Zetia

Drug overview for ZETIA (ezetimibe):

Generic name: ezetimibe (eh-ZET-ih-mibe)
Drug class: Selective Cholesterol Absorption Inhibitor
Therapeutic class: Cardiovascular Therapy Agents

Ezetimibe, a cholesterol absorption inhibitor, is an antilipemic agent.

No enhanced Uses information available for this drug.

DRUG IMAGES

ZETIA 10 MG TABLET

The following indications for ZETIA (ezetimibe) have been approved by the FDA:

Indications:
Heterozygous familial hypercholesterolemia
Homozygous familial hypercholesterolemia
Hypercholesterolemia
Hyperlipidemia
Mixed hyperlipidemia
Sitosterolemia

Professional Synonyms:
Combined hypercholesterolemia and hypertriglyceridemia
Elevated blood cholesterol level
Familial heterozygous hypercholesterolemia
Familial homozygous hypercholesterolemia
Heterozygous familial elevated blood cholesterol
Hyperlipoidemia
Lipemia
Lipidemia
Lipoidemia
Mixed dyslipidemia
Phytosterolemia

The following dosing information is available for ZETIA (ezetimibe):

Dosing
Administration
ZETIA
EZETIMIBE

No enhanced Dosing information available for this drug.

Ezetimibe is administered orally without regard to meals. Ezetimibe in fixed combination with simvastatin (e.g., Vytorin(R)) is administered orally in the evening without regard to meals. Patients should be placed on a standard cholesterol-lowering diet before initiation of ezetimibe therapy and should remain on this diet during treatment with the drug.

When used in combination with a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) or fenofibrate for additive antilipemic effects, ezetimibe may be administered at the same time as the statin or fenofibrate, in accordance with the recommended dosing schedule for these drugs. When used in combination with a bile acid sequestrant, ezetimibe should be administered at least 2 hours before or at least 4 hours after administration of the bile acid sequestrant. The manufacturer states that pending further accumulation of data, use of ezetimibe in combination with a fibric acid derivative other than fenofibrate is not recommended.

(See Drug Interactions: Antilipemic Agents.) Antilipemic therapy is an adjunct to, not a substitute for, lifestyle modification therapies that reduce the risk of atherosclerotic cardiovascular disease (ASCVD). Adherence to lifestyle modifications for ASCVD risk reduction in addition to statin therapy should be reinforced periodically.

Dosing information for ZETIA
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
ZETIA 10 MG TABLET	Maintenance	Adults take 1 tablet (10 mg) by oral route once daily

Generic dosing information for EZETIMIBE
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
EZETIMIBE 10 MG TABLET	Maintenance	Adults take 1 tablet (10 mg) by oral route once daily

The following drug interaction information is available for ZETIA (ezetimibe):

Contraindicated
Severe
Moderate

There are 0 contraindications.

There are 0 severe interactions.

There are 3 moderate interactions. The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.

