Pharmacology: Pharmacodynamics: Mechanism of Action:
Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of sterols, including cholesterol. In patients with homozygous and heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia, and mixed dyslipidemia, atorvastatin reduces total-C, LDL-C, and apo B. Atorvastatin also reduces very low-density lipoprotein cholesterol (VLDL-C) and TG and produces variable increases in HDL-C.
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 for enhanced uptake and catabolism of LDL.
Atorvastatin reduces LDL production and the number of LDL particles. Atorvastatin produces a profound and sustained increase in LDL receptor activity coupled with a beneficial change in the quality of circulating LDL particles. Atorvastatin is effective in reducing LDL in patients with homozygous familial hypercholesterolemia, a population that has not normally responded to lipid-lowering medication.
Atorvastatin and some of its metabolites are pharmacologically active in humans. The primary site of action of atorvastatin is the liver, which is the principal site of cholesterol synthesis and LDL clearance. LDL-C reduction correlates better with drug dose than it does with systemic drug concentration. Individualization of drug dosage should be based on therapeutic response (see Dosage & Administration).
In a dose-response study, atorvastatin, (10 mg-80 mg) reduced total-C (30%-46%), LDL-C (41%-61%), apo B (34%-50%), and TG (14%-33%). These results are consistent in patients with heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia, and mixed hyperlipidemia, including patients with non-insulin dependent diabetes mellitus.
In patients with isolated hypertriglyceridemia, atorvastatin reduces total-C, LDL-C, VLDL-C, apo B, TG, and non-HDL-C, and increases HDL-C. In patients with dysbetalipoproteinemia, atorvastatin reduces intermediate density lipoprotein cholesterol (IDL-C).
In patients with Fredrickson Types IIa and IIb hyperlipoproteinemia pooled from 24 controlled trials, the median percent increases from baseline in HDL-C for atorvastatin (10 mg-80 mg) were 5.1% to 8.7% in a non-dose-related manner. Additionally, analysis of this pooled data demonstrated significant dose related decreases in total-C/HDL-C and LDLC/ HDL-C ratios, ranging from -29% to -44% and -37% to -55%, respectively.
The effects of atorvastatin on ischemic events and total mortality were studied in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering study (MIRACL). This multicenter, randomized, double-blind, placebo-controlled study followed 3086 patients with acute coronary syndromes; unstable angina or non-Q wave MI. Patients were treated with standard care, including diet, and either atorvastatin 80 mg daily or placebo for a median duration of 16 weeks. The final LDL-C, total-C, HDL-C, and TG levels were 72 mg/dL, 147 mg/dL, 48 mg/dL, 139 mg/dL, respectively in the atorvastatin group, and 135 mg/dL, 217 mg/dL, 46 mg/dL, and 187 mg/dL, respectively, in the placebo group. Atorvastatin significantly reduced the risk of ischemic events and death by 16%. The risk of experiencing rehospitalization for angina pectoris with documented evidence of myocardial ischemia was significantly reduced by 26%. Atorvastatin reduced the risk of ischemic events and death to a similar extent across the range of baseline LDL-C. In addition, atorvastatin reduced the risk of ischemic events and death to similar extents in patients with non-Q wave MI and unstable angina, as well as in males and females and in patients ≤65 years of age and >65 years of age.
Prevention of Cardiovascular Complications: In the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA), the effect of atorvastatin on fatal and non-fatal CHD was assessed in 10,305 hypertensive patients 40 to 80 years of age (mean age 63 years), without a previous MI and with total C levels <6.5 mmol/L (251 mg/dL). Additionally, all patients had at least three of the following cardiovascular (CV) risk factors; male gender, age >55 years, smoking, diabetes, history of CHD in a first-degree relative, total C: HDL >6, peripheral vascular disease, left ventricular hypertrophy, prior cerebrovascular event, specific electrocardiogram (ECG) abnormality, proteinuria/albuminuria. In this double-blind, placebo-controlled study, patients were treated with anti-hypertensive therapy (goal BP <140/90 mm Hg for non-diabetic patients, <130/80 mm Hg for diabetic patients) and allocated to either atorvastatin 10 mg daily (n=5168) or placebo (n=5137). As the effect of atorvastatin treatment compared to placebo exceeded the significance threshold during an interim analysis, the ASCOT-LLA was terminated early at 3.3 years instead of 5 years. Additionally, blood pressure was well controlled and similar in patients assigned atorvastatin and placebo. These changes persisted throughout the treatment period.
