Atorvastatin Calcium: Package Insert and Label Information (Page 3 of 7)

7.2 Grapefruit Juice

Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (>1.2 liters per day).

7.3 Cyclosporine

Atorvastatin is a substrate of the hepatic transporters. Atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability of atorvastatin. Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day compared to that of atorvastatin alone [see Clinical Pharmacology (12.3)].

The co-administration of atorvastatin with cyclosporine should be avoided [see Warnings and Precautions (5.1)].

7.4 Glecaprevir and Pibrentasvir, Elbasvir and Grazoprevir

Concomitant administration of glecaprevir and pibrentasvir or elbasvir and grazoprevir may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy.

Coadministration of glecaprevir and pibrentasvir with atorvastatin increase plasma concentrations of atorvastatin by 8.3-fold due in part to BCRP, OATP1B1/1B3, and CYP3A inhibition; therefore, coadministration of atorvastatin in patients receiving concomitant medications with products containing glecaprevir and pibrentasvir is not recommended.

Coadministration of elbasvir and grazoprevir with atorvastatin increase plasma concentrations of atorvastatin by 1.9-fold due in part to BCRP, OATP1B1/1B3, and CYP3A inhibition; therefore, the dose of atorvastatin should not exceed 20 mg daily in patients receiving concomitant medications with products containing elbasvir and grazoprevir [see Dosage and Administration (2.6), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

7.5 Gemfibrozil

Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are co-administered with gemfibrozil, concomitant administration of atorvastatin with gemfibrozil should be avoided [see Warnings and Precautions (5.1)].

7.6 Other Fibrates

Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, atorvastatin should be administered with caution when used concomitantly with other fibrates [see Warnings and Precautions (5.1)].

7.7 Niacin

The risk of skeletal muscle effects may be enhanced when atorvastatin is used in combination with niacin; a reduction in atorvastatin dosage should be considered in this setting [see Warnings and Precautions (5.1)].

7.8 Rifampin or other Inducers of Cytochrome P450 3A4

Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (e.g., efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin. 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.

7.9 Digoxin

When multiple doses of atorvastatin and digoxin were co-administered, steady state plasma digoxin concentrations increased [see Clinical Pharmacology (12.3)]. Patients taking digoxin should be monitored appropriately.

7.10 Oral Contraceptives

Co-administration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol [see Clinical Pharmacology (12.3)]. These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin.

7.11 Warfarin

Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.

7.12 Colchicine

Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine.


8.1 Pregnancy

Risk Summary

Atorvastatin 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 may cause fetal harm when administered to a pregnant woman. Atorvastatin 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/m2). 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.


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/m2). 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 (rotorod 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.

8.2 Lactation

Risk Summary

Atorvastatin use is contraindicated during breastfeeding [see Contraindications (4)]. There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. It is not known whether atorvastatin is present in human milk, but it has been shown that another drug in this class passes into human milk and atorvastatin is present in rat milk. Because of the potential for serious adverse reactions in a breastfed infant, advise women that breastfeeding is not recommended during treatment with atorvastatin.

8.3 Females and Males of Reproductive Potential


Atorvastatin may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with atorvastatin [see Use in Specific Populations (8.1)].

8.4 Pediatric Use

Heterozygous Familial Hypercholesterolemia (HeFH)

The safety and effectiveness of atorvastatin 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 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 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.

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 therapy initiated in childhood to reduce morbidity and mortality in adulthood has not been established.

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

Additional pediatric use information is approved for Pfizer’s LIPITOR (atorvastatin calcium) tablets. However, due to Pfizer’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Homozygous Familial Hypercholesterolemia (HoFH)

Clinical efficacy of atorvastatin 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)].

8.5 Geriatric Use

Of the 39,828 patients who received atorvastatin 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 these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older adults cannot be ruled out. Since advanced age (≥65 years) is a predisposing factor for myopathy, atorvastatin should be prescribed with caution in the elderly.

8.6 Hepatic Impairment

Atorvastatin is contraindicated in patients with active liver disease which may include unexplained persistent elevations in hepatic transaminase levels [see Contraindications (4) and Clinical Pharmacology (12.3)].


There is no specific treatment for atorvastatin overdosage. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin clearance.


Atorvastatin 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 and rate-limiting step in cholesterol biosynthesis.

Atorvastatin calcium, USP is [R-(R*, R*)]-2-(4-fluorophenyl)-ß,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-Pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. The molecular formula of atorvastatin calcium is (C33 H34 FN2 O5 )2 Ca•3H2 O and its molecular weight is 1209.42. Its structural formula is:

(click image for full-size original)

Atorvastatin calcium USP is a white to off-white crystalline powder that is insoluble in aqueous solutions of pH 4 and below. Atorvastatin calcium is very slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile; slightly soluble in ethanol; and freely soluble in methanol.

