Atomoxetine

Before taking atomoxetine,

• tell your doctor and pharmacist if you are allergic to atomoxetine, any other medications, or any of the ingredients in atomoxetine capsules.
• tell your doctor if you are taking monoamine oxidase (MAO) inhibitors, including isocarboxazid (Marplan), phenelzine (Nardil), selegiline (Eldepryl, Emsam, Zelapar), and tranylcypromine (Parnate), or if you have stopped taking them within the past 2 weeks. Your doctor will probably tell you not to take atomoxetine. If you stop taking atomoxetine, you should wait at least 2 weeks before you start taking an MAO inhibitor.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: albuterol syrup or tablets (Proventil, Ventolin), amiodarone (Cordarone, Pacerone), bupropion (Wellbutrin), chlorpheniramine (antihistamine in cold medications),cimetidine (Tagamet), clomipramine (Anafranil), fluoxetine (Prozac, Sarafem), haloperidol (Haldol), metaproterenol syrup or tablets , medications for high blood pressure, methadone (Dolophine), metoclopramide (Reglan), nefazodone, paroxetine (Paxil), quinidine, ritonavir (Norvir), and sertraline (Zoloft). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have or have ever had glaucoma (an eye disease that may cause vision loss), or pheochromocytoma (a tumor on a small gland near the kidneys). Your doctor will probably tell you not to take atomoxetine.
• tell your doctor if anyone in your family has or has ever had an irregular heartbeat or has died suddenly. Tell your doctor if you have recently had a heart attack and if you have or have ever had a heart defect, high blood pressure, an irregular heartbeat, hardening of the arteries, heart or blood vessel disease, or other heart problems. Your doctor will examine you to see if your heart and blood vessels are healthy. Your doctor will probably tell you not to take atomoxetine if you have a heart condition or if there is a high risk that you may develop a heart condition.
• tell your doctor if you or anyone in your family has or has ever had depression, bipolar disorder (manic depressive disorder; a condition that causes episodes of depression, episodes of frenzied, abnormal excitement and other abnormal moods), or has ever thought about or attempted suicide. Also tell your doctor if you have or have ever had seizures, or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking atomoxetine, call your doctor.
• you should know that atomoxetine may make you drowsy. Do not drive a car or operate machinery until you know how this medication affects you.
• you should know that atomoxetine may cause dizziness, lightheadedness, and fainting when you get up too quickly from a lying position. To avoid this problem, get out of bed slowly, resting your feet on the floor for a few minutes before standing up.
• you should know that atomoxetine should be used as part of a total treatment program for ADHD, which may include counseling and special education. Make sure to follow all of your doctor's and/or therapist's instructions.
• you should know that your blood pressure may increase during your treatment with atomoxetine. Your doctor will monitor your blood pressure during your treatment.

• Strattera is taken once or twice daily. It may be taken with or without food. The capsules should never be broken and sprinkled on food. They must be taken whole.
• The recommended starting dose for and children weighing more than 70 kg is 40 mg once daily.  The dose is increased after 3 days to 80 mg PO once daily or divided and given every 12 hours. The dose may be increased up to 100 mg daily to achieve the optimal response.
• Children older than 6 years and weighing 70 kg or less should receive 0.5 mg/kg once daily. The dose may be increased after 3 days to 1.2 mg/kg once daily or divided every 12 hours. The maximum daily dose should not to exceed 1.4 mg/kg or 100 mg, whichever is less.

• In some animal studies (rabbits and rats), very high doses of Strattera (6- to 23-fold higher than those that would be used in humans) were associated with lower birth weight and lower fetal survival. No adequate studies have been done in pregnant women. Therefore, before prescribing Strattera to pregnant women, physicians must weight the potential benefits against the potential and unknown risks.
• Strattera is excreted in the breast milk of animals. Although not similarly studied in humans, it is likely that Strattera is excreted in human breast milk as well. The benefits and potential risks of Strattera therefore must be weighed before it is prescribed to nursing mothers.

Atomoxetine may be found in some form under the following brand names:

• Strattera

Tell your doctor about all the medicines that you take including prescription and nonprescription medicines, vitamins, and herbal supplements. Atomoxetine and some medicines may interact with each other and cause serious side effects. Your doctor will decide whether atomoxetine can be taken with other medicines.

Especially tell your doctor if you take:

• asthma medicines
• anti-depression medicines including MAOIs
• blood pressure medicines
• cold or allergy medicines that contain decongestants


Know the medicines that you take. Keep a list of your medicines with you to show your doctor and pharmacist. Do not start any new medicine while taking atomoxetine without talking to your doctor first.