Drug Interaction	Drug Names
Ezetimibe/Bile Acid Sequestrants SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Bile acid sequestrants may prevent the absorption of ezetimibe.(1) CLINICAL EFFECTS: Simultaneous administration of a bile acid sequestrant and ezetimibe may result in decreased levels and clinical effectiveness of ezetimibe.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: In patients receiving concurrent therapy, the manufacturer of ezetimibe recommends that ezetimibe be administered either 2 or more hours before or 4 or more hours after a bile acid sequestrant.(1) DISCUSSION: In a study in 40 subjects, the simultaneous administration of ezetimibe and cholestyramine decreased the area-under-curve (AUC) of total ezetimibe and ezetimibe by 55% and 80%, respectively. This may reduce the effectiveness of ezetimibe. Therefore, the manufacturer of ezetimibe recommends that ezetimibe be administered either 2 or more hours before or 4 or more hours after a bile acid sequestrant.(1)	CHOLESTYRAMINE, CHOLESTYRAMINE LIGHT, CHOLESTYRAMINE RESIN, COLESTID, COLESTIPOL HCL, PREVALITE, QUESTRAN, QUESTRAN LIGHT
Ezetimibe/Fibrates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Both ezetimibe and fibrates may increase cholesterol excretion in the bile. Fibrates may inhibit the metabolism of ezetimibe.(1) CLINICAL EFFECTS: Concurrent administration of ezetimibe may result in cholelithiasis, elevated levels of ezetimibe, and toxicity.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of ezetimibe states that the concurrent use of ezetimibe and fibrates other than fenofibrate is not recommended.(1) The Australian manufacturer of ezetimibe states that concurrent use with fenofibrate in patients with gall bladder disease is contraindicated.(2) Patients receiving concurrent therapy with any fibrate should be monitored for cholelithiasis and increased ezetimibe side effects. If cholelithiasis is suspected, gallbladder studies are indicated and alternative therapy may need to be utilized.(1) DISCUSSION: Fibrates have been shown to increase cholesterol excretion into the bile, leading to cholelithiasis. Ezetimibe has been shown in dogs to increase cholesterol in the gallbladder bile.(1) In a study in 32 subjects, concurrent fenofibrate and ezetimibe increased the maximum concentration (Cmax) and area-under-curve (AUC) of total ezetimibe by 64% and 48%, respectively. There was no significant effect on fenofibrate pharmacokinetics. Concomitant fenofibrate increased total ezetimibe concentrations by 1.5-fold.(1) In a study in 625 patients for up to 12 weeks and 576 patients for up to an additional 48 weeks, concurrent ezetimibe and fenofibrate was effective at lowering total cholesterol, LDL-C, Apo B, and non-HDL-C. The number of patients was inadequate to assess gallbladder risk; however, 0.6% of patients in the fenofibrate monotherapy group experienced cholecystectomy versus 1.7% during concurrent therapy.(1) In a study in 12 healthy subjects, concurrent gemfibrozil and ezetimibe increased the bioavailability of ezetimibe by 1.7-fold. There was no significant effect on gemfibrozil pharmacokinetics.(1)	FENOFIBRATE, FENOFIBRIC ACID, FENOGLIDE, FIBRICOR, GEMFIBROZIL, LIPOFEN, LOPID, TRICOR, TRILIPIX
Ezetimibe/Cyclosporine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown. CLINICAL EFFECTS: Concurrent use of cyclosporine with ezetimibe may result in elevated levels of and side effects from ezetimibe and cyclosporine.(1) PREDISPOSING FACTORS: Patients with severe renal insufficiency may experience larger increases in ezetimibe levels.(1) PATIENT MANAGEMENT: Carefully weigh the risk of elevated levels of ezetimibe and cyclosporine against benefits of ezetimibe in patients maintained on cyclosporine. Patients receiving concurrent therapy should be monitored for adverse effects. Ezetimibe may need to be discontinued.(1) DISCUSSION: In a study in 8 post-renal transplant patients with mildly impaired or normal renal function (CrCL greater than 50ml/min), stable cyclosporine doses (75 to 150 mg twice daily) increased ezetimibe area-under-curve (AUC) and maximum concentration (Cmax) values by 240% and by 290%, respectively, compared to historical healthy controls. In another study, a renal transplant patient with severe renal impairment (CrCl = 13.2) maintained on cyclosporine experienced a 12-fold greater exposure to ezetimibe than healthy subjects.(1) In a study in 12 healthy subjects, ezetimibe (20 mg daily for 8 days) increased the AUC of a single dose of cyclosporine (100 mg) by 15%.(1)	CYCLOSPORINE, CYCLOSPORINE MODIFIED, GENGRAF, NEORAL, SANDIMMUNE

The following contraindication information is available for ZETIA (ezetimibe):

Overview
Contraindicated
Severe
Moderate

Drug contraindication overview.

Known hypersensitivity to ezetimibe or any ingredient in the formulation. Ezetimibe, in combination with a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin), is contraindicated in patients with active liver disease or unexplained, persistent increases in serum aminotransferase (transaminase) concentrations. All statins are contraindicated in pregnant or nursing women.

If ezetimibe is used in combination with a statin in a woman of childbearing age, the prescribing information for the statin should be consulted for detailed information on contraindications of the drug. Concomitant use of the fixed combination of ezetimibe and simvastatin with potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4, cyclosporine, danazol, or gemfibrozil is contraindicated.

There are 2 contraindications. Absolute contraindication.

Contraindication List
Hepatic failure
Rhabdomyolysis

There are 1 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Myopathy with CK elevation

There are 0 moderate contraindications.

The following adverse reaction information is available for ZETIA (ezetimibe):

Overview
Severe
Less Severe

Adverse reaction overview.

Adverse effects occurring in 2% or more of patients receiving ezetimibe and more frequently with the drug than with placebo include upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity, fatigue, and influenza. Adverse effects occurring in patients receiving ezetimibe in combination with statins generally were similar to those reported in patients receiving statin therapy alone. However, the incidence of increased transaminase concentrations was higher in patients receiving combination therapy (1.3%) than in those who received statin monotherapy (0.4%).

(See Hepatic Effects under Warnings/Precautions: Major Toxicities, in Cautions.) Adverse effects occurring in 2% or more of patients receiving ezetimibe in fixed combination with simvastatin include headache, increased ALT, myalgia, upper respiratory tract infection, and diarrhea. Adverse effects occurring in 2% or more of patients receiving ezetimibe in fixed combination with bempedoic acid include upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, extremity pain, anemia, increased hepatic enzymes, diarrhea, arthralgia, sinusitis, fatigue, and influenza.

