Ezetimibe Sandoz

Ezetimibe Sandoz

ezetimibe

Manufacturer:

Sandoz

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Ezetimibe.
Description
Each tablet contains 10 mg of ezetimibe.
Excipients/Inactive Ingredients: Lactose monohydrate, hypromellose, croscarmellose sodium, microcrystalline cellulose, sodium lauryl sulfate, magnesium stearate.
Excipient(s) with known effect: 68 mg lactose monohydrate.
Action
Pharmacotherapeutic Group: Lipid modifying agents, Other lipid modifying agents. ATC code: C10A X09.
Pharmacology: Pharmacodynamics: Ezetimibe Sandoz is in a new class of lipid-lowering compounds that selectively inhibit the intestinal absorption of cholesterol and related plant sterols. Ezetimibe Sandoz is orally active, and has a mechanism of action that differs from other classes of cholesterol-reducing compounds (e.g. statins, bile acid sequestrants [resins], fibric acid derivatives, and plant stanols). The molecular target of ezetimibe is the sterol transporter, Niemann- Pick C1-Like 1 (NPC1L1), which is responsible for the intestinal uptake of cholesterol and phytosterols.
Ezetimibe localises at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver; statins reduce cholesterol synthesis in the liver and together these distinct mechanisms provide complementary cholesterol reduction. In a 2-week clinical study in 18 hypercholesterolaemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo.
A series of preclinical studies was performed to determine the selectivity of ezetimibe for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of [14C]-cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or fat soluble vitamins A and D.
Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. A beneficial effect of ezetimibe on cardiovascular morbidity and mortality has not yet been demonstrated.
Pharmacokinetics: Absorption: After oral administration, ezetimibe is rapidly absorbed and extensively conjugated to a pharmacologically-active phenolic glucuronide (ezetimibe-glucuronide). Mean maximum plasma concentrations (Cmax) occur within 1 to 2 hours for ezetimibe-glucuronide and 4 to 12 hours for ezetimibe.
The absolute bioavailability of ezetimibe cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection.
Concomitant food administration (high fat or non-fat meals) had no effect on the oral bioavailability of ezetimibe when administered as Ezetimibe Sandoz 10 mg tablets. Ezetimibe Sandoz can be administered with or without food.
Distribution:
Ezetimibe and ezetimibe-glucuronide are bound 99.7% and 88 to 92% to human plasma proteins, respectively.
Biotransformation: Ezetimibe is metabolised primarily in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary excretion. Minimal oxidative metabolism (a phase I reaction) has been observed in all species evaluated. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20 % and 80 to 90 % of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma with evidence of significant enterohepatic recycling. The half-life for ezetimibe and ezetimibe-glucuronide is approximately 22 hours.
Elimination: Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe accounted for approximately 93% of the total radioactivity in plasma. Approximately 78% and 11% of the administered radioactivity were recovered in the faeces and urine, respectively, over a 10-day collection period. After 48 hours, there were no detectable levels of radioactivity in the plasma.
Paediatric population: The absorption and metabolism of ezetimibe are similar between children and adolescents (10 to 18 years) and adults. Based on total ezetimibe, there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the paediatric population <10 years of age are not available. Clinical experience in paediatric and adolescent patients includes patients with HoFH, HeFH, or sitosterolaemia.
Elderly: Plasma concentrations for total ezetimibe are about 2-fold higher in the elderly (≥65 years) than in the young (18 to 45 years). LDL-C reduction and safety profile are comparable between elderly and young subjects treated with ezetimibe. Therefore, no dosage adjustment is necessary in the elderly.
Hepatic impairment: After a single 10 mg dose of ezetimibe, the mean AUC for total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic insufficiency (Child Pugh score 5 or 6), compared to healthy subjects. In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic insufficiency (Child Pugh score 7 to 9), the mean AUC for total ezetimibe was increased approximately 4-fold on Day 1 and Day 14 compared to healthy subjects. No dosage adjustment is necessary for patients with mild hepatic insufficiency. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe (Child Pugh score>9) hepatic insufficiency, Ezetimibe Sandoz is not recommended in these patients (see Precautions).
Renal impairment: After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl ≤ 30 ml/min/1.73m2), the mean AUC for total ezetimibe was increased approximately 1.5-fold, compared to healthy subjects (n=9). This result is not considered clinically significant. No dosage adjustment is necessary for renally impaired patients.
An additional patient in this study (post-renal transplant and receiving multiple medications, including ciclosporin) had a 12-fold greater exposure to total ezetimibe.
Gender: Plasma concentrations for total ezetimibe are slightly higher (approximately 20%) in women than in men. LDL-C reduction and safety profile are comparable between men and women treated with ezetimibe. Therefore, no dosage adjustment is necessary on the basis of gender.
Toxicology: Preclinical safety data: Animal studies on the chronic toxicity of ezetimibe identified no target organs for toxic effects. In dogs treated for four weeks with ezetimibe (≥ 0.03 mg/kg/day) the cholesterol concentration in the cystic bile was increased by a factor of 2.5 to 3.5. However, in a one-year study on dogs given doses of up to 300 mg/kg/day no increased incidence of cholelithiasis or other hepatobiliary effects were observed. The significance of these data for humans is not known. A lithogenic risk associated with the therapeutic use of Ezetimibe Sandoz cannot be ruled out.
In co-administration studies with ezetimibe and statins the toxic effects observed were essentially those typically associated with statins. Some of the toxic effects were more pronounced than observed during treatment with statins alone. This is attributed to pharmacokinetic and pharmacodynamic interactions in co-administration therapy. No such interactions occurred in the clinical studies. Myopathies occurred in rats only after exposure to doses that were several times higher than the human therapeutic dose (approximately 20 times the AUC level for statins and 500 to 2,000 times the AUC level for the active metabolites).
In a series of in vivo and in vitro assays ezetimibe, given alone or co-administered with statins, exhibited no genotoxic potential. Long-term carcinogenicity tests on ezetimibe were negative.
Ezetimibe had no effect on the fertility of male or female rats, nor was it found to be teratogenic in rats or rabbits, nor did it affect prenatal or postnatal development. Ezetimibe crossed the placental barrier in pregnant rats and rabbits given multiple doses of 1,000 mg/kg/day. The co-administration of ezetimibe and statins was not teratogenic in rats. In pregnant rabbits a small number of skeletal deformities (fused thoracic and caudal vertebrae, reduced number of caudal vertebrae) were observed. The co-administration of ezetimibe with lovastatin resulted in embryolethal effects.
Indications/Uses
Primary hypercholesterolaemia: Ezetimibe Sandoz, 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.
Ezetimibe Sandoz 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.
Homozygous Familial Hypercholesterolaemia (HoFH): Ezetimibe Sandoz 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): Ezetimibe Sandoz is indicated as adjunctive therapy to diet for use in patients with homozygous familial sitosterolaemia.
Prevention of Major Cardiovascular Events in Chronic Kidney Disease: Ezetimibe Sandoz, administered with simvastatin, is indicated to reduce the risk of major cardiovascular events in patients with chronic kidney disease.
Prevention of Cardiovascular Disease: Ezetimibe Sandoz administered in combination with a statin, is indicated to reduce the risk of cardiovascular events (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina, or need for revascularization), in patients with coronary heart disease (CHD).
Dosage/Direction for Use
The patient should be on an appropriate lipid lowering diet and should continue on this diet during treatment with Ezetimibe Sandoz.
Route of administration is oral. The recommended dose is one Ezetimibe Sandoz 10 mg tablet daily. Ezetimibe Sandoz can be administered at any time of the day, with or without food.
When Ezetimibe Sandoz 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.
Co-administration with bile acid sequestrants: Dosing of Ezetimibe Sandoz should occur either ≥ 2 hours before or ≥ 4 hours after administration of a bile acid sequestrant.
Use in the elderly: No dosage adjustment is required for elderly patients (see Pharmacology: Pharmacokinetics under Actions).
Paediatric population: Initiation of treatment must be performed under review of a specialist.
Adolescents ≥ 10 years (pertubal status: boys Tanner Stage II and above and girls who are at least one year post-menarche): No dosage adjustment is required (see Pharmacology: Pharmacokinetics under Actions). The clinical experience in paediatric and adolescent patients (aged 10 to 17 years old) is however limited.
When Ezetimibe Sandoz is administered with simvastatin, the dosage instructions for simvastatin, in adolescents should be consulted.
Children < 10 years: Ezetimibe Sandoz is not recommended for use in children below age 10 due to insufficient data on safety and efficacy (see Pharmacology: Pharmacokinetics under Actions).
Use in hepatic impairment: No dosage adjustment is required in patients with mild hepatic insufficiency (Child Pugh score 5 to 6). Treatment with Ezetimibe Sandoz is not recommended in patients with moderate (Child Pugh score 7 to 9) or severe (Child Pugh score>9) liver dysfunction. (See Precautions and Pharmacology: Pharmacokinetics under Actions.)
Use in renal impairment: No dosage adjustment is required for renally impaired patients (see Pharmacology: Pharmacokinetics under Actions).
Overdosage
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 5,000 mg/kg of ezetimibe in rats and mice and 3,000 mg/kg in dogs.
A few cases of overdose with ezetimibe 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.
Contraindications
Hypersensitivity to the active substance or to any of the excipients.
When Ezetimibe Sandoz is co-administered with a statin, please refer to the SmPC for that particular medicinal product.
Therapy with Ezetimibe Sandoz co-administered with a statin is contraindicated during pregnancy and lactation.
Ezetimibe Sandoz co-administered with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases.
Special Precautions
When Ezetimibe Sandoz is co-administered with a statin, please refer to the SmPC for that particular medicinal product.
Liver enzymes: In controlled co-administration trials in patients receiving ezetimibe with a statin, consecutive transaminase elevations (≥ 3 X the upper limit of normal [ULN]) have been observed. When Ezetimibe Sandoz 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 Adverse Reactions.)
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 Adverse Reactions.)
In a controlled clinical study in which over 9000 patients with chronic kidney disease were randomised to receive ezetimibe 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 ezetimibe combined with simvastatin and 0.6% for placebo (see Adverse Reactions).
Skeletal muscle: 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. If myopathy is suspected based on muscle symptoms or is confirmed by a creatine phosphokinase (CPK) level>10 times the ULN, Ezetimibe Sandoz, any statin, and any of these other agents that the patient is taking concomitantly should be immediately discontinued. All patients starting therapy with Ezetimibe Sandoz should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness (see Adverse Reactions).
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 Adverse Reactions.)
In a clinical trial in which over 9000 patients with chronic kidney disease were randomised to receive ezetimibe 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 ezetimibe combined with simvastatin and 0.1% for placebo (see Adverse Reactions).
Fibrates: The safety and efficacy of Ezetimibe Sandoz administered with fibrates have not been established.
If cholelithiasis is suspected in a patient receiving Ezetimibe Sandoz and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued (see Interactions and Adverse Reactions).
Ciclosporin: Caution should be exercised when initiating Ezetimibe Sandoz in the setting of ciclosporin. Ciclosporin concentrations should be monitored in patients receiving Ezetimibe Sandoz and ciclosporin (see Interactions).
Anticoagulants: If Ezetimibe Sandoz is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalised Ratio (INR) should be appropriately monitored (see Interactions).
Excipient: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicine.
Patients with hepatic impairment: Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic impairment, Ezetimibe Sandoz is not recommended (see Pharmacology: Pharmacokinetics under Actions).
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.
Use in Children: Efficacy and safety of ezetimibe in patients 6 to 10 years of age with heterozygous familial or non-familial hypercholesterolemia 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 Adverse Reactions).
Ezetimibe has not been studied in patients younger than 6 years of age (see Adverse Reactions)
Efficacy and safety of ezetimibe co-administered with simvastatin in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia 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 Dosage & Administration and Adverse Reactions).
The safety and efficacy of Ezetimibe Sandoz 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 ezetimibe coadministered with simvastatin have not been studied in paediatric patients < 10 years of age. (See Dosage & Administration and Adverse Reactions).
The long-term efficacy of therapy with Ezetimibe Sandoz in patients below 17 years of age to reduce morbidity and mortality in adulthood has not been studied.
Use In Pregnancy & Lactation
Ezetimibe Sandoz co-administered with a statin is contraindicated during pregnancy and lactation (see Contraindications), please refer to the SmPC for that particular statin.
Use in Pregnancy: Ezetimibe Sandoz should be given to pregnant women only if clearly necessary. No clinical data are available on the use of Ezetimibe Sandoz 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 Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Use in Lactation: Ezetimibe Sandoz 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 Sandoz on human fertility. Ezetimibe had no effect on the fertility of male or female rats (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Adverse Reactions
List of adverse reactions (clinical studies and post-marketing experience): In clinical studies of up to 112 weeks duration, ezetimibe 10 mg daily was administered alone in 2396 patients, or with a statin in 11,308 patients with fenofibrate in 185 patients. Adverse reactions were usually mild and transient. The overall incidence of side effects was similar between ezetimibe and placebo. Similarly, the discontinuation rate due to adverse experiences was comparable between ezetimibe and placebo.
Ezetimibe administered alone or co-administered with a statin: The following adverse reactions were observed in patients treated with ezetimibe (n=2396) and at a greater incidence than placebo (n=1159) or in patients treated with ezetimibe co-administered 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 ezetimibe either administered alone or with a statin.
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).
Ezetimibe monotherapy: Metabolism and nutrition disorders: Uncommon: Decreased appetite.
Vascula disorders: Uncommon: Hot flush; hypertension.
Respiratory, thoracic and mediastinal disorders: Uncommon: Cough.
Gastrointestinal disorders: Common: Abdominal pain; diarrhoea; flatulence; Uncommon: Dyspepsia; gastrooesophageal reflux disease; nausea.
Musculoskeletal and connective tissue disorders: Uncommon: Arthralgia; muscle spasms; neck pain.
General disorders and administration site condition: Common: Fatigue; Uncommon: Chest pain, pain.
Investigations: Uncommon: ALT and/or AST increased; blood CPK increased; gamma-glutamyltransferase increased; liver function test abnormal.
