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CYCLOBENZAPRINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Cyclobenzaprine is a centrally acting skeletal muscle relaxant related pharmacologically and structurally to amitriptyline.

Specific Substances

    1) 3-(5H-Dibenzocyclohepten-5-ylidene)-N,N-dimethylpropylamine
    2) 9715 RP
    3) CBZ
    4) MIC-130
    5) MK-130
    6) Proheptatriene
    7) RO 4-1577
    8) RP 9715
    9) Molecular Formula: C20-H21-N-HCl
    10) CAS 303-53-7
    11) CAS 6202-23-9 (hydrochloride)

Available Forms Sources

    A) FORMS
    1) Cyclobenzaprine is available as 5 mg, 7.5 mg, and 10 mg tablets (Prod Info FLEXERIL(R) oral tablets, 2013).
    2) Cyclobenzaprine extended-release capsules are available in 15 mg and 30 mg strengths (Prod Info AMRIX(R) oral extended release capsules, 2013).
    B) USES
    1) Cyclobenzaprine is used to relieve muscle spasm associated with acute, painful musculoskeletal conditions (Prod Info FLEXERIL(R) oral tablets, 2013).

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: A skeletal muscle relaxant used for pain relief in acute musculoskeletal conditions.
    B) PHARMACOLOGY: Inhibition of alpha and gamma motor neurons via the brain stem.
    C) TOXICOLOGY: Displays anticholinergic, antihistaminergic, and CNS depressant effects in overdose. It is also a weak norepinephrine and serotonin reuptake inhibitor.
    D) EPIDEMIOLOGY: Poisoning is common but rarely severe.
    E) WITH THERAPEUTIC USE
    1) Sedation, flushing, dry mouth, and hallucinations.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: Sedation, anticholinergic effects (ie, mydriasis, flushing, fever, dry mouth, decreased bowel sounds, hallucinations), sinus tachycardia, mild hypertension or hypotension, and nausea and vomiting are common after overdose.
    2) SEVERE POISONING: Severe effects may include significant hypotension, respiratory depression, and coma. Cyclobenzaprine is a cyclic amine with structural similarity to the tricyclic antidepressant amitriptyline. Therefore, theoretically, conduction delays and ventricular dysrhythmias are of concern but are exceedingly rare even in large overdoses.
    0.2.20) REPRODUCTIVE
    A) There are no adequate or well controlled studies of cyclobenzaprine use during human pregnancy. Cyclobenzaprine is classified as FDA Pregnancy Category B. A syndrome of imperforate oropharynx with costovertebral and auricular anomalies was reported in a child of 32 weeks' gestation following first trimester maternal ingestion of cyclobenzaprine and zomepirac. During animal studies, effects on embryofetal development were not observed in mice and rabbits administered cyclobenzaprine approximately 3 and 15 times the maximum recommended human dose, respectively.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) No specific lab work is needed in most patients.
    C) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (agitation, delirium, seizures, coma, hypotension).
    D) Monitor creatinine phosphokinase in patients with prolonged agitation, seizures, or coma.
    E) Monitor renal function and urine output in patients with rhabdomyolysis.
    F) Cyclobenzaprine will cause a urine tricyclic antidepressant screen to be positive.
    G) Cyclobenzaprine plasma levels are not clinically useful or readily available.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) The vast majority of cyclobenzaprine overdoses require only supportive care; activated charcoal is indicated if patients present shortly after ingestion. Treat agitation and delirium with benzodiazepines. Hypotension normally responds well to hydration. Hypertension and tachycardia are generally mild and well tolerated, and do not require specific treatment.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Patients who experience respiratory compromise or significant CNS depression require early endotracheal intubation for airway protection. While activated charcoal is indicated in these cases, it should be performed only in patients who can protect their airway or who are intubated due to the predictable CNS depression and risk of aspiration. Those experiencing severe anticholinergic features, such as delirium and agitation, may require large doses of benzodiazepines for sedation. Physostigmine is an alternative to reverse CNS anticholinergic effects. Seizures are very rare and typically respond to benzodiazepines. Monitor for QRS widening and ventricular dysrhythmias; treat with intravenous sodium bicarbonate (1 to 2 mEq/kg IV bolus starting dose, titrate to blood pH 7.45 to 7.55). Monitor core temperature and treat hyperthermia with aggressive benzodiazepine sedation to control agitation, and external cooling. Clinical manifestations may be prolonged due to prolonged absorption in the setting of anticholinergic ileus.
    C) DECONTAMINATION
    1) PREHOSPITAL: Not recommended because of potential for profound somnolence.
    2) HOSPITAL: Activated charcoal should be given to those who are able to reliably protect their airway. Fatalities are extremely rare, and gastric lavage is generally not indicated.
    D) AIRWAY MANAGEMENT
    1) Perform early in patients with severe intoxication (seizures, dysrhythmias, severe delirium, CNS or respiratory depression).
    E) ANTIDOTE
    1) Physostigmine is indicated to reverse the CNS effects caused by clinical or toxic dosages of agents capable of producing anticholinergic syndrome; however, long lasting reversal of anticholinergic signs and symptoms is generally not achieved because of the relatively short duration of action of physostigmine (45 to 60 minutes). It is most often used diagnostically to distinguish anticholinergic delirium from other causes of altered mental status. CAUTION: If tricyclic antidepressants are coingested, physostigmine may precipitate seizures and dysrhythmias. DOSES: ADULT: 2 mg IV at a slow controlled rate, no more than 1 mg/min. May repeat doses at intervals of 10 to 30 min if severe symptoms recur. For patients with prolonged anticholinergic delirium consider a continuous infusion, start at 2 mg/hr and titrate to effect. CHILD: 0.02 mg/kg by slow IV injection, at a rate no more than 0.5 mg/minute. Repeat dosage at 5 to 10 minute intervals as long as the toxic effect persists and there is no sign of cholinergic effects. MAXIMUM DOSAGE: 2 mg total.
    F) DYSRHYTHMIAS
    1) QRS widening or ventricular tachycardia may respond to sodium bicarbonate. A reasonable starting dose is 1 to 2 mEq/kg bolus, repeat as needed, endpoints include resolution of dysrhythmias, narrowing of QRS complex, and blood pH 7.45 to 7.55. Use lidocaine if sodium bicarbonate is not successful.
    G) SEIZURES
    1) Intravenous benzodiazepines, propofol, or barbiturates
    H) HYPERTHERMIA
    1) Control agitation with benzodiazepines; initiate aggressive external cooling measures.
    I) DELIRIUM
    1) Sedate patient with benzodiazepines as necessary; large doses may be required.
    J) ENHANCED ELIMINATION
    1) Hemodialysis and hemoperfusion are not of value.
    K) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic children (other than mild drowsiness or stimulation) with small ingestions (1 to 2 pills) may be managed at home.
    2) OBSERVATION CRITERIA: Patients with deliberate ingestions or children with significant ingestions should be referred to a healthcare facility for observation for 6 to 8 hours. All symptomatic patients should be sent to a healthcare facility for observation for 6 to 8 hours.
    3) ADMISSION CRITERIA: Patients with significant persistent central nervous system toxicity (hallucinations, somnolence, delirium, coma), or those with persistent abnormal vital signs, such as tachycardia and hypotension, should be admitted. Patients with coma, seizures, dysrhythmias, or delirium should be admitted to an intensive care setting.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (dysrhythmias, severe delirium, coma) or in whom the diagnosis is not clear.
    L) PITFALLS
    1) Physostigmine is generally not advised for long term management as anticholinergic effects generally recur 30 to 45 minutes after physostigmine administration. Overdose of cyclobenzaprine typically responds well to aggressive intensive, supportive care.
    M) PHARMACOKINETICS
    1) Time to peak is 7 to 8 hours following single doses of 15 to 30 mg cyclobenzaprine extended-release capsules. Cyclobenzaprine undergoes extensive first-pass metabolism. Enterohepatic circulation has been described. It is 93% protein bound, and is extensively metabolized and conjugated in the liver. Approximately 50% is excreted in the urine, mainly as metabolites. Elimination half-life for immediate-release tablets is 18 hours (range 8 to 37 hours). Elimination half-lives were 33.4 +/-10.3 hours and 32 +/-10.1 hours following single doses of 15 mg and 30 mg extended release capsules, respectively.
    N) TOXICOKINETICS
    1) Onset of symptoms generally occurs within 4 hours, toxicity may persist for 24 hours, and may last longer in the elderly and in patients with liver disease.
    O) DIFFERENTIAL DIAGNOSIS
    1) Anticholinergic poisoning from other substances, sympathomimetic poisoning (should have less mydriasis, usually no visual hallucinations, usually will have moist skin), CNS infection, ethanol/benzodiazepine/barbiturate withdrawal, or sedatives.

Range Of Toxicity

    A) TOXICITY: ADULTS: Adults who ingest less than 100 mg typically remain asymptomatic, though may be mildly drowsy. Anticholinergic symptoms can be seen in ingestions of more than 100 mg. Fatalities are exceedingly rare.
    B) THERAPEUTIC DOSE: ADULT: 5 to 10 mg 3 times daily for immediate release tablet, and 15 mg once daily for extended-release capsule.

Clinical Effects

Summary Of Exposure

    A) USES: A skeletal muscle relaxant used for pain relief in acute musculoskeletal conditions.
    B) PHARMACOLOGY: Inhibition of alpha and gamma motor neurons via the brain stem.
    C) TOXICOLOGY: Displays anticholinergic, antihistaminergic, and CNS depressant effects in overdose. It is also a weak norepinephrine and serotonin reuptake inhibitor.
    D) EPIDEMIOLOGY: Poisoning is common but rarely severe.
    E) WITH THERAPEUTIC USE
    1) Sedation, flushing, dry mouth, and hallucinations.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: Sedation, anticholinergic effects (ie, mydriasis, flushing, fever, dry mouth, decreased bowel sounds, hallucinations), sinus tachycardia, mild hypertension or hypotension, and nausea and vomiting are common after overdose.
    2) SEVERE POISONING: Severe effects may include significant hypotension, respiratory depression, and coma. Cyclobenzaprine is a cyclic amine with structural similarity to the tricyclic antidepressant amitriptyline. Therefore, theoretically, conduction delays and ventricular dysrhythmias are of concern but are exceedingly rare even in large overdoses.

Vital Signs

    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) HYPOTENSION occasionally occurs following therapeutic use (Molina-Negro & Illingworth, 1973).
    B) WITH POISONING/EXPOSURE
    1) HYPERTENSION developed in 8% of 402 pure cyclobenzaprine overdoses in one series (Spiller et al, 1994).
    2) HYPOTENSION occurs in overdose (Spiller et al, 1994; Levine et al, 1993) .
    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) TACHYCARDIA may commonly occur at therapeutic doses (Katz & Dube, 1988; Nibbelink & Strickland, 1979; Molina-Negro & Illingworth, 1971).
    B) WITH POISONING/EXPOSURE
    1) TACHYCARDIA may occur in overdose (Menard-Katcher et al, 2009; Levine et al, 1993; Stephen et al, 1991; O'Riordan et al, 1986; Heckerling & Bartow, 1984; Linden et al, 1983).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) BLURRED VISION has been reported with therapeutic doses (Prod Info cyclobenzaprine hcl oral tablets, 2005).
    B) WITH POISONING/EXPOSURE
    1) MYDRIASIS has been reported in overdose, but is not a consistent finding (Linden et al, 1983).
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) XEROSTOMIA is common with therapeutic use (Carette et al, 1994; Santandrea et al, 1993; Fossaluzza & De Vita, 1992; Quimby et al, 1989; Rollings et al, 1983; Baratta, 1982; Nibbelink & Strickland, 1979; Azoury, 1979; Basmajian, 1978).
    B) WITH POISONING/EXPOSURE
    1) Dry mucous membranes may develop in overdose (Stephen et al, 1991; Linden et al, 1983) .

