Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

ATOMOXETINE

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Atomoxetine is a selective norepinephrine reuptake inhibitor.

Specific Substances

    1) LY-135252
    2) LY-139602
    3) LY-139603
    4) Atomoxetine Hydrochloride
    5) Tomoxetine
    6) Tomoxetine Hydrochloride
    7) (-)-N-Methyl-gamma-2-methylphenoxy)-benzenepropanamine hydrochloride
    8) CAS 83015-26-3 (atomoxetine)
    9) CAS 82248-59-7 (atomoxetine hydrochloride)
    1.2.1) MOLECULAR FORMULA
    1) C17-H21-N-O-HCl

Available Forms Sources

    A) FORMS
    1) Atomoxetine is available as 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg, and 100 mg capsules (Prod Info STRATTERA(R) oral capsules, 2008).
    B) USES
    1) Atomoxetine is indicated for the treatment of attention-deficit hyperactivity disorder (ADHD) (Prod Info STRATTERA(R) oral capsules, 2008).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Atomoxetine is indicated for the treatment of attention-deficit hyperactivity disorder (ADHD).
    B) PHARMACOLOGY: Atomoxetine is a selective norepinephrine reuptake inhibitor that produces therapeutic effects in patients with attention-deficit/hyperactivity disorder (ADHD). The exact mechanism of how selective inhibition of pre-synaptic norepinephrine exerts effects in ADHD is yet to be determined.
    C) TOXICOLOGY: Excessive synaptic norepinephrine concentration. Tachycardia and hypertension may occur due to the excessive noradrenergic-mediated sympathomimetic syndrome.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) The following adverse effects have been reported following the therapeutic use of atomoxetine: increases in blood pressure and heart rate, somnolence, skin rash, pruritus, weight loss, nausea and vomiting, anorexia, dyspepsia, constipation, dry mouth, abdominal pain, dizziness, mood swings, insomnia, motor tics, paresthesia, somnolence, anxiety, sinus headache, allergic reactions (angioneurotic edema, urticaria, and rash), decreased libido, ejaculatory failure or disorder, dysmenorrhea, urinary hesitation, urinary retention, and/or difficulty in micturition. Drug-induced hepatotoxicity has been reported with therapeutic use.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Drowsiness, mild tachycardia and hypertension, nausea, vomiting, dry mouth, erythema, rash, hyperactivity, drowsiness, dizziness, nystagmus, tremor, anxiety, hyperreflexia, headache, and agitation have been reported.
    2) SEVERE TOXICITY: Seizures have rarely been reported. An adolescent developed generalized seizures and prolonged QTc interval after ingesting 1.2 g of atomoxetine. Sinus tachycardia with mild QRS interval prolongation, generalized tonic clonic seizure, lateral nystagmus, tremor, and hyperreflexia developed in a girl who ingested 2.8 g of atomoxetine.
    0.2.20) REPRODUCTIVE
    A) Atomoxetine is rated FDA Pregnancy Category C.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Monitor serum electrolytes in patients with significant vomiting.
    C) Institute continuous cardiac monitoring and obtain an ECG in patients with moderate to severe toxicity.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat dyskinesias and/or agitation with IV benzodiazepines. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Therapeutic doses of atomoxetine may cause prolongation of the QT interval. In patients with QT prolongation, monitor serum electrolytes including potassium, calcium and magnesium in patients with significant overdose; correct any abnormalities. At the time of this review, torsades de pointes has not been reported with therapy.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with persistent seizures or severe allergic reactions.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION PROCEDURE
    1) Atomoxetine is highly protein-bound and has a large volume of distribution, therefore it is unlikely that hemodialysis or hemoperfusion would be effective.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: An adult patient with an inadvertent exposure to 100 mg or less, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients who have ingested greater than 100 mg of atomoxetine, or greater than 2 capsules should be referred to a healthcare facility. Patients with a deliberate overdose, those who are symptomatic, and those who ingested an unknown amount of atomoxetine should be referred to a healthcare facility for observation until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PHARMACOKINETICS
    1) Tmax: oral: 1 to 2 hours. Bioavailability: 63% in extensive metabolizers; 94% in poor metabolizers. Protein binding: 98%. Vd: approximately 250 L (extensive metabolizers). Metabolism: liver; cytochrome P450 (CYP)-2D6 is involved in the metabolism of atomoxetine. Excretion: Renal: less than 3% unchanged. Most of an oral dose of atomoxetine is excreted in the urine as 4-hydroxyatomoxetine-O-glucuronide (80%). Feces: Less than 17% of a dose is excreted in feces as 4-hydroxyatomoxetine-O-glucuronide. Elimination half-life: 4 to 5 hours in extensive metabolizers; 22 hours in poor metabolizers.
    I) PITFALLS
    1) When managing a suspected overdose, the possibility of multiagent involvement should be considered.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that can cause seizures and dyskinesias.

Range Of Toxicity

    A) TOXICITY: A minimum toxic dose has not been established. Mild to moderate effects have been reported with ingestions up to 750 mg in children and adolescents. A 17-year-old girl developed sinus tachycardia with mild QRS interval prolongation, generalized tonic clonic seizure, lateral nystagmus, tremor, and hyperreflexia after ingesting 2.8 g of atomoxetine. Generalized seizures and prolonged QTc interval developed in a 15-year-old who ingested 1.2 g atomoxetine. A 12-year-old developed mild transient tachycardia and no other effects after ingesting 180 mg.
    B) THERAPEUTIC DOSE: ADULTS OR CHILDREN OVER 70 KG BODY WEIGHT - Initial, 40 mg/day and increased after a minimum of 3 days to a target total daily dose of approximately 80 mg . May increase to 100 mg after 2 to 4 additional weeks of therapy. PEDIATRIC DOSING: UP TO 70 KG BODY WEIGHT: Initial, approximately 0.5 mg/kg/day and increased after a minimum of 3 days to a target total daily dose of approximately 1.2 mg/kg . Max 1.4 mg/kg or 100 milligrams, whichever is less.

Clinical Effects

Summary Of Exposure

    A) USES: Atomoxetine is indicated for the treatment of attention-deficit hyperactivity disorder (ADHD).
    B) PHARMACOLOGY: Atomoxetine is a selective norepinephrine reuptake inhibitor that produces therapeutic effects in patients with attention-deficit/hyperactivity disorder (ADHD). The exact mechanism of how selective inhibition of pre-synaptic norepinephrine exerts effects in ADHD is yet to be determined.
    C) TOXICOLOGY: Excessive synaptic norepinephrine concentration. Tachycardia and hypertension may occur due to the excessive noradrenergic-mediated sympathomimetic syndrome.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) The following adverse effects have been reported following the therapeutic use of atomoxetine: increases in blood pressure and heart rate, somnolence, skin rash, pruritus, weight loss, nausea and vomiting, anorexia, dyspepsia, constipation, dry mouth, abdominal pain, dizziness, mood swings, insomnia, motor tics, paresthesia, somnolence, anxiety, sinus headache, allergic reactions (angioneurotic edema, urticaria, and rash), decreased libido, ejaculatory failure or disorder, dysmenorrhea, urinary hesitation, urinary retention, and/or difficulty in micturition. Drug-induced hepatotoxicity has been reported with therapeutic use.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Drowsiness, mild tachycardia and hypertension, nausea, vomiting, dry mouth, erythema, rash, hyperactivity, drowsiness, dizziness, nystagmus, tremor, anxiety, hyperreflexia, headache, and agitation have been reported.
    2) SEVERE TOXICITY: Seizures have rarely been reported. An adolescent developed generalized seizures and prolonged QTc interval after ingesting 1.2 g of atomoxetine. Sinus tachycardia with mild QRS interval prolongation, generalized tonic clonic seizure, lateral nystagmus, tremor, and hyperreflexia developed in a girl who ingested 2.8 g of atomoxetine.

