Atomoxetine hydrochloride Capsule

Atomoxetine capsules are a selective norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of ADHD in adults and pediatric patients 6 years of age and older. (1) Atomoxetine capsules are indicated for the treatment of attention-deficit/hyperactivity disorder (ADHD) in adults and pediatric patients 6 years of age and older.

Atomoxetine capsules are indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with ADHD.

Contraindicated in patients (4): • With known hypersensitivity to atomoxetine or other constituents of atomoxetine capsules.

• Taking or within 14 days of stopping, a monoamine oxidase inhibitor (MAOI)

• With narrow angle glaucoma

• With pheochromocytoma or history of pheochromocytoma

• With severe cardiac or vascular disorders whose condition would be expected to deteriorate with clinically important increases in blood pressure or heart rate Atomoxetine capsules are contraindicated in patients: • With known hypersensitivity reaction to atomoxetine or other constituents of atomoxetine capsules. Hypersensitivity reactions included anaphylaxis, angioneurotic edema, urticaria, and rash

[see Warnings and Precautions (5.8)].

• Taking, or within 14 days of stopping, a monoamine oxidase inhibitor (MAOI)

[see Drug Interactions (7)].

• With narrow angle glaucoma. In clinical trials, atomoxetine capsules use was associated with an increased risk of mydriasis.

• With pheochromocytoma or a history of pheochromocytoma. Serious reactions, including elevated blood pressure and tachyarrhythmia, have been reported in patients with pheochromocytoma or a history of pheochromocytoma who received atomoxetine capsules.

• With severe cardiac or vascular disorders whose condition would be expected to deteriorate if they had a clinically important increase in blood pressure or heart rate (e.g., 15 to 20 mm Hg in blood pressure or 20 beats per minute in heart rate)

[see Warnings and Precautions (5.4)].

Most common adverse reactions (≥5% and at least twice the incidence of placebo patients): • Pediatric Clinical Studies: Nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence. (6.1)

• Adult Clinical Studies: Constipation, dry mouth, nausea, decreased appetite, dizziness, erectile dysfunction, and urinary hesitation. (6.1)

Patients should be instructed to use caution when driving a car or operating hazardous machinery (because of somnolence) until they are reasonably certain that their performance is not affected by atomoxetine capsules. (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, 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.

Atomoxetine was administered to 5,382 pediatric patients 6 years of age and older in clinical ADHD studies (Studies 1, 2, 3, 4, and 5) [see Clinical Studies (14.1)]

and 1,007 adults in clinical ADHD studies (Studies 6 and 7) [see Clinical Studies (14.2)]. In the ADHD clinical trials, 2,529 pediatric patients were treated for over 6 months which included 1,625 pediatric patients who were treated for longer than 1 year.

Adverse Reactions in the Clinical Trials of Pediatric Patients 6 Years of Age and Older with ADHD

Discontinuation of Treatment Due to Adverse Reactions in the Clinical Studies of Pediatric Patients 6 Years of Age and Older: In the acute placebo-controlled studies of pediatric patients 6 years of age and older with ADHD, 3% (48/1,613) of atomoxetine-treated pediatric patients and 1.4% (13/945) of placebo-treated pediatric patients discontinued due to an adverse reaction. Among atomoxetine-treated patients, irritability (0.3%, N=5); somnolence (0.3%, N=5); aggression (0.2%, N=4); nausea (0.2%, N=4); vomiting (0.2%, N=4); abdominal pain (0.2%, N=4); constipation (0.1%, N=2); fatigue (0.1%, N=2); feeling abnormal (0.1%, N=2); and headache (0.1%, N=2) were the reasons for discontinuation reported by more than one patient.

For all studies, (including open-label and long-term studies), 6% of atomoxetine-treated pediatric patients who were other CYP2D6 metabolizer types (ultrarapid, normal, and intermediate) and 11% of those who were CYP2D6 poor metabolizers discontinued due to an adverse reaction.

Common Adverse Reactions in the Clinical Studies of Pediatric Patients 6 Years of Age and Older: Common adverse reactions (incidence of 2% or greater in atomoxetine-treated patients and with a higher incidence in atomoxetine-treated patients compared to placebo-treated patients) in pediatric patients 6 years of age and older with ADHD are listed in Table 2. The most commonly observed adverse reactions in atomoxetine-treated patients (incidence of ≥5% and ≥ twice the incidence in placebo-treated patients), for either twice daily or once daily dosing were: nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence (see Tables 2 and 3).

a Adverse reactions reported by at least 2% of atomoxetine-treated patients and greater than placebo-treated patients.

bAbdominal pain includes the terms: upper abdominal pain, and epigastric discomfort.

cSomnolence includes the term sedation.

