Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

PROMETHAZINE

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Promethazine is a phenothiazine derivative with antihistaminic properties

Specific Substances

    1) Diprazinum
    2) Proazamine chloride
    3) Promethazini hydrochloridum
    4) Promethazinium chloride
    5) CAS 58-33-3 (hydrochloride)
    6) CAS 60-87-7

Available Forms Sources

    A) FORMS
    1) Promethazine is available as 25 mg/mL and 50 mg/mL solution for injection; 6.25 mg/5 mL oral syrup; 12.5 mg, 25 mg, and 50 mg oral tablet, and 12.5 mg, 25 mg, and 50 mg rectal suppository (Prod Info PHENERGAN intramuscular intravenous injection, 2011; Prod Info promethazine HCl oral tablets, 2009).
    B) USES
    1) Promethazine hydrochloride is indicated for a variety of conditions including nausea and vomiting associated with anesthesia and surgery, motion sickness, pain, and allergic reaction. It is also used for sedation and for reducing the dose of opioids required to treat severe pain (Prod Info PHENERGAN intramuscular intravenous injection, 2011; Prod Info promethazine HCl oral tablets, 2009).

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: Promethazine is used to treat a variety of conditions, including nausea, vomiting, motion sickness, pain, and allergic reaction. It is also used for sedation and for reducing the dose of opioids required to treat severe pain.
    B) PHARMACOLOGY: Promethazine is a competitive inhibitor at histamine type 1 (H1) receptors. The drug has sedative, antiemetic, and anticholinergic effects but has no dopaminergic action.
    C) TOXICOLOGY: Overdose causes anticholinergic effects, including tachycardia, mydriasis, agitation, delirium, sedation, dry skin, and urinary retention.
    D) EPIDEMIOLOGY: Exposure is common but severe manifestations are relatively rare. Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: Drowsiness is the prominent CNS effect. Other effects include, blurred vision, dizziness, confusion, disorientation, and extrapyramidal symptoms (eg, akathisia, torticollis, and tongue protrusion), tinnitus, incoordination, fatigue, euphoria, nervousness, insomnia, tremors, excitation, and hallucinations. Nausea, vomiting, and dry mouth are common gastrointestinal effects.
    2) PARADOXICAL EFFECT: Hyperexcitability and abnormal movements may develop.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE EXPOSURE: Mild to moderate overdose may result in mild sedation, tachycardia, mild hypertension, mydriasis, flushed skin, dry mouth, confusion, and agitation. Adults generally become sedated. Children are more likely to exhibit CNS excitation.
    2) SEVERE EXPOSURE: Severe overdose may result in delirium, severe CNS depression, hypotension, seizures, and rarely respiratory depression.
    0.2.20) REPRODUCTIVE
    A) The neonate may develop respiratory depression, transient behavioral changes, transient EEG changes, or impaired platelet aggregation associated with maternal promethazine administration during labor.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Serum concentrations are not generally available or useful in the acute setting.
    C) Institute continuous cardiac monitoring and obtain an ECG.
    D) Monitor serum electrolytes.
    E) Monitor CK in patients with prolonged agitation, seizures, or severe CNS depression.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Care is symptomatic and supportive. Treat agitation with small doses of benzodiazepines. Treat hypotension with IV fluids. Treat dystonic reactions with diphenhydramine or benztropine.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Hypotension should be treated with an initial bolus of IV fluids. Consider dopamine or norepinephrine if hypotension does not respond to IV fluids. Patients should be monitored frequently for signs of CNS or respiratory depression and the possible need for airway management. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Physostigmine is not indicated for routine treatment. It may be used if an anticholinergic toxidrome is present, and the patient has clearly not coingested a tricyclic antidepressant. Agitated delirium should be treated with benzodiazepines. Dystonic reactions should be treated with benztropine 1 to 4 mg IV or diphenhydramine 25 to 50 mg IV (1.25 mg/kg IV in children).
    C) DECONTAMINATION
    1) PREHOSPITAL: Gastrointestinal decontamination should generally be avoided because of the risk of CNS depression.
    2) HOSPITAL: Administer activated charcoal after recent overdose if the patient is awake and alert and airway is protected.
    D) AIRWAY MANAGEMENT
    1) CNS depression requiring airway protection is rare but does occur.
    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) DRUG-INDUCED DYSTONIA
    1) Adult: Benztropine: 1 to 4 mg IV or IM, max 6 mg/day. Diphenhydramine: Adult: 25 to 50 mg IV over 2 min; max 100 mg/dose or 400 mg/day; Child: 1.25 mg/kg/dose (37.5 mg/M(2)) IV over 2 minutes; max 300 mg/day.
    G) EXTRAVASATION
    1) At present, no proven successful management is available following extravasation or intra-arterial administration of promethazine. Based on animal data with other known arteriolar irritants, sympathetic block and the administration of heparin have been used to manage this condition.
    H) ENHANCED ELIMINATION
    1) The high protein binding and large volume of distribution of promethazine make it a poor candidate for removal by hemodialysis or hemoperfusion.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: Adults and children with inadvertent ingestion of 1 to 2 doses (25 to 50 mg) with only mild symptoms (eg, mild sedation) can be monitored at home.
    2) OBSERVATION CRITERIA: Patients with deliberate overdose, children ingesting greater than 50 mg, and patients with more than mild symptoms or extrapyramidal effects should be referred to a healthcare facility for evaluation.
    3) ADMISSION CRITERIA: Patients exhibiting moderate to severe CNS depression or delirium should be admitted to monitor for respiratory depression and the need for airway protection.
    4) CONSULT CRITERIA: Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    J) PITFALLS
    1) If physostigmine is used to control agitation or delirium, symptoms will likely recur as the duration of action of physostigmine is 45 to 60 minutes. Use benzodiazepines for sedation judiciously because alternating agitation and sedation are common.
    K) PHARMACOKINETICS
    1) Promethazine is well absorbed with 25% bioavailability due to first pass metabolism. Metabolism is primarily hepatic. Metabolites include sulfoxides of promethazine and N-desmethylpromethazine. The metabolites are renally excreted. Protein binding is 93%. The volume of distribution is 13 L/kg. Half life is 9 to 16 hours.
    L) DIFFERENTIAL DIAGNOSIS
    1) Consider overdose of other antihistamines or antipsychotics. Also consider anticholinergic syndrome or withdrawal from ethanol or benzodiazepines.

