Ezesim 10/10, 10/20, 10/40, 10/80 Tablets

Primary Hypercholesterolaemia

EZESIM is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG) and non-high-density lipoprotein cholesterol (non-HDL-C) and to moderately increase high-density lipoprotein cholesterol (HDL-C) in patients with primary (heterozygous familial and non-familial) hypercholesterolaemia or mixed hyperlipidaemia.

Homozygous Familial Hypercholesterolaemia (HoFH)

EZESIM is indicated for the reduction of elevated total-C and LDL-C levels in patients with HoFH.

Posology: The patient should be placed on a standard cholesterol-lowering diet before receiving EZESIM and should continue on this diet during treatment with EZESIM. The dosage should be individualised according to the baseline LDL-C level, the recommended goal of therapy, and the patient's response.

Hypercholesterolaemia: The dosage range is 10/10 mg/day up to 10/80 mg/day. The recommended usual starting dose is 10/20 mg/day. Initiation of therapy with 10/10 mg/day may be considered for patients requiring less aggressive LDL-C reductions.

Patients who require a larger reduction in LDL-C (greater than 55 %) may be started at 10/40 mg/day. After initiation or titration of EZESIM, lipid levels may be analysed after 2 weeks and the dosage adjusted, if needed.

Dosage in patients with Homozygous Familial Hypercholesterolaemia: The recommended dosage for patients with Homozygous Familial Hypercholesterolaemia is EZESIM 10/40 mg/day or 10/80 mg/day in the evening. EZESIM should be used as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) in these patients or if such treatments are unavailable.

Special populations

Use in the elderly: No dosage adjustment is required for elderly patients.

Use in hepatic impairment: No dosage adjustment is required in patients with mild hepatic insufficiency (Child-Pugh score 5 or 6). Treatment with EZESIM is contraindicated in patients with moderate (Child-Pugh score 7 to 9) or severe (Child-Pugh score greater than 9) liver dysfunction as safety and efficacy have not been demonstrated (see section 4.3 and 4.4).

Use in renal impairment: No dosage adjustment is required for patients with moderate renal insufficiency. If treatment in patients with severe renal insufficiency (creatinine clearance less than or equal to 30 mL/min) is deemed necessary, dosages above 10/10 mg/day should be implemented cautiously (see section 5.2).

Paediatric population: Treatment with EZESIM is contraindicated as safety and efficacy have not been demonstrated (see section 4.3).

Co-administration with other medicines: Dosing of EZESIM should occur either 2 or more hours before or 4 or more hours after administration of a bile acid sequestrant. In patients taking ciclosporin, danazol or greater than or equal to 1 g/day of niacin concomitantly with EZESIM, the dose of EZESIM should not exceed 10/10 mg/day (see sections 4.4 and 4.5). In patients taking amiodarone or verapamil concomitantly with EZESIM, the dose of EZESIM should not exceed 10/20 mg/day (see sections 4.4 and 4.5).

Method of administration: EZESIM is for oral use and should be taken as a single daily dose in the evening, with or without food.

• Hypersensitivity to ezetimibe, simvastatin or to any of the ingredients of EZESIM.
• Active liver disease or unexplained persistent elevations of serum transaminases; moderate to severe hepatic impairment.
• Pregnancy and lactation (see section 4.6).
• Children, as safety and efficacy have not been demonstrated.
• Concomitant administration of potent CYP3A4 inhibitors (medicines that increase AUC approximately 5-fold or greater) (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, nefazodone, and medicines containing cobicistat) (see sections 4.4 and 4.5).
• Concomitant administration of gemfibrozil, ciclosporin, or danazol (see sections 4.4 and 4.5).
• In patients with HoFH, concomitant administration of lomitapide with doses > 10/40 mg EZESIM (see sections 4.2, 4.4 and 4.5).