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia is a common adverse effect at therapeutic doses (Katz & Dube, 1988; Nibbelink & Strickland, 1979; Molina-Negro & Illingworth, 1971) .
    2) WITH POISONING/EXPOSURE
    a) Tachycardia is a common finding in overdose (Menard-Katcher et al, 2009; Levine et al, 1993; Stephen et al, 1991; O'Riordan et al, 1986; Heckerling & Bartow, 1984; Linden et al, 1983) .
    b) INCIDENCE: Sinus tachycardia developed in 132 of 402 patients (33%) with pure cyclobenzaprine overdose in one case series (Spiller et al, 1994).
    B) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Unspecified dysrhythmias have been reported at therapeutic doses (Nibbelink & Strickland, 1979).
    2) WITH POISONING/EXPOSURE
    a) Ventricular dysrhythmias are rare, but have been reported.
    b) INCIDENCE: Dysrhythmias other than sinus tachycardia developed in 1% of 402 patients with pure cyclobenzaprine overdose; none were considered life threatening (Spiller et al, 1994).
    c) CASE REPORT: A 19-year-old man developed ventricular tachycardia unresponsive to Advanced Cardiac Life Support (ACLS) treatment after ingesting unknown quantities of cyclobenzaprine, erythromycin, ibuprofen, phenylpropanolamine, and chlorpheniramine (Levine et al, 1993).
    C) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension sometimes occurs following therapeutic use (Molina-Negro & Illingworth, 1973).
    2) WITH POISONING/EXPOSURE
    a) Hypotension has been reported in overdose, but is not common (Levine et al, 1993).
    b) INCIDENCE: Hypotension occurred in 1% of 402 pure cyclobenzaprine overdoses (Spiller et al, 1994).
    D) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) INCIDENCE: Hypertension developed in 8% of 402 pure cyclobenzaprine overdoses in one series (Spiller et al, 1994).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) APNEA
    1) WITH POISONING/EXPOSURE
    a) Respiratory failure is not common, but has been reported in patients with severe mental status depression (Levine et al, 1993).
    b) INCIDENCE: In a series of 402 patients with pure cyclobenzaprine overdose, 13 (3%) required mechanical ventilation (Spiller et al, 1994).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) WITH THERAPEUTIC USE
    a) At therapeutic doses, drowsiness and dizziness are common, occurring in up to 40% and 11% of patients, respectively (Carette et al, 1994; Santandrea et al, 1993; Fossaluzza & De Vita, 1992; Borenstein et al, 1990; Bennett et al, 1988; Rollings et al, 1983; Baratta, 1982; Azoury, 1979; Nibbelink & Strickland, 1979; Basmajian, 1978; Bercel, 1977; Ashby et al, 1972).
    2) WITH POISONING/EXPOSURE
    a) Lethargy is common after overdose (Linden et al, 1983). Coma may develop with severe overdose (Levine et al, 1993).
    b) INCIDENCE: Lethargy developed in 216 of 402 patients (54%) with pure cyclobenzaprine overdose in one series (Spiller et al, 1994).
    c) CASE REPORT: A 19-month-old girl presented with drowsiness, irritability, and an unsteady gait after ingesting an unknown amount of cyclobenzaprine. On admission, tachycardia was noted, and observation of the patient revealed that she would sleep and then wake up screaming and inconsolable before going back to sleep. A comprehensive urine drug screen, using gas chromatography/mass spectrometry, confirmed the presence of cyclobenzaprine. With supportive care, the patient completely recovered and was discharged home (Menard-Katcher et al, 2009).
    B) DYSKINESIA
    1) WITH THERAPEUTIC USE
    a) Tremors have been reported at therapeutic doses (Bercel, 1977; Molina-Negro & Illingworth, 1971).
    b) Ataxia has been described at therapeutic doses (Katz & Dube, 1988; Molina-Negro & Illingworth, 1973) .
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Myoclonic jerks and choreoathetoid movements were reported in a 33-year-old man following ingestion of 260 mg (Linden et al, 1983).
    C) DELIRIUM
    1) WITH THERAPEUTIC USE
    a) Delirium, agitation, disorientation, and hallucinations have developed at therapeutic doses; these effects may persist for several days after cyclobenzaprine is discontinued (Bercel, 1977; Molina-Negro & Illingworth, 1971).
    b) RISK FACTOR: Elderly patients may be more likely to develop delirium at therapeutic doses (Engel & Chapron, 1993).
    c) CASE REPORT: A 76-year-old woman developed acute mental status changes manifesting as hallucinations, sleeplessness, restlessness, and decreased appetite after taking recommended doses of cyclobenzaprine (Douglass & Levine, 2000).
    2) WITH POISONING/EXPOSURE
    a) Agitation, combativeness, disorientation, and hallucinations have been described in overdose (Chabria, 2006; Stephen et al, 1991; O'Riordan et al, 1986; Heckerling & Bartow, 1984; Linden et al, 1983) .
    b) INCIDENCE: In a series of 402 patients with cyclobenzaprine overdose, 50 patients (12%) developed agitation (Spiller et al, 1994).
    c) CASE REPORT: A 19-month-old girl presented with drowsiness, irritability, and an unsteady gait after ingesting an unknown amount of cyclobenzaprine. On admission, tachycardia was noted, and observation of the patient revealed that she would sleep and then wake up screaming and inconsolable before going back to sleep. A comprehensive urine drug screen, using gas chromatography/mass spectrometry, confirmed the presence of cyclobenzaprine. With supportive care, the patient completely recovered and was discharged home (Menard-Katcher et al, 2009).
    D) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 76-year-old woman developed acute mental status changes manifesting as hallucinations, sleeplessness, restlessness, and decreased appetite after taking recommended doses of cyclobenzaprine (Douglass & Levine, 2000).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED ILEUS
    1) WITH POISONING/EXPOSURE
    a) Hypoactive bowel sounds may be noted as an anticholinergic effect in overdose (Linden et al, 1983).
    B) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Epigastric discomfort and nausea have been reported with therapeutic use (Rollings et al, 1983; Baratta, 1982; Azoury, 1979).
    C) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation is occasionally reported at therapeutic doses (Bennett et al, 1988; Molina-Negro & Illingworth, 1973) .
    D) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 76-year-old woman developed acute mental status changes manifesting as hallucinations, sleeplessness, restlessness, and decreased appetite after taking recommended doses of cyclobenzaprine (Douglass & Levine, 2000).

Hepatic

    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATOCELLULAR DAMAGE
    a) High doses administered to rats produced dose-related hepatocyte vacuolization with steatosis (Share, 1978).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RETENTION OF URINE
    1) WITH POISONING/EXPOSURE
    a) Urinary retention may occur as an anticholinergic effect (Linden et al, 1983).
    B) RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Acute renal insufficiency complicated by rhabdomyolysis developed in a 31-year-old woman after overdose with cyclobenzaprine and ibuprofen (O'Riordan et al, 1986).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Metabolic acidosis is reported rarely (Levine et al, 1993; O'Riordan et al, 1986) .

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) The skin may be warm, dry, and flushed (Linden et al, 1983).
    b) Paradoxically, profuse diaphoresis with normal skin coloring was described 1 hour following possible cyclobenzaprine overdose. The skin was warm and dry several hours later (Heckerling & Bartow, 1984).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) Rhabdomyolysis is an uncommon complication that may develop over time in agitated or comatose patients (Chabria, 2006; O'Riordan et al, 1986).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Hypoglycemia has been reported following therapeutic use of cyclobenzaprine (Alim & Edelson, 1993).

