These highlights do not include all the information needed to use ATORVASTATIN CALCIUM safely and effectively. See full prescribing information for ATORVASTATIN CALCIUM. ATORVASTATIN CALCIUM (ATORVASTATIN CALCIUM)

Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Cholesterol and triglycerides circulate in the bloodstream as part of lipoprotein complexes. With ultracentrifugation, these complexes separate into HDL (high-density lipoprotein), IDL (intermediate-density lipoprotein), LDL (low-density lipoprotein), and VLDL (very-low-density lipoprotein) fractions. Triglycerides (TG) and cholesterol in the liver are incorporated into VLDL and released into the plasma for delivery to peripheral tissues. LDL is formed from VLDL and is catabolized primarily through the high-affinity LDL receptor. Clinical and pathologic studies show that elevated plasma levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), and apolipoprotein B (apo B) promote human atherosclerosis and are risk factors for developing cardiovascular disease, while increased levels of HDL-C are associated with a decreased cardiovascular risk.

In animal models, atorvastatin calcium 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 calcium also reduces LDL production and the number of LDL particles. Atorvastatin calcium reduces LDL-C in some patients with homozygous familial hypercholesterolemia (FH), a population that rarely responds to other lipid-lowering medication(s).

A variety of clinical studies have demonstrated that elevated levels of total-C, LDL-C, and apo B (a membrane complex for LDL-C) promote human atherosclerosis. Similarly, decreased levels of HDL-C (and its transport complex, apo A) are associated with the development of atherosclerosis. Epidemiologic investigations have 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.

Atorvastatin calcium reduces total-C, LDL-C, and apo B in patients with homozygous and heterozygous FH, nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia. Atorvastatin calcium also reduces VLDL-C and TG and produces variable increases in HDL-C and apolipoprotein A-1. Atorvastatin calcium reduces total-C, LDL-C, VLDL-C, apo B, TG, and non-HDL-C, and increases HDL-C in patients with isolated hypertriglyceridemia. Atorvastatin calcium reduces intermediate density lipoprotein cholesterol (IDL-C) in patients with dysbetalipoproteinemia.

Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate density lipoprotein (IDL), and remnants, can also promote atherosclerosis. Elevated plasma triglycerides are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease. As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

Atorvastatin, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response [see Dosage and Administration (2)].

Absorption

Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute bioavailability of atorvastatin (parent drug) 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 C_max and AUC, LDL-C reduction is similar whether atorvastatin is given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for C_max and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration [see Dosage and Administration (2)].

Distribution

Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is ≥98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, atorvastatin is likely to be secreted in human milk [see Contraindications, Nursing Mothers (4.4) and Use in Specific Populations, Nursing Mothers (8.3)].

Metabolism

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 cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following co-administration with erythromycin, a known inhibitor of this isozyme [see Drug Interactions (7.1)]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.

Excretion

Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic 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.

Specific Populations 

Geriatric

Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age ≥65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of drug in the elderly patient population compared to younger adults [see Use in Specific Populations, Geriatric Use (8.5)].

Pediatric

Pharmacokinetic data in the pediatric population are not available.

Gender

Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for Cmax and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin between men and women.

Renal Impairment

Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin; thus, dose adjustment in patients with renal dysfunction is not necessary [see Dosage and Administration, Dosage in Patients with Renal Impairment (2.5), Warnings and Precautions, Skeletal Muscle (5.1)].

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 Impairment

In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease [see Contraindications (4.1)].

TABLE 3. Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin

Co-administered drug and dosing regimen	Atorvastatin
	Dose (mg)	Change in AUC &	Change in C max &
& Data given as x-fold change represent a simple ratio between co-administration and atorvastatin alone (i.e., 1-fold = no change). Data given as % change represent % difference relative to atorvastatin alone (i.e., 0% = no change).
# See Sections 5.1 and 7 for clinical significance.
* Greater increases in AUC (up to 2.5 fold) and/or Cmax (up to 71%) have been reported with excessive grapefruit consumption (≥ 750 mL to 1.2 liters per day).
** Single sample taken 8 to 16 h post dose.
† Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.
‡ The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used.
#Cyclosporine 5.2 mg/kg/day, stable dose	10 mg QD for 28 days	↑ 8.7 fold	↑10.7 fold
#Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days	10 mg, SD	↑ 9.4 fold	↑ 8.6 fold
#Telaprevir 750 mg q8h, 10 days	20 mg, SD	↑ 7.88 fold	↑ 10.6 fold
#, ‡Saquinavir 400 mg BID/ ritonavir 400mg BID, 15 days	40 mg QD for 4 days	↑ 3.9 fold	↑ 4.3 fold
#Clarithromycin 500 mg BID, 9 days	80 mg QD for 8 days	↑ 4.4 fold	↑ 5.4 fold
#Darunavir 300 mg BID/ritonavir 100 mg BID, 9 days	10 mg QD for 4 days	↑ 3.4 fold	↑ 2.25 fold
#Itraconazole 200 mg QD, 4 days	40 mg SD	↑ 3.3 fold	↑ 20%
#Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days	10 mg QD for 4 days	↑ 2.53 fold	↑ 2.84 fold
#Fosamprenavir 1400 mg BID, 14 days	10 mg QD for 4 days	↑ 2.3 fold	↑ 4.04 fold
#Nelfinavir 1250 mg BID, 14 days	10 mg QD for 28 days	↑ 74%	↑ 2.2 fold
#Grapefruit Juice, 240 mL QD *	40 mg, SD	↑ 37%	↑ 16%
Diltiazem 240 mg QD, 28 days	40 mg, SD	↑ 51%	No change
Erythromycin 500 mg QID, 7 days	10 mg, SD	↑ 33%	↑ 38%
Amlodipine 10 mg, single dose	80 mg, SD	↑ 15%	↓ 12 %
Cimetidine 300 mg QD, 4 weeks	10 mg QD for 2 weeks	↓ Less than 1%	↓ 11%
Colestipol 10 mg BID, 28 weeks	40 mg QD for 28 weeks	Not determined	↓ 26%**
Maalox TC® 30 mL QD, 17 days	10 mg QD for 15 days	↓ 33%	↓ 34%
Efavirenz 600 mg QD, 14 days	10 mg for 3 days	↓ 41%	↓ 1%
#Rifampin 600 mg QD, 7 days (coadministered) †	40 mg SD	↑ 30%	↑ 2.7 fold
#Rifampin 600 mg QD, 5 days (doses separated) †	40 mg SD	↓ 80%	↓ 40%
#Gemfibrozil 600mg BID, 7 days	40mg SD	↑ 35%	↓ Less than 1%
#Fenofibrate 160mg QD, 7 days	40mg SD	↑ 3%	↑ 2%

TABLE 4. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs

Atorvastatin	Co-administered drug and dosing regimen
	Drug/Dose (mg)	Change in AUC	Change in C max
# See Section 7 for clinical significance.
80 mg QD for 15 days	Antipyrine, 600 mg SD	↑ 3%	↓ 11%
80 mg QD for 14 days	#Digoxin 0.25 mg QD, 20 days	↑ 15%	↑ 20 %
40 mg QD for 22 days	Oral contraceptive QD, 2 months
- norethindrone 1mg	↑ 28%	↑ 23%
- ethinyl estradiol 35mcg	↑ 19%	↑ 30%
10 mg, SD	Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days	No change	No change
10 mg QD for 4 days	Fosamprenavir 1400 mg BID, 14 days	↓ 27%	↓ 18%
10 mg QD for 4 days	Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days	No change	No change

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 AUC (0 to 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 AUC (0 to 24) values of approximately 6 times the mean human plasma drug exposure after an 80 mg oral dose.

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.

Studies in 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.