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AtoMOXetine

Pronunciation

Pronunciation

(AT oh mox e teen)

Index Terms

  • Atomoxetine Hydrochloride
  • LY139603
  • Methylphenoxy-Benzene Propanamine
  • Tomoxetine

Dosage Forms

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

Strattera: 80 mg, 100 mg [contains fd&c blue #2 (indigotine)]

Brand Names: U.S.

  • Strattera

Pharmacologic Category

  • Norepinephrine Reuptake Inhibitor, Selective

Pharmacology

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

Absorption

Rapid

Distribution

Vd: IV: 0.85 L/kg

Metabolism

Hepatic, via CYP2D6 and CYP2C19; forms metabolites (4-hydroxyatomoxetine, active, equipotent to atomoxetine; N-desmethylatomoxetine, limited activity); Note: CYP2D6 poor metabolizers have atomoxetine AUCs that are ~10-fold higher and peak concentrations that are ~fivefold greater than extensive metabolizers; 4-hyroxyatomoxetine plasma concentrations are very low (extensive metabolizers: 1% of atomoxetine concentrations; poor metabolizers: 0.1% of atomoxetine concentrations

Excretion

Urine (80%, as conjugated 4-hydroxy metabolite; <3% is excreted unchanged); feces (17%)

Time to Peak

Plasma: 1-2 hours; delayed 3 hours by high-fat meal

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)

Protein Binding

98%, primarily albumin

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.

Special Populations: Hepatic Function Impairment

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

Use: Labeled Indications

Attention-deficit/hyperactivity disorder: Treatment of attention-deficit/hyperactivity disorder (ADHD)

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; severe cardiac or vascular disorders in which the condition would be expected to deteriorate with clinically important increases in blood pressure (eg, 15 to 20 mm Hg) or heart rate (eg, 20 beats/minute ).

Canadian labeling: Additional contraindications (not in U.S. labeling): Symptomatic cardiovascular diseases, moderate-to-severe hypertension; advanced arteriosclerosis; uncontrolled hyperthyroidism

Dosing: Adult

Attention deficit hyperactivity disorder (ADHD) treatment: Oral: Note: Atomoxetine may be discontinued without the need for tapering dose.

U.S. labeling:

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. Maximum daily dose: 100 mg/day.

Dosage adjustment in patients receiving strong CYP2D6 inhibitors (eg, paroxetine, fluoxetine, quinidine) or patients known to be CYP2D6 poor metabolizers: Initial: 40 mg/day; if tolerating therapy but inadequate response, may increase after minimum of 4 weeks to 80 mg/day.

Canadian labeling:

Initial: 40 mg/day for 7-14 days (Step 1); if tolerated, may increase dose at 7-14 day intervals to 60 mg/day (Step 2) then to 80 mg/day (Step 3). If optimal response is not obtained after 2-4 additional weeks, may increase to a maximum dose of 100 mg/day.

Dosage adjustment in patients receiving strong CYP2D6 inhibitors: Initial: 40 mg/day; may increase to next dosage level after 14 days if previous dose is well tolerated but response is inadequate. Note: Canadian labeling does not include specific dosing recommendations in regards to patients who are poor CYP2D6 metabolizers although similar dose reductions would appear necessary.

Dosing: Geriatric

Use has not been evaluated in the elderly.

Dosing: Pediatric

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

Children ≥6 years and ≤70 kg:

U.S. labeling:

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: Initial: 0.5 mg/kg/day; if tolerating therapy but inadequate response, may increase after minimum of 4 weeks to 1.2 mg/kg/day.

Canadian labeling:

Initial: ~0.5 mg/kg/day for 7-14 days (Step 1); if tolerated, may increase to ~0.8 mg/kg/day for 7-14 days (Step 2), then to ~1.2 mg/kg/day (Step 3); re-evaluate after ≥30 days and adjust for response if necessary. Maximum daily dose: 1.4 mg/kg or 100 mg, whichever is less. Note: Children should weigh at least 20 kg at the time of initiation as 10 mg is the lowest available capsule strength and capsules are to be swallowed whole.

Dosing recommendations according to weight:

Initial (Step 1):

20-29 kg: 10 mg/day

30-44 kg: 18 mg/day

45-64 kg: 25 mg/day

65-70 kg: 40 mg/day

First titration (Step 2):

20-29 kg: 18 mg/day

30-44 kg: 25 mg/day

45-64 kg: 40 mg/day

65-70 kg: 60 mg/day

Second titration (Step 3):

20-29 kg: 25 mg/day

30-44 kg: 40 mg/day

45-64 kg: 60 mg/day

65-70 kg: 80 mg/day

Dosage adjustment in patients receiving strong CYP2D6 inhibitors: Initial: 0.5 mg/kg/day; may increase to next dosage level after 14 days if previous dose is well tolerated but response is inadequate. Note: Canadian labeling does not include specific dosing recommendations in regards to patients who are poor CYP2D6 metabolizers although similar dose reductions would appear necessary.

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

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

Mild impairment (Child-Pugh class A): No dosage adjustment provided in manufacturer’s labeling.

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

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

Administration

Administer with or without food as a single daily dose in the morning or as two evenly divided doses in morning and late afternoon/early evening. Swallow capsules whole; do not open capsules. If opened accidentally, do not touch eyes; wash hands immediately (product is an ocular irritant).