Reproductive

    3.20.1) SUMMARY
    A) There are no adequate or well controlled studies of cyclobenzaprine use during human pregnancy. Cyclobenzaprine is classified as FDA Pregnancy Category B. A syndrome of imperforate oropharynx with costovertebral and auricular anomalies was reported in a child of 32 weeks' gestation following first trimester maternal ingestion of cyclobenzaprine and zomepirac. During animal studies, effects on embryofetal development were not observed in mice and rabbits administered cyclobenzaprine approximately 3 and 15 times the maximum recommended human dose, respectively.
    3.20.2) TERATOGENICITY
    A) MALFORMATIONS MULTIPLE
    1) CASE REPORT: A syndrome of imperforate oropharynx with costovertebral and auricular anomalies was reported in a child of 32 weeks' gestation following first trimester maternal ingestion of cyclobenzaprine and zomepirac (Flannery, 1989). At this time, cyclobenzaprine should be avoided in the first trimester of pregnancy.
    B) LACK OF EFFECT
    1) MICE, RATS, RABBITS: During animal studies, administration of cyclobenzaprine up to 20 times the human dose in mice, rats, and rabbits, did not result in impaired fertility or fetal harm (Prod Info FLEXERIL(R) oral tablets, 2013).
    2) MICE, RATS, RABBITS: During animal studies, cyclobenzaprine administration in rats during pregnancy and lactation resulted in adverse postnatal development in pups. Decreased pup body weight and decreased survival were reported at greater than or equal to 3 times the maximum recommended human dose (MRHD) on a mg/m(2) basis. Treatment related effects on embryofetal development were not observed in mice and rabbits administered cyclobenzaprine approximately 3 and 15 times the MRHD, respectively (Prod Info AMRIX(R) oral extended release capsules, 2013).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Cyclobenzaprine is classified as FDA Pregnancy Category B by the manufacturer (Prod Info AMRIX(R) oral extended release capsules, 2013; Prod Info FLEXERIL(R) oral tablets, 2013).
    2) There are no adequate or well controlled studies of cyclobenzaprine use during human pregnancy. During animal studies, effects on embryofetal development were not observed in mice and rabbits administered cyclobenzaprine approximately 3 and 15 times the maximum recommended human dose, respectively. Adverse effects on postnatal development in pups was observed following administration of cyclobenzaprine during pregnancy and lactation in rats (Prod Info AMRIX(R) oral extended release capsules, 2013). Due to the lack of human data and because animal studies are not always indicative of human response, cyclobenzaprine should only be used during pregnancy only if clearly needed (Prod Info AMRIX(R) oral extended release capsules, 2013; Prod Info FLEXERIL(R) oral tablets, 2013).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Lactation studies have not been conducted with cyclobenzaprine. It is not known whether cyclobenzaprine is excreted in human milk. Cyclobenzaprine is closely related to tricyclic antidepressants, some of which are excreted in human milk. Until more data are available, use caution when considering the use of cyclobenzaprine in lactating women (Prod Info AMRIX(R) oral extended release capsules, 2013; Prod Info FLEXERIL(R) oral tablets, 2013).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS6202-23-9 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    B) IARC Carcinogenicity Ratings for CAS303-53-7 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) No specific lab work is needed in most patients.
    C) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (agitation, delirium, seizures, coma, hypotension).
    D) Monitor creatinine phosphokinase in patients with prolonged agitation, seizures, or coma.
    E) Monitor renal function and urine output in patients with rhabdomyolysis.
    F) Cyclobenzaprine will cause a urine tricyclic antidepressant screen to be positive.
    G) Cyclobenzaprine plasma levels are not clinically useful or readily available.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) No specific lab work is needed in most patients.
    2) Monitor creatinine phosphokinase in patients with prolonged agitation, seizures, or coma.
    3) Monitor renal function and urine output in patients with rhabdomyolysis.
    4) Cyclobenzaprine plasma levels are not clinically useful or readily available.
    4.1.3) URINE
    A) URINALYSIS
    1) Monitor renal function and urine output in patients with rhabdomyolysis.
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (agitation, delirium, seizures, coma, hypotension).
    2) MONITORING
    a) Monitor vital signs and mental status.

Methods

    A) CHROMATOGRAPHY
    1) Methods for quantitating cyclobenzaprine in biologic fluids employing gas-liquid chromatography with flame ionization detection (Hucker & Stauffer, 1976) and nitrogen detection have been described (Constanzer et al, 1985; Hucker & Stauffer, 1976).
    a) Gas chromatography alone can misidentify other compounds (eg, pyrilamine, oxazepam) with similar retention times (Ambre, 1985).
    b) Unidentified peaks in the tricyclic antidepressant time range on gas chromatographic analysis of urine may be noted (Linden et al, 1983).
    c) Elimination of the 58 ion from the mass spectra resulted in detection of cyclobenzaprine at a 215 base peak and amitriptyline at a 202 base peak (Bateh, 1987).
    2) High Performance Liquid Chromatography (HPLC): Cyclobenzaprine can be difficult to distinguish from amitriptyline due to structural similarities between the agents. A technique combining HPLC with UV detection at 2 selected wavelengths was successful in distinguishing between amitriptyline, imipramine, and cyclobenzaprine (Lofland et al, 2001; Demorest, 1987; Puopolo & Flood, 1987).
    a) Another HPLC technique with fast-scan UV detection (REMEDi Drug Profiling System) readily distinguishes between cyclobenzaprine and amitriptyline, but not nortriptyline (Poklis & Edinboro, 1992).
    3) Thin-Layer Chromatography (TLC): Amitriptyline and cyclobenzaprine have similar migration characteristic on the TOXI-LAB TLC system. In stage III, TOXI-LAB A, amitriptyline fluoresces pink while cyclobenzaprine is orange; the fluorescence is concentration dependent and identification can be difficult (Poklis & Edinboro, 1992).
    a) Cyclobenzaprine can be measured in biological tissues using TLC followed by densitometry (Faber, 1972).
    4) Gas chromatography/mass spectrometry (GC/MS): GC/MS can identify cyclobenzaprine (Bateh, 1987). Gas chromatography with nitrogen-phosphorus detection may also be helpful in distinguishing cyclobenzaprine from amitriptyline (Lofland et al, 2001).
    B) IMMUNOASSAY
    1) Cyclobenzaprine cross-reacts in the Enzyme-Multiplied Immunoassay Techique (EMIT) and Abbott ADx tricyclic antidepressant immunoassays (Poklis & Edinboro, 1992)

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 significant persistent central nervous system toxicity (hallucinations, somnolence, delirium, coma), or those with persistent abnormal vital signs, such as tachycardia and hypotension, should be admitted. Patients with coma, seizures, dysrhythmias, or delirium should be admitted to an intensive care setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic children (other than mild drowsiness or stimulation) with small ingestions (1 to 2 pills) may be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (dysrhythmias, severe delirium, coma) or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate ingestions or children with significant ingestions should be referred to a healthcare facility for observation for 6 to 8 hours. All symptomatic patients should be sent to a healthcare facility for observation for 6 to 8 hours.

