Ezentia

Ezetimibe.

Each tablet contains Ezetimibe 10 mg.
EZENTIA contains ezetimibe, which belongs to a class of lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related phytosterols. The chemical name of Ezetimibe is 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. The empirical formula is C₂₄H₂₁F₂NO₃. Its molecular weight is 409.4.
Excipients/Inactive Ingredients: Lactose Monohydrate, Povidone, Croscarmellose Sodium, Sodium Lauryl Sulphate, Pregelatinised Starch, Magnesium Stearate, Purified Water.

Pharmacology: Pharmacodynamics: Mechanism of Action: Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. In hypercholesterolemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54%. Ezetimibe had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and E, and did not impair adrenocortical steroid hormone.
The cholesterol content of the liver is derived predominantly from three sources. The liver can synthesize cholesterol, take up cholesterol from the blood from circulating lipoproteins, or take up cholesterol absorbed by the small intestine. Intestinal cholesterol is derived primarily from cholesterol secreted in the bile and from dietary cholesterol.
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.
Elevated levels of total-C, LDL-C and Apo B, the major protein constituent of LDL, promote human atherosclerosis. In addition, decreased levels of HDL-C are associated with the development of atherosclerosis. It has been established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. The independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.
Ezetimibe reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with hyperlipidemia. Administration of ezetimibe with a statin is effective in improving serum total-C, LDL-C, Apo B, non-HDL-C, TG, and HDL-C beyond either treatment alone. Administration of ezetimibe with fenofibrate is effective in improving serum total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia as compared to either treatment alone. The effects of ezetimibe given either alone or in addition to a statin or fenofibrate on cardiovascular morbidity and mortality have not been established.
Pharmacokinetics: After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After a single 10-mg dose of ezetimibe to fasted adults, mean ezetimibe peak plasma concentrations (C_max) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (T_max). Ezetimibe-glucuronide mean C_max values of 45 to 71 ng/mL were achieved between 1 and 2 hours (T_max). 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.
Concomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as ezetimibe 10-mg tablets. The C_max value of ezetimibe was increased by 38% with consumption of high-fat meals. Ezetimibe can be administered with or without food.
Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins.
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 reported 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 ¹⁴C-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.
Special Populations: Geriatric Patients: It has been reported that with ezetimibe 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were about 2-fold higher in older (≥65 years) healthy subjects compared to younger subjects.
Pediatric Patients: (see Precautions).
Gender: It has been reported that with ezetimibe 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (<20%) in women than in men.
Race: It has been reported that, there were no pharmacokinetic differences between Black and Caucasian subjects. In Asian subjects the pharmacokinetics of ezetimibe were similar to those reported in Caucasian subjects.
Hepatic Impairment: After a single 10-mg dose of ezetimibe, the mean AUC for total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic impairment (Child-Pugh score 5 to 6), compared to healthy subjects. The mean AUC values for total ezetimibe and ezetimibe were increased approximately 3- to 4-fold and 5- to 6-fold, respectively, in patients with moderate (Child-Pugh score 7 to 9) or severe hepatic impairment (Child-Pugh score 10 to 15). In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic impairment, the mean AUC values for total ezetimibe and ezetimibe were increased approximately 4-fold on Day 1 and Day 14 compared to healthy subjects. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic impairment, ezetimibe is not recommended in these patients (see Precautions).
Renal Impairment: After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl ≤30 mL/min/1.73 m²), the mean AUC values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe were increased approximately 1.5-fold, compared to healthy subjects (n=9).
Pharmacokinetic Interactions: (See also Interactions).
Ezetimibe had no significant effect on a series of probe drugs (caffeine, dextromethorphan, tolbutamide, and IV midazolam) known to be metabolized by cytochrome P450 (1A2, 2D6, 2C8/9 and 3A4) in healthy adult males. This indicates that ezetimibe is neither an inhibitor nor an inducer of these cytochrome P450 isozymes, and it is unlikely that ezetimibe will affect the metabolism of drugs that are metabolized by these enzymes. (See Tables 1 and 2.)

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Click on icon to see table/diagram/image

Toxicology: Preclinical Safety: Carcinogenesis, mutagenesis, impairment of fertility: There were no statistically significant increases in tumor incidences has been reported in rats and mice with ezetimibe doses up to 1500 mg/kg/day and 500 mg/kg/day, respectively for 104-weeks.
No evidence of mutagenicity was reported in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was reported in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test.
There was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 X the human exposure at 10 mg daily based on AUC_0-24hr for total ezetimibe).

Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other non-pharmacologic measures alone has been inadequate.
Primary Hyperlipidemia: Monotherapy: Ezetimibe, administered alone, is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with primary (heterozygous familial and non-familial) hyperlipidemia.
Combination Therapy with HMG-CoA Reductase Inhibitors (Statins): Ezetimibe, administered in combination with a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin), is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with primary (heterozygous familial and non-familial) hyperlipidemia.
Combination Therapy with Fenofibrate: Ezetimibe, administered in combination with fenofibrate, is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B, and non-HDL-C in adult patients with mixed hyperlipidemia.
Homozygous Familial Hypercholesterolemia (HoFH): The combination of ezetimibe and atorvastatin or simvastatin is indicated for the reduction of elevated total-C and LDL-C levels in patients with HoFH, as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.
Homozygous Sitosterolemia: Ezetimibe is indicated as adjunctive therapy to diet for the reduction of elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia.
Prevention of Major Cardiovascular Events in Chronic Kidney Disease: Ezetimibe, administered with simvastatin, is indicated to reduce the risk of major cardiovascular events in patients with chronic kidney disease.
Prevention of cardiovascular disease: Administered with a statin, is indicated to reduce the risk of cardiovascular events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, or need for revascularization), in patient with coronary heart disease (CHD).
Limitations of Use: The effect of ezetimibe on cardiovascular morbidity and mortality has not been determined. Ezetimibe has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.

General Dosing Information: The recommended dose of ezetimibe is 10 mg once daily.
Ezetimibe can be administered with or without food.
Concomitant Lipid-Lowering Therapy: Ezetimibe may be administered with a statin (in patients with primary hyperlipidemia) or with fenofibrate (in patients with mixed hyperlipidemia) for incremental effect. For convenience, the daily dose of ezetimibe may be taken at the same time as the statin or fenofibrate, according to the dosing recommendations for the respective medications.
Co-Administration with Bile Acid Sequestrants: Dosing of ezetimibe should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant (see Interactions).
Patients with Hepatic Impairment: No dosage adjustment is necessary in patients with mild hepatic impairment (see Precautions).
Patients with Renal Impairment: No dosage adjustment is necessary in patients with renal impairment (see Pharmacology: Pharmacokinetics under Actions). When given with simvastatin in patients with moderate to severe renal impairment (estimated glomerular filtration rate <60 mL/min/1.73 m²), doses of simvastatin exceeding 20 mg should be used with caution and close monitoring (see Precautions).
Geriatric Patients: No dosage adjustment is necessary in geriatric patients (see Pharmacology: Pharmacokinetics under Actions).

It was reported that administration of ezetimibe, 50 mg/day to healthy subjects for up to 14 days, 40 mg/day to patients with primary hyperlipidemia for up to 56 days, and 40 mg/day to patients with homozygous sitosterolemia for 26 weeks was generally well tolerated. One female patient with homozygous sitosterolemia took an accidental overdose of ezetimibe 120 mg/day for 28 days with no reported clinical or laboratory adverse events.
In the event of an overdose, symptomatic and supportive measures should be employed.

Ezetimibe is contraindicated in the following conditions: Patients with known hypersensitivity to ezetimibe or any of the excipients of this formulation. Hypersensitivity reactions including anaphylaxis, angioedema, rash and urticaria have been reported with ezetimibe (see Adverse Effects).
The combination of ezetimibe with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in hepatic transaminase levels.
Use in Pregnancy: Women who are pregnant or may become pregnant. Because statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, ezetimibe in combination with a statin may cause fetal harm when administered to pregnant women. Additionally, there is no apparent benefit to therapy during pregnancy, and safety in pregnant women has not been established. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy (see Use in Pregnancy & Lactation).
Use in Lactation: Nursing mothers. Because statins may pass into breast milk, and because statins have the potential to cause serious adverse reactions in nursing infants, women who require ezetimibe treatment in combination with a statin should be advised not to nurse their infants (see Use in Pregnancy & Lactation).