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of atomoxetine there are no specific foods that you must exclude from your diet when receiving atomoxetine.

If you take too much atomoxetine, call your local Poison Control Center or seek emergency medical attention right away.

• Store atomoxetine in a safe place at room temperature, 59 to 86°F (15 to 30°C).
• Keep atomoxetine and all medicines out of the reach of children.

Black Box Warnings

Atomoxetine use has been associated with increased risk of suicidal ideation in short-term studies in children or adolescents with ADHD; this risk must be balanced against clinical need in patients with ADHD

Monitor patients closely for suicidal thinking and behavior, clinical worsening, or unusual behavioral changes; families and caregivers should be advised of need for close observation and communication with prescribing healthcare provider

Average risk of suicidal ideation in patients receiving atomoxetine has been shown to be ~0.4% (5/1357 patients)

Contraindications

Hypersensitivity

Narrow-angle glaucoma

Administration concomitantly with or within 14 days of monoamine oxidase inhibitor (MAOI) therapy; risk of potentially fatal reaction, including hyperthermia, myoclonus, altered mental status, and neuroleptic malignant syndrome (NMS)-like symptoms

Pheochromocytoma: Serious reactions, including elevated blood pressure and tachyarrhythmia, have been reported in patients with current or previous pheochromocytoma

Severe cardiovascular disorders where condition would deteriorate because BP increases by 15-20 mm Hg or HR increases by 20 beats/min; risk is greater in poor CYP2D6 metabolizers

Cautions

If drug is given concomitantly with CYP2D6 inhibitor, wait 4 weeks after initiation before adjusting dosage

Liver injury reported within 120 days of initiation of atomoxetine; patients may present with elevated liver enzymes (>20 × ULN) and jaundice with significantly elevated bilirubin levels (>2 × ULN), followed by recovery upon discontinuance of atomoxetine

Orthostatic hypotension and syncope reported

Risk of suicidal thoughts in children and adolescents

Small risk of allergic reaction

Use caution in hypertension, tachycardia (see Contraindications)

Sudden deaths, stroke, and myocardial infarction reported in patients with structural cardiac abnormalities or other serious heart problems taking stimulants at usual doses; patients should have a careful history and physical exam to assess for presence of cardiovascular disease; consider not using atomoxetine in adults with clinically significant cardiac abnormalities

Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation

Particular care should be taken in using stimulants to treat ADHD patients with comorbid bipolar disorder because of concern for possible induction of mixed/manic episode in such patients

Aggressive behavior or hostility is often observed in children and adolescents with ADHD; monitor for the appearance of or worsening of aggressive behavior or hostility

Monitor growth of children ages 7 to 10 years during treatment with stimulants; may need to interrupt therapy in patients not growing or gaining weight as expected

Urinary hesitancy or sexual dysfunction may occur

Rare instances of priapism reported, sometimes necessitating surgical intervention; typically not reported during initiation but often occurring subsequent to dosage increase; immediate medical attention should be sought for abnormally sustained or frequent and painful erections

Drug can be discontinued without being tapered

Hypesthesia, paresthesia in children and adolescents, sensory disturbances

Rare reports of allergic reactions, including anaphylactic reactions, angioneurotic edema, urticaria, and rash

Use with caution in patietns with bipolar disorder, history of hypertension, hepatic impairment, existing anxiety disorder, history of urinary retention, or tics related to Tourette disorder

Pregnancy category: C

Lactation: Unknown whether drug is excreted in milk; use with caution

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Take the medicine at the same time each day, with a full glass of water.

Atomoxetine is usually taken once daily in the morning, or two times per day in the morning and late afternoon. Follow your doctor's instructions.

You may take atomoxetine with or without food.

Do not crush, chew, break, or open an atomoxetine capsule. Swallow it whole. Tell your doctor if you have trouble swallowing the capsules.

Use atomoxetine regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

Do not use a capsule that has been opened or accidentally broken. The medicine from inside the capsule can be dangerous if it gets in your eyes. If this occurs, rinse your eyes with water. Ask your doctor or pharmacist how to safely handle and dispose of a broken capsule.

While taking atomoxetine, your doctor will need to check your progress at regular visits. Your heart rate, blood pressure, height and weight may also need to be checked often.

Store at room temperature away from moisture and heat.

Hypersensitivity

Atomoxetine capsules are contraindicated in patients known to be hypersensitive to Atomoxetine or other constituents of the product [see Warnings and Precautions (5.8)].

