Ezetrol

Ezetimibe.

Each Ezetimibe (EZETROL) Tablet for oral administration contains 10 mg Ezetimibe.
Excipients/Inactive Ingredients: Each 10 mg tablet contains croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and sodium laurilsulfate.

Pharmacotherapeutic group: Ezetimibe (EZETROL) is in a new class of lipid-lowering compounds that selectively inhibit the intestinal absorption of cholesterol and related plant sterols.

Primary Hypercholesterolemia: Ezetimibe (EZETROL) Tablet, 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), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C) and to increase high-density lipoprotein cholesterol (HDL-C) in adult and adolescent (10 to 17 years of age) patients with primary (heterozygous familial and non-familial) hypercholesterolemia.
Ezetimibe (EZETROL) Tablet, administered in combination with fenofibrate, is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B, and non-HDL-C in adult patients with mixed hyperlipidemia.
Prevention of Cardiovascular Disease: Ezetimibe (EZETROL), administered with a statin, is indicated to reduce the risk of cardiovascular events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, or need for revascularization), in patients with coronary heart disease (CHD).
Prevention of Major Cardiovascular Events in Chronic Kidney Disease: Ezetimibe (EZETROL), administered with simvastatin, is indicated to reduce the risk of major cardiovascular events (nonfatal myocardial infarction or cardiac death, stroke, or any revascularization procedure) in patients with chronic kidney disease.
Homozygous Familial Hypercholesterolemia (HoFH): Ezetimibe (EZETROL) Tablet, administered with a statin, is indicated for the reduction of elevated total-C and LDL-C levels in adult and adolescent (10 to 17 years of age) patients with HoFH. Patients may also receive adjunctive treatments (e.g., LDL apheresis).
Homozygous Sitosterolemia (Phytosterolemia): Ezetimibe (EZETROL) Tablet is indicated for the reduction of elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia.

The patient should be on an appropriate lipid-lowering diet and should continue on this diet during treatment with Ezetimibe (EZETROL) Tablet.
Use in Patients with Primary Hypercholesterolemia: The recommended dose of Ezetimibe (EZETROL) Tablet is 10 mg once daily, used alone, with a statin, or with fenofibrate. Ezetimibe (EZETROL) Tablet can be administered at any time of the day, with or without food.
Use in Patients with Renal Impairment/Chronic Kidney Disease: Monotherapy: In patients with renal impairment, no dosage adjustment of Ezetimibe (EZETROL) Tablet is necessary.
Combination Therapy with Simvastatin: In patients with mild renal impairment (estimated GFR ≥60 mL/min/1.73 m²), no dosage adjustment of Ezetimibe (EZETROL) Tablet or simvastatin is necessary. In patients with chronic kidney disease and estimated glomerular filtration rate <60 mL/min/1.73 m², the dose of Ezetimibe (EZETROL) Tablet 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 PRECAUTIONS).
Use in the Elderly: No dosage adjustment is required for elderly patients.
Use in Pediatric Patients: Children and adolescents ≥6 years: No dosage adjustment is required.
Children <6 years: Treatment with Ezetimibe (EZETROL) Tablet is not recommended.
Use in Hepatic Impairment: No dosage adjustment is required in patients with mild hepatic insufficiency (Child-Pugh score 5 to 6). Treatment with ezetimibe is not recommended in patients with moderate (Child-Pugh score 7 to 9) or severe (Child-Pugh score >9) liver dysfunction (see PRECAUTIONS).
Co-administration with bile acid sequestrants: Dosing of Ezetimibe (EZETROL) Tablet should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant.

In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, 40 mg/day to 18 patients with primary hypercholesterolemia for up to 56 days, and 40mg/day to 27 patients with homozygous sitosterolemia for 26 weeks, was generally well tolerated.
A few cases of overdosage with Ezetimibe (EZETROL) Tablet 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.

