Drug Monograph
Ezetimibe
Brand name: Zetia; also available as fixed-dose combinations (Vytorin with simvastatin, Liptruzet with atorvastatin)
Pharmacokinetic Profile
Half-Life
~22 h (ezetimibe + glucuronide)
Metabolism
Glucuronidation (UGT) in intestine & liver; enterohepatic recycling; minimal CYP involvement
Protein Binding
>90% (both ezetimibe and ezetimibe-glucuronide)
Bioavailability
Variable; extensive first-pass glucuronidation
Active Metabolite
Ezetimibe-glucuronide (80–90% of plasma drug, pharmacologically active)
Clinical Information
Drug Class
Selective cholesterol absorption inhibitor
Available Doses
10 mg tablet
Route
Oral
Renal Adjustment
No adjustment needed
Hepatic Adjustment
Not recommended in moderate-to-severe impairment (Child-Pugh B/C)
Pregnancy
Use only if benefit justifies risk; avoid with statin in pregnancy
Lactation
Not recommended unless benefit justifies risk
Schedule / Legal Status
Prescription only (Rx)
Generic Available
Yes
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Primary hyperlipidaemia (including HeFH) | Adults | With statin, or alone when statin not possible | FDA Approved |
| HeFH in paediatric patients | ≥10 years | With statin | FDA Approved |
| Homozygous familial hypercholesterolaemia (HoFH) | Adults and paediatric patients ≥10 years | With statin and other LDL-C lowering therapies | FDA Approved |
| Mixed hyperlipidaemia | Adults | With fenofibrate | FDA Approved |
| Homozygous sitosterolaemia (phytosterolaemia) | Adults | Monotherapy or adjunctive | FDA Approved |
Ezetimibe was FDA-approved in 2002 and remains the most widely used nonstatin lipid-lowering agent. As monotherapy, ezetimibe reduces LDL-C by approximately 13–20%. When added to a statin, it provides an additional 23–24% LDL-C reduction. The landmark IMPROVE-IT trial (NEJM 2015) was the first to demonstrate that adding a nonstatin to statin therapy improves cardiovascular outcomes. The 2018 AHA/ACC cholesterol guideline recommends ezetimibe as a first-line add-on therapy for patients whose LDL-C remains above goal on maximally tolerated statin therapy.
Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Add-on to statin when LDL-C remains above goal | 10 mg once daily | 10 mg once daily | 10 mg/day | Take with or without food at any time of day Additional 23–24% LDL-C reduction when added to statin (IMPROVE-IT); assess LDL-C as early as 4 weeks |
| Monotherapy for primary hyperlipidaemia (statin intolerant or statin not possible) | 10 mg once daily | 10 mg once daily | 10 mg/day | ~13–20% LDL-C reduction as monotherapy Near-maximal response within 2 weeks |
| HeFH or HoFH — add-on to high-intensity statin | 10 mg once daily | 10 mg once daily | 10 mg/day | For HoFH: use with statin and other LDL-C lowering therapies In HoFH trial, ezetimibe + statin reduced LDL-C by 21% vs statin dose-doubling (7%) |
| Paediatric HeFH (≥10 years) | 10 mg once daily | 10 mg once daily | 10 mg/day | Use in combination with a statin Based on 248-patient placebo-controlled trial; no significant effect on growth or sexual maturation |
| Homozygous sitosterolaemia | 10 mg once daily | 10 mg once daily | 10 mg/day | Reduces plasma sitosterol and campesterol by ~21% and ~24% |
| Mixed hyperlipidaemia with fenofibrate | 10 mg once daily | 10 mg once daily | 10 mg/day | Monitor for cholelithiasis with fenofibrate combination Cholecystectomy rate 1.7% with fenofibrate+ezetimibe vs 0.6% fenofibrate alone |
| Co-administration with bile acid sequestrant | 10 mg once daily | 10 mg once daily | 10 mg/day | Dose ezetimibe ≥2 hours before or ≥4 hours after bile acid sequestrant Cholestyramine reduces ezetimibe AUC by ~55% |
Clinical Pearl — One Dose for All Scenarios
Ezetimibe has the simplest dosing of any lipid-lowering agent: 10 mg once daily for every indication, with no dose titration and no dose adjustment for age, sex, renal impairment, or mild hepatic impairment. The only dosing consideration is timing relative to bile acid sequestrants (space by ≥2 hours before or ≥4 hours after). Ezetimibe can be taken at any time of day, with or without food, and can be co-administered directly with any statin or fenofibrate.