Monoamine Oxidase Inhibitors (MAOI)

Atomoxetine capsules should not be taken with an MAOI, or within 2 weeks after discontinuing an MAOI. Treatment with an MAOI should not be initiated within 2 weeks after discontinuing Atomoxetine capsules. With other drugs that affect brain monoamine concentrations, there have been reports of serious, sometimes fatal reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) when taken in combination with an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Such reactions may occur when these drugs are given concurrently or in close proximity [see Drug Interactions (7.1)].

Narrow Angle Glaucoma

In clinical trials, Atomoxetine capsule use was associated with an increased risk of mydriasis and therefore its use is not recommended in patients with narrow angle glaucoma.

Pheochromocytoma

Serious reactions, including elevated blood pressure and tachyarrhythmia, have been reported in patients with pheochromocytoma or a history of pheochromocytoma who received Atomoxetine capsules. Therefore, Atomoxetine capsules should not be taken by patients with pheochromocytoma or a history of pheochromocytoma.

Severe Cardiovascular Disorders

Atomoxetine capsules should not be used in patients with severe cardiac or vascular disorders whose condition would be expected to deteriorate if they experience increases in blood pressure or heart rate that could be clinically important (for example, 15 to 20 mm Hg in blood pressure or 20 beats per minute in heart rate). [See Warnings and Precautions (5.4)].

Clinical Trials Experience

Atomoxetine capsules were administered to 5382 children or adolescent patients with ADHD and 1007 adults with ADHD in clinical studies. During the ADHD clinical trials, 1625 children and adolescent patients were treated for longer than 1 year and 2529 children and adolescent patients were treated for over 6 months.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Child and Adolescent Clinical Trials

Reasons for discontinuation of treatment due to adverse reactions in child and adolescent clinical trials In acute child and adolescent placebo-controlled trials, 3.0% (48/1613) of Atomoxetine subjects and 1.4% (13/945) placebo subjects discontinued for adverse reactions. For all studies, (including open-label and long-term studies), 6.3% of extensive metabolizer (EM) patients and 11.2% of poor metabolizer (PM) patients discontinued because of an adverse reaction. Among Atomoxetine capsule-treated patients, irritability (0.3%, N=5); somnolence (0.3%, N=5); aggression (0.2%, N=4); nausea (0.2%, N=4); vomiting (0.2%, N=4); abdominal pain (0.2%, N=4); constipation (0.1%, N=2); fatigue (0.1%, N=2); feeling abnormal (0.1%, N=2); and headache (0.1%, N=2) were the reasons for discontinuation reported by more than 1 patient.

Seizures Atomoxetine capsules have not been systematically evaluated in pediatric patients with seizure disorder as these patients were excluded from clinical studies during the product's premarket testing. In the clinical development program, seizures were reported in 0.2% (12/5073) of children whose average age was 10 years (range 6 to 16 years). In these clinical trials, the seizure risk among poor metabolizers was 0.3% (1/293) compared to 0.2% (11/4741) for extensive metabolizers.

Commonly observed adverse reactions in acute child and adolescent, placebo-controlled trials Commonly observed adverse reactions associated with the use of Atomoxetine capsules (incidence of 2% or greater) and not observed at an equivalent incidence among placebo-treated patients (Atomoxetine capsule incidence greater than placebo) are listed in Table 2. Results were similar in the BID and the QD trial except as shown in Table 3, which shows both BID and QD results for selected adverse reactions based on statistically significant Breslow-Day tests. The most commonly observed adverse reactions in patients treated with Atomoxetine capsules (incidence of 5% or greater and at least twice the incidence in placebo patients, for either BID or QD dosing) were: nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence (see Tables 2 and 3).

Additional data from ADHD clinical trials (controlled and uncontrolled) has shown that approximately 5 to 10% of pediatric patients experienced potentially clinically important changes in heart rate (≥20 beats per min) or blood pressure (≥15 to 20 mm Hg) [see Contraindications (4) and Warnings and Precautions (5)].

The following adverse reactions occurred in at least 2% of child and adolescent CYP2D6 PM patients and were statistically significantly more frequent in PM patients compared with CYP2D6 EM patients: insomnia (11% of PMs, 6% of EMs); weight decreased (7% of PMs, 4% of EMs); constipation (7% of PMs, 4% of EMs); depression1 (7% of PMs, 4% of EMs); tremor (5% of PMs, 1% of EMs); excoriation (4% of PMs, 2% of EMs); middle insomnia (3% of PMs, 1% of EMs); conjunctivitis (3% of PMs, 1% of EMs); syncope (3% of PMs, 1% of EMs); early morning awakening (2% of PMs, 1% of EMs); mydriasis (2% of PMs, 1% of EMs); sedation (4% of PMs, 2% of EMs).

