Ezetimibe

409.43

409.43

1308068-626-2

EOR26LQQ24

DTXSID1044223

C47529

White solid

C10B|C10AX09|C - Cardiovascular system

29337900

60.8

4

Solid

1.334±0.06 g/cm3(Predicted)

164-166 °C

654.9±55.0 °C(Predicted)

349.9±31.5 °C

1.624

H2O: Insoluble

-20°C Freezer

1.5X10-14 mm Hg at 25 deg C (est)

D22 -33.9° (c = 3 in methanol)

Henry's Law constant = 4.4X10-18 atm-cu m/mole at 25 °C (est)

pKa1 = 9.73 (phenol) (est)

213.6 Ų [M+Na]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

NONH for all modes of transport

36/37/38

26-36-24/25

P201, P202, P260, P263, P264, P270, P273, P281, P308+P313, P391, P405, P501

H361

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl ezetimibe, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Warning|H410 (83.49%): Very toxic to aquatic life with long lasting effects [Warning Hazardous to the aquatic environment, long-term hazard]|P273, P391, and P501|Aggregated GHS information provided by 109 companies from 10 notifications to the ECHA C&L Inventory.

Oral LD50 and intraperitoneal LD50 in rat were >2000 mg/kg. Estimated oral LD50 values in mouse and dog are >5000 mg/kg and >3000 mg/kg, respectively. One case of accidental overdose occurred in clinical studies in one female patient with homozygous sitosterolemia receiving 120 mg/day for 28 days with no reported clinical or laboratory adverse events. In case of overdose, symptomatic treatment is recommended.

Therapy with ezetimibe alone or in combination with other lipid lowering agents is associated with a low rate of serum enzyme elevations (0.5% to 1.5%), but most elevations were self-limited and not associated with jaundice or symptoms. In large randomized controlled trials, ezetimibe by itself has not been associated with a higher rate of serum ALT elevation than occurs with placebo therapy. However, the addition of ezetimibe to statin therapy has been associated with a slight increase in the likelihood of serum aminotransferase elevations or rates of discontinuation due to liver test abnormalities. Clinically apparent acute liver injury due to ezetimibe has been reported, but is rare. Furthermore, because this agent is often used in combination with other cholesterol lowering drugs, the role of ezetimibe in these reports is not always well defined. The latency to onset of clinically apparent liver injury attributed to ezetimibe has ranged from 2 to 10 months and the pattern of serum enzyme elevations has ranged from hepatocellular to cholestatic. Cases of autoimmune hepatitis-like injury have been described in patients taking the combination of ezetimibe and a statin, and the role of ezetimibe in these reactions is difficult to assign (Case 1). A single instance of vanishing bile duct syndrome due to ezetimibe has been described in a patient who continued on ezetimibe for several months despite presence of jaundice.

Pharmacokinetic or pharmacodynamic interaction /with warfarin/ is unlikely, based on one small study. Increased international normalized ratio (INR) with concomitant use of ezetimibe and warfarin has been reported during postmarketing experience; however, most patients also were receiving other drugs. Monitor INR if ezetimibe is initiated in a patient receiving warfarin.|Potential pharmacokinetic interaction (increased peak plasma ezetimibe concentration and AUC, increased cyclosporine AUC). The degree of exposure to ezetimibe may be greater in patients with severe renal insufficiency. Risk of myopathy/rhabdomyolysis is increased following concomitant administration of the fixed combination of ezetimibe and simvastatin (particularly at higher dosages) with cyclosporine. Because of increased exposure to ezetimibe and cyclosporine, use concomitantly with caution and monitor cyclosporine concentrations. If used concomitantly, dosage of the fixed-combination preparation should not exceed 10 mg of ezetimibe and 10 mg of simvastatin daily.|Potential pharmacokinetic (decreased AUC of ezetimibe) and pharmacodynamic (reduced LDL-cholesterol lowering effect) interaction. Ezetimibe should be administered at least 2 hours before or at least 4 hours after administration of the bile acid sequestrant.|Pharmacokinetic interaction (increased plasma ezetimibe concentrations) observed when used concomitantly with fenofibrate or gemfibrozil. Fibric acid derivatives may increase cholesterol excretion into bile, leading to cholelithiasis, and ezetimibe has been shown to increase cholesterol in the gall bladder bile in animals. In clinical studies, cholecystectomy has been reported in 1.7% of patients receiving ezetimibe concomitantly with fenofibrate and in 0.6% of those receiving fenofibrate monotherapy. Concomitant use with a fibric acid derivative other than fenofibrate currently is not recommended pending further accumulation of data in humans. If cholelithiasis is suspected in a patient receiving ezetimibe with fenofibrate, gallbladder studies should be performed, and alternative antilipemic therapy should be considered.|For more Interactions (Complete) data for Ezetimibe (6 total), please visit the HSDB record page.

