Atomoxetine Hydrochloride

Pronunciation: (A-toe-MOX-e-teen HYE-droe-KLOR-ide)
Class: Psychotherapeutic agent

Trade Names

Strattera
- Capsules, oral 10 mg
- Capsules, oral 18 mg
- Capsules, oral 25 mg
- Capsules, oral 40 mg
- Capsules, oral 60 mg
- Capsules, oral 80 mg
- Capsules, oral 100 mg

Pharmacology

Selective inhibition of the presynaptic norepinephrine transporter is suspected.

Pharmacokinetics

Absorption

C _max is reached approximately 1 to 2 h after dosing. Rapidly absorbed with an absolute bioavailability of approximately 63% in extensive metabolizers and 94% in poor metabolizers. Administration with a high-fat meal decreased the rate of absorption (decreased C _max by 37% [adults] and 9% [children] ) and delayed T _max by 3 h (adults). May be administered with or without food.

Distribution

Vd is 0.85 L/kg (IV dose) and 98% is protein bound, primarily to albumin.

Metabolism

Primarily metabolized by CYP2D6; CYP2C19 and other CYP-450 enzymes are involved to a lesser extent. Major metabolite is 4-hydroxyatomoxetine, which is equipotent to atomoxetine but circulates at much lower concentrations.

Elimination

Cl is approximately 0.35 L/h/kg and half-life is 5.2 h for extensive metabolizers. Cl is approximately 0.03 L/h/kg and half-life is 21.6 h for poor metabolizers. More than 80% is excreted in the urine and less than 17% in the feces (as metabolite). Less than 3% is excreted as unchanged atomoxetine.

Special Populations

Renal Function Impairment

Extensive metabolizers with ESRD had higher systemic exposure (approximately a 65% increase), but there was no difference when exposure was corrected for mg/kg dose.

Hepatic Function Impairment

AUC is increased in extensive metabolizers with moderate or severe hepatic impairment. Dosage adjustment is required.

Elderly

Pharmacokinetics in elderly patients have not been evaluated.

Children

Pharmacokinetics in children and adolescents are similar to those in adults.

Gender

Pharmacokinetics are similar in men and women.

Race

Does not affect atomoxetine pharmacokinetics, except poor metabolizing is more common in white patients.

Indications and Usage

Treatment of attention deficit hyperactivity disorder (ADHD).

Unlabeled Uses

Binge eating disorder; nocturnal enuresis; weight reduction in women with obesity.

Contraindications

Narrow-angle glaucoma; use with MAOIs or within 2 weeks after discontinuing an MAOI; pheochromocytoma or a history of pheochromocytoma; hypersensitivity to any component of the product.

Dosage and Administration

Adults and Children (more than 70 kg)

PO Start with 40 mg/day and increase the dose after a minimum of 3 days to a target total daily dosage of approximately 80 mg. After 2 to 4 additional weeks, the dosage may be increased to a max of 100 mg/day in patients who have not achieved an optimal response. In patients receiving a strong CYP2D6 inhibitor (eg, fluoxetine), increase the 40 mg/day dosage to the target dosage of 80 mg/day if symptoms fail to improve after 4 weeks and the initial dosage is well tolerated.

Children (70 kg or less)

PO Start with 0.5 mg/kg/day and increase the dosage after a minimum of 3 days to a target total dosage of approximately 1.2 mg/kg/day (max, 1.4 mg/kg or 100 mg/day, whichever is less). In children receiving a strong CYP2D6 inhibitor (eg, fluoxetine) or known to be CYP2D6 poor metabolizers, increase the 0.5 mg/kg/day dosage to the target dosage of 1.2 mg/kg/day only if symptoms fail to improve after 4 weeks and the initial dosage is well tolerated.

Hepatic Function Impairment

PO In patients with moderate hepatic impairment (Child-Pugh class B), reduce initial and target doses to 50% of the normal dose; in patients with severe hepatic impairment (Child-Pugh class C), reduce the initial dose and target dose to 25% of normal.

