ATOMOXETINE

Atomoxetine capsules, USP are a selective norepinephrine reuptake inhibitor. Atomoxetine hydrochloride is the R (-) isomer as determined by x-ray diffraction. The chemical designation is (-)- N -Methyl-3-phenyl-3-( o -tolyloxy)-propylamine hydrochloride. The molecular formula is C 17 H 21 NO•HCl, which corresponds to a molecular weight of 291.82. The chemical structure is: Atomoxetine hydrochloride, USP is a white to practically white solid, which has a solubility of 27.8 mg/mL in water. Atomoxetine capsules are intended for oral administration only. Each capsule contains atomoxetine hydrochloride equivalent to 10, 18, 25, 40, 60, 80 or 100 mg of atomoxetine. The capsules also contain colloidal silicon dioxide, gelatin, magnesium stearate, pregelatinized starch (corn), sodium lauryl sulfate and titanium dioxide. The 10 mg capsules also contain D&C Yellow No. 10, D&C Red No. 28, D&C Red No. 33, FD&C Red No. 40 and FD&C Yellow No. 6; the 18 mg capsules also contain D&C Red No. 28, D&C Yellow No. 10, FD&C Red No. 40 and FD&C Yellow No. 6; the 25 mg capsules also contain FD&C Blue No. 1 and FD&C Red No. 3; the 40 mg capsules also contain D&C Red No. 28 and FD&C Blue No. 1; the 60 mg capsules also contain D&C Red No. 28, D&C Yellow No. 10, FD&C Blue No. 1 and FD&C Yellow No. 6; the 80 mg capsules also contain D&C Red No. 28, D&C Yellow No. 10 and FD&C Yellow No. 6; the 100 mg capsules also contain D&C Yellow No. 10, FD&C Red No. 3, FD&C Yellow No. 6 and red iron oxide. In addition, the imprinting ink contains the following: black iron oxide, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, D&C Yellow No. 10 Aluminum Lake, propylene glycol and shellac glaze. Image

Atomoxetine is selective norepinephrine reuptake inhibitor indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). (1.1) 1.1 Attention-Deficit/Hyperactivity Disorder (ADHD) Atomoxetine is indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). The efficacy of atomoxetine is established in seven clinical trials in outpatients with ADHD: four 6 to 9-week trials in pediatric patients (ages 6 to 18), two 10-week trial in adults, and one maintenance trial in pediatrics (ages 6 to 15) [see Clinical Studies (14)]. 1.2 Diagnostic Considerations A diagnosis of ADHD (DSM-IV) implies the presence of hyperactive-impulsive or inattentive symptoms that cause impairment and that were present before age 7 years. The symptoms must be persistent, must be more severe than is typically observed in individuals at a comparable level of development, must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and must be present in 2 or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. The specific etiology of ADHD is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but also of special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the patient and not solely on the presence of the required number of DSM-IV characteristics. For the Inattentive Type, at least 6 of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes, lack of sustained attention, poor listener, failure to follow through on tasks, poor organization, avoids tasks requiring sustained mental effort, loses things, easily distracted, forgetful. For the Hyperactive-Impulsive Type, at least 6 of the following symptoms must have persisted for at least 6 months: fidgeting/squirming, leaving seat, inappropriate running/climbing, difficulty with quiet activities, "on the go," excessive talking, blurting answers, can't wait turn, intrusive. For a Combined Type diagnosis, both inattentive and hyperactive-impulsive criteria must be met. 1.3 Need for Comprehensive Treatment Program Atomoxetine is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all patients with this syndrome. Drug treatment is not intended for use in the patient who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential in children and adolescents with this diagnosis and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe drug treatment medication will depend upon the physician's assessment of the chronicity and severity of the patient's symptoms.