Ezetimibe and ezetimibe-glucuronide are >90% bound to human plasma proteins. The mean _in vitro_ protein binding ranged from 99.5% to 99.8% for ezetimibe and 87.8% to 92.0% for ezetimibe-glucuronide.

Ezetimibe's production and use as an antilipemic(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 8.9X10+4(SRC), determined from a structure estimation method(2), indicates that ezetimibe is expected to be immobile in soil(SRC). The estimated pKa of ezetimibe is 9.7(3), indicating that this compound will partially exist in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of ezetimibe from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 4.4X10-18 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Ezetimibe is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.5X10-14 mm Hg at 25 °C(SRC), determined from a fragment constant method(6). Biodegradation data were not available(SRC, 2009).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 8.9X10+4(SRC), determined from a structure estimation method(2), indicates that ezetimibe is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 4.4X10-18 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 109(SRC), from an estimated log Kow of 3.9(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is high, provided the compound is not metabolized by the organism(SRC). Biodegradation data were not available(SRC, 2009).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), ezetimibe, which has an estimated vapor pressure of 1.5X10-14 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase ezetimibe may be removed from the air by wet or dry deposition(SRC). Ezetimibe does not contain chromophores that absorb at wavelengths >290 nm(3) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

Ezetimibe is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Ezetimibe does not contain chromophores that absorb at wavelengths >290 nm(1) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 100 was calculated in fish for ezetimibe(SRC), using an estimated log Kow of 3.9(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is high(SRC), provided the compound is not metabolized by the organism(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of ezetimibe can be estimated to be 8.9X10+4(SRC). According to a classification scheme(2), this estimated Koc value suggests that ezetimibe is expected to be immobile in soil. The estimated pKa of ezetimibe is 9.7(3), indicating that this compound will partially exist in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

The Henry's Law constant for ezetimibe is estimated as 4.4X10-18 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that ezetimibe is expected to be essentially nonvolatile from water surfaces(2). Ezetimibe's Henry's Law constant indicates that volatilization from moist soil surfaces may not occur(SRC). Ezetimibe is not expected to volatilize from dry soil surfaces(SRC) based upon a an estimated vapor pressure of 1.5X10-14 mm Hg(SRC), determined from a fragment constant method(3).

While data specific to ezetimibe were not located(SRC, 2009), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through soils(1).

Occupational exposure to ezetimibe may occur through inhalation of dust and dermal contact with this compound at workplaces where ezetimibe is produced or used. Use data indicate that exposure may be limited to those administered this drug, a lipid regulator. (SRC)

Ezetimibe is indicated to reduce elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with primary hyperlipidemia, alone or in combination with an HMG-CoA reductase inhibitor (statin). It is also indicated to reduce elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia in combination with fenofibrate, and to reduce elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH), in combination with atorvastatin or simvastatin. Ezetimibe may also be used to reduce elevated sitosterol and campesterol in patients with homozygous sitosterolemia (phytosterolemia).|FDA Label|Treatment of hypercholesterolaemia|Treatment of elevated cholesterol|Treatment of mixed dyslipidaemia|Prevention of cardiovascular events|Prevention of coronary heart disease|Treatment of sitosterolaemia, Treatment of hypercholesterolaemia|Treatment of hypercholesterolaemia, Treatment of mixed hyperlipidaemia|Prevention of cardiovascular events in chronic kidney disease|Prevention of coronary artery disease|Nustendi is indicated in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet:in combination with a statin in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin in addition to ezetimibealone in patients who are either statin-intolerant or for whom a statin is contraindicated, and are unable to reach LDL-C goals with ezetimibe alone,in patients already being treated with the combination of bempedoic acid and ezetimibe as separate tablets with or without statin|Prevention of cardiovascular events, Treatment of hypercholesterolaemia|Hypercholesterolaemia, Mixed (combined) hyperlipidaemia, Sitosterolaemia|Prevention of cardiovascular events, Treatment of hypercholesterolemia|Treatment of mixed hyperlipidaemia

Ezetimibe is an inhibitor of intestinal cholesterol absorption that is widely used in the therapy of hypercholesterolemia, usually in combination with other agents. Ezetimibe therapy is associated with a low rate of serum aminotransferase elevations and clinically apparent liver injury due to ezetimibe occurs, but is rare.