General Advice

Administer prescribed dose without regard to meals. Administer with food if GI upset occurs.
May be administered as a single daily dose or as evenly divided doses in the morning and late afternoon or early evening.
Can be discontinued without being tapered.
Should be taken whole; capsules should not be opened.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

Albuterol

Use with caution; the CV effects of albuterol may be potentiated.

CYP2D6 inhibitors (eg, fluoxetine, paroxetine, quinidine)

The AUC and peak plasma level of atomoxetine may be increased. Dosage adjustment may be necessary.

CYP3A4 substrates (eg, midazolam)

Plasma concentrations may be increased by atomoxetine; however, dosage adjustments are not recommended.

Iobenguane

Atomoxetine may reduce uptake and diagnostic efficacy of iobenguane. False-negative iobenguane imaging tests may result. Discontinue atomoxetine approximately 24 h prior to iobenguane administration.

MAOIs (eg, isocarboxazid)

Coadministration is contraindicated. Do not administer atomoxetine within 2 weeks after discontinuing an MAOI and do not initiate treatment with an MAOI within 2 weeks after discontinuing atomoxetine.

Pressor agents (eg, dobutamine, dopamine)

Possible increased BP. Use with caution.

Adverse Reactions

Cardiovascular

Hot flush (8%); palpitations, syncope (3%); orthostatic hypotension, tachycardia (2%); QT prolongation, Raynaud phenomenon (postmarketing).

CNS

Headache (19%); insomnia (15%); somnolence (11%); fatigue (9%); depression (7%); dizziness, irritability (6%); tremor (5%); decreased libido (4%); paresthesia, sinus headache, sleep disorder (3%); feeling jittery, mood swings (2%); anxiety, hypoesthesia, lethargy, seizures, sensory disturbances, tics (postmarketing).

Dermatologic

Hyperhidrosis (4%); rash (2%).

EENT

Conjunctivitis (3%); mydriasis (2%).

GI

Dry mouth, nausea (21%); abdominal pain (18%); vomiting (11%); constipation (9%); dyspepsia (4%); anorexia (3%).

Genitourinary

Erectile dysfunction (9%); urinary hesitancy and/or urinary retention (7%); dysmenorrhea (6%); delayed ejaculation and/or ejaculation disorder, dysuria (3%); menstruation irregularities (2%); male pelvic pain, priapism (postmarketing).

Metabolic-Nutritional

Appetite decreased (16%); weight decrease (7%).

Miscellaneous

Excoriation (4%); chills, unexpected therapeutic response (3%); early morning awakening (2%).

Precautions

Warnings

Atomoxetine increased the risk of suicidal thinking in short-term studies in children and adolescents. When considering the use of atomoxetine, balance the risk with clinical need. Observe children or adolescents closely for suicidal thinking and behavior, clinical worsening, or unusual changes in behavior. Advise families and caregivers of the need for close observation and communication with the prescriber. Atomoxetine is not approved for major depressive disorder.

Monitor

Monitor patients closely for suicidality (suicidal thinking and behavior), clinical worsening, or unusual changes in behavior, especially during the initial few months of therapy or at times of dose changes. Monitor patients beginning therapy for the appearance or worsening of aggressive behavior or hostility. Monitor growth during treatment. Monitor pulse and BP at baseline, following dose increases, and periodically during therapy. Determine liver enzyme levels upon the first sign or symptom of liver dysfunction. Perform a careful history and physical exam to assess for the presence of cardiac disease. Conduct a prompt cardiac evaluation for patients who develop symptoms suggestive of cardiac disease during therapy.

ADHD symptoms

Assess ADHD symptoms before and periodically throughout therapy.

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established in children younger than 6 y.

Elderly

Safety and efficacy have not been established.

