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TABLETS safely and effectively. See full prescribing information for ATORVASTATIN CALCIUM TABLETS ATORVASTATIN CALCIUM tablets, for oral use Initial U.S. Approval: 1996 · NuCare Pharmaceuticals,Inc.

Dosage Form

TABLETS safely and effectively. See full prescribing information for ATORVASTATIN CALCIUM TABLETS ATORVASTATIN CALCIUM tablets, for oral use Initial U.S. Approval: 1996

Manufacturer

NuCare Pharmaceuticals,Inc.

Important Safety Information

This medication contains important usage instructions, warnings, and side effect information that you should review before use.

Full label on DailyMed PDF Full label (ZIP)

Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is recommended as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. In patients with CHD or multiple risk factors for CHD, atorvastatin calcium tablets can be started simultaneously with diet.

Risk Summary

Atorvastatin calcium is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit of lipid lowering drugs during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, atorvastatin calcium may cause fetal harm when administered to a pregnant woman. Atorvastatin calcium should be discontinued as soon as pregnancy is recognized [see Contraindications ( 4)]. Limited published data on the use of atorvastatin are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies in rats and rabbits there was no evidence of embryo-fetal toxicity or congenital malformations at doses up to 30 and 20 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg, based on body surface area (mg/m ²). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development was observed at doses ≥ 6 times the MRHD (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Human Data:

Limited published data on atorvastatin calcium from observational studies, meta-analyses and case reports have not shown an increased risk of major congenital malformations or miscarriage. Rare reports of congenital anomalies have been received following intrauterine exposure to other HMG-CoA reductase inhibitors. In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude a ≥ 3 to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.

Animal Data:

Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. Atorvastatin was administered to pregnant rats and rabbits during organogenesis at oral doses up to 300 mg/kg/day and 100 mg/kg/day, respectively. 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 at the MRHD based on surface area (mg/m ²). In rats, the maternally toxic dose of 300 mg/kg resulted in increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 and 100 mg/kg/day in rabbits, there was increased post-implantation loss, and at 100 mg/kg/day fetal body weights were decreased.

In a study in pregnant rats administered 20, 100, or 225 mg/kg/day from gestation day 7 through to lactation day 20 (weaning), there was decreased survival at birth, postnatal day 4, weaning, and post-weaning in pups of mothers dosed with 225 mg/kg/day, a dose at which maternal toxicity was observed. Pup body weight was decreased through postnatal day 21 at 100 mg/kg/day, and through postnatal day 91 at 225 mg/kg/day. Pup development was delayed (rotarod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225 mg/kg/day). These doses correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human exposure at the MRHD, based on AUC.

Heterozygous Familial Hypercholesterolemia (HeFH)

The safety and effectiveness of atorvastatin calcium have been established in pediatric patients, 10 years to 17 years of age, with HeFH as an adjunct to diet to reduce total cholesterol, LDL-C, and apo B levels when, after an adequate trial of diet therapy, the following are present:

LDL-C ≥ 190 mg/dL, or
LDL-C ≥ 160 mg/dL and
- a positive family history of FH, or premature CVD in a first, or second-degree relative, or
- two or more other CVD risk factors are present.

Use of atorvastatin calcium for this indication is supported by evidence from [see Dosage and Administration ( 2.2), Adverse Reactions ( 6.1), Clinical Pharmacology ( 12.3), and Clinical Studies ( 14.6)]:

A placebo-controlled clinical trial of 6 months duration in 187 boys and postmenarchal girls, 10 years to 17 years of age. Patients treated with 10 mg or 20 mg daily atorvastatin calcium had an adverse reaction profile generally similar to that of patients treated with placebo. In this limited controlled study, there was no significant effect on growth or sexual maturation in boys or on menstrual cycle length in girls.
A three year open-label uncontrolled trial that included 163 pediatric patients 10 to 15 years of age with HeFH who were titrated to achieve a target LDL-C < 130 mg/dL. The safety and efficacy of atorvastatin calcium in lowering LDL-C appeared generally consistent with that observed for adult patients, despite limitations of the uncontrolled study design

Advise postmenarchal girls of contraception recommendations, if appropriate for the patient [see Use in Specific Populations ( 8.1), ( 8.3)].

The long-term efficacy of atorvastatin calcium therapy initiated in childhood to reduce morbidity and mortality in adulthood has not been established.

The safety and efficacy of atorvastatin calcium have not been established in pediatric patients younger than 10 years of age with HeFH.

Homozygous Familial Hypercholesterolemia (HoFH)

Clinical efficacy of atorvastatin calcium with dosages up to 80 mg/day for 1 year was evaluated in an uncontrolled study of patients with HoFH including 8 pediatric patients [see Clinical Studies ( 14.5)].