The dose of EZESIM should not exceed 10/10 mg daily in patients receiving concomitant medicine with ciclosporin, danazol or u2265 1 g/day of niacin. The combined use of EZESIM with these medicines should be avoided (see section 4.5).

Ciclosporin concentrations should be monitored in patients receiving EZESIM and ciclosporin (see section 4.5).

Hepatic impairment: Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, EZESIM is contraindicated in these patients (see section 4.3).

Potent CYP3A4 inhibitors: Use of EZESIM concomitantly with potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors or nefazodone) should be avoided. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with EZESIM should be suspended during the course of treatment. Concomitant use with other medicines labelled as having a potent inhibitory effect on CYP3A4 at therapeutic doses should be avoided.

Fibrates (especially gemfibrozil): There is an increased risk of myopathy when simvastatin is used concomitantly with fibrates, especially gemfibrozil. The safety and effectiveness of ezetimibe administered with fibrates have not been formally studied. Therefore, the concomitant use of EZESIM and fibrates should be avoided (see sections 4.3 and 4.5).

Amiodarone, verapamil: The dose of EZESIM should not exceed 10/20 mg daily in patients receiving concomitant medication with amiodarone or verapamil. The combined use of EZESIM at doses higher than 10/20 mg daily with amiodarone or verapamil should be avoided.

Myopathy/rhabdomyolysis: All patients starting therapy with EZESIM, or whose dose of EZESIM is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. EZESIM should be discontinued immediately if myopathy is diagnosed or suspected. Caution should be exercised in patients with pre-disposing factors for rhabdomyolysis. In order to establish a reference baseline value, a CK level should be measured before starting treatment in the following situations:

• Elderly (age u2265 65 years)
• Female gender
• Renal impairment
• Uncontrolled hypothyroidism
• Personal or familial history of hereditary muscular disorders
• Previous history of muscular toxicity with a statin or fibrate
• Alcohol abuse.

If a patient has previously experienced a muscle disorder on a fibrate or a statin, treatment with any statin-containing medicine (such as EZESIM) should only be initiated with caution. If CK levels are significantly elevated at baseline (> 5 X ULN), treatment should not be started.

Simvastatin may cause myopathy manifested as muscle pain, tenderness or weakness with CK above 10 times the ULN. Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria and rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. The presence of symptoms, and/or a CK level greater than 10 times the ULN indicates myopathy. In most cases, when patients were promptly discontinued from simvastatin treatment, muscle symptoms and CK increases resolved. Periodic CK determinations may be considered in patients starting EZESIM treatment or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.

Creatine Kinase measurement: Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly elevated at baseline (> 5 X ULN), levels should be re-measured within 5 to 7 days later to confirm the results.

Cases of myopathy and rhabdomyolysis have been reported in ezetimibe treatment. Most patients who developed rhabdomyolysis were taking a statin concomitantly with ezetimibe. However, rhabdomyolysis has been reported with ezetimibe monotherapy and with the addition of ezetimibe to other medicines known to be associated with increased risk of rhabdomyolysis.

The risk of myopathy/rhabdomyolysis is increased by use of EZESIM with the following:

• Potent inhibitors of CYP3A4: Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, or nefazodone, particularly with higher doses of EZESIM (see section 4.5).
• Other medicines: Fibrates, or greater than or equal to 1 g/day of niacin, particularly with higher doses of EZESIM (see section 4.5). Acipimox is structurally related to niacin. Although acipimox was not studied, the risk for muscle related toxic effects may be similar to niacin.
• Ciclosporin or danazol particularly with higher doses of EZESIM (see section 4.5).
• Amiodarone or verapamil with higher doses of EZESIM (see section 4.5). In an ongoing clinical trial, myopathy has been reported in 6 % of patients receiving simvastatin 80 mg and amiodarone.
• Diltiazem: Patients on diltiazem treated concomitantly with EZESIM 10/80 mg have a slightly increased risk of myopathy. The risk of myopathy in patients taking simvastatin 40 mg with diltiazem is similar to that in patients taking simvastatin 40 mg without diltiazem (see section 4.5).