Pharmacology
Mechanism of Action
Ezetimibe selectively inhibits the Niemann-Pick C1-Like 1 (NPC1L1) protein, a sterol transporter located at the brush border of the small intestine. NPC1L1 is responsible for the intestinal uptake of cholesterol and phytosterols from the gut lumen. By blocking this transporter, ezetimibe reduces the delivery of intestinal cholesterol to the liver, which in turn upregulates hepatic LDL receptor expression and increases LDL-C clearance from the blood. Ezetimibe does not inhibit cholesterol synthesis (unlike statins) and does not affect absorption of triglycerides, fatty acids, bile acids, fat-soluble vitamins A and D, or steroid hormones. It does not induce cytochrome P450 enzymes. Because statins and ezetimibe lower cholesterol through complementary mechanisms, their combination produces additive LDL-C reduction.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Absorbed and extensively conjugated in intestinal wall; ezetimibe Tmax 4–12 h; glucuronide Tmax 1–2 h | Rapid first-pass glucuronidation; food does not affect bioavailability; can be taken with or without meals |
| Distribution | Protein binding: >90% (both ezetimibe and glucuronide, FDA PI) | Highly protein-bound; enterohepatic recycling produces multiple plasma peaks |
| Metabolism | UGT glucuronidation in intestine and liver to active ezetimibe-glucuronide (80–90% of circulating drug); minimal CYP450 involvement; does not induce CYP450 | Very low drug interaction potential via CYP enzymes; the glucuronide metabolite is pharmacologically active and contributes to cholesterol absorption inhibition |
| Elimination | t½ ~22 h (total ezetimibe); ezetimibe excreted primarily in faeces, glucuronide primarily in urine | Long half-life supports once-daily dosing; no dose adjustment for renal impairment |
Side Effects
1–10%Common — Ezetimibe Monotherapy (2,396 patients)
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Upper respiratory tract infection | 4.3% | Most common reported event; not clearly drug-related |
| Diarrhoea | 4.1% | Usually mild and self-limiting |
| Arthralgia | 3.0% | Monitor; distinguish from statin-related myalgia when co-prescribed |
| Sinusitis | 2.8% | Not clearly drug-related |
| Pain in extremity | 2.7% | Comparable to placebo in controlled studies |
1–10%Common — Ezetimibe + Statin (11,308 patients)
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Nasopharyngitis | 3.7% | Not clearly drug-related |
| Myalgia | 3.2% | Likely statin-related; assess as for statin monotherapy |
| Upper respiratory tract infection | 2.9% | Not clearly drug-related |
| Arthralgia | 2.6% | Monitor; reported in post-marketing as well |
| Diarrhoea | 2.5% | Usually mild and self-limiting |
SeriousSerious (Regardless of Frequency)
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Hepatic transaminase elevation (≥3× ULN) | 0.5% (mono) / 1.3% (with statin) vs 0.4% statin alone | Variable | Perform liver enzymes as clinically indicated; consider discontinuation if persistent ≥3× ULN |
| Myopathy / Rhabdomyolysis | Very rare (post-marketing); CPK >10× ULN: 0.2% (mono) vs 0.1% placebo | Variable | Discontinue ezetimibe and any concomitant statin/fibrate; most post-marketing cases occurred with concomitant statin |
| Cholelithiasis / Cholecystitis | Uncommon; cholecystectomy 1.7% with fenofibrate combination | Months | Gallbladder studies if cholelithiasis suspected; consider alternative therapy; reported with fenofibrate combination |
| Hypersensitivity reactions (anaphylaxis, angioedema, rash, urticaria) | Rare (post-marketing) | Variable | Discontinue permanently; emergency care for anaphylaxis/angioedema |
| Pancreatitis | Rare (post-marketing) | Variable | Discontinue; investigate alternative aetiologies |
| Thrombocytopenia | Rare (post-marketing) | Variable | Check platelet count; discontinue if significant |
DiscontinuationDiscontinuation Rates
Ezetimibe + Statin (11,308 patients)
4.0% vs 3.3% statin alone