1Depression includes the following terms: depression, major depression, depressive symptoms, depressed mood, dysphoria.

Adult Clinical Trials

Reasons for discontinuation of treatment due to adverse reactions in acute adult placebo-controlled trials In the acute adult placebo-controlled trials, 11.3% (61/541) Atomoxetine subjects and 3.0% (12/405) placebo subjects discontinued for adverse reactions. Among Atomoxetine capsule-treated patients, insomnia (0.9%, N=5); nausea (0.9%, N=5); chest pain (0.6%, N=3); fatigue (0.6%, N=3); anxiety (0.4%, N=2); erectile dysfunction (0.4%, N=2); mood swings (0.4%, N=2); nervousness (0.4%, N=2); palpitations (0.4%, N=2); and urinary retention (0.4%, N=2) were the reasons for discontinuation reported by more than 1 patient.

Seizures Atomoxetine capsules have not been systematically evaluated in adult patients with a seizure disorder as these patients were excluded from clinical studies during the product's premarket testing. In the clinical development program, seizures were reported on 0.1% (1/748) of adult patients. In these clinical trials, no poor metabolizers (0/43) reported seizures compared to 0.1% (1/705) for extensive metabolizers.

Commonly observed adverse reactions in acute adult placebo-controlled trials Commonly observed adverse reactions associated with the use of Atomoxetine capsules (incidence of 2% or greater) and not observed at an equivalent incidence among placebo-treated patients (Atomoxetine capsule incidence greater than placebo) are listed in Table 4. The most commonly observed adverse reactions in patients treated with Atomoxetine capsules (incidence of 5% or greater and at least twice the incidence in placebo patients) were: constipation, dry mouth, nausea, decreased appetite, dizziness, erectile dysfunction, and urinary hesitation (see Table 4).

Additional data from ADHD clinical trials (controlled and uncontrolled) has shown that approximately 5 to 10% of adult patients experienced potentially clinically important changes in heart rate (≥20 beats per min) or blood pressure (≥15 to 20 mm Hg) [see Contraindications (4) and Warnings and Precautions (5)].

The following adverse events occurred in at least 2% of adult CYP2D6 poor metaboliser (PM) patients and were statistically significantly more frequent in PM patients compared to CYP2D6 extensive metaboliser (EM) patients: vision blurred (4% of PMs, 1% of EMs); dry mouth (35% of PMs, 17% of EMs); constipation (11% of PMs, 7% of EMs); feeling jittery (5% of PMs, 2% of EMs); decreased appetite (23% of PMs, 15% of EMs); tremor (5% of PMs, 1% of EMs); insomnia (19% of PMs, 11% of EMs); sleep disorder (7% of PMs, 3% of EMs); middle insomnia (5% of PMs, 3% of EMs); terminal insomnia (3% of PMs, 1% of EMs); urinary retention (6% of PMs, 1% of EMs); erectile dysfunction (21% of PMs, 9% of EMs); ejaculation disorder (6% of PMs, 2% of EMs); hyperhidrosis (15% of PMs, 7% of EMs); peripheral coldness (3% of PMs, 1% of EMs).

Male and female sexual dysfunction Atomoxetine appears to impair sexual function in some patients. Changes in sexual desire, sexual performance, and sexual satisfaction are not well assessed in most clinical trials because they need special attention and because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate the actual incidence. Table 4 above displays the incidence of sexual side effects reported by at least 2% of adult patients taking Atomoxetine capsules in placebo-controlled trials.

There are no adequate and well-controlled studies examining sexual dysfunction with Atomoxetine capsule treatment. While it is difficult to know the precise risk of sexual dysfunction associated with the use of Atomoxetine capsules, physicians should routinely inquire about such possible side effects.

Postmarketing Spontaneous Reports

The following adverse reactions have been identified during post approval use of Atomoxetine capsules. Unless otherwise specified, these adverse reactions have occurred in adults and children and adolescents. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiovascular system QT prolongation, syncope.

Peripheral vascular effects Raynaud's phenomenon.

General disorders and administration site conditions Lethargy.

Musculoskeletal system Rhabdomyolysis.

Nervous system disorders Hypoaesthesia; paraesthesia in children and adolescents; sensory disturbances; tics.

Psychiatric disorders Depression and depressed mood; anxiety, libido changes.

Seizures Seizures have been reported in the postmarketing period. The postmarketing seizure cases include patients with pre-existing seizure disorders and those with identified risk factors for seizures, as well as patients with neither a history of nor identified risk factors for seizures. The exact relationship between Atomoxetine capsules and seizures is difficult to evaluate due to uncertainty about the background risk of seizures in ADHD patients.