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) NYSTAGMUS
    a) CASE REPORT: A 17-year-old girl developed profound lateral nystagmus after reportedly ingesting 2840 mg of atomoxetine in a suicide attempt. Lab analysis revealed a serum atomoxetine concentration of 1995 ng/mL. Following supportive care, the nystagmus resolved within 24 hours of admission without sequelae (Kashani & Ruha, 2007).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: An 11-year-old boy, with a 2-year-history of ADHD, became unresponsive briefly with subsequent nausea and vomiting prior to presentation to the emergency department (ED). The patient's medication history included 2 years of atomoxetine therapy at a dose of 0.7 mg/kg/day that was increased, the month prior to presentation, to 1.2 mg/kg/day due to worsening ADHD symptoms. At the ED, the patient was drowsy and confused, with an initial Glasgow Coma Scale score of 10 that increased to 15 within 2 minutes, and hypotensive (76/24 mmHg). An initial ECG revealed sinus bradycardia (56 beats/minute) with QTc prolongation of 500 msec, that progressively worsened 9 hours later with a repeat ECG indicating a QTc interval of 829 msec, continued bradycardia (61 beats/min), inversed T-waves, and multiple premature ventricular contractions (PVCs). Atomoxetine was discontinued, a beta-blocker was administered, and a temporary pacemaker was inserted, resulting in heart rate stabilization without PVCs. The patient continued to show cardiac stability and was discharged 4 weeks post-admission. Five months after atomoxetine discontinuation, Holter ECG monitoring and stress tests indicated continued cardiac stability and the patient remained asymptomatic. The QTc interval normalized (395 msec) 1 year later (Yamaguchi et al, 2014).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 15-year-old boy with a history of major depression and ADHD (medications: sustained-release bupropion 150 mg twice daily; risperidone 0.25 mg twice daily; alprazolam 0.25 mg as needed; atomoxetine 80 mg/day) developed generalized seizures and prolonged QTc interval (607 msec at 3 hours and 435 msec at 6 hours postingestion) after ingesting 1200 mg (22 mg/kg) of atomoxetine. In addition, he experienced anxiety, tremulousness, mild tachycardia (heart rate 110s) and dry mouth (Sawant & Daviss, 2004).
    B) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) Modest increases in blood pressure and heart rate have been reported during oral atomoxetine administration (Kelly et al, 2005; Prod Info Strattera(TM) , 2002; Michelson et al, 2001; Spencer et al, 2001; Zerbe et al, 1985; Spencer et al, 1998; Chouinard et al, 1985). Greater increases in heart rate and systolic pressure have been reported in poor metabolizers in some studies (Michelson et al, 2001; Chouinard et al, 1985).
    b) Chest pain has been reported in one patient following atomoxetine therapy (Biederman et al, 2002) .
    2) WITH POISONING/EXPOSURE
    a) Tachycardia and hypertension have been reported with overdose (Spiller et al, 2013).
    b) CASE SERIES: In a series of 40 children (aged 9 months to 17 years) with atomoxetine only overdose, 6 (15%) developed mild tachycardia (mean maximum heart rate 131 beats/minute) and two (5%) developed mild hypertension (Spiller et al, 2005). Tachycardia and hypertension resolved spontaneously within 5 hours.
    c) CASE REPORT: A 12-year-old boy inadvertently received three tablets of atomoxetine 60 mg (approximately four times the maximum recommended daily dose of 1.4 mg/kg/day) instead of dextroamphetamine. Approximately 90 minutes postingestion, his vital signs were blood pressure 118/74 mmHg, pulse 106 bpm, respirations 19 rpm, and normal oral temperature. His pulse returned to normal soon after arrival to the hospital and he was discharged home following 3 hours of observation (Cantrell & Nestor, 2005).
    d) In a retrospective study of 64 cases of children exposed to atomoxetine reported to a poison center, elevated blood pressure and heart rate occurred in 4.7% of patients (Stojanovski et al, 2006).
    1) Three of 9 patients with recorded blood pressure had hypertension (BP range = 139/96; 144/81; 160/120 mm Hg, respectively). Three patients had heart rate of 100 to 132 bpm (Stojanovski et al, 2006).
    e) According to a retrospective chart review of 17 patients with atomoxetine poisoning, tachycardia was reported in 58% (LoVecchio & Kashani, 2006).
    f) Sinus tachycardia with mild QRS interval prolongation occurred in a 17-year-old girl who reportedly ingested 2840 mg of atomoxetine in a suicide attempt. An initial ECG, obtained 2 to 3 hours post-ingestion, revealed a heart rate of 103 bpm, a QRS duration of 93 ms, and a QTc interval of 476 ms. Following supportive care, a repeat ECG, obtained 14 hours post-ingestion, showed a sinus rhythm with a heart rate of 94 bpm, a QRS duration of 79 ms and a QTc interval of 440 ms (Kashani & Ruha, 2007).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RHINITIS
    1) WITH THERAPEUTIC USE
    a) In one study, rhinitis was reported in 26% of patients (n=31) treated with atomoxetine(Biederman et al, 2002) .