Initial, Target and Maximum Daily Dose (2.1) (Acute and Maintenance/Extended Treatment) Body Weight Initial Daily Dose Target Total Daily Dose Maximum Total Daily Dose Children and adolescents up to 70 kg 0.5 mg/kg 1.2 mg/kg 1.4 mg/kg Children and adolescents over 70 kg and adults 40 mg 80 mg 100 mg Dosing adjustment — Hepatic Impairment, Strong CYP2D6 Inhibitor, and in patients known to be CYP2D6 poor metabolizers (PMs). (2.5, 12.3) 2.1 Acute Treatment Dosing of Children and Adolescents up to 70 kg Body Weight - Atomoxetine should be initiated at a total daily dose of approximately 0.5 mg/kg and increased after a minimum of 3 days to a target total daily dose of approximately 1.2 mg/kg administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening. No additional benefit has been demonstrated for doses higher than 1.2 mg/kg/day [see Clinical Studies (14)] . The total daily dose in children and adolescents should not exceed 1.4 mg/kg or 100 mg, whichever is less. Dosing of Children and Adolescents Over 70 kg Body Weight and Adults - Atomoxetine should be initiated at a total daily dose of 40 mg and increased after a minimum of 3 days to a target total daily dose of approximately 80 mg administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening. After 2 to 4 additional weeks, the dose may be increased to a maximum of 100 mg in patients who have not achieved an optimal response. There are no data that support increased effectiveness at higher doses [see Clinical Studies (14)] . The maximum recommended total daily dose in children and adolescents over 70 kg and adults is 100 mg. 2.2 Maintenance/Extended Treatment It is generally agreed that pharmacological treatment of ADHD may be needed for extended periods. The benefit of maintaining pediatric patients (ages 6-15 years) with ADHD on atomoxetine after achieving a response in a dose range of 1.2 to 1.8 mg/kg/day was demonstrated in a controlled trial. Patients assigned to atomoxetine in the maintenance phase were generally continued on the same dose used to achieve a response in the open label phase. The physician who elects to use atomoxetine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient [see Clinical Studies (14.1)] . 2.3 General Dosing Information Atomoxetine may be taken with or without food. Atomoxetine can be discontinued without being tapered. Atomoxetine capsules are not intended to be opened, they should be taken whole [see Patient Counseling Information (17)] . The safety of single doses over 120 mg and total daily doses above 150 mg have not been systematically evaluated. 2.4 Screen for Bipolar Disorder Prior to Starting Atomoxetine Prior to initiating treatment with atomoxetine, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.6)]. 2.5 Dosing in Specific Populations Dosing Adjustment for Hepatically Impaired Patients - For those ADHD patients who have hepatic insufficiency (HI), dosage adjustment is recommended as follows: For patients with moderate HI (Child-Pugh Class B), initial and target doses should be reduced to 50% of the normal dose (for patients without HI). For patients with severe HI (Child-Pugh Class C), initial dose and target doses should be reduced to 25% of normal [see Use in Specific Populations (8.6)] . Dosing Adjustment for Use with a Strong CYP2D6 Inhibitor or in Patients who are Known to be CYP2D6 PMs - In children and adolescents up to 70 kg body weight administered strong CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine, or in patients who are known to be CYP2D6 PMs, atomoxetine should be initiated at 0.5 mg/kg/day and only increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. In children and adolescents over 70 kg body weight and adults administered strong CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine, atomoxetine should be initiated at 40 mg/day and only increased to the usual target dose of 80 mg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated.

Hypersensitivity to atomoxetine or other constituents of product. (4.1) Atomoxetine use within 2 weeks after discontinuing MAOI or other drugs that affect brain monoamine concentrations. (4.2, 7.1) Narrow Angle Glaucoma. (4.3) Pheochromocytoma or history of pheochromocytoma. (4.4) Severe Cardiovascular Disorders that might deteriorate with clinically important increases in HR and BP. (4.5) 4.1 Hypersensitivity Atomoxetine is contraindicated in patients known to be hypersensitive to atomoxetine or other constituents of the product [see Warnings and Precautions (5.8)] . 4.2 Monoamine Oxidase Inhibitors (MAOI) Atomoxetine should not be taken with an MAOI, or within 2 weeks after discontinuing an MAOI. Treatment with an MAOI should not be initiated within 2 weeks after discontinuing atomoxetine. With other drugs that affect brain monoamine concentrations, there have been reports of serious, sometimes fatal reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) when taken in combination with an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Such reactions may occur when these drugs are given concurrently or in close proximity [see Drug Interactions (7.1)] . 4.3 Narrow Angle Glaucoma In clinical trials, atomoxetine use was associated with an increased risk of mydriasis and therefore its use is not recommended in patients with narrow angle glaucoma. 