ATORVASTATIN CALCIUM- atorvastatin calcium tablet, film coated

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Active ingredient:
ATORVASTATIN CALCIUM TRIHYDRATE (UNII: 48A5M73Z4Q) (ATORVASTATIN - UNII:A0JWA85V8F)
Available from:
NuCare Pharmaceuticals,Inc.
INN (International Name):
ATORVASTATIN CALCIUM TRIHYDRATE
Composition:
ATORVASTATIN 40 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
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. In adult patients without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as age, smoking, hypertension, low HDL-C, or a family history of early coronary heart disease, atorvastatin calcium tablets are indicated to: - Reduce the risk of myocardial infarction - Reduce the risk of stroke - Reduce the risk for revascularization procedures and angina In patients with type 2 diabetes, and without clinically evident coronary heart disease, but
Product summary:
Atorvastatin calcium tablets are available as follows: 40 mg - White to off-white, oval shaped, film-coated tablet, debossed with "TV" on one side and "5058" on the other side of the tablet. Available in bottles of 90 tablets NDC 68071-6671-9 Bottles of 90 Storage Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
Authorization status:
Abbreviated New Drug Application
Authorization number:
68071-3371-9

ATORVASTATIN CALCIUM- atorvastatin calcium tablet, film coated

NuCare Pharmaceuticals,Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use ATORVASTATIN CALCIUM TABLETS

safely and effectively. See full prescribing information for ATORVASTATIN CALCIUM TABLETS.

ATORVASTATIN calcium tablets, for oral use

Initial U.S. Approval: 1996

INDICATIONS AND USAGE

Atorvastatin calcium tablets are an inhibitor of HMG-CoA reductase (statin) indicated as an adjunct therapy to diet to:

Reduce the risk of MI, stroke, revascularization procedures, and angina in patients without CHD, but with multiple risk

factors ( 1.1).

Reduce the risk of MI and stroke in patients with type 2 diabetes without CHD, but with multiple risk factors ( 1.1).

Reduce the risk of non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for CHF, and

angina in patients with CHD ( 1.1).

Reduce elevated total-C, LDL-C, apo B, and TG levels and increase HDL-C in adult patients with primary hyperlipidemia

(heterozygous familial and nonfamilial) and mixed dyslipidemia ( 1.2).

Reduce elevated TG in patients with hypertriglyceridemia and primary dysbetalipoproteinemia ( 1.2).

Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) ( 1.2).

Reduce elevated total-C, LDL-C, and apo B levels in boys and postmenarchal girls, 10 to 17 years of age, with

heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy ( 1.2).

Limitations of Use

Atorvastatin calcium tablets have not been studied in Fredrickson Types I and V dyslipidemias.

DOSAGE AND ADMINISTRATION

Dose range: 10 to 80 mg once daily ( 2.1).

Recommended start dose: 10 or 20 mg once daily ( 2.1).

Patients requiring large LDL-C reduction (> 45%) may start at 40 mg once daily ( 2.1).

Pediatric starting dose: 10 mg once daily; maximum recommended dose: 20 mg once daily ( 2.2).

DOSAGE FORMS AND STRENGTHS

10, 20, 40, and 80 mg tablets ( 3).

CONTRAINDICATIONS

Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels ( 4.1).

Women who are pregnant or may become pregnant ( 4.3).

Nursing mothers ( 4.4).

Hypersensitivity to any component of this medication ( 4.2).

WARNINGS AND PRECAUTIONS

Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase when higher doses are used concomitantly

with cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, HIV protease inhibitors). Predisposing

factors include advanced age (> 65), uncontrolled hypothyroidism, and renal impairment. Rare cases of rhabdomyolysis

with acute renal failure secondary to myoglobinuria have been reported. Advise patients to promptly report to their

physician unexplained and/or persistent muscle pain, tenderness, or weakness. Atorvastatin calcium therapy should be

discontinued if myopathy is diagnosed or suspected ( 5.1, 8.5).

Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before

initiating therapy and as clinically indicated thereafter ( 5.2).

A higher incidence of hemorrhagic stroke was seen in patients without CHD but with stroke or TIA within the previous 6

months in the atorvastatin 80 mg group vs. placebo ( 5.5).

ADVERSE REACTIONS

The most commonly reported adverse reactions (incidence ≥ 2%) in patients treated with atorvastatin calcium in placebo-

controlled trials regardless of causality were: nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract

infection ( 6.1).

To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at 1-866-832-8537

or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Drug Interactions Associated With Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)

Interacting Agents

Prescribing Recommendations

Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease

inhibitor (telaprevir)

Avoid atorvastatin

HIV protease inhibitor (lopinavir plus ritonavir)

Use with caution and lowest dose

ne ce ssary

Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir,

darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)

Do not exceed 20 mg atorvastatin

daily

HIV protease inhibitor (nelfinavir)

Hepatitis C protease inhibitor (boceprevir)

Do not exceed 40 mg atorvastatin

daily

Other Lipid-Lowering Medications: Use with fibrate products or lipid-modifying doses (≥ 1 g/day) of niacin increases the

risk of adverse skeletal muscle effects. Caution should be used when prescribing with atorvastatin calcium ( 7).

Digoxin: Patients should be monitored appropriately ( 7.8).

Oral Contraceptives: Values for norethindrone and ethinyl estradiol may be increased ( 7.9).

Rifampin should be simultaneously coadministered with atorvastatin calcium ( 7.7).

USE IN SPECIFIC POPULATIONS

Hepatic impairment: Plasma concentrations markedly increased in patients with chronic alcoholic liver disease ( 12.3).

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 3/2017

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Prevention of Cardiovascular Disease

1.2 Hyperlipidemia

1.3 Limitations of Use

2 DOSAGE AND ADMINISTRATION

2.1 Hyperlipidemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia ( Fredrickson

Types IIa and IIb)

2.2 Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10 to 17 Years of age)

2.3 Homozygous Familial Hypercholesterolemia

2.4 Concomitant Lipid-Lowering Therapy

2.5 Dosage in Patients With Renal Impairment

2.6 Dosage in Patients Taking Cyclosporine, Clarithromycin, Itraconazole, or Certain Protease

Inhibitors

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Active Liver Disease, Which may Include Unexplained Persistent Elevations in Hepatic

Transaminase Levels

4.2 Hypersensitivity to any Component of This Medication

4.3 Pregnancy

4.4 Nursing Mothers

5 WARNINGS AND PRECAUTIONS

5.1 Skeletal Muscle

5.2 Liver Dysfunction

5.3 Endocrine Function

5.4 CNS Toxicity

5.5 Use in Patients With Recent Stroke or TIA

6 ADVERSE REACTIONS

6.1 Clinical Trial Adverse Experiences

6.2 Postmarketing Experience

6.3 Pediatric Patients (Ages 10 to 17 Years)

7 DRUG INTERACTIONS

7.1 Strong Inhibitors of CYP 3A4

7.2 Grapefruit Juice

7.3 Cyclosporine

7.4 Gemfibrozil

7.5 Other Fibrates

7.6 Niacin

7.7 Rifampin or Other Inducers of Cytochrome P450 3A4

7.8 Digoxin

7.9 Oral Contraceptives

7.10 Warfarin

7.11 Colchicine

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Prevention of Cardiovascular Disease

14.2 Hyperlipidemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (

Fredrickson Types IIa and IIb)

14.3 Hypertriglyceridemia ( Fredrickson Type IV)

14.4 Dysbetalipoproteinemia ( Fredrickson Type III)

14.5 Homozygous Familial Hypercholesterolemia

14.6 Heterozygous Familial Hypercholesterolemia in Pediatric Patients

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Muscle Pain

17.2 Liver Enzymes

17.3 Pregnancy

17.4 Breastfeeding

Atorvastatin Calcium Tablets 10 mg 90s Label Text

FULL PRESCRIBING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS AND USAGE

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.

1.1 Prevention of Cardiovascular Disease

In adult patients without clinically evident coronary heart disease, but with multiple risk factors for

coronary heart disease such as age, smoking, hypertension, low HDL-C, or a family history of early

coronary heart disease, atorvastatin calcium tablets are indicated to:

Reduce the risk of myocardial infarction

Reduce the risk of stroke

Reduce the risk for revascularization procedures and angina

In patients with type 2 diabetes, and without clinically evident coronary heart disease, but with multiple

risk factors for coronary heart disease such as retinopathy, albuminuria, smoking, or hypertension,

atorvastatin calcium tablets are indicated to:

Reduce the risk of myocardial infarction

Reduce the risk of stroke

In patients with clinically evident coronary heart disease, atorvastatin calcium tablets are indicated to:

Reduce the risk of non-fatal myocardial infarction

Reduce the risk of fatal and non-fatal stroke

Reduce the risk for revascularization procedures

Reduce the risk of hospitalization for CHF

Reduce the risk of angina

1.2 Hyperlipidemia

Atorvastatin calcium tablets are indicated:

As an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TG levels and to increase HDL-

C in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed

dyslipidemia ( Fredrickson Types IIa and IIb);

As an adjunct to diet for the treatment of patients with elevated serum TG levels ( Fredrickson Type

IV);

For the treatment of patients with primary dysbetalipoproteinemia ( Fredrickson Type III) who do not

respond adequately to diet;

To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an

adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are

unavailable;

As an adjunct to diet to reduce total-C, LDL-C, and apo B levels in boys and postmenarchal girls, 10

to 17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet

therapy the following findings are present:

LDL-C remains ≥ 190 mg/dL or

LDL-C remains ≥ 160 mg/dL and:

there is a positive family history of premature cardiovascular disease or

two or more other CVD risk factors are present in the pediatric patient

1.3 Limitations of Use

Atorvastatin calcium tablets have not been studied in conditions where the major lipoprotein abnormality

is elevation of chylomicrons ( Fredrickson Types I and V).