Monitoring

    A) Monitor vital signs and mental status.
    B) No specific lab work is needed in most patients.
    C) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (agitation, delirium, seizures, coma, hypotension).
    D) Monitor creatinine phosphokinase in patients with prolonged agitation, seizures, or coma.
    E) Monitor renal function and urine output in patients with rhabdomyolysis.
    F) Cyclobenzaprine will cause a urine tricyclic antidepressant screen to be positive.
    G) Cyclobenzaprine plasma levels are not clinically useful or readily available.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital decontamination is not recommended because of potential for profound somnolence.
    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 and mental status.
    2) No specific lab work is needed in most patients.
    3) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (agitation, delirium, seizures, coma, hypotension).
    4) Monitor creatinine phosphokinase in patients with prolonged agitation, seizures, or coma.
    5) Monitor renal function and urine output in patients with rhabdomyolysis.
    6) Cyclobenzaprine will cause a urine tricyclic antidepressant screen to be positive.
    7) Cyclobenzaprine plasma levels are not clinically useful or readily available.
    B) PHYSOSTIGMINE
    1) PHYSOSTIGMINE/INDICATIONS
    a) Physostigmine is indicated to reverse the CNS effects caused by clinical or toxic dosages of agents capable of producing anticholinergic syndrome; however, long lasting reversal of anticholinergic signs and symptoms is generally not achieved because of the relatively short duration of action of physostigmine (45 to 60 minutes) (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008). It is most often used diagnostically to distinguish anticholinergic delirium from other causes of altered mental status (Frascogna, 2007; Shannon, 1998).
    b) Physostigmine should not be used in patients with suspected tricyclic antidepressant overdose, or an ECG suggestive of tricyclic antidepressant overdose (eg, QRS widening). In the setting of tricyclic antidepressant overdose, use of physostigmine has precipitated seizures and intractable cardiac arrest (Stewart, 1979; Newton, 1975; Pentel & Peterson, 1980; Frascogna, 2007).
    2) DOSE
    a) ADULT: BOLUS: 2 mg IV at slow controlled rate, no more than 1 mg/min. May repeat doses at intervals of 10 to 30 min, if severe symptoms recur (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008). INFUSION: For patients with prolonged anticholinergic delirium, a continuous infusion of physostigmine may be considered. Starting dose is 2 mg/hr, titrate to effect (Eyer et al, 2008)
    b) CHILD: 0.02 mg/kg by slow IV injection, at a rate no more than 0.5 mg/minute. Repeat dosage at 5 to 10 minute intervals as long as the toxic effect persists and there is no sign of cholinergic effects. MAXIMUM DOSAGE: 2 mg total (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
    c) AVAILABILITY: Physostigmine salicylate is available in 2 mL ampules, each mL containing 1 mg of physostigmine salicylate in a vehicle containing sodium metabisulfite 0.1%, benzyl alcohol 2%, and water (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
    3) CAUTIONS
    a) Relative contraindications to the use of physostigmine are asthma, gangrene, diabetes, cardiovascular disease, intestinal or urogenital tract mechanical obstruction, peripheral vascular disease, cardiac conduction defects, atrioventricular block, and in patients receiving choline esters and depolarizing neuromuscular blocking agents (decamethonium, succinylcholine). It may cause anaphylactic symptoms and life-threatening or less severe asthmatic episodes in patients with sulfite sensitivity (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
    b) Too rapid IV administration of physostigmine has resulted in bradycardia, hypersalivation leading to respiratory difficulties, and possible seizures (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
    4) ATROPINE FOR PHYSOSTIGMINE TOXICITY
    a) Atropine should be available to reverse life-threatening physostigmine-induced, toxic cholinergic effects (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008; Frascogna, 2007). Atropine may be given at half the dose of previously given physostigmine dose (Daunderer, 1980).
    C) CONDUCTION DISORDER OF THE HEART
    1) QRS widening or ventricular tachycardia may respond to sodium bicarbonate. A reasonable starting dose is 1 to 2 mEq/kg bolus, repeat as needed, endpoints include resolution of dysrhythmias, narrowing of QRS complex, and blood pH 7.45 to 7.55. Use lidocaine if sodium bicarbonate is not successful.
    2) LIDOCAINE/INDICATIONS
    a) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    3) LIDOCAINE/DOSE
    a) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    1) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    b) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    4) LIDOCAINE/MAJOR ADVERSE REACTIONS
    a) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    5) LIDOCAINE/MONITORING PARAMETERS
    a) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    D) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    7) RECURRING SEIZURES
    a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:
    1) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
    2) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
    3) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
    4) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)
    b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
    c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).
    E) BODY TEMPERATURE ABOVE REFERENCE RANGE
    1) Control agitation with benzodiazepines; initiate aggressive external cooling measures.
    F) DELIRIUM
    1) Sedate patient with benzodiazepines as necessary; large doses may be required.

Enhanced Elimination

    A) ENHANCED ELIMINATION
    1) Hemodialysis and hemoperfusion are not of value.

Abstracts

Case Reports

    A) ADULT
    1) A 31-year-old woman who ingested an unknown amount of cyclobenzaprine along with 100 ibuprofen tablets 24 hours prior to presentation developed supraventricular tachycardia, disorientation, and slurred speech. Approximately 48 hours postingestion decreased urine output developed, as well as increased BUN (50 mg%) and serum creatinine (5.9 mg%) and rhabdomyolysis (CPK 9,400 international units/L). Myoglobinuria was reported on the first hospital day (O'Riordan et al, 1986).
    2) A 19-year-old man developed lethargy, tachycardia, and persistent vomiting after overdose with cyclobenzaprine, erythromycin, ibuprofen, phenylpropanolamine, and chlorpheniramine. He became comatose and developed respiratory failure and hypotension over the next 5 hours. Thirteen minutes after intubation his rhythm deteriorated to pulseless ventricular tachycardia which was unresponsive to Advanced Cardiac Life Support (ACLS) treatment (Levine et al, 1993).

Range Of Toxicity

Summary

    A) TOXICITY: ADULTS: Adults who ingest less than 100 mg typically remain asymptomatic, though may be mildly drowsy. Anticholinergic symptoms can be seen in ingestions of more than 100 mg. Fatalities are exceedingly rare.
    B) THERAPEUTIC DOSE: ADULT: 5 to 10 mg 3 times daily for immediate release tablet, and 15 mg once daily for extended-release capsule.

