Atomoxetine Hydrochloride

Selective norepinephrine reuptake inhibitor.1 2 3 4 5 6 7 8 9 10 11 19

Attention Deficit Hyperactivity Disorder

Treatment of ADHD, alone or combined with behavioral treatment, as an adjunct to psychological, educational, social, and other remedial measures in carefully selected adults1 11 and children ≥6 years of age.1 4 10 12

Contraindications

• Known hypersensitivity to atomoxetine or any ingredient in the formulation.1

• Current or recent (within 2 weeks) therapy with MAO inhibitor.1 Allow ≥2 weeks to elapse after discontinuing atomoxetine before initiating MAO inhibitor therapy.1 (See Specific Drugs under Interactions.)

• Angle-closure glaucoma.1

Warnings/Precautions

Warnings

Increased risk of suicidal thinking observed in a pooled analysis of short-term clinical trials in children and adolescents with ADHD.1 17 (See Pediatric Use under Cautions.) Not known whether risk extends to long-term use of the drug.1

Similar analysis of data from adults with ADHD or major depressive disorder found no increased risk of suicidal ideation or behavior in those receiving atomoxetine.1 17

Balance risk of suicidality against the clinical need for the drug.1

Monitor pediatric patients closely for clinical worsening, suicidal ideation or behaviors, or unusual changes in behavior, particularly during the first few months of therapy and following dosage adjustment.1 16 17 19 Monitoring should include daily observation by family members and caregivers and frequent contact with the prescribing clinician, particularly if the patient’s behavior changes or is a concern.1 17

Manufacturer recommends face-to-face contact between clinicians and patients or their family members or caregivers at least weekly during the first 4 weeks of therapy and then every other week for the next 4 weeks, with subsequent face-to-face contact at 12 weeks and as clinically indicated thereafter; additional contact via telephone may be appropriate between visits.1

Consider discontinuance of therapy in patients with emergent suicidality or manifestations that may be precursors to emerging suicidality (e.g., anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, mania), particularly if such manifestations are severe or abrupt in onset or were not part of the patient’s presenting symptoms.1

Sensitivity Reactions

Angioedema, urticaria, and rash reported rarely.1

Other Warnings and Precautions

Severe hepatic injury rarely reported; manifested by increased hepatic enzymes (up to 40 times ULN) and jaundice (bilirubin up to 12 times ULN).1 15 Risk of progression to acute hepatic failure resulting in death or requiring liver transplantation in a small percentage of patients.1 15 Adverse hepatic effects may occur several months after atomoxetine initiation; laboratory abnormalities may continue to worsen for several weeks after discontinuance.1

Determine hepatic enzyme concentrations after first manifestation of hepatic dysfunction (e.g., pruritus, dark urine, jaundice, right upper quadrant tenderness, unexplained flu-like symptoms).1 15 Discontinue atomoxetine in patients with jaundice or laboratory evidence of hepatic injury and do not reinitiate.1 15

Sudden unexplained death, stroke, and MI reported in adults with ADHD receiving usual dosages of atomoxetine; sudden death also reported in children and adolescents with structural cardiac abnormalities or other serious cardiac conditions receiving usual dosages of the drug.1

Thoroughly review medical history (including evaluation for family history of sudden death or ventricular arrhythmia) and perform physical examination in all children, adolescents, and adults being considered for atomoxetine therapy; if initial findings suggest presence of cardiac disease, perform further cardiac evaluation (e.g., ECG, echocardiogram).1

In general, avoid use in patients with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, CAD, or other serious cardiac conditions.1

Patients who develop exertional chest pain, unexplained syncope, or other manifestations suggestive of cardiac disease during atomoxetine therapy should undergo prompt cardiac evaluation.1

Psychotic symptoms (e.g., hallucinations, delusional thinking) may occur with usual dosages in children and adolescents without prior history of psychotic illness.1 If psychotic symptoms occur, consider causal relationship to atomoxetine, and discontinue therapy as appropriate.1

May precipitate mixed or manic episodes in ADHD patients with comorbid bipolar disorder; use with caution in these patients.1 Prior to initiating therapy, carefully screen patients with ADHD and comorbid depressive symptoms to identify risk for bipolar disorder; screening should include a detailed psychiatric history (e.g., family history of suicide, bipolar disorder, or depression).1

Manic symptoms may occur with usual dosages in children and adolescents without prior history of mania.1 If manic symptoms occur, consider causal relationship to atomoxetine, and discontinue therapy as appropriate.1

