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DULOXETINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI).

Specific Substances

    1) (+)-(S)-N-Methyl-gamma-(1-naphthyloxy)-2-thiophenepropylamine hydrochloride
    2) Duloxetine hydrochloride
    3) LY-248686
    4) CAS 136434-34-9 (duloxetine hydrochloride)
    1.2.1) MOLECULAR FORMULA
    1) C18-H19-N-O-S

Available Forms Sources

    A) FORMS
    1) Duloxetine is available in the United States as a 20 mg, 30 mg, and 60 mg delayed-release capsule (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015).
    B) USES
    1) Duloxetine is indicated for the treatment of major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015).

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: Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) indicated for the treatment of major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathic pain, and fibromyalgia.
    B) PHARMACOLOGY: The exact mechanism of action is unknown but is believed to be related to the potentiation of serotonergic and noradrenergic activity in the CNS.
    C) EPIDEMIOLOGY: Overdose of duloxetine is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Nausea, dry mouth, constipation, fatigue, dizziness, somnolence, and hyperhidrosis. LESS COMMON: Slight increases in blood pressure and heart rate with therapeutic use.
    2) Withdrawal symptoms, following abrupt cessation of duloxetine therapy, may include dizziness, nausea, headache, paresthesias, vomiting, irritability, and the occurrence of nightmares. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) with hyponatremia have been reported in patients receiving duloxetine.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Somnolence, syncope, tachycardia, vomiting, diarrhea, headaches, diaphoresis, agitation, confusion, and hypertension.
    2) SEVERE TOXICITY: Serotonin syndrome (altered mental status, neuromuscular abnormalities and autonomic instability), seizures, hypotension, and coma. Fatalities have occurred.
    0.2.20) REPRODUCTIVE
    A) Duloxetine is classified as FDA pregnancy category C. Although human and animal data of duloxetine use during pregnancy did not reveal substantial teratogenicity, nonteratogenic effects (pulmonary hypertension of the newborn and clinical findings consistent with serotonin syndrome), and increased special or intensive unit care of the infant were demonstrated following maternal use of serotonin and norepinephrine reuptake inhibitors (SNRIs) or SSRIs during the third trimester of pregnancy. Duloxetine is excreted in human breast milk.

Laboratory Monitoring

    A) Monitor vital signs (including temperature) and mental status.
    B) Monitor serum electrolytes (including potassium, bicarbonate) following significant overdose.
    C) Obtain baseline ECG, continuous cardiac monitoring, and serial ECGs following a significant exposure.
    D) Plasma concentration is not readily available and does not correlate well with therapeutic or adverse effects.
    E) Monitor liver enzyme concentrations in symptomatic patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Most patients require only supportive care. Control agitation with either benzodiazepines. Serotonin syndrome generally responds to benzodiazepines, although a serotonin antagonist such as cyproheptadine may also be considered. Hypertension and tachycardia are generally mild and well tolerated, and do not require specific treatment.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Aggressive use of benzodiazepines and serotonin antagonists is required for more severe serotonin syndrome. Early intubation, neuromuscular paralysis, ventilation assistance, and aggressive cooling should be performed if the patient presents with severe muscle rigidity, and severe hyperthermia. Treat hypotension initially with IV fluids, add vasopressors if necessary. Treat seizures with benzodiazepines; use barbiturates or propofol for recurrent seizures. Patients with wide-complex dysrhythmias should be treated with sodium bicarbonate boluses (1 to 2 mEq/kg, monitor arterial blood gases, target pH 7.45 to 7.55). Although QTc interval prolongation is well described, torsade de pointes is rare. If torsade de pointes occurs, patients should be treated using standard interventions (magnesium sulfate 2 g IV, external or internal cardiac pacing).
    C) DECONTAMINATION
    1) PREHOSPITAL: Activated charcoal can be considered within the first hour after large ingestion (1000 mg of duloxetine), if the patient has an appropriate level of consciousness, has a patent airway, and is able to drink the charcoal.
    2) HOSPITAL: Administer activated charcoal if the patient presents early after large ingestion (1000 mg of duloxetine), if the patient has an appropriate level of consciousness, patent airway and can drink the charcoal, or if the patient is intubated. Severe toxicity is rare; gastric lavage is rarely, if ever, warranted.
    D) AIRWAY MANAGEMENT
    1) Perform early with neuromuscular paralysis if the patient presents with respiratory or CNS depression, severe muscle rigidity, or severe hyperthermia.
    E) ANTIDOTE
    1) There is no antidote.
    F) SEIZURE
    1) IV benzodiazepines, barbiturates, or propofol for recurrent seizures.
    G) SEROTONIN SYNDROME
    1) IV benzodiazepines, cooling measures. Cyproheptadine may be considered (ADULT: 12 mg orally or nasogastric (NG) tube, followed by 4 to 8 mg orally or NG tube every 4 to 6 hours if symptoms persist, up to a maximum of 32 mg in 24 hours. CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day). Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with nondepolarizing agents.
    H) TORSADES DE POINTES
    1) Hemodynamically unstable patients require electrical cardioversion. Emergent treatment with magnesium, isoproterenol, or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities.
    I) ENHANCED ELIMINATION
    1) Hemodialysis and hemoperfusion are NOT of value due to the large volume of distribution.
    J) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic children with acute inadvertent ingestions may be monitored at home. Asymptomatic patients or those with mild toxicity following an isolated unintentional acute ingestion of up to 5 times an initial adult therapeutic dose (ie, duloxetine 150 mg) can be observed at home with instructions to call the poison center back if symptoms develop. For patients already on duloxetine with ingestions of up to 5 times their own single therapeutic dose can be observed at home with instructions to call the poison center back if symptoms develop.
    2) OBSERVATION CRITERIA: Symptomatic patients, those with deliberate ingestions, and those with ingestions of more than 5 times their therapeutic dose should be evaluated in a healthcare facility and observed for 6 to 12 hours.
    3) ADMISSION CRITERIA: Patients with severe toxicity need to be admitted to an intensive care unit.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or it the diagnosis is unclear.
    K) PITFALLS
    1) Failure to aggressively control agitation, muscle rigidity, and hyperthermia with adequate benzodiazepines, intubation with neuromuscular paralysis and body cooling. Consider the possibility of ingestion of multiple substances. Patients who are taking another agent that increases CNS serotonin are more likely to develop serotonin syndrome.
    L) PHARMACOKINETICS
    1) There is a median 2-hour lag time until absorption begins when administered orally. The volume of distribution of duloxetine is approximately 1640 L. Duloxetine is extensively metabolized by the liver and the mean elimination half-life is about 12 hours (range 8 to 17 hours).
    M) DIFFERENTIAL DIAGNOSIS
    1) Overdose with another SSRI, serotonin syndrome, neuroleptic malignant syndrome, CNS infection, hypoglycemia, cocaine or amphetamine poisoning can present similar to duloxetine overdose.

