Note: May be considered as an adjunctive agent in patients who do not meet cholesterol treatment goals with dietary modification plus maximally-tolerated statin therapy (Ref).
Homozygous familial hypercholesterolemia: Oral: 10 mg once daily.
Homozygous sitosterolemia: Oral: 10 mg once daily.
Primary hyperlipidemia, including heterozygous familial and nonfamilial hyperlipidemia or mixed hyperlipidemia: Oral: 10 mg once daily.
Secondary prevention of atherosclerotic cardiovascular events after acute coronary syndrome (off-label use): Oral: 10 mg once daily (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: Mild to severe impairment: No dosage adjustment necessary (Ref).
Hemodialysis, intermittent (thrice weekly): Unlikely to be dialyzed (highly protein bound): No supplemental dose or dosage adjustment necessary (Ref).
Peritoneal dialysis: Unlikely to be dialyzed (highly protein bound): No dosage adjustment necessary (Ref).
CRRT: No dosage adjustment necessary (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (Ref).
Mild impairment (Child-Pugh class A): No dosage adjustment necessary.
Moderate to severe impairment (Child-Pugh class B or C): Use of ezetimibe not recommended.
(For additional information see "Ezetimibe: Pediatric drug information")
Hyperlipidemia:
Children 5 to 9 years: Limited data available: Oral: 10 mg once daily; dosing based on two studies of monotherapy; a prospective trial (n=17 including six patients ≤9 years) and a retrospective review (n=36, age range: 8 to 17 years) showed significant decreases in total cholesterol and LDL-C; patients were followed up to a mean of 13.6 months, no untoward effects were noted (Ref).
Children ≥10 years and Adolescents: Oral: 10 mg once daily in combination with simvastatin. Has also been shown in small pediatric trials to decrease TC and LDL-C when used as monotherapy as adjunct to dietary changes (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Children ≥10 years and Adolescents: No dosage adjustments are recommended.
Children ≥10 years and Adolescents:
Mild hepatic impairment (Child-Pugh score 5-6): No dosage adjustments are recommended.
Moderate to severe impairment (Child-Pugh score 7-15): Use is not recommended.
Refer to adult dosing.
Muscle symptoms and/or CPK >10 x ULN: Discontinue immediately if muscle-related effects, including myalgia, myopathy, or rhabdomyolysis, are suspected or confirmed.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Zetia: 10 mg
Generic: 10 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Ezetrol: 10 mg
Generic: 10 mg
Oral: May be administered without regard to meals. May be taken at the same time as a statin or fenofibrate. Administer ≥2 hours before or ≥4 hours after bile acid sequestrants.
Oral: May be taken without regard to meals or time of day; may be administered with an HMG-CoA reductase inhibitor (eg, atorvastatin, simvastatin) or fenofibrate. Administer ≥2 hours before or ≥4 hours after bile acid sequestrants.
Homozygous familial hypercholesterolemia: In combination with a high-intensity statin (eg, atorvastatin) for the reduction of elevated total cholesterol (total-C) and low-density lipoprotein cholesterol (LDL-C) levels in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) or if such treatments are unavailable.
Homozygous sitosterolemia: As adjunctive therapy to diet for the reduction of elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia.
Primary hyperlipidemia: As adjunctive therapy to diet and an HMG-CoA reductase inhibitor or as monotherapy if an HMG-CoA reductase inhibitor is not tolerated for the reduction of total-C, LDL-C, apolipoprotein B, and nonhigh-density lipoprotein cholesterol in patients with primary (heterozygous familial and nonfamilial) hyperlipidemia or mixed hyperlipidemia.
Secondary prevention of atherosclerotic cardiovascular events after acute coronary syndrome
Ezetimibe may be confused with ezogabine
Zetia may be confused with Zebeta, Zestril
Increased serum transaminases and hepatotoxicity have been associated with ezetimibe. A higher incidence of elevated transaminases (≥3 x ULN) has been observed with concurrent use of ezetimibe with statins compared to statin monotherapy (Ref). Acute liver injury, ranging from hepatocellular hepatitis to cholestatic hepatitis, has been reported (Ref). Autoimmune hepatitis-like syndrome has also been described (Ref). Since ezetimibe is frequently administered with other lipid-lowering agents, especially statins, it is difficult to assess the role of ezetimibe in causality of hepatotoxicity. If elevated transaminase levels do occur, they will often return to baseline with or without discontinuation of therapy. In patients with severe hepatotoxicity, resolution of symptoms usually occurs within 1 to 4 months (Ref).
Mechanism: Non–dose-related; unknown. Conjugation defect may lead to accumulation of toxic levels of ezetimibe in the liver in genetically predisposed patients (Ref). An immune-mediated response may be implicated in cases of autoimmune hepatitis-like syndrome (Ref).
Onset: Delayed; ranged from 2 to 10 months (Ref).
Risk factors:
• Concurrent use of statins (Ref)
• Preexisting hepatic impairment (not recommended in patients with moderate [Child-Pugh score 7 to 9] or severe [Child-Pugh score 10 to 15] hepatic impairment)
Ezetimibe, when used alone or in combination with statin therapy, has been linked to several muscle-related effects, including myalgia (Ref), myopathy (Ref), and rhabdomyolysis (Ref). Creatine kinase levels often normalize within 4 weeks of discontinuation of ezetimibe (Ref). Since ezetimibe is frequently co-administered with statins, which are commonly associated with muscle-related adverse effects, it is difficult to assess causality in many cases (Ref).
Mechanism: Unknown; impaired fatty acid oxidation may lead to ezetimibe-induced muscle related effects (Ref).
Onset: Varied; can present hours to 4 months, with most symptoms developing within 2 weeks (Ref).
Risk factors:
• Concurrent use of a statin or fibrate
• Preexisting muscle disease (eg, McArdle disease) (Ref)
• Risk factors for muscle-related effects with statins (eg, older adults, hypothyroidism, kidney impairment)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in children, adolescents, and adults.
1% to 10%:
Hepatic: Increased serum transaminases (monotherapy, ≥3 x ULN: <1%; with HMG-CoA reductase inhibitors; ≥3 x ULN: 1%)
|
Drug (Ezetimibe) |
Placebo |
Comparator (HMG-CoA Reductase Inhibitors) |
Comments |
|---|---|---|---|
|
0.5% |
0.3% |
N/A |
Monotherapy; ≥3 x ULN |
|
1% |
N/A |
0.4% |
Initiated concurrently with HMG-CoA reductase inhibitors; ≥3 x ULN |
Neuromuscular & skeletal: Arthralgia (3%)
Respiratory: Sinusitis (3%), upper respiratory tract infection (4%)
Frequency not defined: Endocrine & metabolic: Increased gamma-glutamyl transferase
Postmarketing:
Dermatologic: Erythema multiforme, skin rash, urticaria
Gastrointestinal: Abdominal pain, cholecystitis, cholelithiasis, nausea, pancreatitis (Ahmad 2007)
Hematologic & oncologic: Thrombocytopenia (Pattis 2008)
Hepatic: Autoimmune hepatitis (Stolk 2006), cholestatic hepatitis (Stolk 2006), hepatocellular hepatitis (Liu 2007)
Hypersensitivity: Anaphylaxis, angioedema
Nervous system: Depression, dizziness, headache, paresthesia
Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen, myalgia (Nissen 2016), myopathy (Brahmachari 2015), rhabdomyolysis (Emerson 2020)
Hypersensitivity to ezetimibe or any component of the formulation; concomitant use with an HMG-CoA reductase inhibitor (statin) in patients with active hepatic disease or unexplained persistent elevations in serum transaminases; pregnancy and breastfeeding (when used concomitantly with a statin)
Disease-related concerns:
• Hepatic impairment: Systemic exposure is increased in hepatic impairment. Use with caution in patients with mild hepatic impairment (Child-Pugh class A); use is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh classes B and C).
• Renal impairment: Use with caution in patients with severe renal impairment (CrCl ≤30 mL/minute/1.73 m2); systemic exposure is increased ~1.5-fold. If using concurrent simvastatin in patients with moderate to severe renal impairment (CrCl <60 mL/minute/1.73m2), the manufacturer of ezetimibe recommends that simvastatin doses exceeding 20 mg be used with caution and close monitoring for adverse events (eg, myopathy).