2 DOSAGE AND ADMINISTRATION

2.1 Hyperlipidemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (

Fredrickson Types IIa and IIb)

The recommended starting dose of atorvastatin calcium tablets is 10 or 20 mg once daily. Patients who

require a large reduction in LDL-C (more than 45%) may be started at 40 mg once daily. The dosage

range of atorvastatin calcium tablets is 10 to 80 mg once daily. Atorvastatin calcium tablets can be

administered as a single dose at any time of the day, with or without food. The starting dose and

maintenance doses of atorvastatin calcium tablets should be individualized according to patient

characteristics such as goal of therapy and response (see current NCEP Guidelines). After initiation

and/or upon titration of atorvastatin calcium tablets, lipid levels should be analyzed within 2 to 4 weeks

and dosage adjusted accordingly.

2.2 Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10 to 17 Years of age)

The recommended starting dose of atorvastatin calcium tablets is 10 mg/day; the maximum recommended

dose is 20 mg/day (doses greater than 20 mg have not been studied in this patient population). Doses

should be individualized according to the recommended goal of therapy [ see current NCEP Pediatric

Panel Guidelines, Clinical Pharmacology ( 12), and Indications and Usage ( 1.2) ]. Adjustments should be

made at intervals of 4 weeks or more.

2.3 Homozygous Familial Hypercholesterolemia

The dosage of atorvastatin calcium tablets in patients with homozygous FH is 10 to 80 mg daily.

Atorvastatin calcium tablets should be used as an adjunct to other lipid-lowering treatments (e.g., LDL

apheresis) in these patients or if such treatments are unavailable.

2.4 Concomitant Lipid-Lowering Therapy

Atorvastatin calcium tablets may be used with bile acid resins. The combination of HMG-CoA

reductase inhibitors (statins) and fibrates should generally be used with caution [ see Warnings and

Precautions, Skeletal Muscle ( 5.1), Drug Interactions ( 7) ].

2.5 Dosage in Patients With Renal Impairment

Renal disease does not affect the plasma concentrations nor LDL-C reduction of atorvastatin calcium;

thus, dosage adjustment in patients with renal dysfunction is not necessary [ see Warnings and

Precautions, Skeletal Muscle ( 5.1), Clinical Pharmacology, Pharmacokinetics ( 12.3) ].

2.6 Dosage in Patients Taking Cyclosporine, Clarithromycin, Itraconazole, or Certain Protease

Inhibitors

In patients taking cyclosporine or the HIV protease inhibitors (tipranavir plus ritonavir) or the hepatitis

C protease inhibitor (telaprevir), therapy with atorvastatin calcium tablets should be avoided. In patients

with HIV taking lopinavir plus ritonavir, caution should be used when prescribing atorvastatin calcium

tablets and the lowest dose necessary employed. In patients taking clarithromycin, itraconazole, or in

patients with HIV taking a combination of saquinavir plus ritonavir, darunavir plus ritonavir,

fosamprenavir, or fosamprenavir plus ritonavir, therapy with atorvastatin calcium tablets should be

limited to 20 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose

necessary of atorvastatin calcium tablets is employed. In patients taking the HIV protease inhibitor

nelfinavir or the hepatitis C protease inhibitor boceprevir, therapy with atorvastatin calcium tablets

should be limited to 40 mg, and appropriate clinical assessment is recommended to ensure that the

lowest dose necessary of atorvastatin calcium tablets is employed [ see Warnings and Precautions,

Skeletal Muscle ( 5.1), Drug Interactions ( 7) ].

3 DOSAGE FORMS AND STRENGTHS

White to off-white, oval shaped, film-coated tablets containing atorvastatin calcium equivalent to 10, 20,

40, and 80 mg atorvastatin.

4 CONTRAINDICATIONS

4.1 Active Liver Disease, Which may Include Unexplained Persistent Elevations in Hepatic

Transaminase Levels

4.2 Hypersensitivity to any Component of This Medication

4.3 Pregnancy

Women who are pregnant or may become pregnant. Atorvastatin calcium tablets may cause fetal harm

when administered to a pregnant woman. Serum cholesterol and triglycerides increase during normal

pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development.

Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy

should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There

are no adequate and well-controlled studies of atorvastatin calcium tablets use during pregnancy;

however in rare reports, congenital anomalies were observed following intrauterine exposure to statins.

In rat and rabbit animal reproduction studies, atorvastatin revealed no evidence of teratogenicity.

ATORVASTATIN CALCIUM TABLETS SHOULD BE ADMINISTERED TO WOMEN OF

CHILDBEARING AGE ONLY WHEN SUCH PATIENTS ARE HIGHLY UNLIKELY TO

CONCEIVE AND HAVE BEEN INFORMED OF THE POTENTIAL HAZARDS. If the patient

becomes pregnant while taking this drug, atorvastatin calcium tablets should be discontinued

immediately and the patient apprised of the potential hazard to the fetus [ see Use in Specific Populations (

8.1) ].

4.4 Nursing Mothers

It is not known whether atorvastatin is excreted into human milk; however a small amount of another drug

in this class does pass into breast milk. Because statins have the potential for serious adverse reactions

in nursing infants, women who require atorvastatin calcium tablet treatment should not breastfeed their

infants [ see Use in Specific Populations ( 8.3) ].

5 WARNINGS AND PRECAUTIONS

5.1 Skeletal Muscle

Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been

reported with atorvastatin calcium and with other drugs in this class. A history of renal impairment

may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for

skeletal muscle effects.

Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or muscle

weakness in conjunction with increases in creatine phosphokinase (CPK) values > 10 times ULN. The

concomitant use of higher doses of atorvastatin with certain drugs such as cyclosporine and strong

CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, and HIV protease inhibitors) increases the risk

of myopathy/rhabdomyolysis.

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune

myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and

elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy

showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive

agents.

Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness,

and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain,

tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and

symptoms persist after discontinuing atorvastatin calcium. Atorvastatin calcium therapy should be

discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.

The risk of myopathy during treatment with drugs in this class is increased with concurrent

administration of cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, the hepatitis C

protease inhibitor telaprevir, combinations of HIV protease inhibitors, including saquinavir plus

ritonavir, lopinavir plus ritonavir, tipranavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, and

fosamprenavir plus ritonavir, niacin, or azole antifungals. Physicians considering combined therapy with

atorvastatin calcium and fibric acid derivatives, erythromycin, clarithromycin, a combination of

saquinavir plus ritonavir, lopinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or

fosamprenavir plus ritonavir, azole antifungals, or lipid-modifying doses of niacin should carefully

weigh the potential benefits and risks and should carefully monitor patients for any signs or symptoms

of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any

periods of upward dosage titration of either drug. Lower starting and maintenance doses of atorvastatin

should be considered when taken concomitantly with the aforementioned drugs [ see Drug Interactions (

7) ]. Periodic creatine phosphokinase (CPK) determinations may be considered in such situations, but

there is no assurance that such monitoring will prevent the occurrence of severe myopathy.

Prescribing recommendations for interacting agents are summarized in Table 1 [ see also Dosage and

Administration ( 2.6), Drug Interactions ( 7), Clinical Pharmacology ( 12.3) ].

Table 1. Drug Interactions Associated With Increased Risk of Myopathy/Rhabdomyolysis

Interacting Agents

Prescribing

Recommendations

Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis

C protease inhibitor (telaprevir)

Avoid atorvastatin

HIV protease inhibitor (lopinavir plus ritonavir)

Use with caution and lowest

dose necessary

Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus

ritonavir

, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus

ritonavir)

Do not exceed 20 mg

atorvastatin daily

HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor

(boceprevir)

Do not exceed 40 mg

atorvastatin daily

Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin coadministered with

colchicine, and caution should be exercised when prescribing atorvastatin with colchicine [ see Drug

Interactions ( 7.11) ].

Atorvastatin calcium therapy should be temporarily withheld or discontinued in any patient with

an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the

development of renal failure secondary to rhabdomyolysis (e.g., severe acute infection,

hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and

uncontrolled seizures).