Range Of Toxicity

    A) TOXICITY: Death has been reported following ingestions of duloxetine doses as low as 1000 mg. In premarketing clinical trials, four patients recovered following acute ingestions of 300 to 1400 mg of duloxetine, as either sole therapy or in combination with other drugs. Somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting have been reported in patients taking duloxetine (alone or with mixed drugs) doses as low as 1000 mg. INFANT: Drowsiness was the only reported symptom in a 1-year-old child following an unintentional duloxetine ingestion of 7.4 mg/kg.
    B) THERAPEUTIC DOSE: The recommended dosage range for duloxetine is 30 to 120 mg daily.

Clinical Effects

Summary Of Exposure

    A) USES: Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) indicated for the treatment of major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathic pain, and fibromyalgia.
    B) PHARMACOLOGY: The exact mechanism of action is unknown but is believed to be related to the potentiation of serotonergic and noradrenergic activity in the CNS.
    C) EPIDEMIOLOGY: Overdose of duloxetine is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Nausea, dry mouth, constipation, fatigue, dizziness, somnolence, and hyperhidrosis. LESS COMMON: Slight increases in blood pressure and heart rate with therapeutic use.
    2) Withdrawal symptoms, following abrupt cessation of duloxetine therapy, may include dizziness, nausea, headache, paresthesias, vomiting, irritability, and the occurrence of nightmares. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) with hyponatremia have been reported in patients receiving duloxetine.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Somnolence, syncope, tachycardia, vomiting, diarrhea, headaches, diaphoresis, agitation, confusion, and hypertension.
    2) SEVERE TOXICITY: Serotonin syndrome (altered mental status, neuromuscular abnormalities and autonomic instability), seizures, hypotension, and coma. Fatalities have occurred.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) ANGIOEDEMA
    1) WITH THERAPEUTIC USE
    a) Angioneurotic edema has been reported with duloxetine use in postmarketing reports; however, a casual relationship to drug exposure has not been established (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015).
    B) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypertensive crisis has been reported with duloxetine use in postmarketing reports; however, a casual relationship to drug exposure has not been established (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015).
    b) Small increases in blood pressure (9 mmHg or less systolic and 5 mmHg or less diastolic) have been infrequently reported in placebo-controlled clinical trials, involving 40 to 120 mg daily doses of duloxetine (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015; Schatzberg, 2003; Sharma et al, 2000).
    2) WITH POISONING/EXPOSURE
    a) Hypertension may occur as an overdose effect in patients taking duloxetine either alone or in combination with other drugs (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015).
    b) ADOLESCENT: An adolescent patient developed hypertension, tachycardia, moderate headache, and diaphoresis after intentionally ingesting 520 mg duloxetine. The patient recovered following observation (Darracq et al, 2013).
    c) In a retrospective review of duloxetine ingestions, as single agent exposures, reported to a poison control center system from 2004 to 2011, hypertension (systolic blood pressure greater than 150 mmHg) was reported in 6 of 27 adult patients with a self-harm ingestion. The median amount ingested was 1030 mg (range, 60 to 2000 mg) (Darracq et al, 2013).
    C) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypotension may occur as an overdose effect in patients taking duloxetine either alone or in combination with other drugs (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015).
    D) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Small increases in heart rate are rare occurrences with duloxetine therapy (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015; Goldstein et al, 2004; Chalon et al, 2003).
    2) WITH POISONING/EXPOSURE
    a) Tachycardia may occur as an overdose effect in patients taking duloxetine either alone or in combination with other drugs (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015).
    b) ADOLESCENT: An adolescent patient developed hypertension, tachycardia, moderate headache, and diaphoresis after intentionally ingesting 520 mg duloxetine. The patient recovered following observation (Darracq et al, 2013).
    c) In a retrospective review of duloxetine ingestions, as single agent exposures, reported to a poison control center system from 2004 to 2011, tachycardia (heart rate greater than 110 beats/minute) was reported in 3 of 27 adult self-harm ingestions. The median amount ingested was 1030 mg (range, 60 to 2000 mg) (Darracq et al, 2013).
    E) SUPRAVENTRICULAR ARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) Supraventricular arrhythmia has been reported in postmarketing reports; however, a casual relationship to drug exposure has not been established (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PULMONARY EMBOLISM
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 75-year-old woman was found dead in her apartment following a suspected overdose ingestion of duloxetine (24 60-mg capsules). A post-mortem examination, performed 1 day later, attributed the cause of death due to a massive pulmonary embolism that the coroner postulated to be secondary to duloxetine intoxication (Mari et al, 2012).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) COMA
    1) WITH POISONING/EXPOSURE
    a) Coma may occur as an overdose effect in patients taking duloxetine either alone or in combination with other drugs (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015).
    B) EXTRAPYRAMIDAL DISEASE
    1) WITH THERAPEUTIC USE
    a) Extrapyramidal disorder has been reported in postmarketing reports; however, casual relationship with drug exposure has not been established (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015).
    C) FATIGUE
    1) WITH THERAPEUTIC USE
    a) Fatigue has been reported frequently with duloxetine use. In pooled data from placebo-controlled clinical trials involving duloxetine-treated patients, fatigue (including asthenia) was reported in 9% of patients in the treatment group (n=8100) compared with 5% in patients taking placebo (n=5655) (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015).
    D) HALLUCINATIONS
    1) WITH THERAPEUTIC USE
    a) Hallucinations have been reported in postmarketing reports; however, a casual relationship with drug exposure has not been established (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015).
    E) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headaches have frequently occurred with therapeutic administration of duloxetine and appear to be a common reason for discontinuation of therapy (Millard et al, 2004; Huffman & Perlis, 2003; Zinner, 2003).
    b) In the premarketing acute phase of fibromyalgia placebo-controlled trials, incidence of headache reported in duloxetine-treated patients (n=876) was 20% compared with 12% in patients treated with placebo (n=535) (Prod Info Cymbalta(R) delayed-release oral capsules, 2010).
    c) Headaches occurred in 30.4% of patients (n=1279) who were taking duloxetine 40 mg twice daily to 60 mg twice daily for up to 1 year during an open-label clinical trial (Raskin et al, 2003). According to one study, headaches appeared to be more prevalent in patients younger than 65 years of age (10.6%) as compared with patients 65 years of age or older (5%) (Skinner et al, 2003).
    2) WITH POISONING/EXPOSURE
    a) ADOLESCENT: An adolescent patient developed hypertension, tachycardia, moderate headache, and diaphoresis after intentionally ingesting 520 mg duloxetine. The patient recovered following observation (Darracq et al, 2013).
    b) In a retrospective review of duloxetine ingestions, as single agent exposures, reported to a poison control center system from 2004 to 2011, headache was reported in 1 of 27 adult self-harm ingestions. The median amount ingested was 1030 mg (range, 60 to 2000 mg) (Darracq et al, 2013).
    F) DROWSY
    1) WITH THERAPEUTIC USE
    a) Somnolence has been reported in several patients who were receiving duloxetine therapy. In pooled data from placebo-controlled clinical trials involving duloxetine-treated patients, somnolence was reported in 10% of patients in the treatment group (n=8100) compared with 3% in patients receiving placebo (n=5655)(Prod Info CYMBALTA(R) oral delayed-release capsules, 2015; Huffman & Perlis, 2003) and, according to one study, appeared to be more prevalent in patients 65 years of age and older (8.3%) as compared with patients younger than 65 years of age (1.9%) (Skinner et al, 2003).
    2) WITH POISONING/EXPOSURE
    a) Somnolence may occur as an overdose effect in patients taking duloxetine either alone or in combination with other drugs (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015).
    b) ADOLESCENT: Mild drowsiness was reported in an adolescent following an intentional ingestion of 720 mg duloxetine. The patient recovered within 2 hours following emergency department presentation (Darracq et al, 2013).
    1) INFANT: Drowsiness was also reported in a 1-year-old child following an unintentional duloxetine ingestion (7.4 mg/kg). The drowsiness resolved within 2 hours postingestion (Darracq et al, 2013).
    c) In a retrospective review of duloxetine ingestions, as single agent exposures, reported to a poison control center system from 2004 to 2011, drowsiness was reported in 9 of 27 adult self-harm ingestions. The median amount ingested was 1030 mg (range, 60 to 2000 mg) (Darracq et al, 2013).
    G) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness has been reported frequently with duloxetine therapy and has resulted in discontinuation of therapy in several patients (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015; Millard et al, 2004).
