EZETROL

Ezetimibe is a lipid-lowering compound that inhibits intestinal cholesterol and phytosterol absorption.

The discovery and research of this drug began in the early 1990s, after the intravenous administration of radiolabelled ezetimibe in rats revealed that it was being localized within enterocytes of the intestinal villi.

• this prompted studies investigating the effect of ezetimibe on intestinal cholesterol absorption.

Ezetimibe is used as an adjunctive therapy to a healthy diet to lower cholesterol levels in primary hyperlipidemia, mixed hyperlipidemia, homozygous familial hypercholesterolemia (HoFH), and homozygous sitosterolemia (phytosterolemia).

Unlike other classes of cholesterol-reducing compounds including statins and bile acid sequestrants, ezetimibe has a distinct mechanism of action involving the sterol transporter Niemann-Pick C1-Like 1 (NPC1L1), and is unique in that it does not affect the absorption of fat-soluble nutrients such as fat-soluble vitamins, triglycerides, or bile acids.

In genetically

NPC1L1-deficient mice, a 70% reduction in intestinal cholesterol absorption was seen, and these mice were insensitive to ezetimibe treatment.

• it was determined based on these findings that NPC1L1 plays an essential role in promoting intestinal cholesterol uptake via an ezetimibe-sensitive pathway.

By interfering with the intestinal uptake of cholesterol and phytosterols, ezetimibe reduces the delivery of intestinal cholesterol to the liver.

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). 5, 6, 7 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.

In combination with bempedoic acid, ezetimibe is indicated as an adjunct to diet, with or without other lipid-lowering therapies, to reduce LDL-C in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH).

Ezetimibe may also be used to reduce elevated sitosterol and campesterol in patients with homozygous sitosterolemia (phytosterolemia).

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.

NPC1-like intracellular cholesterol transporter 1 Inhibitor Sterol O-acyltransferase 1 Inhibitor.

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 ).

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.

The relative volume of distribution of ezetimibe is 107.5 L.

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 5, and about 20% of the drug distributed is reabsorbed due to enterohepatic recirculation.

Hover over products below to view reaction partners Ezetimibe Ezetimibe glucuronide SCH 57871 SCH 57871-glucuronide SCH 488128.

Approximately 78% and 11% of Oral 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.

Both ezetimibe and ezetimibe-glucuronide display an approximate half-life of 22 hours.

There are no pharmacokinetic data available on the clearance of ezetimibe.

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Oral LD and intraperitoneal

LD 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.

• Concomitant administration of strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and cobicistat-containing products) .

• Concomitant administration of gemfibrozil, cyclosporine, or danazol.

• Hypersensitivity to any component of this medication.

• Active liver disease or unexplained persistent elevations in hepatic transaminase levels.

• Women who are pregnant or may become pregnant.

Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development.

HMG-CoA reductase inhibitors (statins), such as simvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, ezetimibe and simvastatin tablets may cause fetal harm when administered to a pregnant woman.

Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia.

There are no adequate and well-controlled studies of ezetimibe and simvastatin tablet use during pregnancy; however, in rare reports congenital anomalies were observed following intrauterine exposure to statins.

In rat and rabbit animal reproduction studies, simvastatin revealed no evidence of teratogenicity.

Ezetimibe and simvastatin tablets should be administered to women of childbearing age only when such patients are highly unlikely to conceive.

If the patient becomes pregnant while taking this drug, ezetimibe and simvastatin tablets should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus.

• Nursing mothers.

It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk.

Because statins have the potential for serious adverse reactions in nursing infants, women who require ezetimibe and simvastatin tablet treatment should not breastfeed their infants.

• Concomitant administration of strong CYP3A4 inhibitors.

• Active liver disease or unexplained persistent elevations of hepatic transaminase levels.

• Dose range is 10 mg/10 mg/day to 10 mg/40 mg/day.

• Recommended usual starting dose is 10 mg/10 mg or 10 mg/20 mg/day.

• Due to the increased risk of myopathy, including rhabdomyolysis, use of the 10 mg/80 mg dose of ezetimibe and simvastatin tablets should be restricted to patients who have been taking ezetimibe and simvastatin tablets 10 mg/80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity.

• Patients who are currently tolerating the 10 mg/80 mg dose of ezetimibe and simvastatin tablets who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin or statin-based regimen with less potential for the drug-drug interaction.

• Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 10 mg/80 mg dose of ezetimibe and simvastatin tablets, patients unable to achieve their LDL-C goal utilizing the 10 mg/40 mg dose of ezetimibe and simvastatin tablets should not be titrated to the 10 mg/80 mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering.

• Dosing of ezetimibe and simvastatin tablets should occur either ≥ 2 hours before or ≥ 4 hours after administration of a bile acid sequestrant. 2.1 Recommended Dosing The usual dosage range is 10 mg/10 mg/day to 10 mg/40 mg/day. The recommended usual starting dose is 10 mg/10 mg/day or 10 mg/20 mg/day. Ezetimibe and simvastatin tablets should be taken as a single daily dose in the evening, with or without food.