Atorvastatin Calcium Tablets, USP for oral administration contain 10 mg, 20 mg, 40 mg, or 80 mg atorvastatin and the following inactive ingredients: calcium carbonate, croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, Opadry White YS-1-7040 (hypromellose, polyethylene glycol, talc, titanium dioxide) and polysorbate 80.

FDA approved dissolution test specifications differ from USP.


12.1 Mechanism of Action

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. 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.

12.2 Pharmacodynamics

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)].

12.3 Pharmacokinetics

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 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 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 (4) and Use in Specific Populations, (8.2)].

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 is 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 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 (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 since the drug is extensively bound to plasma proteins.

Hepatic Impairment: In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin is 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 4: 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.
Once daily
Twice daily
Single dose
Every 8 hours
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.
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).
Four times daily
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.
Three times daily
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 for 28 days 8.69 10.66
Tipranavir 500 mg BID §/ritonavir 200 mg BID §, 7 days 10 mg, SD 9.36 8.58
Glecaprevir 400 mg QD /pibrentasvir 120 mg QD , 7 days 10 mg, QD for 7 days 8.28 22.00
Telaprevir 750 mg q8h #, 10 days 20 mg, SD 7.88 10.60
, ÞSaquinavir 400 mg BID §/ ritonavir 400 mg BID §, 15 days 40 mg QD for 4 days 3.93 4.31
Elbasvir 50 mg QD /grazoprevir 200 mg QD , 13 days 10 mg SD 1.94 4.34
Simeprevir 150 mg QD , 10 days 40 mg SD 2.12 1.70
Clarithromycin 500 mg BID §, 9 days 80 mg QD for 8 days 4.54 5.38
Darunavir 300 mg BID §/ritonavir 100 mg BID §, 9 days 10 mg QD for 4 days 3.45 2.25
Itraconazole 200 mg QD , 4 days 40 mg SD 3.32 1.20
Fosamprenavir 700 mg BID §/ritonavir 100 mg BID §, 14 days 10 mg QD for 4 days 2.53 2.84
Fosamprenavir 1,400 mg BID §, 14 days 10 mg QD for 4 days 2.30 4.04
Nelfinavir 1,250 mg BID §, 14 days 10 mg QD for 28 days 1.74 2.22
Grapefruit Juice, 240 mL QD ,ß 40 mg, SD 1.37 1.16
Diltiazem 240 mg QD , 28 days 40 mg, SD 1.51 1.00
Erythromycin 500 mg QID à, 7 days 10 mg, SD 1.33 1.38
Amlodipine 10 mg, single dose 80 mg, SD 1.18 0.91
Cimetidine 300 mg QID à, 2 weeks 10 mg QD for 2 weeks 1.00 0.89
Colestipol 10 g BID §, 24 weeks 40 mg QD for 8 weeks NA 0.74è
MaaloxTC® 30 mL QID à, 17 days 10 mg QD for 15 days 0.66 0.67
Efavirenz 600 mg QD , 14 days 10 mg for 3 days 0.59 1.01
Rifampin 600 mg QD , 7 days (co-administered)ð 40 mg SD 1.12 2.90
Rifampin 600 mg QD , 5 days (doses separated)ð 40 mg SD 0.20 0.60
Gemfibrozil 600 mg BID §, 7 days 40 mg SD 1.35 1.00
Fenofibrate 160 mg QD , 7 days 40 mg SD 1.03 1.02
Boceprevir 800 mg TID ø, 7 days 40 mg SD 2.32 2.66
TABLE 5. Effect of Atorvastatin on the Phamacokinetics of Co-administered Drugs
Once daiy
Single dose
See Section 7 for clinical significance.
Twice daily
Atorvastatin Co-administered drug and dosing regimen
Drug/Dose (mg) Ratio of AUC Ratio of Cmax
80 mg QD * for 15 days Antipyrine, 600 mg SD * 1.03 0.89
80 mg QD * for 10 days Digoxin 0.25 mg QD *, 20 days 1.15 1.20
40 mg QD * for 22 days Oral contraceptive QD *, 2 months
— norethindrone 1mg 1.28 1.23
— ethinyl estradiol 35mcg 1.19 1.30
10 mg, SD Tipranavir 500 mg BID §/ritonavir 200 mg BID §, 7 days 1.08 0.96
10 mg QD * for 4 days Fosamprenavir 1,400 mg BID §, 14 days 0.73 0.82
10 mg QD * for 4 days Fosamprenavir 700 mg BID/ritonavir 100 mg BID §, 14 days 0.99 0.94 provides trustworthy package insert and label information about marketed drugs as submitted by manufacturers to the US Food and Drug Administration. Package information is not reviewed or updated separately by Every individual package label entry contains a unique identifier which can be used to secure further details directly from the US National Institutes of Health and/or the FDA.

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