Atorvastatin reduced the rate of the following events: See Table 1.
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The total mortality and CV mortality have not been significantly reduced although a favorable trend was observed.
In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of atorvastatin on fatal and non-fatal CVD was assessed in 2838 patients with type 2 diabetes 40 to 75 years of age, without prior history of CVD and with LDL ≤4.14 mmol/L (160 mg/dL) and TG ≤6.78 mmol/L (600 mg/dL). Additionally, all patients had at least one of the following risk factors: hypertension, current smoking, retinopathy, microalbuminuria, or macroalbuminuria.
In this randomized, double-blind, multicenter, placebo-controlled trial, patients were treated with either atorvastatin 10 mg daily (n=1428) or placebo (n=1410) for a median follow-up of 3.9 years. As the effect of atorvastatin treatment on the primary endpoint reached the predefined stopping rules for efficacy, CARDS was terminated 2 years earlier than anticipated.
The absolute and relative risk reduction effects of atorvastatin are as follows: See Table 2.
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There was no evidence of a difference in the treatment effect by patient's gender, age, or baseline LDL-C level.
A relative risk reduction in death of 27% (82 deaths in the placebo group compared to 61 deaths in the treatment arm) has been observed with a borderline statistical significance (p=0.0592). The overall incidence of adverse events or serious adverse events was similar between the treatment groups.
CKD: CARDS Study Sub-analysis on Cardiovascular Events in CKD Patients at Baseline: Of the CARDS participants, slightly more than one-third (34%) of participants had stage 3, i.e., moderate kidney damage (eGFR, 20-60 mL/min/1.73 m2
) and slightly more than one-fifth had albuminuria at baseline. This sub-analysis examines whether atorvastatin affects diabetic kidney disease and whether the effect of atorvastatin on cardiovascular disease varies by kidney status in patients with diabetes.
In 970 patients with a moderately decreased eGFR of 30-60 mL/min/1.73 m2
, there was a 42% reduction in major CVD events with treatment, including a 61% reduction in stroke. This treatment effect was similar to the 37% (95% CI, 17-52; p<0.001) reduction in CVD observed in the study overall.
Sub-analysis on the effect of atorvastatin on kidney function: At baseline, 34% of patients had an eGFR of 30-60 mL/min/1.73 m2
Atorvastatin treatment was associated with a modest but significant improvement in annual change in eGFR (net, 0.18 mL/min/1.73 m2
/year; 95% CI, 0.04 to 0.32; p = 0.01) that was most apparent in those with albuminuria (net improvement, 0.38 mL/min/1.73 m2
/year; p = 0.03).
TNT: Study Sub-analysis on Cardiovascular Events in Patients with CKD at baseline: In a subanalysis of the Treating to New Targets (TNT) study, patients with CKD were identified at baseline on the basis of an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2
using the Modification of Diet in Renal Disease equation. The primary efficacy outcome was time to first major cardiovascular event. Of 9,656 patients with complete renal data, 3,107 had CKD at baseline and demonstrated greater cardiovascular co-morbidity than those with normal eGFR (n = 6,549). After a median follow-up of 5.0 years, 351 patients with CKD (11.3%) experienced a major cardiovascular event, compared with 561 patients with normal eGFR (8.6%) (hazard ratio [HR] = 1.35; 95% confidence interval [CI] 1.18 to 1.54; p <0.0001). Compared with atorvastatin 10 mg, atorvastatin 80 mg reduced the relative risk of major cardiovascular events by 32% in patients with CKD (HR = 0.68; 95% CI 0.55 to 0.84; p = 0.0003) and 15% in patients with normal eGFR (HR = 0.85; 95% CI 0.72 to 1.00; p = 0.049). Both doses of atorvastatin were well tolerated in patients with CKD.
Safety of atorvastatin 80 mg in patients with CKD was similar to that reported for the overall TNT population, with no unexpected safety concerns identified. Rates of treatment-related adverse events and discontinuations due to treatment-related adverse events were similar between patients with CKD and patients with normal eGFR for each treatment group. Incidences of hematuria and albuminuria were similar between patients with CKD and patients with normal eGFR for each treatment group. There were no reports of serious adverse events associated with these urinary abnormalities in either treatment group.
