Atomoxetine - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS • Suicidal Ideation – Monitor for suicidality, clinical worsening, and unusual changes in behavior. • Severe Liver Injury – Should be discontinued and not restarted in patients with jaundice or laboratory evidence of liver injury. • Serious Cardiovascular Events – Sudden death, stroke and myocardial infarction have been reported in association with atomoxetine treatment.

Patients should have a careful history and physical exam to assess for presence of cardiovascular disease.

Atomoxetine generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to its noradrenergic effects.

Consideration should be given to not using atomoxetine in adults with clinically significant cardiac abnormalities. • Emergent Cardiovascular Symptoms – Patients should undergo prompt cardiac evaluation. • Effects on Blood Pressure and Heart Rate – Increase in blood pressure and heart rate; orthostasis and syncope may occur.

Use with caution in patients with hypertension, tachycardia, or cardiovascular or cerebrovascular disease. • Psychotic or Manic Symptoms – Consider discontinuing atomoxetine if such new symptoms occur. • Bipolar Disorder – Screen patients for bipolar disorder. • Aggressive behavior or hostility – Monitor for the appearance or worsening of aggressive behavior or hostility. • Possible allergic reactions, including anaphylactic reactions, angioneurotic edema, urticaria, and rash. • Effects on Urine Outflow – Urinary hesitancy and retention may occur. • Priapism – Prompt medical attention is required in the event of suspected priapism. ( 5.10 , 17 ) • Growth – Height and weight should be monitored in pediatric patients. • Concomitant Use of Potent CYP2D6 Inhibitors or Use in patients known to be CYP2D6 PMs – Dose adjustment of atomoxetine may be necessary.

5.1 Suicidal Ideation Atomoxetine increased the risk of suicidal ideation in short-term studies in children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD).

Pooled analyses of short-term (6 to 18 weeks) placebo-controlled trials of atomoxetine in children and adolescents have revealed a greater risk of suicidal ideation early during treatment in those receiving atomoxetine.

There were a total of 12 trials (11 in ADHD and 1 in enuresis) involving over 2200 patients (including 1357 patients receiving atomoxetine and 851 receiving placebo).

The average risk of suicidal ideation in patients receiving atomoxetine was 0.4% (5/1357 patients), compared to none in placebo-treated patients.

There was 1 suicide attempt among these approximately 2200 patients, occurring in a patient treated with atomoxetine.

No suicides occurred in these trials.

All reactions occurred in children 12 years of age or younger.

All reactions occurred during the first month of 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 for either ADHD or major depressive disorder (MDD) did not reveal an increased risk of suicidal ideation or behavior in association with the use of atomoxetine.

All pediatric patients being treated with atomoxetine should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms have been reported with 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.

Thus, patients being treated with atomoxetine should be observed for the emergence of such symptoms.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who are experiencing emergent suicidality or symptoms that might be precursors to emerging suicidality, especially if these symptoms are severe or abrupt in onset, or were not part of the patient's presenting symptoms.

Families and caregivers of pediatric patients being treated with atomoxetine should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers.

Such monitoring should include daily observation by families and caregivers.

5.2 Severe Liver Injury Postmarketing reports indicate that atomoxetine can cause severe liver injury.

Although no evidence of liver injury was detected in clinical trials of about 6000 patients, there have been rare cases of clinically significant liver injury that were considered probably or possibly related to atomoxetine use in postmarketing experience.

Rare cases of liver failure have also been reported, including a case that resulted in a liver transplant.