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CNS SYMPTOM
    1) WITH THERAPEUTIC USE
    a) In collective clinical-study data provided by the manufacturer, the most frequent CNS adverse effects of atomoxetine given twice daily in children and adolescents with ADHD (n=340) were dizziness (6%) and mood swings (2%). In adults with ADHD (n=269), the most common effects were insomnia (16%), dizziness (6%), and paresthesia (4%); the frequency of dosing was not specified in adults (Prod Info Strattera(TM) , 2002). All of these effects occurred at higher frequency than with placebo.
    b) Other adverse CNS effects which have tended to occur more often with atomoxetine than placebo in several studies were somnolence (possibly dose-related), anxiety and sinus headache(Prod Info Strattera(TM) , 2002; Michelson et al, 2001; Spencer et al, 1998; Zerbe et al, 1985).
    c) Mania was described in one patient with major depression after more than a year of atomoxetine therapy (up to 80 mg daily) (Steinberg & Chouinard, 1985). However, a causal relationship to the drug was not established; numerous other factors may have contributed to the manic episode.
    d) In one study, headache was reported in 26% of patients (n=31) treated with atomoxetine (Biederman et al, 2002) .
    e) Suicidal thinking has been associated with atomoxetine in children and adolescents (US Food and Drug Administration, 2005).
    f) CASE REPORT – A 12- year-old boy with a history of ADHD, major depression, and bipolar disorder was treated with atomoxetine 40 mg daily. After six weeks, the patient developed a rapid brief neck motor tic which worsened over the next 2 weeks and stopped within 5 days of discontinuation of the drug (Ledbetter, 2005).
    2) WITH POISONING/EXPOSURE
    a) According to a retrospective chart review, involving 17 patients (ages ranging from 9 months to 28 years), hyperactivity, drowsiness, dizziness, and tremor were reported following overdose ingestions of atomoxetine. The doses of atomoxetine ingested ranged from 10 to 1200 mg. All neurological symptoms appeared to be preceded by tachycardia. All symptoms resolved within 30 hours post-ingestion (LoVecchio & Kashani, 2006).
    B) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Seizures have been reported with overdose (Spiller et al, 2013).
    b) CASE REPORT: A 15-year-old boy with a history of major depression and ADHD (medications: sustained-release bupropion 150 mg twice daily; risperidone 0.25 mg twice daily; alprazolam 0.25 mg as needed; atomoxetine 80 mg/day) developed two generalized seizures 3 and 5 hours after ingestion of 1200 mg (22 mg/kg) atomoxetine. The first seizure resolved spontaneously and for the second he was treated with two 5 mg doses of diazepam and a loading dose of phenytoin. He also developed a prolonged QTc interval, mild tachycardia, anxiety, tremulousness, and dry mouth. The authors suggested that bupropion may have contributed to the generalized seizures (Sawant & Daviss, 2004).
    c) CASE REPORT: A 4-year-old boy had a generalized seizure shortly after being started on atomoxetine 36 milligrams/day. Metabolic and neurologic evaluation was normal, the medication was stopped, and there were no further seizures in 6 months of follow up(Spiller et al, 2005).
    d) A 19-month-old with a history of petit mal seizures treated with phenobarbital developed myoclonus of the arms after ingesting 54 milligrams of atomoxetine (Spiller et al, 2005).
    e) CASE REPORT: A 17-year-old girl experienced a generalized tonic clonic seizure, one minute in duration, approximately 2 to 3 hours after reportedly ingesting 2840 mg of atomoxetine in a suicide attempt. A CT scan of her brain was negative. Laboratory analysis revealed a serum atomoxetine concentration of 1995 ng/mL. Following supportive care, the patient recovered without sequelae (Kashani & Ruha, 2007).
    C) TREMOR
    1) WITH POISONING/EXPOSURE
    a) Tremor has been reported with overdose (Spiller et al, 2013).
    b) According to a retrospective chart review, involving 17 patients (ages ranging from 9 months to 28 years), hyperactivity, drowsiness, dizziness, and tremor were reported following overdose ingestions of atomoxetine. The doses of atomoxetine ingested ranged from 10 to 1200 mg. All neurological symptoms appeared to be preceded by tachycardia. All symptoms resolved within 30 hours post-ingestion (LoVecchio & Kashani, 2006).
    c) CASE REPORT: A 17-year-old girl developed a diffuse resting tremor along with hyperreflexia after reportedly ingesting 2840 mg of atomoxetine in a suicide attempt. Lab analysis revealed a serum atomoxetine concentration of 1995 ng/mL. Following supportive care, the patient recovered within 24 hours of admission without sequelae (Kashani & Ruha, 2007).
    D) HYPERREFLEXIA
    1) WITH POISONING/EXPOSURE
    a) Hyperreflexia has been reported with overdose (Spiller et al, 2013).
    b) CASE REPORT: A 17-year-old girl developed hyperreflexia along with a diffuse resting tremor after reportedly ingesting 2840 mg of atomoxetine in a suicide attempt. Lab analysis revealed a serum atomoxetine concentration of 1995 ng/mL. Following supportive care, the patient recovered within 24 hours of admission without sequelae (Kashani & Ruha, 2007).
    E) DROWSY
    1) WITH POISONING/EXPOSURE
    a) Drowsiness has been reported with overdose and is the most common effect in children (Spiller et al, 2013).
    b) CASE SERIES: In a series of 40 children (aged 9 months to 17 years) with atomoxetine only overdose, 10 (25%) developed drowsiness (Spiller et al, 2005).
    c) In a retrospective study of 64 cases of children exposed to atomoxetine, lethargy occurred in 12.5% of patients (Stojanovski et al, 2006).
    1) Body weights were known in 51 patients. Group 1 (n=43) received greater than 1.4 mg/kg (higher than the maximum recommended dose; mean dose 2.9 +/- 1.2 mg/kg; range 1.57 to 7.04 mg/kg). Group 2 (n=8) received equal or less than 1.4 mg/kg (mean dose 1.06 +/- 0.32 mg/kg; range 0.52 to 1.35). Adverse effects were observed as frequently among children with doses up to the maximum recommended dose, as among children with overdoses. Lethargy occurred in 14% and 12.5% of patients in group 1 and 2, respectively (p=0.99) (Stojanovski et al, 2006).
    F) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) In a retrospective study of 64 cases of children exposed to atomoxetine, headache occurred in 1.6% of patients (Stojanovski et al, 2006).
    1) Body weights were known in 51 patients. Group 1 (n=43) received greater than 1.4 mg/kg (higher than the maximum recommended dose; mean dose 2.9 +/- 1.2 mg/kg; range 1.57 to 7.04 mg/kg). Group 2 (n=8) received equal or less than 1.4 mg/kg (mean dose 1.06 +/- 0.32 mg/kg; range 0.52 to 1.35). Adverse effects were observed as frequently among children with doses up to the maximum recommended dose, as among children with overdoses. Headache occurred in 2.3% and 0% of patients in group 1 and 2 respectively (p=0.99) (Stojanovski et al, 2006).
    G) PSYCHOMOTOR AGITATION
    1) WITH POISONING/EXPOSURE
    a) Hyperactivity and agitation have been reported with overdose (Spiller et al, 2013).
    b) In a retrospective study of 64 cases of children exposed to atomoxetine, agitation occurred in 1.6% of patients (Stojanovski et al, 2006).
    1) Body weights were known in 51 patients. Group 1 (n=43) received greater than 1.4 mg/kg (higher than the maximum recommended dose; mean dose 2.9 +/- 1.2 mg/kg; range 1.57 to 7.04 mg/kg). Group 2 (n=8) received equal or less than 1.4 mg/kg (mean dose 1.06 +/- 0.32 mg/kg; range 0.52 to 1.35). Adverse effects were observed as frequently among children with doses up to the maximum recommended dose, as among children with overdoses. Agitation occurred in 2.3% and 0% of patients in group 1 and 2, respectively (p=0.99) (Stojanovski et al, 2006).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH THERAPEUTIC USE
    a) Gastrointestinal upset has been reported with overdose (Spiller et al, 2013).
    b) Weight loss and anorexia (dose-related) have been reported more often with atomoxetine than placebo in limited controlled studies (Michelson et al, 2001; Spencer et al, 1998; Zerbe et al, 1985).
    c) In collective clinical-study data provided by the manufacturer, the most frequent adverse GI effects associated with atomoxetine given twice daily in children and adolescents with ADHD (n=340) were dyspepsia (4%), constipation (3%), and reduced appetite (14%). In adults with ADHD (n=269), the most common GI effects were constipation (10%), dry mouth (21%), nausea (12%), and reduced appetite (10%)(Prod Info Strattera(TM) , 2002) . All of these effects occurred at higher frequency than with placebo.
    d) In other studies, GI adverse effects have included dry mouth, nausea, vomiting, and abdominal pain (Biederman et al, 2002; Michelson et al, 2001; Spencer et al, 1998; Zerbe et al, 1985), although their frequency was often similar to that observed in placebo recipients.
    e) A meta-analysis of 13 previous atomoxetine trials showed that the most common events resulting in discontinuation were nausea and upper-abdominal pain (Wilens et al, 2006).
    B) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a series of 40 children (aged 9 months to 17 years) with atomoxetine only overdose, 3 (8%) developed nausea and 2 (5%) vomited(Spiller et al, 2005).
    b) In a retrospective study of 64 cases of children exposed to atomoxetine, nausea and vomiting occurred in 10.9% of patients (Stojanovski et al, 2006).
    1) Body weights were known in 51 patients. Group 1 (n=43) received greater than 1.4 mg/kg (higher than the maximum recommended dose; mean dose 2.9 +/- 1.2 mg/kg; range 1.57 to 7.04 mg/kg). Group 2 (n=8) received equal or less than 1.4 mg/kg (mean dose 1.06 +/- 0.32 mg/kg; range 0.52 to 1.35). Adverse effects were observed as frequently among children with doses up to the maximum recommended dose, as among children with overdoses. Vomiting occurred in 9.3% and 12.5% of patients in group 1 and 2, respectively (p=0.99). Nausea occurred in 11.6% and 0% of patients in group 1 and 2, respectively (p=0.58) (Stojanovski et al, 2006).
    c) According to a retrospective chart review, 6 of 17 patients (34%) reported vomiting following overdose ingestions of atomoxetine (LoVecchio & Kashani, 2006).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ACUTE HEPATITIS
    1) WITH THERAPEUTIC USE
    a) PEDIATRIC: Three cases of acute hepatitis were reported with the use of atomoxetine (Lim et al, 2006; Stojanovski et al, 2007).
    1) The first case was a 12-year-old girl with ADHD. She presented with conjunctival icterus, jaundice, right upper quadrant pain, diarrhea, and vomiting three weeks after restarting atomoxetine. She was previously on atomoxetine for a year without issue but had run out of the medication and stopped taking atomoxetine for a six week period. The patient was advised to discontinue atomoxetine and symptoms resolved over a four week period with no further intervention.
    2) The second case involved an 11-year-old girl with ADHD who presented with elevated liver enzymes after restarting atomoxetine. She had previously been on the medication but had discontinued the atomoxetine due to fatigue, weight loss, and arthralgias. Atomoxetine therapy was restarted and tapered up to 30 mg daily. Laboratory tests showed increased liver enzymes with worsening coagulation function. A liver biopsy showed marked acute and chronic hepatitis, focal portal inflammation bridging, and slight fibrosis. The patient's atomoxetine was discontinued. She was started on prednisone and azathioprine as her evaluation was suggestive of type 1 autoimmune hepatitis. Liver enzymes returned to normal within a few weeks.
    3) An 8-year-old girl complained of abdominal pain and experienced occasional emesis since starting therapy with atomoxetine 25 mg daily one month prior. She presented to her primary care physician. Laboratory values were as follows: alkaline phosphatase 528 IU/L (normal: 20 to 150 IU/L), AST 5156 IU/L (normal: 10 to 45 IU/L), ALT 5182 IU/L (normal: 30 to 65 IU/L), total bilirubin 10.8 mg/dL (normal: 0 to 1 mg/dL), and direct bilirubin 9.0 mg/dL (normal: 0 to 0.3 mg/dL). She was admitted to the hospital. Her physical exam was significant for scleral icterus, jaundice, and hepatomegaly. Viral causes were ruled out. A liver biopsy showed hepatitis with moderate piecemeal necrosis. The atomoxetine therapy was discontinued. Transaminases and bilirubin returned to normal with supportive care (Stojanovski et al, 2007).
    b) Potential for severe liver injury which may progress to liver failure resulting in death or the need for a liver transplant in a small percentage of people may exist. The medication should be discontinued in patients who develop jaundice or laboratory evidence of liver injury (US Food and Drug Administration, 2005).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) LACK OF LIBIDO
    1) WITH THERAPEUTIC USE
    a) In clinical trials, decreased libido occurred in 6% (n=269) of atomoxetine patients (2% placebo) (Prod Info Strattera(TM) , 2002).
    B) ABNORMAL EJACULATION
    1) WITH THERAPEUTIC USE
    a) In clinical trials, ejaculatory failure or disorder occurred in 5% (n=269) of atomoxetine patients (2% placebo)(Prod Info Strattera(TM) , 2002) .
    C) DISORDER OF MENSTRUATION
    1) WITH THERAPEUTIC USE
    a) In clinical trials, dysmenorrhea occurred in 7% (n=269) of atomoxetine patients (3% placebo)(Prod Info Strattera(TM) , 2002).
    D) RETENTION OF URINE
    1) WITH THERAPEUTIC USE
    a) In clinical trials, urinary hesitation and/or urinary retention and/or difficulty in micturition occurred in 8% (n=269) of atomoxetine patients (0% placebo)(Prod Info Strattera(TM) , 2002).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Skin rash and pruritus have been reported in some patients during atomoxetine therapy in both open and controlled studies (Kratochvil et al, 2001; Michelson et al, 2001) . Rash occurred upon rechallenge in one patient (Kratochvil et al, 2001).
    2) WITH POISONING/EXPOSURE
    a) In a retrospective study of 64 cases of children exposed to atomoxetine, erythema and rash occurred in 1.6% of patients (Stojanovski et al, 2006).
    1) Body weights were known in 51 patients. Group 1 (n=43) received greater than 1.4 mg/kg (higher than the maximum recommended dose; mean dose 2.9 +/- 1.2 mg/kg; range 1.57 to 7.04 mg/kg). Group 2 (n=8) received equal or less than 1.4 mg/kg (mean dose 1.06 +/- 0.32 mg/kg; range 0.52 to 1.35). Adverse effects were observed as frequently among children with doses up to the maximum recommended dose, as among children with overdoses. Erythema occurred in 0% and 12.5% of patients in group 1 and 2, respectively (p=0.157) (Stojanovski et al, 2006).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Allergic reactions (angioneurotic edema, urticaria, and rash) have been reported in patients taking atomoxetine(Prod Info Strattera(TM) , 2002).