Therapeutic Dose

    7.2.1) ADULT
    A) IMMEDIATE-RELEASE TABLETS
    1) 5 to 10 mg 3 times daily. It is not recommended for use beyond 2 or 3 weeks (Prod Info cyclobenzaprine HCl oral tablets, 2013).
    B) EXTENDED-RELEASE CAPSULES
    1) 15 to 30 mg once daily. It is not recommended for use beyond 2 or 3 weeks (Prod Info AMRIX(R) oral extended release capsules, 2013).
    7.2.2) PEDIATRIC
    A) IMMEDIATE-RELEASE TABLETS
    1) 15 YEARS AND OLDER
    a) 5 to 10 mg 3 times daily. It is not recommended for use beyond 2 or 3 weeks (Prod Info cyclobenzaprine HCl oral tablets, 2013).
    2) LESS THAN 15-YEARS-OLD
    a) LESS THAN 15-YEARS-OLD: Safety and efficacy have not been established (Prod Info cyclobenzaprine HCl oral tablets, 2013).
    B) EXTENDED-RELEASE CAPSULES
    1) Safety and efficacy in pediatric patients have not been established (Prod Info AMRIX(R) oral extended release capsules, 2013).

Minimum Lethal Exposure

    A) CASE REPORTS
    1) A 26-year-old man died after taking 100 mg of cyclobenzaprine and 20 tablets of naproxen. The serum cyclobenzaprine level was 260 nanograms/mL (Tech Info, 1984).

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) ADULT: Three adult patients ingesting 260 to 900 mg developed toxicity but recovered fully (Linden et al, 1983).
    2) PEDIATRIC: A 12-year-old girl developed sinus tachycardia and lethargy after ingestion of 250 mg but recovered (Tech Info, 1984).
    3) ADULT: A 48-year-old man who ingested 1000 mg survived (Tech Info, 1984).
    4) CASE SERIES: In a series of 402 cases, adults ingesting less than 100 mg remained asymptomatic (Spiller et al, 1994).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) GENERAL
    a) Therapeutic blood levels following 40 mg oral doses range from 10 to 40 nanograms/mL and peak in 4 to 6 hours (Hucker et al, 1977).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORTS
    a) A 26-year-old man died after taking 100 mg of cyclobenzaprine and 20 tablets of naproxen. The serum cyclobenzaprine level was 260 nanograms/mL (Tech Info, 1984).
    b) A 19-year-old man died after overdose of cyclobenzaprine, erythromycin, ibuprofen, phenylpropanolamine, and chlorpheniramine . At autopsy blood cyclobenzaprine concentration was 0.3 mg/L (Levine et al, 1993).
    c) A 56-year-old woman and a 37-year-old man developed cardiopulmonary arrest following intentional ingestions of cyclobenzaprine. Cardiac resuscitation was unsuccessful in both patients. Postmortem cyclobenzaprine blood concentrations were 0.96 mg/L and 0.8 mg/L, respectively (Spiller & Cutino, 2003).
    d) A 35-year-old woman was found dead in the bathtub with her face submerged in water. Toxicologic analysis revealed a serum ethanol level of 215 mg/dL and a serum cyclobenzaprine level of 1.79 mg/dL (Winek et al, 1999).

Workplace Standards

    A) ACGIH TLV Values for CAS6202-23-9 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) ACGIH TLV Values for CAS303-53-7 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    C) NIOSH REL and IDLH Values for CAS6202-23-9 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    D) NIOSH REL and IDLH Values for CAS303-53-7 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    E) Carcinogenicity Ratings for CAS6202-23-9 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    F) Carcinogenicity Ratings for CAS303-53-7 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    G) OSHA PEL Values for CAS6202-23-9 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    H) OSHA PEL Values for CAS303-53-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 90 mg/kg (RTECS, 2000)
    2) LD50- (ORAL)MOUSE:
    a) 250 mg/kg (RTECS, 2000)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Cyclobenzaprine is a tricyclic amine similar in structure and pharmacology to amitriptyline. It has strong anticholinergic, antihistaminic, and sedative properties, but only weak antidepressant effects.
    B) Cyclobenzaprine is a weak inhibitor of presynaptic norepinephrine and serotonin reuptake.
    C) Skeletal muscle relaxant activity is due to brainstem-mediated inhibition of gamma and alpha motor neurons (Share & McFarlane, 1975).
    D) Animal data suggest that cyclobenzaprine reduces tonic somatic motor activity, influencing both gamma and alpha motor neuron systems (Share & McFarlane, 1975). Animal data also suggests that the inhibitory effects of cyclobenzaprine on monosynaptic and polysynaptic reflex potentials are due to inhibition of descending serotonergic systems through 5-HT2 receptors in the spinal cord (Honda et al, 2003).