Fusidic acid: Patients on fusidic acid treated concomitantly with EZESIM may have an increased risk of myopathy and rhabdomyolysis (see section 4.5). Patients should be closely monitored; temporary suspension of EZESIM treatment may be considered.

For patients with HoFH, this risk may be increased by concomitant use of lomitapide with EZESIM (see section 4.5). Patients should be closely monitored; temporary suspension of EZESIM treatment may be considered.

Many patients who developed rhabdomyolysis on therapy with simvastatin had complicated medical histories, including renal insufficiency, usually as a consequence of long-standing diabetes mellitus. Such patients taking EZESIM need closer monitoring. Therapy with EZESIM should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.

Daptomycin: Cases of myopathy and/or rhabdomyolysis have been reported with HMG-CoA reductase inhibitors (e.g. simvastatin and ezetimibe/simvastatin) co-administered with daptomycin. Caution should be used when prescribing HMG-CoA reductase inhibitors with daptomycin, as either medicine can cause myopathy and/or rhabdomyolysis when given alone. Consideration should be given to temporarily suspend EZESIM in patients taking daptomycin. Consult the prescribing information of daptomycin to obtain further information about this potential interaction with HMG-CoA reductase inhibitors (e.g. simvastatin and ezetimibe/simvastatin) and for further guidance related to monitoring.

Reduced function of transport proteins: Reduced function of hepatic OATP transport proteins can increase the systemic exposure of simvastatin acid and increase the risk of myopathy and rhabdomyolysis. Reduced function can occur as the result of inhibition by interacting medicines (e.g. ciclosporin) or in patients who are carriers of the SLCO1B1 c.521T>C genotype. Patients carrying the SLCO1B1 gene allele (c.521T>C) coding for a less active OATP1B1 protein have an increased systemic exposure of simvastatin acid and increased risk of myopathy. The risk of high dose (80 mg) simvastatin (as contained in EZESIM) related myopathy is about 1 % in general, without genetic testing. Homozygote C allele carriers (also called CC) treated with 80 mg have a 15 % risk of myopathy within one year, while the risk in heterozygote C allele carriers (CT) is 1.5 %. The corresponding risk is 0.3 % in patients having the most common genotype (TT). Where available, genotyping for the presence of the C allele should be considered prior to prescribing 10/80 mg EZESIM for individual patients and high doses avoided in those found to carry the CC genotype. However, absence of this gene upon genotyping does not exclude that myopathy can still occur.

Simvastatin (as contained in EZESIM) is a substrate of the Breast Cancer Resistant Protein (BCRP) efflux transporter. Concomitant administration of medicines that are inhibitors of BCRP (e.g. elbasvir and grazoprevir) may lead to increased plasma concentrations of simvastatin and an increased risk of Myopathy, therefore, a dose adjustment of EZESIM should be considered depending on the prescribed dose. Co-administration of elbasvir and grazoprevir with simvastatin has not been studied, however, the dose of EZESIM should not exceed 10/20 mg daily in patients receiving EZESIM concomitantly with medicines containing elbasvir or grazoprevir (see section 4.5).

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

Liver enzymes: In controlled co-administration trials in patients receiving ezetimibe with simvastatin, consecutive transaminase elevations (u2265 3 times the ULN) have been observed (see section 4.8). It is recommended that liver function tests be performed before treatment with EZESIM begins and thereafter when clinically indicated. Patients titrated to the 10/80 mg dose should receive an additional test prior to titration, 3 months after titration to the 10/80 mg dose, and periodically thereafter (e.g. semi-annually) for the first year of treatment. Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients measurements should be repeated promptly and then performed more frequently. If the transaminase levels show evidence of progression, particularly if they rise to 3 times the ULN and are persistent, EZESIM should be discontinued. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy. There have been reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinaemia or jaundice occurs during treatment with EZESIM, promptly interrupt therapy. If an alternate aetiology is not found, do not restart EZESIM. EZESIM should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained persistent transaminase elevations are contraindications to the use of EZESIM (see section 4.3).