Range Of Toxicity

    A) TOXICITY: ADULT: In adults, there is a 55% incidence of delirium at doses of 1 g. PEDIATRIC: A fatality occurred in a 2-year-old patient (unknown weight) who ingested up to 200 mg of promethazine. Anticholinergic effects have been reported in children after ingestions of 200 to 500 mg of promethazine.
    B) THERAPEUTIC DOSE: ADULTS: Varies by indication; range, 12.5 to 50 mg. Rectal dosing ranges from 6.25 to 25 mg/dose. Elderly: 6.25 to 12.5 mg. IV or IM: Up to 75 mg/dose; MAX: 100 mg/24 hours. CHILDREN: Promethazine is contraindicated in children less than 2 years of age. PARENTERAL: 1.1 mg/kg IM or IV and is expected to cause sedation. ORAL OR RECTAL: 6.25 to 25 mg as once daily or divided doses OR 0.5 mg/pound of body weight.

Clinical Effects

Summary Of Exposure

    A) USES: Promethazine is used to treat a variety of conditions, including nausea, vomiting, motion sickness, pain, and allergic reaction. It is also used for sedation and for reducing the dose of opioids required to treat severe pain.
    B) PHARMACOLOGY: Promethazine is a competitive inhibitor at histamine type 1 (H1) receptors. The drug has sedative, antiemetic, and anticholinergic effects but has no dopaminergic action.
    C) TOXICOLOGY: Overdose causes anticholinergic effects, including tachycardia, mydriasis, agitation, delirium, sedation, dry skin, and urinary retention.
    D) EPIDEMIOLOGY: Exposure is common but severe manifestations are relatively rare. Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: Drowsiness is the prominent CNS effect. Other effects include, blurred vision, dizziness, confusion, disorientation, and extrapyramidal symptoms (eg, akathisia, torticollis, and tongue protrusion), tinnitus, incoordination, fatigue, euphoria, nervousness, insomnia, tremors, excitation, and hallucinations. Nausea, vomiting, and dry mouth are common gastrointestinal effects.
    2) PARADOXICAL EFFECT: Hyperexcitability and abnormal movements may develop.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE EXPOSURE: Mild to moderate overdose may result in mild sedation, tachycardia, mild hypertension, mydriasis, flushed skin, dry mouth, confusion, and agitation. Adults generally become sedated. Children are more likely to exhibit CNS excitation.
    2) SEVERE EXPOSURE: Severe overdose may result in delirium, severe CNS depression, hypotension, seizures, and rarely respiratory depression.

Vital Signs

    3.3.3) TEMPERATURE
    A) HYPERTHERMIA
    1) WITH POISONING/EXPOSURE
    a) Elevated temperature has been reported in overdose (Swaiman, 1960; Dollberg et al, 1989).
    2) WITH THERAPEUTIC USE
    a) Hyperthermia is one of the clinical events that may occur with neuroleptic malignant syndrome which has been associated with promethazine therapy (Prod Info promethazine hcl oral tablets, 2006).
    B) HEAT STROKE
    1) WITH THERAPEUTIC USE
    a) Heat stroke in an athlete running a mini-marathon race on a cold day was attributed to ingestion of 18 mg of promethazine just before beginning the race (Weaving et al, 1980).
    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) Hypertension or hypotension may develop with therapeutic use.
    B) WITH POISONING/EXPOSURE
    1) Hypertension or hypotension may be observed in overdose.
    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) Tachycardia is commonly observed with therapeutic use (Prod Info promethazine hcl oral tablets, 2006).
    B) WITH POISONING/EXPOSURE
    1) Tachycardia is commonly observed in overdose (Page et al, 2009; Scott et al, 2007).
    2) In an 11-year retrospective review of promethazine abuse and intentional misuse, 95 cases of exposure to promethazine alone (PA) and 259 cases of exposure to promethazine-containing combination products (PC) were identified. Most patients were 10 to 19 years of age and young adults (69.5% of PA and 57.5% of PC). Tachycardia was reported in 7 (7.4%) nonmedical PA cases (Tsay et al, 2015).