Adverse reaction in the atomoxetine-treated patients who received twice daily, and once daily dosing are shown in Table 3 (adverse reactions based on statistically significant Breslow-Day tests).

aAbdominal pain included the terms: upper abdominal pain, and epigastric discomfort.

bMood swings didn’t meet the statistical significance on Breslow-Day test at 0.05 level, but p-value was <0.1 (trend).

cConstipation didn’t meet the statistical significance on Breslow-Day test but is included in the table because of pharmacologic plausibility.

Common Adverse Reactions by CYP2D6 Metabolizer Status in the Clinical Studies of Pediatric Patients 6 Years of Age and Older: Table 4 displays adverse reactions that occurred in at least 2% of atomoxetine-treated pediatric patients who were CYP2D6 poor metabolizers and were statistically significantly more frequent in CYP2D6 poor metabolizers compared with other CYP2D6 metabolizer types (ultrarapid, normal, and intermediate).

a Adverse reactions that occurred in at least 2% of atomoxetine-treated pediatric patients who were CYP2D6 poor metabolizers and were statistically significantly more frequent in poor metabolizers compared with other CYP2D6 metabolizer types (ultrarapid, normal, and intermediate).

bDepression included the following terms: major depression, depressive symptoms, depressed mood, dysphoria.

Less Common Adverse Reactions in the Clinical Studies of Pediatric Patients 6 Years of Age and Older: The following reactions did not meet this criterion but were reported by more atomoxetine-treated patients than placebo-treated patients and are possibly related to atomoxetine treatment: blood pressure increased, early morning awakening (terminal insomnia), flushing, mydriasis, sinus tachycardia, asthenia, palpitations, mood swings, constipation, and dyspepsia. The following reactions were reported by at least 2% of patients treated with atomoxetine, and equal to or less than placebo: pharyngolaryngeal pain, insomnia (insomnia includes the terms, insomnia, initial insomnia, middle insomnia). The following reaction did not meet this criterion but shows a statistically significant dose relationship: pruritus.

Seizures in the Clinical Studies of Pediatric Patients 6 Years of Age and Older: Atomoxetine has not been systematically evaluated in pediatric patients with seizure disorder as these patients were excluded from atomoxetine studies. In the clinical development program, seizures were reported in 0.2% (12/5,073) of atomoxetine-treated pediatric patients whose average age was 10 years old (range 6 to 16 years of age). In these clinical trials, the seizure incidence among CYP2D6 poor metabolizers was 0.3% (1/293) compared to 0.2% (11/4,741) for other CYP2D6 metabolizer types.

Heart Rate and Blood Pressure Increases in the Clinical Studies of Pediatric Patients 6 Years of Age and Older: Additional data from ADHD clinical trials (controlled and uncontrolled) has shown that approximately 5 to 10% of pediatric patients experienced potentially clinically important changes in heart rate (≥20 beats per minute) or blood pressure (≥15 to 20 mm Hg)

[see Contraindications (4) and Warnings and Precautions (5.4)].

Adverse Reactions in the Clinical Trials of Adults with ADHD

Discontinuation of Treatment Due to Adverse Reactions in the Clinical Studies of Adults: In the acute adult placebo-controlled trials, 11.3% (61/541) atomoxetine-treated patients and 3% (12/405) placebo-treated patients discontinued for adverse reactions. Among atomoxetine-treated patients, insomnia (0.9%, N=5); nausea (0.9%, N=5); chest pain (0.6%, N=3); fatigue (0.6%, N=3); anxiety (0.4%, N=2); erectile dysfunction (0.4%, N=2); mood swings (0.4%, N=2); nervousness (0.4%, N=2); palpitations (0.4%, N=2); and urinary retention (0.4%, N=2) were the reasons for discontinuation reported by more than 1 patient.

Common Adverse Reactions in the Clinical Studies of Adults: Commonly observed adverse reactions associated with the use of atomoxetine (incidence of 2% or greater) and not observed at an equivalent incidence among placebo-treated patients (atomoxetine incidence greater than placebo) are listed in Table 5. The most commonly observed adverse reactions in patients treated with atomoxetine (incidence of 5% or greater and at least twice the incidence in placebo patients) were: constipation, dry mouth, nausea, decreased appetite, dizziness, erectile dysfunction, and urinary hesitation (see Table 5).

aReactions reported by at least 2% of patients treated with atomoxetine, and greater than placebo. The following reactions did not meet this criterion but were reported by more atomoxetine-treated patients than placebo-treated patients and are possibly related to atomoxetine-treatment: peripheral coldness, tachycardia, prostatitis, testicular pain, orgasm abnormal, flatulence, asthenia, feeling cold, muscle spasm, dysgeusia, agitation, restlessness, micturition urgency, pollakiuria, pruritus, urticaria, flushing, tremor, menstruation irregular, rash, and urinary retention.

bInsomnia includes the terms initial insomnia, middle insomnia, terminal insomnia and other related terms.

cBased on total number of males (atomoxetine group, N=943; placebo group, N=869).

dSomnolence includes related terms.

eAbdominal pain includes the terms: upper abdominal pain and other related terms.

f Urinary hesitation includes the term decreased urine flow.

g Based on total number of females (atomoxetine, N=754; placebo, N=691).