Context: Median treatment 8 weeks; discontinuation rate only marginally higher than statin alone
IMPROVE-IT (18,144 patients, median 6 years)
No excess safety signal
Key safety: Rates of muscle, gallbladder, hepatic adverse events, and cancer were similar between ezetimibe/simvastatin and simvastatin alone
Favourable Long-Term Safety Profile
In the IMPROVE-IT trial involving 18,144 patients followed for a median of 6 years, ezetimibe combined with simvastatin showed no increase in muscle-related adverse events, gallbladder disease, hepatic adverse events, or incident cancer compared with simvastatin alone. This provides strong reassurance for long-term use.
Drug Interactions
Ezetimibe is metabolised primarily by glucuronidation (UGT enzymes), not by CYP450. It does not induce CYP450 enzymes. Consequently, ezetimibe has a remarkably low drug interaction profile. No clinically significant PK interactions occur with any statin (lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, or rosuvastatin). The most important interactions involve drugs that affect enterohepatic recycling or OATP1B1 transport.
MajorCyclosporine
MechanismMutual pharmacokinetic interaction; cyclosporine increases total ezetimibe AUC 3.4-fold (range 2.3–7.9-fold)
EffectMarkedly increased ezetimibe exposure; ezetimibe may also increase cyclosporine levels
ManagementMonitor cyclosporine concentrations; weigh increased ezetimibe exposure against lipid benefits; a 12-fold AUC increase was seen in one patient with severe renal insufficiency
FDA PIModerateCholestyramine (Bile Acid Sequestrants)
MechanismCholestyramine decreases ezetimibe AUC by approximately 55% via GI binding
EffectReduced ezetimibe efficacy if taken simultaneously
ManagementAdminister ezetimibe ≥2 hours before or ≥4 hours after bile acid sequestrant
FDA PIModerateFenofibrate
MechanismFenofibrate increases total ezetimibe concentrations approximately 1.5-fold
EffectPotential increased risk of cholelithiasis; cholecystectomy rate 1.7% (vs 0.6% fenofibrate alone)
ManagementIf cholelithiasis suspected, perform gallbladder studies; consider alternative therapy
FDA PIModerateGemfibrozil
MechanismGemfibrozil increases total ezetimibe concentrations approximately 1.7-fold
EffectIncreased ezetimibe exposure; limited clinical data on combination
ManagementNo specific dose adjustment; monitor for adverse effects
FDA PIMinorStatins (All)
MechanismNo significant pharmacokinetic interaction in either direction
EffectNo change in exposure of ezetimibe or any statin tested (lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, rosuvastatin)
ManagementNo dose adjustment; can be co-administered at same time
FDA PIMinorWarfarin
MechanismNo significant pharmacokinetic interaction
EffectNo clinically significant effect on INR expected
ManagementFDA PI recommends monitoring INR when ezetimibe is added to warfarin
FDA PIMonitoring
- Lipid PanelBaseline, as early as 4 weeks, then periodically
RoutineFasting lipid panel. Near-maximal LDL-C response usually achieved within 2 weeks. Adjust overall lipid therapy as needed based on LDL-C goal. - Liver Enzymes (ALT/AST)As clinically indicated; at initiation when combined with statin
RoutineConsecutive transaminase elevations ≥3× ULN occurred in 1.3% of ezetimibe+statin vs 0.4% statin alone. Consider discontinuation if elevations persist. Generally asymptomatic and reversible. - Creatine Kinase (CK)When clinically indicated (muscle symptoms)
Trigger-basedCK >10× ULN was 0.2% with ezetimibe monotherapy vs 0.1% placebo. Rhabdomyolysis very rarely reported post-marketing, mostly with concomitant statin. - Cyclosporine LevelsAt initiation and periodically when co-prescribed
Trigger-basedCyclosporine increases ezetimibe AUC 3.4-fold; ezetimibe may increase cyclosporine levels. Monitor trough levels closely. - INR (with warfarin)When ezetimibe is added or stopped
Trigger-basedMonitor INR per FDA PI recommendation when ezetimibe is added to warfarin, although no significant PK interaction has been demonstrated.
