EZETROL (ezetimibe) is indicated as an adjunct to lifestyle changes, including 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 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 for the reduction of elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia.

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 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 Warnings and Precautions, Special Populations, Pregnant Women).

When EZETROL 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 Warnings and Precautions, Special Populations, Pregnant Women).

Concomitant Administration with a Statin: When EZETROL is initiated in a patient already taking a statin, liver function tests should be considered at initiation of EZETROL therapy, and then as indicated (see Adverse Reactions,Abnormal Hematologic and Clinical Chemistry Findings).

When EZETROL is initiated at the same time as a statin, liver function tests should be performed at initiation of therapy and according to the recommendations of that statin (see Adverse Reactions, Abnormal Hematologic and Clinical Chemistry Findings).

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 (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 × ULN) was 1.3% compared to 0.4% in patients on a statin alone.

Patients with Liver Impairment: The pharmacokinetics of ezetimibe were examined in patients with impaired liver function as defined by the Child-Pugh scoring system.

• In patients with mild hepatic insufficiency (Child-Pugh score 5 or 6), the mean area under the curve (AUC) for total ezetimibe (after a single 10 mg dose of EZETROL) was increased approximately 1.7-fold compared to healthy subjects. No dosage adjustment is necessary for patients with mild hepatic insufficiency.

  
  

• In patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), the mean AUC for total ezetimibe (after multiple doses of 10 mg daily) 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.

  
  

• No pharmacokinetic studies with ezetimibe have been carried out in patients with either active liver disease or unexplained and persistent elevations in serum transaminases. It is recommended that care be exercised in such 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.

Post-marketing reports of adverse events have included rare cases of hepatitis in patients taking EZETROL, although causality has not been proven. If patients develop signs or symptoms of hepatitis, liver function should be evaluated.

Pancreatitis: Post-marketing reports of adverse events have included rare cases of acute pancreatitis occurring in patients taking EZETROL, although causality has not been proven. The diagnosis of acute pancreatitis should be considered in patients taking EZETROL who develop sudden acute abdominal pain.

Myopathy/Rhabdomyolysis: Myopathy and rhabdomyolysis are known adverse effects of statins. Post-marketing reports of adverse events have included rare cases of myopathy/rhabdomyolysis occurring in patients taking EZETROL with or without a statin, regardless of causality. Myopathy/Rhabdomyolysis should be considered in patients presenting with muscle pain during treatment with EZETROL with or without a statin, and consideration given to discontinuation of the drugs. Most cases of myopathy/rhabdomyolysis resolved when drugs were discontinued.

Myalgia: In controlled clinical trials, the incidence of myalgia was 5.0% for EZETROL vs 4.6% for placebo (see Adverse Reactions, Table 2). Post-marketing reports of adverse events have included myalgia in patients taking EZETROL with or without a statin, regardless of causality. Patients should be instructed to contact their physician if they experience persistent and severe muscle pains with no obvious cause.

A number of patients treated with EZETROL, in whom myalgia occurred had previously experienced myalgia (with or without elevated CK levels) with statin therapy. Patients with a history of statin intolerance (myalgia with or without elevated CK levels) should be closely monitored for adverse muscle events during treatment with EZETROL.

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.

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.

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).

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.

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.

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.

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

The most commonly reported adverse events in clinical studies were upper respiratory tract infection, headache, myalgia and back pain. In post-marketing use, serious adverse events reported rarely or very rarely, regardless of causality, included hepatitis, hypersensitivity reactions, pancreatitis and myopathy/rhabdomyolysis.

When EZETROL is to be administered with a statin, please refer also to the Product Monograph for that statin.

EZETROL clinical trial experience involved 2486 patients in placebo-controlled monotherapy trials (1691 treated with EZETROL) and 3922 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%).

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.

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.

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.

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 Warnings and Precautions, Hepatic/Pancreatic, 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.

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.

In controlled clinical monotherapy trials, the incidence of clinically important consecutive elevations in serum transaminases (ALT and/or AST ≥3 × 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 levels 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 CK >10 × 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.

The following adverse events have been reported rarely or very rarely, regardless of causality: increased CK (creatine phosphokinase); myalgia (see Warnings and Precautions); myopathy/rhabdomyolysis (see Warnings and Precautions); elevations of liver transaminases; hepatitis (see Warnings and Precautions); hypersensitivity reactions, including anaphylaxis, angioedema, rash and urticaria; nausea; pancreatitis (see Warnings and Precautions); thrombocytopenia; arthralgia; cholelithiasis; cholecystitis.

Drug-drug interactions are known or suspected with cholestyramine, cyclosporine and fibrates.

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.

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. As with the initiation of any medication in patients treated with warfarin or another coumarin anticoagulant, additional International Normalised Ratio (INR) measurements are recommended for patients administered warfarin or another coumarin anticoagulant concomitantly with EZETROL.

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, fluvastatin or rosuvastatin.

Cyclosporine: Caution should be exercised when initiating ezetimibe in the setting of cyclosporine. Cyclosporine concentrations should be monitored in patients receiving EZETROL and 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 contrast, 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.

• 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, 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.

Use in the Elderly: No dosage adjustment is required for elderly patients (see Warnings and Precautions, Special Populations, Geriatrics).

Use in Pediatric Patients: Children and adolescents ≥ 10 years: No dosage adjustment is required (see Warnings and Precautions, Special Populations, Pediatrics).

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 Warnings and Precautions, Hepatic/Pancreatic, Patients with Liver Impairment).

Use in Patients with Renal Impairment: No dosage adjustment is required for patients with renal impairment (see Warnings and Precautions, Renal, 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 Drug Interactions, Drug-Drug Interactions, Cholestyramine).

The recommended dosing regimen is one tablet, once daily. If a dose is missed, the patient should be counselled to resume the usual schedule of one tablet daily.

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 hypercholesterolemia for up to 56 days, was generally well tolerated.

A few cases of overdosage with EZETROL 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.

EZETROL 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. 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.

Although ezetimibe is rapidly absorbed and is extensively metabolized to an active phenolic glucuronide which reaches the systemic circulation after oral administration (see Action and Clinical Pharmacology, Pharmacokinetics, Absorption), its action is localized at the brush border of the small intestine where it 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.

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.

Ezetimibe and ezetimibe-glucuronide are bound 99.7% and 88 to 92% to human plasma proteins, respectively.

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.

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.

Store between 15 and 30°C. Protect from moisture.

Ezetrol.