    H) FEELING AGITATED
    1) WITH POISONING/EXPOSURE
    a) In a retrospective review of duloxetine ingestions, as single agent exposures, reported to a poison control center system from 2004 to 2011, agitation and confusion were reported in 1 and 3 adults (n=27), respectively, following self-harm ingestions. The median amount ingested was 1030 mg (range 60 to 2000 mg) (Darracq et al, 2013).
    I) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) Insomnia has been reported as a common adverse effect following therapeutic administration of duloxetine. In pooled data from placebo-controlled clinical trials involving duloxetine-treated patients, insomnia was reported in 11% of patients in the treatment group (n=4843) compared with 6% in patients receiving placebo (n=3048)(Millard et al, 2004; Goldstein et al, 2004; Huffman & Perlis, 2003).
    J) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) During a randomized placebo-controlled duloxetine clinical trial, paresthesias were reported in 11.3% of patients (n=91) as an adverse effect that occurred after discontinuation of duloxetine therapy (80 mg daily) (Goldstein et al, 2004).
    K) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Seizures may occur as an overdose effect in patients taking duloxetine either alone or in combination with other drugs (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015).
    b) A single tonic-clonic seizure occurred in a 31-year-old woman who intentionally ingested an unknown amount of duloxetine. The patient was also confused and hypertensive (157/91 mmHg). The patient recovered with supportive care (Darracq et al, 2013).
    L) SYNCOPE
    1) WITH POISONING/EXPOSURE
    a) Syncope may occur as an overdose effect in patients taking duloxetine either alone or in combination with other drugs (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015).
    M) DELIRIUM
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 30-year-old woman who ingested 1680 mg of duloxetine with other substances (380 mg pipamperone and 250 mg of amitriptyline) developed delirium, agitation and hallucinations. She recovered within 24 hours following supportive care (Paulzen et al, 2009).
    N) SEROTONIN SYNDROME
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 70-year-old woman who was taking lithium carbonate developed serotonin syndrome after taking duloxetine 60 mg/day for 2 days. Medications prior to duloxetine treatment included sertraline, ziprasidone, sodium valproate, and escitalopram. She experienced marked tremors, agitation, hypertonia, hyperreflexia and diaphoresis. Following the discontinuation of duloxetine, her symptoms rapidly resolved over the next 24 hours. The patient was rechallenged with duloxetine and redeveloped symptoms after one dose (Hadikusumo & Ng, 2009)
    2) WITH POISONING/EXPOSURE
    a) Serotonin syndrome may occur as an overdose effect in patients taking duloxetine either alone or in combination with other drugs (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH POISONING/EXPOSURE
    a) Vomiting may occur as an overdose effect in patients taking duloxetine either alone or in combination with other drugs (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015).
    b) In a retrospective review of duloxetine ingestions, as single agent exposures, reported to a poison control center system from 2004 to 2011, vomiting was reported in 4 of 27 adult self-harm ingestions. The median amount ingested was 1030 mg (range, 60 to 2000 mg) (Darracq et al, 2013).
    B) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Nausea is the most commonly occurring adverse effect with duloxetine therapy and has frequently resulted in discontinuation of therapy. It generally occurs early following initiation of duloxetine therapy, is mild to moderate in severity, and typically resolves within one week to one month of therapy in the majority of cases (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015; van Kerrebroeck, 2004; van Kerrebroeck et al, 2004; Moore, 2004; Mallinckrodt et al, 2003; Nemeroff et al, 2002).
    b) In pooled data from placebo-controlled clinical trials involving duloxetine-treated patients, nausea was reported in 23% of patients in the treatment group (n=8100), compared with 8% in patients receiving placebo (n=5655) (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015).
    2) WITH POISONING/EXPOSURE
    a) In a retrospective review of duloxetine ingestions, as single agent exposures, reported to a poison control center system from 2004 to 2011, nausea was reported in 3 of 27 adult self-harm ingestions. The median amount ingested was 1030 mg (range, 60 to 2000 mg) (Darracq et al, 2013).
    C) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation is a frequent occurrence with duloxetine therapy. In pooled data from placebo-controlled clinical trials involving duloxetine-treated patients, constipation was reported in 9% of patients in the treatment group (n=8100) compared with 4% in patients receiving placebo (n=5655)(Prod Info CYMBALTA(R) oral delayed-release capsules, 2015; Millard et al, 2004; Raskin et al, 2003).
    D) APTYALISM
    1) WITH THERAPEUTIC USE
    a) Dry mouth has been reported frequently with duloxetine therapy. In pooled data from placebo-controlled clinical trials involving duloxetine-treated patients, dry mouth was reported in 13% of patients in the treatment group (n=8100) compared with 5% in patients receiving placebo (n=5655) (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015; Millard et al, 2004; Huffman & Perlis, 2003) and, according to one study, appeared to be more prevalent in patients 65 years of age and older (11.7%) as compared with patients younger than 65 years of age (5%) (Skinner et al, 2003).
    E) ABDOMINAL PAIN
    1) WITH POISONING/EXPOSURE
    a) In a retrospective review of duloxetine ingestions, as single agent exposures, reported to a poison control center system from 2004 to 2011, abdominal pain was reported in 2 of 27 adult self-harm ingestions. The median amount ingested was 1030 mg (range, 60 to 2000 mg) (Darracq et al, 2013).
    F) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) In a retrospective review of duloxetine ingestions, as single agent exposures, reported to a poison control center system from 2004 to 2011, diarrhea was reported in 1 of 27 adult self-harm ingestions. The median amount ingested was 1030 mg (range, 60 to 2000 mg) (Darracq et al, 2013).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ABNORMAL LIVER FUNCTION
    1) WITH THERAPEUTIC USE
    a) Transient elevations of hepatic enzyme levels are uncommon occurrences with duloxetine therapy (Millard et al, 2004; Karpa et al, 2002).
    b) During randomized controlled trials for determining duloxetine's efficacy in the treatment of major depressive disorder, elevations of alanine transaminase (ALT) levels of greater than 3 times the upper limit of normal (ULN) occurred in 8 of 930 duloxetine-treated patients (0.9%) as compared with 2 of 652 placebo-treated patients (0.3%). During randomized controlled trials for determining duloxetine's efficacy in the management of diabetic peripheral neuropathy, elevations of ALT levels greater than 3 times the ULN occurred in 8 of 477 duloxetine -treated patients (1.68%) as compared with none of the placebo-treated patients (Prod Info Cymbalta(R) delayed-release oral capsules, 2010).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) MICTURITION
    1) WITH THERAPEUTIC USE
    a) Two patients reported difficulty in micturition within 3 days of beginning combined duloxetine and tolterodine therapy, during a double-blind, randomized, crossover study (Hua et al, 2004).
    B) RETENTION OF URINE
    1) WITH THERAPEUTIC USE
    a) Urinary retention or other obstructive voiding symptoms have been reported in 20 of 2097 patients (1%) who received duloxetine therapy during placebo-controlled clinical studies as compared with 6 of 1732 patients (0.4%) who received a placebo. The majority of patients reported the urinary retention within 2 weeks of starting duloxetine therapy, with a duration of a few days to several months (Viktrup et al, 2004). Some of the patients were also taking concomitant medications which may have contributed to the development of urinary retention.
    C) ABNORMAL SEXUAL FUNCTION
    1) WITH THERAPEUTIC USE
    a) Male sexual dysfunction, including decreased libido, ejaculation failure, and erectile dysfunction, has been reported as a rare occurrence with duloxetine therapy (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015; Raskin et al, 2003).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERYTHEMA MULTIFORME
    1) WITH THERAPEUTIC USE
    a) Erythema multiforme has been reported in post marketing reports; however, a casual relationship with drug exposure has not been established (Prod Info Cymbalta(R) delayed-release oral capsules, 2010).
    B) EXCESSIVE SWEATING
    1) WITH THERAPEUTIC USE
    a) Hyperhidrosis has been reported in several patients following therapeutic administration of duloxetine (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015; Goldstein et al, 2004).
    2) WITH POISONING/EXPOSURE
    a) ADOLESCENT: An adolescent patient developed hypertension, tachycardia, moderate headache, and diaphoresis after intentionally ingesting 520 mg duloxetine. The patient recovered following observation (Darracq et al, 2013).
    C) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) Stevens-Johnson Syndrome that required hospitalization and discontinuation has been reported with duloxetine use in postmarketing reports; however, a causal relationship between with drug exposure has not been established (Prod Info Cymbalta(R) delayed-release oral capsules, 2010).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) Asthenia has been reported with duloxetine therapy (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015; Huffman & Perlis, 2003).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLAXIS
    1) WITH THERAPEUTIC USE
    a) Anaphylaxis has been reported in postmarketing reports (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015).

