ATORVASTATIN CALCIUM tablet, film coated

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Active ingredient:
ATORVASTATIN CALCIUM TRIHYDRATE (UNII: 48A5M73Z4Q) (ATORVASTATIN - UNII:A0JWA85V8F)
Available from:
DirectRX
INN (International Name):
ATORVASTATIN CALCIUM PROPYLENE GLYCOL SOLVATE
Composition:
ATORVASTATIN 80 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. 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 clini
Authorization status:
Abbreviated New Drug Application
Authorization number:
61919-531-30, 61919-531-90

ATORVASTATIN CALCIUM- atorvastatin calcium tablet, film coated

DirectRX

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ATORVASTATIN CALCIUM

INDICATIONS & USAGE SECTION

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

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:

a. LDL-C remains ≥ 190 mg/dL or

b. 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).

DOSAGE & ADMINISTRATION SECTION

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

Types IIa and IIb)

The recommended starting dose of atorvastatin calcium tablets are 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 are 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; 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 should be avoided. In patients

with HIV taking lopinavir plus ritonavir, caution should be used when prescribing atorvastatin 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 should be limited to 20 mg, and

appropriate clinical assessment is recommended to ensure that the lowest dose necessary of

atorvastatin is employed. In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C

protease inhibitor boceprevir, therapy with atorvastatin should be limited to 40 mg, and appropriate

clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin is

employed [see Warnings and Precautions, Skeletal Muscle (5.1), Drug Interactions (7)].

DOSAGE FORMS & STRENGTHS SECTION

White, oval, biconvex, film-coated tablets containing 10, 20, 40, and 80 mg atorvastatin calcium.

CONTRAINDICATIONS SECTION

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 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 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 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 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 treatment should not breastfeed their

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

WARNINGS AND PRECAUTIONS SECTION

5.1 Skeletal Muscle

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

reported with atorvastatin 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. Atorvastatin 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 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

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

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 co-administered

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

Drug Interactions (7.11)].

Atorvastatin 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).

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 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.

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

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

Atorvastatin 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 [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.

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

steroid production. Clinical studies have shown that atorvastatin 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 to 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 to 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 calcium 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 calcium 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)].

ADVERSE REACTIONS SECTION

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 patents treated with any dose of atorvastatin

calcium 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

* Adverse Reaction ≥ 2% in any dose greater than placebo

Nasopharyngitis 8.3 12.9 5.3 7.0 4.2 8.2

Arthralgia 6.9 8.9 11.7 10.6 4.3 6.5

Diarrhea 6.8 7.3 6.4 14.1 5.2 6.3

Pain in extremity 6.0 8.5 3.7 9.3 3.1 5.9

Urinary tract infection 5.7 6.9 6.4 8.0 4.1 5.6

Dyspepsia 4.7 5.9 3.2 6.0 3.3 4.3

Nausea 4.0 3.7 3.7 7.1 3.8 3.5

Musculoskeletal pain 3.8 5.2 3.2 5.1 2.3 3.6

Muscle Spasms 3.6 4.6 4.8 5.1 2.4 3.0

Myalgia 3.5 3.6 5.9 8.4 2.7 3.1

Insomnia 3.0 2.8 1.1 5.3 2.8 2.9

Pharyngolaryngeal pain 2.3 3.9 1.6 2.8 0.7 2.1

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 calcium 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 calcium 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 calcium 10 mg daily (n=5006) or atorvastatin calcium 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 calcium

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 calcium 80 mg (n=2365) or placebo

(n=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 calcium 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 calcium 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 calcium 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 calcium 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 calcium 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)].