Hypersensitivity to any component of this medication.
When Ezetimibe (EZETROL) Tablet is to be administered with a statin or with fenofibrate, please refer to the Package Insert for that particular medication.

When Ezetimibe (EZETROL) Tablet is to be administered with a statin or with fenofibrate, please refer to the Package Insert for that particular medication.
Liver Enzymes: In controlled co-administration trials in patients receiving Ezetimibe (EZETROL) Tablet with a statin, consecutive transaminase elevations (≥3 X the upper limit of normal [ULN]) have been observed. When Ezetimibe (EZETROL) Tablet 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 SIDE EFFECTS).
In the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), 18,144 patients with CHD were randomized 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 SIDE EFFECTS).
In a controlled clinical study in which over 9000 patients with chronic kidney disease were randomized to receive Ezetimibe (EZETROL) Tablet 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 (EZETROL) Tablet combined with simvastatin and 0.6% for placebo (see SIDE EFFECTS).
Skeletal Muscle: In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with Ezetimibe (EZETROL) Tablet compared with the relevant control arm (placebo or statin alone). However, myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs. In clinical trials, the incidence of CPK >10 X ULN was 0.2% for Ezetimibe (EZETROL) Tablet vs 0.1% for placebo, and 0.1% for Ezetimibe (EZETROL) Tablet co-administered with a statin vs 0.4% for statins alone.
In post-marketing experience with Ezetimibe (EZETROL) Tablet, cases of myopathy and rhabdomyolysis have been reported regardless of causality. Most patients who developed rhabdomyolysis were taking a statin prior to initiating Ezetimibe (EZETROL) Tablet. However, rhabdomyolysis has been reported very rarely with Ezetimibe (EZETROL) Tablet monotherapy and very rarely with the addition of Ezetimibe (EZETROL) Tablet to agents known to be associated with increased risk of rhabdomyolysis. All patients starting therapy with Ezetimibe (EZETROL) Tablet should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. Ezetimibe (EZETROL) Tablet 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.
In IMPROVE-IT, 18,144 patients with CHD were randomized 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 X ULN and <10 X ULN on two consecutive occasions with evidence of renal injury or CK ≥10,000 IU/L without evidence of renal injury (see SIDE EFFECTS).
In a clinical trial in which over 9000 patients with chronic kidney disease were randomized to receive Ezetimibe (EZETROL) Tablet 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 (EZETROL) Tablet combined with simvastatin and 0.1% for placebo (see SIDE EFFECTS).
Hepatic Insufficiency: Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, Ezetimibe (EZETROL) Tablet is not recommended in these patients.
Fibrates: The co-administration of ezetimibe with fibrates other than fenofibrate has not been studied. Therefore, co-administration of Ezetimibe (EZETROL) Tablet and fibrates (other than fenofibrate) is not recommended (see INTERACTIONS).
Fenofibrate: If cholelithiasis is suspected in a patient receiving Ezetimibe (EZETROL) Tablet and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered (see SIDE EFFECTS and the Package Insert for fenofibrate).
Cyclosporine: Caution should be exercised when initiating ezetimibe in the setting of cyclosporine. Cyclosporine concentrations should be monitored in patients receiving Ezetimibe (EZETROL) Tablet and cyclosporine (see INTERACTIONS).
Anticoagulants: If Ezetimibe (EZETROL) Tablet is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalized Ratio (INR) should be appropriately monitored (see INTERACTIONS).
Pediatric Use: Safety and effectiveness of Ezetimibe (EZETROL) Tablet in patients 6 to 10 years of age with heterozygous familial or non-familial hypercholesterolemia have been evaluated in a 12-week controlled clinical trial. Children treated with Ezetimibe (EZETROL) Tablet had an adverse experience profile similar to that of adult patients treated with Ezetimibe (EZETROL) Tablet. In this study, there was generally no detectable effect on growth or sexual maturation in either boys or girls. However the effects of ezetimibe for a treatment period greater than 12 weeks on growth and sexual maturation have not been studied (see DOSAGE & ADMINISTRATION and SIDE EFFECTS).
Safety and effectiveness of Ezetimibe (EZETROL) Tablet 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 and in girls who were at least one year post-menarche. Adolescent patients treated with Ezetimibe (EZETROL) Tablet and up to 40 mg/day simvastatin had an adverse experience profile similar to that of adult patients treated with Ezetimibe (EZETROL) Tablet and simvastatin. In this controlled study, there was no detectable effect on growth or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls (see DOSAGE & ADMINISTRATION and SIDE EFFECTS).

