ATOZET (ezetimibe/atorvastatin) is a lipid-lowering product that selectively inhibits the intestinal absorption of cholesterol and related plant sterols and inhibits the endogenous synthesis of cholesterol.
Pharmacology: Pharmacodynamics: Mechanism of Action:
ATOZET: Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. ATOZET contains ezetimibe and atorvastatin, two lipid-lowering compounds with complementary mechanisms of action. ATOZET reduces elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and increases HDL-C through dual inhibition of cholesterol absorption and synthesis.
Ezetimibe: Ezetimibe inhibits the intestinal absorption of cholesterol. Ezetimibe is orally active and has a mechanism of action that differs from other classes of cholesterol-reducing compounds (e.g., 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; statins reduce cholesterol synthesis in the liver and together these distinct mechanisms provide complementary cholesterol reduction.
In a 2-week clinical study in 18 hypercholesterolemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo.
A series of preclinical studies was performed to determine the selectivity of ezetimibe for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of [14
C]-cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or the fat-soluble vitamins A and D.
Atorvastatin: Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In animal models, atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL; atorvastatin also reduces LDL production and the number of LDL particles.
In controlled clinical studies, ATOZET significantly reduced total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C), and increased high-density lipoprotein cholesterol (HDL-C) in patients with hypercholesterolemia.
Primary Hypercholesterolemia: ATOZET: In a multicenter, double-blind, placebo-controlled, clinical study in patients with hyperlipidemia, 628 patients were treated for up to 12 weeks and 246 for up to an additional 48 weeks. Patients were randomized to receive placebo, ezetimibe (10 mg), atorvastatin (10 mg, 20 mg, 40 mg, or 80 mg), or coadministered ezetimibe and atorvastatin equivalent to ATOZET (10/10, 10/20, 10/40, and 10/80) in the 12-week study. After completing the 12-week study, eligible patients were assigned to coadministered ezetimibe and atorvastatin equivalent to ATOZET (10/10-10/80) or atorvastatin (10-80 mg/day) for an additional 48 weeks.
Patients receiving all doses of ATOZET were compared to those receiving all doses of atorvastatin. ATOZET lowered total C, LDL C, Apo B, TG, and non-HDL C, and increased HDL-C significantly more than atorvastatin alone. (See Table 1.)
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The changes in lipid endpoints after an additional 48 weeks of treatment with ATOZET (all doses) or with atorvastatin (all doses) were generally consistent with the 12-week data previously displayed.
A multicenter, double-blind, controlled, 14-week study was conducted in 621 patients with heterozygous familial hypercholesterolemia (HeFH), coronary heart disease (CHD), or multiple cardiovascular risk factors (≥2), adhering to an NCEP Step I or stricter diet. All patients received atorvastatin 10 mg for a minimum of 4 weeks prior to randomization. Patients were then randomized to receive either coadministered ezetimibe and atorvastatin (equivalent to ATOZET 10/10) or atorvastatin 20 mg/day monotherapy. Patients who did not achieve their LDL-C target goal after 4 and/or 9 weeks of randomized treatment were titrated to double the atorvastatin dose.
ATOZET 10/10 was significantly more effective than doubling the dose of atorvastatin to 20 mg in further reducing total-C, LDL-C, TG, and non-HDL-C. Results for HDL-C between the two treatment groups were not significantly different. (See Table 2.) In addition, at Week 4 significantly more patients receiving ATOZET 10/10 attained LDL-C <2.6 mmol/L (<100 mg/dL) compared to those receiving atorvastatin 20 mg, 12% vs. 2%. The baseline mean LDL-C levels for patients receiving ATOZET 10/10 and atorvastatin 20 mg were 186 mg/dL and 187 mg/dL, respectively. (See Table 2.)
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The Titration of Atorvastatin Versus Ezetimibe Add-On to Atorvastatin in Patients with Hypercholesterolemia (TEMPO) study, a multicenter, double-blind, controlled, 6-week study, included 184 patients with an LDL-C level ≥2.6 mmol/L and ≤4.1 mmol/L (≥100 mg/dL and ≤160 mg/dL) and at moderate high risk for coronary heart disease (CHD). All patients received atorvastatin 20 mg for a minimum of 4 weeks prior to randomization. Patients not at the optional NCEP ATP III LDL-C level (<2.6 mmol/L [<100 mg/dL]) were randomized to receive either coadministered ezetimibe and atorvastatin (equivalent to ATOZET 10/20) or atorvastatin 40 mg for 6 weeks.