Use with caution and with the lowest dose necessary ( 12.3)

5.2 Liver Dysfunction

Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities

of liver function. Persistent elevations (> 3 times the upper limit of normal [ULN] occurring on 2

or more occasions) in serum transaminases occurred in 0.7% of patients who received

atorvastatin calcium in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%,

0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively.

One patient in clinical trials developed jaundice. Increases in liver function tests (LFT) in other patients

were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug

interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without

sequelae. Eighteen of 30 patients with persistent LFT elevations continued treatment with a reduced

dose of atorvastatin calcium.

It is recommended that liver enzyme tests be obtained prior to initiating therapy with atorvastatin calcium

and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal

hepatic failure in patients taking statins, including atorvastatin. If serious liver injury with clinical

symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with atorvastatin calcium,

promptly interrupt therapy. If an alternate etiology is not found, do not restart atorvastatin calcium.

Atorvastatin calcium should be used with caution in patients who consume substantial quantities of

alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent

transaminase elevations are contraindications to the use of atorvastatin calcium [ see Contraindications (

4.1) ].

5.3 Endocrine Function

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase

inhibitors, including atorvastatin calcium.

Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid

production. Clinical studies have shown that atorvastatin calcium does not reduce basal plasma cortisol

concentration or impair adrenal reserve. The effects of statins on male fertility have not been studied in

adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women

are unknown. Caution should be exercised if a statin is administered concomitantly with drugs that may

decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone,

and cimetidine.

5.4 CNS Toxicity

Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg/kg/day. Brain hemorrhage

and optic nerve vacuolation were seen in another female dog that was sacrificed in moribund condition

after 11 weeks of escalating doses up to 280 mg/kg/day. The 120 mg/kg dose resulted in a systemic

exposure approximately 16 times the human plasma area-under-the-curve (AUC, 0-24 hours) based on

the maximum human dose of 80 mg/day. A single tonic convulsion was seen in each of 2 male dogs (one

treated at 10 mg/kg/day and one at 120 mg/kg/day) in a 2 year study. No CNS lesions have been observed

in mice after chronic treatment for up to 2 years at doses up to 400 mg/kg/day or in rats at doses up to

100 mg/kg/day. These doses were 6 to 11 times (mouse) and 8 to 16 times (rat) the human AUC (0-24)

based on the maximum recommended human dose of 80 mg/day.

CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell

infiltration of perivascular spaces, have been observed in dogs treated with other members of this class.

A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of

retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion at a dose that produced

plasma drug levels about 30 times higher than the mean drug level in humans taking the highest

recommended dose.

5.5 Use in Patients With Recent Stroke or TIA

In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels

(SPARCL) study where atorvastatin 80 mg vs. placebo was administered in 4,731 subjects without CHD

who had a stroke or TIA within the preceding 6 months, a higher incidence of hemorrhagic stroke was

seen in the atorvastatin 80 mg group compared to placebo (55, 2.3% atorvastatin vs. 33, 1.4% placebo;

HR: 1.68, 95% CI: 1.09, 2.59; p = 0.0168). The incidence of fatal hemorrhagic stroke was similar

across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence

of nonfatal hemorrhagic stroke was significantly higher in the atorvastatin group (38, 1.6%) as

compared to the placebo group (16, 0.7%). Some baseline characteristics, including hemorrhagic and

lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in the

atorvastatin group [ see Adverse Reactions ( 6.1) ].

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the label:

Rhabdomyolysis and myopathy [ see Warnings and Precautions ( 5.1) ]

Liver enzyme abnormalities [ see Warnings and Precautions ( 5.2) ]

6.1 Clinical Trial Adverse Experiences

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates

observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of

another drug and may not reflect the rates observed in clinical practice.

In the atorvastatin calcium placebo-controlled clinical trial database of 16,066 patients (8755

atorvastatin calcium vs. 7311 placebo; age range 10 to 93 years, 39% women, 91% Caucasians, 3%

Blacks, 2% Asians, 4% other) with a median treatment duration of 53 weeks, 9.7% of patients on

atorvastatin calcium and 9.5% of the patients on placebo discontinued due to adverse reactions

regardless of causality. The five most common adverse reactions in patients treated with atorvastatin

calcium that led to treatment discontinuation and occurred at a rate greater than placebo were: myalgia

(0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase increase (0.4%), and hepatic enzyme

increase (0.4%).

The most commonly reported adverse reactions (incidence ≥ 2% and greater than placebo) regardless

of causality, in patients treated with atorvastatin calcium in placebo controlled trials (n = 8755) were:

nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), pain in extremity (6.0%), and urinary tract

infection (5.7%).

Table 2 summarizes the frequency of clinical adverse reactions, regardless of causality, reported in ≥

2% and at a rate greater than placebo in patients treated with atorvastatin calcium (n = 8755), from

seventeen placebo-controlled trials.

Table 2. Clinical Adverse Reactions Occurring in ≥ 2% in Patients Treated With any Dose of

Atorvastatin and at an Incidence Greater Than Placebo Regardless of Causality (% of Patients).

Adverse Reaction

Any dose

N = 8755

10 mg

N = 3908

20 mg

N = 188

40 mg

N = 604

80 mg

N = 4055

Placebo

N = 7311

Nasopharyngitis

12.9

Arthralgia

11.7

10.6

Diarrhea

14.1

Pain in extremity

Urinary tract infection

Dyspepsia

Nausea

Musculoskeletal pain

Muscle Spasms

Myalgia

Insomnia

Pharyngolaryngeal pain

Other adverse reactions reported in placebo-controlled studies include:

Body as a whole: malaise, pyrexia; Digestive system: abdominal discomfort, eructation, flatulence,

hepatitis, cholestasis; Musculoskeletal system: musculoskeletal pain, muscle fatigue, neck pain, joint

swelling; Metabolic and nutritional system: transaminases increase, liver function test abnormal, blood

alkaline phosphatase increase, creatine phosphokinase increase, hyperglycemia; Nervous system:

nightmare; Respiratory system: epistaxis; Skin and appendages: urticaria; Special senses: vision blurred,

tinnitus; Urogenital system: white blood cells urine positive.

Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

In ASCOT [ see Clinical Studies ( 14.1) ] involving 10,305 participants (age range 40 to 80 years, 19%

women; 94.6% Caucasians, 2.6% Africans, 1.5% South Asians, 1.3% mixed/other) treated with

atorvastatin 10 mg daily (n = 5,168) or placebo (n = 5,137), the safety and tolerability profile of the

group treated with atorvastatin calcium was comparable to that of the group treated with placebo during

a median of 3.3 years of follow-up.

Collaborative Atorvastatin Diabetes Study (CARDS)

In CARDS [ see Clinical Studies ( 14.1) ] involving 2,838 subjects (age range 39 to 77 years, 32%

women; 94.3% Caucasians, 2.4% South Asians, 2.3% Afro-Caribbean, 1.0% other) with type 2 diabetes

treated with atorvastatin 10 mg daily (n = 1,428) or placebo (n = 1,410), there was no difference in the

overall frequency of adverse reactions or serious adverse reactions between the treatment groups

during a median follow-up of 3.9 years. No cases of rhabdomyolysis were reported.

Treating to New Targets Study (TNT)

In TNT [ see Clinical Studies ( 14.1) ] involving 10,001 subjects (age range 29 to 78 years, 19% women;

94.1% Caucasians, 2.9% Blacks, 1.0% Asians, 2.0% other) with clinically evident CHD treated with

atorvastatin 10 mg daily (n = 5006) or atorvastatin 80 mg daily (n = 4995), there were more serious

adverse reactions and discontinuations due to adverse reactions in the high-dose atorvastatin group (92,

1.8%; 497, 9.9%, respectively) as compared to the low-dose group (69, 1.4%; 404, 8.1%,

respectively) during a median follow-up of 4.9 years. Persistent transaminase elevations (≥ 3 x ULN

twice within 4 to 10 days) occurred in 62 (1.3%) individuals with atorvastatin 80 mg and in nine (0.2%)

individuals with atorvastatin 10 mg. Elevations of CK (≥ 10 x ULN) were low overall, but were higher

in the high-dose atorvastatin treatment group (13, 0.3%) compared to the low-dose atorvastatin group (6,

0.1%).

Incremental Decrease in Endpoints through Aggressive Lipid Lowering Study (IDEAL)

In IDEAL [ see Clinical Studies ( 14.1) ] involving 8,888 subjects (age range 26 to 80 years, 19%

women; 99.3% Caucasians, 0.4% Asians, 0.3% Blacks, 0.04% other) treated with atorvastatin 80

mg/day (n = 4439) or simvastatin 20 to 40 mg daily (n = 4449), there was no difference in the overall

frequency of adverse reactions or serious adverse reactions between the treatment groups during a

median follow-up of 4.8 years.

Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)

In SPARCL involving 4731 subjects (age range 21 to 92 years, 40% women; 93.3% Caucasians, 3.0%

Blacks, 0.6% Asians, 3.1% other) without clinically evident CHD but with a stroke or transient ischemic

attack (TIA) within the previous 6 months treated with atorvastatin 80 mg (n = 2365) or placebo (n =

Adverse Reaction ≥ 2% in any dose greater than placebo

2366) for a median follow-up of 4.9 years, there was a higher incidence of persistent hepatic

transaminase elevations (≥ 3 x ULN twice within 4 to 10 days) in the atorvastatin group (0.9%)

compared to placebo (0.1%). Elevations of CK (> 10 x ULN) were rare, but were higher in the

atorvastatin group (0.1%) compared to placebo (0.0%). Diabetes was reported as an adverse reaction in

144 subjects (6.1%) in the atorvastatin group and 89 subjects (3.8%) in the placebo group [ see Warnings

and Precautions ( 5.5) ].

In a post-hoc analysis, atorvastatin 80 mg reduced the incidence of ischemic stroke (218/2365, 9.2% vs.

274/2366, 11.6%) and increased the incidence of hemorrhagic stroke (55/2365, 2.3% vs. 33/2366, 1.4%)

compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17

atorvastatin calcium vs. 18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly

greater in the atorvastatin group (38 non-fatal hemorrhagic strokes) as compared to the placebo group

(16 non-fatal hemorrhagic strokes). Subjects who entered the study with a hemorrhagic stroke appeared

to be at increased risk for hemorrhagic stroke [7 (16%) atorvastatin calcium vs. 2 (4%) placebo].

There were no significant differences between the treatment groups for all-cause mortality: 216 (9.1%)

in the atorvastatin 80 mg/day group vs. 211 (8.9%) in the placebo group. The proportions of subjects

who experienced cardiovascular death were numerically smaller in the atorvastatin 80 mg group (3.3%)

than in the placebo group (4.1%). The proportions of subjects who experienced non-cardiovascular

death were numerically larger in the atorvastatin 80 mg group (5.0%) than in the placebo group (4.0%).

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of atorvastatin calcium.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always

possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions associated with atorvastatin calcium therapy reported since market introduction, that

are not listed above, regardless of causality assessment, include the following: anaphylaxis,

angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and

toxic epidermal necrolysis), rhabdomyolysis, myositis, fatigue, tendon rupture, fatal and non-fatal

hepatic failure, dizziness, depression, peripheral neuropathy, and pancreatitis.

There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [ see

Warnings and Precautions ( 5.1) ].

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness,

amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been

reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation,

with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

6.3 Pediatric Patients (Ages 10 to 17 Years)

In a 26 week controlled study in boys and postmenarchal girls (n = 140, 31% female; 92% Caucasians,

1.6% Blacks, 1.6% Asians, 4.8% other), the safety and tolerability profile of atorvastatin 10 to 20 mg

daily was generally similar to that of placebo [ see Clinical Studies ( 14.6) and Use in Special Populations,

Pediatric Use ( 8.4) ].

7 DRUG INTERACTIONS

The risk of myopathy during treatment with statins is increased with concurrent administration of fibric

acid derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP 3A4 inhibitors (e.g.,

clarithromycin, HIV protease inhibitors, and itraconazole) [ see Warnings and Precautions, Skeletal

Muscle ( 5.1) and Clinical Pharmacology ( 12.3) ].

7.1 Strong Inhibitors of CYP 3A4

Atorvastatin calcium is metabolized by cytochrome P450 3A4. Concomitant administration of

atorvastatin calcium with strong inhibitors of CYP 3A4 can lead to increases in plasma concentrations of

atorvastatin. The extent of interaction and potentiation of effects depend on the variability of effect on

CYP 3A4.

Clarithromycin: Atorvastatin AUC was significantly increased with concomitant administration of

atorvastatin 80 mg with clarithromycin (500 mg twice daily) compared to that of atorvastatin calcium

alone [ see Clinical Pharmacology ( 12.3) ]. Therefore, in patients taking clarithromycin, caution should

be used when the atorvastatin dose exceeds 20 mg [ see Warnings and Precautions, Skeletal Muscle ( 5.1)

and Dosage and Administration ( 2.6) ].

Combination of Protease Inhibitors: Atorvastatin AUC was significantly increased with concomitant

administration of atorvastatin calcium with several combinations of HIV protease inhibitors, as well as

with the hepatitis C protease inhibitor telaprevir, compared to that of atorvastatin calcium alone [ see

Clinical Pharmacology ( 12.3) ]. Therefore, in patients taking the HIV protease inhibitor tipranavir plus

ritonavir, or the hepatitis C protease inhibitor telaprevir, concomitant use of atorvastatin calcium should

be avoided. In patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used

when prescribing atorvastatin calcium and the lowest dose necessary should be used. In patients taking

the HIV protease inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or

fosamprenavir plus ritonavir, the dose of atorvastatin should not exceed 20 mg and should be used with

caution [ see Warnings and Precautions, Skeletal Muscle ( 5.1) and Dosage and Administration ( 2.6) ]. In

patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, the

dose of atorvastatin should not exceed 40 mg and close clinical monitoring is recommended.

Itraconazole: Atorvastatin AUC was significantly increased with concomitant administration of

atorvastatin 40 mg and itraconazole 200 mg [ see Clinical Pharmacology ( 12.3) ]. Therefore, in patients

taking itraconazole, caution should be used when the atorvastatin dose exceeds 20 mg [ see Warnings

and Precautions, Skeletal Muscle ( 5.1) and Dosage and Administration ( 2.6) ].

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 and 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 calcium alone [ see Clinical Pharmacology ( 12.3) ]. The

coadministration of atorvastatin calcium with cyclosporine should be avoided [ see Warnings and

Precautions, Skeletal Muscle ( 5.1) ].

7.4 Gemfibrozil

Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are

coadministered with gemfibrozil, concomitant administration of atorvastatin calcium with gemfibrozil

should be avoided [ see Warnings and Precautions ( 5.1) ].

7.5 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 calcium should be administered

with caution when used concomitantly with other fibrates [ see Warnings and Precautions ( 5.1) ].

7.6 Niacin

The risk of skeletal muscle effects may be enhanced when atorvastatin calcium is used in combination

with niacin; a reduction in atorvastatin calcium dosage should be considered in this setting [ see

Warnings and Precautions ( 5.1) ].

7.7 Rifampin or Other Inducers of Cytochrome P450 3A4

Concomitant administration of atorvastatin calcium 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 coadministration of atorvastatin calcium with

rifampin is recommended, as delayed administration of atorvastatin calcium after administration of

rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.

7.8 Digoxin

When multiple doses of atorvastatin calcium and digoxin were coadministered, steady state plasma

digoxin concentrations increased by approximately 20%. Patients taking digoxin should be monitored

appropriately.

7.9 Oral Contraceptives

Coadministration of atorvastatin calcium 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 calcium.

7.10 Warfarin

Atorvastatin calcium had no clinically significant effect on prothrombin time when administered to

patients receiving chronic warfarin treatment.

7.11 Colchicine

Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin coadministered with

colchicine, and caution should be exercised when prescribing atorvastatin with colchicine.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category X

Atorvastatin calcium is contraindicated in women who are or may become pregnant. Serum cholesterol

and triglycerides increase during normal pregnancy. Lipid lowering drugs offer no benefit during

pregnancy because cholesterol and cholesterol derivatives are needed for normal fetal development.

Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy

should have little impact on long-term outcomes of primary hypercholesterolemia therapy.

There are no adequate and well-controlled studies of atorvastatin use during pregnancy. There have

been rare reports of congenital anomalies following intrauterine exposure to statins. In a review of

about 100 prospectively followed pregnancies in women exposed to other statins, the incidences of

congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected

in the general population. However, this study was only able to exclude a three-to-four-fold increased

risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started

before pregnancy and stopped during the first trimester when pregnancy was identified.

Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal

plasma. 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/m

) [ see Contraindications, Pregnancy ( 4.3) ].

In a study in rats given 20, 100, or 225 mg/kg/day, from gestation day 7 through to lactation day 21

(weaning), there was decreased pup survival at birth, neonate, weaning, and maturity in pups of mothers

dosed with 225 mg/kg/day. Body weight was decreased on days 4 and 21 in pups of mothers dosed at

100 mg/kg/day; pup body weight was decreased at birth and at days 4, 21, and 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 AUC at 80 mg/day.

Statins may cause fetal harm when administered to a pregnant woman. Atorvastatin calcium should be

administered to women of childbearing potential only when such patients are highly unlikely to

conceive and have been informed of the potential hazards. If the woman becomes pregnant while taking

atorvastatin calcium, it should be discontinued immediately and the patient advised again as to the

potential hazards to the fetus and the lack of known clinical benefit with continued use during pregnancy.