There are 15 severe adverse reactions.

More Frequent	Less Frequent
None.	None.

Rare/Very Rare
Abnormal hepatic function tests Acute pancreatitis Anaphylaxis Angioedema Biliary calculus Cholecystitis DRESS syndrome Erythema multiforme Hepatitis Hypersensitivity drug reaction Myopathy Rhabdomyolysis Stevens-johnson syndrome Thrombocytopenic disorder Toxic epidermal necrolysis

There are 21 less severe adverse reactions.

More Frequent	Less Frequent
None.	Arthralgia Back pain Cough Diarrhea Fatigue Increased creatine kinase level Influenza Myalgia Pain in extremities Pharyngitis Sinusitis Upper respiratory infection Viral infection

Rare/Very Rare
Acute abdominal pain Depression Dizziness Headache disorder Nausea Paresthesia Skin rash Urticaria

The following precautions are available for ZETIA (ezetimibe):

Pediatric
Pregnant
Lactation
Geriatric

There are no differences in the pharmacokinetics of ezetimibe between adolescents and adults. Pharmacokinetic data are not available for pediatric patients younger than 10 years of age. Use of ezetimibe in combination with simvastatin has been evaluated in a limited number of adolescent boys and girls with heterozygous familial hypercholesterolemia.

In a randomized, double-blind, controlled study in boys and postmenarchal girls 10-17 years of age with heterozygous familial hypercholesterolemia, discontinuance of therapy because of adverse effects occurred in more patients receiving ezetimibe in combination with simvastatin (10-40 mg daily) (6%) than in those receiving simvastatin monotherapy (2%); in addition, increases in aminotransferase or CK concentrations also occurred more frequently in patients receiving combination therapy (3 or 2%, respectively) than in those receiving simvastatin monotherapy (2 or 0%, respectively). There were no detectable adverse effects on growth or sexual maturation in adolescent boys or girls or on duration of menstrual cycle in girls. Use of ezetimibe in combination with simvastatin dosages exceeding 40 mg daily has not been evaluated in adolescents; safety and efficacy of ezetimibe, alone or in fixed combination with simvastatin, have not been evaluated in prepubertal girls or in children younger than 10 years of age. Safety and efficacy of ezetimibe in fixed combination with bempedoic acid have not been established in pediatric patients.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

Category C. (See Users Guide.) Category X for fixed combination of ezetimibe and simvastatin (due to simvastatin component). (See Users Guide.)

Ezetimibe is distributed into milk in rats. It is not known whether ezetimibe is distributed into milk in humans. Because many drugs are distributed into human milk, caution should be used if ezetimibe is used in nursing women; the drug should not be used in nursing women unless the potential benefits justify the possible risks to the infant.

In clinical studies in patients receiving ezetimibe, 28% of patients were 65 years of age or older, and 5% of patients were 75 years of age or older. Following administration of ezetimibe (10 mg daily for 10 days), plasma concentrations of the drug were approximately twofold higher in geriatric individuals (65 years of age or older) than in younger adults; however, no overall differences in safety and efficacy of ezetimibe have been observed in geriatric patients relative to younger adults. Nevertheless, the manufacturer states that the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.

In clinical studies in patients receiving ezetimibe in fixed combination with simvastatin, 32% of patients were 65 years of age or older, and 8% of patients were 75 years of age or older. No substantial differences in safety or efficacy of the fixed-combination preparation were observed in geriatric patients relative to younger patients; however, greater sensitivity in some older patients cannot be ruled out. Because advanced age (65 years of age or older) is a risk factor for myopathy, including rhabdomyolysis, ezetimibe in fixed combination with simvastatin should be used with caution in geriatric patients.

The following icd codes are available for ZETIA (ezetimibe)'s list of indications:

Heterozygous familial hypercholesterolemia
E78.01	Familial hypercholesterolemia
Homozygous familial hypercholesterolemia
E78.01	Familial hypercholesterolemia
Hypercholesterolemia
E78.0	Pure hypercholesterolemia
E78.00	Pure hypercholesterolemia, unspecified
E78.01	Familial hypercholesterolemia
Hyperlipidemia
E78.2	Mixed hyperlipidemia
E78.4	Other hyperlipidemia
E78.49	Other hyperlipidemia
E78.5	Hyperlipidemia, unspecified
Mixed hyperlipidemia
E78.2	Mixed hyperlipidemia
Sitosterolemia
E75.5	Other lipid storage disorders