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) MYDRIASIS
    a) Anticholinergic effects include fixed and dilated pupils, visual disturbances; blurred vision, and diplopia (Prod Info PHENERGAN intramuscular intravenous injection, 2011; Prod Info promethazine HCl oral tablets, 2009; Scott et al, 2007; Shawn & McGuigan, 1984; Cowen, 1979).
    2) OCULOGYRIC CRISIS
    a) Oculogyric crisis has been reported after overdose (Darwish et al, 1980) and as an idiosyncratic dystonic reaction during therapeutic use.
    3.4.5) NOSE
    A) WITH POISONING/EXPOSURE
    1) DRYING EFFECT
    a) Anticholinergic effects include dryness of the nose and nasal stuffiness (Dominikovich, 1962; Leak & Carroll, 1967).
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) DRYING EFFECT
    a) Anticholinergic effects include dryness of mouth and throat (Scott et al, 2007; Shawn & McGuigan, 1984).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Tachycardia can occur with oral or parenteral administration of promethazine (Prod Info PHENERGAN intramuscular intravenous injection, 2011; Prod Info promethazine HCl oral tablets, 2009).
    b) Irregular heart rate and tachycardia are clinical events that may occur with neuroleptic malignant syndrome which has been associated with promethazine therapy (Prod Info PHENERGAN intramuscular intravenous injection, 2011; Prod Info promethazine HCl oral tablets, 2009).
    c) QT INTERVAL PROLONGATION: A double-blind midazolam-controlled prospective study was conducted to determine promethazine's effect on cardiac repolarization and involved 40 patients who either received intravenous promethazine or midazolam as premedication prior to surgery. Using the Bazetts formula for calculating the QTc interval, significant QTc interval prolongation greater than 450 ms occurred in 11 of 20 patients in the promethazine group as compared with 2 of 20 patients in the midazolam control group (p=0.007). Using the Fridericia's formula for calculating the QTc interval, significant QTc interval prolongation greater than 450 ms occurred in 7 promethazine group patients as compared with 1 patient in the midazolam group (p=0.013). However, despite the significant QTc prolongation in the promethazine group, there were no significant differences in the time between the peak of the T-wave and the end of the T-wave (T peak - T end), indicating no significant changes in transmural dispersion of repolarization (TDR). Based on the results of this study, although promethazine may induce QTc interval prolongation following intravenous administration, the risk of torsadogenic action is very low due to minimal changes in TDR (Owczuk et al, 2009).
    2) WITH POISONING/EXPOSURE
    a) DYSRHYTHMIAS: Tachycardia and extrasystoles have been reported following overdose (Scott et al, 2007; Pan et al, 1989; Shawn & McGuigan, 1984; Page et al, 2009; Scott et al, 2007).
    b) In an 11-year retrospective review of promethazine abuse and intentional misuse, 95 cases of exposure to promethazine alone (PA) and 259 cases of exposure to promethazine-containing combination products (PC) were identified. Most patients were 10 to 19 years of age and young adults (69.5% of PA and 57.5% of PC). Tachycardia was reported in 7 (7.4%) nonmedical PA cases (Tsay et al, 2015).
    B) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) Bradycardia has been reported following oral or parenteral administration of promethazine (Prod Info PHENERGAN intramuscular intravenous injection, 2011; Prod Info promethazine HCl oral tablets, 2009).
    C) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Increased or decreased blood pressure may develop with oral or parenteral therapy (Prod Info PHENERGAN intramuscular intravenous injection, 2011; Prod Info promethazine HCl oral tablets, 2009).
    2) WITH POISONING/EXPOSURE
    a) Profound hypotension may develop following overdoses of promethazine (Prod Info PHENERGAN intramuscular intravenous injection, 2011; Prod Info promethazine HCl oral tablets, 2009; Mills, 1988).
    b) In an 11-year retrospective review of promethazine abuse and intentional misuse, 95 cases of exposure to promethazine alone (PA) and 259 cases of exposure to promethazine-containing combination products (PC) were identified. Most patients were 10 to 19 years of age and young adults (69.5% of PA and 57.5% of PC). Hypotension was reported in 1 (1%) nonmedical PA case (Tsay et al, 2015).
    D) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Transient minor increase in blood pressure have been reported after therapeutic use, and are more likely to occur with parenteral administration (Prod Info promethazine hcl injection, 2006).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: No cases of hypotension or tachycardia were noted in 100 patients given 25 to 50 mg promethazine IV to control nausea and vomiting. A few patients experienced mild to moderate hypertension which was transient and could not be explained (Adelman et al, 1959).
    b) CASE REPORT: An 82-year-old man with a history of congestive heart failure, chronic renal failure, anemia and colon cancer developed hypertension (196/120) after inadvertently receiving 200 mg of promethazine IV (Plant & MacLeod, 1994).
    c) In an 11-year retrospective review of promethazine abuse and intentional misuse, 95 cases of exposure to promethazine alone (PA) and 259 cases of exposure to promethazine-containing combination products (PC) were identified. Most patients were 10 to 19 years of age and young adults (69.5% of PA and 57.5% of PC). Hypertension was reported in 5 (5.3%) nonmedical PA cases (Tsay et al, 2015).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) Stridor, wheezing, and urticaria developed after a single 25 mg dose (ADRAC, 1982).
    B) SLEEP APNEA
    1) WITH THERAPEUTIC USE
    a) The observation that promethazine and other phenothiazines may cause episodes of sleep apnea in infants has led to speculation that some cases of SIDS may actually be promethazine-induced apneic events. Available data are suggestive, but inconclusive (Cantu, 1989).
    b) A consensus of European drug monitoring centers concluded that a link with promethazine was not confirmed, but apnea is a risk factor related to the use of sedative agents (Cockfield, 1986). Further studies including larger patient populations and measurement of drug levels will be necessary to prove a relationship.
    c) PEDIATRIC