4.4 Pheochromocytoma Serious reactions, including elevated blood pressure and tachyarrhythmia, have been reported in patients with pheochromocytoma or a history of pheochromocytoma who received atomoxetine. Therefore, atomoxetine should not be taken by patients with pheochromocytoma or a history of pheochromocytoma. 4.5 Severe Cardiovascular Disorders Atomoxetine capsules should not be used in patients with severe cardiac or vascular disorders whose condition would be expected to deteriorate if they experience increases in blood pressure or heart rate that could be clinically important (for example, 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) Child and Adolescent Clinical Trials – Nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence. (6.1) Adult Clinical Trials – Constipation, dry mouth, nausea, decreased appetite, dizziness, erectile dysfunction, and urinary hesitation. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Strides Pharma Inc. at 1-877-244-9825 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Atomoxetine was administered to 5382 children or adolescent patients with ADHD and 1007 adults with ADHD in clinical studies. During the ADHD clinical trials, 1625 children and adolescent patients were treated for longer than 1 year and 2529 children and adolescent patients were treated for over 6 months. 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. Child and Adolescent Clinical Trials: Reasons for Discontinuation of Treatment Due to Adverse Reactions in Child and Adolescent Clinical Trials - In acute child and adolescent placebo-controlled trials, 3.0% (48/1613) of atomoxetine subjects and 1.4% (13/945) placebo subjects discontinued for adverse reactions. For all studies, (including open-label and long-term studies), 6.3% of extensive metabolizer (EM) patients and 11.2% of poor metabolizer (PM) patients discontinued because of 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 1 patient. Seizures - Atomoxetine has not been systematically evaluated in pediatric patients with seizure disorder as these patients were excluded from clinical studies during the product's premarket testing. In the clinical development program, seizures were reported in 0.2% (12/5073) of children whose average age was 10 years (range 6 to 16 years). In these clinical trials, the seizure risk among poor metabolizers was 0.3% (1/293) compared to 0.2% (11/4741) for extensive metabolizers. Commonly Observed Adverse Reactions in Acute Child and Adolescent, Placebo-Controlled Trials - 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 2. Results were similar in the BID and the QD trial except as shown in Table 3, which shows both BID and QD results for selected adverse reactions based on statistically significant Breslow-Day tests. 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, for either BID or QD dosing) were: nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence ( see Tables 2 and 3). 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 min) or blood pressure (≥ 15 to 20 mm Hg) [see Contraindications (4) and Warnings and Precautions (5)] . Table 2: Common Treatment-Emergent Adverse Reactions Associated with the Use of Atomoxetine in Acute (up to 18 weeks) Child and Adolescent Trials Adverse Reaction Reactions 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: 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. Percentage of Patients Reporting Reaction Atomoxetine (N = 1597) Placebo (N = 934) Gastrointestinal Disorders Abdominal pain Abdominal pain includes the terms: abdominal pain upper, abdominal pain, stomach discomfort, abdominal discomfort, epigastric discomfort. 18 10 Vomiting 11 6 Nausea 10 5 General Disorders and Administration Site Conditions Fatigue 8 3 Irritability 6 3 Therapeutic response unexpected 2 1 Investigations Weight decreased 3 0 Metabolism and Nutritional Disorders Decreased appetite 16 4 Anorexia 3 1 Nervous System Disorders Headache 19 15 Somnolence Somnolence includes the terms: sedation, somnolence. 11 4 Dizziness 5 2 Skin and Subcutaneous Tissue Disorders Rash 2 1 Table 3: Common Treatment-Emergent Adverse Reactions Associated with the Use of Atomoxetine in Acute (up to 18 weeks) Child and Adolescent Trials Adverse Reaction Percentage of Patients Reporting Reaction from BID Trials Percentage of Patients Reporting Reaction from QD Trials Atomoxetine (N = 715) Placebo (N = 434) Atomoxetine (N = 882) Placebo (N = 500) Gastrointestinal Disorders Abdominal pain Abdominal pain includes the terms: abdominal pain upper, abdominal pain, stomach discomfort, abdominal discomfort, epigastric discomfort. 17 13 18 7 Vomiting 11 8 11 4 Nausea 7 6 13 4 Constipation Constipation didn't meet the statistical significance on Breslow-Day test but is included in the table because of pharmacologic plausibility. 2 1 1 0 General Disorders Fatigue 6 4 9 2 Psychiatric Disorders Mood swings Mood swings didn't meet the statistical significance on Breslow-Day test at 0.05 level but p‑value was < 0.1 (trend). 