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

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.

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 ZETIA.

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.

Coadministration 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.

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.

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.

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.

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.

The safety and effectiveness of ezetimibe coadministered with fenofibrate have been evaluated in a clinical study (see Warnings and Precautions and Adverse Reactions); coadministration 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, coadministration of ZETIA with fibrates (other than fenofibrate) is not recommended until use in patients is studied.

In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. This increase is not considered clinically significant.

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.

No clinically significant pharmacokinetic interactions were seen when ezetimibe was coadministered with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin or rosuvastatin.

Caution should be exercised when initiating ezetimibe in the setting of cyclosporine. Cyclosporine concentrations should be monitored in patients receiving ZETIA 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 ZETIA, and should continue on this diet during treatment with ZETIA. If appropriate, a program of weight control and physical exercise should be implemented.

  
  

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

  
  

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

No dosage adjustment is required for elderly patients (see Warnings and Precautions, Special Populations, Geriatrics).

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

No dosage adjustment is required in patients with mild hepatic insufficiency (Child-Pugh score 5 to 6). Treatment with ZETIA 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/Biliary/Pancreatic, Patients with Liver Impairment).

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

ZETIA 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 ZETIA 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.

ZETIA is in a new class of lipid-lowering compounds that selectively inhibit the intestinal absorption of cholesterol and related plant sterols. ZETIA 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. ZETIA and statins have distinct mechanisms of action that provide complementary cholesterol reduction. Administration of ZETIA with fenofibrate is effective in improving serum total-C, LDL-C, Apo-B, TG, HDL-C, and non-HDL-C in patients with mixed hyperlipidemia.

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 or fenofibrate 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, ZETIA inhibited intestinal cholesterol absorption by 54%, compared with placebo. ZETIA 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 (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax). Ezetimibe-glucuronide mean Cmax values of 45 to 71 ng/mL were achieved between 1 and 2 hours (Tmax). 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 ZETIA 10 mg tablets. Cmax 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.

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.