Atomoxetine hydrochloride

1 INDICATIONS AND USAGE Atomoxetine oral solution is indicated for the treatment of attention-deficit/hyperactivity disorder (ADHD) in adult and pediatric patients 6 years of age and older. Atomoxetine oral solution is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with ADHD. Atomoxetine oral solution is a selective norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of ADHD in adults and pediatric patients 6 years of age and older. ( 1 )

2 DOSAGE AND ADMINISTRATION Prior to initiating treatment with atomoxetine oral solution: Screen patients for a personal or family history of bipolar disorder, mania, or hypomania. ( 2.1 , 5.6 ) Consider genetic testing to determine the patient’s CYP2D6 metabolizer status prior to dosing. ( 2.1 , 2.5 ) See table below for the recommended atomoxetine oral solution 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 Oral Solution Treatment Prior to initiating treatment with atomoxetine oral solution: Screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.6) ] . Consider genetic testing to determine the patient’s CYP2D6 metabolizer status [see Dosage and Administration (2.5) ] . 2.2 Administration Instructions Atomoxetine oral solution may be taken with or without food. Instruct patients to only use the supplied syringe and bottle adapter to measure and take atomoxetine oral solution [see Instructions for Use ] . 2.3 Recommended Dosage Table 1 includes the recommended dosage of atomoxetine oral solution in adult patients and pediatric patients 6 years of age and older for treatment of ADHD. Table 1: Recommended Dosage of Atomoxetine Oral Solution for the 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 a Administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening. b No additional benefit has been demonstrated with atomoxetine 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 dosage to a maximum of 100 mg/day. There are no data that support increased effectiveness at a dosage higher than 100 mg/day [see Clinical Studies (14) ] . The health care provider who elects to use atomoxetine oral solution for extended periods should periodically reevaluate the long-term usefulness of atomoxetine oral solution for the individual patient. 2.4 Recommended Dosage in Patients with Hepatic Impairment For patients 6 years of age or older with: Severe hepatic impairment (HI) (Child-Pugh Class C), the recommended initial and target 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 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 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 Table 2 includes the recommended atomoxetine oral solution dosage in adult patients and pediatric patients aged 6 years of age or older with concomitant use of a strong CYP2D6 inhi…

5 WARNINGS AND PRECAUTIONS Severe Liver Injury: Atomoxetine oral solution should be discontinued and not restarted in patients with jaundice or laboratory evidence of liver injury. ( 5.2 ) Serious Cardiovascular Reactions: Prior to atomoxetine oral solution treatment, patients should have a careful history and physical exam to assess for presence of cardiovascular (CV) disease. Atomoxetine oral solution generally should not be used in pediatric patients with known serious cardiac abnormalities, cardiomyopathy, serious arrhythmias. Consideration should be given to not using atomoxetine oral solution in adults with clinically significant cardiac abnormalities. Patients who develop symptoms suggestive of cardiac disease during atomoxetine oral solution treatment should stop atomoxetine oral solution 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 oral solution dosage increases, 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 oral solution. ( 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. ( 5.8 ) Priapism: Prompt medical attention is required in the event of suspected priapism. ( 5.9 ) 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 pediatric patients 6 years of age and older treated with atomoxetine oral solution should be monitored observed closely for clinical worsening, suicidal thoughts and behavior, and unusual changes in behavior, especially during the initial few months of atomoxetine oral solution therapy, or at times of dose changes, either increases or decreases. Families and caregivers of pediatric patients 6 years of age and older treated with atomoxetine oral solution 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 oral solution, 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 increased the risk of suicidal ideation in pediatric patients 6 years of age 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 in another clinical study ) with over 2,200 pediatric patients, the mean incidence of suicidal ideation in pediatric patients treated with another atomoxetine product was 0.4% (5/1357) (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 treatment with the other atomoxetine product. 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 for ADHD did not reveal an increased risk of suicidal ideation or behavior. The following psychiatric symptoms have been reported with the use of atomoxetine: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania and mania…

4 CONTRAINDICATIONS Atomoxetine oral solution is contraindicated in patients: With known hypersensitivity reaction to atomoxetine oral solution or other components of atomoxetine oral solution. Hypersensitivity reactions that occurred with atomoxetine oral solution use 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 oral solution 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 oral solution. With severe cardiac or vascular disorders whose condition would be expected to deteriorate if they had 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) ] . Contraindicated in patients ( 4 ): With known hypersensitivity to atomoxetine oral solution or other components of atomoxetine oral solution 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.