Common Adverse Reactions by CYP2D6 Metabolizer Status in the Clinical Studies of Adults: Table 6 displays adverse reactions that occurred in at least 2% of atomoxetine-treated adult patients who were CYP2D6 poor metabolizers and were statistically significantly more frequent compared to other CYP2D6 metabolizer types (ultrarapid, normal, and intermediate).

aAdverse reactions that occurred in at least 2% of atomoxetine-treated adult patients who were CYP2D6 poor metabolizers and were statistically significantly more frequent in CYP2D6 poor metabolizers compared with other CYP2D6 metabolizer types (ultrarapid, normal, and intermediate).

Less Common Adverse Reactions in the Clinical Studies of Adults: The following reactions did not meet this criterion but were reported by more atomoxetine-treated patients than placebo-treated patients and are possibly related to atomoxetine treatment: peripheral coldness, tachycardia, prostatitis, testicular pain, orgasm abnormal, flatulence, asthenia, feeling cold, muscle spasm, dysgeusia, agitation, restlessness, micturition urgency, pollakiuria, pruritus, urticaria, flushing, tremor, menstruation irregular, rash, and urinary retention.

Seizures in the Clinical Studies of Adults: Atomoxetine capsules have not been systematically evaluated in adult patients with a seizure disorder as these patients were excluded from clinical studies during the product’s premarket testing. In the clinical development program, seizures were reported on 0.1% (1/748) of adult patients. In these clinical trials, no CYP2D6 poor metabolizers (0/43) reported seizures compared to 0.1% (1/705) for other CYP2D6 metabolizer types.

Heart Rate and Blood Pressure Increases in the Clinical Studies of Adults: Table 7 displays the proportion of atomoxetine-treated and placebo-treated patients who had an increase in diastolic blood pressure (DBP) ≥15 mm Hg, systolic blood pressure (SBP) ≥20 mm Hg, or heart rate ≥ 20 bpm in short-term, placebo-controlled clinical studies in pediatric and adult patients with ADHD

[see Warnings and Precautions (5.4)].

aAbbreviations: bpm=beats per minute; DBP=diastolic blood pressure; HR=heart rate; mm Hg=millimeters mercury; SBP=systolic blood pressure.

bProportion of patients meeting threshold at any one time during the clinical studies.

Additional data from ADHD clinical trials (controlled and uncontrolled) showed that approximately 5 to 10% of adult patients had potentially clinically important changes in heart rate (≥20 beats per minute) or blood pressure (≥15 to 20 mm Hg) [see Contraindications (4) and Warnings and Precautions (5.4)].

Male and Female Sexual Dysfunction in the Clinical Studies of Adults: Atomoxetine impaired sexual function in some patients. Estimates of the incidence of untoward sexual experience and performance in these studies are likely to underestimate their actual incidence because patients and health care providers may be reluctant to discuss them. Table 5 displays the incidence of sexual adverse reactions (reported by at least 2% of atomoxetine-treated adult patients in the placebo-controlled studies of adults with ADHD (i.e., erectile dysfunction, dysmenorrhea, and ejaculation delayed and/or ejaculation disorder).

There are no adequate and well-controlled studies examining sexual dysfunction with atomoxetine treatment. While it is difficult to know the precise risk of sexual dysfunction associated with the use of atomoxetine, health care providers should routinely inquire about sexual dysfunction. 6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of atomoxetine. Unless otherwise specified, these adverse reactions have occurred in adults and pediatric patients. 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.

• Cardiovascular system: QT prolongation, syncope.

• Peripheral vascular effects: Raynaud’s phenomenon.

• General disorders and administration site conditions: Lethargy.

• Musculoskeletal system: Rhabdomyolysis.

• Nervous system disorders: Hypoaesthesia; paraesthesia in pediatric patients; sensory disturbances; tics.

• Psychiatric disorders: Depression and depressed mood; anxiety, libido changes.

• Seizures: Seizures have been reported and included patients with pre-existing seizure disorders, those with identified risk factors for seizures, and patients with neither a history of nor identified risk factors for seizures. The exact relationship between atomoxetine and seizures is difficult to evaluate due to uncertainty about the background risk of seizures in ADHD patients.

• Skin and subcutaneous tissue disorders: Alopecia, hyperhidrosis.

• Urogenital system: Male pelvic pain; urinary hesitation in pediatric patients; urinary retention in pediatric patients.