ATOZET 10/20 was significantly more effective than doubling the dose of atorvastatin to 40 mg in further reducing total-C, LDL-C, Apo B and non-HDL-C. Results for HDL-C and TG between the two treatment groups were not significantly different. (See Table 3.) In addition, significantly more patients receiving ATOZET 10/20 attained LDL-C <2.6 mmol/L (<100 mg/dL) compared to those receiving atorvastatin 40 mg, 84% vs. 49%. (See Table 3.)
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The Ezetimibe Plus Atorvastatin Versus Atorvastatin Titration in Achieving Lower LDL-C Targets in Hypercholesterolemic Patients (EZ-PATH) study, a multicenter, double-blind, controlled, 6-week study, included 556 patients with an LDL-C level ≥1.8 mmol/L and ≤4.1 mmol/L (≥70 mg/dL and ≤160 mg/dL) and at high risk for coronary heart disease (CHD). All patients received atorvastatin 40 mg for a minimum of 4 weeks prior to randomization. Patients not at the optional NCEP ATP III LDL-C level <1.8 mmol/L (<70 mg/dL) were randomized to receive either coadministered ezetimibe and atorvastatin (equivalent to ATOZET 10/40) or atorvastatin 80 mg for 6 weeks.
ATOZET 10/40 was significantly more effective than doubling the dose of atorvastatin to 80 mg in further reducing total-C, LDL-C, Apo B, TG, and non-HDL-C. Results for HDL-C between the two treatment groups were not significantly different. (See Table 4.) In addition, significantly more patients receiving ATOZET 10/40 attained LDL-C <1.8 mmol/L (<70 mg/dL) compared to those receiving atorvastatin 80 mg, 74% vs. 32%. (See Table 4.)
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In a double-blind, placebo-controlled, 8-week study, 308 patients with hypercholesterolemia already receiving atorvastatin monotherapy and not at National Cholesterol Education Program (NCEP) LDL-C goal (LDL-C goal based upon baseline LDL-C and CHD risk status) were randomized to receive either ezetimibe 10 mg or placebo in addition to their on-going atorvastatin therapy.
Among atorvastatin-treated patients not at LDL-C goal at baseline (~83%), significantly more patients randomized to ezetimibe coadministered with atorvastatin achieved their LDL-C goal at study endpoint compared to patients randomized to placebo coadministered with atorvastatin, 72% vs. 27%. Ezetimibe added to atorvastatin therapy lowered LDL-C significantly more than placebo added to atorvastatin therapy, 25% vs. 4%. In addition, ezetimibe added to atorvastatin therapy significantly decreased total-C, Apo B, and TG compared with placebo added to atorvastatin therapy.
In a multicenter, double-blind, controlled, 12-week, 2-phase study, 1539 high-cardiovascular-risk patients, with a LDL-C level between 100 and 160 mg/dL at baseline on atorvastatin 10 mg daily, were randomized to one of three treatment groups: atorvastatin 20 mg, rosuvastatin 10 mg, or coadministered ezetimibe and atorvastatin (equivalent to ATOZET 10/10). After 6 weeks of treatment (Phase I), based on a random allocation schedule established at the start of Phase I, patients taking atorvastatin 20 mg who failed to achieve a LDL-C level <100 mg/dL were switched to either atorvastatin 40 mg or coadministered ezetimibe and atorvastatin (equivalent to ATOZET 10/20) for 6 weeks (Phase II), and similar patients taking rosuvastatin 10 mg during Phase I were switched to either rosuvastatin 20 mg or coadministered ezetimibe and atorvastatin (equivalent to ATOZET 10/20) during Phase II. Reductions in LDL-C and comparisons between the ATOZET group and other treatment groups studied are shown in Table 5. (See Table 5.)
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Table 5 does not contain data comparing the effects of ATOZET 10/10 or 10/20 to doses higher than atorvastatin 40 mg or rosuvastatin 20 mg.