Reproductive

    3.20.1) SUMMARY
    A) Duloxetine is classified as FDA pregnancy category C. Although human and animal data of duloxetine use during pregnancy did not reveal substantial teratogenicity, nonteratogenic effects (pulmonary hypertension of the newborn and clinical findings consistent with serotonin syndrome), and increased special or intensive unit care of the infant were demonstrated following maternal use of serotonin and norepinephrine reuptake inhibitors (SNRIs) or SSRIs during the third trimester of pregnancy. Duloxetine is excreted in human breast milk.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) In a prospective, observational, multicenter, cohort study (n=624), the rate of major malformations among duloxetine-exposed offspring was similar to that of women in 2 control groups with no duloxetine exposure during pregnancy (p=.992). Incidence of major malformations (ie, clubfoot, kidney agenesis, hydronephrosis) was 1.8% among 165 duloxetine-exposed infants . Most women (99%) received duloxetine before pregnancy and continued treatment through early pregnancy (n=206), with 74.5% of women discontinuing duloxetine treatment by the end of the first trimester (n=155); 24.5% of women continued duloxetine therapy throughout pregnancy (n=51); and 1% of women only received duloxetine during the second or third trimester (n=2) (Einarson et al, 2012).
    B) ANIMAL STUDIES
    1) RATS, RABBITS: There was no evidence of teratogenicity when duloxetine was administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 45 mg/kg/day (4 times and 7 times the maximum recommended human dose (MRHD) of 120 mg/day on a mg/m(2) basis for rats and rabbits, respectively), although fetal weights were decreased (Prod Info CYMBALTA(R) oral delayed-release capsules, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified duloxetine as an FDA pregnancy category C (Prod Info CYMBALTA(R) oral delayed-release capsules, 2014).
    2) Due to the lack of adequate, well-controlled studies in pregnant women, it is recommended that duloxetine be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. Because adverse serotonergic-like effects have been reported in SSRI- and SNRI-exposed neonates late in the third trimester, the potential risks and benefits of duloxetine therapy during this time should be taken into account. The manufacturer has established a pregnancy registry to evaluate safety outcomes of women who become pregnant while receiving duloxetine. Healthcare providers are encouraged to register their patients by contacting the registry at 1-866-814-6975 or by visiting www.cymbaltapregnancyregistry.com (Prod Info CYMBALTA(R) oral delayed-release capsules, 2014).
    B) NEONATAL COMPLICATIONS
    1) A full-term infant developed neonatal withdrawal syndrome following prenatal exposure to duloxetine 90 mg/day, lamotrigine 100 mg/day, and quetiapine 200 mg 4 times daily throughout the pregnancy. Jitteriness and uncoordinated suckling and swallowing during bottle-feeding manifested within 36 hours of birth. Blood glucose levels and CBCs were normal; a toxicology screen was negative. The infant also received 24 hours of phototherapy for unconjugated hyperbilirubinemia at 2 days of age. Neonatal withdrawal scores ranged from 5 to 7 up to age 5 days as symptoms progressed to tremors, hyperreflexia, spasticity, tachypnea, and irritability, accompanied by a 17% loss of birth weight. Feeding difficulties gradually resolved following 2 weeks of care in the neonatal intensive care unit, and she was discharged at 23 days of age. Growth and development were normal at followup at age 3 (Abdy & Gerhart, 2013).
    2) Exposure to SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs) during the third trimester of pregnancy has resulted in a variety of neonatal complications, including respiratory distress, cyanosis, apnea, seizures, vomiting, hypoglycemia, hypotonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These complications appear to be consistent with either a direct toxic effect of the SSRI or SNRI or as a result of a drug discontinuation syndrome. In some cases, clinical findings have been consistent with serotonin syndrome (Prod Info CYMBALTA(R) oral delayed-release capsules, 2014).
    C) ANIMAL STUDIES
    1) RATS, RABBITS: When pregnant rats were treated with duloxetine 30 mg/kg/day (2 times the MRHD) throughout gestation and lactation, pup weights decreased, and the incidence of stillborn pups and pup mortality increased. Maternal exposure to 30 mg/kg/day also increased rat pup reactivity (increased startle response to noise and decreased habituation of locomotor activity) (Prod Info CYMBALTA(R) oral delayed-release capsules, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Duloxetine was found in human breast milk during a study of 6 lactating women (ranging in age from 22 to 35 years old; at least 12 weeks postpartum) who received duloxetine 40 mg twice daily for 3.5 days. Duloxetine levels in breast milk were approximately 7 mcg/day (Prod Info CYMBALTA(R) oral delayed-release capsules, 2014) (range, 4 to 15 mcg/day). The estimated daily infant dose was 2 mcg/kg/day (range, 0.6 to 3 mcg/kg/day), which was approximately 0.14% (maximum 0.25%) of the maternal dose. The mean steady-state milk-to-plasma exposure ratio for duloxetine was 0.25 (95% CI, 0.18 to 0.35). Excretion of duloxetine metabolites into breast milk was not evaluated (Lobo et al, 2008)
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) Duloxetine did not alter mating or fertility in male or female rats given oral doses up to 45 mg/kg/day (4 times the MRHD on a mg/m(2) basis) prior to and throughout mating (Prod Info CYMBALTA(R) oral delayed-release capsules, 2014).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS116539-59-4 (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
    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) Administration of duloxetine to female mice at a dose of 140 mg/kg/day (11 times the maximum recommended human dose [MHRD, 60 mg/day] and 6 times the human dose of 120 mg/day on a mg/m(2) basis) for 2 years resulted in an increased incidence of hepatocellular adenomas and carcinomas (Prod Info Cymbalta(R), 2004).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs (including temperature) and mental status.
    B) Monitor serum electrolytes (including potassium, bicarbonate) following significant overdose.
    C) Obtain baseline ECG, continuous cardiac monitoring, and serial ECGs following a significant exposure.
    D) Plasma concentration is not readily available and does not correlate well with therapeutic or adverse effects.
    E) Monitor liver enzyme concentrations in symptomatic patients.

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 with severe toxicity need to be admitted to an intensive care unit.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic children with acute inadvertent ingestions may be monitored at home. Asymptomatic patients or those with mild toxicity following an isolated unintentional acute ingestion of up to 5 times an initial adult therapeutic dose (ie, duloxetine 150 mg) can be observed at home with instructions to call the poison center back if symptoms develop. For patients already on duloxetine with ingestions of up to 5 times their own single therapeutic dose can be observed at home with instructions to call the poison center back if symptoms develop (Nelson et al, 2007).
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or it the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Symptomatic patients, those with deliberate ingestions, and those with ingestions of more than 5 times their therapeutic dose should be evaluated in a healthcare facility and observed for 6 to 12 hours.

Monitoring

    A) Monitor vital signs (including temperature) and mental status.
    B) Monitor serum electrolytes (including potassium, bicarbonate) following significant overdose.
    C) Obtain baseline ECG, continuous cardiac monitoring, and serial ECGs following a significant exposure.
    D) Plasma concentration is not readily available and does not correlate well with therapeutic or adverse effects.
    E) Monitor liver enzyme concentrations in symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    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).
    6.5.2) 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) MONITORING OF PATIENT
    1) Monitor vital signs (including temperature) and mental status.
    2) Monitor serum electrolytes (including potassium, bicarbonate) following significant overdose.
    3) Obtain baseline ECG, continuous cardiac monitoring, and serial ECGs following a significant exposure.
    4) Plasma concentration is not readily available and does not correlate well with therapeutic or adverse effects.
    5) Monitor liver enzyme concentrations in symptomatic patients.
    B) SUPPORT
    1) In case of duloxetine overdose, treatment should be SYMPTOMATIC and SUPPORTIVE.
    C) SEROTONIN SYNDROME
    1) SUMMARY
    a) Benzodiazepines are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, is also commonly used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents(Claassen & Gelissen, 2005).
    2) HYPERTHERMIA
    a) Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
    b) MUSCLE ACTIVITY: Benzodiazepines are the drug of choice to control agitation and muscle activity. DIAZEPAM: ADULT: 5 to 10 mg IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. CHILD: 0.25 mg/kg IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
    c) Non-depolarizing paralytics may be used in severe cases.
    3) CYPROHEPTADINE
    a) Cyproheptadine is a non-specific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Goldberg & Huk, 1992). There are no controlled human trials substantiating its efficacy.
    b) ADULT: 12 mg initially followed by 2 mg every 2 hours if symptoms persist, up to a maximum of 32 mg in 24 hours. Maintenance dose 8 mg orally repeated every 6 hours (Boyer & Shannon, 2005).
    c) CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day (Mills, 1997).
    4) HYPERTENSION
    a) Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is usually not necessary.
    5) HYPOTENSION
    a) Administer 10 to 20 mL/kg 0.9% saline bolus and place patient supine. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
    b) Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution. Direct acting agents (norepinephrine, epinephrine, phentolamine) are theoretically preferred.
    c) NOREPINEPHRINE
    1) PREPARATION: Add 4 mL of 0.1% solution to 1000 mL of dextrose 5% in water to produce 4 mcg/mL.
    2) INITIAL DOSE
    a) ADULT: 2 to 3 mL (8 to 12 mcg)/minute.
    b) ADULT or CHILD: 0.1 to 0.2 mcg/kg/min. Titrate to maintain adequate blood pressure.
    3) MAINTENANCE DOSE
    a) 0.5 to 1 mL (2 to 4 mcg)/minute.
    6) SEIZURES
    a) DIAZEPAM
    1) MAXIMUM RATE: Administer diazepam IV over 2 to 3 minutes (maximum rate: 5 mg/min).
    2) ADULT DIAZEPAM DOSE: 5 to 10 mg initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
    3) PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 mg/kg, repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
    4) RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (not FDA approved), or lorazepam may be given intramuscularly.
    b) LORAZEPAM
    1) MAXIMUM RATE: The rate of IV administration of lorazepam should not exceed 2 mg/min (Prod Info Ativan(R), 1991).
    2) ADULT LORAZEPAM DOSE: 2 to 4 mg IV. Initial doses may be repeated in 10 to 15 minutes, if seizures persist (Prod Info ATIVAN(R) injection, 2003).
    3) PEDIATRIC LORAZEPAM DOSE: 0.1 mg/kg IV push (range: 0.05 to 0.1 mg/kg; maximum dose 4 mg); may repeat dose in 5 to 10 minutes if seizures continue. It has also been given rectally at the same dose in children with no IV access (Sreenath et al, 2010; Chin et al, 2008; Wheless, 2004; Qureshi et al, 2002; De Negri & Baglietto, 2001; Mitchell, 1996; Appleton, 1995; Giang & McBride, 1988).
    c) RECURRING SEIZURES
    1) If seizures cannot be controlled with diazepam or recur, give phenobarbital or propofol.
    d) PHENOBARBITAL
    1) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 mcg/mL).
    2) ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 mg of phenobarbital IV initially (10 to 20 mg/kg) diluted in 60 mL of 0.9% saline given at 25 to 50 mg/minute.
    3) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 mg may be given every 20 minutes.
    4) MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 mg/min until seizure control was achieved or a total dose of 10 mg/kg.
    5) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 mg/kg of phenobarbital intravenously at a rate of 25 to 50 mg/min.
    6) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 mg/kg may be given every 20 minutes.
    7) MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 mg/kg within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
    8) NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 mg/kg IV at a rate of no more than 1 mg/kg/min in patients with no preexisting phenobarbital serum levels.
    9) NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 mg/kg every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 mcg/mL.
    10) MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 mg/kg/min up to a total of 30 mg/kg have been tolerated in neonates.
    11) CAUTION: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.
    7) CHLORPROMAZINE
    a) Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Controlled human trial documenting its efficacy are lacking.
    b) ADULT: 25 to 100 mg intramuscularly repeated in 1 hour if necessary.
    c) CHILD: 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours not to exceed 2 mg/kg/day.
    8) NOT RECOMMENDED
    a) BROMOCRIPTINE: It has been used in the treatment of neuroleptic malignant syndrome but is NOT RECOMMENDED in the treatment of serotonin syndrome as it has serotonergic effects (Gillman, 1997). In one case the use of bromocriptine was associated with a fatal outcome (Kline et al, 1989).