• Severe Liver Injury: Atomoxetine capsules should be discontinued and not restarted in patients with jaundice or laboratory evidence of liver injury. (5.2)

• Serious Cardiovascular Reactions: Prior to atomoxetine capsules treatment, patients should have a careful history and physical exam to assess for presence of cardiovascular (CV) disease. Atomoxetine capsules generally should not be used in pediatric patients with known serious cardiac abnormalities, cardiomyopathy, serious arrhythmias. Consideration should be given to not using atomoxetine capsules in adults with clinically significant cardiac abnormalities. Patients who develop symptoms suggestive of cardiac disease during atomoxetine capsules treatment should stop atomoxetine capsules and undergo a prompt cardiac evaluation. (5.3)

• Increase in Blood Pressure and Heart Rate: Heart rate and blood pressure should be measured at baseline, following atomoxetine dosage increase, and periodically while on therapy. (5.4)

• New Psychotic or Manic Symptoms and Activation of Mania: If psychotic or manic symptoms occur, consider discontinuing atomoxetine capsules. (5.5)

• Aggressive Behavior or Hostility: Monitor for the appearance or worsening of aggressive behavior or hostility. (5.7)

• Effects on Urine Outflow: Urinary retention or hesitancy may occur. (5.9)

• Priapism: Prompt medical attention is required in the event of suspected priapism. (5.10)

• Effect on Growth in Pediatric Patients: Closely monitor growth (e.g., weight, height) in pediatric patients. (5.11) 5.1 Suicidal Thoughts and Behaviors in Pediatric Patients 6 Years of Age and Older

• All atomoxetine-treated pediatric patients should be monitored and observed closely for clinical worsening, suicidal thoughts and behavior, and unusual changes in behavior, especially during the initial few months of atomoxetine therapy, or at times of dosage changes, either increases or decreases.

• Families and caregivers of atomoxetine-treated pediatric patients should be alerted about the need to monitor patients daily for the emergence of agitation, irritability, unusual changes in behavior, and mental health-related symptoms, as well as the emergence of suicidal thoughts and behavior, and to report such symptoms immediately to a health care provider.

• Consider changing the therapeutic regimen, including stopping atomoxetine capsules, in patients who experience emergent suicidality or symptoms that might be precursors to emerging suicidal thoughts and behavior, especially if these symptoms are severe or abrupt in onset, or were not part of the patient’s presenting symptoms.

Atomoxetine capsules increased the risk of suicidal ideation in pediatric patients 6 years and older with ADHD in pooled placebo-controlled short-term studies (6 to 18 weeks). In 12 studies (11 studies in patients with ADHD and 1 study in another population) with over 2,200 pediatric patients, the mean incidence of suicidal ideation in atomoxetine-treated pediatric patients was 0.4% (5/1,357) (including one patient with a suicide attempt) compared to 0% (0/851) in placebo-treated pediatric patients. No suicides occurred in these studies. All the suicidal ideations occurred in pediatric patients 6 to 12 years of age, and all occurred during the first month of atomoxetine capsules treatment. It is unknown whether the risk of suicidal ideation in pediatric patients extends to longer-term use. A similar analysis in adult patients treated with atomoxetine capsules for ADHD did not reveal an increased risk of suicidal ideation or behavior.

The following psychiatric symptoms have been reported with atomoxetine capsules: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania and mania. Although a causal link between the emergence of such symptoms and the emergence of suicidal impulses has not been established, there is a concern that such symptoms may represent precursors to emerging suicidality. 5.2 Severe Liver Injury

Atomoxetine capsules should be discontinued and not restarted in patients with jaundice or laboratory evidence of liver injury. Liver enzyme and function tests should be obtained upon the first symptom or sign of liver dysfunction (e.g., pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained “flu like” symptoms).

Postmarketing reports indicate that atomoxetine can cause severe liver injury.

Although no evidence of liver injury was detected in clinical trials of about 6,000 patients, there have been rare cases of clinically significant liver injury that were considered probably or possibly related to atomoxetine use during postmarketing use: • Rare cases of liver failure have been reported during postmarketing use, including a case that resulted in a liver transplant.

• Reported cases of liver injury occurred within 120 days of initiation of atomoxetine in most cases and some patients presented with markedly elevated liver enzymes (>20 times upper limit of normal (ULN)), and jaundice with significantly elevated bilirubin levels (>2 times ULN), followed by recovery upon atomoxetine discontinuation. In one patient, liver injury, manifested by elevated hepatic enzymes up to 40 times ULN and jaundice with bilirubin up to 12 times ULN, recurred upon rechallenge, and was followed by recovery upon atomoxetine discontinuation, providing evidence that atomoxetine likely caused the liver injury. Such reactions may occur several months after atomoxetine is started, but laboratory abnormalities may continue to worsen for several weeks after atomoxetine is stopped. 5.3 Serious Cardiovascular Reactions

Risk Management Recommendations for Serious Cardiovascular Reactions

Prior to atomoxetine capsules treatment, adults or pediatric patients 6 years of age or older should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiovascular disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram, echocardiogram).