8.3 Nursing Mothers

It is not known whether atorvastatin is excreted in human milk, but a small amount of another drug in this

class does pass into breast milk. Nursing rat pups had plasma and liver drug levels of 50% and 40%,

respectively, of that in their mother’s milk. Animal breast milk drug levels may not accurately reflect

human breast milk levels. Because another drug in this class passes into human milk and because statins

have a potential to cause serious adverse reactions in nursing infants, women requiring atorvastatin

calcium treatment should be advised not to nurse their infants [ see Contraindications ( 4) ].

8.4 Pediatric Use

Safety and effectiveness in patients 10 to 17 years of age with heterozygous familial

hypercholesterolemia have been evaluated in a controlled clinical trial of 6 months’ duration in

adolescent boys and postmenarchal girls. Patients treated with atorvastatin calcium had an adverse

experience profile generally similar to that of patients treated with placebo. The most common adverse

experiences observed in both groups, regardless of causality assessment, were infections. Doses

greater than 20 mg have not been studied in this patient population. In this limited controlled study,

there was no significant effect on growth or sexual maturation in boys or on menstrual cycle length in

girls [ see Clinical Studies ( 14.6); Adverse Reactions, Pediatric Patients (Ages 10 to 17 Years) ( 6.3); and

Dosage and Administration, Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10 to 17

Years of age) ( 2.2) ]. Adolescent females should be counseled on appropriate contraceptive methods

while on atorvastatin calcium therapy [ see Contraindications, Pregnancy ( 4.3) and Use in Specific

Populations, Pregnancy ( 8.1) ]. Atorvastatin calcium has not been studied in controlled clinical trials

involving pre-pubertal patients or patients younger than 10 years of age.

Clinical efficacy with doses up to 80 mg/day for 1 year have been evaluated in an uncontrolled study of

patients with homozygous FH including 8 pediatric patients [ see Clinical Studies, Homozygous Familial

Hypercholesterolemia ( 14.5) ].

8.5 Geriatric Use

Of 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 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 calcium should be prescribed with caution in the elderly.

8.6 Hepatic Impairment

Atorvastatin calcium is contraindicated in patients with active liver disease which may include

unexplained persistent elevations in hepatic transaminase levels [ see Contraindications ( 4) and

Pharmacokinetics ( 12.3) ].

10 OVERDOSAGE

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 binding to plasma proteins, hemodialysis is not expected to significantly enhance

atorvastatin calcium clearance.

11 DESCRIPTION

Atorvastatin calcium tablets are 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 is (3 R,5 R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-(propan-2-yl)-

1 H-pyrrol-1-yl]-3,5-dihydroxyheptanoate calcium trihydrate. Its structural formula is:

3H

O M.W. 1209.42

Atorvastatin calcium trihydrate (Form I) is a white to off-white powder that is insoluble in aqueous

solutions of pH 4.5 and below. Atorvastatin calcium is very slightly soluble in distilled water, pH 7.8

phosphate buffer, and acetonitrile; slightly soluble in ethanol; and freely soluble in methanol.

Atorvastatin calcium tablets for oral administration contain 10, 20, 40 or 80 mg atorvastatin and the

following inactive ingredients: calcium carbonate, croscarmellose sodium, hydroxypropyl cellulose,

hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene

glycol, polysorbate, talc and titanium dioxide.

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. 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.

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 C

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 C

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, Nursing Mothers ( 4.4) and Use in Specific

Populations, Nursing Mothers ( 8.3) ].

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 coadministration 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 C

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 calcium in women differ from those in men

(approximately 20% higher for C

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, 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 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. C

and AUC are each 4 fold greater in patients with

Child-Pugh A disease. C

and AUC are approximately 16 fold and 11 fold increased, respectively,

in patients with Child-Pugh B disease [ see Contraindications ( 4.1) ].

Table 3. Effect of Coadministered Drugs on the Pharmacokinetics of Atorvastatin

Coadministered drug and

dosing regimen

Atorvas tatin

Dose (mg)

Change in

AUC

Change in

C

Cyclosporine 5.2 mg/kg/day, stable dose

10 mg QD for 28

↑ 8.7 fold

↑ 10.7 fold

max

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 400 mg 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 QID, 2 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 600 mg BID, 7 days

40 mg SD

↑ 35%

↓ Less than

Fenofibrate 160 mg QD, 7 days

40 mg SD

↑ 3%

↑ 2%

Boceprevir 800 mg TID, 7 days

40 mg SD

↑ 2.30 fold

↑ 2.66 fold

Table 4. Effect of Atorvastatin on the Pharmacokinetics of Coadministered Drugs

Atorvas tatin

Coadministered drug and dosing regimen

Drug/Dose (mg)

Change in

AUC

Change in C

Data given as x-fold change represent a simple ratio between coadministration 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.

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 (up to 2.5 fold) and/or C max (up to 71%) have been reported with excessive grapefruit

consumption (≥ 750 mL to 1.2 liters per day).

Single sample taken 8 to 16h post dose.

Due to the dual interaction mechanism of rifampin, simultaneous coadministration 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.

†,‡

max

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 1 mg

- ethinyl estradiol 35 mcg

↑ 28%

↑ 19%

↑ 23%

↑ 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

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 (0-24) 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 (0-24) 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.

14 CLINICAL STUDIES

14.1 Prevention of Cardiovascular Disease

In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of atorvastatin calcium on fatal

and non-fatal coronary heart disease was assessed in 10,305 hypertensive patients 40 to 80 years of age

(mean of 63 years), without a previous myocardial infarction and with TC levels ≤ 251 mg/dL (6.5

mmol/L). Additionally, all patients had at least 3 of the following cardiovascular risk factors: male

gender (81.1%), age > 55 years (84.5%), smoking (33.2%), diabetes (24.3%), history of CHD in a first-

degree relative (26%), TC:HDL > 6 (14.3%), peripheral vascular disease (5.1%), left ventricular

hypertrophy (14.4%), prior cerebrovascular event (9.8%), specific ECG abnormality (14.3%),

See Section 7 for clinical significance.

proteinuria/albuminuria (62.4%). 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), using

a covariate adaptive method which took into account the distribution of nine baseline characteristics of

patients already enrolled and minimized the imbalance of those characteristics across the groups.

Patients were followed for a median duration of 3.3 years.

The effect of 10 mg/day of atorvastatin on lipid levels was similar to that seen in previous clinical

trials.

Atorvastatin calcium significantly reduced the rate of coronary events [either fatal coronary heart

disease (46 events in the placebo group vs. 40 events in the atorvastatin calcium group) or non-fatal MI

(108 events in the placebo group vs. 60 events in the atorvastatin calcium group)] with a relative risk

reduction of 36% [(based on incidences of 1.9% for atorvastatin calcium vs. 3.0% for placebo), p =

0.0005 (see Figure 1)]. The risk reduction was consistent regardless of age, smoking status, obesity, or

presence of renal dysfunction. The effect of atorvastatin calcium was seen regardless of baseline LDL

levels. Due to the small number of events, results for women were inconclusive.

Atorvastatin calcium also significantly decreased the relative risk for revascularization procedures by

42%. Although the reduction of fatal and non-fatal strokes did not reach a pre-defined significance

level (p = 0.01), a favorable trend was observed with a 26% relative risk reduction (incidences of 1.7%

for atorvastatin calcium and 2.3% for placebo). There was no significant difference between the

treatment groups for death due to cardiovascular causes (p = 0.51) or noncardiovascular causes (p =

0.17).

In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of atorvastatin calcium on

cardiovascular disease (CVD) endpoints was assessed in 2838 subjects (94% white, 68% male), ages

40 to 75 with type 2 diabetes based on WHO criteria, without prior history of cardiovascular disease

and with LDL ≤ 160 mg/dL and TG ≤ 600 mg/dL. In addition to diabetes, subjects had 1 or more of the

following risk factors: current smoking (23%), hypertension (80%), retinopathy (30%), or

microalbuminuria (9%) or macroalbuminuria (3%). No subjects on hemodialysis were enrolled in the

study. In this multicenter, placebo-controlled, double-blind clinical trial, subjects were randomly

allocated to either atorvastatin 10 mg daily (1429) or placebo (1411) in a 1:1 ratio and were followed

for a median duration of 3.9 years. The primary endpoint was the occurrence of any of the major

cardiovascular events: myocardial infarction, acute CHD death, unstable angina, coronary

revascularization, or stroke. The primary analysis was the time to first occurrence of the primary

endpoint.

Baseline characteristics of subjects were: mean age of 62 years, mean HbA

7.7%; median LDL-C

120 mg/dL; median TC 207 mg/dL; median TG 151 mg/dL; median HDL-C 52 mg/dL.

The effect of atorvastatin 10 mg/day on lipid levels was similar to that seen in previous clinical trials.