Enhanced Elimination

    A) LACK OF EFFECT
    1) Due to the high percentage of duloxetine that is protein bound and its large volume of distribution, it is unlikely that any enhanced elimination techniques, including forced diuresis, dialysis and hemoperfusion, will be of any benefit (Prod Info Cymbalta(R) oral delayed-release capsules, 2011).

Range Of Toxicity

Summary

    A) TOXICITY: Death has been reported following ingestions of duloxetine doses as low as 1000 mg. In premarketing clinical trials, four patients recovered following acute ingestions of 300 to 1400 mg of duloxetine, as either sole therapy or in combination with other drugs. Somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting have been reported in patients taking duloxetine (alone or with mixed drugs) doses as low as 1000 mg. INFANT: Drowsiness was the only reported symptom in a 1-year-old child following an unintentional duloxetine ingestion of 7.4 mg/kg.
    B) THERAPEUTIC DOSE: The recommended dosage range for duloxetine is 30 to 120 mg daily.

Therapeutic Dose

    7.2.1) ADULT
    A) DIABETIC PERIPHERAL NEUROPATHIC PAIN
    1) Recommended dose is 60 mg orally once daily; MAXIMUM DOSE: 60 mg daily (Prod Info CYMBALTA(R) oral delayed-release capsules, 2014).
    B) FIBROMYALGIA
    1) Recommended dose is 30 to 60 mg orally once daily; MAXIMUM DOSE: 60 mg daily (Prod Info CYMBALTA(R) oral delayed-release capsules, 2014).
    C) GENERALIZED ANXIETY DISORDER
    1) Initially, 30 to 60 mg orally once daily. If adjustment is required, may increase by increments of 30 mg once daily, with a MAX dose of 120 mg once daily (Prod Info CYMBALTA(R) oral delayed-release capsules, 2014).
    D) MAJOR DEPRESSIVE DISORDER
    1) Recommended dose is 40 mg/day orally (20 mg twice daily) to 60 mg/day orally (once daily or 30 mg twice daily) ; MAXIMUM DOSE: 120 mg daily (Prod Info CYMBALTA(R) oral delayed-release capsules, 2014).
    7.2.2) PEDIATRIC
    A) GENERALIZED ANXIETY DISORDER
    1) 7 YEARS OF AGE OR OLDER: Initially, 30 mg orally once daily for 2 weeks, and then may increase to 60 mg orally once daily. If further adjustment is required, may increase by increments of 30 mg once daily, with a MAX dose of 120 mg once daily (Prod Info CYMBALTA(R) oral delayed-release capsules, 2014).

Minimum Lethal Exposure

    A) ADULTS
    1) Death has been reported following ingestions of duloxetine, either alone in combination with other drugs, at doses as low as 1000 mg (Prod Info CYMBALTA(R) oral delayed-release capsules, 2015).

Maximum Tolerated Exposure

    A) INFANT
    1) INFANT: Drowsiness was reported in a 1-year-old child following an unintentional duloxetine ingestion (7.4 mg/kg). The drowsiness resolved within 2 hours postingestion (Darracq et al, 2013).
    B) ADOLESCENTS
    1) A retrospective analysis of duloxetine ingestions reported to a poison control center database from 2004 to 2011, as single agent exposures, was conducted. Of the 106 duloxetine only ingestions included in the analysis, 8 cases were intentional adolescent ingestions (median age 16 years [range 14 to 18 years]). The following signs and symptoms were reported: drowsiness, agitation, headache, diaphoresis, hypertension (systolic blood pressure greater than 150 mmHg), and tachycardia (heart rate greater than 110 beats/minute). Median duloxetine amount ingested was 720 mg (range, 240 to 1200 mg) (Darracq et al, 2013).
    C) ADULTS
    1) In premarketing clinical trials, four patients recovered following acute ingestions of 300 to 1400 mg of duloxetine, as either sole therapy or in combination with other drugs(Prod Info Cymbalta(R), 2004).
    2) CASE REPORT: A 30-year-old woman who ingested 1680 mg of duloxetine with other substances (380 mg pipamperone and 250 mg of amitriptyline) developed delirium, agitation and hallucinations. She recovered within 24 hours following supportive care (Paulzen et al, 2009).
    3) A retrospective analysis of duloxetine ingestions reported to a poison control center database from 2004 to 2011, as single agent exposures, was conducted. Of the 106 duloxetine only ingestions included in the analysis, 27 cases were adult self-harm ingestions (median age 47 years [range 25 to 69 years]). The following signs and symptoms were reported: nausea, vomiting, abdominal pain, diarrhea, drowsiness, agitation, confusion, seizure, headache, hypertension (systolic blood pressure greater than 150 mmHg), and tachycardia (heart rate greater than 110 beats/minute). Median duloxetine amount ingested was 1030 mg (range, 60 to 2000 mg) (Darracq et al, 2013).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORT: A 30-year-old woman who ingested 1680 mg of duloxetine with other substances (380 mg pipamperone and 250 mg of amitriptyline), had duloxetine concentrations of greater than 2000 ng/mL (therapeutic range, 20 to 80 ng/mL) and a cerebrospinal fluid (CSF) level of 15 ng/mL (the ratio between plasma and CSF levels, greater than 130), measured about 20 hours after ingestion. She recovered following supportive care (Paulzen et al, 2009)

Workplace Standards

    A) ACGIH TLV Values for CAS116539-59-4 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS116539-59-4 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS116539-59-4 :
    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

    D) OSHA PEL Values for CAS116539-59-4 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Duloxetine is a dual-selective serotonin (5HT) and norepinephrine reuptake inhibitor. It is the (+) isomer of the racemic compound and bears structural similarity to fluoxetine (Wong et al, 1993). In vitro, duloxetine has not shown significant affinity for histamine H1, dopamine D2, cholinergic, alpha-1 adrenergic, 5HT-1A, 5HT-1B, 5HT-1D, 5HT-2A, 5HT-2C, or opioid receptors (Schatzberg, 2003; Goodnick, 1999; Artigas, 1995; Wong et al, 1993).
    B) Duloxetine has increased neural sphincter activity and bladder capacity in animal studies (Karpa et al, 2002; Andersson et al, 1999; Voelker, 1998). It is believed that duloxetine's inhibition of the re-uptake of 5-HT and norepinephrine at the sacral spinal cord of the CNS may increase the urethral closure pressure and, thereby, reduce or prevent the occurrence of stress urinary incontinence (Zinner, 2003).