• Although some serious heart problems alone carry an increased risk of sudden death, atomoxetine capsules generally should not be used in pediatric patients with known serious structural cardiac abnormalities, cardiomyopathy, serious arrhythmias, or other serious cardiac problems.

• Consideration should be given to not treating adults with atomoxetine capsules with clinically significant cardiac abnormalities.

Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during atomoxetine capsules treatment should stop atomoxetine capsules and undergo a prompt cardiac evaluation.

Sudden Death and Pre-existing Structural Cardiac Abnormalities or Other Serious Heart Problems

Pediatric Patients 6 Years of Age and Older: Sudden death has been reported in association with atomoxetine treatment at the recommended dosage in pediatric patients 6 years of age and older with structural cardiac abnormalities or other serious heart problems.

Adults: Sudden deaths, stroke, and myocardial infarction have been reported in atomoxetine-treated adults at the recommended ADHD dosage. Although the role of atomoxetine in these adult cases is also unknown, adults have a greater likelihood than pediatric patients of having serious structural cardiac abnormalities, cardiomyopathy, serious arrhythmias, coronary artery disease, or other serious cardiac problems. 5.4 Increase in Blood Pressure and Heart Rate

Atomoxetine capsules are contraindicated in patients with severe cardiac or vascular disorders whose condition would be expected to deteriorate if they had a clinically important increase in blood pressure or heart rate. Atomoxetine capsules should be used with caution in any condition that may predispose patients to hypotension, or conditions associated with abrupt heart rate or blood pressure changes. Atomoxetine should be used with caution in patients whose underlying medical conditions could be worsened by increases in blood pressure or heart rate such as certain patients with hypertension, tachycardia, or cardiovascular or cerebrovascular disease. Heart rate and blood pressure should be measured at baseline, following atomoxetine dosage increases, and periodically while on therapy to detect possible clinically important increases in heart rate and blood pressure.

In the pediatric and adult patients in short-term, placebo-controlled clinical studies of ADHD, there were a greater proportion of atomoxetine-treated patients, compared to placebo-treated patients, who had an increase in diastolic blood pressure (DBP) ≥15 mm Hg, systolic blood pressure (SBP) ≥20 mm Hg and heart rate ≥20 bpm

[see Adverse Reactions (6.1)].

Increase in Blood Pressure and Heart Rate

• In placebo-controlled studies of pediatric patients 6 years of age and older with ADHD, tachycardia was identified as an adverse reaction in 0.3% (5/1,597) of atomoxetine-treated patients compared with 0% (0/934) of placebo-treated patients.

• In placebo-controlled adult ADHD studies, tachycardia was identified as an adverse reaction in 1.5% (8/540) of atomoxetine-treated patients compared with 0.5% (2/402) of placebo-treated patients.

• Orthostatic hypotension and syncope have been reported in atomoxetine-treated patients. In ADHD studies in pediatric patients 6 years of age and older, 0.2% (12/5,596) of atomoxetine-treated patients had orthostatic hypotension and 0.8% (46/5,596) had syncope. In short-term ADHD studies in pediatric patients 6 years of age and older, 1.8% (6/340) of atomoxetine-treated patients had orthostatic hypotension compared with 0.5% (1/207) of placebo-treated patients. Syncope was not reported during these studies.

Increase in Blood Pressure and Heart Rate in CYP2D6 Poor Metabolizers

• In placebo-controlled studies of pediatric patients 6 years of age and older with ADHD, the mean heart rate increase was 9.4 beats/minute in CYP2D6 poor metabolizers and was 5 beats/minute in other CYP2D6 metabolizer types (ultrarapid, normal, and intermediate).

• In adult clinical trials where CYP2D6 metabolizer status was available, the mean heart rate increase in CYP2D6 poor metabolizers was significantly higher than in other CYP2D6 metabolizer types (11 beats/minute versus 7.5 beats/minute, respectively).

In adult clinical trials where CYP2D6 metabolizer status was available, the mean change from baseline in DBP in CYP2D6 poor metabolizers was higher than in other CYP2D6 metabolizer types (4.2 versus 2.1 mm Hg) as was the mean change from baseline in SBP (CYP2D6 poor metabolizers: 2.8 versus other CYP2D6 metabolizer types: 2.4 mm Hg). 5.5 New Psychotic or Manic Symptoms and Activation of Mania

If psychotic or manic symptoms occur, consider discontinuing atomoxetine capsules.

Psychotic symptoms (e.g., hallucinations, delusional thinking) manic symptoms (e.g., mania) in patients without a prior history of psychotic illness or mania can be caused by atomoxetine capsules at the recommended dosage. 5.6 Screening Patients for Bipolar Disorder

Before initiating treatment with atomoxetine capsules, patients should be adequately screened for risk factors for bipolar disorder such as a personal or family history of mania and depression.

