Ezetrol

Ezetrol

ezetimibe

Manufacturer:

Merck Sharp & Dohme

Marketer:

Transfarma Medica Indah
Full Prescribing Info
Contents
Ezetimibe.
Action
Ezetrol is a new class of lipid-lowering compounds that selectively inhibit the intestinal absorption of cholesterol and related plant sterols.
Pharmacology: Mechanism of Action: Ezetimibe is orally active and potent, with a unique mechanism of action that differs from other classes of cholesterol-reducing compounds [eg, statins, bile acid sequestrants (resins), fibric acid derivatives and plant stanols]. The molecular target of ezetimibe is the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is responsible for the intestinal uptake of cholesterol and phytosterols.
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. Ezetimibe does not increase bile acid excretion (like bile acid sequestrants) and does not inhibit cholesterol synthesis in the liver (like statins).
In a 2-week clinical study in 18 hypercholesterolemic patients, Ezetrol inhibited intestinal cholesterol absorption by 54%, compared with placebo. By inhibiting the absorption of intestinal cholesterol, ezetimibe reduces the delivery of cholesterol to the liver. Statins reduce cholesterol synthesis in the liver. Together, these distinct mechanisms provide complementary cholesterol reduction. Ezetrol, administered with a statin, reduces total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG) and increases high-density lipoprotein cholesterol (HDL-C) in patients with hypercholesterolemia, beyond either treatment alone. Administration of Ezetrol with fenofibrate is effective in improving serum total-C, LDL-C, Apo B, TG, HDL-C and non-HDL-C in patients with mixed hyperlipidemia. The effect of ezetemibe given either alone or in addition to an HMG-CoA reductase inhibitor or cardiovascular morbidity and mortality have not been established.
Clinical studies demonstrate that 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. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the levels 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.
A series of preclinical studies was performed to determine the selectivity of ezetimibe for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of [14C]-cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or the fat-soluble vitamins A and D.
Animal Pharmacology: The hypocholesterolemic effect of ezetimibe was evaluated in Rhesus monkeys, a model for the human metabolism of cholesterol, as well as in dogs. Rhesus monkeys were fed a cholesterol-containing diet that mimics a human Western diet. Ezetimibe was found to have an ED50 of 0.0005 mg/kg/day for inhibiting the rise in plasma cholesterol levels (ED100=0.003 mg/kg/day). The ED50 in dogs was found to be 0.007 mg/kg/day. These results are consistent with Ezetrol being an extremely potent cholesterol absorption inhibitor.
In dogs given ezetimibe (≥0.03 mg/kg/day), the concentration of cholesterol in gallbladder bile increased ~2- to 3-fold. However, a dose of 300 mg/kg/day administered to dogs for 1 year did not result in gallstone formation or any adverse hepatobiliary effect. In mice given ezetimibe (0.3-5 mg/kg/day) and fed a normal or cholesterol-rich diet, the concentration of cholesterol in gallbladder bile was either unaffected or reduced to normal levels, respectively. The relevance of these preclinical findings to humans is unknown.
Pharmacokinetics: Absorption: After oral administration, ezetimibe is rapidly absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). Mean maximum plasma concentrations (Cmax) occur within 1-2 hrs for ezetimibe-glucuronide and 4-12 hrs for ezetimibe. 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 nonfat meals) had no effect on the oral bioavailability of ezetimibe when administered as Ezetrol 10-mg tablets. Ezetrol can be administered with or without food.
Distribution: Ezetimibe and ezetimibe-glucuronide are bound 99.7% and 88-92% to human plasma proteins, respectively.
Metabolism: Ezetimibe is metabolized primarily in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary excretion. Minimal oxidative metabolism (a phase I reaction) has been observed in all species evaluated. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10-20% and 80-90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma with evidence of significant enterohepatic recycling. The t½ for ezetimibe and ezetimibe-glucuronide is approximately 22 hrs.
Elimination: Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe accounted for approximately 93% of the total radioactivity in plasma. Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. After 48 hrs, there were no detectable levels of radioactivity in the plasma.
Characteristics in Patients (Special Populations): Pediatric Patients: The absorption and metabolism of ezetimibe are similar between children and adolescents (10-18 years) and adults. Based on total ezetimibe, there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population <10 years of age are not available. Clinical experience in pediatric and adolescent patients (9-17 years) has been limited to patients with HoFH.
Geriatric Patients: Plasma concentrations for total ezetimibe are about 2-fold higher in the elderly (≥65 years) than in the young (18-45 years). LDL-C reduction and safety profile are comparable between elderly and young subjects treated with Ezetrol. Therefore, no dosage adjustment is necessary in the elderly.
Hepatic Insufficiency: After a single 10-mg dose of ezetimibe, the mean area under the curve (AUC) for total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic insufficiency (Child-Pugh score 5 or 6), compared to healthy subjects. In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic insufficiency (Child-Pugh score 7-9), the mean AUC for total ezetimibe was increased approximately 4-fold on Day 1 and Day 14 compared to healthy subjects. No dosage adjustment is necessary for patients with mild hepatic insufficiency. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe (Child-Pugh score >9) hepatic insufficiency, ezetimibe is not recommended in these patients (see Precautions).
Renal Insufficiency: After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean creatinine clearance ≤30 mL/min/1.73 m2), the mean AUC for total ezetimibe was increased approximately 1.5-fold, compared to healthy subjects (n=9). This result is not considered clinically significant. No dosage adjustment is necessary for renally impaired patients.
An additional patient in this study (post-renal transplant and receiving multiple medications, including cyclosporine) had a 12-fold greater exposure to total ezetimibe.
Gender: Plasma concentrations for total ezetimibe are slightly higher (<20%) in women than in men. LDL-C reduction and safety profile are comparable between men and women treated with ezetimibe. Therefore, no dosage adjustment is necessary on the basis of gender.
Race: Based on a meta-analysis of pharmacokinetic studies, there were no pharmacokinetic differences between Blacks and Caucasians.
Clinical Studies: Primary Hypercholesterolemia Monotherapy: In 2 multicenter, double-blind, placebo-controlled 12-week studies in 1719 patients with primary hypercholesterolemia, Ezetrol 10 mg significantly lowered total-C, LDL-C, Apo B and TG and increased HDL-C compared to placebo (see Table 1). Reduction in LDL-C was consistent across age, sex, race and baseline LDL-C. In addition, Ezetrol had no effect on the plasma concentrations of the fat-soluble vitamins A, D and E, had no effect on prothrombin time and did not impair adrenocortical steroid hormone production.