2 0 1 1 The following adverse reactions occurred in at least 2% of child and adolescent CYP2D6 PM patients and were statistically significantly more frequent in PM patients compared with CYP2D6 EM patients: insomnia (11% of PMs, 6% of EMs); weight decreased (7% of PMs, 4% of EMs); constipation (7% of PMs, 4% of EMs); depression 1 (7% of PMs, 4% of EMs); tremor (5% of PMs, 1% of EMs); excoriation (4% of PMs, 2% of EMs); middle insomnia (3% of PMs, 1% of EMs); conjunctivitis (3% of PMs, 1% of EMs); syncope (3% of PMs, 1% of EMs); early morning awakening (2% of PMs, 1% of EMs); mydriasis (2% of PMs, 1% of EMs); sedation (4% of PMs, 2% of EMs). 1 Depression includes the following terms: depression, major depression, depressive symptoms, depressed mood, dysphoria. Adult Clinical Trials Reasons for Discontinuation of Treatment Due to Adverse Reactions in Acute Adult Placebo-Controlled Trials - In the acute adult placebo-controlled trials, 11.3% (61/541) atomoxetine subjects and 3.0% (12/405) placebo subjects 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. Seizures - Atomoxetine has 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 poor metabolizers (0/43) reported seizures compared to 0.1% (1/705) for extensive metabolizers. Commonly Observed Adverse Reactions in Acute Adult Placebo-Controlled Trials - 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 4. 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 4). Additional data from ADHD clinical trials (controlled and uncontrolled) has shown that approximately 5 to 10% of adult patients experienced potentially clinically important changes in heart rate (≥ 20 beats per min) or blood pressure (≥ 15 to 20 mm Hg) [see Contraindications (4) and Warnings and Precautions (5)] . Table 4: Common Treatment-Emergent Adverse Reactions Associated with the Use of Atomoxetine in Acute (up to 25 weeks) Adult Trials Adverse Reaction Percentage of Patients Reporting Reaction Atomoxetine (N = 1697) Placebo (N = 1560) Cardiac Disorders Palpitations 3 1 Gastrointestinal Disorders Dry mouth 20 5 Nausea 26 6 Constipation 8 3 Abdominal pain Abdominal pain includes the terms: abdominal pain upper, abdominal pain, stomach discomfort, abdominal discomfort, epigastric discomfort. 7 4 Dyspepsia 4 2 Vomiting 4 2 General Disorders and Administration Site Conditions Fatigue 10 6 Chills 3 0 Feeling jittery 2 1 Irritability 5 3 Thirst 2 1 Investigations Weight decreased 2 1 Metabolism and Nutritional Disorders Decreased appetite 16 3 Nervous System Disorders Dizziness 8 3 Somnolence Somnolence includes the terms: sedation, somnolence. 8 5 Paraesthesia 3 0 Psychiatric Disorders Abnormal dreams 4 3 Insomnia Insomnia includes the terms: insomnia, initial insomnia, middle insomnia, and terminal insomnia. 15 8 Libido decreased 3 1 Sleep disorder 3 1 Renal and Urinary Disorders Urinary hesitation Urinary hesitation includes the terms: urinary hesitation, urine flow decreased. 6 1 Dysuria 2 0 Reproductive System and Breast Disorders Erectile dysfunction Based on total number of males (atomoxetine, N=943; placebo, N=869). 8 1 Dysmenorrhea Based on total number of females (atomoxetine, N=754; placebo, N=691). 3 2 Ejaculation delayed and/or ejaculation disorder 4 1 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 4 1 Vascular Disorders Hot flush 3 0 The following adverse events occurred in at least 2% of adult CYP2D6 poor metabolizer (PM) patients and were statistically significantly more frequent in PM patients compared to CYP2D6 extensive metabolizer (EM) patients: vision blurred (4% of PMs, 1% of EMs); dry mouth (35% of PMs, 17% of EMs); constipation (11% of PMs, 7% of EMs); feeling jittery (5% of PMs, 2% of EMs); decreased appetite (23% of PMs, 15% of EMs); tremor (5% of PMs, 1% of EMs); insomnia (19% of PMs, 11% of EMs); sleep disorder (7% of PMs, 3% of EMs); middle insomnia (5% of PMs, 3% of EMs); terminal insomnia (3% of PMs, 1% of EMs); urinary retention (6% of PMs, 1% of EMs); erectile dysfunction (21% of PMs, 9% of EMs); ejaculation disorder (6% of PMs, 2% of EMs); hyperhidrosis (15% of PMs, 7% of EMs); peripheral coldness (3% of PMs, 1% of EMs). Male and Female Sexual Dysfunction - Atomoxetine appears to impair sexual function in some patients. Changes in sexual desire, sexual performance, and sexual satisfaction are not well assessed in most clinical trials because they need special attention and because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate the actual incidence. Table 4 above displays the incidence of sexual side effects reported by at least 2% of adult patients taking atomoxetine in placebo-controlled trials. 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, physicians should routinely inquire about such possible side effects. 6.2 Postmarketing Spontaneous Reports The following adverse reactions have been identified during post approval use of atomoxetine. Unless otherwise specified, these adverse reactions have occurred in adults and children and adolescents. 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 children and adolescents; sensory disturbances; tics. Psychiatric disorders – Depression and depressed mood; anxiety; libido changes. Seizures – Seizures have been reported in the postmarketing period. The postmarketing seizure cases include patients with pre-existing seizure disorders and those with identified risk factors for seizures, as well as 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 children and adolescents; urinary retention in children and adolescents.