Patients with bipolar disorder or risk factors for bipolar disorder may be at increased risk of developing mania or mixed episodes during treatment with atomoxetine. It may not be possible to determine whether a manic or mixed episode that appears during treatment with atomoxetine is due to an adverse reaction to atomoxetine or a patient’s underlying bipolar disorder. 5.7 Aggressive Behavior or Hostility

Patients beginning treatment with atomoxetine should be monitored for the appearance or worsening of aggressive behavior or hostility.

There is evidence that atomoxetine may cause the emergence or worsening of aggressive behavior or hostility. ADHD and other mental illnesses can be associated with irritability, which can make it difficult to determine if atomoxetine or the underlying psychiatric condition is causing the emergence or worsening of aggressive behavior or hostility in specific patients. If such symptoms occur during treatment, consider a possible causal role of atomoxetine. 5.8 Hypersensitivity Reactions

Atomoxetine capsules are contraindicated in patients with known hypersensitivity reaction to atomoxetine or other constituents of atomoxetine capsules.

Although uncommon, hypersensitivity reactions, including anaphylaxis, angioneurotic edema, urticaria, and rash, have been reported in atomoxetine-treated patients. 5.9 Effects on Urine Outflow

A complaint of urinary retention or urinary hesitancy should be considered potentially related to atomoxetine.

In adult ADHD controlled studies, the incidence of urinary retention (1.7%, 9/540) and urinary hesitation (5.6%, 30/540) were increased among atomoxetine-treated patients compared with placebo-treated patients (0%, 0/402; 0.5%, 2/402, respectively). Two atomoxetine-treated adult patients and no placebo-treated patients discontinued from controlled clinical studies because of urinary retention. 5.10 Priapism

Prompt medical attention is required in the event of suspected priapism in atomoxetine-treated patients.

Rare postmarketing cases of priapism, defined as painful and nonpainful penile erection lasting more than 4 hours, have been reported for pediatric and adult patients treated with atomoxetine. The erections resolved in cases in which follow-up information was available, some following discontinuation of atomoxetine. 5.11 Effect on Growth in Pediatric Patients

Closely monitor growth (e.g., weight, height) in pediatric patients during atomoxetine treatment.

Weight and Height in Long-Term Open-Label Studies in Pediatric Patients

Data on the long-term effects of atomoxetine on growth in pediatric patients from open-label studies in which weight and height changes were compared to normative pediatric population data. In general, the weight and height gain of atomoxetine-treated pediatric patients lagged behind that predicted by normative population data for about the first 9 to 12 months of treatment and subsequently (see Figure 1 below): • Weight gain rebounded. At about 3 years of atomoxetine treatment, patients gained a mean of 17.9 kg, which was 0.5 kg more than predicted by their baseline data.

• Height gain stabilized. At 3 years of atomoxetine treatment, patients gained a mean of 19.4 cm, which was 0.4 cm less than predicted by their baseline data.

Figure 1: Mean Weight and Height Percentiles Over Time for Atomoxetine-Treated Pediatric Patients in Comparison to Normative Pediatric Population Values

After three years of atomoxetine treatment in the long-term open-label studies, patients who were: • Pre-pubertal at the start of treatment (girls ≤8 years old, boys ≤9 years old) gained weight and height; however, the mean weight gain was 2.1 kg less than predicted and the mean height gain was 1.2 cm less than predicted.

• Pubertal (girls >8 to ≤13 years old, boys >9 to ≤14 years old) or late pubertal (girls >13 years old, boys >14 years old), the mean weight and height gains were close to or exceeded predicted weight and height gains.

CYP2D6 poor metabolizers and other CYP2D6 metabolizer types (ultrarapid, normal, and intermediate) treated with atomoxetine for at least two years gained weight and height. However, in: • CYP2D6 poor metabolizers the mean weight gain was 2.4 kg less than predicted and the mean height gain was 1.1 cm less than predicted

• Other CYP2D6 metabolizer types the mean weight gain was 0.2 kg less than predicted and the mean height gain was 0.4 cm less than predicted.

In the long-term open-label studies, the growth pattern was generally similar regardless of pubertal status at the time of atomoxetine treatment initiation.

Weight and Height in Short-Term, Placebo-Controlled Studies in Pediatric Patients

In short-term, placebo-controlled studies (up to 9 weeks), atomoxetine-treated patients lost an average of 0.4 kg in weight and gained an average of 0.9 cm in height, compared to a gain of 1.5 kg in weight and 1.1 cm in height in the placebo-treated patients.

