1 INDICATIONS AND USAGE Atorvastatin Calcium Tablets are indicated: To reduce the risk of: Myocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD MI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD Non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure, and angina in adults with clinically evident CHD As an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) in: Adults with primary hyperlipidemia.

Adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH).

As an adjunct to other LDL-C-lowering therapies, or alone if such treatments are unavailable, to reduce LDL-C in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia (HoFH).

As an adjunct to diet for the treatment of adults with: Primary dysbetalipoproteinemia Hypertriglyceridemia Atorvastatin calcium tablets are an HMG-CoA reductase inhibitor (statin) indicated ( 1 ): To reduce the risk of: Myocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD.

MI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD.

Non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure, and angina in adults with clinically evident CHD.

As an adjunct to diet to reduce low-density lipoprotein (LDL-C) in: Adults with primary hyperlipidemia.

Adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH).

As an adjunct to other LDL-C-lowering therapies to reduce LDL-C in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia.

As an adjunct to diet for the treatment of adults with: Primary dysbetalipoproteinemia.

Hypertriglyceridemia.

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Myopathy and Rhabdomyolysis [see Warnings and Precautions ( 5.1 )] Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions ( 5.2 )] Hepatic Dysfunction [see Warnings and Precautions ( 5.3 )] Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions ( 5.4 )] Most common adverse reactions (incidence ≥ 5%) are nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract infection ( 6.1 ).

To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp.

at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In the atorvastatin calcium placebo-controlled clinical trial database of 16,066 patients (8,755 atorvastatin calcium vs.

7,311 placebo; age range 10 to 93 years, 39% female, 91% White, 3% Black or African American, 2% Asian, 4% other) with a median treatment duration of 53 weeks, the 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%).

Table 1 summarizes adverse reactions reported in ≥ 2% and at a rate greater than placebo in patients treated with atorvastatin calcium (n=8,755), from seventeen placebo-controlled trials.

Table 1: Adverse Reactions Occurring in ≥ 2% in Patients Atorvastatin Calcium-Treated with any Dose and Greater than Placebo Adverse Reaction % Placebo N=7,311 % 10 mg N=3,908 % 20 mg N=188 % 40 mg N=604 % 80 mg N=4,055 % Any dose N=8,755 Nasopharyngitis 8.2 12.9 5.3 7.0 4.2 8.3 Arthralgia 6.5 8.9 11.7 10.6 4.3 6.9 Diarrhea 6.3 7.3 6.4 14.1 5.2 6.8 Pain in extremity 5.9 8.5 3.7 9.3 3.1 6.0 Urinary tract infection 5.6 6.9 6.4 8.0 4.1 5.7 Dyspepsia 4.3 5.9 3.2 6.0 3.3 4.7 Nausea 3.5 3.7 3.7 7.1 3.8 4.0 Musculoskeletal pain 3.6 5.2 3.2 5.1 2.3 3.8 Muscle spasms 3.0 4.6 4.8 5.1 2.4 3.6 Myalgia 3.1 3.6 5.9 8.4 2.7 3.5 Insomnia 2.9 2.8 1.1 5.3 2.8 3.0 Pharyngolaryngeal pain 2.1 3.9 1.6 2.8 0.7 2.3 Other adverse reactions reported in placebo-controlled trials 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 Elevations in Liver Enzyme Tests Persistent elevations in serum transaminases, defined as more than 3 times the ULN and occurring on 2 or more occasions, 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 enzyme tests 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 liver enzyme elevations continued treatment with a reduced dose of atorvastatin calcium.

Treating to New Targets Study (TNT) In TNT, [see Clinical Studies ( 14.1 )] 10,001 patients (age range 29 to 78 years, 19% female; 94% White, 3% Black or African American, 1% Asian, 2% other) with clinically evident CHD were treated with atorvastatin calcium 10 mg daily (n=5,006) or atorvastatin calcium 80 mg daily (n=4,995).

In the high-dose atorvastatin calcium group there were more patients with serious adverse reactions (1.8%) and discontinuations due to adverse reactions (9.9%) as compared to the low-dose group (1.4%; 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 1.3% of individuals with atorvastatin calcium 80 mg and in 0.2% of individuals with atorvastatin calcium 10 mg.

Elevations of CK (≥ 10 x ULN) were higher in the high-dose atorvastatin calcium group (0.3%) compared to the low-dose atorvastatin calcium group (0.1%).

Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) In SPARCL, 4,731 patients (age range 21 to 92 years, 40% female; 93% White, 3% Black or African American, 1% Asian, 3% other) without clinically evident CHD but with a stroke or transient ischemic attack (TIA) within the previous 6 months were treated with atorvastatin calcium 80 mg (n=2,365) or placebo (n=2,366) 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 calcium group (0.9%) compared to placebo (0.1%).

Elevations of CK (>10 x ULN) were rare, but were higher in the atorvastatin calcium group (0.1%) compared to placebo (0%).

Diabetes was reported as an adverse reaction in 6.1% of subjects in the atorvastatin calcium group and 3.8% of subjects in the placebo group.

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

11.6%) and increased the incidence of hemorrhagic stroke (2.3% vs.

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 calcium group (38 non-fatal hemorrhagic strokes) as compared to the placebo group (16 non-fatal hemorrhagic strokes).

Patients who entered the trial with a hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke (16% atorvastatin calcium vs.

4% placebo).

Adverse Reactions from Clinical Studies of Atorvastatin Calcium in Pediatric Patients with HeFH In a 26-week controlled study in pediatric patients with HeFH (ages 10 years to 17 years) (n=140, 31% female; 92% White, 1.6% Black or African American, 1.6% Asian, 4.8% other), the safety and tolerability profile of atorvastatin calcium 10 to 20 mg daily, as an adjunct to diet to reduce total cholesterol, LDL-C, and apo B levels, was generally similar to that of placebo [see Use in Specific Populations ( 8.4 ) and Clinical Studies ( 14.6 )] .

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval 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.

Gastrointestinal Disorders : pancreatitis General Disorders : fatigue Hepatobiliary Disorders : fatal and non-fatal hepatic failure Immune System Disorders : anaphylaxis Injury : tendon rupture Musculoskeletal and Connective Tissue Disorders : rhabdomyolysis, myositis.

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

Nervous System Disorders : dizziness, peripheral neuropathy.

There have been rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with the use of all statins.

Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered.

Psychiatric Disorders : depression Respiratory Disorders : interstitial lung disease Skin and Subcutaneous Tissue Disorders : angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis).