Ezetimibe

C10B - Lipid modifying agents, combinations ATC C10AX09 Small molecule approved 2002 Oral

JFDA label: Ezetrol Tab

Mechanism of Action

Inhibitor of NPC1-like intracellular cholesterol transporter 1 — Niemann-Pick C1-like protein 1 inhibitor

Target	Action	Gene / class
NPC1-like intracellular cholesterol transporter 1 efficacy	INHIBITOR	NPC1L1 · Other membrane protein

Indications

Approved

Combination therapy with HMG-CoA reductase inhibitors
Combination therapy with fenofibrate
Homozygous familial hypercholesterolemia
Homozygous sitosterolemia
Monotherapy
Primary hyperlipidemia

Contraindications

Source: Lexicomp

Hypersensitivity to ezetimibe or any component of the formulation Absolute
concomitant use with an HMG-CoA reductase inhibitor (statin) in patients with active hepatic disease or unexplained persistent elevations in serum transaminases Absolute
pregnancy and breast-feeding (when used concomitantly with a statin) Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Nervous system disorders (1)

Common Fatigue

Hepatobiliary disorders (1)

Common Increased serum transaminases

Gastrointestinal disorders (1)

Common Diarrhea

Musculoskeletal and connective tissue disorders (2)

Common Arthralgia · limb pain

Infections and infestations (1)

Common Influenza

Respiratory, thoracic and mediastinal disorders (2)

Common sinusitis · Upper respiratory tract infection

Dosing

Source: Lexicomp

Homozygous familial hypercholesterolemia, primary hyperlipidemia, homozygous sitosterolemia: Oral: 10 mg once daily

(For additional information see "Ezetimibe: Pediatric drug information") Children ≥10 years and Adolescents: Refer to adult dosing.

Refer to adult dosing.

No dosage adjustment necessary.

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.

Warnings & Precautions

Source: Lexicomp

Elevated hepatic transaminases

A higher incidence of elevated transaminases (≥3 x ULN) has been observed with concomitant use of ezetimibe and statins compared to statin monotherapy; transaminase changes were generally not associated with symptoms or cholestasis and returned to baseline with or without discontinuation of therapy. Consider discontinuation of ezetimibe and/or the statin for persistently elevated transaminases (ALT or AST ≥3 x ULN).

Myopathy

Myopathy, including rhabdomyolysis, has been reported (rarely) with ezetimibe monotherapy; risk may be increased with concomitant use of a statin or fibrate. Discontinue ezetimibe and statin or fibrate immediately if myopathy is suspected or confirmed (symptomatic patient with CPK >10 x ULN). 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 2), the manufacturer of ezetimibe recommends that simvastatin doses exceeding 20 mg be used with caution and close monitoring for adverse events (eg, myopathy). Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant drug interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Other warnings/precautions:

Hyperlipidemia

Secondary causes of hyperlipidemia should be ruled out prior to therapy.

Pregnancy & Lactation

Pregnancy

FDA category C Contraindicated

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).

Lactation

Contraindicated

It is not known if ezetimibe is excreted in breast milk. According to the manufacturer, the decision to continue or discontinue breast-feeding 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 nursing women who require combination therapy with an HMG-CoA reductase inhibitor.

Monitoring

Clinical pearl	Total cholesterol profile prior to therapy, and when clinically indicated and/or periodically thereafter. When used in combination with fenofibrate, monitor LFTs and signs and symptoms of cholelithiasis. 2013 ACC/AHA Blood Cholesterol Guideline recommendations (Stone, 2013): 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.

Clinical pearl

Total cholesterol profile prior to therapy, and when clinically indicated and/or periodically thereafter. When used in combination with fenofibrate, monitor LFTs and signs and symptoms of cholelithiasis. 2013 ACC/AHA Blood Cholesterol Guideline recommendations (Stone, 2013): 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.