DRUG INTERACTIONS SECTION

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 is metabolized by cytochrome P450 3A4. Concomitant administration of atorvastatin

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 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 with

several combinations of HIV protease inhibitors, as well as with the hepatitis C protease inhibitor

telaprevir, compared to that of atorvastatin 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 should be avoided. In patients taking the HIV

protease inhibitor lopinavir plus ritonavir, caution should be used when prescribing atorvastatin 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 alone [see Clinical Pharmacology (12.3)]. The co-

administration of atorvastatin 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 co-

administered with gemfibrozil, concomitant administration of atorvastatin 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 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 is used in combination with

niacin; a reduction in atorvastatin 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 with inducers of cytochrome P450 3A4 (e.g., efavirenz,

rifampin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual

interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is

recommended, as delayed administration of atorvastatin after administration of rifampin has been

associated with a significant reduction in atorvastatin plasma concentrations.

7.8 Digoxin

When multiple doses of atorvastatin and digoxin were co-administered, steady state plasma digoxin

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

appropriately.

7.9 Oral Contraceptives

Co-administration of atorvastatin and an oral contraceptive increased AUC values for norethindrone

and ethinyl estradiol [see Clinical Pharmacology (12.3)]. These increases should be considered

when selecting an oral contraceptive for a woman taking atorvastatin.

7.10 Warfarin

Atorvastatin 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 co-administered

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

USE IN SPECIFIC POPULATIONS SECTION

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/m2) [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 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

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 therapy [see Contraindications, Pregnancy

(4.3) and Use in Specific Populations, Pregnancy (8.1)]. Atorvastatin 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)].

OVERDOSAGE SECTION

There is no specific treatment for atorvastatin overdosage. In the event of an overdose, the patient

should be treated symptomatically, and supportive measures instituted as required. Due to extensive

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

clearance.

DESCRIPTION SECTION

Atorvastatin calcium is a synthetic lipid-lowering agent. Atorvastatin is an inhibitor of 3-hydroxy-3-

methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-

CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis.

The drug substance used in atorvastatin calcium tablets is atorvastatin calcium in the form of propylene

glycol solvate. The chemical name for atorvastatin calcium propylene glycol solvate is calcium

bis((3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-

dihydroxyheptanoate) propylene glycol solvate. The empirical formula of atorvastatin calcium

propylene glycol solvate is C66H68CaF2N4O10 * C3H8O2 and its molecular weight is 1231.46. Its

structural formula is:

chemical-structure

Atorvastatin calcium is a white to off-white solid that is insoluble in aqueous solutions of pH 4 and

below. Atorvastatin calcium is slightly soluble in distilled water, pH 7.4 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 acetate, croscarmellose sodium, sodium carbonate,

microcrystalline cellulose, magnesium stearate (vegetable source), colloidal silicon dioxide,

hypromellose, hydroxypropyl cellulose, polyethylene glycol and titanium dioxide.

CLINICAL PHARMACOLOGY SECTION

12.1 Mechanism of Action

Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme

that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols,

including cholesterol. 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, as well as some of its metabolites, are pharmacologically active in humans. The liver

is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug

dosage, rather than systemic drug concentration, correlates better with LDL-C reduction.

Individualization of drug dosage should be based on therapeutic response [see Dosage and

Administration (2)].

12.3 Pharmacokinetics

Absorption

Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur

within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute

bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of

HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is

attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism.

Although food decreases the rate and extent of drug absorption by approximately 25% and 9%,

respectively, as assessed by Cmax and AUC, LDL-C reduction is similar whether atorvastatin is

given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for

Cmax and AUC) following evening drug administration compared with morning. However, LDL-C

reduction is the same regardless of the time of day of drug administration [see Dosage and

Administration (2)].

Distribution

Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is ≥98% bound

to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into

red blood cells. Based on observations in rats, atorvastatin is likely to be secreted in human milk

[see Contraindications, Nursing Mothers (4.4) and Use in Specific Populations, Nursing Mothers

(8.3)].

Metabolism

Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-

oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated

metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity

for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance

of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma

concentrations of atorvastatin in humans following co-administration with erythromycin, a known

inhibitor of this isozyme [see Drug Interactions (7.1)]. In animals, the ortho-hydroxy metabolite

undergoes further glucuronidation.

Excretion

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

hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation.

Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-

life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of

active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral

administration.

Specific Populations

Geriatric

Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC)

in healthy elderly subjects (age ≥65 years) than in young adults. Clinical data suggest a greater

degree of LDL-lowering at any dose of drug in the elderly patient population compared to younger

adults [see Use in Specific Populations, Geriatric Use (8.5)].

Pediatric

Pharmacokinetic data in the pediatric population are not available.

Gender

Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher

for Cmax and 10% lower for AUC); however, there is no clinically significant difference in LDL-C

reduction with atorvastatin between men and women.

Renal Impairment

Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin;

thus, dose adjustment in patients with renal dysfunction is not necessary [see Dosage and

Administration, Dosage in Patients with Renal Impairment (2.5), Warnings and Precautions, Skeletal

Muscle (5.1)].

Hemodialysis

While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not

expected to significantly enhance clearance of atorvastatin since the drug is extensively bound to

plasma proteins.

Hepatic Impairment

In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly

increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and

AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B

disease [see Contraindications (4.1)].

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

Co-administered drug and dosing

regimen

Atorvas tatin

Dose (mg)

Change in

AUC&

Change in

Cmax&

#Cyclosporine 5.2 mg/kg/day, stable

dose

10 mg QD for 28 days

↑ 8.7 fold

↑10.7 fold

#Tipranavir 500 mg BID/ritonavir

200 mg BID, 7 days

10 mg, SD

↑ 9.4 fold

↑ 8.6 fold

#Telaprevir 750 mg q8h, 10 days

20 mg, SD

↑ 7.88 fold

↑ 10.6 fold

#, ‡Saquinavir 400 mg BID/ ritonavir

400mg BID, 15 days

40 mg QD for 4 days

↑ 3.9 fold

↑ 4.3 fold

#Clarithromycin 500 mg BID, 9 days

80 mg QD for 8 days

↑ 4.4 fold

↑ 5.4 fold

#Darunavir 300 mg BID/ritonavir 100

mg BID, 9 days

10 mg QD for 4 days

↑ 3.4 fold

↑ 2.25 fold

#Itraconazole 200 mg QD, 4 days

40 mg SD

↑ 3.3 fold

↑ 20%

#Fosamprenavir 700 mg

BID/ritonavir 100 mg BID, 14 days

10 mg QD for 4 days

↑ 2.53 fold

↑ 2.84 fold

#Fosamprenavir 1400 mg BID, 14

days

10 mg QD for 4 days

↑ 2.3 fold

↑ 4.04 fold

#Nelfinavir 1250 mg BID, 14 days

10 mg QD for 28 days

↑ 74%

↑ 2.2 fold

#Grapefruit Juice, 240 mL QD *

40 mg, SD

↑ 37%

↑ 16%

Diltiazem 240 mg QD, 28 days

40 mg, SD

↑ 51%

No change

Erythromycin 500 mg QID, 7 days

10 mg, SD

↑ 33%

↑ 38%

Amlodipine 10 mg, single dose

80 mg, SD

↑ 15%

↓ 12 %

Cimetidine 300 mg QID, 2 weeks

10 mg QD for 2 weeks

↓ Less than

↓ 11%

Colestipol 10 mg BID, 28 weeks

40 mg QD for 28 weeks

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 (co-

administered) †

40 mg SD

↑ 30%

↑ 2.7 fold

#Rifampin 600 mg QD, 5 days (doses

separated) †

40 mg SD

↓ 80%

↓ 40%

#Gemfibrozil 600mg BID, 7 days

40mg SD

↑ 35%

↓ Less than

#Fenofibrate 160mg QD, 7 days

40mg SD

↑ 3%

↑ 2%

Boceprevir 800 mg TID, 7 days

40 mg SD

↑2.30 fold

↑2.66 fold

& Data given as x-fold change represent a simple ratio between co-administration and atorvastatin

alone (i.e., 1-fold = no change). Data given as % change represent % difference relative to

atorvastatin alone (i.e., 0% = no change).