Additional adverse reactions with ezetimibe coadministered with a statin: 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.
Investigations: Common: ALT and/or AST increased.
Post-marketing experience (with or without a statin): Blood and lymphatic system disorders: Not known: Thrombocytopenia.
Immune system disorders: Not known: Hypersensitivity, including rash, urticaria, anaphylaxis and angioedema.
Psychiatric disorders: Not known: Depression.
Nervous system disorders: Not known: Dizziness; paraesthesia.
Respiratory, thoracic and mediastinal disorders: Not known: Dyspnoea.
Gastro-intestinal disorders: Not known: Pancreatitis; constipation.
Hepatobiliary disorders: Not known: Hepatitis, cholelithiasis, cholecystitis.
Skin and subcutaneous tissue disorders: Not known: Erythema multiforme.
Musculoskeletal and connective tissue disorders: Not known: Myalgia; myopathy/rhabdomyolysis (see Precautions).
General disorders and administration site conditions: Not known: Asthenia.
Ezetimibe coadministered with fenofibrate: Gastrointestinal disorders: Common: Abdominal pain.
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 ezetimibe and fenofibrate completed 12 weeks of therapy, and 230 patients treated with ezetimibe and fenofibrate (including 109 who received ezetimibe 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 ezetimibe 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 ezetimibe coadministered with fenofibrate, respectively (see Precautions and Interactions).
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 (≥ 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.
These trials were not suited for comparison of rare adverse reactions.
Patients with Coronary Heart Disease and ACS Event History: In the IMPROVE-IT study, involving 18,144 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 Precautions). 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), involving over 9000 patients treated with a fixed dose combination of ezetimibe 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 ezetimibe combined with simvastatin, 9.8% in patients treated with placebo). The incidence of myopathy/rhabdomyolysis was 0.2% in patients treated with ezetimibe combined with simvastatin and 0.1% in patients treated with placebo. Consecutive elevations of transaminases (>3 x ULN) occurred in 0.7% of patients treated with ezetimibe combined with simvastatin compared with 0.6% of patients treated with placebo. In this trial, there were no statistically significant increases in the incidence of pre-specified adverse events, including cancer (9.4% for ezetimibe 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 ezetimibe (0.5%) and placebo (0.3%). In co-administration trials, the incidence was 1.3% for patients treated with ezetimibe coadministered 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 Precautions.)
In clinical trials, CPK>10 X ULN was reported for 4 of 1,674 (0.2%) patients administered ezetimibe alone vs 1 of 786 (0.1%) patients administered placebo, and for 1 of 917 (0.1%) patients co-administered ezetimibe and a statin vs 4 of 929 (0.4%) patients administered a statin alone. There was no excess of myopathy or rhabdomyolysis associated with ezetimibe compared with the relevant control arm (placebo or statin alone) (see Precautions).
Drug Interactions
In preclinical studies, it has been shown that ezetimibe does not induce cytochrome P450 medicinal products metabolising enzymes. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and medicinal products 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 Ezetimibe Sandoz to cholestyramine may be lessened by this interaction (see Dosage & Administration).
Fibrates: In patients receiving fenofibrate and Ezetimibe Sandoz, physicians should be aware of the possible risk of cholelithiasis and gallbladder disease (see Precautions and Adverse Reactions).
If cholelithiasis is suspected in a patient receiving Ezetimibe Sandoz and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued (see Adverse Reactions).
Concomitant fenofibrate or gemfibrozil administration modestly increased total ezetimibe concentrations (approximately 1.5- and 1.7-fold respectively).
Co-administration of Ezetimibe Sandoz 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 Pharmacology: Toxicology: Preclinical Safety Data under Actions). A lithogenic risk associated with the therapeutic use of Ezetimibe Sandoz cannot be ruled out.
Statins: No clinically significant pharmacokinetic interactions were seen when ezetimibe was coadministered 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 ezetimibe 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 Ezetimibe Sandoz in the setting of ciclosporin. Ciclosporin concentrations should be monitored in patients receiving Ezetimibe Sandoz and ciclosporin (see Precautions).
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 ezetimibe added to warfarin or fluindione. If Ezetimibe Sandoz is added to warfarin, another coumarin anticoagulant, or fluindione, INR should be appropriately monitored (see Precautions).
Paediatric population: Interaction studies have only been performed in adults.
Caution For Usage
Special precautions for disposal and other handling: No special requirements.
Incompatibilities: Not applicable.
Storage
Store below 30°C. Protect from moisture.
ATC Classification
C10AX09 - ezetimibe ; Belongs to the class of other lipid modifying agents.
Presentation/Packing
Tab (white to almost white, oval with debossing "10" on one side and "EZT" on the other side) 10 mg x 30's.
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in