Physicochemical

Physical Characteristics

    A) Duloxetine hydrochloride is a white to slightly brownish white solid, and is slightly soluble in water (Prod Info Cymbalta(R), 2004).

Molecular Weight

    A) 333.88 (Prod Info Cymbalta(R), 2004)

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) Abdy NA & Gerhart K: Duloxetine withdrawal syndrome in a newborn. Clin Pediatr (Phila) 2013; 52(10):976-977.
    14) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    15) 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.
    16) Andersson K-E, Appell R, Cardozo LD, et al: The pharmacological treatment of urinary incontinence. BJU Intl 1999; 84:923-947.
    17) Appleton R: Lorazepam vs diazepam in the acute treatment of epileptic seizures and status epilepticus.. Dev Med Child Neuro 1995; 37:682-688.
    18) Artigas F: Selective serotonin/noradrenaline reuptake inhibitors (SNRIs). CNS Drugs 1995; 4(2):79-89.
    19) Boyer EW & Shannon M: The serotonin syndrome. N Eng J Med 2005; 352(11):1112-1120.
    20) Chalon SA, Granier L-A, Vandenhende FR, et al: Duloxetine increases serotonin and norepinephrine availability in healthy subjects: a double-blind, controlled study. Neuropsychopharmacol 2003; 28:1685-1693.
    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) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    23) Claassen JAHR & Gelissen HPMM: The serotonin syndrome (letter). N Eng J Med 2005; 352(23):2455.
    24) 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.
    25) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    26) Darracq MA, Clark A, Qian L, et al: A retrospective review of isolated duloxetine-exposure cases. Clin Toxicol (Phila) 2013; 51(2):106-110.
    27) De Negri M & Baglietto MG: Treatment of status epilepticus in children. Paediatr Drugs 2001; 3(6):411-420.
    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) Einarson A, Smart K, Vial T, et al: Rates of major malformations in infants following exposure to duloxetine during pregnancy: a preliminary report. J Clin Psychiatry 2012; 73(11):1471-1471.
    30) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    31) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    32) Giang DW & McBride MC : Lorazepam versus diazepam for the treatment of status epilepticus. Pediatr Neurol 1988; 4(6):358-361.
    33) Gillman PK: Ecstasy, serotonin syndrome and the treatment of hyperpyrexia (letter). MJA 1997; 167:109-111.
    34) Gillman PK: Successful treatment of serotonin syndrome with chlorpromazine (letter). MJA 1996; 165:345.
    35) Goldberg RJ & Huk M: Serotonin syndrome from trazodone and buspirone (letter). Psychosomatics 1992; 33:235-236.
    36) Goldstein DJ, Lu Y, Detke MJ, et al: Duloxetine in the treatment of depression: a double-blind placebo-controlled comparison with paroxetine. J Clin Psychopharmacol 2004; 24:389-399.
    37) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    38) Goodnick PJ: Psychopharmacology of depression in the next millenium. CNS Spectrums 1999; 4(7):21-35.
    39) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    40) Graham PM: Successful treatment of the toxic serotonin syndrome with chlorpromazine (letter). Med J Australia 1997; 166:166-167.
    41) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    42) Hadikusumo B & Ng B: Serotonin syndrome induced by duloxetine. Aust N Z J Psychiatry 2009; 43(6):581-582.
    43) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    44) Hirschfeld RMA & Vornik LA: Newer antidepressants: review of efficacy and safety of escitalopram and duloxetine. J Clin Psychiatry 2004; 65 (suppl 4):46-52.
    45) Hua TC, Pan A, Chan C, et al: Effect of duloxetine on tolterodine pharmacokinetics in healthy volunteers. Br J Clin Pharmacol 2004; 57:652-656.
    46) Huffman JC & Perlis RH: The development of new antidepressants: focus on duloxetine and escitalopram. Harv Rev Psychiatry 2003; 11:30-36.
    47) 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.
    48) 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.
    49) 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.
    50) 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.
    51) 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.
    52) 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.
    53) 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.
    54) 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.
    55) Johnson JT, DeLong AF, Oldham SW, et al: Disposition of 14C duloxetine after oral administration in man. Pharmaceut Res 1995; 12(suppl 387):387.
    56) Karpa KD, Cavanaugh JE, & Lakoski JM: Duloxetine pharmacology: profile of a dual monoamine modulator. CNS Drug Rev 2002; 8:361-376.
    57) Kline SS, Mauro LS, & Scala-Barnett DM: Serotonin syndrome versus neuroleptic malignant syndrome as a cause of death. Clin Pharmac 1989; 8:510-514.
    58) Kruger S & Lindstaedt M: Duloxetine and hyponatremia: a report of 5 cases. J Clin Psychopharmacol 2007; 27(1):101-104.
    59) Kuo F, Gillespie TA, Kulanthaivel P, et al: Synthesis and biological activity of some known and putative duloxetine metabolites. Bioorgan Med Chem Let 2004; 14:3481-3486.
    60) Lantz RJ, Gillespie TA, Rash TJ, et al: Metabolism, excretion, and pharmacokinetics of duloxetine in healthy human subjects. Drug Metab Dispos 2003; 31:1142-1150.
    61) Lobo ED, Loghin C, Knadler MP, et al: Pharmacokinetics of duloxetine in breast milk and plasma of healthy postpartum women. Clin Pharmacokinet 2008; 47(2):103-109.
    62) Mallinckrodt CH, Goldstein DJ, Detke MJ, et al: Duloxetine: a new treatment for the emotional and physical symptoms of depression. Prim Care Comp/J Clin Psychiatry 2003; 5:19-28.
    63) Maramattom BV: Duloxetine-induced syndrome of inappropriate antidiuretic hormone secretion and seizures. Neurology 2006; 66(5):773-774.
    64) Mari F, Gualco B, Rensi R, et al: Acute massive pulmonary thromboembolism due to acute intoxication by duloxetine: a case report. Cardiovasc Toxicol 2012; 12(3):258-262.
    65) Millard RJ, Moore K, Rencken R, et al: Duloxetine vs placebo in the treatment of stress urinary incontinence: a four-continent randomized clinical trial. BJU Intl 2004; 93:311-318.
    66) Mills KC: Serotonin syndrome: a clinical update. Med Toxicol 1997; 13:763-783.
    67) Mitchell WG: Status epilepticus and acute repetitive seizures in children, adolescents, and young adults: etiology, outcome, and treatment. Epilepsia 1996; 37(S1):S74-S80.
    68) Moore K: Duloxetine: a new approach for treating stress urinary incontinence. Intl J Gynecol Obstet 2004; 86 (Suppl 1):S53-S62.
    69) NFPA: Fire Protection Guide to Hazardous Materials, 13th ed., National Fire Protection Association, Quincy, MA, 2002.
    70) 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.
    71) 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.
    72) 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.
    73) 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.
    74) 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.
    75) 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.
    76) 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.
    77) 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.
    78) 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.
    79) 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.
    80) 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.
    81) 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.
    82) 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.
    83) 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.
    84) 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.
    85) 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.
    86) 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.
    87) 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.
    88) 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.
    89) 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.
    90) 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.
    91) 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.
    92) 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.
    93) 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.
    94) 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.
    95) 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.
    96) 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.
    97) 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.
    98) 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.