Antilipemic Agents

Ezetimibe is used alone or in combination with other antilipemic agents (i.e., a hydroxymethylglutaryl-coenzyme A [HMG-CoA] reductase inhibitor (statin), fenofibrate) as an adjunct to dietary therapy in the treatment of primary hypercholesterolemia and mixed dyslipidemia, homozygous familial hypercholesterolemia, and/or homozygous familial sitosterolemia. /Included in US product label/|Ezetimibe is used alone or in combination with a statin as an adjunct to dietary therapy to decrease elevated serum total cholesterol, low-density lipoprotein (LDL)-cholesterol, and apolipoprotein B (apo B) concentrations in the treatment of primary (heterozygous familial and nonfamilial) hypercholesterolemia. Ezetimibe in fixed combination with simvastatin is used as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, apo B, triglyceride, and non-HDL-cholesterol concentrations, and to increase HDL-cholesterol concentrations in the treatment of primary hypercholesterolemia or mixed dyslipidemia. Ezetimibe also is used in combination with fenofibrate as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, apo B, and non-HDL-cholesterol concentrations in the treatment of mixed dyslipidemia. /Included in US product label/|Ezetimibe is used as an adjunct to dietary therapy to decrease elevated serum sitosterol and campesterol concentrations in patients with homozygous familial sitosterolemia. /Included in US product label/|Ezetimibe may be used in combination with atorvastatin or simvastatin to decrease elevated serum total and LDL-cholesterol concentrations in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering therapies (e.g., plasma LDL apheresis) or when such therapies are not available. /Included in US product label/|This is a retrospective review of all pediatric patients who received ezetimibe monotherapy as treatment for hypercholesterolemia and for whom follow-up clinical and lipid results were available. Of 36 identified patients, 26 had lipoprotein profiles suggestive of familial hypercholesterolemia (FH), and 10 had profiles suggestive of familial combined hyperlipidemia (FCHL). After a mean 105 days of treatment with ezetimibe (range, 32-175 days), total cholesterol (TC) levels decreased from 7.3 +/- 1.0 mmol/L to 5.7 +/- 1.0 mmol/L (P < .0001), and low-density lipoprotein cholesterol (LDL-C) levels decreased from 5.3 +/- 0.9 mmol/L to 3.9 +/- 0.8 (P < .0001) in patients with FH. In patients with FCHL, TC levels decreased from 6.4 +/- 2.0 mmol/L to 5.6 +/- 0.4 mmol/L (P < or = .002), and LDL-C levels decreased from 4.7 +/- 1.0 mmol/L to 3.8 +/- 0.6 mmol/L (P < or = .005). For all patients, the mean decrease in individual LDL-C values was 1.5 +/- 0.9 mmol/L or 28%. There was no significant change in triglyceride or high-density lipoprotein cholesterol levels with ezetimibe. Patients were maintained on ezetimibe with no adverse effects attributable to the medication for as long as 3.5 years. At a mean of 13.6 months (range, 1-44 months) after the initiation of ezetimibe, LDL-C levels remained decreased at 4.0 +/- 0.6 mmol/L. In this small retrospective series of children and adolescents with hypercholesterolemia, ezetimibe was safe and effective in lowering LDL-C levels.