Use with Statins or Fenofibrate: Concurrent administration of ezetimibe with a specific statin or fenofibrate should be in accordance with the prescribing information for that medication.
Liver Enzymes: The reported incidence of consecutive elevations (≥3 X the upper limit of normal [ULN]) in hepatic transaminase levels was 0.5% for ezetimibe.
It was reported that when ezetimibe initiated concurrently with a statin, the incidence of consecutive elevations (≥3 X ULN) in hepatic transaminase levels was 1.3% for patients treated with ezetimibe administered with statins and 0.4% for patients treated with statins alone. These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment. When ezetimibe is co-administered with a statin, liver tests should be performed at initiation of therapy and according to the recommendations of the statin. Should an increase in ALT or AST ≥3 X ULN persist, consider withdrawal of ezetimibe and/or the statin.
Myopathy/Rhabdomyolysis: There was no excess of myopathy or rhabdomyolysis associated with ezetimibe compared with the relevant control arm (placebo or statin alone). However, myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs. The reported incidence of creatine phosphokinase (CPK) >10 X ULN was 0.2% for ezetimibe vs 0.1% for placebo, and 0.1% for ezetimibe co-administered with a statin vs 0.4% for statins alone. Risk for skeletal muscle toxicity increases with higher doses of statin, advanced age (>65), hypothyroidism, renal impairment, and depending on the statin used, concomitant use of other drugs.
Cases of myopathy and rhabdomyolysis have been reported with ezetimibe. Most patients who developed rhabdomyolysis were taking a statin prior to initiating ezetimibe. However, rhabdomyolysis has been reported with ezetimibe monotherapy and with the addition of ezetimibe to agents known to be associated with increased risk of rhabdomyolysis, such as fibrates. Ezetimibe 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 X the ULN indicates myopathy.
Hepatic Impairment: Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate to severe hepatic impairment, ezetimibe is not recommended in these patients (see Pharmacology: Pharmacokinetics under Actions).
Ezetimibe given concomitantly with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations of hepatic transaminase levels (see Contraindications, Precautions and Pharmacology: Pharmacokinetics under Actions).
Fibrates: The safety and efficacy of ezetimibe administered with fibrates have not been established (see Interactions and Adverse Reactions).
Lactose: EZENTIA tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Renal Impairment: When used as monotherapy, no dosage adjustment of ezetimibe is necessary.
Use in Children: Efficacy and safety of ezetimibe co-administered with simvastatin in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia have been reported in adolescent boys (Tanner stage II or above) and in girls who were at least one year post-menarche.
In this limited information, there was generally no detectable effect on growth or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls. However, the effects of ezetimibe for a treatment period > 33 weeks on growth and sexual maturation have not been studied.
The safety and efficacy of ezetimibe co-administered with doses simvastatin above 40 mg daily have not been reported in paediatric patients 10 to 17 years of age.
Ezetimibe has not been studied in patients younger than 10 years of age or in pre-menarchal girls.
The long-term efficacy of therapy with ezetimibe in patients below 17 years of age to reduce morbidity and mortality in adulthood has not been studied.
Use in Elderly: No overall differences in safety and effectiveness were reported between these patients and younger patients, 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 (see Pharmacology: Pharmacokinetics under Actions).

Pregnancy: Pregnancy Category C: There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus.
No evidence of embryolethal effects with 250, 500, 1000 mg/kg/day (during organogenesis) has been reported in rats and rabbits. In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were reported at 1000 mg/kg/day (~10 X the human exposure at 10 mg daily based on AUC_0-24hr for total ezetimibe). In rabbits, an increased incidence of extra thoracic ribs was reported at 1000 mg/kg/day ezetimibe (150 X the human exposure at 10 mg daily based on AUC_0-24hr for total ezetimibe). Ezetimibe crossed the placenta in pregnant rats and rabbits.
Higher ezetimibe and statin exposures have been reported in rats and rabbits on ezetimibe and statins combination during organogenesis. Reproductive findings have been reported at lower doses in combination therapy vs monotherapy.
Lactation: All statins are contraindicated in pregnant and nursing women. When ezetimibe is administered with a statin in a woman of childbearing potential, refer to the pregnancy category and prescribing information for the statin (see Contraindications).
It is not known whether ezetimibe is excreted into human breast milk. In rat, exposure to total ezetimibe in nursing pups was up to half of that reported in maternal plasma. Because many drugs are excreted in human milk, caution should be exercised when ezetimibe is administered to a nursing woman. Ezetimibe should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant.

The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information: Liver enzyme abnormalities (see Precautions).
Rhabdomyolysis and myopathy (see Precautions).
In patients with a median treatment duration of 12 weeks (range 0 to 39 weeks), 3.3% of patients on ezetimibe discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with ezetimibe that led to treatment discontinuation were: Arthralgia (0.3%), Dizziness (0.2%), Gamma-glutamyltransferase increased (0.2%).
The most commonly reported adverse reactions (incidence ≥2%) with ezetimibe monotherapy were: upper respiratory tract infection (4.3%), diarrhea (4.1%), arthralgia (3.0%), sinusitis (2.8%), and pain in extremity (2.7%).
In patients with a median treatment duration of 8 weeks (range 0 to 112 weeks), 4.0% of patients on ezetimibe+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 ezetimibe+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) with ezetimibe+statin were: nasopharyngitis (3.7%), myalgia (3.2%), upper respiratory tract infection (2.9%), arthralgia (2.6%) and diarrhea (2.5%).
Monotherapy: Patients with primary hyperlipidemia (age range 9-86 years, 50% women, 90% Caucasians, 5% Blacks, 3% Hispanics, 2% Asians) and elevated LDL-C were treated with ezetimibe 10 mg/day for a median treatment duration of 12 weeks (range 0 to 39 weeks).
Adverse reactions reported in ≥2% of patients treated with ezetimibe regardless of causality assessment, are shown in Table 3. (See Table 3.)

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Patients with primary hyperlipidemia (age range 10-93 years, 48% women, 85% Caucasians, 7% Blacks, 4% Hispanics, 3% Asians) and elevated LDL-C were treated with ezetimibe 10 mg/day concurrently with or added to on-going statin therapy for a median treatment duration of 8 weeks (range 0 to 112 weeks).
The incidence of consecutive increased transaminases (≥3 X ULN) was higher in patients receiving ezetimibe administered with statins (1.3%) than in patients treated with statins alone (0.4%) (see Precautions).
Clinical adverse reactions reported in ≥2% of patients treated with ezetimibe + statin and at an incidence greater than statin, regardless of causality assessment, are shown in Table 4. (See Table 4.)

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Combination with Fenofibrate: In patients with mixed dyslipidemia (age range 20-76 years, 44% women, 79% Caucasians, 0.1% Blacks, 11% Hispanics, 5% Asians) treated for up to 12 weeks and patients treated for up to an additional 48 weeks evaluated co-administration of ezetimibe and fenofibrate. This study was not designed to compare treatment groups for infrequent events. Incidence rates (95% CI) for clinically important elevations (≥3 X ULN, consecutive) in hepatic transaminase levels were 4.5% (1.9, 8.8) and 2.7% (1.2, 5.4) for fenofibrate monotherapy and ezetimibe co-administered with fenofibrate, respectively, adjusted for treatment exposure. Corresponding incidence rates for cholecystectomy were 0.6% (95% CI: 0.0%, 3.1%) and 1.7% (95% CI: 0.6%, 4.0%) for fenofibrate monotherapy and ezetimibe co-administered with fenofibrate, respectively (see Interactions). The numbers of patients exposed to co-administration therapy as well as fenofibrate and ezetimibe monotherapy were inadequate to assess gallbladder disease risk. There were no CPK elevations >10 X ULN in any of the treatment groups.
The following additional adverse reactions have also been reported ezetimibe: Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria; erythema multiforme; arthralgia; myalgia; elevated creatine phosphokinase; myopathy/rhabdomyolysis (see Precautions); elevations in liver transaminases; hepatitis; abdominal pain; thrombocytopenia; pancreatitis; nausea; dizziness; paresthesia; depression; headache; cholelithiasis; cholecystitis.
In addition to the adverse events mentioned above cough, flatulence, dyspepsia; gastroesophageal reflux disease; constipation, dyspnoea, muscle spasms; neck pain, decreased appetite, hot flush, hypertension, chest pain, pain, dry mouth, gastritis, pruritis, muscular weakness, asthenia and edema peripheral have also been reported.

(See Pharmacology: Pharmacokinetics under Actions).
It has been reported that ezetimibe does not induce cytochrome P450 drug metabolising enzymes. No clinically significant pharmacokinetic interactions have been reported between ezetimibe and drugs known to be metabolized by cytochromes P450 1A2, 2D6, 2C8, 2C9, and 3A4, or N-acetyltransferase.
Ezetimibe had no effect on the pharmacokinetics of dapsone, dextromethorphan, digoxin, oral contraceptives (ethinyl estradiol and levonorgestrel), glipizide, tolbutamide, or midazolam, during co-administration. Cimetidine, co-administered with ezetimibe, had no effect on the bioavailability of ezetimibe.
Antacids: Concomitant antacid administration decreased the rate of absorption of ezetimibe but had no effect on the bioavailability of ezetimibe. This decreased rate of absorption is not considered clinically significant.
Cyclosporine: Caution should be exercised when using ezetimibe and cyclosporine concomitantly due to increased exposure to both ezetimibe and cyclosporine. Cyclosporine concentrations should be monitored in patients receiving ezetimibe and cyclosporine.
The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the benefits of alterations in lipid levels provided by ezetimibe.
Fibrates: The efficacy and safety of co-administration of ezetimibe with fibrates other than fenofibrate have not been reported.
Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. It was reported that in dogs, ezetimibe increased cholesterol in the gallbladder bile [see Pharmacology: Toxicology: Preclinical Saftey Data under Actions). Coadministration of ezetimibe with fibrates other than fenofibrate is not recommended until use in patients is adequately reported.
Fenofibrate: If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered (see Adverse Effects and the prescribing information for fenofibrate).
Statins: No clinically significant pharmacokinetic interactions were reported when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin or rosuvastatin.
Cholestyramine: Concomitant cholestyramine administration decreased the mean area under the curve (AUC) of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction.
Anticoagulants: Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males. However, there have been post-marketing reports of increased International Normalised Ratio (INR) in patients who had ezetimibe added to warfarin or fluindione. If ezetimibe is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalized Ratio (INR) should be appropriately monitored.

Do not store above 30°C.

Dyslipidaemic Agents

C10AX09 - ezetimibe ; Belongs to the class of other lipid modifying agents.

D