Hepatic impairment: Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic impairment, EZESIM is contraindicated (see section 4.3).

Diabetes mellitus: Some evidence suggests that statins as a class raise blood glucose and, in some patients at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping EZESIM treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L, BMI > 30 kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically.

Interstitial lung disease: Cases of interstitial lung disease have been reported with some statins, including simvastatin (as contained in EZESIM), especially with long term therapy (see section 4.8). Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, EZESIM therapy should be discontinued.

Porphyria: Simvastatin has been classified as probably porphyrinogenic and should therefore only be prescribed for compelling reasons and precautions should be considered in all patients.

Myasthenia gravis and ocular myasthenia: There is a risk of myasthenia gravis and ocular myasthenia with the use of statin containing medicines, such as EZESIM.

Paediatric population: The safety and efficacy of ezetimibe co-administered with doses of simvastatin above 40 mg daily have not been studied in paediatric patients aged 10 to 17 years. Ezetimibe has not been studied in patients younger than 10 years of age or in pre-menarche girls (see sections 4.2 and 4.8). The long-term efficacy of therapy with ezetimibe in patients below 17 years of age to reduce morbidity and mortality in adulthood has not been studied.

Excipient warnings: EZESIM contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

No clinically significant pharmacokinetic interaction was seen when ezetimibe was co-administered with simvastatin. EZESIM is bioequivalent to co-administered ezetimibe and simvastatin.

CYP3A4 Interactions: No clinically significant pharmacokinetic interactions have been observed between ezetimibe and medicines known to be metabolised by cytochromes P450 1A2, 2D6, 2C8, 2C9 and 3A4, or N-acetyltransferase. Simvastatin is metabolised by CYP3A4 but has no CYP3A4 inhibitory activity, therefore, it is not expected to affect the plasma concentrations of other medicines metabolised by CYP3A4.

Pharmacodynamic Interactions: Interactions with lipid-lowering medicinal products that can cause myopathy when given alone. The risk of myopathy, including rhabdomyolysis, is increased during concomitant administration of simvastatin with fibrates. Additionally, there is a pharmacokinetic interaction of simvastatin with gemfibrozil resulting in increased simvastatin plasma levels (see below Pharmacokinetic interactions and sections 4.3 and 4.4). Cases of myopathy/rhabdomyolysis have been associated with simvastatin co-administered with lipid-modifying doses (u2265 1 g/day) of niacin (see section 4.4). Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Although the relevance of this preclinical finding to humans is unknown, co-administration of EZESIM with fibrates is not recommended (see section 4.4).

Pharmacokinetic Interactions: Prescribing recommendations for interacting medicines are summarised in the table below:

Medicine Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis

Interacting medicines Prescribing recommendations

Potent CYP3A4 inhibitors, e.g. Itraconazole* Ketoconazole* Posaconazole Voriconazole *If treatment is unavoidable, then EZESIM should be discontinued. All other potent CYP3A4 Inhibitors should be avoided.

Erythromycin* Clarithromycin* Telithromycin* HIV protease inhibitors (e.g. nelfinavir) Boceprevir Telaprevir Nefazodone Cobicistat Ciclosporin Danazol Gemfibrozil Other Fibrates Fusidic acid Not recommended with EZESIM Niacin (nicotinic acid) (u2265 1 g/day) For Asian patients, not recommended with EZESIM Amiodarone Amlodipine Verapamil Diltiazem Niacin (u22651 g/day) Elbasvir Grazoprevir Do not exceed 10/20 mg EZESIM daily Lomitapide Daptomycin For patients with HoFH, do not exceed 10/40 mg EZESIM daily Grapefruit juice Avoid grapefruit juice when taking EZESIM

Ezetimibe: Concomitant antacid administration with EZESIM 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 AUC of total ezetimibe (ezetimibe + ezetimibe glucuronide) by approximately 55 %. The incremental LDL-C reduction due to adding EZESIM to cholestyramine may be lessened by this interaction.