Sub-Analysis on the effect of atorvastatin treatment on renal function. This is a post-hoc
analysis of the TNT study to investigate renoprotective effect of atorvastatin treatment. A total of 10,001 patients with coronary heart disease and LDL cholesterol levels of <130 mg/dL were randomly assigned to double-blind therapy with 10 or 80 mg/dL atorvastatin. Estimated GFR using the Modification of Diet in Renal Disease equation was compared at baseline and at the end of follow-up in 9656 participants with complete renal data. Renal function was assessed using the Modification of Diet in Renal Disease (MDRD) equation, a serum creatinine–based estimate of GFR. The Cockcroft-Gault equation, another creatinine-based estimate of GFR, incorporating patient weight, was also used. Serum creatinine measurements using a modified alkaline picrate method of Jaffe were taken at baseline and after 12, 24, 36, 48, 60, and 72 months of treatment by individuals at a central study laboratory who were blinded to treatment assignment.
Mean estimated GFR at baseline was 65.6 ±11.4 ml/min per 1.73 m2
in the 10-mg group and 65.0 ±11.2 ml/min per 1.73 m2
in the 80-mg group. At the end of follow-up (median time to final creatinine measurement 59.5 months), mean change in estimated GFR showed an increase of 3.5 ± 0.14 ml/min per 1.73 m2
with 10 mg and 5.2 ± 0.14 ml/min per 1.73 m2
with 80 mg (p <0.0001 for treatment difference). In the 80-mg arm, estimated GFR improved to ≥60 ml/min per 1.73 m2
in significantly more patients and declined to <60 ml/min per 1.73 m2
in significantly fewer patients than in the 10-mg arm.
ALLIANCE Renal Study. A post-hoc
analysis of the Aggressive Lipid-Lowering Initiation Abates New Cardiac Events (ALLIANCE) Study in patients with coronary heart disease (CHD) with and without chronic kidney disease (CKD). This is a Prospective randomized open-label study with a median follow-up, 54.3 months. The study was conducted at the Managed care or Veterans Affairs facilities with 2,442 patients with CHD with dyslipidemia and a mean age of 61.6 years. The intervention was a focused atorvastatin therapy to a low-density lipoprotein cholesterol goal of less than 80 mg/dL or a maximum dose of 80 mg/dL versus usual care as deemed appropriate by patients' regular physicians. The baseline estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease Study equation of less than 60 mL/min/1.73 m2
(for patients with CKD) and 60 mL/min/1.73 m2
or greater (for patients without CKD). The primary end point was time to first cardiovascular event. Change from baseline eGFR was assessed in 1,768 patients with follow-up renal data. The Results showed that at baseline, 579 patients (23.7%) had CKD: 31.6% of these patients experienced a primary cardiovascular event during the study versus 23.6% of patients without CKD (hazard ratio [HR], 1.41; 95% confidence interval [CI], 1.18 to 1.68; P <0.001). Compared with usual care, atorvastatin therapy reduced the relative risk of a primary outcome by 28% in patients with CKD (HR, 0.72; 95% CI, 0.54 to 0.97; P = 0.02) and 11% in patients without CKD (HR, 0.89; 95% CI, 0.74 to 1.07; P = 0.3) (P for treatment by CKD interaction = 0.2). There was no decrease in eGFR in atorvastatin-treated patients during the course of the study. Conclusions: Patients with CHD and CKD are at increased risk of cardiovascular events. Compared with usual care, focused atorvastatin treatment decreased cardiovascular risk for established patients in real world settings, with no significant difference in treatment effects observed between patients with and without CKD.
Atherosclerosis: In the Reversing Atherosclerosis with Aggressive Lipid-Lowering Study (REVERSAL) study, the effect of atorvastatin 80 mg and pravastatin 40 mg on coronary atherosclerosis was assessed by intravascular ultrasound (IVUS), during angiography, in patients with CHD. In this randomized, double-blind, multicenter, controlled clinical trial, IVUS was performed at baseline and at 18 months in 502 patients. In the atorvastatin group (n = 253), the median percent change, from baseline, in total atheroma volume (the primary study criteria), was -0.4% (p = 0.98) in the atorvastatin group and +2.7% (p = 0.001) in the pravastatin group (n=249). When compared to pravastatin, the effects of atorvastatin were statistically significant (p=0.02).