In a fixed-dose controlled trial, 1.3%, 7.1%, 19.3%, and 29.1% of patients in the placebo, 0.5, 1.2, and 1.8 mg/kg/day atomoxetine groups, respectively, lost at least 3.5% of their body weight. atomfig1.jpg

• Prior to initiating treatment with atomoxetine capsules, screen patients for a personal or family history of bipolar disorder, mania, or hypomania. (2.1, 5.6) • See table below for the recommended atomoxetine capsule dosage. (2.3) Age and Body Weight Starting Dosage Target Dosage 1 Maximum Total Daily Dose 1 Pediatrics who weigh less than 70 kg 0.5 mg/kg/day 1.2 mg/kg/day 1.4 mg/kg/day or 100 mg/day (whichever is less) Pediatrics who weigh 70 kg or more and adults 40 mg/day 80 mg/day 100 mg/day 1 Administer either as once daily dosage in the morning or as evenly divided twice daily dosage in the morning and late afternoon/early evening. • For the recommended dosage in patients with hepatic impairment, see Full Prescribing Information. (2.4) • For the recommended dosage with concomitant use of a strong CYP2D6 inhibitor or in CYP2D6 poor metabolizers, see Full Prescribing Information. (2.5) 2.1 Recommendations Prior to Initiating Atomoxetine Capsules Treatment Prior to initiating treatment with atomoxetine capsules, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.6)]. 2.2 Administration Instructions Atomoxetine capsules may be taken with or without food. Take atomoxetine capsules whole; do not open the capsules. 2.3 Recommended Dosage Table 1 includes the recommended atomoxetine capsules dosage in adult patients and pediatric patients 6 years of age and older for acute treatment of ADHD. Table 1: Recommended Dosage of Atomoxetine Capsules for Acute Treatment of ADHD Age and Body Weight Starting Dosage Titration Interval Target Dosage Maximum Dosage Pediatric patients who weigh less than 70 kg 0.5 mg/kg/day Minimum of 3 days 1.2 mg/kg/day a,b 1.4 mg/kg/day or 100 mg/day, whichever is less a Pediatric patients who weigh 70 kg or more and adult patients 40 mg/day Minimum of 3 days 80 mg/day a 100 mg/day a,c aAdminister either as once daily dosage in the morning or as evenly divided twice daily dosage in the morning and late afternoon/early evening. bNo additional benefit has been demonstrated with atomoxetine capsules dosages higher than 1.2 mg/kg/day [see Clinical Studies (14)]. c If a patient has not achieved an optimal response at 80 mg/day after 2 to 4 additional weeks, may increase the dosage to a maximum of 100 mg/day. There is no data that supports increased effectiveness at a dosage higher than 100 mg/day [see Clinical Studies (14)]. The health care provider who elects to use atomoxetine capsules for extended periods should periodically reevaluate the long-term usefulness of atomoxetine capsules for the individual patient. 2.4 Recommended Dosage in Patients with Hepatic Impairment For patients aged 6 years of age or older with: • Severe hepatic impairment (HI) (Child-Pugh Class C), the recommended initial and target atomoxetine capsules dosage is 25% of recommended dosage in patients with normal hepatic function [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. • Moderate HI (Child-Pugh Class B), the recommended initial and target atomoxetine capsules dosage is 50% of the recommended dosage in patients with normal hepatic function [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. • Mild HI (Child-Pugh Class A), the recommended initial and target atomoxetine capsules dosage is the same as those with normal hepatic function. 2.5 Recommended Dosage with Concomitant Use of Strong CYP2D6 Inhibitors or in CYP2D6 Poor Metabolizers Consider genetic testing to determine the patient’s CYP2D6 metabolizer status. In patients taking a concomitant strong CYP2D6 inhibitor or who are CYP2D6 poor metabolizers, a longer titration interval of 4 weeks is recommended, if ADHD symptoms fail to improve and the initial atomoxetine capsules dosage is well tolerated. The recommended starting, target, and maximum atomoxetine capsules dosages are the same as outlined in Table 1 [see Dosage and Administration (2.3)]. For other CYP2D6 metabolizer types (ultrarapid, normal, and intermediate), follow the recommended dosage, including the recommended titration interval (minimum of 3 days), as outlined in Table 1 [see Dosage and Administration (2.3)]. 2.6 Switching to or from a Monoamine Oxidase Inhibitor Antidepressant At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of atomoxetine capsules. In addition, at least 14 days must elapse after stopping atomoxetine capsules before starting an MAOI antidepressant. 2.7 Recommendations for a Missed Dose If an atomoxetine capsule dose is missed, take the dose as soon as possible, but do not take more than the prescribed total daily amount of atomoxetine capsules in any 24-hour period. 2.8 Recommendations for Discontinuation When discontinuing atomoxetine capsules, no taper is needed [see Drug Abuse and Dependence (9.2, 9.3)].

Table 1 includes the recommended atomoxetine capsules dosage in adult patients and pediatric patients 6 years of age and older for acute treatment of ADHD.

Table 1: Recommended Dosage of Atomoxetine Capsules for Acute Treatment of ADHD

^aAdminister either as once daily dosage in the morning or as evenly divided twice daily dosage in the morning and late  afternoon/early evening.