Ezetimibe: In two multicenter, double-blind, placebo-controlled, 12-week studies in 1719 patients with primary hypercholesterolemia, ezetimibe significantly lowered total-C (-13%), LDL-C (-19%), Apo B (-14%), TG (-8%), and non-HDL-C (-17%) and increased HDL-C (+3%) compared to placebo. Reduction in LDL-C was consistent across age, sex, and baseline LDL-C.
Atorvastatin: In a placebo-controlled study, the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of atorvastatin 10 mg on fatal and non-fatal coronary heart disease was assessed in 10,305 hypertensive patients, 40-80 years old, with TC levels ≤251 mg/dL (6.5 mmol/L) and at least three cardiovascular risk factors. Patients were followed for a median duration of 3.3 years. Atorvastatin 10 mg significantly (p=0.0005) reduced the rate of coronary events (either fatal coronary heart disease [46 events in the placebo group vs. 40 events in the atorvastatin group] or nonfatal MI [108 events in the placebo group vs. 60 events in the atorvastatin group]) by 36% (based on incidences of 1.9% for atorvastatin vs. 3.0% for placebo).
In a placebo-controlled study, the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of atorvastatin 10 mg on cardiovascular disease (CVD) endpoints was assessed in 2838 patients, 40-75 years old, with type 2 diabetes, one or more cardiovascular risk factors, LDL ≤160 mg/dL, and TG ≤600 mg/dL. Patients were followed for a median duration of 3.9 years. Atorvastatin 10 mg significantly (p<0.05) reduced: the rate of major cardiovascular events (MCVE) by 37%; the risk of stroke by 48%; and the risk of MI by 42%.
In the Treating to New Targets Study (TNT), the effect of atorvastatin 80 mg/day vs. atorvastatin 10 mg/day on the reduction in cardiovascular events was assessed in 10,001 subjects with clinically evident CHD and an LDL-C level <130 mg/dL while receiving atorvastatin 10 mg. Patients were followed for a median duration of 4.9 years. Atorvastatin 80 mg significantly (p≤0.05) reduced the rate of: MCVE by 22%; nonfatal, non-procedure related MI by 22%; fatal and non-fatal stroke by 25%; coronary revascularization by 28%; angina by 12%; and hospitalization for heart failure by 26%.
In a multicenter, double-blind, placebo-controlled, clinical study, the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study, patients with an acute coronary syndrome (non Q-wave MI or unstable angina) were randomized to receive atorvastatin 80 mg/day (n=1538) or placebo (n=1548). Treatment was initiated during the acute phase after hospital admission and lasted for a period of 16 weeks. Atorvastatin 80 mg/day provided a 16% (p=0.048) reduction in risk of the combined primary endpoint, defined as death from any cause, nonfatal MI, resuscitated cardiac arrest, or angina pectoris with evidence of myocardial ischemia requiring hospitalization. This was mainly due to a 26% reduction in re-hospitalization for angina pectoris with evidence of myocardial ischemia (p=0.018).
In the Incremental Decrease in Endpoints Through Aggressive Lipid Lowering Study (IDEAL), treatment with atorvastatin 80 mg/day was compared to treatment with simvastatin 20-40 mg/day in 8,888 patients up to 80 years of age with a history of CHD to assess whether reduction in CV risk could be achieved. In this prospective, randomized, open-label, blinded endpoint trial, patients, 76% of whom were on statin therapy at randomization, were followed for a median duration of 4.8 years. There was no significant difference between the treatment groups for the rate of first major coronary event (fatal CHD, nonfatal MI, and resuscitated cardiac arrest): 411 (9.3%) in the atorvastatin 80 mg/day group vs. 463 (10.4%) in the simvastatin 20-40 mg/day group or for all-cause mortality: 366 (8.2%) in the atorvastatin 80 mg/day group vs. 374 (8.4%) in the simvastatin 20-40 mg/day group. The proportions of subjects who experienced CV or non-CV death were similar for the atorvastatin 80 mg group and the simvastatin 20-40 mg group.
Homozygous Familial Hypercholesterolemia (HoFH): A double-blind, randomized, 12-week study was performed in patients with a clinical and/or genotypic diagnosis of HoFH. Data were analyzed from a subgroup of patients (n=36) receiving atorvastatin 40 mg at baseline. Increasing the dose of atorvastatin from 40 to 80 mg (n=12) produced a reduction of LDL-C of 2% from baseline on atorvastatin 40 mg. Coadministered ezetimibe and atorvastatin equivalent to ATOZET (10/40 and 10/80 pooled, n=24), produced a reduction of LDL-C of 19% from baseline on atorvastatin 40 mg. In those patients coadministered ezetimibe and atorvastatin equivalent to ATOZET (10/80, n=12), a reduction of LDL-C of 25% from baseline on atorvastatin 40 mg was produced.