    99) 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.
    100) 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.
    101) 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.
    102) 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.
    103) 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.
    104) 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.
    105) 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.
    106) 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.
    107) 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.
    108) 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.
    109) 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.
    110) 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.
    111) 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.
    112) 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.
    113) 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.
    114) 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.
    115) 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.
    116) 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.
    117) 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.
    118) 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.
    119) 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.
    120) 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.
    121) 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.
    122) 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.
    123) 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.
    124) 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.
    125) 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.
    126) 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.
    127) 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.
    128) 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.
    129) 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.
    130) 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.
    131) 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.
    132) 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.
    133) 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.
    134) 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.
    135) 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.
    136) 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.
    137) 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.
    138) 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.
    139) 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.
    140) 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.
    141) 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.
    142) 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.
    143) 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.
    144) 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.
    145) 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.
    146) 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.
    147) 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.
    148) 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.
    149) National Research Council : Acute exposure guideline levels for selected airborne chemicals, 5, National Academies Press, Washington, DC, 2007.
    150) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 6, National Academies Press, Washington, DC, 2008.
    151) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 7, National Academies Press, Washington, DC, 2009.
    152) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 8, National Academies Press, Washington, DC, 2010.
    153) Nelson LS, Erdman AR, Booze LL, et al: Selective serotonin reuptake inhibitor poisoning: An evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2007; 45(4):315-332.
    154) Nemeroff CB, Schatzberg AF, Goldstein DJ, et al: Duloxetine for the treatment of major depressive disorder. Psychopharmacol Bull 2002; 36:106-132.
    155) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    156) Paulzen M, Hiemke C, & Grunder G: Plasma levels and cerebrospinal fluid penetration by duloxetine in a patient with a non-fatal overdose during a suicide attempt. Int J Neuropsychopharmacol 2009; 12(10):1431-1432.
    157) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    158) Product Information: ATIVAN(R) injection, lorazepam injection. Baxter Healthcare Corporation, Deerfield, IL, 2003.
    159) Product Information: CYMBALTA(R) oral delayed-release capsules, duloxetine oral delayed-release capsules. Lilly USA, LLC (per FDA), Indianapolis, IN, 2014.
    160) Product Information: CYMBALTA(R) oral delayed-release capsules, duloxetine oral delayed-release capsules. Lilly USA, LLC (per FDA), Indianapolis, IN, 2015.
    161) Product Information: Cymbalta(R) delayed-release oral capsules, duloxetine hydrochloride delayed-release oral capsules. Eli Lilly and Company, Indianapolis, IN, 2010.
    162) Product Information: Cymbalta(R) oral delayed-release capsules, duloxetine HCl oral delayed-release capsules. Eli Lilly and Company, Indianapolis, IN, 2011.
    163) Product Information: Cymbalta(R), duloxetine. Eli Lilly and Company, Indianapolis, IN, 2004.
    164) Qureshi A, Wassmer E, Davies P, et al: Comparative audit of intravenous lorazepam and diazepam in the emergency treatment of convulsive status epilepticus in children. Seizure 2002; 11(3):141-144.
    165) Raskin J, Goldstein DJ, Mallinckrodt CH, et al: Duloxetine in the long-term treatment of major depressive disorder. J Clin Psychiatry 2003; 64:1237-1244.
    166) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    167) Schatzberg AF: Efficacy and tolerability of duloxetine, a novel dual reuptake inhibitor, in the treatment of major depressive disorder. J Clin Psychiatry 2003; 64 (Suppl 13):30-37.
    168) Sharma A, Goldberg MJ, & Cerimele BJ: Pharmacokinetics and safety of duloxetine, a dual-serotonin and norepinephrine reuptake inhibitor. J Clin Pharmacol 2000; 40:161-167.
    169) Skinner MH, Kuan H-Y, Pan A, et al: Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers. Clin Pharmacol Ther 2003a; 73:170-177.
    170) Skinner MH, Kuan H-Y, Skerjanec A, et al: Effect of age on the pharmacokinetics of duloxetine in women. Br J Clin Pharmacol 2003; 57:54-61.
    171) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    172) 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.
    173) Sternbach H: The serotonin syndrome. Am J Psychiatr 1991; 148:705-713.
    174) Stovall R, Brahm NC, & Crosby KM: Recurrent episodes of serotonin-reuptake inhibitor-mediated hyponatremia in an elderly patient. Consult Pharm 2009; 24(10):765-768.
    175) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    176) 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.
    177) 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.
    178) 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-.
    179) 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.
    180) 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.
    181) 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.
    182) 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.
    183) 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-.
    184) U.S. Occupational Safety, and Health Administration (OSHA): Process safety management of highly hazardous chemicals. 29 CFR 2010 2010; 29(1910.119):348-.
    185) 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.
    186) Viktrup L, Pangallo BA, Detke MJ, et al: Urinary side effects of duloxetine in the treatment of depression and stress urinary incontinence. Prim Care Comp/J Clin Psychiatry 2004; 6:65-73.
    187) Voelker R: International group seeks to dispel incontinence "taboo". JAMA 1998; 280(11):951-953.
    188) Wheless JW : Treatment of status epilepticus in children. Pediatr Ann 2004; 33(6):376-383.
    189) Wong DT, Bymaster FP, Mayle DA, et al: LY248686, a new inhibitor of serotonin and norepinephrine uptake. Neuropsychopharmacology 1993; 8(1):23-33.
    190) Zinner NR: Duloxetine: a serotonin-noradrenaline re-uptake inhibitor for the treatment of stress urinary incontinence. Expert Opin Investig Drugs 2003; 12:1559-1566.
    191) van Kerrebroeck P, Abrams P, Lange R, et al: Duloxetine versus placebo in the treatment of European and Canadian women with stress urinary incontinence. Br J Obstet Gynaecol 2004; 111:249-257.
    192) van Kerrebroeck P: Duloxetine: an innovative approach for treating stress urinary incontinence. BJU Intl 2004; 94 (Suppl 1):31-37.