1 INDICATIONS AND USAGE Amlodipine and atorvastatin tablets are indicated in patients for whom treatment with both amlodipine and atorvastatin is appropriate.

Amlodipine Hypertension Amlodipine is indicated for the treatment of hypertension, to lower blood pressure.

Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions.

These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including amlodipine.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake.

Many patients will require more than one drug to achieve blood pressure goals.

For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits.

The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit.

Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease).

These considerations may guide selection of therapy.

Amlodipine may be used alone or in combination with other antihypertensive agents.

Coronary Artery Disease (CAD) Chronic Stable Angina Amlodipine is indicated for the symptomatic treatment of chronic stable angina.

Amlodipine may be used alone or in combination with other antianginal agents.

Vasospastic Angina (Prinzmetal’s or Variant Angina) Amlodipine is indicated for the treatment of confirmed or suspected vasospastic angina.

Amlodipine may be used as monotherapy or in combination with other antianginal agents.

Angiographically Documented CAD In patients with recently documented CAD by angiography and without heart failure or an ejection fraction < 40%, amlodipine is indicated to reduce the risk of hospitalization for angina and to reduce the risk of a coronary revascularization procedure.

Atorvastatin Atorvastatin is 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 Amlodipine and atorvastatin tablets are a combination of amlodipine besylate, a calcium channel blocker, and atorvastatin calcium, a HMG CoA-reductase inhibitor (statin), indicated in patients for whom treatment with both amlodipine and atorvastatin is appropriate ( 1 ).

Amlodipine is indicated for the treatment of hypertension, to lower blood pressure.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

Amlodipine is indicated for the treatment of Coronary Artery Disease ( 1 ).

Atorvastatin is 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 ( 5.6 )] Most common adverse reaction to amlodipine is edema which occurred in a dose related manner ( 6.1 ).

Most common adverse reactions (incidence ≥5%) are nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract infection to atorvastatin ( 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.

Amlodipine and Atorvastatin Amlodipine and atorvastatin has been evaluated for safety in 1,092 patients in double-blind placebo-controlled studies treated for co-morbid hypertension and dyslipidemia.

In general, treatment with amlodipine and atorvastatin was well tolerated.

For the most part, adverse reactions have been mild or moderate in severity.

In clinical trials with amlodipine and atorvastatin, no adverse reactions peculiar to this combination have been observed.

Adverse reactions are similar in terms of nature, severity, and frequency to those reported previously with amlodipine and atorvastatin.

The following information is based on the clinical experience with amlodipine and atorvastatin.

Amlodipine Amlodipine has been evaluated for safety in more than 11,000 patients in U.S.

and foreign clinical trials.

In general, treatment with amlodipine was well tolerated at doses up to 10 mg daily.

Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity.

In controlled clinical trials directly comparing amlodipine (N=1,730) at doses up to 10 mg to placebo (N=1,250), discontinuation of amlodipine because of adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%).

The most commonly reported side effects more frequent than placebo are dizziness and edema.

The incidence (%) of side effects that occurred in a doserelated manner are as follows: Amlodpine 2.5 mg N=275 5 mg N=296 10 mg N=268 Placebo N=520 Edema 1.8 3 10.8 0.6 Dizziness 1.1 3.4 3.4 1.5 Flushing 0.7 1.4 2.6 0 Palpitations 0.7 1.4 4.5 0.6 Other adverse reactions that were not clearly dose related but were reported at an incidence greater than 1.0% in placebo-controlled clinical trials include the following: Amlodipine (%) (N=1,730) Placebo (%) (N=1,250) Fatigue 4.5 2.8 Nausea 2.9 1.9 Abdominal Pain 1.6 0.3 Somnolece 1.4 0.6 Edema, flushing, palpitations, and somnolence appear to be more common in women than in men.

The following events occurred in < 1% but > 0.1% of patients treated with amlodipine in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship: Cardiovascular : arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, tachycardia, vasculitis.

Central and Peripheral Nervous System : hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo.

Gastrointestinal : anorexia, constipation, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.

General : allergic reaction, asthenia, 2 back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease.

Musculoskeletal System : arthralgia, arthrosis, muscle cramps, 2 myalgia.

Psychiatric : sexual dysfunction (male 2 and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization.

Respiratory System : dyspnea, 2 epistaxis.

Skin and Appendages : angioedema, erythema multiforme, pruritus, 2 rash, 2 rash erythematous, rash maculopapular.

Special Senses : abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus.

Urinary System : micturition frequency, micturition disorder, nocturia.

Autonomic Nervous System : dry mouth, sweating increased.

Metabolic and Nutritional : hyperglycemia, thirst.

Hemopoietic : leukopenia, purpura, thrombocytopenia.

2 These events occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies.

Amlodipine therapy has not been associated with clinically significant changes in routine laboratory tests.

No clinically relevant changes were noted in serum potassium, serum glucose, total TG, TC, HDL-C, uric acid, blood urea nitrogen, or creatinine.

Atorvastatin In the atorvastatin placebo-controlled clinical trial database of 16,066 patients (8,755 atorvastatin 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 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 2 summarizes adverse reactions, reported in ≥ 2% and at a rate greater than placebo in patients treated with atorvastatin (n=8,755), from seventeen placebo-controlled trials.

Table 2.

Adverse Reactions Occurring in ≥ 2% in Patients Atorvastatin-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 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 Urinary tract infection 5.6 6.9 6.4 8 4.1 5.7 Dyspepsia 4.3 5.9 3.2 6 3.3 4.7 Nausea 3.5 3.7 3.7 7.1 3.8 4 Musculoskeletal pain 3.6 5.2 3.2 5.1 2.3 3.8 Muscle spasms 3 4.6 4.8 5.1 2.4 3.6 Myalgia 3.1 3.6 5.9 8.4 2.7 3.5 Insomnia 3.9 2.8 1.1 5.3 2.8 3 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 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.

Treating to New Targets Study (TNT) In TNT [see Clinical Studies ( 14.6 )] 10,001 subjects (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 10 mg daily (n=5,006) or atorvastatin 80 mg daily (n=4,995).

In the high-dose atorvastatin 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 80 mg and in 0.2% of individuals with atorvastatin 10 mg.

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

Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) In SPARCL involving 4,731 patients (age range 21 years 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 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 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 6.1% of subjects in the atorvastatin group and 3.8% of subjects in the placebo group.

In a post-hoc analysis, atorvastatin 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 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).

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

4% placebo).

Adverse Reactions from Clinical Studies of Atorvastatin 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 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 ( 14.11 )].

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of amlodipine and atorvastatin.

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.

Amlodipine The following postmarketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia.

In postmarketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.

Postmarketing reporting has also revealed a possible association between extrapyramidal disorder and amlodipine.

Amlodipine has been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.

Atorvastatin 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)