In the atorvastatin group, LDL-C was reduced to a mean of 2.04 mmol/L ± 0.8 (78.9 mg/dL ± 30) from baseline 3.89 mmol/L ± 0.7 (150 mg/dL ± 28) and in the pravastatin group, LDL-C was reduced to a mean of 2.85 mmol/L ± 0.7 (110 mg/dL ± 26) from baseline 3.89 mmol/L ± 0.7 (150 mg/dL ± 26) (p <0.0001). Atorvastatin also significantly reduced mean total C by 34.1% (pravastatin: -18.4%, p <0.0001), mean TG levels by 20% (pravastatin: -6.8%, p<0.0009), and mean apo B by 39.1% (pravastatin: -22.0%, p<0.0001). Atorvastatin increased mean HDL-C by 2.9% (pravastatin: + 5.6%, p=NS). There was a 36.4% mean reduction in C-reactive protein (CRP) in the atorvastatin group compared to a 5.2% reduction in the pravastatin group (p <0.0001).
The safety and tolerability profiles of the two treatment groups were comparable.
Recurrent Stoke: In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study, the effect of atorvastatin 80 mg daily or placebo on stroke was evaluated in 4731 patients who had a stroke or TIA within the preceding 6 months and no history of CHD. Patients were 60% male, 21 to 92 years of age (mean age 63 years), and had an average baseline LDL of 133 mg/dL (3.4 mmol/L). The mean LDL-C was 73 mg/dL (1.9 mmol/L) during treatment with atorvastatin and 129 mg/dL (3.3 mmol/L) during treatment with placebo. Median follow-up was 4.9 years.
Atorvastatin 80 mg reduced the risk of the primary endpoint of fatal or non-fatal stroke by 15% (hazard ratio [HR] 0.85; 95% CI, 0.72-1.00; p = 0.05 or HR 0.84; 95% CI, 0.71-0.99; p = 0.03 after adjustment for baseline factors) compared to placebo. Atorvastatin 80 mg significantly reduced the risk of major coronary events (HR 0.67; 95% CI, 0.51-0.89; p = 0.006), any CHD event (HR 0.60; 95% CI, 0.48-0.74; p <0.001), and revascularization procedures (HR 0.57; 95% CI, 0.44-0.74; p <0.001).
In a post-hoc analysis, atorvastatin 80 mg reduced the incidence of ischemic stroke (218/2365, 9.2% vs. 274/2366, 11.6%, p = 0.01) and increased the incidence of hemorrhagic stroke (55/2365, 2.3% vs. 33/2366, 1.4%, p = 0.02) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 atorvastatin vs. 18 placebo). Reduction in the risk of CV events with atorvastatin 80 mg was demonstrated in all patient groups except in patients who entered the study with a hemorrhagic stroke and had a recurrent hemorrhagic stroke (7 atorvastatin vs. 2 placebo).
In patients treated with atorvastatin 80 mg, there were fewer strokes of any type (265 atorvastatin vs. 311 placebo) and fewer CHD events (123 atorvastatin vs. 204 placebo). Overall mortality was similar across treatment groups (216 atorvastatin vs. 211 placebo). The overall incidence of adverse events and serious adverse events was similar between treatment groups.
Secondary Prevention of Cardiovascular Events: In the Treating to New Targets Study (TNT), the effect of atorvastatin 80 mg/day vs. atorvastatin 10 mg/day on the reduction in CV events was assessed in 10,001 subjects (94% white, 81% male, 38% ≥65 years) with clinically evident CHD who had achieved a target LDL-C level <130 mg/dL after completing an 8-week, open-label, run-in period with atorvastatin 10 mg/day. Subjects were randomly assigned to either 10 mg/day or 80 mg/day of atorvastatin and followed for a median duration of 4.9 years. The mean LDL-C, total C, TG, non-HDL and HDL cholesterol levels at 12 weeks were 73 mg/dL, 145 mg/dL, 128 mg/dL, 98 mg/dL and 47 mg/dL respectively, during treatment with 80 mg atorvastatin and 99 mg/dL, 177 mg/dL, 152 mg/dL, 129 mg/dL and 48 mg/dL respectively, during treatment with 10 mg atorvastatin.
Treatment with atorvastatin 80 mg/day significantly reduced the rate of major cardiovascular events (MCVE) (434 events in the 80 mg/day group vs. 548 events in the 10 mg/day group) with a relative risk reduction of 22%.
Atorvastatin 80 mg significantly reduced the risk of the following: See Table 3.
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There was no significant difference between the treatment groups for all-cause mortality: 282 (5.6%) in the atorvastatin 10 mg/day group vs. 284 (5.7%) in the atorvastatin 80 mg/day group. The proportions of subjects who experienced CV death, including the components of CHD death and fatal stroke were numerically smaller in the atorvastatin 80 mg group than in the atorvastatin 10 mg treatment group. The proportions of subjects who experienced non-CV death were numerically larger in the atorvastatin 80 mg group than in the atorvastatin 10 mg treatment group.
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 mg/day to 40 mg/day in 8888 subjects up to 80 years of age with a history of CHD to assess whether reduction in CV risk could be achieved. Patients were mainly male (81%), white (99%) with an average age of 61.7 years, and an average LDL-C of 121.5 mg/dL at randomization; 76% were on statin therapy. In this prospective, randomized, open-label, blinded endpoint (PROBE) trial with no run-in period, subjects were followed for a median duration of 4.8 years. The mean LDL-C, total C, TG, HDL and non-HDL C levels at Week 12 were 78 mg/dL, 145 mg/dL, 115 mg/dL, 45 mg/dL and 100 mg/dL respectively during treatment with 80 mg atorvastatin and 105 mg/dL, 179 mg/dL, 142 mg/dL, 47 mg/dL and 132 mg/dL respectively during treatment with 20 mg to 40 mg of simvastatin.
There was no significant difference between the treatment groups for the primary endpoint; the rate of first major coronary event (fatal CHD, non-fatal MI and resuscitated cardiac arrest): 411 (9.3%) in the atorvastatin 80 mg/day group vs. 463 (10.4%) in the simvastatin 20 mg/day to 40 mg/day group, HR 0.89, 95% CI (0.78-1.01), p=0.07.
There were no significant differences between the treatment groups for all-cause mortality: 366 (8.2%) in the atorvastatin 80 mg/day group vs. 374 (8.4%) in the simvastatin 20 mg/day to 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 mg to 40 mg group.
Heterozygous Familial Hypercholesterolemia in Pediatric Patients: In a double-blind, placebo-controlled study followed by an open-label phase, 187 boys and post-menarchal girls 10 to 17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia or severe hypercholesterolemia were randomized to atorvastatin (n = 140) or placebo (n = 47) for 26 weeks and then all received atorvastatin for 26 weeks. Inclusion in the study required 1) a baseline LDL-C level ≥190 mg/dL or 2) a baseline LDL-C ≥ 160 mg/dL and positive family history of familial hypercholesterolemia or documented premature CVD in a first- or second-degree relative. The mean baseline LDL-C value was 218.6 mg/dL (range: 138.5-385.0 mg/dL) in the atorvastatin group compared to 230.0 mg/dL (range: 160.0-324.5 mg/dL) in the placebo group. The dosage of atorvastatin (once daily) was 10 mg for the first 4 weeks and up-titrated to 20 mg if the LDL-C level was >130 mg/dL. The number of atorvastatin-treated patients who required up-titration to 20 mg after Week 4 during the double-blind phase was 78 (55.7%).
Atorvastatin significantly decreased plasma levels of total-C, LDL-C, TG, and apo B during the 26-week double-blind phase (see Table 4).
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The mean achieved LDL-C value was 130.7 mg/dL (range: 70.0-242.0 mg/dL) in the atorvastatin group compared to 228.5 mg/dL (range: 152.0-385.0 mg/dL) in the placebo group during the 26-week double-blind phase.
In this limited controlled study, there was no detectable effect on growth or sexual maturation in boys or on menstrual cycle length in girls. Atorvastatin has not been studied in controlled clinical trials involving pre-pubertal patients or patients younger than 10 years of age. The safety and efficacy of doses above 20 mg have not been studied in controlled trials in children. The long-term efficacy of atorvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.
Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. The extent of absorption and plasma atorvastatin concentrations increases in proportion to atorvastatin dose. Atorvastatin tablets are 95% to 99% bioavailable compared to solutions. The absolute bioavailability of atorvastatin is approximately 14% 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. Although food decreases the rate and extent of drug absorption by approximately 25% and 9% respectively, as assessed by Cmax
and AUC, LDL-C reduction is similar whether atorvastatin is given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax
and AUC) following evening drug administration compared to morning. However, LDL-C reduction is the same regardless of the time of day for drug administration (see Dosage & Administration).
Mean volume of distribution of atorvastatin is approximately 381 Liters. Atorvastatin is ≥98% bound to plasma proteins. A red blood cell/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells.
Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. 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. In vitro
studies suggest the importance of atorvastatin metabolism by hepatic CYP 3A4, consistent with increased plasma concentrations of atorvastatin in humans following co-administration with erythromycin, a known inhibitor of this isozyme. In vitro
studies also indicate that atorvastatin is a weak inhibitor of CYP 3A4. Atorvastatin coadministration did not produce a clinically significant effect in plasma concentrations of terfenadine, a compound predominantly metabolized by CYP 3A4; therefore, it is unlikely that atorvastatin will significantly alter the pharmacokinetics of other CYP 3A4 substrates (see Interactions). In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.
Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extrahepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration.
Elderly: Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax
and 30% for AUC) in healthy, elderly subjects (aged ≥65 years) than in young adults. The ACCESS study specifically evaluated elderly patients with respect to reaching their National Cholesterol Education Program (NCEP) treatment goals. The study included 1087 patients under 65 years of age, 815 patients over 65 years of age, and 185 patients over 75 years of age. No differences in safety, efficacy or lipid treatment goal attainment were observed between elderly patients and the overall population.
Children: Pharmacokinetic studies have not been conducted in the pediatric population.
Gender: Plasma concentrations of atorvastatin in women differ (approximately 20% higher for Cmax
and 10% lower for AUC) from those in men. However, there were no clinically significant differences in lipid effects between men and women.
Renal Insufficiency: Renal disease has no influence on the plasma concentrations or lipid effects of atorvastatin. Thus, dose adjustment in patients with renal dysfunction is not necessary (see Dosage & Administration).
Hemodialysis: 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.
Hepatic Insufficiency: Plasma concentrations of atorvastatin are markedly increased (approximately 16-fold in Cmax
and 11-fold in AUC) in patients with chronic alcoholic liver disease (Childs-Pugh Class B) (see Contraindications).
Drug Interactions: The effect of co-administered drugs on the pharmacokinetics of atorvastatin as well as the effect of atorvastatin on the pharmacokinetics of co-administered drugs are summarized below (see Precautions and Interactions). (See Tables 5 and 6.)
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Toxicology: Preclinical Safety Data:
Carcinogenesis, Mutagenesis, Impairment of Fertility: Atorvastatin was not carcinogenic in rats. The maximum dose used was 63-fold higher than the highest human dose (80 mg/day) on a mg/kg body-weight basis and 8 to 16-fold higher based on AUC (0-24) values. In a 2-year study in mice, the incidences of hepatocellular adenomas in males and hepatocellular carcinomas in females were increased at the maximum dose used, which was 250-fold higher than the highest human dose, on a mg/kg body-weight basis. Systemic exposure was 6- to 11-fold higher based on AUC (0-24).
All other chemically similar drugs in this class have induced tumors in both mice and rats at multiples of 12 to 125 times their highest recommended clinical doses, on a mg/kg body weight basis.
Atorvastatin did not demonstrate mutagenic or clastogenic potential in four in vitro
tests with and without metabolic activation or in one in vivo
assay. It was negative in the Ames test with Salmonella typhimurium
and Escherichia coli
, and in the in vitro
hypoxanthine-guanine phosphoribosyltranferase (HGPRT) forward mutation assay in Chinese hamster lung cells. Atorvastatin did not produce significant increases in chromosomal aberrations in the in vitro
Chinese hamster lung cell assay and was negative in the in vivo
mouse micronucleus test.
No adverse effects on fertility or reproduction were observed in male rats given doses of atorvastatin up to 175 mg/kg/day or in female rats given doses up to 225 mg/kg/day. These doses are 100 to 140 times the maximum recommended human dose on a mg/kg basis. Atorvastatin caused no adverse effects on sperm or semen parameters, or on reproductive organ histopathology in dogs given doses of 10 mg/kg, 40 mg/kg, or 120 mg/kg for 2 years.