    1) CASE SERIES: In a case-control study of 52 sudden infant death syndrome victims and 175 control infants, a history of phenothiazine use within 2 days of admission or death was obtained for 23% of SIDS victims and 2% of control infants (p less than 0.001). The specific phenothiazines were not individually tabulated, but two were mentioned as being in common usage over-the-counter (promethazine and alimenazine). In a preliminary report of 7 cases from the same population, the phenothiazine derivative was alimenazine in all cases mentioned (Kahn & Blum, 1982). However, numerous flaws in the methodology of the above study were reported (Shannon & Bergman, 1991).
    2) CASE SERIES: The administration of promethazine syrup 1 mg/kg/day to 4 normal infants resulted in an increase in the mean number of episodes of apnea. The duration of apnea was not increased, and in no case was the apnea monitor triggered (set at 20 seconds). The duration of apneas ranged from 3 to 10 seconds. Promethazine serum concentrations were not measured (Kahn et al, 1985).
    3) CASE REPORT: Two siblings developed promethazine-associated apnea in two separate incidents ; both had past medical history of premature birth, apnea, and gastroesophageal reflux (Buck & Blumer, 1991).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: PEDIATRIC: The therapeutic use of promethazine 10 mg orally at bedtime for 2 days was noted in a 14-month-old infant whose cause of death was determined to be SIDS. he promethazine serum concentration obtained at autopsy was 15.6 mcg/dL, approximately 28 times the therapeutic level, suggesting the possibility of overdose or deliberate abuse. This underscores the need to measure serum concentrations before concluding a relationship between therapeutic use of promethazine and SIDS (Degouffe & Rice, 1982).
    C) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH THERAPEUTIC USE
    a) Promethazine may cause respiratory depression with therapeutic use, especially in neurologically impaired pediatric patients (Terndrup et al, 1989; Nahata et al, 1985).
    2) WITH POISONING/EXPOSURE
    a) Respiratory arrest has been reported following overdose (Darwish et al, 1980; Dominikovich, 1962).
    b) CASE SERIES: In a series of 25 promethazine overdoses which were a combination of promethazine-only and mixed ingestions (e.g., alcohol, sedative hypnotics), 12 patients were admitted to intensive care with 8 requiring intubation for airway management. All but one patient required less than 24 hours of critical care support. No mortalities were reported (Bergman & Wallman, 1998).
    c) CASE REPORT: INFANT: Intentional administration of 25 mg of promethazine rectally and 50 mg of meperidine orally resulted in apnea, necessitating intubation, in a 24-day-old infant (Hickson et al, 1989).
    d) CASE REPORT: PEDIATRIC: A two-year-old child ingested up to 200 mg of promethazine tablets. He was admitted after a 2-hour history of rigidity and alternate tightening and loosening of the hands. On admission, manifestations included restlessness, irritability, purposeless limb movements, and blocked nasal airways. Gastric lavage was performed 2.5 hours after admission, with no return of tablets. Three hours after this procedure, he was found in respiratory failure, and could not be resuscitated. An autopsy showed tablet fragments in the stomach (Dominikovich, 1962).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DROWSINESS
    1) WITH THERAPEUTIC USE
    a) Drowsiness is the prominent CNS event with therapy (Prod Info PHENERGAN intramuscular intravenous injection, 2011; Prod Info promethazine HCl oral tablets, 2009).
    b) Drowsiness is a common side effect of therapeutic use of promethazine in adults. In one study of 10 normal volunteers given 25 mg IM, 6 reported drowsiness. Decreases in performance on various operational tasks were equivalent to that produced by blood ethanol concentration of 25 to 50 mg/dL after either IM or oral promethazine doses (Wood et al, 1984).
    2) WITH POISONING/EXPOSURE
    a) CNS depression commonly occurs early in the intoxication. Drowsiness, confusion, and coma have been reported (Prod Info promethazine hcl oral tablets, 2006; Leak & Carroll, 1967). Periods of excitation may be alternated with somnolence and catatonia (Mantz et al, 1964).
    b) CASE REPORT: INFANT: Application of 26 mg/kg of promethazine to 30% of total body surface area to a 16-month-old boy resulted in drowsiness within 30 minutes. Upon awakening, 2 hours after application, he was irritable and ataxic. Signs and symptoms on admission 8 hours after exposure included irritability, drowsiness, agitation, and tachycardia. All manifestations resolved by 18 hours postexposure. A urine specimen taken 10 hours postexposure did not contain promethazine (Shawn & McGuigan, 1984).
    c) In an 11-year retrospective review, 95 cases of exposures to promethazine alone (PA) and 259 cases of exposures to promethazine in a co-formulation with other medications (PC) were identified. Most patients were 10 to 19 years of age and young adults (69.5% of PA and 57.5% of PC). Drowsiness was reported in 41 (43.2%) nonmedical PA cases (Tsay et al, 2015).
    B) COMA
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a series of 30 antihistamine overdoses, grade 3 and 4 coma was observed in 15 patients. Coma lasted a mean of 3.9 hours (range 1 to 14 hours) (Jacobsen et al, 1984).
    b) Coma lasting at least 6 hours was reported in an adult who ingested an unknown amount (Cowen, 1979).
    c) CASE REPORTS
    1) PEDIATRIC: Coma was seen in a 14-year-old boy who ingested 200 mg of promethazine (Pan et al, 1989) and in an 11-year-old girl who ingested 500 mg (Cleghorn & Bourke, 1980).
    2) ADULT: Coma (Glasgow coma score 7) developed in an 82-year-old man who inadvertently received 200 mg of promethazine IV (Plant & MacLeod, 1994). CNS depression reversed with 0.5 mg of IV flumazenil.
    3) ADULT: A 40-year-old woman ingested an unknown amount of promethazine, and was admitted in coma, responding slightly to pain, with mydriasis and extensor plantar reflexes. Six hours after admission, she was arousable but restless and aggressive. Examination 24 hours after admission showed confusion, disorientation, and visual hallucinations. A 0.5 mg dose of physostigmine IM resolved the delirium within 15 minutes. Confusion and drowsiness returned after 2 hours. By the following day, all symptoms had resolved (Cowen, 1979).
    C) CENTRAL STIMULANT ADVERSE REACTION
    1) WITH POISONING/EXPOSURE
    a) Overdosage may result in CNS stimulation (Prod Info PHENERGAN intramuscular intravenous injection, 2011; Prod Info promethazine HCl oral tablets, 2009), usually occurring as the patient emerges from coma. Patients may become agitated, hyperreflexic, restless, delirious, and nervous (Prod Info promethazine hcl oral tablets, 2006; Leak & Carroll, 1967).
    b) CASE REPORT: A 6-week-old developed irritability after receiving promethazine (25 mg/5mL) 3/4 to 1 teaspoon every 6 hours for colic (Gesell & Stephan, 1996).