Reproductive

    3.20.1) SUMMARY
    A) Atomoxetine is rated FDA Pregnancy Category C.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RABBITS: Slight increases in the incidence of atypical origin of carotid artery and absent subclavian artery were observed in rabbits administered up to 100 mg/kg/day (approximately 23 times the maximum human dose, based on mg/m(2)) by gavage throughout organogenesis (Prod Info STRATTERA(R) oral capsules, 2014).
    2) RATS: An increase in the incidence of incomplete ossification of the vertebral arch was observed in rats administered 40 mg/kg/day (approximately 5 times the maximum human dose, based on mg/mg(2)) from either 2 weeks or 10 weeks prior to mating in females and males, respectively, throughout organogenesis (Prod Info STRATTERA(R) oral capsules, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Atomoxetine is rated FDA Pregnancy Category C (Prod Info STRATTERA(R) oral capsules, 2014)
    2) Do not administer to a pregnant woman unless the potential benefit outweighs the potential fetal risk (Prod Info STRATTERA(R) oral capsules, 2014).
    B) ANIMAL STUDIES
    1) RABBITS: A decrease in live fetuses and an increase in early resorptions were observed in rabbits administered up to 100 mg/kg/day (approximately 23 times the maximum human dose, based on mg/m(2)) by gavage throughout organogenesis (Prod Info STRATTERA(R) oral capsules, 2014).
    2) RATS: Decreases in pup weight and survival were observed in rats administered up to 50 mg/kg/day (approximately 6 times the maximum human dose, based on mg/m(2)) from either 2 weeks or 10 weeks prior to mating in females and males, respectively, throughout organogenesis and lactation. Decreased pup survival was also observed at 25 mg/kg doses. A decrease in the female fetal weight was observed in rats administered 40 mg/kg/day (approximately 5 times the maximum human dose, based on mg/mg(2)) from either 2 weeks or 10 weeks prior to mating in females and males, respectively, throughout organogenesis (Prod Info STRATTERA(R) oral capsules, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown if atomoxetine is excreted in human milk. Exercise caution when administered to a nursing woman (Prod Info STRATTERA(R) oral capsules, 2014).
    B) ANIMAL STUDIES
    1) RATS: Atomoxetine and/or its metabolites were excreted in the milk of lactating rats (Prod Info STRATTERA(R) oral capsules, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS: No impairment of fertility was observed in rats administered doses up to 57 mg/kg/day (approximately 6 times the maximum human dose, based on mg/m(2)). In a separate study, no effects on fertility or reproductive performance were observed in rats administered doses between 10 and 50 mg/kg; however, slight delays in vaginal patency and preputial separation, slight decreased in epididymal weight and sperm number, and a slight decrease in corpora lutea were reported (Prod Info STRATTERA(R) oral capsules, 2014).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS83015-26-3 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    B) IARC Carcinogenicity Ratings for CAS82248-59-7 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Monitor serum electrolytes in patients with significant vomiting.
    C) Institute continuous cardiac monitoring and obtain an ECG in patients with moderate to severe toxicity.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) An adult patient with an inadvertent exposure of 100 mg or less, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) SUMMARY: Patients who have ingested greater than 100 mg of atomoxetine, or greater than 2 capsules should be referred to a healthcare facility. Patients with a deliberate overdose, those who are symptomatic, and those who ingested an unknown amount of atomoxetine should be referred to a healthcare facility for observation until they are clearly improving and clinically stable.
    B) Based on information from a retrospective review of adult atomoxetine ingestions reported to the Texas Poison Control Centers from 2003 to 2005, patients 20 years of age or older should be referred to a healthcare facility for the following reasons (Forrester, 2006):
    1) The ingestion was intentional
    2) The patient is symptomatic at the time of first call
    3) Unable to estimate the maximum amount ingested
    4) The dose is unknown
    5) The possible maximum amount ingested is greater than 100 mg, or greater than 2 capsules