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Co-Administration with a Statin: Ezetrol Initiated Concurrently with a Statin: In 4 multicenter, double-blind, placebo-controlled, 12-week trials in 2382 patients with hypercholesterolemia, Ezetrol 10 mg or placebo was administered alone or with various doses of atorvastatin, simvastatin, pravastatin or lovastatin. In general, the incremental effect on LDL-C reduction was independent of the dose or specific statin used. In addition, LDL-C reduction for Ezetrol co-administered with the lowest tested dose (10 mg) of any of the statins was similar to or greater than the LDL-C reduction of the highest tested dose of the corresponding statin administered alone (see Table 2).


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In a pooled analysis of all Ezetrol + statin doses, Ezetrol had a beneficial effect on total-C, Apo B, TG and HDL-C (see Table 3).


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Ezetrol Added to Ongoing Statin Therapy: In a multicenter, double-blind, placebo-controlled, 8-week study, 769 patients with hypercholesterolemia already receiving statin monotherapy and not at National Cholesterol Education Program (NCEP) LDL-C goal (100-160 mg/dL, depending on baseline characteristics) were randomized to receive either Ezetrol 10 mg or placebo in addition to their ongoing statin therapy.
Among statin-treated patients not at LDL-C goal at baseline (~82%), LDL-C goal at study endpoint was achieved by 72% and 19% of patients randomized to Ezetrol and placebo, respectively.
Ezetrol, added to ongoing statin therapy, significantly lowered total-C, LDL-C, Apo B and TG and increased HDL-C, compared with placebo (see Table 4). LDL-C reductions were consistent across all statins.