    c) In an 11-year retrospective review of promethazine abuse and intentional misuse, 95 cases of exposure to promethazine alone (PA) and 259 cases of exposure to promethazine-containing combination products (PC) were identified. Most patients were 10 to 19 years of age and young adults (69.5% of PA and 57.5% of PC). Agitation was reported in 13 (13.7%) nonmedical PA cases (Tsay et al, 2015).
    D) CLOUDED CONSCIOUSNESS
    1) WITH POISONING/EXPOSURE
    a) In an 11-year retrospective review of promethazine abuse and intentional misuse, 95 cases of exposure to promethazine alone (PA) and 259 cases of exposure to promethazine-containing combination products (PC) were identified. Most patients were 10 to 19 years of age and young adults (69.5% of PA and 57.5% of PC). Confusion was reported in 13 (13.7%) nonmedical PA cases (Tsay et al, 2015).
    E) ATAXIA
    1) WITH POISONING/EXPOSURE
    a) In an 11-year retrospective review of promethazine abuse and intentional misuse, 95 cases of exposure to promethazine alone (PA) and 259 cases of exposure to promethazine-containing combination products (PC) were identified. Most patients were 10 to 19 years of age and young adults (69.5% of PA and 57.5% of PC). Ataxia was reported in 4 (4.2%) nonmedical PA cases (Tsay et al, 2015).
    F) DIZZINESS
    1) WITH POISONING/EXPOSURE
    a) In an 11-year retrospective review of promethazine abuse and intentional misuse, 95 cases of exposure to promethazine alone (PA) and 259 cases of exposure to promethazine-containing combination products (PC) were identified. Most patients were 10 to 19 years of age and young adults (69.5% of PA and 57.5% of PC). Dizziness was reported in 7 (7.4%) nonmedical PA cases (Tsay et al, 2015).
    G) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures have been reported with therapeutic use (Prod Info PHENERGAN intramuscular intravenous injection, 2011; Prod Info promethazine HCl oral tablets, 2009).
    b) CASE SERIES: Three obstetric patients developed seizures after administration of promethazine following spinal anesthesia; a cause-effect relationship could not be established (Adelman et al, 1959). Similarly, a combination of chlorpromazine and promethazine "lytic cocktail", used in the treatment of eclampsia, increased seizure occurrence (El-Kadre & Giordano, 1985).
    c) CASE SERIES: Three cases of seizures were described in children who received higher than normally recommended doses of promethazine as anesthetic premedication. Doses given were 0.65 to 0.85 mg/kg IM (Waterhouse, 1967).
    H) SLURRED SPEECH
    1) WITH POISONING/EXPOSURE
    a) In an 11-year retrospective review of promethazine abuse and intentional misuse, 95 cases of exposure to promethazine alone (PA) and 259 cases of exposure to promethazine-containing combination products (PC) were identified. Most patients were 10 to 19 years of age and young adults (69.5% of PA and 57.5% of PC). Slurred speech was reported in 12 (12.6%) nonmedical PA cases (Tsay et al, 2015).
    I) DELIRIUM
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Abrupt onset of incoherent speech, inability to recognize parents, combative behavior, mydriasis, ankle clonus, and hyperactive deep tendon reflexes were reported 2 hours after administration of promethazine 25 mg per rectum to a 5-year-old child (Fisher, 1972).
    2) WITH POISONING/EXPOSURE
    a) In adults there is a 55% incidence of delirium at doses of 1g (Page et al, 2009).
    b) CASE SERIES: A retrospective analysis of 237 consecutive admissions for promethazine overdose showed that 30% presented with delirium. Patients, admitted with promethazine as their only ingestant, presented with delirium 42% of the time (Page et al, 2009).
    c) PEDIATRIC CASE REPORTS
    1) Topical application of 12.9 to 19.4 mg/kg of promethazine to 13% of total body surface area to a 44-month-old girl resulted in visual hallucinations 3 hours later. Some peripheral anticholinergic signs were also present (dry mucous membranes, mydriasis, and urinary retention). Screaming, hallucinations, and excitomotor symptoms persisted until 12 hours after admission. Promethazine was identified qualitatively in the urine (Shawn & McGuigan, 1984).
    2) A 5-year-old girl ingested 500 mg (28 mg/kg) of promethazine tablets. On admission, she was noted to have hallucinations, choreoathetoid movements, slurred speech, and ataxia. Sinus tachycardia and extensor plantar reflexes were present. She was given a single IV dose of physostigmine, and became quiet and oriented with an uncomplicated course (Cleghorn & Bourke, 1980).
    3) A 6-year-old girl ingested 200 mg (20 mg/kg) of promethazine tablets and became delirious, hyperactive, disoriented, ataxic, and hypertonic. She received physostigmine 0.5 mg IV and improved with discharge 24 hours after admission (Cleghorn & Bourke, 1980).
    4) An 11-year-old girl ingested 500 mg (12.5 mg/kg) of promethazine tablets, along with imipramine 375 mg. Within 6 hours she was noted to have irritability, extensor plantar reflexes, mydriasis, and tachycardia. One hour later, she was in coma, responding slowly to pain. She improved within 5 minutes of a single 2 mg dose of physostigmine IV. Eight hours after the dose, and 24 hours postingestion, hallucinations and choreoathetoid movements were noted. Improvement was noted after a second dose of physostigmine 0.5 mg (Cleghorn & Bourke, 1980).
    5) A 12-year-old boy developed delirium and hallucinations four hours after ingestion of 200 mg of promethazine. Hallucinations were both visual and tactile (hyperaesthesia, hyperalgesia). Slurred speech, restlessness, violent activity, agitation, and sinus tachycardia were also present. Other anticholinergic findings included dry mouth and stuffy nose. Hallucinations and extensor plantar reflexes resolved 22 hours after onset (Leak & Carroll, 1967).
    6) A 14-year-old girl intentionally ingested 200 mg of cyproheptadine and 1150 mg of promethazine and subsequently developed depressed consciousness (Glasgow Coma Scale of 8) and prolonged delirium, consisting of agitation, confusion, disorientation, rapid and unintelligible speech, and visual hallucinations. With supportive care, the delirium gradually resolved over a 7-day period. In conjunction with the overdose, the patient had also been taking fluvoxamine at a dose of 150 mg daily. It is speculated that concurrent administration of promethazine, predominantly metabolized by CYP2D6, and fluvoxamine, a CYP2D6 inhibitor, may have contributed to the development of the prolonged delirium (Scott et al, 2007).
    J) DYSTONIA
    1) WITH THERAPEUTIC USE
