Atomoxetine

New or worsening symptoms of hostility or aggressive behaviors have been associated with atomoxetine, particularly with the initiation of therapy.

Anaphylactic reactions, angioneurotic edema, urticaria, and rash may occur (rare).

In clinical trials, at therapeutic doses, atomoxetine consistently did not prolong the QT/QTc interval; however, one placebo-controlled study in healthy CYP2D6 poor metabolizers demonstrated a statistically significant increase in QTc with increasing atomoxetine concentrations (Loghin 2012; Martinez-Raga 2013). Case reports suggest that atomoxetine overdose may increase the QT interval; however, this occurred when atomoxetine was combined with other agents known to have QT prolongation potential or inhibit CYP2D6 (Barker 2004; Sawant 2004). Atomoxetine, at high concentrations ex vivo, has demonstrated hERG channel block (Scherer 2009).

Atomoxetine has been associated with serious cardiovascular events including sudden death in patients with preexisting structural cardiac abnormalities or other serious heart problems (sudden death in children and adolescents; sudden death, stroke, and MI in adults). Atomoxetine should be avoided in patients with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that could increase the risk of sudden death that these conditions alone carry. Patients should be carefully evaluated for cardiac disease prior to initiation of therapy. Perform a prompt cardiac evaluation in patients who develop symptoms of exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during treatment.

Use may be associated with rare but severe hepatotoxicity, including hepatic failure; discontinue and do not restart if signs or symptoms of hepatotoxic reaction (eg, jaundice, pruritus, flu-like symptoms, dark urine, right upper quadrant tenderness) or laboratory evidence of liver injury are noted. The majority of reported cases occurred within 120 days of initiation of therapy.

Orthostasis and subsequent syncope may occur. Use with caution in patients predisposed to hypotension, or with conditions associated with abrupt heart rate or blood pressure changes.

Prolonged and painful erections (priapism), sometimes requiring surgical intervention, have been reported (rarely) with methylphenidate and atomoxetine use in pediatric and adult patients. Priapism has been reported to develop after some time on the drug, often subsequent to an increase in dose but also during a period of drug withdrawal (drug holidays or discontinuation). Patients with certain hematological dyscrasias (eg, sickle cell disease), malignancies, perineal trauma, or concomitant use of alcohol, illicit drugs, or other medications associated with priapism may be at increased risk. Patients who develop abnormally sustained or frequent and painful erections should discontinue therapy and seek immediate medical attention. An emergent urological consultation should be obtained in severe cases. Priapism has been associated with different dosage forms and products; it is not known if rechallenge with a different formulation will risk recurrence. Avoidance of stimulants and atomoxetine may be preferred in patients with severe cases that were slow to resolve and/or required detumescence (Eiland, 2014).

Treatment-emergent psychotic or manic symptoms (eg, hallucinations, delusional thinking, mania) may occur in children and adolescents without a prior history of psychotic illness or mania. Consider discontinuation of treatment if symptoms occur. Disease-related concerns:

Randomized, controlled trials have demonstrated that atomoxetine does not worsen anxiety in patients with existing anxiety disorders or tics related to Tourette’s disorder.

Use caution in patients with comorbid bipolar disorder; therapy may induce mixed/manic episodes. Atomoxetine is not approved for major depressive disorder; patients presenting with depressive symptoms should be screened for bipolar disorder.

Use with caution in patients with hepatic impairment; dosage adjustments necessary in moderate and severe hepatic insufficiency.

Use with caution in patients with hypertension and other cardiovascular or cerebrovascular conditions that might be exacerbated by increases in blood pressure or heart rate. CYP2D6 poor metabolizers may experience greater increases in blood pressure and heart rate effects.

Use with caution in patients with a history of urinary retention or bladder outlet obstruction; may cause urinary retention/hesitancy. Special populations:

Dosage adjustments are recommended in CYP2D6 poor metabolizers; these patients have increased exposure to atomoxetine.

[US. Boxed Warning]: Use with caution in pediatric patients; may be an increased risk of suicidal ideation. Closely monitor for clinical worsening, suicidality, or 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 family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. Growth should be monitored during treatment. Height and weight gain may be reduced during the first 9 to 12 months of treatment, but should recover by 3 years of therapy. Other warnings/precautions:

Appropriate use: Recommended to be used as part of a comprehensive treatment program for attention deficit disorders.