Hypersensitivity

Reactions, including angioneurotic edema, rash, and urticaria, can occur.

Hepatic Function

Dosage adjustment is recommended in patients with moderate to severe hepatic insufficiency.

Aggression or hostility

Aggressive behavior or hostility was observed more frequently among children and adolescents treated with atomoxetine compared with placebo.

Bipolar disorder

Use with caution in patients with ADHD and comorbid bipolar disorder because of possible induction of a mixed/manic episode in patients at risk for bipolar disorder.

Cardiac effects

Sudden death has been associated with atomoxetine treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Sudden death, stroke, and MI have been reported in adults taking atomoxetine at usual doses for ADHD. In addition, because therapy can increase BP and heart rate, use with caution in patients with hypertension, tachycardia, or CV or cerebrovascular disease.

CYP2D6 metabolism

Poor CYP2D6 metabolizers have a 10-fold higher AUC and 5-fold higher C _max to a given dose of atomoxetine compared with extensive metabolizers. The higher plasma levels in the poor metabolizers lead to a higher rate of some adverse reactions.

Growth

Monitor growth during treatment; mean weight and growth changes have been reported to be less than those occurring with placebo administration.

Hepatic effects

Rare cases of clinically significant liver injury have been reported during postmarketing use. Discontinue in patients with jaundice or laboratory evidence of liver injury; do not restart.

Mydriasis

Use was associated with increased risk of mydriasis. Contraindicated in patients with narrow-angle glaucoma.

Peripheral vascular effects

Reports of new-onset and exacerbation of Raynaud phenomenon.

Pheochromocytoma

Elevated blood pressure and tachyarrhythmia have been reported in patients with pheochromocytoma taking atomoxetine. Use is contraindicated.

Priapism

Painful and nonpainful penile erection lasting more than 4 h has been reported for adults and children receiving atomoxetine.

Psychotic or manic symptoms

Treatment-emergent psychotic or manic symptoms in children and adolescents without a history of psychotic illness or mania can occur.

Urinary effects

Rate of occurrence of urinary retention and hesitancy may be increased.

Overdosage

Symptoms

Abnormal behavior; agitation; dizziness; GI symptoms; hyperactivity; mental changes, including disorientation and hallucinations; QT prolongation; somnolence; sympathetic nervous system activation (eg, blood pressure increased, dry mouth, mydriasis, tachycardia); tremor.

Patient Information

Advise patient, family, or caregiver that the medication is started at a low dose and gradually increased as needed and tolerated.
Advise patients, families, or caregivers that the medication should be taken as prescribed and not to stop taking or change the dose unless advised by their health care provider.
Instruct patients that if they miss a dose, they should take it as soon as possible, but should not take more than the prescribed total daily amount in any 24-hour period.
Advise patients, families, or caregivers to be alert for symptoms of aggressiveness, agitation, anxiety, depression, hostility, hypomania, insomnia, irritability, lack of impulse control, mania, panic attacks, psychomotor restlessness, suicidal thoughts, or other unusual changes in behavior, and to report such symptoms to their health care provider immediately.
Advise patient, family, or caregiver that this drug is part of a total treatment program that should also include psychological, educational, and social interventions.
Advise patient that drug may cause dizziness or other CNS disorders and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.
Advise patient that the drug may cause eye irritation if capsules are opened. If capsule content comes into contact with the eyes, flush eyes immediately with water and obtain medical advice. Wash hands and any potentially contaminated surfaces.
Tell patients that the drug may be taken with or without food.
Instruct patients that severe liver injury may develop while on therapy and to contact their health care provider if they develop dark urine, jaundice, right upper quadrant tenderness, or unexpected flu-like illness.
Inform patients that rare cases of painful and nonpainful penile erection lasting more than 4 h have been reported and to contact their health care provider immediately if this occurs.
Instruct patients to contact their health care provider if they are breast-feeding, pregnant, or thinking of becoming pregnant while taking this medication.