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity to ezetimibe or any excipient (anaphylaxis, angioedema reported post-marketing)
- When used with a statin: active liver disease or unexplained persistent transaminase elevations (refer to statin PI)
- When used with a statin in pregnancy or nursing: statins are contraindicated in pregnancy
Relative Contraindications (Specialist Input Recommended)
- Moderate-to-severe hepatic impairment (Child-Pugh B or C) — AUC of total ezetimibe increases 3–4-fold and unconjugated ezetimibe 5–6-fold; ezetimibe is not recommended in these patients due to unknown effects of increased exposure (FDA PI)
- Co-administration with cyclosporine — ezetimibe AUC increased 3.4-fold (up to 12-fold in severe renal insufficiency); requires careful monitoring
Use with Caution
- Pregnancy (monotherapy) — use only if benefit justifies risk; no adequate human data
- Co-administration with fenofibrate — increased cholelithiasis risk; cholecystectomy rate 1.7% vs 0.6%
- Co-administration with bile acid sequestrants — separate dosing by ≥2 hours before or ≥4 hours after
FDA Safety Advisory
Hepatic Transaminases with Ezetimibe + Statin Combination
In controlled clinical combination studies, the incidence of consecutive transaminase elevations ≥3× ULN was 1.3% for ezetimibe + statin compared with 0.4% for statin alone. These elevations were generally asymptomatic, not associated with cholestasis, and resolved after discontinuation. Perform liver enzyme testing as clinically indicated and consider withdrawal if elevations persist.
Patient Counselling
Purpose of Therapy
Ezetimibe helps lower cholesterol by blocking its absorption from the food you eat. It works differently from statins and is often used alongside them for better cholesterol control. In a large clinical trial, adding ezetimibe to statin therapy reduced the risk of heart attack and stroke in people who had already experienced a cardiac event.
How to Take
Take one 10 mg tablet once daily, at any time of day, with or without food. If you also take a bile acid sequestrant (such as cholestyramine), take ezetimibe at least 2 hours before or 4 hours after. If you miss a dose, take it as soon as you remember; do not double the next dose.
Muscle Pain or Weakness
Tell patientMuscle problems are uncommon with ezetimibe alone but may occur when combined with a statin. Report any unexplained muscle pain, tenderness, or weakness.
Call prescriberIf persistent muscle pain develops, especially if accompanied by fever, malaise, or dark-coloured urine.
Liver Effects
Tell patientBlood tests may be done to check liver function, especially when ezetimibe is combined with a statin. Serious liver problems are very rare.
Call prescriberIf you develop unusual tiredness, loss of appetite, upper abdominal pain, dark urine, or yellowing of skin or eyes.
GI Symptoms
Tell patientDiarrhoea is one of the more common side effects. It is usually mild. Maintain adequate fluid intake.
Call prescriberIf diarrhoea is severe, persistent, or associated with abdominal pain.
Allergic Reactions
Tell patientAllergic reactions including skin rash are rare. Very rarely, more serious reactions such as swelling of the face, lips, or throat can occur.
Call prescriberSeek emergency care immediately if swelling of the face, lips, tongue, or throat occurs, or if you have difficulty breathing.
