Ezetrol™

Ezetimibe

Cholesterol Absorption Inhibitor

Merck Frosst

http://www.merck.com/

Ezetrol Monograph PDF download here.

 

 

Schering

 

CPS:PIS_m210100

 

 

 

Pharmacology

EZETROL (ezetimibe) is in a new class of lipid-lowering compounds that selectively inhibit the intestinal absorption of cholesterol and related plant sterols. EZETROL is orally active, with a unique mechanism of action that differs from other classes of cholesterol-reducing compounds e.g., HMG-CoA reductase inhibitors (statins), bile acid sequestrants (resins), fibric acid derivatives, 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 results in a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood. Ezetimibe does not increase bile acid excretion in contrast to bile acid sequestrants and does not inhibit cholesterol synthesis in the liver as do statins. EZETROL and statins have distinct mechanisms of action that provide complementary cholesterol reduction.

     Clinical studies have demonstrated that elevated levels of total-C, low density lipoprotein cholesterol (LDL-C) and apolipoprotein B (Apo B; the major protein constituent of LDL), promote atherosclerosis in humans. In addition, decreased levels of high density lipoprotein cholesterol (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. The effects of ezetimibe given either alone or in addition to a statin on cardiovascular morbidity and mortality have not been established.

     Preclinical studies in animals were 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.

     In a study of hypercholesterolemic patients, EZETROL inhibited intestinal cholesterol absorption by 54%, compared with placebo. EZETROL had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and E, and did not impair adrenocortical steroid hormone production.

 

Pharmacokinetics

Absorption

After oral administration, ezetimibe is rapidly absorbed and extensively conjugated to a phenolic glucuronide (ezetimibe-glucuronide) form which is at least as pharmacologically active as the parent drug. Mean ezetimibe peak plasma concentrations (C_max) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (T_max). Ezetimibe-glucuronide mean C_max values of 45 to 71 ng/mL were achieved between 1 and 2 hours (T_max). The extent of absorption and 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 extent of absorption of ezetimibe when administered as EZETROL 10 mg tablets. C_max of ezetimibe was increased by 38% when taken with high fat meals.

Distribution

Ezetimibe and ezetimibe-glucuronide are bound 99.7% and 88 to 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 and renal excretion. Minimal oxidative metabolism (a phase I reaction) has been observed in all species evaluated. Ezetimibe and ezetimibe-glucuronide are the major compounds detected in plasma. The conjugated ezetimibe-glucuronide constitutes 80-90% of plasma drug levels with ezetimibe the remaining 10-20%. 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.

Excretion

Following oral administration of ¹⁴C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) 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. Ezetimibe was the major component in faeces (69% of the administered dose) while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose.

 

Indications

EZETROL (ezetimibe) is indicated as an adjunct to lifestyle changes, including diet at least equivalent to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) TLC diet, when the response to diet and other non-pharmacological measures alone has been inadequate.

Primary Hypercholesterolemia

EZETROL, administered alone or with an HMG-CoA reductase inhibitor (statin), 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), and triglycerides (TG) and to increase high density lipoprotein cholesterol (HDL-C) in patients with primary (heterozygous familial and non-familial) hypercholesterolemia.

Homozygous Familial Hypercholesterolemia (HoFH)

EZETROL, administered with a statin, is indicated for the reduction of elevated total-C and LDL-C levels in patients with HoFH as an adjunct to treatments such as LDL apheresis or if such treatments are not possible.

Homozygous Sitosterolemia (Phytosterolemia)

EZETROL is indicated as adjunctive therapy for the reduction of elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia.

 

Contraindications

Hypersensitivity to any component of this medication.

     When EZETROL is to be administered with a statin, the contraindications to that statin should be reviewed before starting concomitant therapy.

     The combination of EZETROL (ezetimibe) with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases.

     All statins are contraindicated in pregnant and nursing women. When EZETROL is administered with a statin in a woman of childbearing potential, refer to the product labeling for that statin (see Precautions, Pregnancy).

 

Warnings

Liver Enzymes

In controlled monotherapy studies, the incidence of consecutive elevations (≥  3 times the upper limit of normal [ULN]) in serum transaminases was similar between EZETROL (ezetimibe) (0.5%) and placebo (0.3%).

     In controlled co-administration trials in patients receiving EZETROL with a statin, the incidence of consecutive transaminase elevations (≥  3 X ULN) was 1.3% compared to 0.4% in patients on a statin alone.

     When EZETROL is co-administered with a statin, liver function tests should be performed at initiation of therapy and according to the recommendations of that statin (see Adverse Effects, Laboratory Values).

 

Precautions

Concomitant Administration with a Statin

When EZETROL (ezetimibe) is to be administered with a statin, please refer also to the Product Monograph for that statin. Note that all statins are contraindicated in pregnant women (see the Product Monograph for the statin; see Precautions, Pregnancy).