    a) DYSTONIC REACTIONS have included opisthotonus, oculogyric crisis (Prod Info promethazine hcl oral tablets, 2006; Darwish et al, 1980), decorticate posturing (Cohen et al, 1982), trismus (Cohen et al, 1982; DeGrandi & Simon, 1987), orofacial dystonias (Yung, 1983; Darwish et al, 1980), extremity tremor (Schwinghammer et al, 1984a), and torticollis (DeGrandi & Simon, 1987).
    b) A dystonic reaction was reported in 1 of 1,194 patients who received promethazine for preoperative sedation (Miller & Greenblatt, 1976).
    c) Idiosyncratic dystonic reactions have occurred after single therapeutic doses, and are typically delayed in onset for 24 hours or more after initiation of therapy (Swaiman, 1960; Yung, 1983; DeGrandi & Simon, 1987; Schwinghammer et al, 1984a; Cohen et al, 1982).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: An acute dystonic reaction, characterized by opisthotonus, and facial dyskinesias (tongue-darting, lip smacking), was reported in a 2-year-old child 24 hours after a large promethazine overdose (Darwish et al, 1980).
    b) In an 11-year retrospective review of promethazine abuse and intentional misuse, 95 cases of exposure to promethazine alone (PA) and 259 cases of exposure to promethazine-containing combination products (PC) were identified. Most patients were 10 to 19 years of age and young adults (69.5% of PA and 57.5% of PC). Dystonia was reported in 2 (2.1%) nonmedical PA cases (Tsay et al, 2015).
    K) HYPERREFLEXIA
    1) WITH POISONING/EXPOSURE
    a) ABNORMAL REFLEXES: Extensor plantar reflexes and hyperreflexia may occur following overdose (Prod Info PHENERGAN intramuscular intravenous injection, 2011; Prod Info promethazine HCl oral tablets, 2009; Plant & MacLeod, 1994; Cowen, 1979; Leak & Carroll, 1967; Mantz et al, 1964).
    L) CHOREOATHETOSIS
    1) WITH THERAPEUTIC USE
    a) Athetoid movements have also been noted following therapeutic use (Adelman et al, 1959).
    2) WITH POISONING/EXPOSURE
    a) Choreoathetosis has been noted in children following promethazine overdose; in one case movements did not occur until 24 hours after the overdose (Cleghorn & Bourke, 1980).
    M) HALLUCINATIONS
    1) WITH THERAPEUTIC USE
    a) Visual and tactile hallucinations and toxic psychosis symptoms have been described after therapeutic use in children (Prod Info promethazine hcl oral tablets, 2006; Kalikow & Kisco, 1988), and in adults with renal failure (McAllister et al, 1978).
    2) WITH POISONING/EXPOSURE
    a) Visual and tactile hallucinations and toxic psychosis have been reported with promethazine toxicity (Shawn & McGuigan, 1984; Leak & Carroll, 1967).
    b) In an 11-year retrospective review of promethazine abuse and intentional misuse, 95 cases of exposure to promethazine alone (PA) and 259 cases of exposure to promethazine-containing combination products (PC) were identified. Most patients were 10 to 19 years of age and young adults (69.5% of PA and 57.5% of PC). Hallucinations were reported in 7 (7.4%) nonmedical PA cases (Tsay et al, 2015).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting may occur with therapeutic use (Prod Info PHENERGAN intramuscular intravenous injection, 2011; Prod Info promethazine HCl oral tablets, 2009; Prod Info promethazine hcl oral tablets, 2006).
    2) WITH POISONING/EXPOSURE
    a) In an 11-year retrospective review of promethazine abuse and intentional misuse, 95 cases of exposure to promethazine alone (PA) and 259 cases of exposure to promethazine-containing combination products (PC) were identified. Most patients were 10 to 19 years of age and young adults (69.5% of PA and 57.5% of PC). Vomiting was reported in 6 (6.3%) nonmedical PA cases (Tsay et al, 2015).
    B) DRUG-INDUCED ILEUS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 6-week-old developed a tender, distended abdomen with decreased bowel sounds after receiving promethazine (25 mg/5mL) 3/4 to 1 teaspoon every 6 hours for colic (Gesell & Stephan, 1996).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) JAUNDICE
    1) WITH THERAPEUTIC USE
    a) Jaundice has been reported with therapy (Prod Info PHENERGAN intramuscular intravenous injection, 2011; Prod Info promethazine HCl oral tablets, 2009; S Sweetman , 2000).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RETENTION OF URINE
    1) WITH POISONING/EXPOSURE
    a) Anticholinergic effects of urinary retention have been reported with promethazine toxicity (Prod Info promethazine hcl oral tablets, 2006; Prod Info promethazine hcl injection, 2006; Shawn & McGuigan, 1984; Mantz et al, 1964).
    B) ABNORMAL URINE
    1) WITH POISONING/EXPOSURE
    a) COLOR CHANGE: Promethazine overdose is reported to produce a characteristic rose color; however this was due to hematuria in one case (Cliche, 1961).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) AGRANULOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) A case of an adult treated with a total of 8,725 g in approximately 4 weeks who developed reversible agranulocytosis was reported (Engel, 1976).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) URTICARIA
    1) WITH THERAPEUTIC USE
    a) Urticaria has occurred with therapeutic use (Prod Info PHENERGAN intramuscular intravenous injection, 2011; Prod Info promethazine HCl oral tablets, 2009).
    B) FLUSHING
    1) WITH POISONING/EXPOSURE
    a) Facial erythema has been observed after overdose (Prod Info promethazine hcl oral tablets, 2006; Mantz et al, 1964; Cliche, 1961).
    C) PHOTOSENSITIVITY
    1) WITH THERAPEUTIC USE
    a) Photosensitivity can develop with therapeutic use (Prod Info PHENERGAN intramuscular intravenous injection, 2011; Prod Info promethazine HCl oral tablets, 2009).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MYOCLONUS
    1) WITH POISONING/EXPOSURE
    a) Myoclonus has been reported following overdose (Scott et al, 2007; Pan et al, 1989; VanSweden & Dumon-Radermecker, 1982).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLAXIS
    1) WITH THERAPEUTIC USE
    a) An anaphylactic reaction to promethazine may include urticaria, dermatitis, wheezing and bronchospasm, and photosensitivity. Angioneurotic edema has also been reported (Prod Info promethazine hcl oral tablets, 2006).
    b) Promethazine injection contains sodium metabisulfite which may produce an allergic reaction in sensitive individuals resulting in life-threatening anaphylaxis or bronchospastic episodes. Individuals with asthma appear may be more sensitive to sulfites (Prod Info PHENERGAN intramuscular intravenous injection, 2011).
    c) CASE REPORT: A 39-year-old woman developed burning skin, tightness of the throat and chest, palpitations, and generalized itching 15 minutes after promethazine 25 mg orally, in combination with temazepam 30 mg. She became unconscious, hypotensive, and tachycardic. Facial edema was noted on recovery, persisting the following day (Mills, 1988).