Patients who require a larger reduction in LDL-C (greater than 55%) may be started at 10 mg/40 mg/day in the absence of moderate to severe renal impairment (estimated glomerular filtration rate less than 60 mL/min/1.73 m 2 ).

After initiation or titration of ezetimibe and simvastatin tablets, lipid levels may be analyzed after 2 or more weeks and dosage adjusted, if needed. 2.2 Restricted Dosing for 10 mg/80 mg Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, use of the 10 mg/80 mg dose of ezetimibe and simvastatin tablets should be restricted to patients who have been taking ezetimibe and simvastatin tablets 10 mg/80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity.

Patients who are currently tolerating the 10 mg/80 mg dose of ezetimibe and simvastatin tablets who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin or statin-based regimen with less potential for the drug-drug interaction.

Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 10 mg/80 mg dose of ezetimibe and simvastatin tablets, patients unable to achieve their LDL-C goal utilizing the 10 mg/40 mg dose of ezetimibe and simvastatin tablets should not be titrated to the 10 mg/80 mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering. 2.3 Coadministration with Other Drugs Patients taking Verapamil, Diltiazem, or Dronedarone.

• The dose of ezetimibe and simvastatin tablets should not exceed 10 mg/10 mg/day.

Patients taking

• The dose of ezetimibe and simvastatin tablets should not exceed 10 mg/20 mg/day.

Patients taking Bile Acid

• Dosing of ezetimibe and simvastatin tablets should occur either greater than or equal to 2 hours before or greater than or equal to 4 hours after administration of a bile acid sequestrant. 2.4 Patients with Homozygous Familial Hypercholesterolemia The recommended dosage for patients with homozygous familial hypercholesterolemia is ezetimibe and simvastatin tablets 10 mg/40 mg/day in the evening.

Ezetimibe and simvastatin tablets should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

Simvastatin exposure is approximately doubled with concomitant use of lomitapide; therefore, the dose of ezetimibe and simvastatin tablets should be reduced by 50% if initiating lomitapide.

Ezetimibe and simvastatin tablet dosage should not exceed 10 mg/20 mg/day (or 10 mg/40 mg/day for patients who have previously taken simvastatin 80 mg/day chronically, e.g., for 12 months or more, without evidence of muscle toxicity) while taking lomitapide. 2.5 Patients with Renal Impairment/Chronic Kidney Disease In patients with mild renal impairment (estimated GFR greater than or equal to 60 mL/min/1.73 m 2 ), no dosage adjustment is necessary.

In patients with chronic kidney disease and estimated glomerular filtration rate less than 60 mL/min/1.73 m 2, the dose of ezetimibe and simvastatin tablets is 10 mg/20 mg/day in the evening.

In such patients, higher doses should be used with caution and close monitoring. 2.6 Geriatric Patients No dosage adjustment is necessary in geriatric patients.

Ezetimibe and simvastatin tablets are available as follows: 10 mg/10 mg.

• white to off-white, capsule-shaped tablets, debossed with "DRL" on one side of the tablet and with "583" on the other side.

They contain 10 mg of ezetimibe and 10 mg of simvastatin.

They are available in

Bottles of 30 NDC 43598-742-30 Bottles of 90 NDC 43598-742-90 Bottles of 1000 NDC 43598-742-10 10 mg/20 mg.

• white to off-white, capsule-shaped tablets, debossed with "DRL" on one side of the tablet and with "584" on the other side.

They contain 10 mg of ezetimibe and 20 mg of simvastatin.

Bottles of 30 NDC 43598-744-30 Bottles of 90 NDC 43598-744-90 Bottles of 1000 NDC 43598-744-10 10 mg/40 mg.

• white to off-white, capsule-shaped tablets, debossed with "DRL" on one side of the tablet and with "585" on the other side.

They contain 10 mg of ezetimibe and 40 mg of simvastatin.

Bottles of 30 NDC 43598-743-30 Bottles of 90 NDC 43598-743-90 Bottles of 500 NDC 43598-743-05 10 mg/80 mg.

• white to off-white, capsule-shaped tablets, debossed with "DRL" on one side of the tablet and with "586" on the other side.

They contain 10 mg of ezetimibe and 80 mg of simvastatin.

Bottles of 30 NDC 43598-745-30 Bottles of 90 NDC 43598-745-90 Bottles of 500 NDC 43598-745-05 Storage Store at to 25°C (68 to 77°F) .

Keep container tightly closed.

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Ezetimibe and Simvastatin Tablets Ezetimibe and simvastatin tablets are contraindicated in women who are or may become pregnant.

Lipid-lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development.

Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy.

There are no adequate and well-controlled studies of ezetimibe and simvastatin tablet use during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to statins in utero.

Animal reproduction studies of simvastatin in rats and rabbits showed no evidence of teratogenicity.

Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development.

Because statins, such as simvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, ezetimibe and simvastatin tablets may cause fetal harm when administered to a pregnant woman.

If ezetimibe and simvastatin tablets are used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Women of childbearing potential, who require ezetimibe and simvastatin tablet treatment for a lipid disorder, should be advised to use effective contraception.

For women trying to conceive, discontinuation of ezetimibe and simvastatin tablets should be considered.