References

General Bibliography

    1) 40 CFR 372.28: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Lower thresholds for chemicals of special concern. National Archives and Records Administration (NARA) and the Government Printing Office (GPO). Washington, DC. Final rules current as of Apr 3, 2006.
    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
    3) 49 CFR 172.101 - App. B: Department of Transportation - Table of Hazardous Materials, Appendix B: List of Marine Pollutants. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 29, 2005.
    4) 62 FR 58840: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 1997.
    5) 65 FR 14186: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    6) 65 FR 39264: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    7) 65 FR 77866: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    8) 66 FR 21940: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2001.
    9) 67 FR 7164: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2002.
    10) 68 FR 42710: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2003.
    11) 69 FR 54144: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2004.
    12) AIHA: 2006 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook, American Industrial Hygiene Association, Fairfax, VA, 2006.
    13) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    14) Alim M & Edelson G: Syncope in a young woman with chronic back pain. Hosp Pract 1993; 28:80-82.
    15) Ambre JJ: Cyclobenzaprine overdosage (letter). Ann Intern Med 1985; 102:559-560.
    16) 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.
    17) Ashby P, Burke D, & Rao S: Assessment of cyclobenzaprine in the treatment of spasticity. J Neurol Neurosurg Psychiatry 1972; 35:599-605.
    18) Azoury FJ: Double-blind comparison of parafon forte and flexeril in the treatment of acute musculoskeletal disorders. Curr Ther Res 1979; 26:189-197.
    19) Baratta RR: A double-blind study of cyclobenzaprine and placebo in the treatment of acute musculoskeletal conditions of the low back. Curr Ther Res 1982; 32:646-652.
    20) Basmajian JV: Cyclobenzaprine hydrochloride effect on skeletal muscle spasm in the lumbar region and neck: two double-blind controlled clinical and laboratory studies. Arch Phys Med Rehabil 1978; 59:58-63.
    21) Bateh RP: Distinguishing cyclobenzaprine and amitriptyline (letter). J Anal Toxicol 1987; 11:235-236.
    22) Beeber AR & Manring JM Jr: Psychosis following cyclobenzaprine use. J Clin Psychiatry 1983; 44:151-152.
    23) Bennett RM, Gatter RA, & Campbell SM: A comparison of cyclobenzaprine and placebo in the management of fibrositis. Arthritis Rheum 1988; 31:1535-1542.
    24) Bercel NA: Cyclobenzaprine in the treatment of skeletal muscle spasm in osteoarthritis of the cervical and lumbar spine. Curr Ther Res 1977; 22:462-468.
    25) Borenstein DG, Lacks S, & Wiesel SW: Cyclobenzaprine and naproxen versus naproxen alone in the treatment of acute low back pain and muscle spasm. Clin Ther 1990; 12:125-131.
    26) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    27) Carette S, Bell MJ, & Reynolds WJ: Comparison of amitriptyline, cyclobenzaprine, and placebo in the treatment of fibromyalgia: a randomized, double-blind clinical trial. Arthritis Rheum 1994; 37:32-40.
    28) Chabria SB: Rhabdomyolysis: a manifestation of cyclobenzaprine toxicity. J Occup Med Toxicol 2006; 1:16-.
    29) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    30) 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.
    31) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    32) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    33) Constanzer Ml, Vincek WC, & Bayne WF: Determination of cyclobenzaprine in plasma and urine using capillary gas chromatography with nitrogen-selective detection. J Chromatogr 1985; 339:414-418.
    34) 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.
    35) Daunderer M: Physostigmine salicylate as an antidote. Int J Clin Pharmacol Ther Toxicol 1980; 18(12):523-535.
    36) Demorest DM: Distinguishing cyclobenzaprine from anitriptyline and imipramine by liquid chromatography with UV multi-wavelength or full-spectrum detection. Blood levels of cyclobenzaprine in emergency screens (letter). J Anal Toxicol 1987; 11:133-134.
    37) Douglass MA & Levine DP: Hallucinations in an elderly patient taking recommended doses of cyclobenzaprine. Arch Intern Med 2000; 160:1373.
    38) 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/.
    39) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    40) Engel PA & Chapron D: Cyclobenzaprine-induced delirium in two octogenarians (letter). J Clin Psychiatry 1993; 54:39.
    41) Eyer F, Jetzinger E, Pfab R, et al: Withdrawal from high-dose tranylcypromine. Clin Toxicol (Phila) 2008; 46(3):261-263.
    42) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    43) Faber DB: Separation of cyclobenzaprine from biological samples and its determination by thin-layer chromatography followed by densitometry. J Chromatogr 1972; 74(1):85-98.
    44) Flannery DB: Syndrome of imperforate oropharynx with costovertebral and auricular anomalies. Am J Med Genetics 1989; 32:189-191.
    45) Fossaluzza V & De Vita S: Combined therapy with cyclobenzaprine and ibuprofen in primary fibromyalgia syndrome. Int J Clin Pharm Res 1992; 12:99-102.
    46) Frascogna N: Physostigmine: is there a role for this antidote in pediatric poisonings?. Curr Opin Pediatr 2007; 19(2):201-205.
    47) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    48) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    49) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    50) Harsch HH: Mania in two patients following cyclobenzaprine. Psychosomatics 1984; 25:791-793.
    51) Heckerling PS & Bartow TJ: Paradoxical diaphoresis in cyclobenzaprine poisoning (letter). Ann Intern Med 1984; 101:881.
    52) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    53) Honda M, Nishida T, & Ono H: Tricyclic analogs cyclobenzaprine, amitriptyline and cyproheptadine inhibit the spinal reflex transmission through 5-HT2 receptors. Europ J Pharmacol 2003; 458:91-99.
    54) Hucker HB & Stauffer SC: GLC determination of cyclobenzaprine in plasma and urine. J Pharm Sci 1976; 65:1253-1255.
    55) Hucker HB, Stauffer SC, & Albert KS: Plasma levels and bioavailability of cyclobenzaprine in human subjects. J Clin Pharmacol 1977; 17:719-727.
    56) Hucker HB, Stauffer SC, & Balletto AJ: Physiological disposition and metabolism of cyclobenazprine in the rat, dog, rhesus monkey, and man. Drug Metab Dispos 1978; 6:659-672.
    57) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    58) 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.
    59) 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.
    60) 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.
    61) 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.
    62) 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.
    63) 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.
    64) 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.
    65) 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.
    66) Katz WA & Dube J: Cyclobenzaprine in the treatment of acute muscle spasm: review of a decade of clinical experience. Clin Ther 1988; 10:216-229.
    67) Levine B, Jones R, & Smith ML: A multiple drug intoxication involving cyclobenzaprine and ibuprofen. Am J Forensic Med Pathol 1993; 14:246-248.
    68) Linden CH, Mitchiner JC, & Lindzon RD: Cyclobenzaprine overdosage. J Toxicol Clin Toxicol 1983; 20:281-288.
    69) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    70) Lofland JH, Szarlej D, Buttaro T, et al: Cyclobenzaprine hydrochloride is a commonly prescribed centrally acting muscle relaxant which is structurally similar to tricyclic antidepressants (TCAs) and differs from amitriptyline by only one double bond. Clin J Pain 2001; 17:103-104.
    71) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    72) Menard-Katcher C, Henretig FM, & Osterhoudt KC: A 19-month-old girl with recurrent illness: over the hills and through the woods. Pediatr Emerg Care 2009; 25(12):869-871.
    73) Molina-Negro P & Illingworth RA: A new drug for the treatment of muscular hypertonus. Preliminary study in 10 patients with spasticity of spinal origin. Union Med Can 1971; 100:1947-1951.
    74) Molina-Negro P & Illingworth RA: Preliminary communication of the action of cyclobenzaprine (MK-130) in Parkinson's disease. Union Med Can 1973; 102:303-308.
    75) NFPA: Fire Protection Guide to Hazardous Materials, 13th ed., National Fire Protection Association, Quincy, MA, 2002.
    76) 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.
    77) 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.
    78) 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.
    79) 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.
    80) 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.
    81) 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.
    82) 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.
    83) 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.
    84) 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.
    85) 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.
    86) 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.
    87) 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.
    88) 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.
    89) 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.
    90) 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.
    91) 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.
    92) 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.
    93) 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.
    94) 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.
    95) 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.
    96) 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.
    97) 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.