Fibrates: Concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations approximately 1.5 and 1.7-fold respectively, however these increases are not considered clinically significant. The safety and effectiveness of EZESIM administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Although the relevance of this preclinical finding to humans is unknown, co-administration of EZESIM with fibrates is not recommended until use in patients is studied.

Simvastatin: CYP3A4 interactions: Simvastatin is metabolised by CYP3A4 but has no CYP3A4 inhibitory activity, therefore it is not expected to affect the plasma concentrations of other medicines metabolised by CYP3A4. The following potent inhibitors of CYP3A4 increase the risk of myopathy by reducing the elimination of the simvastatin component of EZESIM (see sections 4.3 and 4.4): itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors and nefazodone.

Fluconazole: Cases of rhabdomyolysis associated with concomitant administration of simvastatin and fluconazole have been reported (see section 4.4).

Ciclosporin or danazol: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of ciclosporin or danazol, particularly with higher doses of EZESIM (see sections 4.3 and 4.4). In a study of 8 post-renal transplant patients with creatinine clearance of greater than 50 mL/min on a stable dose of ciclosporin, a single 10 mg dose of ezetimibe resulted in a 3.4-fold (range 2.3 to 7.9-fold) increase in the mean AUC for total ezetimibe compared to healthy patients. In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) receiving multiple medicines, including ciclosporin, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects. In a two-period crossover study in 12 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 (see section 4.4).

Fusidic acid: Patients on fusidic acid treated concomitantly with EZESIM, may have an increased risk of myopathy and rhabdomyolysis (see section 4.4). The mechanism of this interaction (whether it is pharmacodynamics or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination. Co-administration of fusidic acid and EZESIM may cause increased plasma concentrations of both medicines. If treatment with systemic fusidic acid is necessary, EZESIM treatment should be discontinued throughout the duration of the fusidic acid treatment.

Amiodarone or verapamil: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone or verapamil with higher doses of EZESIM therefore, the dose of EZESIM should not exceed 10/20 mg daily in patients receiving concomitant medicine with amiodarone (see section 4.4).

Diltiazem: Patients on diltiazem treated concomitantly with EZESIM 10/80 mg have a slightly increased risk of myopathy, therefore, the dose of EZESIM should not exceed 10/20 mg daily in patients receiving concomitant medicine with diltiazem (see section 4.4).

Amlodipine: Patients on amlodipine treated concomitantly with simvastatin (as contained in EZESIM) have an increased risk of myopathy. In a pharmacokinetic study, concomitant administration of amlodipine caused a 1.6-fold increase in exposure of simvastatin acid. Therefore, the dose of EZESIM should not exceed 10/20 mg daily in patients receiving concomitant medicine with amlodipine.

Lomitapide: The risk of myopathy and rhabdomyolysis may be increased by concomitant administration of lomitapide with simvastatin (see sections 4.3 and 4.4). Therefore, in patients with HoFH, the dose of EZESIM must not exceed 10/40 mg daily in patients receiving concomitant medication with lomitapide.

Moderate Inhibitors of CYP3A4: Patients taking other medicines labelled as having a moderate inhibitory effect on CYP3A4 concomitantly with EZESIM, particularly higher EZESIM doses, may have an increased risk of myopathy (see section 4.4).

Inhibitors of the Transport Protein OATP1B1: Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of medicines that are inhibitors of the transport protein OATP1B1 may lead to increased plasma concentrations of simvastatin acid and an increased risk of myopathy (see sections 4.3 and 4.4).

