The precise mechanism by which atomoxetine produces its therapeutic effects in ADHD is unknown, but is thought to be related to selective inhibition of the pre-synaptic norepinephrine transporter, as determined in ex vivo uptake and neurotransmitter depletion studies.

ALERT: U.S. Boxed Warning

The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.

U.S. Brand Names

Strattera®

Medication Safety Issues

Sound-alike/look-alike issues:

Atomoxetine may be confused with atorvastatin

Medication Guide

An FDA-approved patient medication guide, which is available with the product information and at file://www.fda.gov/downloads/Drugs/DrugSafety/ucm089138.pdf, must be dispensed with this medication.

Pharmacologic Category

Norepinephrine Reuptake Inhibitor, Selective

Dosing: Adult

Treatment of ADHD: Oral: Initial: 40 mg/day, increased after minimum of 3 days to ~80 mg/day; may administer as either a single daily dose or 2 evenly divided doses in morning and late afternoon/early evening. May increase to 100 mg/day in 2-4 additional weeks to achieve optimal response.

Dosage adjustment in patients receiving strong CYP2D6 inhibitors (eg, paroxetine, fluoxetine, quinidine) or patients known to be CYP2D6 poor metabolizers: Do not exceed 80 mg/day; dose adjustments should occur only after 4 weeks.

Note: Atomoxetine may be discontinued without the need for tapering dose.

Dosing: Pediatric

Treatment of ADHD:

Children ≥6 years and ≤70 kg: Oral: Initial: 0.5 mg/kg/day, increase after minimum of 3 days to ~1.2 mg/kg/day; may administer as either a single daily dose or 2 evenly divided doses in morning and late afternoon/early evening. Maximum daily dose: 1.4 mg/kg or 100 mg, whichever is less.

Dosage adjustment in patients receiving strong CYP2D6 inhibitors (eg, paroxetine, fluoxetine, quinidine) or patients known to be CYP2D6 poor metabolizers: Do not exceed 1.2 mg/kg/day; dose adjustments should occur only after 4 weeks.

Children ≥6 years and >70 kg: Refer to adult dosing.

Note: Atomoxetine may be discontinued without the need for tapering dose.

Dosing: Geriatric

Use has not been evaluated in the elderly.

Dosing: Renal Impairment

No adjustment needed.

Dosing: Hepatic Impairment

Moderate hepatic insufficiency (Child-Pugh class B): All doses should be reduced to 50% of normal.

Severe hepatic insufficiency (Child-Pugh class C): All doses should be reduced to 25% of normal.

Dosage Forms: U.S.

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, oral:

Strattera®: 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg, 100 mg

Generic Equivalent Available: U.S.

No

Administration

May be administered with or without food. Swallow capsules whole; do not open capsules. Powder in capsules is an ocular irritant.

Use

Treatment of attention deficit/hyperactivity disorder (ADHD)

Adverse Reactions Significant

Percentages as reported in children and adults; some adverse reactions may be increased in “poor metabolizers” (CYP2D6).

>10%:

Central nervous system: Headache (2% to 19%), insomnia (2% to 15%), somnolence (4% to 11%)

Gastrointestinal: Xerostomia (21%), nausea (7% to 21%), abdominal pain (7% to 18%), appetite decreased (11% to 16%), vomiting (3% to 11%)

1% to 10%:

Cardiovascular: Systolic blood pressure increased (4% to 5%), diastolic pressure increased (≤4%), palpitation (3%), flushing (≥2%), tachycardia (≤2%), orthostatic hypotension (<2%)

Central nervous system: Fatigue/lethargy (6% to 9%), dizziness (5% to 6%), irritability (≤6%), chills (3%), sleep disturbance (3%), mood swings (1% to 2%)

Dermatologic: Hyperhidrosis (4%), rash (2%)

Endocrine & metabolic: Hot flashes (8%), dysmenorrhea (6%), libido decreased (4%), menstruation disturbance (2%), orgasm abnormal (2%)

Gastrointestinal: Constipation (1% to 9%), dyspepsia (4%), anorexia (<3%), weight loss (2% to 3%)

Genitourinary: Erectile disturbance (9%), urinary hesitation/retention (7%), dysuria (3%), ejaculatory disturbance (3%), prostatitis (2%)

Neuromuscular & skeletal: Paresthesia (3% adults; postmarketing observation in children), tremor (2%)

Ocular: Mydriasis (≥2%)

Respiratory: Sinus headache (3%)

Miscellaneous: Jittery feeling (2%)

Postmarketing and/or case reports: Aggressiveness, agitation, akathisia, allergic reactions, allergy, anaphylaxis, angioedema, anxiety, delusional thinking, depression, growth suppression (children), hallucinations, hepatotoxicity, hostility, hyperhidrosis, hypoesthesia, hypomania, impulsiveness, jaundice, mania, MI, panic attacks, paresthesia, pelvic pain, peripheral vascular instability, priapism, pruritus, QT prolongation, Raynaud’s phenomenon, seizure (including patients with no prior history or known risk factors for seizure), stroke, suicidal ideation, syncope, tics, urticaria

Contraindications

Hypersensitivity to atomoxetine or any component of the formulation; use with or within 14 days of MAO inhibitors; narrow-angle glaucoma; current or past history of pheochromocytoma

Warnings/Precautions

Boxed warnings:

• Pediatrics: See “Special populations” below.

Concerns related to adverse effects:

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

• Allergic reactions: Angioneurotic edema, urticaria, and rash may occur (rare).

• Cardiovascular events: CNS stimulant use has been associated with serious cardiovascular events including sudden death in patients with pre-existing structural cardiac abnormalities or other serious heart problems (sudden death in children and adolescents; sudden death, stroke, and MI in adults). These products 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.

