezetimibe. However, rhabdomyolysis has been reported very rarely with ezetimibe monotherapy and very rarely with the addition of ezetimibe to other agents known to be associated with increased risk of rhabdomyolysis.

Ezetimibe/Simvastatin contains simvastatin. Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above 10 X the upper limit of normal (ULN).

Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and very rare fatalities have occurred. e. 5). As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related for simvastatin.

61 % at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded. 02% for patients on 20 mg/day. Approximately half of these myopathy cases occurred during the first year of treatment.

1%. 1). The risk of myopathy is greater in patients on Ezetimibe/Simvastatin 10/80 mg compared with other statin- based therapies with similar LDL-C-lowering efficacy. Therefore, the 10/80-mg dose of Ezetimibe/Simvastatin should only be used in patients with severe hypercholesterolemia and at high risk for cardiovascular complications who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks.

5).

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). 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.

1. 6). Active liver disease or unexplained persistent elevations in serum transaminases. g. 5). 5). 5).