Inhibitors of Breast Cancer Resistant Protein (BCRP): Concomitant administration of medicines that are inhibitors of BCRP, including medicines containing elbasvir or grazoprevir, may lead to increased plasma concentrations of simvastatin and an increased risk of myopathy (see sections 4.2 and 4.4).

Grapefruit juice: Grapefruit juice inhibits cytochrome P450 3A4. Concomitant intake of large quantities (over 1 litre daily) of grapefruit juice and simvastatin resulted in a 7-fold increase in exposure to simvastatin acid. Intake of 240 mL of grapefruit juice in the morning and administration of simvastatin in the evening also resulted in a 1.9-fold increase. Intake of grapefruit juice during treatment with EZESIM should therefore be avoided.

Colchicine: There have been reports of myopathy and rhabdomyolysis with the concomitant administration of colchicine and simvastatin, in patients with renal impairment. Close clinical monitoring of such patients taking this combination is advised.

Rifampicin: Because rifampicin is a potent CYP3A4 inducer, patients undertaking long-term rifampicin therapy (e.g. treatment of tuberculosis) may experience loss of efficacy of simvastatin. In a pharmacokinetic study in normal volunteers, the area under the plasma concentration curve (AUC) for simvastatin acid was decreased by 93 % with concomitant administration of rifampicin.

Niacin: Cases of myopathy/rhabdomyolysis have been observed with simvastatin co-administered with lipid-modifying doses (u2265 1 g/day) of niacin (see section 4.4).

Daptomycin: The risk of myopathy and/or rhabdomyolysis may be increased by concomitant administration of HMG-CoA reductase inhibitors (e.g. simvastatin and ezetimibe/simvastatin) and daptomycin (see section 4.4).

Effect of EZESIM on the pharmacokinetics of other products

Anticoagulants: Ezetimibe: 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 Normalized Ratio in patients who had ezetimibe added to warfarin or fluindione (see section 4.4).

The effect of EZESIM on prothrombin time has not been studied.

Simvastatin: In two clinical studies, one in healthy subjects and the other in hypercholesterolaemic patients, simvastatin 20 to 40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalised Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. In patients taking coumarin anticoagulants, prothrombin time should be determined before starting EZESIM and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of EZESIM is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.

Paediatric population: Interaction studies have only been performed in adults.

Pregnancy: EZESIM is contraindicated during pregnancy (see section 4.3). No controlled clinical trials with simvastatin have been conducted in pregnant women. Reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. The safety of EZESIM in pregnant women has not been established. Maternal treatment with EZESIM may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. For this reason, EZESIM should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with EZESIM should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant.

No clinical data on exposed pregnancies are available for ezetimibe.

Breastfeeding: EZESIM is contraindicated during lactation (see section 4.3.). Studies in rats have shown that ezetimibe is excreted in milk. It is not known whether the active ingredients of EZESIM are excreted into human breast milk; therefore, women who are nursing should not take EZESIM.

Fertility: No clinical trial data are available on the effects of ezetimibe or simvastatin on human fertility.

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 when taking EZESIM.

a. Summary of the safety profile

The most common adverse effects include headache, abdominal pain and diarrhoea. The commonest adverse effect with simvastatin is gastrointestinal disturbances.

b. Tabulated summary of adverse reactions

Adverse effects with EZESIM:

System Organ Class Frequency Side effects

Blood and lymphatic system disorders Frequency unknown Thrombocytopenia, anaemia

Immune system disorders Frequency unknown Hypersensitivity, anaphylaxis, hypersensitivity syndrome

Metabolism and nutrition disorders Less frequent Frequency unknown Decreased weight Decreased appetite

Psychiatric disorders Less frequent Frequency unknown Sleep disorder, insomnia Depression, memory loss, forgetfulness, amnesia, memory impairment, confusion, sleep disturbances, nightmares

Nervous system disorders Frequent Less frequent Frequency unknown Headache Dizziness, paraesthesia Peripheral neuropathy, memory impairment, myasthenia gravis