# See Sections 5.1 and 7 for clinical significance.

* Greater increases in AUC (up to 2.5 fold) and/or Cmax (up to 71%) have been reported with

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

** Single sample taken 8 to 16 h post dose.

† Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin

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

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

‡ The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in

atorvastatin exposure when used clinically is likely to be higher than what was observed in this

study. Therefore, caution should be applied and the lowest dose necessary should be used.

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

Atorvas tatin

Co-administered drug

and dosing regimen

Drug/Dose (mg)

Change in AUC

Change in Cmax

80 mg QD for 15 days

Antipyrine, 600 mg SD ↑ 3%

↓ 11%

80 mg QD for 14 days

#Digoxin 0.25 mg QD,

20 days

↑ 15%

↑ 20 %

40 mg QD for 22 days

Oral contraceptive QD,

2 months

- norethindrone 1mg

- ethinyl estradiol

35mcg

↑ 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

# See Section 7 for clinical significance.

NONCLINICAL TOXICOLOGY SECTION

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year carcinogenicity study in rats at dose levels of 10, 30, and 100 mg/kg/day, 2 rare tumors were

found in muscle in high-dose females: in one, there was a rhabdomyosarcoma and, in another, there was

a fibrosarcoma. This dose represents a plasma AUC (0 to 24) value of approximately 16 times the mean

human plasma drug exposure after an 80 mg oral dose.

A 2-year carcinogenicity study in mice given 100, 200, or 400 mg/kg/day resulted in a significant

increase in liver adenomas in high-dose males and liver carcinomas in high-dose females. These

findings occurred at plasma AUC (0 to 24) values of approximately 6 times the mean human plasma drug

exposure after an 80 mg oral dose.

In vitro, atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic

activation: the Ames test with Salmonella typhimurium and Escherichia coli, the HGPRT forward

mutation assay in Chinese hamster lung cells, and the chromosomal aberration assay in Chinese hamster

lung cells. Atorvastatin was negative in the in vivo mouse micronucleus test.

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.

CLINICAL STUDIES SECTION

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%), 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 calcium 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 calcium 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.

Figure 1: Effect of Atorvastatin Calcium 10 mg/day on Cumulative Incidence of Non-Fatal

Myocardial Infarction or Coronary Heart Disease Death (in ASCOT-LLA)

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 calcium 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 HbA1c 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 calcium 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% 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).

Figure 2: Effect of Atorvastatin Calcium 10 mg/day on Time to Occurrence of Major

Cardiovascular Event (myocardial infarction, acute CHD death, unstable angina, coronary

revascularization, or stroke) in CARDS

In the Treating to New Targets Study (TNT), the effect of atorvastatin calcium 80 mg/day vs.

atorvastatin calcium 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 calcium 10 mg/day. Subjects were randomly assigned to either 10 mg/day or

80 mg/day of atorvastatin calcium 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 calcium and 99,

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

Treatment with atorvastatin calcium 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.

Figure 3: Effect of Atorvastatin Calcium 80 mg/day vs. 10 mg/day on Time to Occurrence of Major

Cardiovascular Events (TNT)

TABLE 5. Overview of Efficacy Results in TNT

Endpoint

Atorvas tatin

10

mg

(N=5006)

Atorvas tatin

80

mg

(N=4995)

HRa

(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

procedureb

(18.1)

(13.4)

0.72 (0.65, 0.80)

First documented angina

endpointb

(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)

a Atorvastatin 80 mg: atorvastatin 10 mg

b Component of other secondary endpoints

* Secondary endpoints not included in primary endpoint

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

Of the events that comprised the primary efficacy endpoint, treatment with atorvastatin calcium 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 calcium 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 calcium 80 mg group than in

the atorvastatin calcium 10 mg treatment group. The proportions of subjects who experienced

noncardiovascular death were numerically larger in the atorvastatin calcium 80 mg group than in the

atorvastatin calcium 10 mg treatment group.

In the Incremental Decrease in Endpoints Through Aggressive Lipid Lowering Study (IDEAL),

treatment with atorvastatin calcium 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 calcium 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 calcium 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 calcium 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 calcium 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

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)a

Dos e

N TC LDL-C

Apo B TG HDL-C

Non-HDL-C/HDL-C

Placebo

22 -29

20 -33

21 -37

23 -45

a Results are pooled from 2 dose-response studies.

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

trials, the median (25th and 75th 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)

N

Total-C

LDL-C

Apo B

TG

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

Study 1

Atorvastatin 10 mg 707

-27a

-36a

-28a

-17a

-37a

Lovastatin 20 mg

95% CI for Diff1

-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 222

-25b

-35b

-27b

-17b

-36b

Pravastatin 20 mg

95% CI for Diff1

-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 132

-29c

-37c

-34c

-23c

-39c

Simvastatin 10 mg

95% CI for Diff1

-8.7, -2.7 -10.1, -2.6 -8.0, -1.1 -15.1, -0.7 -4.3, 3.9

-9.6, -1.9

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

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

indicates a statistically significant difference.

a Significantly different from lovastatin, ANCOVA, p ≤0.05

b Significantly different from pravastatin, ANCOVA, p ≤0.05

c Significantly different from simvastatin, 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)

Triglycerides -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 calcium. 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

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 calcium group compared to 230.0 mg/dL (range:

160.0 to 324.5 mg/dL) in the placebo group. The dosage of atorvastatin calcium (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 calcium-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

N Total-C LDL-C HDL-C TG Apolipoprotein B

Placebo

-1.5

-0.4

-1.9

Atorvastatin Calcium Tablets 140

-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

calcium 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 therapy in childhood to reduce morbidity and mortality in

adulthood has not been established.

PATIENT MEDICATION INFORMATION SECTION

Patients taking atorvastatin calcium tablets 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 tablets.

17.1 Muscle Pain

All patients starting therapy with atorvastatin calcium tablets 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

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

tablets and if signs or symptoms of liver injury occur. All patients treated with atorvastatin calcium

tablets 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 tablets. Discuss future pregnancy plans with your

patients, and discuss when to stop atorvastatin calcium tablets if they are trying to conceive. Patients

should be advised that if they become pregnant, they should stop taking atorvastatin calcium tablets

and call their healthcare professional.

17.4 Breastfeeding

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

who have a lipid disorder and are breast-feeding, should be advised to discuss the options with their

healthcare professional.

Maalox TC® is a registered trademark of Novartis Consumer Health Inc.

APOTEX INC.

ATORVASTATIN CALCIUM TABLETS

10 mg, 20 mg, 40 mg, and 80 mg

Manufactured By Manufactured For

Apotex Inc.

Apotex Corp.

Toronto, ON

Weston, Florida

Canada, M9L 1T9 33326

Revised: July 2015

Rev. 8

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

ATORVASTATIN CALCIUM

atorvastatin calcium tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 19 19 -531(NDC:6 0 50 5-26 71)

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

8 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

CALCIUM ACETATE (UNII: Y8 8 2YXF34X)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

SO DIUM CARBO NATE (UNII: 45P326 1C7T)

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

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

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

HYDRO XYPRO PYL CELLULO SE ( 16 0 0 0 0 0 WAMW) (UNII: RFW2ET6 71P)

PO LYETHYLENE GLYCO L 8 0 0 0 (UNII: Q6 6 2QK8 M3B)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

Product Characteristics

Color

white

S core

no sco re

S hap e

OVAL

S iz e

19 mm

Flavor

Imprint Code

APO;ATV8 0

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 19 19 -531-30

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

0 1/0 1/20 15

2

NDC:6 19 19 -531-9 0

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

0 1/0 1/20 15

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 9 0 548

0 1/0 1/20 15

Labeler -

DirectRX (079254320)

Dire ctRX

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Dire c tRX

0 79 254320

re pa c k(6 19 19 -531)

Revised: 10/2019

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