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Package codes (NDC)

68071-2439-9

Full prescribing information (for healthcare professionals)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Atorvastatin calcium 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. 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.

12.2 Pharmacodynamics

Atorvastatin calcium, 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) ].

12.3 Pharmacokinetics

Absorption

Atorvastatin calcium is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin calcium 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 Cmax and AUC, LDL-C reduction is similar whether atorvastatin calcium is given with or without food. Plasma atorvastatin calcium concentrations are lower (approximately 30% for Cmax 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 calcium is approximately 381 liters. Atorvastatin calcium 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 calcium is likely to be secreted in human milk [see Contraindications ( 4) and Use in Specific Populations ( 8.2) ].

Metabolism

Atorvastatin calcium 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 calcium. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin calcium metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin calcium 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 calcium 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 calcium 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 calcium is recovered in urine following oral administration.

Specific Populations

Geriatric: Plasma concentrations of atorvastatin calcium 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 ( 8.5) ].

Pediatric: 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.

Gender: Plasma concentrations of atorvastatin calcium 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 calcium between men and women.

Renal Impairment: Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin calcium; thus, dose adjustment in patients with renal dysfunction is not necessary [see Dosage and Administration ( 2.5 ) and Warnings and Precautions ( 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 calcium since the drug is extensively bound to plasma proteins.

Hepatic Impairment: In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin calcium 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) ].

Drug Interaction Studies: 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 transporter BCRP, which may limit the intestinal absorption and biliary clearance of atorvastatin.

Table 6: Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin

^& Represents ratio of treatments (co-administered drug plus atorvastatin vs. atorvastatin alone).
^# See Sections 5.1 and 7 for clinical significance.
^* Greater increases in AUC (ratio of AUC up to 2.5) and/or Cmax (ratio of Cmax up to 1.71) have been reported with excessive grapefruit consumption (≥ 750 mL to 1.2 liters per day).
^** Ratio based on a 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.
a Once daily
b Twice daily
c Single dose
d Three times daily
e Four times daily
f Every 8 hours
Co-administered drug and dosing regimen	Atorvastatin
Dose (mg)	Ratio of AUC ^&	Ratio of Cmax ^&
^#Cyclosporine 5.2 mg/kg/day, stable dose	10 mg QD ^a for 28 days	8.69	10.66
^#Tipranavir 500 mg BID ^b/ritonavir 200 mg BID ^b, 7 days	10 mg, SD ^c	9.36	8.58
^#Glecaprevir 400 mg QD ^a/pibrentasvir 120 mg QD ^a, 7 days	10 mg QD ^a for 7 days	8.28	22.00
^#Telaprevir 750 mg q8h ^f, 10 days	20 mg, SD ^c	7.88	10.60
^#,‡Saquinavir 400 mg BID ^b/ ritonavir 400 mg BID ^b, 15 days	40 mg QD ^a for 4 days	3.93	4.31
^#Elbasvir 50 mg QD ^a/grazoprevir 200 mg QD ^a, 13 days	10 mg SD ^c	1.94	4.34
^#Simeprevir 150 mg QD ^a , 10 days	40 mg SD ^c	2.12	1.70
^#Clarithromycin 500 mg BID ^b, 9 days	80 mg QD ^a for 8 days	4.54	5.38
^#Darunavir 300 mg BID ^b/ritonavir 100 mg BID ^b, 9 days	10 mg QD ^a for 4 days	3.45	2.25
^#Itraconazole 200 mg QD ^a, 4 days	40 mg SD ^c	3.32	1.20
#Letermovir 480 mg QD ^a, 10 days	20 mg SD ^c	3.29	2.17
^#Fosamprenavir 700 mg BID ^b/ritonavir 100 mg BID ^b, 14 days	10 mg QD ^a for 4 days	2.53	2.84
^#Fosamprenavir 1400 mg BID ^b, 14 days	10 mg QD ^a for 4 days	2.30	4.04
^#Nelfinavir 1250 mg BID ^b, 14 days	10 mg QD ^a for 28 days	1.74	2.22
^#Grapefruit Juice, 240 mL QD ^a,*	40 mg, SD ^c	1.37	1.16
Diltiazem 240 mg QD ^a, 28 days	40 mg, SD ^c	1.51	1.00
Erythromycin 500 mg QID ^e, 7 days	10 mg, SD ^c	1.33	1.38
Amlodipine 10 mg, single dose	80 mg, SD ^c	1.18	0.91
Cimetidine 300 mg QID ^e, 2 weeks	10 mg QD ^a for 2 weeks	1.00	0.89
Colestipol 10 g BID ^b, 24 weeks	40 mg QD ^a for 8 weeks	NA	0.74**
Maalox TC ^® 30 mL QID ^e, 17 days	10 mg QD ^a for 15 days	0.66	0.67
Efavirenz 600 mg QD ^a, 14 days	10 mg for 3 days	0.59	1.01
^#Rifampin 600 mg QD ^a, 7 days (co-administered) ^†	40 mg SD ^c	1.12	2.90
^#Rifampin 600 mg QD ^a, 5 days (doses separated) ^†	40 mg SD ^c	0.20	0.60
^#Gemfibrozil 600 mg BID ^b, 7 days	40 mg SD ^c	1.35	1.00
^#Fenofibrate 160 mg QD ^a, 7 days	40 mg SD ^c	1.03	1.02
Boceprevir 800 mg TID ^d, 7 days	40 mg SD ^c	2.32	2.66