Pregnancy: No clinical data on exposed pregnancies are available. Animal studies of ezetimibe administered alone do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development. However, caution should be exercised when prescribing to pregnant women. When ezetimibe was given with lovastatin, simvastatin, pravastatin or atorvastatin, no teratogenic effects were observed in embryo-fetal development studies in pregnant rats. In pregnant rabbits, a low incidence of skeletal malformations was observed.
When ezetimibe is to be administered with a statin, please refer to the Package Insert for that particular statin.
Nursing Mothers: Studies in rats have shown that ezetimibe is excreted in milk. It is not known whether ezetimibe is excreted into human breast milk, therefore, Ezetimibe (EZETROL) Tablet should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant.

Clinical studies of up to 112 weeks duration in which Ezetimibe (EZETROL) Tablet 10 mg daily was administered alone (n=2396), with a statin (n=11,308), or with fenofibrate (n=185), patients demonstrated: Ezetimibe (EZETROL) Tablet was generally well tolerated, adverse reactions were usually mild and transient, the overall incidence of side effects reported with Ezetimibe (EZETROL) Tablet was similar to that reported with placebo, and the discontinuation rate due to adverse experiences was comparable between Ezetimibe (EZETROL) Tablet and placebo.
The following common (≥1/100, <1/10) or uncommon (≥1/1,000, <1/100); drug-related adverse experiences were reported in patients taking Ezetimibe (EZETROL) Tablet alone (n=2396) and at a greater incidence than placebo (n=1159), or in patients taking Ezetimibe (EZETROL) Tablet co-administered with a statin (n=11,308) and at a greater incidence than statin administered alone (n=9361).
Ezetimibe (EZETROL) Tablet administered alone: Investigations: Uncommon: ALT and/or AST increased; blood CPK increased; gamma-glutamyltransferase increased; liver function test abnormal.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: cough.
Gastrointestinal Disorders: Common: Abdominal pain; diarrhea; 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 Condition: Common: Fatigue. Uncommon: Chest pain; pain.
Ezetimibe (EZETROL) Tablet co-administered with a statin: Investigations: Common: ALT and/or AST increased.
Nervous System Disorders: Common: Headache. Uncommon: Paresthesia.
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; edema peripheral.
Ezetimibe (EZETROL) Tablet co-administered with fenofibrate: Gastrointestinal Disorders: Common: Abdominal pain.
In a multicenter, double-blind, placebo-controlled, clinical study in patients with mixed hyperlipidemia, 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, 8.8) and 2.7% (1.2, 5.4) for fenofibrate monotherapy and Ezetimibe (EZETROL) Tablet 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 (EZETROL) Tablet co-administered with fenofibrate, respectively (see PRECAUTIONS). There were no CPK elevations >10 X ULN in either treatment group in this study.
Patients with Coronary Heart Disease: In the IMPROVE-IT study, involving 18,144 patients treated with either ezetimibe/simvastatin 10/40 mg (n=9067; of whom 6% were uptitrated toezetimibe/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 X ULN and <10 X 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 hospitalizations 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 (EZETROL) Tablet 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 (EZETROL) Tablet combined with simvastatin, 9.8% in patients treated with placebo). The incidence of myopathy/rhabdomyolysis was 0.2% in patients treated with Ezetimibe (EZETROL) Tablet 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 (EZETROL) Tablet combined with simvastatin compared with 0.6% of patients treated with placebo. (See PRECAUTIONS). In this trial, there were no statistically significant increases in the incidence of pre-specified adverse events, including cancer (9.4% for Ezetimibe (EZETROL) Tablet combined with simvastatin, 9.5% for placebo), hepatitis, cholecystectomy or complications of gallstones or pancreatitis.
Pediatric (6 to 17 Years of Age) Patients: In a study involving pediatric (6 to10 years of age) patients with heterozygous familial or non-familial hypercholesterolemia (n=138), the safety and tolerability profile of the group treated with Ezetimibe (EZETROL) Tablet was similar to that of adult patients treated with Ezetimibe (EZETROL) Tablet (see Pediatric Use under PRECAUTIONS).
In a study involving adolescent (10 to 17 years of age) patients with heterozygous familial hypercholesterolemia (n=248), the safety and tolerability profile of the group co-administered Ezetimibe (EZETROL) Tablet and simvastatin was similar to that of adult patients co-administered Ezetimibe (EZETROL) Tablet and simvastatin (see USE IN CHILDREN under PRECAUTIONS).
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 (EZETROL) Tablet (0.5 %) and placebo (0.3%). In co-administration trials, the incidence was 1.3% for patients treated with Ezetimibe (EZETROL) Tablet 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 PRECAUTIONS).
Clinically important elevations of CPK (≥10 X ULN) in patients treated with Ezetimibe (EZETROL) Tablet administered alone or co-administered with a statin were similar to elevations seen with placebo or statin administered alone, respectively.
Post-marketing Experience: The following adverse reactions have been reported in post-marketing experience, regardless of causality assessment: Blood and Lymphatic System Disorders: Thrombocytopaenia.
Nervous System Disorders: Dizziness; paraesthesia.
Gastrointestinal Disorders: Pancreatitis; constipation.
Skin and Subcutaneous Tissue Disorders: Erythema multiforme.
Musculoskeletal and Connective Tissue Disorders: Myalgia; myopathy/rhabdomyolysis (see PRECAUTIONS).
General Disorders and Administration Site Conditions: Asthenia.
Immune System Disorders: Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria.
Hepatobiliary Disorders: Hepatitis; cholelithiasis; cholecystitis.
Psychiatric Disorders: Depression.