Chemistry & Properties

Formula	C24H21F2NO3
Molecular weight	409.43 g/mol
IUPAC name	(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one
CAS	163222-33-1
PubChem CID	150311
InChIKey	`OLNTVTPDXPETLC-XPWALMASSA-N`
logP	4.89 (XLogP 4.0)
Polar surface area	60.77 Å²
H-bond acceptors / donors	3 / 2
Drug-likeness (QED)	0.57
Lipinski violations	0

SMILES

O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(O)cc2)N1c1ccc(F)cc1

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	10.0%
Half-life	0.731 h
Volume of distribution	1.207 L/kg
Protein binding	90.5%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP2B6	Inhibitor	—
CYP2C8	Inhibitor	—
CYP2D6	Inhibitor	—
CYP2D6	Substrate	—

Receptor binding (top 1)

Target	Action	Affinity
NPC1 like intracellular cholesterol transporter 1 (NPC1L1)	Antagonist	pKd 6.7

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)NTCP (Inhibitor)OATP (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OATP2B1 (Inhibitor)P-gp (Inhibitor)BCRP (Substrate)MDR1 (Substrate)OATP (Substrate)P-gp (Substrate)

Drug–drug interactions (17, DDInter)

Interacting drug	Severity	Management
Apalutamide	moderate
Chenodeoxycholic acid	moderate
Cyclosporine	moderate
Darolutamide	moderate
Eltrombopag	moderate
Eluxadoline	moderate
Enasidenib	moderate
Encorafenib	moderate
Entrectinib	moderate
Midostaurin	moderate
Rosuvastatin	moderate
Simvastatin	moderate
Sirolimus	moderate
Temsirolimus	moderate
Teriflunomide	moderate
Dicoumarol	minor
Warfarin	minor

Registered Products (17)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Superstat Plus	Tablet 10.00 mg, 5 mg	30 tab	Hikma Pharmaceuticals Co.Ltd/Jordan	7.470
Zetex	Tablet 10 mg	30 tab	Sukhtian Group	11.230
Ezetrol Tab	Tablet 10 mg	28 tab	Adatco Drug Store	12.010
Xitrol	Tablet 10 mg	30 tab	UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN	12.630
Zeechol	Tablet 10.0 mg	30 tab	SAVVY PHARMA/JORDAN	12.630
Superstat Plus	Tablet Rosuvastatin Calcium 10.40 mg, Ezetimibe 10.00 mg	30 tab	Hikma Pharmaceuticals LLC P.O. Box: 182400 Amman 11118 - Jordan	12.670
Superstat Plus	Tablet Ezetimibe 10.00 mg, Rosuvastatin Calcium 20.80 mg	30 tab	Hikma Pharmaceuticals LLC P.O. Box: 182400 Amman 11118 - Jordan	14.140
Atozet 10/10 mg F.C Tab	Film-Coated Tablet 10 mg, 10 mg	30 tab	Adatco Drug Store	15.030
Superstat Plus	Tablet 10.00 mg, 40 mg	30 tab	Hikma Pharmaceuticals Co.Ltd/Jordan	15.690
Inegy Tablets	Tablet 20 mg, 10 mg	28 tab	Adatco Drug Store	16.650
Zympass	Tablet 10 mg, 10 mg	30 tab	Ulfa Pharma Co.	16.860
Zympass	Tablet 20 mg, 10 mg	30 tab	Ulfa Pharma Co.	18.820
Atozet	Tablet 20 mg, 10 mg	30 tab	Adatco Drug Store	18.940
Atozet 10/40mg F.c Tab	Film-Coated Tablet 40 mg, 10 mg	30 tab	Adatco Drug Store	18.940
Inegy Tablets	Tablet 40 mg, 10 mg	28 tab	Adatco Drug Store	20.470
Zympass	Tablet 40 mg, 10 mg	30 tab	Ulfa Pharma Co.	20.880
Averto Plus	Tablet 180/10 mg	30 tab	Hikma Pharmaceuticals // شركة أدوية الحكمة	40.000