Reproductive

    3.20.1) SUMMARY
    A) The neonate may develop respiratory depression, transient behavioral changes, transient EEG changes, or impaired platelet aggregation associated with maternal promethazine administration during labor.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) In Hungary, a retrospective study was conducted to determine the potential embryo-fetal effects of promethazine on children born to mothers who intentionally ingested promethazine as a suicide attempt during their pregnancy. Of 89 women exposed, 32 live births were reported. Among this group, the dose of promethazine ranged between 125 mg and 1750 mg (mean of 544 mg). Of the 32 children exposed, a total of 9 (28.1%) children had congenital abnormalities. Although the number of adverse events appeared high, only 11 of the 32 women attempted suicide between the 3rd and 12th postconceptional weeks (a critical time period for the development of major congenital anomalies). Of those mothers, only 3 infants were born with congenital anomalies. Two boys had undescended testes of which one had a familial tendency and the third case was a boy with XY karyotype with complex cardiac anomalies. The authors concluded that there was no significant evidence that promethazine was a potential human teratogen, nor could any specific teratogenic effects be determined (Petik et al, 2008).
    3.20.3) EFFECTS IN PREGNANCY
    A) SUMMARY
    1) The neonate may develop respiratory depression, transient behavioral changes, transient EEG changes, or impaired platelet aggregation associated with maternal promethazine administration during labor.
    B) RESPIRATORY DEPRESSION
    1) The use of promethazine during labor has been associated rarely with neonatal respiratory depression (Hall, 1987).
    C) PERSONALITY DISORDER
    1) Transient behavioral changes have also been described in neonates (Borgstedt & Rosen, 1986).
    D) EEG ABNORMAL
    1) EEG changes have also been described in neonates (Borgstedt & Rosen, 1986).
    E) PLATELETS ABNORMAL
    1) Significantly impaired platelet aggregation has been observed in neonates after use of promethazine during labor (Corby & Schulman, 1971; Whaun et al, 1980).
    F) PREGNANCY CATEGORY
    PROMETHAZINEC
    Reference: Briggs et al, 1998