Increased BP and heart rate reported in children, adolescents, and adults.1 4 7 9 10 11 Use with caution in patients with hypertension, tachycardia, or cardiovascular or cerebrovascular disease.1 Measure BP and pulse rate before initiation of atomoxetine, following any increase in dosage, and periodically during therapy.1

Orthostatic hypotension and syncope reported;1 use with caution in patients with conditions that would predispose them to hypotension.1

Exacerbation or precipitation of Raynaud’s phenomenon reported.1

Possible urinary retention and urinary hesitation.1

Monitor growth of pediatric patients receiving atomoxetine.1 Potential for temporary suppression of normal height and/or weight patterns following initiation of therapy.1 (See Pediatric Use under Cautions.)

Aggressive behavior and hostility frequently are observed in pediatric patients with ADHD and have been reported in patients receiving drug therapy (including atomoxetine) for the disorder.1

Monitor patients beginning treatment for ADHD for the appearance or worsening of aggressive behavior or hostility.1

Priapism reported rarely in pediatric and adult patients; requires prompt medical attention.1 (See Advice to Patients.)

In a controlled study, atomoxetine did not worsen tics in patients with ADHD and comorbid Tourette’s disorder.1

Specific Populations

Category C.1

Distributed into milk in rats; not known whether atomoxetine is distributed into human milk.1 Caution if used in nursing women.1

Safety and efficacy not established in children <6 years of age.1

Increased risk of suicidal ideation observed in a pooled analysis of 12 short-term controlled clinical trials in pediatric patients with ADHD (11 studies) or enuresis (1 study); risk of suicidal ideation was about 0.4% in those receiving atomoxetine versus 0% in those receiving placebo.1 17 One child receiving the drug attempted suicide; no completed suicides were reported.1 17 All events representing suicidal behavior or thinking occurred in children ≤12 years of age and occurred during the first month of therapy.1 Not known whether the risk extends to long-term use of the drug.1 Balance risk of suicidality against the clinical need for the drug.1 (See Suicidality Risk under Cautions.)

Sudden death reported in children and adolescents with structural cardiac abnormalities or other serious cardiac conditions receiving usual dosages of stimulants.1 (See Sudden Death and Serious Cardiovascular Events under Cautions.)

Potential for temporary (e.g., 9–12 months) suppression of normal height and/or weight patterns following initiation of atomoxetine therapy in pediatric patients; rebound in height and weight gains reported with continued therapy.1 Pattern observed regardless of metabolizer phenotype (poor or extensive metabolizer of the drug) or pubertal status upon initiation of therapy.1 Monitor growth of patients receiving atomoxetine therapy.1 19

Safety and efficacy not established.1

Increased systemic exposure to atomoxetine in patients with moderate or severe hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration and Special Populations under Pharmacokinetics.)

Common Adverse Effects

In children and adolescents, abdominal pain, decreased appetite, vomiting, somnolence, nausea, fatigue, irritability, dizziness.1

In adults, dry mouth, nausea, insomnia, decreased appetite, constipation, fatigue, erectile dysfunction, hot flush, urinary hesitation and/or retention, dysmenorrhea.1

Metabolized principally by CYP2D6.1 Does not cause clinically important inhibition or induction of CYP enzymes, including 1A2, 3A, 2D6, and 2C9.1

Drugs Affecting Hepatic Microsomal Enzymes

Potential for increased plasma atomoxetine concentrations during concomitant therapy with CYP2D6 inhibitors in individuals with extensive metabolizer CYP2D6 phenotype (concentrations may be similar to those achieved in poor metabolizers).1

If used concomitantly with a potent CYP2D6 inhibitor or in patients with poor metabolizer CYP2D6 phenotype, initiate atomoxetine therapy at usual initial daily dosage (approximately 0.5 mg/kg daily in children and adolescents weighing ≤70 kg; 40 mg daily in adults and children and adolescents weighing >70 kg); increase dosage to usual target dosage (approximately 1.2 mg/kg daily [maximum 100 mg daily] in children and adolescents weighing ≤70 kg; 80 mg daily in adults and children and adolescents weighing >70 kg) only if ADHD symptoms fail to improve after 4 weeks of therapy and initial dosage is well tolerated.1

Specific Drugs

Storage

Oral

25°C (may be exposed to 15–30°C).1