If pregnancy occurs, ezetimibe and simvastatin tablets should be immediately discontinued.

In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day).

In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~ 10 times the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe).

In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe).

Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses.

Multiple-dose studies of ezetimibe coadministered with statins in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures.

Reproductive findings occur at lower doses in coadministration therapy compared to monotherapy.

Simvastatin was not teratogenic in rats or rabbits at doses (25, 10 mg/kg/day, respectively) that resulted in 3 times the human exposure based on mg/m 2 surface area.

However, in studies with another structurally-related statin, skeletal malformations were observed in rats and mice.

There are rare reports of congenital anomalies following intrauterine exposure to statins.

In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or another structurally-related statin, the incidences of congenital anomalies, spontaneous abortions and fetal deaths/stillbirths did not exceed what would be expected in the general population.

The number of cases is adequate only to exclude a to 4 fold increase in congenital anomalies over the background incidence.

In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.

Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy, Reproductive Toxicology, 10:439-446, 1996.

It is not known whether simvastatin is excreted in human milk.

Because a small amount of another drug in this class is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women taking simvastatin should not nurse their infants.

A decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother.

In rat studies, exposure to ezetimibe in nursing pups was up to half of that observed in maternal plasma.

It is not known whether ezetimibe or simvastatin are excreted into human breast milk.

Because a small amount of another drug in the same class as simvastatin is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women who are nursing should not take ezetimibe and simvastatin tablets.

The effects of ezetimibe coadministered with simvastatin (n = 126) compared to simvastatin monotherapy (n = 122) have been evaluated in adolescent boys and girls with heterozygous familial hypercholesterolemia (HeFH).

In a multicenter, double-blind, controlled study followed by an open-label phase, 142 boys and 106 postmenarchal girls, 10 to 17 years of age (mean age 14.2 years, 43% females, 82% Caucasians, 4% Asian, 2% Blacks, 13% multiracial) with HeFH were randomized to receive either ezetimibe coadministered with simvastatin or simvastatin monotherapy.

Inclusion in the study required 1) a baseline LDL-C level between and 400 mg/dL and 2) a medical history and clinical presentation consistent with HeFH.

The mean baseline

LDL-C value was 225 mg/dL (range: 161 to 351 mg/dL) in the ezetimibe coadministered with simvastatin group compared to 219 mg/dL (range: 149 to 336 mg/dL) in the simvastatin monotherapy group.

The patients received coadministered ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40 mg) for 6 weeks, coadministered ezetimibe and 40 mg simvastatin or 40 mg simvastatin monotherapy for the next 27 weeks, and open-label coadministered ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter.

The results of the study at Week are summarized in Table 3.

Results at Week were consistent with those at Week 6.

Table 3: Mean Percent Difference at Week 6 Between the Pooled Ezetimibe Coadministered with Simvastatin Group and the Pooled Simvastatin Monotherapy Group in Adolescent Patients with Heterozygous Familial Hypercholesterolemia Total-C LDL-C Apo B Non-HDL-C TG 1 HDL-C Mean percent difference between treatment groups -12% -15% -12% -14% -2% +0.1% 95% Confidence Interval (-15%, -9%) (-18%, -12%) (-15%, -9%) (-17%, -11%) (-9, +4) (-3, +3) 1.

For triglycerides, median % change from baseline.

From the start of the trial to the end of Week 33, discontinuations due to an adverse reaction occurred in 7 (6%) patients in the ezetimibe coadministered with simvastatin group and in 2 (2%) patients in the simvastatin monotherapy group.

During the trial, hepatic transaminase elevations (two consecutive measurements for ALT and/or AST ≥ 3 X ULN) occurred in four (3%) individuals in the ezetimibe coadministered with simvastatin group and in two (2%) individuals in the simvastatin monotherapy group.

Elevations of

CPK (≥ 10 X ULN) occurred in two (2%) individuals in the ezetimibe coadministered with simvastatin group and in zero individuals in the simvastatin monotherapy group.

In this limited controlled study, there was no significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls.

Coadministration of ezetimibe with simvastatin at doses greater than 40 mg/day has not been studied in adolescents.

Also, ezetimibe and simvastatin tablets have not been studied in patients younger than 10 years of age or in pre-menarchal girls.

Based on total ezetimibe (ezetimibe + ezetimibe-glucuronide) there are no pharmacokinetic differences between adolescents and adults.

Pharmacokinetic data in the pediatric population < 10 years of age are not available.

The pharmacokinetics of simvastatin has not been studied in the pediatric population.

Of the 10,189 patients who received ezetimibe and simvastatin tablets in clinical studies, 3,242 (32%) were and older (this included 844 (8%) who were and older).

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients but greater sensitivity of some older individuals cannot be ruled out.

Since advanced age (≥ 65 years) is a predisposing factor for myopathy, ezetimibe and simvastatin tablets should be prescribed with caution in the elderly.

Because advanced age (≥ 65 years) is a predisposing factor for myopathy, including rhabdomyolysis, ezetimibe and simvastatin tablets should be prescribed with caution in the elderly.

In a clinical trial of patients treated with simvastatin 80 mg/day, patients ≥ 65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients < 65 years of age.