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Ezetrol or placebo added to statin therapy reduced median C-reactive protein by 10% or 0% from the baseline, respectively.
In a multicenter, double-blind 14-week study, 621 patients with hypercholesterolemia receiving atorvastation 10 mg daily with an LDL-C >130 mg/dL were randomized to receive atorvastatin 20 mg or Ezetrol 10 mg added to atorvastatin 10-mg therapy. The atorvastatin dose could be titrated up to 80 mg in the atorvastatin arm and up to 40 mg in the Ezetrol plus atorvastatin co-administration arm, based on patients not attaining LDL-C goal (<100 mg/dL). The mean baseline LDL-C was 187 mg/dL and approximately 60% of the patients had heterozygous familial hypercholesterolemia (HeFH). At study end, there was a significant difference in attainment of LDL-C goal between patients in the Ezetrol co-administration arm (22%) and patients on atorvastatin monotherapy (7%). At week 4, there was a significant difference in LDL-C reductions between co-administration patients (24%; Ezetrol + atorvastatin 10 mg) and monotherapy patients (9%; atorvastatin 20 mg). In the subgroup of patients with HeFH, similar results for LDL-C goal attainment and LDL-C reductions were achieved.
In a similarly designed study in 100 patients with hypercholesterolemia receiving simvastatin 20 mg and not at LDL-C goal, the addition of Ezetrol 10 mg to simvastatin titration compared to titration of simvastatin alone produced similar advantages to those observed in the atorvastatin study described previously. For example, significant differences in LDL-C goal attainment (27% for Ezetrol + simvastatin vs 3% for simvastatin alone) and LDL-C reductions (24% for Ezetrol + simvastatin vs 11% for simvastatin alone) were achieved.
Homozygous Familial Hypercholesterolemia (HoFH): A study was conducted to assess the efficacy of Ezetrol in the treatment of HoFH. This double-blind, randomized 12-week study enrolled 50 patients with a clinical and/or genotypic diagnosis of HoFH, with or without concomitant LDL apheresis, already receiving atorvastatin or simvastatin (40 mg). Patients were randomized to 1 of 3 treatment groups, atorvastatin or simvastatin (80 mg), Ezetrol 10 mg administered with atorvastatin or simvastatin (40 mg), or Ezetrol 10 mg administered with atorvastatin or simvastatin (80 mg). Results are shown in Table 5. Ezetrol, administered with atorvastatin (40 or 80 mg) or simvastatin (40 or 80 mg), significantly reduced LDL-C compared with increasing the dose of simvastatin or atorvastatin monotherapy from 40-80 mg.


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Co-Administration with Fenofibrate: In a multicenter, double-blind, placebo-controlled clinical study in patients with mixed hyperlipidemia, 625 patients were treated for up to 12 weeks and 576 for up to 1 year. Patients were randomized to receive placebo, Ezetrol alone, fenofibrate 160 mg alone, or Ezetrol and fenofibrate 160 mg.
Ezetrol co-administered with fenofibrate significantly lowered total-C, LDL-C, Apo B and non-HDL-C compared to fenofibrate administered alone. The percent decrease in TG and percent increase in HDL-C for Ezetrol co-administered with fenofibrate were comparable to those for fenofibrate administered alone (see Table 6).


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Improvements in lipid endpoints after 1 year of treatment were consistent with the 12-week data mentioned previously.
Toxicology: Acute Toxicity: In animals, no toxicity was observed after single oral doses of ezetimibe 5000 mg/kg in rats and mice and 3000 mg/kg in dogs.
Chronic Toxicity: Ezetimibe was well tolerated by mice, rats and dogs. No target organs of toxicity were identified in chronic studies at daily doses up to 1500 (males) and 500 mg/kg (females) in rats, up to 500 mg/kg in mice, or up to 300 mg/kg in dogs.
The safety of concomitant administration of ezetimibe and statins was assessed in rats and dogs. When ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin or lovastatin, for 3 months, toxicologic findings were consistent with those seen with statins administered alone.
Carcinogenicity: In 2-year studies conducted in mice and rats, ezetimibe was not carcinogenic.
Mutagenicity: Ezetimibe was not genotoxic in a series of in vivo and in vitro tests.
Combinations of ezetimibe with atorvastatin, simvastatin, pravastatin or lovastatin were not genotoxic in a series of in vitro and in vivo assays.
Reproduction: Ezetimibe did not affect the fertility of male or female rats.
Development: Ezetamibe was not teratogenic in rats or rabbits and had no effect on prenatal or postnatal development.
Concomitant administration of ezetimibe and statins was not teratogenic in rats. In pregnant rabbits, a low incidence of skeletal malformations (fused sternebrae, fused caudal vertebrae, reduced number of caudal vertebrae) was observed when ezetimibe (1000 mg/kg; ≥146 times the human exposure at 10 mg daily based on AUC0-24hrs for total ezetimibe) was administered with lovastatin (2.5 and 25 mg/kg), simvastatin (5 and 10 mg/kg), pravastatin (25 and 50 mg/kg), or atorvastatin (5, 25 and 50 mg/kg). Exposure to the pharmacologically active form of the statin ranged from 1.4 (atorvastatin) to 547 (lovastatin) times the human exposure at 10 mg daily (simvastatin or atorvastatin) or 20 mg daily (lovastatin or pravastatin) based on AUC0-24hrs.
Indications/Uses
Primary Hypercholesterolemia: Ezetrol administered with an HMG-CoA reductase inhibitor (statin) or alone, is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B and TG and to increase HDL-C in patients with primary (heterozygous familial and nonfamilial) hypercholesterolemia.
Administered in combination with fenofibrate as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B and non-HDL-C in patients with mixed hyperlipidemia.
Homozygous Familial Hypercholesterolemia (HoFH): Ezetrol administered with a statin for the reduction of elevated total-C and LDL-C levels in patients with HoFH. Patients may also receive adjunctive treatments (eg, LDL apheresis).
Dosage/Direction for Use
The patient should be on an appropriate lipid-lowering diet and should continue on this diet during treatment with Ezetrol.
The recommended dose of Ezetrol is 10 mg once daily, used alone or with a statin or with fenofibrate. Ezetrol can be administered at any time of the day, with or without food.
Hepatic Impairment: No dosage adjustment is required in patients with mild hepatic insufficiency (Child-Pugh scores 5-6). Treatment with ezetimibe is not recommended in patients with moderate (Child-Pugh scores 7-9) or severe (Child-Pugh score >9) liver dysfunction. [See Precautions and Pharmacokinetics: Characteristics in Patients (Special Populations) under Actions.]
Renal Impairment: No dosage adjustment is required for renally impaired patients. [See Pharmacokinetics: Characteristics in Patients (Special Populations) under Actions.]
Children and Adolescents ≥10 years: No dosage adjustment is required [See Pharmacokinetics: Characteristics in Patients (Special Populations) under Actions.]
Elderly: No dosage adjustment is required for the elderly. [See Pharmacokinetics: Characteristics in Patients (Special Populations) under Actions.]
Co-Administration with Bile Acid Sequestrants: Dosing of Ezetrol should occur either ≥2 hrs before or ≥4 hrs after administration of a bile acid sequestrant.
Overdosage
In clinical studies, administration of ezetimibe 50 mg/day to 15 healthy subjects for up to 14 days or 40 mg/day to 18 patients with primary hypercholesterolemia for up to 56 days was generally well tolerated.
A few cases of overdosage with Ezetrol have been reported; most have not been associated with adverse experiences. Reported adverse experiences have not been serious. In the event of an overdose, symptomatic and supportive measures should be employed.
Contraindications
Hypersensitivity to any component of Ezetrol.
When Ezetrol is to be administered with a statin or with fenofibrate, which is contraindicated during pregnancy and lactation, refer to the product information.
Special Precautions
When Ezetrol is to be administered with a statin or with fenofibrate, which is contraindicated during pregnancy and lactation, refer to the information for that particular statin or fibrate.
Liver Enzymes: In controlled co-administration trials in patients receiving Ezetrol with a statin, consecutive transaminase elevations [≥3 times the upper limit of normal (ULN)] have been observed. When Ezetrol is co-administered with a statin, liver function tests should be performed at initiation of therapy and according to the recommendations of the statin. (See Side Effects.)
Skeletal Muscle: In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with Ezetrol 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. In clinical trials, the incidence of creatinine phosphokinase level (CPK) >10 times ULN was 0.2% for Ezetrol versus 0.1% for placebo and 0.1% for Ezetrol co-administered with a statin vs 0.4% for statins alone.
In post-marketing experience with Ezetrol, cases of myopathy and rhabdomyolysis have been reported regardless of causality. Most patients who developed rhabdomyolysis were taking a statin prior to initiating Ezetrol. However, rhabdomyolysis has been reported very rarely with Ezetrol monotherapy and very rarely with the addition of Ezetrol to agents known to be associated with increased risk of rhabdomyolysis. All patients starting therapy with Ezetrol should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. Ezetrol and any statin that the patient is taking concomitantly should be immediately discontinued if myopathy is diagnosed or suspected. The presence of these symptoms and a CPK level >10 times the ULN indicates myopathy.
Hepatic Insufficiency: Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, Ezetrol is not recommended in these patients [see Pharmacokinetics: Characteristics in Patients (Special Populations) under Actions].
Fibrates: The co-administration of ezetimibe with fibrates other than fenofibrate has not been studied. Therefore, co-administration of Ezetrol and fibrates (other fenofibrate) is not recommended (see Interactions).
Fenofibrates: If cholelithiasis is suspected in a patient receiving Ezetrol and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered (see Side Effects and product information for fenofibrate).
Cyclosporine: Caution should be exercised when initiating ezetimibe in the setting of cyclosporine. Cyclosporine concentrations should be monitored in patients receiving Ezetrol and cyclosporine (see Interactions).
Anticoagulants: If Ezetrol is added to warfarin, another coumarin anticoagulant or fluindione, the International Normalized Ratio (INR) should be appropriately monitored (see Interactions).
Effects on the Ability to Drive or Operate Machinery: No studies of the effects on the ability to drive and use of machines have been performed. However, ezetimibe is not expected to affect the ability to drive and use machines.
Use in pregnancy: No clinical data on exposed pregnancies are available. Animal studies of ezetimibe administered alone do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development. However, caution should be exercised when prescribing to pregnant women.
When ezetimibe was given with lovastatin, simvastatin, pravastatin or atorvastatin, no teratogenic effects were observed in embryo-fetal development studies in pregnant rats. In pregnant rabbits, a low incidence of skeletal malformations was observed.
When ezetimibe is to be administered with a statin, which is contraindicated during pregnancy and lactation, please refer to the information for that particular statin.
Use in lactation: Studies in rats have shown that ezetimibe is excreted in milk. It is not known whether ezetimibe is excreted into human breast milk. Therefore, Ezetrol should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant.
Use In Pregnancy & Lactation
Use in pregnancy: No clinical data on exposed pregnancies are available. Animal studies of ezetimibe administered alone do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development. However, caution should be exercised when prescribing to pregnant women.
When ezetimibe was given with lovastatin, simvastatin, pravastatin or atorvastatin, no teratogenic effects were observed in embryo-fetal development studies in pregnant rats. In pregnant rabbits, a low incidence of skeletal malformations was observed.
When ezetimibe is to be administered with a statin, which is contraindicated during pregnancy and lactation, please refer to the information for that particular statin.
Use in lactation: Studies in rats have shown that ezetimibe is excreted in milk. It is not known whether ezetimibe is excreted into human breast milk. Therefore, Ezetrol should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant.
Side Effects
Clinical studies of 8-14 weeks duration in which Ezetrol 10 mg daily was administered alone, with a statin or with fenofibrate in 3551 patients demonstrated: Ezetrol was generally well tolerated, adverse reactions were usually mild and transient, the overall incidence of side effects reported with Ezetrol was similar to that reported with placebo and the discontinuation rate due to adverse experiences was comparable between Ezetrol and placebo.
The following common (≥1/100, <1/10) drug-related adverse experiences were reported in patients taking Ezetrol alone (n=1691), co-administered with a statin (n=1675), or co-administered with fenofibrate (n=185).
Ezetrol Administered Alone: Headache; abdominal pain, diarrhea.
Ezetrol Co-Administered with a Statin: Headache, fatigue; abdominal pain, constipation, diarrhea, flatulence, nausea; increased ALT and AST; myalgia.
Ezetrol Co-Administered with Fenofibrate: Abdominal pain.
In a multicenter, double-blind, placebo-controlled clinical study in patients with mixed hyperlipidemia, 625 patients were treated for up to 12 weeks and 576 for up to 1 year. This study was not designed to compare treatment groups for infrequent events. Incidence rates (95% CI) for clinically important elevations (>3 times ULN, consecutive) in serum transaminases were 4.5% (1.9, 8.8) and 2.7% (1.2, 5.4) for fenofibrate monotherapy and Ezetrol co-administered with fenofibrate, respectively, adjusted for treatment exposure. Corresponding incidence rates for cholecystectomy were 0.6% (0, 3.1) and 1.7% (0.6, 4) for fenofibrate monotherapy and Ezetrol co-administered with fenofibrate, respectively (see Precautions). There were no CPK elevations >10 times ULN in either treatment group in this study.
Laboratory Values: In controlled clinical monotherapy trials, the incidence of clinically important elevations in serum transaminases (ALT and/or AST ≥3 times ULN, consecutive) was similar between Ezetrol (0.5%) and placebo (0.3%). In co-administration trials, the incidence was 1.3% for patients treated with Ezetrol co-administered with a statin and 0.4% for patients treated with a statin alone. These elevations were generally asymptomatic, not associated with cholestasis and returned to baseline after discontinuation of therapy or with continued treatment. (See Precautions.)
Clinically important elevations of CPK (≥10 times ULN) in patients treated with Ezetrol administered alone or co-administered with a statin were similar to elevations seen with placebo or statin administered alone, respectively.
Post-Marketing Experience: The following adverse reactions have been reported in post-marketing experience, regardless of causality assessment: Hypersensitivity reactions, including anaphylaxis, angioedema and rash; myalgia; increased CPK; elevations of liver transaminases; hepatitis; thrombocytopenia; pancreatitis; nausea and very rarely, myopathy/rhabdomyolysis (see Precautions).
Drug Interactions
In preclinical studies, it has been shown that ezetimibe does not induce cytochrome P-450 drug metabolizing enzymes. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and drugs known to be metabolized by cytochromes P-450 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.
Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe (ezetimibe + ezetimibe glucuronide) approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be lessened by this interaction.
Cyclosporine: In a study of 8 post-renal transplant patients with creatinine clearance >50 mL/min on a stable dose of cyclosporine, a single 10-mg dose of ezetimibe resulted in a 3.4-fold (range 2.3- to 7.9-fold) increase in the mean AUC for total ezetimibe compared to a healthy control population from another study (n=17). In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to concurrent controls. In a 2-period crossover study in 12 healthy subjects, daily administration of ezetimibe 20 mg for 8 days with a single 100-mg dose of cyclosporine on Day 7 resulted in a mean 15% increase in cyclosporine AUC (range 10% decrease to 51% increase) compared to a single 100-mg dose of cyclosporine alone (see Precautions).
Fibrates: The safety and effectiveness of ezetimibe co-administered with fenofibrates have been evaluated in a clinical study (see Side Effects and Pharmacokinetics: Co-Administration with Fenofibrate under Actions); co-administration of ezetimibe with other fibrates have not been studied. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile (see Animal Pharmacology under Actions). Although the relevance of this preclinical finding to humans is unknown, co-administration of Ezetrol with fibrates (other than fenofibrate) is not recommended until use in patients is studied.
Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. This increase is not considered clinically significant.
Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. This increase is not considered clinically significant. No clinical data are available.
Statins: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin or rosuvastatin.
Anticoagulants: Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of 12 healthy adult males. There have been post-marketing reports of increased INR in patients who had Ezetrol added to warfarin or fluindione. Most of these patients were also on other medications (see Precautions).
Storage
Do not store above 30°C. Store in the original packaging.
ATC Classification
C10AX09 - ezetimibe ; Belongs to the class of other lipid modifying agents.
Presentation/Packing
Tab 10 mg x 30's.
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