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.|In the Zetia controlled clinical trials database (placebo-controlled) of 2396 patients with a median treatment duration of 12 weeks (range 0 to 39 weeks), 3.3% of patients on Zetia and 2.9% of patients on placebo discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with Zetia that led to treatment discontinuation and occurred at a rate greater than placebo were: Arthralgia (0.3%); dizziness (0.2%); and gamma-glutamyltransferase increased (0.2%) The most commonly reported adverse reactions (incidence =2% and greater than placebo) in the Zetia monotherapy controlled clinical trial database of 2396 patients were: upper respiratory tract infection (4.3%), diarrhea (4.1%), arthralgia (3.0%), sinusitis (2.8%), and pain in extremity (2.7%).|In the Zetia + statin controlled clinical trials database of 11,308 patients with a median treatment duration of 8 weeks (range 0 to 112 weeks), 4.0% of patients on Zetia + statin and 3.3% of patients on statin alone discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with Zetia + statin that led to treatment discontinuation and occurred at a rate greater than statin alone were: Alanine aminotransferase increased (0.6%) Myalgia (0.5%) Fatigue, aspartate aminotransferase increased, headache, and pain in extremity (each at 0.2%) The most commonly reported adverse reactions (incidence =2% and greater than statin alone) in the Zetia + statin controlled clinical trial database of 11,308 patients were: nasopharyngitis (3.7%), myalgia (3.2%), upper respiratory tract infection (2.9%), arthralgia (2.6%) and diarrhea (2.5%).|In post-marketing experience with Zetia, cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin prior to initiating Zetia. However, rhabdomyolysis has been reported with Zetia monotherapy and with the addition of Zetia to agents known to be associated with increased risk of rhabdomyolysis, such as fibrates. Zetia and any statin or fibrate that the patient is taking concomitantly should be immediately discontinued if myopathy is diagnosed or suspected. The presence of muscle symptoms and a CPK level >10 times the upper limit of normal (ULN) indicates myopathy.|For more Drug Warnings (Complete) data for Ezetimibe (15 total), please visit the HSDB record page.

Ezetimibe was shown to reduce the levels of total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apoprotein B (Apo B), non-high-density lipoprotein cholesterol (non-HDL-C), and triglycerides (TG), and increase high-density lipoprotein cholesterol (HDL-C) in patients with hyperlipidemia. This therapeutic effect was more profound when ezetimibe was co-administered with a statin or fenofibrate compared to either treatment alone. In clinical trials involving patients with homozygous and heterozygous familial hypercholesterolemia and in those with sitosterolemia, a recommended therapeutic dose of ezetimibe was effective in reducing the LDL levels by 15-20% while increasing HDL-C by 2.5-5%. The effects of increased exposure to ezetimibe secondary to moderate-severe hepatic impairment have not been assessed - patients meeting these criteria should avoid the use of ezetimibe. Post-marketing reports indicate the potential for myopathy and rhabdomyolysis in patients taking ezetimibe, and this risk appears to be exacerbated in patients concurrently receiving, or having recently received, statin therapy.

Substances used to lower plasma cholesterol levels. (See all compounds classified as Anticholesteremic Agents.)