Eye disorders Frequency unknown Ocular myasthenia

Respiratory, thoracic and mediastinal disorders Frequency unknown Cough, dyspnoea, interstitial lung disease

Vascular disorders Frequency unknown Hot flush, hypertension

Gastrointestinal disorders Frequent Less frequent Frequency unknown Flatulence Abdominal pain, abdominal discomfort, upper abdominal pain, dyspepsia, nausea, Frequency unknown vomiting, abdominal distension, diarrhoea, dry mouth, gastroesophageal reflux disease Constipation, pancreatitis, gastritis

Hepato-biliary disorders Frequency unknown Hepatitis, jaundice, fatal and non-fatal hepatic failure, cholelithiasis, cholecystitis

Skin and subcutaneous tissue disorders Less frequent Frequency unknown Pruritus, rash, urticaria Alopecia, erythema multiforme, angioedema

Musculoskeletal, connective tissue and bone disorders Frequent Less frequent Frequency unknown Myalgia, pain in limb Arthralgia, muscle spasms, muscular weakness, musculoskeletal pain and discomfort, neck pain, pain in extremity, back pain Muscle cramps, myopathy, myositis, rhabdomyolysis (with or without renal failure), tendinopathy, tendon rupture, immune-mediated necrotising myopathy

Reproductive system and breast disorders Frequency unknown Erectile dysfunction, sexual dysfunction

General disorders Less frequent Asthenia, fatigue, malaise, and administrative site conditions Frequency unknown peripheral oedema, chest pain Pain

Investigations Frequent Less frequent Frequency unknown Increased ALT and/or AST, increased blood creatinine kinase (CK) Increased blood bilirubin blood uric acid, gamma-glutamyl transferase and international normalised ratio, protein present in the urine Elevated alkaline phosphatase, abnormal liver function test results, increases in HbA1c and fasting serum glucose levels, diabetes mellitus

Adverse effects with Ezetimibe:

System Organ Class Frequency Side effects

Infections and Infestations Frequent Viral infection, pharyngitis, sinusitis, upper respiratory tract infection

Immune system disorders Less frequent Hypersensitivity reactions, anaphylaxis and angioedema

Blood and lymphatic system disorders Less frequent Thrombocytopenia

Psychiatric disorders Less frequent Depression

Nervous system disorders Frequent Less frequent Headache Dizziness, paraesthesia

Respiratory, thoracic and mediastinal disorders Frequent Coughing

Gastrointestinal disorders Frequent Less frequent Abdominal pain, diarrhoea Nausea, pancreatitis

Hepato-biliary disorders Less frequent Frequency unknown Hepatitis, cholelithiasis, cholecystitis Raised liver enzymes

Skin and subcutaneous tissue disorders Less frequent Frequency unknown Rash and urticaria, erythema multiforme

Musculoskeletal, and connective tissue disorders Frequent Less frequent Back pain, myalgia Arthralgia, myopathy/rhabdomyolysis (see section 4.4)

General disorders and administration site conditions Frequent Fatigue, chest pain

Investigations Less frequent Increased CPK, elevations of liver transaminases

Signs and symptoms: Ezetimibe: 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. A few cases of overdosage have been reported; most have not been associated with adverse experiences. Reported adverse experiences have not been serious.

Simvastatin: A few cases of overdosage have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae.

Management of overdose: No specific treatment of overdosage with EZESIM can be recommended. In the event of an overdose, symptomatic and supportive measures should be employed. Co-administration of ezetimibe (1 000 mg/kg) and simvastatin (1 000 mg/kg) was well-tolerated in acute, oral toxicity studies in mice and rats. No clinical signs of toxicity were observed in these animals. The estimated oral LD50 for both species was ezetimibe greater than or equal to 1 000 mg/kg and simvastatin greater than or equal to 1 000 mg/kg.