Skin and subcutaneous tissue disorders Alopecia, hyperhidrosis.

Urogenital system Male pelvic pain; urinary hesitation in children and adolescents; urinary retention in children and adolescents.

Monoamine Oxidase Inhibitors

With other drugs that affect brain monoamine concentrations, there have been reports of serious, sometimes fatal reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) when taken in combination with an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Such reactions may occur when these drugs are given concurrently or in close proximity [see Contraindications (4.2)].

Effect of CYP2D6 Inhibitors on Atomoxetine

In extensive metabolizers (EMs), inhibitors of CYP2D6 (e.g., paroxetine, fluoxetine, and quinidine) increase Atomoxetine steady-state plasma concentrations to exposures similar to those observed in poor metabolizers (PMs). In EM individuals treated with paroxetine or fluoxetine, the AUC of Atomoxetine is approximately 6- to 8-fold and Css, max is about 3- to 4-fold greater than Atomoxetine alone.

In vitro studies suggest that coadministration of cytochrome P450 inhibitors to PMs will not increase the plasma concentrations of Atomoxetine.

Antihypertensive Drugs and Pressor Agents

Because of possible effects on blood pressure, Atomoxetine capsules should be used cautiously with antihypertensive drugs and pressor agents (e.g., dopamine, dobutamine) or other drugs that increase blood pressure.

Albuterol

Atomoxetine capsules should be administered with caution to patients being treated with systemically-administered (oral or intravenous) albuterol (or other beta2 agonists) because the action of albuterol on the cardiovascular system can be potentiated resulting in increases in heart rate and blood pressure. Albuterol (600 mcg iv over 2 hours) induced increases in heart rate and blood pressure. These effects were potentiated by Atomoxetine (60 mg BID for 5 days) and were most marked after the initial coadministration of albuterol and Atomoxetine. However, these effects on heart rate and blood pressure were not seen in another study after the coadministration with inhaled dose of albuterol (200-800 mcg) and Atomoxetine (80 mg QD for 5 days) in 21 healthy Asian subjects who were excluded for poor metabolizer status.

Effect of Atomoxetine on P450 Enzymes

Atomoxetine did not cause clinically important inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9.

CYP3A Substrate (e.g., Midazolam) Coadministration of Atomoxetine capsules (60 mg BID for 12 days) with midazolam, a model compound for CYP3A4 metabolized drugs (single dose of 5 mg), resulted in 15% increase in AUC of midazolam. No dose adjustment is recommended for drugs metabolized by CYP3A.

CYP2D6 Substrate (e.g., Desipramine) Coadministration of Atomoxetine capsules (40 or 60 mg BID for 13 days) with desipramine, a model compound for CYP2D6 metabolized drugs (single dose of 50 mg), did not alter the pharmacokinetics of desipramine. No dose adjustment is recommended for drugs metabolized by CYP2D6.

Alcohol

Consumption of ethanol with Atomoxetine capsules did not change the intoxicating effects of ethanol.

Methylphenidate

Coadministration of methylphenidate with Atomoxetine capsules did not increase cardiovascular effects beyond those seen with methylphenidate alone.

Drugs Highly Bound to Plasma Protein

In vitro drug-displacement studies were conducted with Atomoxetine and other highly-bound drugs at therapeutic concentrations. Atomoxetine did not affect the binding of warfarin, acetylsalicylic acid, phenytoin, or diazepam to human albumin. Similarly, these compounds did not affect the binding of Atomoxetine to human albumin.

Drugs that Affect Gastric pH

Drugs that elevate gastric pH (magnesium hydroxide/aluminum hydroxide, omeprazole) had no effect on Atomoxetine capsule bioavailability.

Atomoxetine capsules are a selective norepinephrine reuptake inhibitor. Atomoxetine HCl is the R(-) isomer as determined by x-ray diffraction. The chemical designation is (-)-N-Methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride. The molecular formula is C17H21NO•HCl, which corresponds to a molecular weight of 291.82. The chemical structure is:

Atomoxetine HCl is a white to practically white solid, which has a solubility of 27.8 mg/mL in water.

Atomoxetine capsules are intended for oral administration only.

Each capsule contains Atomoxetine HCl equivalent to 10, 18, 25, 40, 60, 80, or 100 mg of Atomoxetine. The capsules also contain pregelatinized starch and dimethicone. The capsule shells contain gelatin, sodium lauryl sulfate, and other inactive ingredients. The capsule shells also contain one or more of the following:

FD&C Blue No. 2, synthetic yellow iron oxide, titanium dioxide, red iron oxide. The capsules are imprinted with edible black ink.

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.

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.

No adjustment recommended.