After completing the 12 week study, eligible patients (n=35), who were receiving atorvastatin 40 mg at baseline, were assigned to coadministered ezetimibe and atorvastatin equivalent to ATOZET 10/40 for up to an additional 24 months. Following at least 4 weeks of treatment, the atorvastatin dose could be doubled to a maximum dose of 80 mg. At the end of the 24 months, ATOZET (10/40 and 10/80 pooled) produced a reduction of LDL-C that was consistent with that seen in the 12-week study.
Pharmacokinetics: General Introduction:
ATOZET: ATOZET has been shown to be bioequivalent to coadministration of corresponding doses of ezetimibe and atorvastatin tablets.
ATOZET: The effects of a high-fat meal on the pharmacokinetics of ezetimibe and atorvastatin when administered as ATOZET tablets are comparable to those reported for the individual tablets.
Ezetimibe: 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 to 2 hours for ezetimibe-glucuronide and 4 to 12 hours 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 non-fat meals) had no effect on the oral bioavailability of ezetimibe when administered as ezetimibe 10-mg tablets.
Atorvastatin: Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations (Cmax
) occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. After oral administration, atorvastatin film-coated tablets are 95% to 99% bioavailable compared to the oral solution. The absolute bioavailability of atorvastatin is approximately 12% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism.
Ezetimibe: Ezetimibe and ezetimibe-glucuronide are bound 99.7% and 88 to 92% to human plasma proteins, respectively.
Atorvastatin: Mean volume of distribution of atorvastatin is approximately 381 l. Atorvastatin is ≥98% bound to plasma proteins.
Ezetimibe: 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 to 20 % and 80 to 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 half-life for ezetimibe and ezetimibe-glucuronide is approximately 22 hours.
Atorvastatin: Atorvastatin is metabolized by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and various beta-oxidation products. Apart from other pathways these products are further metabolized via glucuronidation. In vitro
, inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites.
Ezetimibe: Following oral administration of 14
C-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 hours, there were no detectable levels of radioactivity in the plasma.
Atorvastatin: Atorvastatin is eliminated primarily in bile following hepatic and/or extrahepatic metabolism. However, the medicinal product does not appear to undergo significant enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours. The half-life of inhibitory activity for HMG-CoA reductase is approximately 20 to 30 hours due to the contribution of active metabolites.
Atorvastatin is a substrate of the hepatic transporters, OATP1B1 and OATP1B3 transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporters MDR1 and BCRP, which may limit the intestinal absorption and biliary clearance of atorvastatin.
Ezetimibe: 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 for total ezetimibe was increased approximately 1.5-fold, compared to healthy subjects (n=9).
An additional patient in this study (post-renal transplant and receiving multiple medications, including cyclosporine) had a 12-fold greater exposure to total ezetimibe.
Atorvastatin: Renal disease has no influence on the plasma concentrations or lipid effects of atorvastatin and its active metabolites.
Ezetimibe: 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 impairment (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 impairment (Child-Pugh score 7 to 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 impairment. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe (Child-Pugh score >9) hepatic impairment, ezetimibe is not recommended in these patients [see Hepatic Impairment under Precautions].
Atorvastatin: Plasma concentrations of atorvastatin and its active metabolites are markedly increased (approx. 16-fold in Cmax
and approx. 11-fold in AUC) in patients with chronic alcoholic liver disease (Child-Pugh B).
Pediatric: Ezetimibe: The pharmacokinetics of ezetimibe are similar between children ≥6 years and adults. Pharmacokinetic data in the pediatric population <6 years of age are not available.
Atorvastatin: Apparent oral clearance of atorvastatin in pediatric subjects appeared similar to that of adults when scaled allometrically by body weight as the body weight was the only significant covariate in atorvastatin population PK model with data including pediatric HeFH patients (ages 10 years to 17 years of age, n=29) in an open-label, 8-week study.