Administration of a single 10-mg dose of ezetimibe in fasted adults resulted in peak plasma concentrations (C_max) of 3.4-5.5 ng/mL within 4-12 hours (T_max). The C_max of the major pharmacologically-active metabolite, ezetimibe-glucuronide, was 45-71 ng/mL and its T_max was 1-2 hours. Food consumption has minimal effect on ezetimibe absorption, but the C_max is increased by 38% when administered alongside a high-fat meal. The true bioavailability of ezetimibe cannot be determined, as it is insoluble in aqueous media suitable for intravenous injection.|Approximately 78% and 11% of orally administered radiolabelled ezetimibe are recovered in the feces and urine, respectively. Unchanged parent drug is the major component in feces and accounts for approximately 69% of an administered dose, while ezetimibe-glucuronide is the major component in urine and accounts for approximately 9% of an administered dose. High recovery of unchanged parent drug in feces suggests low absorption and/or hydrolysis of ezetimibe-glucuronide secreted in the bile.|The relative volume of distribution of ezetimibe is 107.5L.|There are no pharmacokinetic data available on the clearance of ezetimibe.|Ezetimibe is the first member of a new class of selective cholesterol absorption inhibitors. The drug and its active glucuronide metabolite impair the intestinal reabsorption of both dietary and hepatically excreted biliary cholesterol through inhibition of a membrane transporter yet to be identified. Absorption of ezetimibe is rapid and not altered by food content following oral administration. The drug is not metabolized by the cytochrome P450 system but extensive glucuronidation takes place in the intestine. Consequently, plasma concentrations of ezetimibe represent approximately 10% of total ezetimibe in plasma. Enterohepatic recirculation observed for ezetimibe and its glucuronimide significantly increases the residence time of these compounds in the intestine, at their site of action. Elimination of ezetimibe glucuronimide appears impaired in elderly patients and patients with renal insufficiency with plasma concentrations increased 1.5- to 2-fold. So far, no drug interaction study has been associated with major changes in either the pharmokinetics of ezetimibe or coadministered drugs.|Ezetimibe lowers plasma cholesterol levels by inhibiting the uptake of cholesterol in the intestine. Due to extensive enterohepatic circulation of ezetimibe, relative low doses are required to be effective. In blood and bile the majority of ezetimibe is present as a glucuronide-conjugate, which is formed in the enterocyte. Presently, it is not clear which mechanisms are responsible for this efficient enterohepatic circulation. Abcc2, Abcc3 and Abcg2 are ABC transporters, which are expressed in both liver and intestine and are capable of transporting glucuronidated compounds. The aim of this study was to investigate the contribution of these transporters in the enterohepatic cycling of ezetimibe-glucuronide (Ez-gluc). Transport studies were performed in plasma membrane vesicles from ABCC2, ABCC3 and ABCG2 expressing Sf21 insect cells. Furthermore, intestinal explants from wild-type and Abcc3-/- mice were used to study vectorial transport in an Ussing chamber setup. Finally, biliary excretion of Ez-gluc was measured in vivo after duodenal delivery of ezetimibe in wild-type, Abcc3-/-, Abcc2-/-, Abcg2-/- and Abcg2-/-/Abcc2-/- mice. ABCC3-, ABCC2- and ABCG2-mediated transport was dose dependently inhibited by Ez-gluc. In the Ussing chamber Ez-gluc recovered from the basolateral side was significantly reduced in duodenal (2.2%), in jejunal (23%) and in ileal (23%) tissue of Abcc3-/- compared to wild-type mice. Biliary excretion of Ez-gluc was significantly reduced in Abcc3-/- (34%), Abcc2-/- (56%) and Abcg2-/-/Abcc2-/- (2.5%) compared to wild-type mice. These data demonstrate that enterohepatic circulation of Ez-gluc strongly depends on the joint function of Abcc3, Abcc2 and Abcg2.|It is not known whether ezetimibe is excreted into human breast milk. In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma.|After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After a single 10-mg dose of Zetia to fasted adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax). Ezetimibe-glucuronide mean Cmax values of 45 to 71 ng/mL were achieved between 1 and 2 hours (Tmax). There was no substantial deviation from dose proportionality between 5 and 20 mg. The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection.

In humans, ezetimibe is rapidly and extensively metabolized via a phase II glucuronide conjugation reaction in the small intestine and liver to form its main phenolic metabolite, ezetimibe glucuronide. The main human liver and/or intestinal uridine 5′-diphosphate (UDP)-glucuronosyltransferase (UGT) enzymes responsible for the glucuronidation of ezetimibe were shown to be UGT1A1, 1A3, and 2B15 _in vitro_. Minimal phase I reaction involving oxidation of ezetimibe also occurs to form SCH 57871, and human jejunum microsomes also produced trace levels of a benzylic glucuronide (SCH 488128). Ezetimibe glucuronide accounts for 80-90% of the total circulating compound in plasma, and retains some pharmacological activity in inhibiting intestinal cholesterol uptake. In humans, ezetimibe and ezetimibe-glucuronide constitutes approximately 93% of the total drug in plasma. Plasma concentration-time profiles exhibit multiple peaks, suggestive of enterohepatic recycling, and about 20% of the drug distributed is reabsorbed due to enterohepatic recirculation.|Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary and renal excretion. Minimal oxidative metabolism (a phase I reaction) has been observed in all species evaluated. In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling. Following oral administration of (14)C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours, there were no detectable levels of radioactivity in the plasma. Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose.|Ezetimibe has known human metabolites that include Ezetimibe-glucuronide.

Both ezetimibe and ezetimibe-glucuronide display an approximate half-life of 22 hours.|Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide.

