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warnings and cautions
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. 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 oral solution 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 oral solution is started, but laboratory abnormalities may continue to worsen for several weeks after atomoxetine oral solution is stopped. 5.3 Serious Cardiovascular Reactions Risk Management Recommendations for Serious Cardiovascular Reactions Prior to atomoxetine oral solution 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 oral solution 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 oral solution 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 treatment should stop atomoxetine oral solution 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 Increases in Blood Pressure and Heart Rate Atomoxetine oral solution is 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 oral solution 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 oral solution 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 oral solution 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 patients treated with another atomoxetine product, 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 patients treated with another atomoxetine product compared with 0% (0/934) of placebo-treated patients. In placebo-controlled adult ADHD studies, tachycardia was identified as an adverse reaction for 1.5% (8/540) of patients treated with another atomoxetine product compared with 0.5% (2/402) of placebotreated 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 patients treated with another atomoxetine product 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 patients treated with another atomoxetine product had orthostatic hypotension compared with 0.5% (1/207) of placebotreated 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 treated with another atomoxetine product, 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, for patients treated with another atomoxetine product 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, for patients treated with another atomoxetine product 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 oral solution. 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 oral solution at the recommended dosage. 5.6 Screening Patients for Bipolar Disorder Before initiating treatment with atomoxetine oral solution, 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 oral solution. It may not be possible to determine whether a manic or mixed episode that appears during treatment with atomoxetine oral solution is due to an adverse reaction to atomoxetine oral solution or a patient’s underlying bipolar disorder. 5.7 Aggressive Behavior or Hostility Patients beginning treatment with atomoxetine oral solution should be monitored for the appearance or worsening of aggressive behavior or hostility. There is evidence that atomoxetine oral solution 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 oral solution 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 oral solution. 5.8 Hypersensitivity Reactions Atomoxetine oral solution is contraindicated in patients with a known hypersensitivity reaction to atomoxetine oral solution or other components of atomoxetine oral solution. 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 oral solution. In adult ADHD controlled studies, the incidence of urinary retention (1.7% (9/540)) and urinary hesitation (5.6% (30/540)) were increased among patients treated with another atomoxetine product compared with placebo-treated patients (0% (0/402); 0.5% (2/402), respectively). Two adult patients treated with another atomoxetine product 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 oral solution-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 oral solution treatment. Weight and Height in Long-Term Open-Label Studies in Pediatric Patients Data on the long-term effects of another atomoxetine product on growth in pediatric patients from open-label studies in which weight and height changes were compared to normative pediatric population data are presented below. In general, the weight and height gain of atomoxetine-treated pediatric patients treated with another atomoxetine product lagged behind that predicted by normative population data for about the first 9-12 months of treatment, and subsequently (see Figure 1 below): Weight gain rebounded. At about 3 years of treatment with another atomoxetine product, 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 treatment with another atomoxetine product, 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 treatment with another atomoxetine product 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 another atomoxetine product 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 treatment initiation with another atomoxetine product. Weight and Height in Short-Term, Placebo-Controlled Studies in Pediatric Patients In short-term, placebo-controlled studies (up to 9 weeks), patients treated with another atomoxetine product 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 other atomoxetine product groups, respectively, lost at least 3.5% of their body weight. "Image Description"