Monitoring

    A) Monitor vital signs and mental status.
    B) Monitor serum electrolytes in patients with significant vomiting.
    C) Institute continuous cardiac monitoring and obtain an ECG in patients with moderate to severe toxicity.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Treat dyskinesias and/or agitation with IV benzodiazepines. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Therapeutic doses of atomoxetine may cause prolongation of the QT interval. In patients with QT prolongation, monitor serum electrolytes including potassium, calcium and magnesium in patients with significant overdose; correct any abnormalities. At the time of this review, torsades de pointes has not been reported with therapy.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) Monitor serum electrolytes in patients with significant vomiting.
    3) Institute continuous cardiac monitoring and obtain an ECG in patients with moderate to severe toxicity.
    C) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    D) TORSADES DE POINTES
    1) In patients with QT prolongation, monitor serum electrolytes including potassium, calcium and magnesium in patients with significant overdose; correct any abnormalities. At the time of this review, torsades de pointes has not been reported with therapy.
    2) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    3) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    4) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
    5) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    6) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    7) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    8) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Atomoxetine is highly protein-bound and has a large volume of distribution, therefore it is unlikely that hemodialysis or hemoperfusion would be effective.

Range Of Toxicity

Summary

    A) TOXICITY: A minimum toxic dose has not been established. Mild to moderate effects have been reported with ingestions up to 750 mg in children and adolescents. A 17-year-old girl developed sinus tachycardia with mild QRS interval prolongation, generalized tonic clonic seizure, lateral nystagmus, tremor, and hyperreflexia after ingesting 2.8 g of atomoxetine. Generalized seizures and prolonged QTc interval developed in a 15-year-old who ingested 1.2 g atomoxetine. A 12-year-old developed mild transient tachycardia and no other effects after ingesting 180 mg.
    B) THERAPEUTIC DOSE: ADULTS OR CHILDREN OVER 70 KG BODY WEIGHT - Initial, 40 mg/day and increased after a minimum of 3 days to a target total daily dose of approximately 80 mg . May increase to 100 mg after 2 to 4 additional weeks of therapy. PEDIATRIC DOSING: UP TO 70 KG BODY WEIGHT: Initial, approximately 0.5 mg/kg/day and increased after a minimum of 3 days to a target total daily dose of approximately 1.2 mg/kg . Max 1.4 mg/kg or 100 milligrams, whichever is less.

Therapeutic Dose

    7.2.1) ADULT
    A) Initial total daily dose of 40 mg orally and increased after a minimum of 3 days to a target total daily dose of approximately 80 mg, as either a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening. The dose may be increased to 100 mg after 2 to 4 additional weeks of therapy. Maximum recommended total daily dose is 100 mg (Prod Info STRATTERA(R) oral capsules, 2014)
    7.2.2) PEDIATRIC
    A) CHILDREN AND ADOLESCENTS UP TO 70 KG BODY WEIGHT: Initial total daily dose of approximately 0.5 mg/kg orally and increased after a minimum of 3 days to a target total daily dose of approximately 1.2 mg/kg , as either a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening. Maximum recommended total daily dose is either 1.4 mg/kg or 100 mg, whichever is less (Prod Info STRATTERA(R) oral capsules, 2014)
    B) CHILDREN AND ADOLESCENTS OVER 70 KG BODY WEIGHT: Initial total daily dose of 40 mg orally and increased after a minimum of 3 days to a target total daily dose of approximately 80 mg, as either a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening. The dose may be increased to 100 mg after 2 to 4 additional weeks of therapy. Maximum recommended total daily dose is 100 mg (Prod Info STRATTERA(R) oral capsules, 2014)

Maximum Tolerated Exposure

    A) CASE REPORT: A 15-year-old boy with a history of major depression and ADHD (medications: sustained-release bupropion 150 mg twice daily; risperidone 0.25 mg twice daily; alprazolam 0.25 mg as needed; atomoxetine 80 mg/day) developed generalized seizures and prolonged QTc interval after ingesting 1200 mg (22 mg/kg) of atomoxetine. In addition, he experienced anxiety, tremulousness, mild tachycardia, and dry mouth. The authors suggested that bupropion may have contributed to the generalized seizures (Sawant & Daviss, 2004).
    B) CASE REPORT: A 12-year-old boy inadvertently received three tablets of atomoxetine 60 mg (approximately four times the maximum recommended daily dose of 1.4 mg/kg/day) instead of dextroamphetamine. Approximately 90 minutes postingestion, his vital signs were blood pressure 118/74 mmHg, pulse 106 bpm, respirations 19 rpm, and normal oral temperature. His pulse returned to normal soon after arrival to the hospital and he was discharged home following 3 hours of observation (Cantrell & Nestor, 2005).
    C) CASE SERIES: In a series of 40 patients with atomoxetine only overdose, 22 remained asymptomatic (mean dose 40 mg, range 18 to 162 mg), 15 had mild effects such as nausea, vomiting, drowsiness and mild tachycardia (mean dose 167 mg, range 25 to 750 mg), and 3 had moderate effects of hypertension or seizures (mean dose 249 mg, range 18 to 480 mg). Most of these cases were toddlers with unintentional ingestions (23, 58%) or unintentional therapeutic errors (10, 25%). Only 7 patients were older children who intentionally ingested large (>100 mg) doses(Spiller et al, 2005).
    D) In a retrospective study of 64 cases of children exposed to atomoxetine reported to a poison center, 21 (33%) patients developed an adverse reaction (15 at dosage range 0.52-6.25 mg/kg); agitation (1.6%), headache (1.6%), erythema (1.6%), rash (1.6%), elevated blood pressure and heart rate (4.7%), nausea (10.9%), vomiting (10.9%), and lethargy (12.5%) (Stojanovski et al, 2006).
    1) Body weights were known in 51 patients. Group 1 (n=43) received greater than 1.4 mg/kg (higher than the maximum recommended dose; mean dose 2.9 +/- 1.2 mg/kg; range 1.57 to 7.04 mg/kg). Group 2 (n=8) received equal or less than 1.4 mg/kg (mean dose 1.06 +/- 0.32 mg/kg; range 0.52 to 1.35). Adverse effects were observed as frequently among children with doses up to the maximum recommended dose, as among children with overdoses. The following adverse effects were observed in group 1 and group 2, respectively: vomiting (9.3% vs 12.5%, p=0.99), nausea (11.6% vs 0%, p=0.58), agitation (2.3% vs 0%, p=0.99), lethargy (14% vs 12.5%, p=0.99), headache (2.3% vs 0%, p=0.99), increased heart rate (2.3% vs 0%, p=0.99), increased blood pressure (2.3% vs 0%, p=0.99), and erythema (0% vs 12.5%, p=0.157). Three of 9 patients with recorded blood pressure had hypertension (BP range = 139/96; 144/81; 160/120 mm Hg, respectively). Three patients had heart rate of 100 to 132 beats per minute (Stojanovski et al, 2006).
    E) According to a retrospective chart review, involving 17 patients (ages ranging from 9 months to 28 years) exposed to atomoxetine, 9 patients reported symptoms including gastrointestinal distress, hyperactivity, drowsiness, throat irritation, dizziness, tremors, and tachycardia, following overdose ingestions of atomoxetine. The doses ingested ranged from 10 to 1200 mg. The majority of patients reported the onset of symptoms occurring within 1 hour post-ingestion, although, in 3 patients, the onset was delayed up to 3 hours post-ingestion. All symptoms resolved within 30 hours (LoVecchio & Kashani, 2006).
    F) CASE REPORT: A 17-year-old girl developed sinus tachycardia with mild QRS interval prolongation, a generalized tonic clonic seizure lasting one minute in duration, lateral nystagmus, resting tremor, and hyperreflexia after reportedly ingesting 2840 mg of atomoxetine in a suicide attempt. Lab analysis revealed a serum atomoxetine concentration of 1995 ng/mL. Following supportive care, the patient recovered within 24 hours of admission without sequelae (Kashani & Ruha, 2007).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) The serum atomoxetine concentration in a 17-year-old girl who developed a seizure, tremors, nystagmus and hyperreflexia after a reported ingestion of 2840 mg of atomoxetine, was 1995 ng/mL (Kashani & Ruha, 2007).

Workplace Standards

    A) ACGIH TLV Values for CAS83015-26-3 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) ACGIH TLV Values for CAS82248-59-7 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    C) NIOSH REL and IDLH Values for CAS83015-26-3 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    D) NIOSH REL and IDLH Values for CAS82248-59-7 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    E) Carcinogenicity Ratings for CAS83015-26-3 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    F) Carcinogenicity Ratings for CAS82248-59-7 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    G) OSHA PEL Values for CAS83015-26-3 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    H) OSHA PEL Values for CAS82248-59-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Atomoxetine is a methylphenoxy-benzene propanamine derivative with antidepressant activity(Zerbe et al, 1985; Chouinard et al, 1985); its structure is unlike that of other antidepressants. The exact mechanism by which produces its therapeutic effects in ADHD is unknown; however, atomoxetine purportedly enhances noradrenergic function via selective inhibition of the presynaptic norepinephrine transporter (Ki of 4.5 nanomols (nM))(Michelson et al, 2001; Kratochvil et al, 2001).
    B) It has minimal-to-no affinity for other neuronal transporters or neurotransmitter receptor sites (eg, muscarinic, histaminic, dopaminergic, serotonergic, alpha-adrenergic)(Zerbe et al, 1985; Cusack et al, 1994; Spencer et al, 1998a; Chouinard et al, 1985; Spencer et al, 1998).
    C) Animal and human studies suggest a low propensity for anticholinergic and adverse cardiovascular effects with atomoxetine(Zerbe et al, 1985; Kratochvil et al, 2001; Spencer et al, 2001). No significant hypertensive effects were seen in healthy subjects given single doses of 20 or 40 mg twice daily for one week in one study(Zerbe et al, 1985).

Physicochemical

Physical Characteristics

    A) A white to practically white solid; solubility of 27.8 mg/mL in water(Prod Info Strattera(TM) , 2002)

Molecular Weight

    A) 291.82(Prod Info Strattera(TM) , 2002)

References

General Bibliography

    1) 40 CFR 372.28: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Lower thresholds for chemicals of special concern. National Archives and Records Administration (NARA) and the Government Printing Office (GPO). Washington, DC. Final rules current as of Apr 3, 2006.
    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
    3) 49 CFR 172.101 - App. B: Department of Transportation - Table of Hazardous Materials, Appendix B: List of Marine Pollutants. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 29, 2005.
    4) 62 FR 58840: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 1997.
    5) 65 FR 14186: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    6) 65 FR 39264: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    7) 65 FR 77866: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    8) 66 FR 21940: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2001.
    9) 67 FR 7164: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2002.
    10) 68 FR 42710: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2003.
    11) 69 FR 54144: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2004.
    12) AIHA: 2006 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook, American Industrial Hygiene Association, Fairfax, VA, 2006.
    13) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    14) American Conference of Governmental Industrial Hygienists : ACGIH 2010 Threshold Limit Values (TLVs(R)) for Chemical Substances and Physical Agents and Biological Exposure Indices (BEIs(R)), American Conference of Governmental Industrial Hygienists, Cincinnati, OH, 2010.
    15) American Heart Association: 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2005; 112(24 Suppl):IV 1-203. Available from URL: http://circ.ahajournals.org/content/vol112/24_suppl/. As accessed 12/14/2005.
    16) Biederman J, Heiligenstein JH, Faries DE, et al: Efficacy of atomoxetine versus placebo in school-age girls with attention-deficit/hyperactivity disorder.. Pediatrics 2002; 110(6):1-7.
    17) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    18) Cantrell FL & Nestor M: Benign clinical course following atomoxetine overdose (letter). Clin Toxicol 2005; 1:57.
    19) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    20) Charlton NP , Lawrence DT , Brady WJ , et al: Termination of drug-induced torsades de pointes with overdrive pacing. Am J Emerg Med 2010; 28(1):95-102.
    21) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    22) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    23) Chouinard G, Annable L, Bradwejn J, et al: An early phase II clinical trial with follow-up of tomoxetine (LY139603) in the treatment of newly admitted depressed patients.. Psychopharmacol Bull 1985; 21:73-76.
    24) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    25) Cusack B, Nelson A, & Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. . Psychopharmacology 1994; 114:559-565.
    26) DFG: List of MAK and BAT Values 2002, Report No. 38, Deutsche Forschungsgemeinschaft, Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area, Wiley-VCH, Weinheim, Federal Republic of Germany, 2002.
    27) Drew BJ, Ackerman MJ, Funk M, et al: Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2010; 55(9):934-947.
    28) EPA: Search results for Toxic Substances Control Act (TSCA) Inventory Chemicals. US Environmental Protection Agency, Substance Registry System, U.S. EPA's Office of Pollution Prevention and Toxics. Washington, DC. 2005. Available from URL: http://www.epa.gov/srs/.
    29) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    30) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    31) Farid NA, Bergstrom RF, Ziege EA, et al: Single-dose and steady-state pharmacokinetics of tomoxetine in normal subjects.. J Clin Pharmacol 1985; 25:296-301.
    32) Forrester MB: Adult atomoxetine ingestions reported to Texas Poison Control Centers, 2003-2005. Ann Pharmacother 2006; 40(12):2136-2141.
    33) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    34) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    35) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    36) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    37) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    38) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: 1,3-Butadiene, Ethylene Oxide and Vinyl Halides (Vinyl Fluoride, Vinyl Chloride and Vinyl Bromide), 97, International Agency for Research on Cancer, Lyon, France, 2008.
    39) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Formaldehyde, 2-Butoxyethanol and 1-tert-Butoxypropan-2-ol, 88, International Agency for Research on Cancer, Lyon, France, 2006.
    40) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Household Use of Solid Fuels and High-temperature Frying, 95, International Agency for Research on Cancer, Lyon, France, 2010a.
    41) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Smokeless Tobacco and Some Tobacco-specific N-Nitrosamines, 89, International Agency for Research on Cancer, Lyon, France, 2007.
    42) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Some Non-heterocyclic Polycyclic Aromatic Hydrocarbons and Some Related Exposures, 92, International Agency for Research on Cancer, Lyon, France, 2010.
    43) IARC: List of all agents, mixtures and exposures evaluated to date - IARC Monographs: Overall Evaluations of Carcinogenicity to Humans, Volumes 1-88, 1972-PRESENT. World Health Organization, International Agency for Research on Cancer. Lyon, FranceAvailable from URL: http://monographs.iarc.fr/monoeval/crthall.html. As accessed Oct 07, 2004.
    44) International Agency for Research on Cancer (IARC): IARC monographs on the evaluation of carcinogenic risks to humans: list of classifications, volumes 1-116. International Agency for Research on Cancer (IARC). Lyon, France. 2016. Available from URL: http://monographs.iarc.fr/ENG/Classification/latest_classif.php. As accessed 2016-08-24.
    45) International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. World Health Organization. Geneva, Switzerland. 2015. Available from URL: http://monographs.iarc.fr/ENG/Classification/. As accessed 2015-08-06.
    46) Kashani J & Ruha A: Isolated atomoxetine overdose resulting in seizure. J Emerg Med 2007; 32(2):175-178.
    47) Kelly RP, Yeo KP, Teng CH, et al: Hemodynamic effects of acute administration of atomoxetine and methylphenidate. J Clin Pharmacol 2005; 45(7):851-855.
    48) Keren A, Tzivoni D, & Gavish D: Etiology, warning signs and therapy of torsade de pointes: a study of 10 patients. Circulation 1981; 64:1167-1174.
    49) Khan IA & Gowda RM: Novel therapeutics for treatment of long-QT syndrome and torsade de pointes. Int J Cardiol 2004; 95(1):1-6.
    50) Kratochvil CJ, Bohac D, Harrington M, et al: An open-label trial of tomoxetine in pediatric attention deficit hyperactivity disorder. . J Child Adolesc Psychopharmacol 2001; 11(2):167-170.
    51) Ledbetter M: Atomoxetine use associated with onset of a motor tic. J Child Adolesc Psychopharmacol 2005; 15(2):331-333.
    52) Lim JR, Faught PR, Chalasani NP, et al: Severe liver injury after initiating therapy with atomoxetine in two children. J Pediatr 2006; 148(6):831-834.
    53) Link MS, Berkow LC, Kudenchuk PJ, et al: Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S444-S464.
    54) Liu CC, Lan CC, & Chen YS: Atomoxetine-induced mania with auditory hallucination in an 8-year-old boy with attention-deficit/hyperactivity disorder and tic disorder. J Child Adolesc Psychopharmacol 2014; 24(8):466-467.
    55) LoVecchio F & Kashani J: Isolated atomoxetine (Strattera) ingestions commonly result in toxicity. J Emerg Med 2006; 31(3):267-268.
    56) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    57) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    58) Michelson D, Faries D, Wernicke J, et al: Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study.. Pediatrics 2001; 108(5):U33-U41.
    59) NFPA: Fire Protection Guide to Hazardous Materials, 13th ed., National Fire Protection Association, Quincy, MA, 2002.
    60) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 1, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2001.
    61) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 2, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2002.
    62) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 3, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2003.
    63) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 4, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2004.
    64) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2,3-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    65) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2,4-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    66) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2-Butylene Oxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648083cdbb&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    67) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2-Dibromoethane (Proposed). United States Environmental Protection Agency. Washington, DC. 2007g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064802796db&disposition=attachment&contentType=pdf. As accessed 2010-08-18.
    68) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,3,5-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    69) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 2-Ethylhexyl Chloroformate (Proposed). United States Environmental Protection Agency. Washington, DC. 2007b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648037904e&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    70) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Acrylonitrile (Proposed). United States Environmental Protection Agency. Washington, DC. 2007c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648028e6a3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    71) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Adamsite (Proposed). United States Environmental Protection Agency. Washington, DC. 2007h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    72) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Agent BZ (3-quinuclidinyl benzilate) (Proposed). United States Environmental Protection Agency. Washington, DC. 2007f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ad507&disposition=attachment&contentType=pdf. As accessed 2010-08-18.
    73) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Allyl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648039d9ee&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    74) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Aluminum Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    75) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Arsenic Trioxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2007m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480220305&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    76) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Automotive Gasoline Unleaded (Proposed). United States Environmental Protection Agency. Washington, DC. 2009a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cc17&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    77) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Biphenyl (Proposed). United States Environmental Protection Agency. Washington, DC. 2005j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064801ea1b7&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    78) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bis-Chloromethyl Ether (BCME) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006n. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648022db11&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    79) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Boron Tribromide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ae1d3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    80) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bromine Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2007d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648039732a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    81) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bromoacetone (Proposed). United States Environmental Protection Agency. Washington, DC. 2008e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809187bf&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    82) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Calcium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    83) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Carbonyl Fluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ae328&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    84) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Carbonyl Sulfide (Proposed). United States Environmental Protection Agency. Washington, DC. 2007e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648037ff26&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    85) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Chlorobenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2008c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803a52bb&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    86) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Cyanogen (Proposed). United States Environmental Protection Agency. Washington, DC. 2008f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809187fe&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    87) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Dimethyl Phosphite (Proposed). United States Environmental Protection Agency. Washington, DC. 2009. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbf3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    88) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Diphenylchloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    89) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648091884e&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    90) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyl Phosphorodichloridate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480920347&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    91) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2008g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809203e7&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    92) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    93) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Germane (Proposed). United States Environmental Protection Agency. Washington, DC. 2008j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963906&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    94) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Hexafluoropropylene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064801ea1f5&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    95) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ketene (Proposed). United States Environmental Protection Agency. Washington, DC. 2007. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ee7c&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    96) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Magnesium Aluminum Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    97) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Magnesium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    98) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Malathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2009k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809639df&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    99) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Mercury Vapor (Proposed). United States Environmental Protection Agency. Washington, DC. 2009b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a8a087&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    100) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl Isothiocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963a03&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    101) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl Parathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2008l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963a57&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    102) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl tertiary-butyl ether (Proposed). United States Environmental Protection Agency. Washington, DC. 2007a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064802a4985&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    103) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methylchlorosilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2005. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5f4&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    104) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    105) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyldichlorosilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2005a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c646&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    106) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN1 CAS Reg. No. 538-07-8) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    107) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN2 CAS Reg. No. 51-75-2) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    108) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN3 CAS Reg. No. 555-77-1) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    109) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Tetroxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008n. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648091855b&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    110) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Trifluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963e0c&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    111) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Parathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2008o. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963e32&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    112) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Perchloryl Fluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e268&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    113) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Perfluoroisobutylene (Proposed). United States Environmental Protection Agency. Washington, DC. 2009d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e26a&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    114) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008p. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096dd58&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    115) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyl Mercaptan (Proposed). United States Environmental Protection Agency. Washington, DC. 2006d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020cc0c&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    116) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    117) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phorate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008q. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096dcc8&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    118) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phosgene (Draft-Revised). United States Environmental Protection Agency. Washington, DC. 2009e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a8a08a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    119) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phosgene Oxime (Proposed). United States Environmental Protection Agency. Washington, DC. 2009f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e26d&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    120) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Potassium Cyanide (Proposed). United States Environmental Protection Agency. Washington, DC. 2009g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbb9&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    121) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Potassium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    122) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Propargyl Alcohol (Proposed). United States Environmental Protection Agency. Washington, DC. 2006e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec91&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    123) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Selenium Hexafluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2006f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec55&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    124) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Silane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d523&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    125) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sodium Cyanide (Proposed). United States Environmental Protection Agency. Washington, DC. 2009h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbb9&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    126) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sodium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    127) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Strontium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    128) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sulfuryl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2006h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec7a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    129) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tear Gas (Proposed). United States Environmental Protection Agency. Washington, DC. 2008s. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e551&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    130) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tellurium Hexafluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e2a1&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    131) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tert-Octyl Mercaptan (Proposed). United States Environmental Protection Agency. Washington, DC. 2008r. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e5c7&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    132) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tetramethoxysilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d632&disposition=attachment&contentType=pdf. As accessed 2010-08-17.
    133) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethoxysilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d632&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    134) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethyl Phosphite (Proposed). United States Environmental Protection Agency. Washington, DC. 2009j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7d608&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    135) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethylacetyl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008t. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e5cc&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    136) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Zinc Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    137) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for n-Butyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064808f9591&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    138) National Institute for Occupational Safety and Health: NIOSH Pocket Guide to Chemical Hazards, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Cincinnati, OH, 2007.
    139) National Research Council : Acute exposure guideline levels for selected airborne chemicals, 5, National Academies Press, Washington, DC, 2007.
    140) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 6, National Academies Press, Washington, DC, 2008.
    141) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 7, National Academies Press, Washington, DC, 2009.
    142) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 8, National Academies Press, Washington, DC, 2010.
    143) Neumar RW , Otto CW , Link MS , et al: Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S729-S767.
    144) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    145) Perticone F, Ceravolo R, & Cuccurullo O: Prolonged magnesium sulfate infusion in the treatment of ventricular tachycardia in acquired long QT syndrome. Clin Drug Inverst 1997; 13:229-236.
    146) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    147) Product Information: Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, isoproterenol HCl intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection. Hospira, Inc. (per FDA), Lake Forest, IL, 2013.
    148) Product Information: STRATTERA(R) oral capsules, atomoxetine hcl oral capsules. Eli Lilly and Company, Indianapolis, IN, 2008.
    149) Product Information: STRATTERA(R) oral capsules, atomoxetine oral capsules. Lilly USA, LLC (per FDA), Indianapolis, IN, 2014.
    150) Product Information: Strattera(TM) , atomoxetine. Eli Lilly & Co, Indianapolis, IN, 2002.
    151) Product Information: Strattera(TM) , atomoxetine. Eli Lilly & Co, Indianapolis, IN, 2003.
    152) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    153) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    154) Product Information: magnesium sulfate heptahydrate IV, IM injection, solution, magnesium sulfate heptahydrate IV, IM injection, solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2009.
    155) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    156) Sawant S & Daviss SR: Seizures and prolonged QTc with atomoxetine overdose. Am J Psychiatry 2004; 161(4):757.
    157) Scott R, Besag FMC, & Neville BGR: Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet 1999; 353:623-626.
    158) Smith WM & Gallagher JJ: "Les torsades de pointes": an unusual ventricular arrhythmia. Ann Intern Med 1980; 93:578-584.
    159) Spencer T, Biederman J, Heiligenstein J, et al: An open-label, dose-ranging study of atomoxetine in children with attention deficit hyperactivity disorder.. J Child Adolesc Psychopharmacol 2001; 11(3):251-265.
    160) Spencer T, Biederman J, Wilens T, et al: Effectiveness and tolerability of tomoxetine in adults with attention deficit hyperactivity disorder.. Am J Psychiatry 1998; 155:693-695.
    161) Spencer T, Biederman J, Wilens TE, et al: Adults with attention-deficit/hyperactivity disorder: a controversial diagnosis.. J Clin Psychiatry 1998a; 59(suppl 7):59-68.
    162) Spiller HA, Hays HL, & Aleguas A Jr: Overdose of drugs for attention-deficit hyperactivity disorder: clinical presentation, mechanisms of toxicity, and management. CNS Drugs 2013; 27(7):531-543.
    163) Spiller HA, Lintner CP, & Winter ML: Atomoxetine ingestions in children: a report from poison centers. Ann Pharmacother 2005; 39:1045-1048.
    164) Sreenath TG, Gupta P, Sharma KK, et al: Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: A randomized controlled trial. Eur J Paediatr Neurol 2010; 14(2):162-168.
    165) Steinberg S & Chouinard G: A case of mania associated with tamoxetine (letter).. Am J Psychiatry 1985; 142:1517-1518.
    166) Stojanovski SD, Casavant MJ, & Mousa HM: Atomoxetine-induced hepatitis in a child. Clin Toxicol (Phila) 2007; 45(1):51-55.
    167) Stojanovski SD, Robinson RF, Baker SD, et al: Children and adolescent exposures to atomoxetine hydrochloride reported to a poison control center. Clin Toxicol (Phila) 2006; 44(3):243-247.
    168) U.S. Department of Energy, Office of Emergency Management: Protective Action Criteria (PAC) with AEGLs, ERPGs, & TEELs: Rev. 26 for chemicals of concern. U.S. Department of Energy, Office of Emergency Management. Washington, DC. 2010. Available from URL: http://www.hss.doe.gov/HealthSafety/WSHP/Chem_Safety/teel.html. As accessed 2011-06-27.
    169) U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project : 11th Report on Carcinogens. U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program. Washington, DC. 2005. Available from URL: http://ntp.niehs.nih.gov/INDEXA5E1.HTM?objectid=32BA9724-F1F6-975E-7FCE50709CB4C932. As accessed 2011-06-27.
    170) U.S. Environmental Protection Agency: Discarded commercial chemical products, off-specification species, container residues, and spill residues thereof. Environmental Protection Agency's (EPA) Resource Conservation and Recovery Act (RCRA); List of hazardous substances and reportable quantities 2010b; 40CFR(261.33, e-f):77-.
    171) U.S. Environmental Protection Agency: Integrated Risk Information System (IRIS). U.S. Environmental Protection Agency. Washington, DC. 2011. Available from URL: http://cfpub.epa.gov/ncea/iris/index.cfm?fuseaction=iris.showSubstanceList&list_type=date. As accessed 2011-06-21.
    172) U.S. Environmental Protection Agency: List of Radionuclides. U.S. Environmental Protection Agency. Washington, DC. 2010a. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-sec302-4.pdf. As accessed 2011-06-17.
    173) U.S. Environmental Protection Agency: List of hazardous substances and reportable quantities. U.S. Environmental Protection Agency. Washington, DC. 2010. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-sec302-4.pdf. As accessed 2011-06-17.
    174) U.S. Environmental Protection Agency: The list of extremely hazardous substances and their threshold planning quantities (CAS Number Order). U.S. Environmental Protection Agency. Washington, DC. 2010c. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-part355.pdf. As accessed 2011-06-17.
    175) U.S. Occupational Safety and Health Administration: Part 1910 - Occupational safety and health standards (continued) Occupational Safety, and Health Administration's (OSHA) list of highly hazardous chemicals, toxics and reactives. Subpart Z - toxic and hazardous substances. CFR 2010 2010; Vol6(SEC1910):7-.
    176) U.S. Occupational Safety, and Health Administration (OSHA): Process safety management of highly hazardous chemicals. 29 CFR 2010 2010; 29(1910.119):348-.
    177) US Food and Drug Administration: Updates. US Food and Drug Administration. Rockville, MD. 2005. Available from URL: http://www.fda.gov/fdac/departs/2005/205_upd.html.
    178) US Food and Drug Administration: Updates. US Food and Drug Administration. Rockville, MD. 2005a. Available from URL: http://www.fda.gov/fdac/departs/2005/605_upd.html.
    179) United States Environmental Protection Agency Office of Pollution Prevention and Toxics: Acute Exposure Guideline Levels (AEGLs) for Vinyl Acetate (Proposed). United States Environmental Protection Agency. Washington, DC. 2006. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6af&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    180) Wilens TE, Newcorn JH, Kratochvil CJ, et al: Long-term atomoxetine treatment in adolescents with attention-deficit/hyperactivity disorder. J Pediatr 2006; 149(1):112-119.
    181) Yamaguchi H, Nagumo K, Nakashima T, et al: Life-threatening QT prolongation in a boy with attention-deficit/hyperactivity disorder on atomoxetine. Eur J Pediatr 2014; 173(12):1631-1634.
    182) Zerbe RL, Rowe H, Enas GG, et al: Clinical pharmacology of tomoxetine, a potential antidepressant.. J Pharmacol Exp Ther 1985; 232(1):39-143.