Ezetimibe mediates its blood cholesterol-lowering effect via selectively inhibiting the absorption of cholesterol and phytosterol by the small intestine without altering the absorption of fat-soluble vitamins and nutrients. The primary target of ezetimibe is the cholesterol transport protein Niemann-Pick C1-Like 1 (NPC1L1) protein. NPC1L1 is expressed on enterocytes/gut lumen (apical) as well as the hepatobiliary (canalicular) interface and plays a role in facilitating internalization of free cholesterol into the enterocyte in conjunction with the adaptor protein 2 (AP2) complex and clathrin. Once cholesterol in the gut lumen or bile is incorporated into the cell membrane of enterocytes, it binds to the sterol-sensing domain of NPC1L1 and forms a NPC1L1/cholesterol complex. The complex is then internalized or endocytosed by joining to AP2 clathrin, forming a vesicle complex that is translocated for storage in the endocytic recycling compartment. Ezetimibe does not require exocrine pancreatic function for its pharmacological activity; rather, it localizes and appears to act at the brush border of the small intestine. Ezetimibe selectively blocks the NPC1L1 protein in the jejunal brush border, reducing the uptake of intestinal lumen micelles into the enterocyte. Overall, ezetimibe causes a decrease in the delivery of intestinal cholesterol to the liver and reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood. While the full mechanism of action of ezetimibe in reducing the entry of cholesterol into both enterocytes and hepatocytes is not fully understood, one study proposed that ezetimibe prevents the NPC1L1/sterol complex from interacting with AP2 in clathrin coated vesicles and induces a conformational change in NPC1L1, rendering it incapable of binding to sterols. Another study suggested that ezetimibe disrupts the function of other protein complexes involved in regulating cholesterol uptake, including the CAV1–annexin 2 heterocomplex.|Niemann-Pick C1-like 1 (NPC1L1) is a polytopic transmembrane protein that plays a critical role in cholesterol absorption. Ezetimibe, a hypocholesterolemic drug, has been reported to bind NPC1L1 and block cholesterol absorption. However, the molecular mechanism of NPC1L1-mediated cholesterol uptake and how ezetimibe inhibits this process are poorly defined. Here we find that cholesterol specifically promotes the internalization of NPC1L1 and that this process requires microfilaments and the clathrin/AP2 complex. Blocking NPC1L1 endocytosis dramatically decreases cholesterol internalization, indicating that NPC1L1 mediates cholesterol uptake via its vesicular endocytosis. Ezetimibe prevents NPC1L1 from incorporating into clathrin-coated vesicles and thus inhibits cholesterol uptake. ...|Niemann-Pick C1-like protein (NPC1L1) mediates the absorption of dietary cholesterol in the proximal region of the intestine, a process that is blocked by cholesterol absorption inhibitors (CAIs), including ezetimibe. Using a proteomic approach, /it is/ demonstrated that NPC1L1 is the protein to which ezetimibe and its analogs bind. Next, ... the site of interaction of ezetimibe analogs /was determined/ with NPC1L1 by exploiting the different binding affinities of mouse and dog NPC1L1 for the radioligand analog of ezetimibe, [(3)H]AS. Chimeric and mutational studies indicate that high-affinity binding of [(3)H]AS to dog NPC1L1 depends on molecular determinants present in a 61-aa region of a large extracellular domain (loop C), where Phe-532 and Met-543 appear to be key contributors. These data suggest that the [(3)H]AS-binding site resides in the intestinal lumen and are consistent with preclinical data demonstrating in vivo efficacy of a minimally bioavailable CAI. Furthermore, these determinants of [(3)H]AS binding lie immediately adjacent to a hotspot of human NPC1L1 polymorphisms correlated with hypoabsorption of cholesterol. These observations, taken together with the recently described binding of cholesterol to the N terminus (loop A) of the close NPC1L1 homologue, NPC1, may provide a molecular basis for understanding ezetimibe inhibition of NPC1L1-mediated cholesterol absorption. Specifically, ezetimibe binding to an extracellular site distinct from where cholesterol binds prevents conformational changes in NPC1L1 that are necessary for the translocation of cholesterol across the membrane.|Ezetimibe has a mechanism of action that differs from those of other classes of cholesterol-reducing compounds (statins, bile acid sequestrants [resins], fibric acid derivatives, and plant stanols). The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. Ezetimibe does not inhibit cholesterol synthesis in the liver, or increase bile acid excretion. Instead, ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood; this distinct mechanism is complementary to that of statins and of fenofibrate.