Table 7: Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs

^# See Section 7 for clinical significance.
^a Once daily
^b Twice daily
^c Single dose
Atorvastatin	Co-administered drug and dosing regimen
	Drug/Dose (mg)	Ratio of AUC	Ratio of Cmax
80 mg QD ^a for 15 days	Antipyrine, 600 mg SD ^c	1.03	0.89
80 mg QD ^a for 10 days	^#Digoxin 0.25 mg QD ^a, 20 days	1.15	1.20
40 mg QD ^a for 22 days	Oral contraceptive QD ^a, 2 months - norethindrone 1mg - ethinyl estradiol 35 mcg	1.28 1.19	1.23 1.30
10 mg, SD ^c	Tipranavir 500 mg BID ^b/ritonavir 200 mg BID ^b, 7 days	1.08	0.96
10 mg QD ^a for 4 days	Fosamprenavir 1400 mg BID ^b, 14 days	0.73	0.82
10 mg QD ^a for 4 days	Fosamprenavir 700 mg BID ^b/ritonavir 100 mg BID ^b, 14 days	0.99	0.94

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

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.

14 CLINICAL STUDIES

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Tablet Strength	Identifying Features
10 mg of atorvastatin	"LU" on one side and "A16" on the other
20 mg of atorvastatin	"LU" on one side and "A17" on the other
40 mg of atorvastatin	"LU" on one side and "A18" on the other
80 mg of atorvastatin	"LU" on one side and "A19" on the other

Important Safety Information

What this medicine is forThe uses this medicine is approved for.

How to take itDosage and administration instructions.

Available doses and formsAtorvastatin calcium tablets, USP are white to off white, elliptical, film-coated, and are available in four strengths (see Table 1). Table 1: Atorvastatin Calcium Tablet, USP Strengths and Identifying Features Tablet St…

Do not use if…Contraindications.Active Liver Disease, Which May Include Unexplained Persistent Elevations in Hepatic Transaminase Levels Hypersensitivity to Any Component of This Medication Pregnancy [see Use in Specific Population s ( 8.1, 8.3)]. Lact…

Drug interactions

Important warnings and precautions

Possible side effectsThe following serious adverse reactions are discussed in greater detail in other sections of the label: Myopathy and Rhabdomyolysis [see Warnings and Precautions ( 5.1) ] Liver enzyme abnormalities [see Warnings and Prec…

Use during pregnancyRisk Summary Atorvastatin calcium is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit of lipid lowering drugs during pregnancy. Because HM…

Use in childrenHeterozygous Familial Hypercholesterolemia (HeFH) The safety and effectiveness of atorvastatin calcium have been established in pediatric patients, 10 years to 17 years of age, with HeFH as an adjunct to diet to reduce t…

Use in older adultsOf the 39,828 patients who received atorvastatin calcium in clinical studies, 15,813 (40%) were ≥65 years old and 2,800 (7%) were ≥75 years old. No overall differences in safety or effectiveness were observed between the…

Use in specific groups

If you take too much (overdose)There is no specific treatment for atorvastatin calcium overdosage. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required. Due to extensive drug bindin…

Patient informationAdvise the patient to read the FDA-approved patient labeling (Patient Information). Patients taking atorvastatin calcium should be advised that cholesterol is a chronic condition and they should adhere to their medicatio…

What's in this medicineAtorvastatin calcium is a synthetic lipid-lowering agent. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early…

Package label

How it's supplied40 mg tablets (40 mg of atorvastatin): white to off white, elliptical, film coated tablets debossed with "LU" on one side and "A18" on the other side. NDC 68071-2439-9 BOTTLES OF 90 Storage Store at 25°C (77°F); excursio…