    98) 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.
    99) 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.
    100) 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.
    101) 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.
    102) 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.
    103) 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.
    104) 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.
    105) 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.
    106) 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.
    107) 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.
    108) 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.
    109) 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.
    110) 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.
    111) 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.
    112) 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.
    113) 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.
    114) 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.
    115) 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.
    116) 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.
    117) 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.
    118) 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.
    119) 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.
    120) 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.
    121) 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.
    122) 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.
    123) 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.
    124) 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.
    125) 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.
    126) 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.
    127) 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.
    128) 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.
    129) 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.
    130) 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.
    131) 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.
    132) 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.
    133) 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.
    134) 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.
    135) 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.
    136) 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.
    137) 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.
    138) 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.
    139) 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.
    140) 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.
    141) 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.
    142) 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.
    143) 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.
    144) 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.
    145) 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.
    146) 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.
    147) 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.
    148) 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.
    149) 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.
    150) 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.
    151) 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.
    152) 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.
    153) 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.
    154) 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.
    155) National Research Council : Acute exposure guideline levels for selected airborne chemicals, 5, National Academies Press, Washington, DC, 2007.
    156) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 6, National Academies Press, Washington, DC, 2008.
    157) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 7, National Academies Press, Washington, DC, 2009.
    158) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 8, National Academies Press, Washington, DC, 2010.
    159) Neumar RW , Otto CW , Link MS , et al: Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S729-S767.
    160) Newton RW: Physostigmine salicylate in the treatment of tricyclic antidepressant overdosage. JAMA 1975; 231:941-943.
    161) Nibbelink DW & Strickland SC: Cyclobenzaprine postmarketing surveillance program. Curr Ther Res 1979; 25:564-570.
    162) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    163) O'Neil BA, Knudson GA, & Bhaskara SM: First episode psychosis following cyclobenzaprine use. Can J Psychiatry 2000; 45:763-764.
    164) O'Riordan W, Gillette P, & Calderon J: Overdose of cyclobenzaprine, the tricyclic muscle relaxant. Ann Emerg Med 1986; 15:592-593.
    165) Pentel P & Peterson CD: Asystole complicating physostigmine treatment of tricyclic antidepressant overdose. Ann Emerg Med 1980; 9:588-590.
    166) Poklis A & Edinboro LE: REMEDI drug profilling system readily distinguishes between cyclobenzaprine and amitriptyline in emergency toxicology urine specimens (letter). Clin Chem 1992; 38:2349-2350.
    167) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    168) Product Information: AMRIX(R) extended-release oral capsules, cyclobenzaprine hcl extended-release oral capsules. ECR Pharmaceuticals, Richmond, VA, 2006.
    169) Product Information: AMRIX(R) oral extended release capsules, cyclobenzaprine HCl oral extended release capsules. Teva Pharmaceuticals USA, Inc. (per FDA), North Wales, PA, 2013.
    170) Product Information: AMRIX(R) oral extended release capsules, cyclobenzaprine HCl oral extended release capsules. Teva Pharmaceuticals USA, Inc. (per FDA), North Wales, PA, 2016.
    171) Product Information: CYCLOBENZAPRINE HCl oral film coated tablets, cyclobenzapine HCl oral film coated tablets. Amneal Pharmaceuticals of New York (per DailyMed), Bridgewater, NJ, 2015.
    172) Product Information: FLEXERIL(R) oral tablets, cyclobenzaprine HCl oral tablets. McNeil Pediatrics (per FDA), Titusville, NJ, 2013.
    173) Product Information: Lidocaine HCl intravenous injection solution, lidocaine HCl intravenous injection solution. Hospira (per manufacturer), Lake Forest, IL, 2006.
    174) Product Information: cyclobenzaprine HCl oral tablets, cyclobenzaprine HCl oral tablets. KLE 2 Inc (per DailyMed), Culver City, CA, 2013.
    175) Product Information: cyclobenzaprine hcl oral tablets, cyclobenzaprine hcl oral tablets. Mutual Pharmaceutical Company,Inc, Philadelphia, PA, 2005.
    176) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    177) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    178) Product Information: physostigmine salicylate intravenous injection, intramuscular injection, physostigmine salicylate intravenous injection, intramuscular injection. Akorn, Inc. (per Manufacturer), Lake Forest, IL, 2008.
    179) Puopolo PR & Flood JG: Detection of interference by cyclobenzaprine in liquid-chromatographic assays of tricyclic antidepressants. Clin Chem 1987; 33:819-820.
    180) Quimby LG, Gratwick GM, & Whitney CD: A randomized trial of cyclobenzaprine for the treatment of fibromyalgia. J Rheumatol 1989; 16(Suppl 19):140-143.
    181) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    182) Rollings HE, Glassman JM, & Soyka JP: Management of acute musculoskeletal conditions - thoracolumbar strain or sprain: a double-blind evaluation comparing the efficacy and safety of carisoprodol with cyclobenzaprine hydrochloride. Curr Ther Res 1983; 34:917-928.
    183) Santandrea S, Montrone F, & Sarzi-Puttini P: A double-blind crossover study of two cyclobenzaprine regimens in primary fibromyalgia syndrome. J Int Med Res 1993; 21:74-80.
    184) Scott R, Besag FMC, & Neville BGR: Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet 1999; 353:623-626.
    185) Shannon M: Toxicology reviews: physostigmine. Pediatr Emerg Care 1998; 14(3):224-226.
    186) Share NN & McFarlane CS: Cyclobenzaprine: a novel centrally acting skeletal muscle relaxant. Neuropharmacol 1975; 12:675-684.
    187) Share NN: Pharmacological properties of cyclobenzaprine, in clinical evaluation of Flexeril(R) (cyclobenzaprine HCL/MSD). Postgrad Med Comm 1978; 14-18.
    188) Spiller HA & Cutino L: Fatal cyclobenzaprine overdose with postmortem values. J Forensic Sci 2003; 48:883-884.
    189) Spiller HA, Winter ML, & Mann KV: Five year multicenter retrospective review of cyclobenazprine toxicity. Vet Human Toxicol 1994; 36:370.
    190) 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 2009; Epub:Epub.
    191) Stephen JM, Ghezzi KT, & Bailey K: Post-triathalon delirium. J Emer Med 1991; 9:265-269.
    192) Stewart GO: Convulsions after physostigmine (letter). Anaesth Intens Care 1979; 7:283.
    193) 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.
    194) 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.
    195) 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-.
    196) 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.
    197) 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.
    198) 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.
    199) 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.
    200) 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-.
    201) U.S. Occupational Safety, and Health Administration (OSHA): Process safety management of highly hazardous chemicals. 29 CFR 2010 2010; 29(1910.119):348-.
    202) 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.
    203) Vanden Hoek TL, Morrison LJ, Shuster M, et al: Part 12: cardiac arrest in special situations: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S829-S861.
    204) Winek CL Jr, Wahba WW, & Winek CL: Drowning due to cyclobenzaprine and ethanol. Forensic Sci Intl 1999; 100:105-108.
    205) de Caen AR, Berg MD, Chameides L, et al: Part 12: Pediatric Advanced Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S526-S542.