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/CASE REPORTS/ Ezetimibe is a cholesterol-lowering agent that modulates intestinal absorption of sterols. It is well tolerated but hepatic toxicity has been reported when ezetimibe is used in conjunction with a statin medication. In this case report, ... severe isolated hyperbilirubinaemia occurred in a patient with occult cirrhosis, probably owing to nonalcoholic steatohepatitis, who was treated with ezetimibe alone. The adverse event started after ezetimibe therapy was initiated and resolved when the drug was stopped. ...|/CASE REPORTS/ Ezetimibe is the first member of a new family of lipid-lowering drugs that inhibits uptake of dietary and biliary cholesterol. It was approved by the FDA in 2002 for hypercholesterolemia alone or in combination with statins. Its use has been spreading over the last years. Ezetimibe was considered a safe drug. ... A case of a woman who developed a serious hepatocellular drug-induced liver disease after 4 mo therapy with 10 mg daily of ezetimibe /is reported/. After withdrawal of the drug, the patient recovered slowly. Ezetimibe may produce serious toxic hepatitis and prompt withdrawal is mandatory in case of a significant abnormality in liver testing after beginning or during treatment with ezetimibe.|/CASE REPORTS/ A 72-year-old man presented with severe thrombocytopenia (platelets 3 x 10(3)/uL) and "wet purpura" 4 weeks after being started on daily therapy using a combination of ezetimibe 10 mg/simvastatin 20 mg. Platelet counts normalized after administration of ezetimibe/simvastatin was stopped. Nine months later, the patient was restarted on simvastatin because of uncorrected dyslipidemia. Platelet counts remained within the normal range following that rechallenge. ... This case illustrates the probable occurrence of ezetimibe-induced thrombocytopenia. Platelet counts dropped significantly when ezetimibe therapy was initiated, then resolved upon discontinuation of therapy. Other causes of thrombocytopenia were ruled out, and rechallenge with simvastatin further supports the presence of a causal relationship between thrombocytopenia and ezetimibe. Use of the Naranjo probability scale indicated a probable relationship between thrombocytopenia and ezetimibe therapy. An adverse reaction scale specific for evaluation of drug-induced thrombocytopenia also indicated the probable likelihood of ezetimibe-induced thrombocytopenia. This patient was not rechallenged with ezetimibe due to the highly suggestive timeline present and unnecessary risk for him. Ezetimibe-associated thrombocytopenia cannot be ruled out in the patient reported here. ...|/CASE REPORTS/ Two cases of myopathy associated with ezetimibe are reported. In the first case, a woman on ezetimibe monotherapy presented with muscle pain and an elevated concentration of creatine kinase (CK) on two occasions, with ezetimibe 10 mg and with ezetimibe 5 mg after a washout period. The recurrence of muscle pain after washout and the CK increase both supported the hypothesis that ezetimibe alone can be linked to myalgia. In the second case, a man had been treated with atorvastatin, and ezetimibe 10 mg was added to improve his lipid profile. Two months later, the patient complained of muscle pain and a CK increase was noted. The appearance of symptoms when adding ezetimibe to atorvastatin supports a potential pharmacokinetic and/or a pharmacodynamic interaction between these two drugs. These cases suggest that ezetimibe monotherapy as well as ezetimibe associated with the use of a statin may induce myalgia. The mechanism by which ezetimibe could cause muscle pain is not known.|For more Human Toxicity Excerpts (Complete) data for Ezetimibe (7 total), please visit the HSDB record page.

(1-(4-fluorophenyl)-(3R)-(3-(4-fluorophenyl)-(3S)-hydroxypropyl)-(4S)-(4-hydroxyphenyl)-2-azetidinone)

Oral: Tablets: 10 mg with Simvastatin 10 mg Vytorin (Merck/Schering-Plough); 10 mg with Simvastatin 20 mg Vytorin (Merck/Schering-Plough); 10 mg with Simvastatin 40 mg Vytorin (Merck/Schering-Plough); 10 mg with Simvastatin 80 mg Vytorin (Merck/Schering-Plough). /Ezetimibe combinations/|Oral: Tablets: 10 mg Zetia (Merck/Schering-Plough).

Analyte: ezetimibe; matrix: blood (plasma); procedure: high-performance liquid chromatography with mass spectrometric detection; limit of quantitation: 1 ng/mL (unconjugated, 5.02 ng/mL (total))|Analyte: ezetimibe; matrix: bile; procedure: high-performance liquid chromatography with ultraviolet detection at 247 nm; limit of detection: 2 ng; limit of quantitation 10 ng/mL

Human Drugs -> EU pediatric investigation plans|Human drugs -> Nustendi -> EMA Drug Category|Lipid modifying agents -> Human pharmacotherapeutic group|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients