Zetia (ezetimibe)

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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.

When using the fixed-combination preparation containing ezetimibe and simvastatin, the drug interactions associated with simvastatin should be considered. No formal drug interaction studies have been performed to date with the fixed-combination preparation other than that with extended-release niacin. (See Niacin under Drug Interactions: Antilipemic Agents.)

When using the fixed-combination preparation containing ezetimibe and bempedoic acid, the drug interactions associated with bempedoic acid should be considered.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Agents That Increase Cpk/Aumolertinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Aumolertinib may increase blood CPK levels leading to myopathy and rhabdomyolysis. Other agents that also increase CPK may contribute to additive effects on CPK levels.(1) In addition, aumolertinib may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1) Taletrectinib and zidesamtinib may prolong the QTc interval.

CLINICAL EFFECTS: Concurrent use of aumolertinib and other agents that also increase CPK levels may increase the risk of myopathy or rhabdomyolysis, which is characterized by progressive muscle weakness and pain in the presence of a normal neurological exam.(1) In addition, the concurrent use of aumolertinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1) Taletrectinib and zidesamtinib may prolong the QTc interval.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may also be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, and advanced age.(1,2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Concurrent use of aumolertinib and other agents that increase CPK levels should be avoided. Prior to initiation of aumolertinib, blood CPK levels should be obtained and periodically monitored during treatment and as clinically indicated.(1) If the patient develops elevated CPK levels or rhabdomyolysis, the following is recommended: For Grade 3 with muscular symptoms: - Withhold aumolertinib for up to 2 weeks. - If muscular symptoms resolve and CPK increase is <= Grade 3, resume at 110 mg dose for the first occurrence; resume at 55 mg for the second occurrence. - Permanently discontinue aumolertinib if symptoms/signs recur at anytime while on the reduced dose. - If muscular symptoms do not resolve and CPK increase does not improve to <= Grade 2, permanently discontinue aumolertinib. For Grade 4 with or without muscular symptoms: - Withhold aumolertinib for up to 2 weeks. - If muscular symptoms resolve and CPK increase is <= Grade 3, resume at 55 mg for the first occurrence. - Permanently discontinue aumolertinib if symptoms/signs recur at anytime while on the reduced dose. - If muscular symptoms do not resolve and CPK remains >= Grade 3, permanently discontinue aumolertinib. If rhabdomyolysis occurs, hold aumolertinib and initiate treatment for rhabdomyolysis.(1) In concurrent use is warranted, carefully monitor for myopathy or rhabdomyolysis. Patients should be instructed to report any symptoms of myopathy such as unexplained muscle aches, tenderness, weakness, or the onset of tingling/numbness in the fingers or toes.(1) The manufacturer of aumolertinib states that concurrent use of other drugs that are known to prolong the QTc interval should be avoided. Taletrectinib and zidesamtinib may also prolong the QTc interval. If a suitable alternative is not available, consider increasing the frequency of ECG and electrolyte monitoring.(1) Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If QTc prolongation occurs, follow recommended dose modifications: - Grade 2 (QTc interval >480 to 500 ms): Withhold aumolertinib for up to 2 weeks. If QTc interval has not recovered to <= 480 ms, permanently discontinue aumolertinib. If QTc interval recovers to <= 480 ms or within 30 ms of baseline, resume aumolertinib treatment at 110 mg. Monitor ECGs at least weekly for 2 weeks following return to <= 480 ms. Monitor and correct electrolytes and/or change concomitant medications. - Grade 3 (QTc interval > 500 ms or QTc interval increase of > 60 ms from baseline): Withhold aumolertinib for up to 2 weeks. If QTc interval has not recovered to <= 480 ms or within 30 ms of baseline, permanently discontinue aumolertinib. If QTc interval recovers to <= 480 ms and it is the first occurrence, resume treatment at 110 mg dose. If QTc interval recovers to <= 480 ms and it is the second occurrence or the first occurrence in patients with risk factors, resume treatment at 55 mg dose. Permanently discontinue aumolertinib if signs or symptoms recur at any time on the 55 mg dose. Monitor ECGs at least weekly for 2 weeks following return to <= 480 ms. Monitor and correct electrolytes and/or change concomitant medications. - QT interval prolongation associated with torsade de pointes, polymorphic ventricular tachycardia, or signs/symptoms of other serious arrhythmia: permanently discontinue aumolertinib.(1)

DISCUSSION: Aumolertinib increased blood CPK levels in 31.7% of patients in clinical studies at recommended doses. Patients developed Grade 3 CPK elevations with muscular symptoms (7.5% of patients) and Grade 4 CPK elevations with or without muscular symptoms. Elevated CPK levels led to interruption or dose reduction in 6.1% and 2.0% of patients, respectively. Rhabdomyolysis occurred in 2.6% of patients.(1) A concentration-QT analysis predicted a QTc interval prolongation at 110 mg aumolertinib of 9.06 ms (upper confidence interval = 11.01 ms) in 49 subjects.(1) In clinical studies (n=545), QT prolongation was reported in 51 patients (9.4%) treated with aumolertinib 110 mg. Seven patients (1.3%) had symptomatic events, including cardiac arrest, syncope, and ventricular arrhythmia. One patient with cardio-respiratory arrest and one patient with sudden cardiac death died. QTcF increase >60 ms occurred in 4.2% of patients, and increase in QTcF to >500 ms occurred in 0.9% of patients.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)

Moderate Interaction: Assess the risk to the patient and take action as needed.

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)

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)

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 gallbladder disease is contraindicated.(2) The US manufacturer of bempedoic acid-ezetimibe (Nexlizet) states monitor triglycerides and high-density lipoprotein cholesterol (HDL-C) four weeks after initial concomitant use of bempedoic acid-ezetimibe (Nexlizet) and a fibrate and periodically thereafter. If increased triglycerides or decreased HDL-C levels are detected, discontinue bempedoic acid-ezetimibe (Nexlizet) or fibrate therapy based on clinical judgment. Monitor triglycerides and HDL-C levels until levels return to baseline.(3) 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)

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.

• Hepatic failure
• Rhabdomyolysis

• Myopathy with CK elevation

There are no moderate contraindications for this drug.

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.

Rare or 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

Less Frequent

• Arthralgia
• Back pain
• Cough
• Diarrhea
• Fatigue
• Increased creatine kinase level
• Influenza
• Myalgia
• Pain in extremities
• Pharyngitis
• Sinusitis
• Upper respiratory infection
• Viral infection

Rare or Very Rare

• Acute abdominal pain
• Depression
• Dizziness
• Headache disorder
• Nausea
• Paresthesia
• Skin rash
• Urticaria

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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.

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.