Patients with Liver Impairment

After a single 10-mg dose of EZETROL, 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. No dosage adjustment is necessary for patients with mild hepatic insufficiency. In a 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. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate (Child-Pugh score 7 to 9) or severe (Child-Pugh score > 9) hepatic insufficiency, ezetimibe is not recommended in these patients.

     The co-administration of EZETROL and a statin is contraindicated in patients with active liver disease or unexplained and persistent elevations in serum transaminases.

Renal Insufficiency

After a single 10 mg dose of EZETROL in patients with severe renal disease, the mean AUC for total ezetimibe was increased approximately 1.5-fold, compared to healthy subjects. Accordingly, no dosage adjustment is necessary for renal impaired patients.

 

Pregnancy

No clinical data on exposed pregnancies are available for EZETROL. The effects of ezetimibe on labour and delivery in pregnant women are unknown. Note that all statins are contraindicated in pregnant women (see the Product Monograph for the statin). Caution should be exercised when prescribing to pregnant women.

 

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, EZETROL should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Note that all statins are contraindicated in nursing women (see the Product Monograph for the statin).

Geriatrics

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 EZETROL. Therefore, no dosage adjustment is necessary in the elderly.

 

Children

The pharmacokinetics of EZETROL in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with EZETROL in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with EZETROL in children (< 10 years) is not recommended.

Sex

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 sex.

Race

Based on a meta-analysis of pharmacokinetic studies, there were no pharmacokinetic differences between Blacks and Caucasians.

 

Drug Interactions

Cytochrome P450 System

No clinically significant pharmacokinetic interactions have been observed between ezetimibe and drugs known to be metabolized via CYP 1A2, 2D6, 2C8, 2C9, and 3A4 isoenzymes, or N-acetyltransferase such as caffeine, dextromethorphan, tolbutamide, and IV midazolam. It has been shown that ezetimibe neither induces, nor inhibits, these cytochrome P450 isoenzymes.

Warfarin

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.

Digoxin

Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on the bioavailability of digoxin and the ECG parameters (HR, PR, QT, and QTc intervals) in a study of twelve healthy adult males.

Oral Contraceptives

Co-administration of ezetimibe (10 mg once daily) with oral contraceptives had no significant effect on the bioavailability of ethinyl estradiol or levonorgestrel in a study of eighteen healthy adult females.

Cimetidine

Multiple doses of cimetidine (400 mg twice daily) had no significant effect on the oral bioavailability of ezetimibe and total ezetimibe in a study of twelve healthy adults.

Antacids

Concomitant antacid (aluminum and magnesium hydroxide) 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.

Glipizide

In a study of twelve healthy adult males, steady-state levels of ezetimibe (10 mg once daily) had no significant effect on the pharmacokinetics and pharmacodynamics of glipizide. A single dose of glipizide (10 mg) had no significant effect on the exposure to total ezetimibe or ezetimibe.

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.

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 ezetimibe 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.

Cyclosporine

Caution should be exercised when initiating ezetimibe in the setting of cyclosporine, and patients should be carefully monitored.

     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.

 

Adverse Effects

EZETROL (ezetimibe) clinical trial experience involved 2486 patients in placebo-controlled monotherapy trials (1691 treated with EZETROL) and 3379 patients in active controlled trials (262 of whom were treated with EZETROL alone and 1708 treated with EZETROL plus a statin). The studies were of 8 to 14 weeks duration. The overall incidence of adverse events reported with EZETROL was similar to that reported with placebo and the discontinuation rates due to treatment related adverse events was similar between EZETROL (2.3%) and placebo (2.1%).

Monotherapy

Adverse experiences reported in ≥  2% of patients treated with EZETROL and at an incidence greater than placebo in placebo-controlled studies of EZETROL, regardless of causality assessment, are shown in  Table 1.

     The frequency of less common adverse events was comparable between EZETROL and placebo.

     Only two patients out of the 1691 patients treated with EZETROL alone reported serious adverse reactions-one with abdominal pain plus panniculitis, and one with arm pain and palpitation.

     In monotherapy placebo-controlled clinical trials, 4% of patients treated with EZETROL and 3.8% of patients treated with placebo were withdrawn from therapy due to adverse events.

CPS:Ezetrol_t1Click here for Table 1

Table 1: EZETROL^a

Clinical Adverse Events Occurring in ≥  2% of Patients Treated with EZETROL and at an Incidence Greater than Placebo, Regardless of Causality

 

Body System/Organ Class Adverse Event	Placebo (%) n=795	EZETROL 10 mg (%) n=1691
Body as a Whole—General Disorders
Fatigue	1.8	2.2
Gastrointestinal System Disorders
Abdominal pain	2.8	3.0
Diarrhea	3.0	3.7
Infection and Infestations
Infection viral	1.8	2.2
Pharyngitis	2.1	2.3
Sinusitis	2.8	3.6
Musculoskeletal System Disorders
Arthralgia	3.4	3.8
Back pain	3.9	4.1
Respiratory System Disorders
Coughing	2.1	2.3

 

 ^a Includes patients who received placebo or EZETROL alone reported in  Table 2.