^bNo additional benefit has been demonstrated with atomoxetine capsules dosages higher than 1.2 mg/kg/day [see Clinical Studies ( 14)].

^c If a patient has not achieved an optimal response at 80 mg/day after 2 to 4 additional weeks, may increase the dosage to a  maximum of 100 mg/day. There is no data that supports increased effectiveness at a dosage higher than 100 mg/day [see Clinical  Studies ( 14)].

The health care provider who elects to use atomoxetine capsules for extended periods should periodically reevaluate the long-term usefulness of atomoxetine capsules for the individual patient.

For patients aged 6 years of age or older with:

1. Severe hepatic impairment (HI) (Child-Pugh Class C), the recommended initial and target atomoxetine capsules dosage is 25% of recommended dosage in patients with normal hepatic function [see Use in Specific Populations ( 8.6) and Clinical Pharmacology ( 12.3)].
2. Moderate HI (Child-Pugh Class B), the recommended initial and target atomoxetine capsules dosage is 50% of the recommended dosage in patients with normal hepatic function [see Use in Specific Populations ( 8.6) and Clinical Pharmacology ( 12.3)].
3. Mild HI (Child-Pugh Class A), the recommended initial and target atomoxetine capsules dosage is the same as those with normal hepatic function.

Consider genetic testing to determine the patient’s CYP2D6 metabolizer status.

In patients taking a concomitant strong CYP2D6 inhibitor or who are CYP2D6 poor metabolizers, a longer titration interval of 4 weeks is recommended, if ADHD symptoms fail to improve and the initial atomoxetine capsules dosage is well tolerated. The recommended starting, target, and maximum atomoxetine capsules dosages are the same as outlined in Table 1 [see Dosage and Administration ( 2.3)].

For other CYP2D6 metabolizer types (ultrarapid, normal, and intermediate), follow the recommended dosage, including the recommended titration interval (minimum of 3 days), as outlined in Table 1 [see Dosage and Administration ( 2.3)].

Each capsule contains atomoxetine hydrochloride, USP equivalent to:

1. 10 mg of atomoxetine (Opaque White, Opaque White)
2. 18 mg of atomoxetine (Opaque Gold, Opaque White)
3. 25 mg of atomoxetine (Opaque Blue, Opaque White)
4. 40 mg of atomoxetine (Opaque Blue, Opaque Blue)
5. 60 mg of atomoxetine (Opaque Blue, Opaque Gold)
6. 80 mg of atomoxetine (Opaque Orange, Opaque White)
7. 100 mg of atomoxetine (Opaque Orange, Opaque Orange)

• Monoamine Oxidase Inhibitors: Concomitant use contraindicated. (4, 7)

• Strong CYP2D6 Inhibitors: With concomitant use of atomoxetine capsules and strong CYP2D6 inhibitors, increase the titration intervals. (7)

• Antihypertensives: Increase the frequency of monitoring blood pressure and adjust atomoxetine capsules dosage as clinically appropriate. (7)

• Albuterol (or other beta2 agonists): Increase the frequency of monitoring blood pressure and heart rate. (7) See Table 8 for clinically significant drug interactions with atomoxetine and other drugs.

Table 8: Clinically Significant Drug Interactions with Atomoxetine and Other Drugs

Monoamine Oxidase Inhibitors (MAOIs)

Prevention or Management

Atomoxetine is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue, or in patients who stopped an MAOI within 14 days.

Mechanism and Clinical Effect(s)

As with other drugs affecting brain monoamine concentrations, there have been reports of serious, sometimes fatal reactions (hyperthermia, rigidity, myoclonus, autonomic instability with fluctuations of vital signs, extreme agitation progressing to delirium/coma) with concomitant use of atomoxetine and an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome.

Strong CYP2D6 Inhibitors

Prevention or Management

With concomitant use of atomoxetine and a strong CYP2D6 inhibitor, increase the titration interval

[see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

Mechanism and Clinical Effect(s)

Atomoxetine is a CYP2D6 substrate. The concomitant use of atomoxetine and a strong CYP2D6 inhibitor increases atomoxetine exposure

[see Clinical Pharmacology (12.3)].

Antihypertensive Drugs

Prevention or Management

Increase the frequency of monitoring blood pressure and adjust atomoxetine dosage as clinically appropriate.

Mechanism and Clinical Effect(s)

Because of increased risk of increased blood pressure, atomoxetine should be used cautiously with antihypertensive drugs, other drugs that increase blood pressure or pressor drugs (e.g., dopamine, dobutamine).

Albuterol or Other Beta2 Agonists

Prevention or Management

Increase the frequency of monitoring blood pressure and heart rate and adjust atomoxetine dosage as clinically appropriate.

Mechanism and Clinical Effect(s)

Systemically administered albuterol (e.g., oral) can be potentiated by atomoxetine, resulting in increases in heart rate and blood pressure [see Clinical Pharmacology (12.3)].