Pregnancy
Tell patientIf you are taking ezetimibe with a statin, the statin must be stopped if you become pregnant or plan to become pregnant. Discuss contraception with your prescriber.
Call prescriberIf you become pregnant or are planning a pregnancy while on combination therapy.
Sources
Regulatory (PI / SmPC)
- ZETIA (ezetimibe) tablets — Full Prescribing Information. Organon LLC. Revised 2024. FDA LabelPrimary reference for dosing, PK, adverse reactions, drug interactions, hepatic impairment data, and indications.
- ZETIA (ezetimibe) tablets — Full Prescribing Information. Merck/Schering-Plough. 2012. FDA LabelEarlier label version with detailed SHARP trial safety data in CKD populations.
Key Clinical Trials
- Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes (IMPROVE-IT). N Engl J Med. 2015;372(25):2387-2397. doi:10.1056/NEJMoa1410489Landmark 18,144-patient RCT demonstrating that ezetimibe + simvastatin reduces MACE by 6.4% (HR 0.936, P=0.016) vs simvastatin alone post-ACS; first trial proving nonstatin add-on therapy improves CV outcomes.
- Murphy SA, Cannon CP, Blazing MA, et al. Reduction in Total Cardiovascular Events With Ezetimibe/Simvastatin Post-Acute Coronary Syndrome: The IMPROVE-IT Trial. J Am Coll Cardiol. 2016;67(4):353-361. doi:10.1016/j.jacc.2015.10.077Pre-specified analysis showing 9% reduction in total (first + recurrent) CV events with ezetimibe/simvastatin over median 6-year follow-up.
- Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (SHARP). Lancet. 2011;377(9784):2181-2192. doi:10.1016/S0140-6736(11)60739-39,270-patient RCT in CKD showing ezetimibe/simvastatin reduced major atherosclerotic events by 17% and confirming long-term safety in renal impairment.
- Kastelein JJP, Akdim F, Stroes ESG, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia (ENHANCE). N Engl J Med. 2008;358(14):1431-1443. doi:10.1056/NEJMoa0800742Trial in HeFH showing greater LDL-C lowering but no difference in carotid IMT with ezetimibe/simvastatin vs simvastatin; generated initial uncertainty about ezetimibe outcomes, later resolved by IMPROVE-IT.
Guidelines
- Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. J Am Coll Cardiol. 2019;73(24):e285-e350. doi:10.1016/j.jacc.2018.11.003Current US cholesterol guideline recommending ezetimibe as first-line nonstatin add-on therapy for patients not at LDL-C goal on maximally tolerated statin.
- Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering. J Am Coll Cardiol. 2022;80(14):1366-1418. doi:10.1016/j.jacc.2022.07.006ACC nonstatin pathway positioning ezetimibe as first step after maximally tolerated statin, before PCSK9 inhibitors.
Mechanistic / Basic Science
- Altmann SW, Davis HR Jr, Zhu LJ, et al. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption. Science. 2004;303(5661):1201-1204. doi:10.1126/science.1093131Seminal study identifying NPC1L1 as the molecular target of ezetimibe and its role in intestinal cholesterol uptake.
- Jarcho JA, Keaney JF Jr. Proof That Lower Is Better — LDL Cholesterol and IMPROVE-IT. N Engl J Med. 2015;372(25):2448-2450. doi:10.1056/NEJMe1507041Editorial discussing IMPROVE-IT as evidence supporting the LDL hypothesis that lower cholesterol through any mechanism reduces CV risk.
Pharmacokinetics / Special Populations
- Kosoglou T, Statkevich P, Johnson-Levonas AO, et al. Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions. Clin Pharmacokinet. 2005;44(5):467-494. doi:10.2165/00003088-200544050-00002Comprehensive PK review detailing glucuronidation pathway, enterohepatic recycling, and drug interaction studies.
- LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. NIDDK. Ezetimibe. NCBI BookshelfNIH resource on ezetimibe hepatotoxicity patterns and post-marketing hepatic safety data.