Substrate of OATP1B1/1B3 (SLCO1B1/1B3)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Bile Acid Sequestrants: May decrease the absorption of Ezetimibe. Management: Administer ezetimibe at least 2 hours before or 4 hours after any bile acid sequestrant. Risk D: Consider therapy modification
CycloSPORINE (Systemic): Ezetimibe may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Ezetimibe. Risk C: Monitor therapy
Darolutamide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Eltrombopag: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Encorafenib: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Fenofibrate and Derivatives: May enhance the adverse/toxic effect of Ezetimibe. Specifically, the risk of myopathy and cholelithiasis may be increased. Fenofibrate and Derivatives may increase the serum concentration of Ezetimibe. Risk C: Monitor therapy
Fibric Acid Derivatives: May enhance the adverse/toxic effect of Ezetimibe. Specifically, the risk of myopathy and cholelithiasis may be increased. Fibric Acid Derivatives may increase the serum concentration of Ezetimibe. Risk X: Avoid combination
Leflunomide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Teriflunomide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Voclosporin: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Adverse events were observed in some animal reproduction studies. Use is contraindicated in pregnant women who require combination therapy with an HMG-CoA reductase inhibitor. If treatment for familial hypercholesterolemia is needed during pregnancy, other agents are preferred (Wiegman 2015).
It is not known if ezetimibe is present in breast milk. According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should take into account the risk of exposure to the infant and the benefits of treatment to the mother. Use is contraindicated in breastfeeding women who require combination therapy with an HMG-CoA reductase inhibitor.
Before initiation of therapy, patients should be placed on a standard cholesterol-lowering diet for 6 weeks and the diet should be continued during drug therapy.
Signs or symptoms of myopathy, CPK.
ACC/AHA blood cholesterol guideline recommendations (ACC/AHA [Grundy 2018]; ACC/AHA [Stone 2013]):
Lipid panel (total cholesterol, HDL, LDL, triglycerides): Lipid profile (fasting or nonfasting) before initiating treatment. Fasting lipid profile should be rechecked 4 to 12 weeks after starting therapy and every 3 to 12 months thereafter (AHA/ACC [Grundy 2018]).
Hepatic transaminase levels: Baseline LFTs (reasonable); when used in combination with statin therapy, monitor LFTs when clinically indicated; discontinue use of ezetimibe if ALT elevations >3 times upper limit of normal persist. When used in combination with fenofibrate, monitor LFTs and signs and symptoms of cholelithiasis.
Treatment goals: May vary depending on clinical condition, different clinical practice guidelines, and expert opinion. Refer to clinical practice guidelines for specific treatment goals.
Inhibits absorption of cholesterol at the brush border of the small intestine via the sterol transporter, Niemann-Pick C1-Like1 (NPC1L1). This leads to a decreased delivery of cholesterol to the liver, reduction of hepatic cholesterol stores and an increased clearance of cholesterol from the blood; decreases total C, LDL-cholesterol (LDL-C), ApoB, and triglycerides (TG) while increasing HDL-cholesterol (HDL-C).
Note: Pharmacokinetic data in children and adolescents ≥10 years of age are reported to be similar to that in adult patients.
Onset of action: Within 1 week; Maximum effect: 2 to 4 weeks.
Protein binding: >90% to plasma proteins.
Metabolism: Undergoes glucuronide conjugation in the small intestine and liver; forms metabolite (active); may undergo enterohepatic recycling.
Half-life elimination: 22 hours (ezetimibe and metabolite).
Time to peak, plasma: 4-12 hours (ezetimibe); 1-2 hours (active metabolite); Effects: ~2 weeks.
Excretion: Feces (78%, 69% as ezetimibe); urine (11%, 9% as metabolite).
Altered kidney function: Severe renal dysfunction (CrCl <30 mL/minute/1.73 m2): AUC increased 1.5 times.
Hepatic impairment: Moderate hepatic impairment (Child-Pugh score 7 to 9): AUC increased 3 to 4 times; severe hepatic impairment (Child-Pugh 10 to 15): AUC increased 5 to 6 times.
Older adult: Plasma concentrations are approximately 2-fold higher.
Sex: Plasma concentrations for total ezetimibe were slightly higher (less than 20%) in women than in men.
Tablets (Ezetimibe Oral)
10 mg (per each): $2.62 - $11.30
Tablets (Zetia Oral)
10 mg (per each): $14.48
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