 

 

Combination with a Statin

EZETROL has been evaluated for safety in combination studies in more than 2000 patients. In general, adverse experiences were similar between EZETROL administered with a statin and a statin alone. However, the frequency of increased transaminases was slightly higher in patients receiving EZETROL administered with a statin than in patients treated with a statin alone (see Precautions, Patients with Liver Impairment).

     Clinical adverse experiences reported in ≥  2% of patients and at an incidence greater than placebo in four placebo-controlled trials where EZETROL was administered alone or initiated concurrently with various statins, regardless of causality assessment, are shown in  Table 2.

CPS:Ezetrol_t2Click here for Table 2

Table 2: EZETROL^a

Clinical Adverse Events Occurring in ≥  2% of Patients and at an Incidence Greater than Placebo, Regardless of Causality, in EZETROL/Statin Combination Studies

 

Body System/Organ Class  Adverse Event	Placebo  (%)  n=259	EZETROL 10 mg  (%)  n=262	All Statinsb  (%) n=936	EZETROL + All Statinsb (%)  n=925
Body as a Whole—General Disorders
Chest pain	1.2	3.4	2.0	1.8
Dizziness	1.2	2.7	1.4	1.8
Fatigue	1.9	1.9	1.4	2.8
Headache	5.4	8.0	7.3	6.3
Gastrointestinal System Disorders
Abdominal pain	2.3	2.7	3.1	3.5
Diarrhea	1.5	3.4	2.9	2.8
Infection and Infestations
Pharyngitis	1.9	3.1	2.5	2.3
Sinusitis	1.9	4.6	3.6	3.5
Upper respiratory tract infection	10.8	13.0	13.6	11.8
Musculoskeletal System Disorders
Arthralgia	2.3	3.8	4.3	3.4
Back pain	3.5	3.4	3.7	4.3
Myalgia	4.6	5.0	4.1	4.5

 

 ^a Includes four placebo-controlled combination studies in which EZETROL was initiated concurrently with a statin.

 ^b All statins=all doses of all statins.

 

 

     In co-administration placebo-controlled clinical trials, 5.7% of patients treated with EZETROL co-administered with a statin, 4.3% of patients treated with statin alone, 5.0% of patients treated with EZETROL alone, and 6.2% of patients treated with placebo were withdrawn from therapy due to adverse events.

Laboratory Values

In controlled clinical monotherapy trials, the incidence of clinically important consecutive elevations in serum transaminases (ALT and/or AST ≥  3 X ULN) was similar between EZETROL (0.5%) and placebo (0.3%). In co-administration trials, the incidence was 1.3% 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.

     In clinical trials there was no excess of myopathy or rhabdomyolysis associated with EZETROL 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 EZETROL vs 0.1% for placebo, and 0.1% for EZETROL co-administered with a statin vs 0.4% for statin alone.

Post-marketing Experience

The following adverse reactions have been reported in post-marketing experience: hypersensitivity reactions, including angioedema and rash.

 

Overdose

 

 

Symptoms

No cases of overdosage with EZETROL (ezetimibe) have been reported. Administration of ezetimibe, 50 mg/day, to 15 subjects for up to 14 days was generally well tolerated.

 

 

Treatment

In the event of an overdose, symptomatic and supportive measures should be employed.

 

Dosage

Patients should be placed on a standard cholesterol-lowering diet at least equivalent to the NCEP Adult Treatment Panel III (ATP III) TLC diet before receiving EZETROL (ezetimibe), and should continue on this diet during treatment with EZETROL. If appropriate, a program of weight control and physical exercise should be implemented.

     Prior to initiating therapy with EZETROL, secondary causes for elevations in plasma lipid levels should be excluded. A lipid profile should also be performed.

     The recommended dose of EZETROL is 10 mg once daily orally, alone or with a statin. EZETROL can be taken with or without food at any time of the day but preferably at the same time each day.

 

Geriatrics

No dosage adjustment is required for elderly patients (see Precautions, Geriatrics).

 

Children

Children and adolescents ≥  10 years: No dosage adjustment is required (see Precautions, Children).

Use in Patients with Hepatic Impairment

No dosage adjustment is required in patients with mild hepatic insufficiency (Child-Pugh score 5 to 6). Treatment with EZETROL is not recommended in patients with moderate (Child-Pugh score 7 to 9) or severe (Child-Pugh score > 9) liver dysfunction (see Precautions, Patients with Liver Impairment).

Use in Patients with Renal Impairment

No dosage adjustment is required for patients with renal impairment (see Precautions, Renal Insufficiency).

Co-administration with Bile Acid Sequestrants

EZETROL should be administered either 2 hours or longer before or 4 hours or longer after administration of a bile acid sequestrant (see Precautions, Drug Interactions, Cholestyramine).

 

Supplied

Each white to off-white, capsule-shaped tablet, debossed with “414” on one side, contains: ezetimibe 10 mg. Nonmedicinal ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium laurylsulfate. Blisters of 7 (as professional sample) and 30. HDPE bottles of 100. Store between 15°C and 30°C. Protect from moisture.