7 DRUG INTERACTIONS See Table 9 for clinically significant drug interactions with atomoxetine oral solution and other drugs. Table 9: Clinically Significant Drug Interactions with Atomoxetine Oral Solution and Other Drugs​​​​​​​ Monoamine Oxidase Inhibitors (MAOIs) Prevention or Management Atomoxetine oral solution 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 oral solution and an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Strong CYP2D6 Inhibitors Prevention or Management With concomitant use of atomoxetine oral solution and a strong CYP2D6 inhibitor 1 , 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. Concomitant use of atomoxetine oral solution and a strong CYP2D6 inhibitor increases atomoxetine exposure [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ] . Antihypertensive Drugs Prevention or Management Increase the frequency of monitoring blood pressure and adjust atomoxetine oral solution dosage as clinically appropriate. Mechanism and Clinical Effect(s) Because of increased risk of increased blood pressure, atomoxetine oral solution should be used cautiously with antihypertensive drugs, other drugs that increase blood pressure or pressor drugs (e.g., dopamine, dobutamine). Albuterol or Other Beta 2 (β2) Agonists Prevention or Management Increase the frequency of monitoring blood pressure and heart rate and adjust atomoxetine oral solution dosage as clinically appropriate. Mechanism and Clinical Effect(s) Systemically administered albuterol (e.g., oral) can be potentiated by atomoxetine oral solution, resulting in increases in heart rate and blood pressure [see Clinical Pharmacology (12.3) ] . 1 See www.fda.gov/CYPandTransporterInteractingDrugs for examples of strong CYP2D6 inhibitors. Monoamine Oxidase Inhibitors: Concomitant use contraindicated. ( 4 , 7 ) Strong CYP2D6 Inhibitors: With concomitant of atomoxetine oral solution and strong CYP2D6 inhibitors, increase the titration intervals. ( 7 ) Antihypertensives: Increase the frequency of monitoring blood pressure and adjust atomoxetine oral solution dosage as clinically appropriate. ( 7 ) Albuterol (or other beta 2 agonists): Increase the frequency of monitoring blood pressure and heart rate. ( 7 )

6 ADVERSE REACTIONS 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 oral solution ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Advagen Pharma Ltd, at 1-866-488-0312 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. The safety of atomoxetine oral solution has been established from adequate and well-controlled studies of atomoxetine capsules (also referred to as another atomoxetine product) in patients 6 years of age and older with ADHD [see Clinical Studies (14) ] . Below is a display of the adverse reactions of [atomoxetine capsules in these adequate and well-controlled studies. Atomoxetine capsules were 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 capsules-treated pediatric patients and 1.4% (13/945) of placebo-treated pediatric patients discontinued due to an adverse reaction. Among atomoxetine capsules-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 capsules-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 capsules-treated patients and with a higher incidence in atomoxetine capsules-treated patients compared to placebo-treated patients) in pediatric patients 6 years of age and older with ADHD are listed in Table 3. The most commonly observed adverse reactions in atomoxetine capsules-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 3 and 4). Table 3: Common Adverse Reactions a in Acute Studies (up to 18 weeks) in Pediatric Patients 6 Years and Older with ADHD Atomoxetine Capsules (N=1,597) Placebo (N=934) Headache 19% 15% Abdominal pain b 18% 10% Decreased appetite 16% 4% Somnolence c 11% 4% Vomiting 11% 6% Nausea 10% 5% Fatigue 8% 3% Irritability 6% 3% Dizziness 5% 2% Decreas…