Ezetimibe: Plasma concentrations for total ezetimibe are about 2-fold higher in the elderly (≥65 years) than in the young (18 to 45 years). LDL-C reduction and safety profile are comparable between elderly and young subjects treated with ezetimibe.
Atorvastatin: Plasma concentrations of atorvastatin and its active metabolites are higher in healthy elderly subjects than in young adults while the lipid effects were comparable to those seen in younger patient populations.
Based on a meta analysis of pharmacokinetic studies with ezetimibe, there were no pharmacokinetic differences between Blacks and Caucasians.
Ezetimibe: 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.
Atorvastatin: Concentrations of atorvastatin and its active metabolites in women differ from those in men (women: approx. 20% higher for Cmax
and approx. 10% lower for AUC). These differences were of no clinical significance, resulting in no clinically significant differences in lipid effects among men and women.
Hemodialysis: Atorvastatin: While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin since the drug is extensively bound to plasma proteins.
Toxicology: 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 ezetimibe 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 one year did not result in gallstone formation or any other adverse hepatobiliary effects. In mice given ezetimibe (0.3 to 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.
In animals, no toxicity was observed after single oral doses of 5000 mg/kg of ezetimibe in rats and mice and 3000 mg/kg in dogs.
ATOZET: The safety of concomitant administration of ezetimibe and atorvastatin was assessed in rats and dogs. When ezetimibe was coadministered with atorvastatin, simvastatin, pravastatin or lovastatin, for three months, toxicologic findings were consistent with those seen with statins administered alone.
Ezetimibe: 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.
Ezetimibe: In two-year studies conducted in mice and rats, ezetimibe was not carcinogenic.
Atorvastatin: In a 2-year carcinogenicity study in rats at dose levels of 10, 30, and 100 mg/kg/day, 2 rare tumors were found in muscle in high-dose females: in one, there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma. This dose represents a plasma AUC0-24
value of approximately 16 times the mean human plasma drug exposure after an 80 mg oral dose.
A 2-year carcinogenicity study in mice given 100, 200, or 400 mg/kg/day resulted in a significant increase in liver adenomas in high-dose males and liver carcinomas in high-dose females. These findings occurred at plasma AUC0-24
values of approximately 6 times the mean human plasma drug exposure after an 80 mg oral dose.
ATOZET: Combination of ezetimibe with atorvastatin was not genotoxic in a series of in vitro
and in vivo
Ezetimibe: Ezetimibe was not genotoxic in a series of in vivo and in vitro tests.
Atorvastatin: In vitro
, atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation: the Ames test with Salmonella typhimurium
and Escherichia coli
, the HGPRT forward mutation assay in Chinese hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in the in vivo
mouse micronucleus test.
Ezetimibe: Ezetimibe did not affect the fertility of male or female rats.
Atorvastatin: In female rats, atorvastatin at doses up to 225 mg/kg (56 times the human exposure) did not cause adverse effects on fertility. Studies in male rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no changes in fertility. There was aplasia and aspermia in the epididymis of 2 of 10 rats treated with 100 mg/kg/day of atorvastatin for 3 months (16 times the human AUC at the 80-mg dose); testis weights were significantly lower at 30 and 100 mg/kg and epididymal weight was lower at 100 mg/kg. Male rats given 100 mg/kg/day for 11 weeks prior to mating had decreased sperm motility, spermatid head concentration, and increased abnormal sperm. Atorvastatin caused no adverse effects on semen parameters, or reproductive organ histopathology in dogs given doses of 10, 40, or 120 mg/kg for two years.
ATOZET: Concomitant administration of ezetimibe and atorvastatin was not teratogenic in rats. In pregnant rabbits, a low incidence of skeletal malformations (fused sternebrae and fused caudal vertebrae) was observed when ezetimibe (1000 mg/kg; ≥146 times the human exposure at 10 mg daily based on AUC0-24hr
for total ezetimibe) was administered with atorvastatin (5, 25 and 50 mg/kg). Exposure to the pharmacologically active form of atorvastatin was ≥1.4 times the human exposure at 10 mg daily based on AUC0-24hr
Ezetimibe: Ezetimibe was not teratogenic in rats or rabbits and had no effect on prenatal or postnatal development.
Atorvastatin: Atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure based on surface area (mg/m2