• Hepatotoxicity: Use may be associated with rare but severe hepatotoxicity; discontinue and do not restart if signs or symptoms of hepatotoxic reaction (eg, jaundice, pruritus, flu-like symptoms) or laboratory evidence of liver injury are noted. The majority of reported cases occurred within 120 days of initiation of therapy. Use with caution in patients with hepatic impairment; dosage adjustments may be necessary. Use with caution in patients who are poor metabolizers of CYP2D6 metabolized drugs ("poor metabolizers"); bioavailability increases.

• Orthostasis: Orthostasis and subsequent syncope may occur. Avoid use in patients predisoposed to hypotension, or with conditions associated with abrupt heart rate or blood pressure changes.

• Priapism: Priapism has been associated with use (rarely).

Disease-related concerns:

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

• Hypertension: Use with caution in patients with hypertension and other cardiovascular conditions that might be exacerbated by increases in blood pressure or heart rate.

• Psychiatric disorders: Use caution in patients with a history of psychotic illness or bipolar disorder; therapy may induce mixed/manic disorder or psychotic symptoms. Atomoxetine is not approved for major depressive disorder; patients presenting with depressive symptoms should be screened for bipolar disorder.

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

Special populations:

• Pediatrics: [U.S. 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 9-12 months of treatment, but should recover by 3 years of therapy. Safety and efficacy have not been evaluated in pediatric patients <6 years of age.

Other warnings/precautions:

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

Metabolism/Transport Effects

Substrate of CYP2C19 (minor), 2D6 (major)

Drug Interactions

(For additional information: Launch Lexi-Interact™ Drug Interactions Program )

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Risk D: Consider therapy modification

Beta2-Agonists: Atomoxetine may enhance the tachycardic effect of Beta2-Agonists. Risk C: Monitor therapy

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Risk C: Monitor therapy

CYP2D6 Inhibitors (Strong): May increase the serum concentration of Atomoxetine. Management: Initiate atomoxetine at a reduced dose (adult doses -- patients up to 70kg: 0.5mg/kg/day; patients 70kg or more: 40mg/day) in patients receiving a strong CYP2D6 inhibitor. Risk D: Consider therapy modification

Darunavir: May increase the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

Iobenguane I 123: Antidepressants (Selective Norepinephrine Reuptake Inhibitor) may diminish the therapeutic effect of Iobenguane I 123. Risk X: Avoid combination

MAO Inhibitors: May enhance the neurotoxic (central) effect of Atomoxetine. Risk X: Avoid combination

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

Sympathomimetics: Atomoxetine may enhance the hypertensive effect of Sympathomimetics. Atomoxetine may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy

Ethanol/Nutrition/Herb Interactions

Ethanol: May increase CNS depression; monitor for increased effects with coadministration. Caution patients about effects.

Pregnancy Risk Factor

C (show table)

Pregnancy Implications

Decreased pup weight and survival were observed in animal studies. There are no adequate and well-controlled studies in pregnant women. Use only if potential benefit to the mother outweighs possible risk to fetus.

Lactation

Excretion in breast milk unknown/use caution

Dietary Considerations

May be taken with or without food.

Pricing: U.S. (www.drugstore.com)

Capsules (Strattera)

10 mg (30): $190.00

18 mg (30): $201.98

25 mg (30): $190.99

40 mg (30): $202.98

60 mg (30): $199.98

80 mg (30): $217.99

100 mg (30): $217.99

Monitoring Parameters

Patient growth (weight/height gain in children); attention, hyperactivity, anxiety, worsening of aggressive behavior or hostility; blood pressure and pulse (baseline and following dose increases and periodically during treatment)

Family members and caregivers need to monitor patient daily for emergence of irritability, agitation, unusual changes in behavior, and suicide ideation. Pediatric patients should be monitored closely for suicidality, clinical worsening, or unusual changes in behavior, especially during the initial for months of therapy or at times of dose changes. Appearance of symptoms needs to be immediately reported to healthcare provider. Weekly office visits from patient or caregiver are necessary for the first 4 weeks, then every other week for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact may be required between office visits.

When used for the treatment of ADHD, thoroughly evaluate for cardiovascular risk. Monitor heart rate, blood pressure, and consider obtaining ECG prior to initiation (Vetter, 2008)

Canadian Brand Names

Strattera®

International Brand Names

Attentrol (IN); Passiva (PE); Recit (AR); Strattera (AR, AU, BE, BG, CH, CL, CN, CO, CR, CZ, DE, DK, DO, EE, FI, GB, GR, GT, HK, HN, IE, KP, MX, MY, NI, NL, NO, PA, PE, PH, PT, SE, SG, SV, TH, TW)

Mechanism of Action

Selectively inhibits the reuptake of norepinephrine (Ki 4.5nM) with little to no activity at the other neuronal reuptake pumps or receptor sites.

Pharmacodynamics/Kinetics

Absorption: Rapid

Distribution: Vd: I.V.: 0.85 L/kg

Protein binding: 98%, primarily albumin

Metabolism: Hepatic, via CYP2D6 and CYP2C19; forms metabolites (4-hydroxyatomoxetine, active, equipotent to atomoxetine; N-desmethylatomoxetine in poor metabolizers, limited activity)

Bioavailability: 63% in extensive metabolizers; 94% in poor metabolizers

Half-life elimination: Atomoxetine: 5 hours (up to 24 hours in poor metabolizers); Active metabolites: 4-hydroxyatomoxetine: 6-8 hours; N-desmethylatomoxetine: 6-8 hours (34-40 hours in poor metabolizers)

Time to peak, plasma: 1-2 hours

Excretion: Urine (80%, as conjugated 4-hydroxy metabolite); feces (17%)