Zetia Drug Information

The recommended dose of ZETIA is 10 mg orally once daily, administered with or without food. If as dose is missed, take the missed dose as soon as possible. Do not double the next dose.

Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ZETIA. Administer ZETIA at least 2 hours before or 4 hours after administration of a bile acid sequestrant. 10-mg orally once daily, with or without food Administer ZETIA either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant.

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. Adverse reactions reported in ≥2% of patients treated with ZETIA and at an incidence greater than placebo in placebo-controlled studies of ZETIA are shown in Table 1. The incidence of consecutive increased transaminases (≥3 × ULN) was higher in patients receiving ZETIA administered with statins (1.3%) than in patients treated with statins alone (0.4%).

Incidence rates for clinically important elevations (≥3 × ULN, consecutive) in hepatic transaminase levels were 4.5% and 2.7% for fenofibrate monotherapy (n=188) and ZETIA coadministered with fenofibrate (n=183), respectively, adjusted for treatment exposure. Corresponding incidence rates for cholecystectomy were 0.6% and 1.7% for fenofibrate monotherapy and ZETIA coadministered with fenofibrate, respectively.

Post-Marketing Experience Because the reactions below are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following additional adverse reactions have been identified during post-approval use of ZETIA: Blood Disorders: thrombocytopenia Gastrointestinal Disorders: abdominal pain; pancreatitis; nausea Hepatobiliary Disorders: elevations in liver transaminases, including elevations more than 5 X ULN; hepatitis; cholelithiasis; cholecystitis Immune System Disorders: Hypersensitivity reactions including: anaphylaxis, angioedema, rash, and urticaria Musculoskeletal Disorders: elevated creatine phosphokinase; myopathy/rhabdomyolysis Nervous System Disorders: dizziness; paresthesia; depression; headache Skin and Subcutaneous Tissue Disorders: erythema multiforme

Table 3 includes a list of drugs with clinically important drug interactions when administered concomitantly with ZETIA and instructions for preventing or managing them. Table 3: Clinically Important Drug Interactions with ZETIA Cyclosporine Clinical Impact: Concomitant use of ZETIA and cyclosporine increases ezetimibe and cyclosporine concentrations. The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency.

Intervention: Monitor cyclosporine concentrations in patients receiving ZETIA and cyclosporine. Fibrates Clinical Impact: Both fenofibrate and ezetimibe may increase cholesterol excretion into the bile, leading to cholelithiasis. Co-administration of ZETIA with fibrates other than fenofibrate is not recommended.

Intervention: If cholelithiasis is suspected in a patient receiving ZETIA and fenofibrate, gallbladder studies are indicated, and alternative lipid-lowering therapy should be considered. Bile Acid Sequestrants Clinical Impact: Concomitant cholestyramine administration decreased the mean exposure of total ezetimibe. This may result in a reduction of efficacy.

Intervention: In patients taking a bile acid sequestrant, administer ZETIA at least 2 hours before or 4 hours after the bile acid sequestrant. Cyclosporine: Combination increases exposure of ZETIA and cyclosporine. Cyclosporine concentrations should be monitored in patients taking ZETIA concomitantly.

Fibrates: Coadministration of ZETIA with fibrates other than fenofibrate is not recommended until use in patients is adequately studied. Bile Acid Sequestrants: Cholestyramine combination decreases exposure of ZETIA.

Pregnancy Risk Summary There are insufficient data on ezetimibe use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed in pregnant rats and rabbits orally administered ezetimibe during the period of organogenesis at doses that resulted in up to 10 and 150 times, respectively, the human exposure at the MRHD, based on AUC (see Data ). ZETIA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

When ZETIA is administered with a statin, refer to the Prescribing Information for the statin. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively.

In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1,000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1,000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). The animal-to-human exposure multiple for total ezetimibe at the no-observed effect level was 6 times for rat and 134 times for rabbit.

Fetal exposure to ezetimibe (conjugated and unconjugated) was confirmed in subsequent placental transfer studies conducted using a maternal dose of 1,000 mg/kg/day. No maternal toxicity or adverse developmental outcomes were observed up to and including the highest dose tested (17 times the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). Multiple-dose studies of ezetimibe given in combination with statins in rats and rabbits during organogenesis resulted in higher ezetimibe and statin exposures.

Reproductive findings occurred at lower doses in combination therapy compared to monotherapy.

Pediatric Use The safety and effectiveness of ZETIA in combination with a statin as an adjunct to diet to reduce LDL-C have been established in pediatric patients 10 years of age and older with HeFH. In this limited controlled trial, there was no significant effect on growth or sexual maturation in the adolescent males or females, or on menstrual cycle length in females. The safety and effectiveness of ZETIA in combination with a statin, and other LDL-C lowering therapies, to reduce LDL-C have been established in pediatric patients 10 years of age and older with HoFH.

Use of ZETIA for this indication is based on a 12-week double-blind, placebo-controlled clinical trial followed by an uncontrolled extension period in 7 pediatric patients 11 years of age and older with HoFH. The safety and effectiveness of ZETIA as an adjunct to diet for the reduction of elevated sitosterol and campesterol levels have been established in adults and pediatric patients 9 years of age and older with homozygous familial sitosterolemia. Use of ZETIA for this indication is based on an 8-week double-blind, placebo-controlled clinical trial in 4 patients 9 years of age and older with homozygous sitosterolemia with elevated plasma sitosterol levels (>5 mg/dL).

The safety and effectiveness of ZETIA have not been established in pediatric patients younger than 10 years of age with HeFH or HoFH, in pediatric patients younger than 9 years of age with homozygous familial sitosterolemia, or in pediatric patients with other types of hyperlipidemia.

ZETIA is contraindicated in patients with a known hypersensitivity to ezetimibe or any of the excipients in ZETIA. Hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria have been reported. When used in combination with a statin, fenofibrate, or other LDL-C lowering therapy, ZETIA is contraindicated in patients for whom a statin, fenofibrate, or other LDL-C lowering therapy are contraindicated.

Refer to the Prescribing Information of these products for a list of their contraindications. Hypersensitivity to ezetimibe or any excipient of ZETIA.

In the event of overdose, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.