In preclinical studies, it has been shown that ezetimibe does not induce cytochrome P450 drug metabolizing enzymes. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and drugs known to be metabolized by cytochromes P450 1A2, 2D6, 2C8, 2C9, and 3A4, or N-acetyltransferase.
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 AUC of total ezetimibe (ezetimibe + ezetimibe glucuronide) approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be lessened by this interaction.
Cyclosporine: In a study of eight post-renal transplant patients with creatinine clearance of  >50 mL/min on a stable dose of cyclosporine, 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 from another study (n=17). In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m²) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to concurrent controls. 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 cyclosporine on Day 7 resulted in a mean 15% increase in cyclosporine AUC (range 10% decrease to 51% increase) compared to a single 100-mg dose of cyclosporine alone (see PRECAUTIONS).
Fibrates: The safety and effectiveness of ezetimibe co-administered with fenofibrate have been evaluated in a clinical study (see SIDE EFFECTS); co-administration of ezetimibe with other fibrates has not been studied. 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 Ezetimibe (EZETROL) Tablet with fibrates (other than fenofibrate) is not recommended until use in patients is studied.
Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. This increase is not considered clinically significant.
Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. This increase is not considered clinically significant. No clinical data are available.
Statins: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, or rosuvastatin.
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. There have been post-marketing reports of increased International Normalized Ratio in patients who had Ezetimibe (EZETROL) Tablet added to warfarin or fluindione. Most of these patients were also on other medications (see PRECAUTIONS).

Store at temperature not exceeding 30°C. Store in the original package.

Dyslipidaemic Agents

C10AX09 - ezetimibe ; Belongs to the class of other lipid modifying agents.

Rx