Atomoxetine

Product Type: HUMAN PRESCRIPTION DRUG

Route: ORAL

Dosage Form:

NDC: 50090-6143

Application: ANDA202682

Effective: 20231101

1 INDICATIONS AND USAGE Atomoxetine capsule is a selective norepinephrine reuptake inhibitor indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). ( 1.1 ) 1.1 Attention-Deficit/Hyperactivity Disorder (ADHD) Atomoxetine capsule is indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). The efficacy of atomoxetine capsules was 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 capsule 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.

2 DOSAGE AND ADMINISTRATION 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). ( 2.4 , 12.3 ) 2.1 Acute Treatment Dosing of children and adolescents up to 70 kg body weight - Atomoxetine capsules 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 capsules 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 to 15 years) with ADHD on atomoxetine capsules 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 capsules 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 capsules 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 capsules may be taken with or without food. Atomoxetine capsules 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 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 capsule 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 capsule 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.

4 CONTRAINDICATIONS • Hypersensitivity to atomoxetine or other constituents of product. ( 4.1 ) • Atomoxetine capsules 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 capsules are 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 capsules 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 capsules. 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 capsules 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 capsules. Therefore, atomoxetine capsules 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 )].

Not available.

6 ADVERSE REACTIONS 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 Annora Pharma Private Limited at 1-866-495-1995 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 a Percentage of Patients Reporting Reaction Atomoxetine (N=1597) Placebo (N=934) Gastrointestinal Disorders Abdominal Pain b 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 c 11 4 Dizziness 5 2 Skin and Subcutaneous Tissue Disorders Rash 2 1 a 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. b Abdominal pain includes the terms: abdominal pain upper, abdominal pain, stomach discomfort, abdominal discomfort, epigastric discomfort. c Somnolence includes the terms: sedation, somnolence. 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 a 17 13 18 7 Vomiting 11 8 11 4 Nausea 7 6 13 4 Constipation b 2 1 1 0 General Disorders Fatigue 6 4 9 2 Psychiatric Disorders Mood swings c 2 0 1 1 a Abdominal pain includes the terms: abdominal pain upper, abdominal pain, stomach discomfort, abdominal discomfort, epigastric discomfort. b Constipation didn’t meet the statistical significance on Breslow-Day test but is included in the table because of pharmacologic plausibility. c Mood swings didn’t meet the statistical significance on Breslow-Day test at 0.05 level but p-value was <0.1 (trend). 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); depression1 (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). 1Depression 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% (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 a 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 b 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 c 8 5 Paraesthesia 3 0 Psychiatric Disorders Abnormal dreams 4 3 Insomnia d 15 8 Libido decreased 3 1 Sleep disorder 3 1 Renal and Urinary Disorders Urinary hesitation e 6 1 Dysuria 2 0 Reproductive System and Breast Disorders Erectile dysfunction f 8 1 Dysmenorrhea g 3 2 Ejaculation delayed f and/or ejaculation disorder f 4 1 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 4 1 Vascular Disorders Hot flush 3 0 a 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: 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. The following reactions were reported by at least 2% of patients treated with atomoxetine, and equal to or less than placebo: anxiety, diarrhea, back pain, headache, and oropharyngeal pain. b Abdominal pain includes the terms: abdominal pain upper, abdominal pain, stomach discomfort, abdominal discomfort, epigastric discomfort. c Somnolence includes the terms: sedation, somnolence. d Insomnia includes the terms: insomnia, initial insomnia, middle insomnia, and terminal insomnia. e Urinary hesitation includes the terms: urinary hesitation, urine flow decreased. f Based on total number of males (atomoxetine, N=943; placebo, N=869). g Based on total number of females (atomoxetine, N=754; placebo, N=691). The following adverse events occurred in at least 2% of adult CYP2D6 poor metaboliser (PM) patients and were statistically significantly more frequent in PM patients compared to CYP2D6 extensive metaboliser (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.