Monoamine Oxidase Inhibitors. (4.2, 7.1) CYP2D6 Inhibitors – Concomitant use may increase atomoxetine steady-state plasma concentrations in EMs. (7.2) Antihypertensive Drugs and Pressor Agents – Possible effects on blood pressure. (7.3) Albuterol (or other beta 2 agonists) – Action of albuterol on cardiovascular system can be potentiated. (7.4) 7.1 Monoamine Oxidase Inhibitors With other drugs that affect brain monoamine concentrations, there have been reports of serious, sometimes fatal reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) when taken in combination with an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Such reactions may occur when these drugs are given concurrently or in close proximity [see Contraindications (4.2)]. 7.2 Effect of CYP2D6 Inhibitors on Atomoxetine In extensive metabolizers (EMs), inhibitors of CYP2D6 (e.g., paroxetine, fluoxetine, and quinidine) increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in poor metabolizers (PMs). In EM individuals treated with paroxetine or fluoxetine, the AUC of atomoxetine is approximately 6- to 8-fold and C ss,max is about 3- to 4-fold greater than atomoxetine alone. In vitro studies suggest that coadministration of cytochrome P450 inhibitors to PMs will not increase the plasma concentrations of atomoxetine. 7.3 Antihypertensive Drugs and Pressor Agents Because of possible effects on blood pressure, atomoxetine should be used cautiously with antihypertensive drugs and pressor agents (e.g., dopamine, dobutamine) or other drugs that increase blood pressure. 7.4 Albuterol Atomoxetine should be administered with caution to patients being treated with systemically-administered (oral or intravenous) albuterol (or other beta 2 agonists) because the action of albuterol on the cardiovascular system can be potentiated resulting in increases in heart rate and blood pressure. Albuterol (600 mcg iv over 2 hours) induced increases in heart rate and blood pressure. These effects were potentiated by atomoxetine (60 mg BID for 5 days) and were most marked after the initial coadministration of albuterol and atomoxetine. However, these effects on heart rate and blood pressure were not seen in another study after the coadministration with inhaled dose of albuterol (200-800 mcg) and atomoxetine (80 mg QD for 5 days) in 21 healthy Asian subjects who were excluded for poor metabolizer status. 7.5 Effect of Atomoxetine on P450 Enzymes Atomoxetine did not cause clinically important inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9. CYP3A Substrate (e.g., Midazolam) - Coadministration of atomoxetine (60 mg BID for 12 days) with midazolam, a model compound for CYP3A4 metabolized drugs (single dose of 5 mg), resulted in 15% increase in AUC of midazolam. No dose adjustment is recommended for drugs metabolized by CYP3A. CYP2D6 Substrate (e.g., Desipramine) - Coadministration of atomoxetine (40 or 60 mg BID for 13 days) with desipramine, a model compound for CYP2D6 metabolized drugs (single dose of 50 mg), did not alter the pharmacokinetics of desipramine. No dose adjustment is recommended for drugs metabolized by CYP2D6. 7.6 Alcohol Consumption of ethanol with atomoxetine did not change the intoxicating effects of ethanol. 7.7 Methylphenidate Coadministration of methylphenidate with atomoxetine did not increase cardiovascular effects beyond those seen with methylphenidate alone. 7.8 Drugs Highly Bound to Plasma Protein In vitro drug-displacement studies were conducted with atomoxetine and other highly-bound drugs at therapeutic concentrations. Atomoxetine did not affect the binding of warfarin, acetylsalicylic acid, phenytoin, or diazepam to human albumin. Similarly, these compounds did not affect the binding of atomoxetine to human albumin. 7.9 Drugs that Affect Gastric pH Drugs that elevate gastric pH (magnesium hydroxide/aluminum hydroxide, omeprazole) had no effect on atomoxetine bioavailability.

16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.