Ezetrol

Ezetrol

ezetimibe

Manufacturer:

Merck Sharp & Dohme

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Ezetimibe.
Action
Ezetrol is a new class of lipid-lowering compounds that selectively inhibit the intestinal absorption of cholesterol and related plant sterols.
Pharmacology: Mechanism of Action: Ezetimibe is orally active and potent, with a unique mechanism of action that differs from other classes of cholesterol-reducing compounds [eg, statins, bile acid sequestrants (resins), fibric acid derivatives and plant stanols].
Ezetimibe localizes 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. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood. Ezetimibe does not increase bile acid excretion (like bile acid sequestrants) and does not inhibit cholesterol synthesis in the liver (like statins).
In a 2-week clinical study in 18 hypercholesterolemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo. By inhibiting the absorption of intestinal cholesterol, ezetimibe reduces the delivery of cholesterol to the liver. Statins reduce cholesterol synthesis in the liver. Together these distinct mechanisms provide complementary cholesterol reduction. Ezetimibe, administered with a statin, reduces total-C, LDL-C, Apo B and TG and increases HDL-C in patients with hypercholesterolemia, beyond either treatment alone.
Clinical studies demonstrate that elevated levels of total-C, LDL-C and Apo B, the major protein constituent of LDL, promote human atherosclerosis. In addition, decreased levels of HDL-C are associated with the development of atherosclerosis. 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. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including very low density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis.
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 the fat soluble vitamins A and D.
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 1-2 hrs for ezetimibe-glucuronide and 4-12 hrs 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 10-mg tablets. Ezetimibe can be administered with or without food.
Distribution: Ezetimibe and ezetimibe-glucuronide are bound 99.7% and 88-92% to human plasma proteins, respectively.
Metabolism: Ezetimibe is metabolized 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 10-20% and 80-90% 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 hrs.
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 feces and urine, respectively, over a 10-day collection period. After 48 hrs, there were no detectable levels of radioactivity in the plasma.
Characteristics in Patients (Special Populations): Pediatric Patients: The absorption and metabolism of ezetimibe are similar between children and adolescents (10-18 years) and adults. Based on total ezetimibe, there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population <10 years are not available. Clinical experience in pediatric and adolescent patients (9-17 years) has been limited to patients with HoFH or sitosterolemia.
Geriatric Patients: Plasma concentrations for total ezetimibe are about 2-fold higher in the elderly (≥65 years) than in the young (18-45 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 Insufficiency: After a single 10-mg dose of ezetimibe, the mean area under the curve (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 7-9), 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 is not recommended in these patients (see Precautions).
Renal Insufficiency: After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl ≤30 mL/min), 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 cyclosporine) had a 12-fold greater exposure to total ezetimibe.
Gender: Plasma concentrations for total ezetimibe are slightly higher (<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.
Race: Based on a meta-analysis of pharmacokinetic studies, there were no pharmacokinetic differences between Blacks and Caucasians.
Indications/Uses
Primary Hypercholesterolaemia: Ezetrol, administered alone, or with an HMG-CoA reductase inhibitor (statin), is indicated as adjunctive therapy to diet in patients with primary (heterozygous familial and non-familial) hypercholesterolaemia.
Ezetrol, 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 patients with mixed hyperlipedemia. Homozygous Familial Hypercholesterolaemia (HoFH): Ezetrol, administered with a statin, is indicated for patients with HoFH. Patients may also receive adjunctive treatments (eg, LDL apheresis).
Homozygous Sitosterolaemia (Phytosterolaemia): Ezetrol is indicated for the reduction of elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolaemia.
Dosage/Direction for Use
The patient should be on an appropriate lipid-lowering diet and should continue on this diet during treatment with Ezetrol.
The recommended dose of Ezetrol is 10 mg once daily, used alone or with a statin. Ezetrol can be administered at any time of the day, with or without food.
Ezetrol may be administered with an HMG-CoA reductase inhibitor for incremental effect. For convenience, the daily dose of Ezetrol may be taken at the same time as the HMG-CoA reductase inhibitor, according to the dosing recommendations for the HMG-CoA reductase inhibitor.
If Ezetrol 10 mg tablets are used in combination with a statin therapy, the dosage instructions for that particular statin should be consulted.
When initiating lipid-lowering treatment, which includes Ezetrol 10 mg tablets and a statin in combination, the indicated usual initial dose of that particular statin should be used or the already established higher statin dose should be continued.
If the statin dose is to be increased for the first time or further the dosage instructions of that particular statin should be followed (eg, dose increase only after 4 weeks of regular use of the combination without any change).
The stepwise increase of the statin dose in combination treatment results in a relatively small additional decrease of LDL-C, but increases the risk of dose-related adverse events of the statin. This has to be considered for the risk-benefit-assessment when the statin dose is considered.
If Ezetimibe is used in combination with bile acid sequestrants, dosing of ezetimibe should occur either ≥2 hrs before or ≥4 hrs after administration of bile acid sequestrants.
Children and Adolescents ≥10 years: No dosage adjustment is required (see Special Populations under Actions).