Atorvastatin calcium significantly reduced the rate of major cardiovascular events (primary endpoint

events) (83 events in the atorvastatin calcium group vs. 127 events in the placebo group) with a relative

risk reduction of 37%, HR 0.63, 95% CI (0.48, 0.83) (p = 0.001) (see Figure 2). An effect of

atorvastatin calcium was seen regardless of age, sex, or baseline lipid levels.

Atorvastatin calcium significantly reduced the risk of stroke by 48% (21 events in the atorvastatin

calcium group vs. 39 events in the placebo group), HR 0.52, 95.1% CI (0.31, 0.89) (p = 0.016) and

reduced the risk of MI by 42% (38 events in the atorvastatin calcium group vs. 64 events in the placebo

group), HR 0.58, 95.1% CI (0.39, 0.86) (p = 0.007). There was no significant difference between the

treatment groups for angina, revascularization procedures, and acute CHD death.

There were 61 deaths in the atorvastatin calcium group vs. 82 deaths in the placebo group (HR 0.73, p =

0.059).

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 (94% white, 81%

male, 38% ≥ 65 years) with clinically evident coronary heart disease 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 primary endpoint was the time-to-first occurrence of any of the

following major cardiovascular events (MCVE): death due to CHD, non-fatal myocardial infarction,

resuscitated cardiac arrest, and fatal and non-fatal stroke. The mean LDL-C, TC, TG, non-HDL, and

HDL cholesterol levels at 12 weeks were 73, 145, 128, 98, and 47 mg/dL during treatment with 80 mg

of atorvastatin and 99, 177, 152, 129, and 48 mg/dL during treatment with 10 mg of atorvastatin.

Treatment with atorvastatin 80 mg/day significantly reduced the rate of 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%, HR 0.78,

95% CI (0.69, 0.89), p = 0.0002 (see Figure 3 and Table 5). The overall risk reduction was consistent

regardless of age (< 65, ≥ 65) or gender.

Table 5. Overview of Efficacy Results in TNT

Endpoint

Atorvas tatin

10 mg

(N = 5006)

Atorvas tatin

80 mg

(N = 4995)

HR (95% CI)

PRIMARY ENDPOINT

First major cardiovascular endpoint

(10.9)

(8.7)

0.78 (0.69, 0.89)

Components of the Primary Endpoint

CHD death

(2.5)

(2.0)

0.80 (0.61, 1.03)

Non-fatal, non-procedure related MI

(6.2)

(4.9)

0.78 (0.66, 0.93)

Resuscitated cardiac arrest

(0.5)

(0.5)

0.96 (0.56, 1.67)

Stroke (fatal and non-fatal)

(3.1)

(2.3)

0.75 (0.59, 0.96)

SECONDARY ENDPOINTS

First CHF with hospitalization

(3.3)

(2.4)

0.74 (0.59, 0.94)

First PVD endpoint

(5.6)

(5.5)

0.97 (0.83, 1.15)

First CABG or other coronary revascularization

(18.1)

(13.4)

0.72 (0.65, 0.80)

HR = hazard ratio; CHD = coronary heart disease; CI = confidence interval; MI = myocardial infarction;

CHF = congestive heart failure; CV = cardiovascular; PVD = peripheral vascular disease; CABG =

coronary artery bypass graft Confidence intervals for the Secondary Endpoints were not adjusted for

multiple comparisons

procedure

First documented angina endpoint

(12.3)

(10.9)

0.88 (0.79, 0.99)

All-cause mortality

(5.6)

(5.7)

1.01 (0.85, 1.19)

Components of All-Cause Mortality

Cardiovascular death

(3.1)

(2.5)

0.81 (0.64, 1.03)

Noncardiovascular death

(2.5)

(3.2)

1.25 (0.99, 1.57)

Cancer death

(1.5)

(1.7)

1.13 (0.83, 1.55)

Other non-CV death

(0.9)

(1.2)

1.35 (0.91, 2.00)

Suicide, homicide, and other traumatic non-CV death

(0.2)

(0.3)

1.67 (0.73, 3.82)

Of the events that comprised the primary efficacy endpoint, treatment with atorvastatin 80 mg/day

significantly reduced the rate of non-fatal, non-procedure related MI and fatal and non-fatal stroke, but

not CHD death or resuscitated cardiac arrest (Table 5). Of the predefined secondary endpoints,

treatment with atorvastatin 80 mg/day significantly reduced the rate of coronary revascularization,

angina, and hospitalization for heart failure, but not peripheral vascular disease. The reduction in the

rate of CHF with hospitalization was only observed in the 8% of patients with a prior history of CHF.

There was no significant difference between the treatment groups for all-cause mortality (Table 5). The

proportions of subjects who experienced cardiovascular 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 noncardiovascular 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 to 40 mg/day in

8,888 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, TC, TG, HDL, and non-HDL cholesterol levels at

Week 12 were 78, 145, 115, 45, and 100 mg/dL during treatment with 80 mg of atorvastatin and 105,

179, 142, 47, and 132 mg/dL during treatment with 20 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 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 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 to 40 mg group.

14.2 Hyperlipidemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (

Fredrickson Types IIa and IIb)

Atorvastatin calcium reduces total-C, LDL-C, VLDL-C, apo B, and TG, and increases HDL-C in

Atorvastatin 80 mg; atorvastatin 10 mg

Secondary endpoints not included in primary endpoint

Component of other secondary endpoints

patients with hyperlipidemia and mixed dyslipidemia. Therapeutic response is seen within 2 weeks, and

maximum response is usually achieved within 4 weeks and maintained during chronic therapy.

Atorvastatin calcium is effective in a wide variety of patient populations with hyperlipidemia, with and

without hypertriglyceridemia, in men and women, and in the elderly.

In two multicenter, placebo-controlled, dose-response studies in patients with hyperlipidemia,

atorvastatin calcium given as a single dose over 6 weeks, significantly reduced total-C, LDL-C, apo B,

and TG. (Pooled results are provided in Table 6.)

Table 6. Dose Response in Patients With Primary Hyperlipidemia (Adjusted Mean % Change

From Baseline)

Dose

LDL-C

Apo B

HDL-C

Non-HDL-

C/HDL-C

Placebo

In patients with Fredrickson Types IIa and IIb hyperlipoproteinemia pooled from 24 controlled trials, the

median (25

and 75

percentile) percent changes from baseline in HDL-C for atorvastatin calcium 10,

20, 40, and 80 mg were 6.4 (-1.4, 14), 8.7 (0, 17), 7.8 (0, 16), and 5.1 (-2.7, 15), respectively.

Additionally, analysis of the pooled data demonstrated consistent and significant decreases in total-C,

LDL-C, TG, total-C/HDL-C, and LDL-C/HDL-C.

In three multicenter, double-blind studies in patients with hyperlipidemia, atorvastatin calcium was

compared to other statins. After randomization, patients were treated for 16 weeks with either

atorvastatin calcium 10 mg per day or a fixed dose of the comparative agent (Table 7).

Table 7. Mean Percentage Change From Baseline at Endpoint (Double-Blind, Randomized,

Active-Controlled Trials)

Treatment

(Daily Dose)

Total-C

LDL-C

Apo B

HDL-C Non-HDL-C/HDL-C

Study 1

Atorvastatin 10 mg

Lovastatin 20 mg

95% CI for Diff

-9.2, -6.5

-10.7, -7.1

-10.0, -6.5

-15.2, -7.1

-1.7, 2.0

-11.1, -7.1

Study 2

Atorvastatin 10 mg

Pravastatin 20 mg

95% CI for Diff

-10.8, -6.1

-14.5, -8.2

-13.4, -7.4

-14.1, -0.7

-4.9, 1.6

-11.5, -4.1

Study 3

Atorvastatin 10 mg

Simvastatin 10 mg

95% CI for Diff

-8.7, -2.7

-10.1, -2.6

-8.0, -1.1

-15.1, -0.7

-4.3, 3.9

-9.6, -1.9

*

Results are pooled from 2 dose-response studies.

A negative value for the 95% CI for the difference between treatments favors atorvastatin calcium for all except

HDL-C, for which a positive value favors atorvastatin calcium. If the range does not include 0, this indicates a

statistically significant difference.

Significantly different from lovastatin, ANCOVA, p ≤ 0.05

The impact on clinical outcomes of the differences in lipid-altering effects between treatments shown in

Table 7 is not known. Table 7 does not contain data comparing the effects of atorvastatin 10 mg and

higher doses of lovastatin, pravastatin, and simvastatin. The drugs compared in the studies summarized

in the table are not necessarily interchangeable.

14.3 Hypertriglyceridemia ( Fredrickson Type IV)

The response to atorvastatin calcium in 64 patients with isolated hypertriglyceridemia treated across

several clinical trials is shown in the table below (Table 8). For the atorvastatin calcium-treated

patients, median (min, max) baseline TG level was 565 (267 to 1502).