Storage

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

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. Consider therapy modification

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates. Consider therapy modification

Beta2-Agonists: AtoMOXetine may enhance the tachycardic effect of Beta2-Agonists. Monitor therapy

Cobicistat: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. 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. Consider therapy modification

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

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Imatinib: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

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

MAO Inhibitors: May enhance the neurotoxic (central) effect of AtoMOXetine. Avoid combination

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Panobinostat: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of sensitive CYP2D6 substrates when possible, particularly those substrates with a narrow therapeutic index. Consider therapy modification

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

Perhexiline: CYP2D6 Substrates may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Sympathomimetics: AtoMOXetine may enhance the hypertensive effect of Sympathomimetics. AtoMOXetine may enhance the tachycardic effect of Sympathomimetics. Monitor therapy

Adverse Reactions

Percentages as reported in children and adults; some adverse reactions may be increased in "poor metabolizers" (CYP2D6). Frequency not always defined.

>10%:

Central nervous system: Headache (19%; children and adolescents), insomnia (1% to 19%), drowsiness (8% to 11%)

Dermatologic: Hyperhidrosis (4% to 15%)

Gastrointestinal: Xerostomia (17% to 35%), nausea (7% to 26%), decreased appetite (15% to 23%), abdominal pain (7% to 18%), vomiting (4% to 11%), constipation (1% to 11%)

Genitourinary: Erectile dysfunction (8% to 21%)

1% to 10%:

Cardiovascular: Increased diastolic blood pressure (5% to 9%; ≥15 mm Hg), systolic hypertension (4% to 5%), palpitations (3%), cold extremities (1% to 3%), syncope (≤3%), flushing (≥2%), orthostatic hypotension (≤2%), tachycardia (≤2%), prolonged Q-T interval on ECG

Central nervous system: Fatigue (6% to 10%), dizziness (5% to 8%), depression (4% to 7%), disturbed sleep (3% to 7%), irritability (5% to 6%), jitteriness (2% to 5%), abnormal dreams (4%), chills (3%), paresthesia (adults 3%; postmarketing observation in children), anxiety (≥2%), hostility (children and adolescents 2%), emotional lability (1% to 2%), agitation, restlessness, sensation of cold

Dermatologic: Excoriation (2% to 4%), skin rash (2%), pruritus, urticaria

Endocrine & metabolic: Weight loss (2% to 7%), decreased libido (3%), hot flash (3%), increased thirst (2%), menstrual disease

Gastrointestinal: Dyspepsia (4%), anorexia (3%), dysgeusia, flatulence

Genitourinary: Ejaculatory disorder (2% to 6%), urinary retention (1% to 6%), dysmenorrhea (3%), dysuria (2%), orgasm abnormal, pollakiuria, prostatitis, testicular pain, urinary frequency

Neuromuscular & skeletal: Tremor (1% to 5%), muscle spasm, weakness

Ophthalmic: Blurred vision (1% to 4%), conjunctivitis (1% to 3%), mydriasis

Respiratory: Pharyngolaryngeal pain

Miscellaneous: Therapeutic response unexpected (2%)

<1% (Limited to important or life-threatening): Cerebrovascular accident, delusions, growth suppression (children), hallucination, hepatotoxicity, hypersensitivity reaction, hypomania, impulsivity, mania, myocardial infarction, panic attack, pelvic pain, priapism, Raynaud's phenomenon, rhabdomyolysis, seizure (including patients with no prior history or known risk factors for seizure), severe hepatic disease, suicidal ideation, tics

ALERT: U.S. Boxed Warning

Suicidal ideation in children and adolescents:

Atomoxetine increased the risk of suicidal ideation in short-term studies in children or adolescents with attention deficit hyperactivity disorder (ADHD). Anyone considering the use of atomoxetine in a child or adolescent must balance this risk with the clinical need. Comorbidities occurring with ADHD may be associated with an increase in the risk of suicidal ideation and/or behavior. Closely monitor patients who are started on therapy for suicidality (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 prescribing health care provider. Atomoxetine is approved for ADHD in pediatric and adult patients. Atomoxetine is not approved for major depressive disorder (MDD).

Pooled analyses of short-term (6- to 18-week), placebo-controlled trials of atomoxetine in children and adolescents (12 trials involving more than 2,200 patients, including 11 trials in ADHD and 1 trial in enuresis) have revealed a greater risk of suicidal ideation early during treatment in those receiving atomoxetine compared with placebo. The average risk of suicidal ideation in patients receiving atomoxetine was 0.4% compared with none in placebo-treated patients. No suicides occurred in these trials.

Warnings/Precautions

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

• Altered cardiac conduction: 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).

• Cardiovascular events: 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.

• Hepatotoxicity: 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: 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.

• Priapism: 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).

• Psychiatric effects: 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:

• 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.

• Bipolar 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.

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

• Hypertension: 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.

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

Special populations:

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

• Pediatric: [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:

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

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.

Thoroughly evaluate for cardiovascular risk. Monitor heart rate, blood pressure, and consider obtaining ECG prior to initiation (Martinez-Raga, 2013; Vetter, 2008). Periodically reevaluate the long-term usefulness of the drug for the individual patient.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Information related to atomoxetine use in pregnancy is limited; appropriate contraception is recommended for sexually active women of childbearing potential (Heiligenstein, 2003).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience abdominal pain, insomnia, nausea, vomiting, lack of appetite, dry mouth, constipation, sexual dysfunction, loss of strength and energy, or fatigue. Have patient report immediately to prescriber signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), behavioral changes, irritability, agitation, panic attacks, hallucinations, tachycardia, abnormal heartbeat, severe headache, difficult urination, priapism, signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), angina, shortness of breath, severe dizziness, or passing out (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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