Children <10 years: Treatment with Ezetrol is not recommended.
Elderly: No dosage adjustment is required for elderly patients (see Special Populations under Actions). However, greater sensitivity of the same older individuals cannot be ruled out.
Hepatic Impairment: No dosage adjustment is required in patients with mild hepatic insufficiency (Child Pugh score 5-6). Treatment with Ezetrol is not recommended in patients with moderate (Child Pugh score 7-9) or severe (Child Pugh score >9) liver dysfunction. (See Special Populations under Actions and Precautions).
Renal Impairment: No dosage adjustment is required for renally impaired patients (see Special Populations under Actions).
Co-administration with bile acid sequestrants: Dosing of Ezetrol should occur either ≥2 hrs before or ≥4 hrs after administration of a bile acid sequestrant.
Overdosage
No cases of overdosage with Ezetrol have been reported. Administration of Ezetrol, 50 mg/day, to 15 subjects for up to 14 days was generally well tolerated. In the event of an overdose, symptomatic and supportive measures should be employed.
Contraindications
Patients with known hypersensitivity to any component of Ezetrol.
The combination of ezetimibe with an HMG-CoA reductase inhibitor is contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases.
All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ezetimibe is administered with an HMG-CoA reductase inhibitors in a woman of childbearing potential, refer to Use in pregnancy under Precautions and the product labeling for HMG-CoA reductase inhibitors.
Special Precautions
When ezetimibe is to be administered with a statin, refer to the information for that particular statin.
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 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).
Hepatic Insufficiency: Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, ezetimibe is not recommended in these patients (see Special Populations under Actions).
Fibrates: The safety and efficacy of ezetimibe administered with fibrates have not been established, therefore, co-administration of ezetimibe and fibrates is not recommended (see Interactions).
Cyclosporine: Caution should be exercised when initiating ezetimibe in the setting of cyclosporine (see Interactions).
Skeletal Muscle: In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with ezetimibe compared with the relevant control arm (placebo or HMG-CoA reductase inhibitor alone). However, myopathy and rhabdomyolysis are known adverse reactions to HMG-CoA reductase inhibitors and other lipid-lowering drugs. In clinical trials, the incidence of CPK >10 x ULN was 0.2% for ezetimibe versus 0.1% for placebo, and 0.1% for ezetimibe co-administered with an HMG-CoA reductase inhibitor versus 0.4% for HMG-CoA reductase inhibitor.
Use in pregnancy: There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus.
In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24 hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24 hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses.
Multiple-dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy.
Use in lactation: 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 should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant.
Use In Pregnancy & Lactation
Use in pregnancy: There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus.
In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24 hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24 hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses.
Multiple-dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy.
Use in lactation: 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 should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant.
Side Effects
Clinical studies of 8-14 weeks duration in which Ezetrol 10 mg daily was administered alone or with a statin in 3366 patients demonstrated: Ezetrol was generally well tolerated, adverse reactions were usually mild and transient, the overall incidence of side effects reported with Ezetrol was similar to that reported with placebo and the discontinuation rate due to adverse experiences was comparable between Ezetrol and placebo.
The following common (≥1/100, <1/10) drug-related adverse experiences were reported in patients taking Ezetrol alone (n=1691) or co-administered with a statin (n=1675).
Ezetrol Administered Alone: Headache; abdominal pain, diarrhea.
Ezetrol Co-administered With a Statin: Headache, fatigue, abdominal pain, constipation, diarrhea, flatulence, nausea, increased ALT, increased AST, myalgia.
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 Ezetrol (0.5%) and placebo (0.3%). In co-administration trials, the incidence was 1.2% for patients treated with Ezetrol co-administered with a statin and 0.4% for patients treated with a statin alone. These elevations were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment. (See Precautions).
Clinically important elevations of CPK (≥10 x ULN) in patients treated with Ezetrol administered alone or co-administered with a statin were similar to elevations seen with placebo or statin administered alone, respectively.
Post-Marketing Experience: The following adverse reactions have been reported in post-marketing experience: Hypersensitivity reactions, including angioedema and rash.
Drug Interactions
In preclinical studies, it has been shown that ezetimibe does not induce cytochrome P-450 drug metabolizing enzymes. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and drugs known to be metabolized by cytochromes P-450 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, midazolam, or warfarin 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 8 postrenal 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.
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 Ezetrol 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 Ezetrol with fibrates is not recommended until use in patients is studied.
Statins: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin.
Storage
Do not store above 30°C (86°F). Store in original package.
ATC Classification
C10AX09 - ezetimibe ; Belongs to the class of other lipid modifying agents.
Presentation/Packing
Tab 10 mg (white to off-white, capsule-shaped, debossed) x 30's.
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