Atomoxetine Hydrochloride

Trade Names:Strattera- Capsules 10 mg (as base)- Capsules 18 mg (as base)- Capsules 25 mg (as base)- Capsules 40 mg (as base)- Capsules 60 mg (as base)- Capsules 80 mg (as base)- Capsules 100 mg (as base)

Pharmacology

Selective inhibition of the presynaptic norepinephrine transporter is suspected.

Pharmacokinetics

Absorption

C _max is reached approximately 1 to 2 h after dosing.

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

Special Populations

Extensive metabolizers with end-stage renal disease had higher systemic exposure (about a 65% increase), but there was no difference when exposure was corrected for mg/kg dose.

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

Pharmacokinetics are similar in men and women.

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

Weight reduction in women with obesity.

Contraindications

Narrow-angle glaucoma; MAOIs or within 2 wk after discontinuing an MAOI; hypersensitivity to any component of the product.

Dosage and Administration

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 wk, the dosage may be increased to a max of 100 mg/day in patients who have not achieved an optimal response. In children more than 70 kg or adults 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 wk and the initial dosage is well tolerated.

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 up to 70 kg receiving a strong CYP2D6 inhibitor (eg, fluoxetine), 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 wk and the initial dosage is well tolerated.

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

General Advice

• Discontinue MAOIs at least 14 days before initiating therapy.
• Administer prescribed dose without regard to meals. Administer with food if GI upset occurs.
• Medication can be administered as a single daily dose or as evenly divided doses in the morning and late afternoon or early evening.
• Medication can be discontinued without being tapered.
• Medications should be taken whole; capsules should not be opened.

Storage/Stability

Store at controlled room temperature (59° to 86°F).

Drug Interactions

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

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

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

Coadministration is contraindicated.

Possible increased BP.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hot flush (8%); palpitations (3%); QT prolongation, syncope (postmarketing).

CNS

Headache (19%); decreased appetite (16%); insomnia (15%); somnolence (11%); fatigue (9%); dizziness, irritability (6%); decreased libido (4%); anorexia, sinus headache, sleep disorder (3%); feeling jittery, mood swings, tremor (2%); seizures (postmarketing).

Dermatologic

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

GI

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

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

Weight decrease (3%).

Miscellaneous

Chills, unexpected therapeutic response (3%).

Precautions

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established in children younger than 6 yr of age.

Elderly

Safety and efficacy have not been evaluated.

Renal Function

No dosage adjustments are needed in patients with renal insufficiency or end-stage renal disease.

Hepatic Function

Dosage adjustment is recommended in patients with moderate to severe hepatic insufficiency. Discontinue in patients with jaundice or laboratory evidence of liver injury; do not restart.

Aggression or hostility

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

Allergic reactions

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

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.

Peripheral vascular effects

Reports of new-onset and exacerbation of Raynaud phenomenon.

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 outflow

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

Overdosage

Symptoms

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

Patient Information

• Advise patient, family, or caregiver that medication is started at a low dose and gradually increased as needed and tolerated.
• Advise patient, family, or caregiver that medication should be taken as prescribed and not to stop taking or change the dose unless advised by 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 patient, family, or caregiver 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 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 parents to inform school or childcare personnel about medication use and administration.
• 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.

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