Table 8. Combined Patients With Isolated Elevated TG: Median (min, max) Percentage Change

From Baseline

Placebo

(N = 12)

Atorvastatin 10 mg

(N = 37)

Atorvastatin 20 mg

(N = 13)

Atorvastatin 80 mg

(N = 14)

T riglycerides

-12.4 (-36.6, 82.7)

-41.0 (-76.2, 49.4)

-38.7 (-62.7, 29.5)

-51.8 (-82.8, 41.3)

Total-C

-2.3 (-15.5, 24.4)

-28.2 (-44.9, -6.8)

-34.9 (-49.6, -15.2)

-44.4 (-63.5, -3.8)

LDL-C

3.6 (-31.3, 31.6)

-26.5 (-57.7, 9.8)

-30.4 (-53.9, 0.3)

-40.5 (-60.6, -13.8)

HDL-C

3.8 (-18.6, 13.4)

13.8 (-9.7, 61.5)

11.0 (-3.2, 25.2)

7.5 (-10.8, 37.2)

VLDL-C

-1.0 (-31.9, 53.2)

-48.8 (-85.8, 57.3)

-44.6 (-62.2, -10.8)

-62.0 (-88.2, 37.6)

non-HDL-C

-2.8 (-17.6, 30.0)

-33.0 (-52.1, -13.3)

-42.7 (-53.7, -17.4)

-51.5 (-72.9, -4.3)

14.4 Dysbetalipoproteinemia ( Fredrickson Type III)

The results of an open-label crossover study of 16 patients (genotypes: 14 apo E2/E2 and 2 apo E3/E2)

with dysbetalipoproteinemia ( Fredrickson Type III) are shown in the table below (Table 9).

Table 9. Open-Label Crossover Study of 16 Patients With Dysbetalipoproteinemia (Fredrickson

Type III)

Median % Change (min, max)

Median (min, max) at Baseline (mg/dL)

Atorvastatin

10 mg

Atorvastatin

80 mg

Total-C

442 (225, 1320)

-37 (-85, 17)

-58 (-90, -31)

T riglycerides

678 (273, 5990)

-39 (-92, -8)

-53 (-95, -30)

IDL-C + VLDL-C

215 (111, 613)

-32 (-76, 9)

-63 (-90, -8)

non-HDL-C

411 (218, 1272)

-43 (-87, -19)

-64 (-92, -36)

14.5 Homozygous Familial Hypercholesterolemia

In a study without a concurrent control group, 29 patients ages 6 to 37 years with homozygous FH

received maximum daily doses of 20 to 80 mg of atorvastatin. The mean LDL-C reduction in this study

was 18%. Twenty-five patients with a reduction in LDL-C had a mean response of 20% (range of 7% to

53%, median of 24%); the remaining 4 patients had 7% to 24% increases in LDL-C. Five of the 29

patients had absent LDL-receptor function. Of these, 2 patients also had a portacaval shunt and had no

significant reduction in LDL-C. The remaining 3 receptor-negative patients had a mean LDL-C

reduction of 22%.

14.6 Heterozygous Familial Hypercholesterolemia in Pediatric Patients

Significantly different from pravastatin, ANCOVA, p ≤ 0.05

Significantly different from simvastatin, ANCOVA, p ≤ 0.05

In a double-blind, placebo-controlled study followed by an open-label phase, 187 boys and

postmenarchal girls 10 to 17 years of age (mean age 14.1 years) with heterozygous familial

hypercholesterolemia (FH) or severe hypercholesterolemia, were randomized to atorvastatin calcium (n

= 140) or placebo (n = 47) for 26 weeks and then all received atorvastatin calcium for 26 weeks.

Inclusion in the study required 1) a baseline LDL-C level ≥ 190 mg/dL or 2) a baseline LDL-C level ≥

160 mg/dL and positive family history of FH or documented premature cardiovascular disease in a first

or second-degree relative. The mean baseline LDL-C value was 218.6 mg/dL (range: 138.5 to 385.0

mg/dL) in the atorvastatin group compared to 230.0 mg/dL (range: 160.0 to 324.5 mg/dL) in the placebo

group. The dosage of atorvastatin (once daily) was 10 mg for the first 4 weeks and uptitrated to 20 mg

if the LDL-C level was > 130 mg/dL. The number of atorvastatin-treated patients who required

uptitration to 20 mg after Week 4 during the double-blind phase was 78 (55.7%).

Atorvastatin calcium significantly decreased plasma levels of total-C, LDL-C, triglycerides, and

apolipoprotein B during the 26 week double-blind phase (see Table 10).

Table 10. Lipid-Altering Effects of Atorvastatin Calcium in Adolescent Boys and Girls With

Heterozygous Familial Hypercholesterolemia or Severe Hypercholesterolemia (Mean Percentage

Change From Baseline at Endpoint in Intention-to-Treat Population)

DOSAGE

Total-C

LDL-C

HDL-C

Apolipoprotein B

Placebo

-1.5

-0.4

-1.9

Atorvastatin calcium

-31.4

-39.6

-12.0

-34.0

The mean achieved LDL-C value was 130.7 mg/dL (range: 70.0 to 242.0 mg/dL) in the atorvastatin

group compared to 228.5 mg/dL (range: 152.0 to 385.0 mg/dL) in the placebo group during the 26 week

double-blind phase.

The safety and efficacy of doses above 20 mg have not been studied in controlled trials in children. The

long-term efficacy of atorvastatin calcium therapy in childhood to reduce morbidity and mortality in

adulthood has not been established.

15 REFERENCES

National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on

Blood Cholesterol Levels in Children and Adolescents, Pediatrics. 89(3):495-501. 1992.

16 HOW SUPPLIED/STORAGE AND HANDLING

Atorvastatin calcium tablets are available as follows:

40 mg - White to off-white, oval shaped, film-coated tablet, debossed with "TV" on one side and

"5058" on the other side of the tablet. Available in bottles of 90 tablets

NDC 68071-6671-9 Bottles of 90

Storage

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as

required).

17 PATIENT COUNSELING INFORMATION

Patients taking atorvastatin calcium should be advised that cholesterol is a chronic condition and they

should adhere to their medication along with their National Cholesterol Education Program (NCEP)-

recommended diet, a regular exercise program as appropriate, and periodic testing of a fasting lipid

panel to determine goal attainment.

Patients should be advised about substances they should not take concomitantly with atorvastatin

[ see Warnings and Precautions ( 5.1) ]. Patients should also be advised to inform other healthcare

professionals prescribing a new medication that they are taking atorvastatin calcium.

17.1 Muscle Pain

All patients starting therapy with atorvastatin calcium should be advised of the risk of myopathy and told

to report promptly any unexplained muscle pain, tenderness, or weakness particularly if accompanied by

malaise or fever or if these muscle signs or symptoms persist after discontinuing atorvastatin calcium.

The risk of this occurring is increased when taking certain types of medication or consuming larger

quantities (> 1 liter) of grapefruit juice. They should discuss all medication, both prescription and over

the counter, with their healthcare professional.

17.2 Liver Enzymes

It is recommended that liver enzyme tests be performed before the initiation of atorvastatin calcium and

if signs or symptoms of liver injury occur. All patients treated with atorvastatin calcium should be

advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right

upper abdominal discomfort, dark urine, or jaundice.

17.3 Pregnancy

Women of childbearing age should be advised to use an effective method of birth control to prevent

pregnancy while using atorvastatin calcium. Discuss future pregnancy plans with your patients, and

discuss when to stop atorvastatin calcium if they are trying to conceive. Patients should be advised that

if they become pregnant, they should stop taking atorvastatin calcium and call their healthcare

professional.

17.4 Breastfeeding

Women who are breastfeeding should be advised to not use atorvastatin calcium. Patients who have a

lipid disorder and are breastfeeding, should be advised to discuss the options with their healthcare

professional.

All brand names listed are the registered trademarks of their respective owners and are not trademarks

of Teva Pharmaceuticals USA, Inc.

Manufactured In Israel By:

Teva Pharmaceutical Ind. Ltd.

Jerusalem, 9777402, Israel

Manufactured For:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

Rev. A 8/2016

PATIENT INFORMATION

Atorvastatin Calcium Tablets

(a TOR va sta tin)

Read the Patient Information that comes with atorvastatin calcium tablets before you start taking them and

each time you get a refill. There may be new information. This leaflet does not take the place of talking

with your doctor about your condition or treatment.

If you have any questions about atorvastatin calcium tablets, ask your doctor or pharmacist.

What are Atorvastatin Calcium Tablets?

Atorvastatin calcium tablets are a prescription medicine that lowers cholesterol in your blood. They

lower the LDL-C ("bad" cholesterol) and triglycerides in your blood. They can raise your HDL-C

("good" cholesterol) as well. Atorvastatin calcium tablets are for adults and children over 10 whose

cholesterol does not come down enough with exercise and a low-fat diet alone.

Atorvastatin calcium tablets can lower the risk for heart attack, stroke, certain types of heart surgery,

and chest pain in patients who have heart disease or risk factors for heart disease such as:

age, smoking, high blood pressure, low HDL-C, heart disease in the family.

Atorvastatin calcium tablets can lower the risk for heart attack or stroke in patients with diabetes and risk

factors such as:

eye problems, kidney problems, smoking, or high blood pressure.

Atorvastatin calcium tablets start to work in about 2 weeks.

What is Cholesterol?

Cholesterol and triglycerides are fats that are made in your body. They are also found in foods. You

need some cholesterol for good health, but too much is not good for you. Cholesterol and triglycerides

can clog your blood vessels. It is especially important to lower your cholesterol if you have heart

disease, smoke, have diabetes or high blood pressure, are older, or if heart disease starts early in your

family.

Who Should Not Take Atorvastatin Calcium Tablets?

Do not take atorvastatin calcium tablets if you:

are pregnant or think you may be pregnant, or are planning to become pregnant. Atorvastatin calcium

tablets may harm your unborn baby. If you get pregnant, stop taking atorvastatin calcium tablets and

call your doctor right away.

are breast feeding. Atorvastatin can pass into your breast milk and may harm your baby.

have liver problems.

are allergic to atorvastatin calcium tablets or any of their ingredients. The active ingredient is

atorvastatin. See the end of this leaflet for a complete list of ingredients in atorvastatin calcium

tablets.

Atorvastatin calcium tablets have not been studied in children under 10 years of age.

Before You Start Atorvastatin Calcium Tablets

Tell your doctor if you:

have muscle aches or weakness

drink more than 2 glasses of alcohol daily

have diabetes

have a thyroid problem

have kidney problems

Some medicines should not be taken with atorvastatin calcium tablets. Tell your doctor about all the

medicines you take, including prescription and non-prescription medicines, vitamins, and herbal

supplements. Atorvastatin calcium tablets and certain other medicines can interact causing serious side

effects. Especially tell your doctor if you take medicines for:

your immune system

cholesterol

infections

birth control

heart failure

HIV or AIDS

Know all the medicines you take. Keep a list of them with you to show your doctor and pharmacist.

How Should I Take Atorvastatin Calcium Tablets?

Take atorvastatin calcium tablets exactly as prescribed by your doctor. Do not change your dose or

stop atorvastatin calcium tablets without talking to your doctor. Your doctor may do blood tests to

check your cholesterol levels during your treatment with atorvastatin calcium tablets. Your dose of

atorvastatin calcium tablets may be changed based on these blood test results.

Take atorvastatin calcium tablets each day at any time of day at about the same time each day.

Atorvastatin calcium tablets can be taken with or without food.

Don't break atorvastatin calcium tablets before taking.

Your doctor should start you on a low-fat diet before giving you atorvastatin calcium tablets. Stay

on this low-fat diet when you take atorvastatin calcium tablets.

If you miss a dose of atorvastatin calcium tablets, take it as soon as you remember. Do not take

atorvastatin calcium tablets if it has been more than 12 hours since you missed your last dose. Wait

and take the next dose at your regular time. Do not take 2 doses of atorvastatin calcium tablets at the

same time.

If you take too many atorvastatin calcium tablets or overdose, call your doctor or Poison Control

Center right away. Or go to the nearest emergency room.

What Should I Avoid While Taking Atorvastatin Calcium Tablets?

Talk to your doctor before you start any new medicines. This includes prescription and non-

prescription medicines, vitamins, and herbal supplements. Atorvastatin calcium tablets and certain

other medicines can interact causing serious side effects.

Do not get pregnant. If you get pregnant, stop taking atorvastatin calcium tablets right away and call

your doctor.

What are the Possible Side Effects of Atorvastatin Calcium Tablets?

Atorvastatin calcium tablets can cause serious side effects. These side effects have happened

only to a small number of people. Your doctor can monitor you for them. These side effects

usually go away if your dose is lowered or atorvastatin calcium tablets are stopped. These

serious side effects include:

Muscle problems. Atorvastatin calcium tablets can cause serious muscle problems that can lead to

kidney problems, including kidney failure. You have a higher chance for muscle problems if you are

taking certain other medicines with atorvastatin calcium tablets.

Liver problems. Your doctor should do blood tests to check your liver before you start taking

atorvastatin calcium tablets and if you have symptoms of liver problems while you take atorvastatin

calcium tablets. Call your doctor right away if you have the following symptoms of liver problems:

feel tired or weak

loss of appetite

upper belly pain

dark amber colored urine

yellowing of your skin or the whites of your eyes

Call your doctor right away if you have:

muscle problems like weakness, tenderness, or pain that happen without a good reason, especially if

you also have a fever or feel more tired than usual. This may be an early sign of a rare muscle

problem.

muscle problems that do not go away even after your doctor has advised you to stop taking

atorvastatin calcium tablets. Your doctor may do further tests to diagnose the cause of your muscle

problems.

allergic reactions including swelling of the face, lips, tongue, and/or throat that may cause difficulty

in breathing or swallowing which may require treatment right away.

nausea and vomiting.

passing brown or dark-colored urine.

you feel more tired than usual

your skin and whites of your eyes get yellow.

stomach pain.

allergic skin reactions.

In clinical studies, patients reported the following common side effects while taking atorvastatin

calcium tablets: diarrhea, upset stomach, muscle and joint pain, and alterations in some laboratory blood

tests.

The following additional side effects have been reported with atorvastatin calcium tablets: tiredness,

tendon problems, memory loss, and confusion.

Talk to your doctor or pharmacist if you have side effects that bother you or that will not go away.

These are not all the side effects of atorvastatin calcium tablets. Ask your doctor or pharmacist for a

complete list.

How do I store Atorvastatin Calcium Tablets

Store atorvastatin calcium tablets at room temperature, 68º to 77ºF (20º to 25ºC).

Do not keep medicine that is out of date or that you no longer need.

Keep atorvastatin calcium tablets and all medicines out of the reach of children. Be sure that if

you throw medicine away, it is out of the reach of children.

General Information About Atorvastatin Calcium Tablets

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets.

Do not use atorvastatin calcium tablets for a condition for which they were not prescribed. Do not give

atorvastatin calcium tablets to other people, even if they have the same problem you have. They may

harm them.

This leaflet summarizes the most important information about atorvastatin calcium tablets. If you would

like more information, talk with your doctor. You can ask your doctor or pharmacist for information

about atorvastatin calcium tablets that is written for health professionals. Or you can call 1-888-838-

2872.

What are the Ingredients in Atorvastatin Calcium Tablets?

Active Ingredient: atorvastatin calcium

Inactive Ingredients: calcium carbonate, croscarmellose sodium, hydroxypropyl cellulose,

hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene

glycol, polysorbate, talc and titanium dioxide

Manufactured In Israel By:

Teva Pharmaceutical Ind. Ltd.

Jerusalem, 9777402, Israel

Manufactured For:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

Rev. A 8/2016

Package/Label Display Panel

Atorvastatin Calcium Tablets 10 mg 90s Label Text

NDC 0093 -5056-98

Atorvastatin

Calcium Tablets

10 mg*

PHARMACIST: PLEASE DISPENSE

WITH ATTACHED PATIENT

INFORMATION LEAFLET

Rx only

90 TABLETS

TEVA

ATORVASTATIN CALCIUM

atorvastatin calcium tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 8 0 71-3371(NDC:0 0 9 3-50 58 )

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of

Stre ng th

Stre ng th

ATO RVASTATIN CALCIUM TRIHYDRATE (UNII: 48 A5M73Z4Q) (ATORVASTATIN -

UNII:A0 JWA8 5V8 F)

ATORVASTATIN

40 mg

NuCare Pharmaceuticals,Inc.

Inactive Ingredients

Ingredient Name

Stre ng th

CALCIUM CARBO NATE (UNII: H0 G9 379 FGK)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

HYDRO XYPRO PYL CELLULO SE ( 2 0 0 0 0 0 MW) (UNII: 5Y0 9 74F5PW)

HYPRO MELLO SE 2 9 10 ( 6 MPA.S) (UNII: 0 WZ8 WG20 P6 )

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

PO LYETHYLENE GLYCO L 6 0 0 0 (UNII: 30 IQX730 WE)

PO LYSO RBATE 8 0 (UNII: 6 OZP39 ZG8 H)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

Product Characteristics

Color

white (white to o ff-white)

S core

no sco re

S hap e

OVAL

S iz e

16 mm

Flavor

Imprint Code

TV;50 58

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 8 0 71-3371-9

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/20 /20 17

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 530 0

0 4/26 /20 17

Labeler -

NuCare Pharmaceuticals,Inc. (010632300)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

NuCare Pharmaceuticals,Inc.

0 10 6 3230 0

re la be l(6 8 0 71-3371)

Revised: 7/2017

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