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Serum concentrations are not generally available or useful in the acute setting.
    C) Institute continuous cardiac monitoring and obtain an ECG.
    D) Monitor serum electrolytes.
    E) Monitor CK in patients with prolonged agitation, seizures, or severe CNS depression.
    4.1.2) SERUM/BLOOD
    A) SUMMARY
    1) Serum concentrations are not generally available or useful in the acute setting.
    2) Monitor serum electrolytes.
    3) Monitor CK in patients with prolonged agitation, seizures, or severe CNS depression.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor vital signs and mental status.
    b) Institute continuous cardiac monitoring and obtain an ECG.

Methods

    A) CHROMATOGRAPHY
    1) The most frequently used assay methods are nitrogen specific gas chromatography and liquid chromatography. A spurious second peak of promethazine may be seen with the gas chromatography procedure, secondary to thermal degradation of promethazine sulfoxide to promethazine (Patel & Welling, 1981).
    B) OTHER
    1) WHOLE BLOOD/PAROTID SALIVA: A sensitive method for the detection and quantitation of promethazine in whole blood and parotid saliva after oral or intramuscular administration in human volunteers has been described (DiGregorio & Ruch, 1980).

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 exhibiting moderate to severe CNS depression or delirium should be admitted to monitor for respiratory depression and the need for airway protection.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Adults and children with inadvertent ingestion of 1 to 2 doses (25 to 50 mg) with only mild symptoms (eg, mild sedation) can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate overdose, children ingesting greater than 50 mg, and patients with more than mild symptoms or extrapyramidal effects should be referred to a healthcare facility for evaluation.
    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients exhibiting moderate to severe CNS depression or delirium should be admitted to monitor for respiratory depression and the need for airway protection.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) Adults and children with inadvertent ingestion of 1 to 2 doses (25 to 50 mg) with only mild symptoms (eg, mild sedation) can be monitored at home.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Patients with deliberate overdose, children ingesting greater than 50 mg, and patients with more than mild symptoms or extrapyramidal effects should be referred to a healthcare facility for evaluation.

Monitoring

    A) Monitor vital signs and mental status.
    B) Serum concentrations are not generally available or useful in the acute setting.
    C) Institute continuous cardiac monitoring and obtain an ECG.
    D) Monitor serum electrolytes.
    E) Monitor CK in patients with prolonged agitation, seizures, or severe CNS depression.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination should generally be avoided because of the risk of CNS depression.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) Prompt administration of activated charcoal may decrease the risk of developing delirium following promethazine overdose and decrease overall length of stay (Page et al, 2009).
    a) In a retrospective study of 199 patients with 237 presentations of promethazine overdose, the clinical events associated with overdose were analyzed along with evaluating the potential benefits of charcoal administration. Delirium was observed in 33 (42%) promethazine alone overdoses and 71 (30%) cases of promethazine and a coingestant. Of the cases of promethazine alone overdoses, the median dose was 875 mg as compared to 500 mg in patients who did not develop delirium. The probability of developing delirium was found to be based on a dose-response relationship. Univariate analysis showed that the administration of charcoal within 1 or 2 hours and any coingestant or benzodiazepine coingestant, in particular, was associated with a decreased risk of delirium. The administration of activated charcoal reduced the probability of delirium by approximately 20% (relative risk 0.47) as compared to 9% if administered within 4 hours. Although studies trials are suggested, the authors concluded that the administration of activated charcoal within the 2 hours of exposure, if no significant CNS depression is present, may decrease the probability of delirium (Page et al, 2009).
    2) 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.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. Symptoms typically appear within 20 minutes of oral administration and last for approximately 4 to 6 hours. However, effects may be present up to 12 hours (Prod Info promethazine HCl oral tablets, 2009).
    B) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) Serum concentrations are not generally available or useful in the acute setting.
    3) Institute continuous cardiac monitoring and obtain an ECG.
    4) Monitor serum electrolytes.
    5) Monitor CK in patients with prolonged agitation, seizures, or severe CNS depression.
    C) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    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).
    E) 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).
    F) DELIRIUM
    1) Severely agitated patients should be treated with benzodiazepines for sedation with careful monitoring for respiratory depression. Anticholinergic delirium will respond to physostigmine, but will generally recur within one hour due to the short duration of action of physostigmine; benzodiazepines are generally preferred.
    a) DIAZEPAM
    1) ADULT DIAZEPAM DOSE: 5 to 10 mg slow intravenous push, repeat if necessary with small incremental doses of IV diazepam.
    2) PEDIATRIC DIAZEPAM DOSE: 0.1 mg/kg, repeat if necessary with small incremental doses of intravenous diazepam.
    b) LORAZEPAM
    1) ADULT LORAZEPAM DOSE: 2 to 4 mg by IV bolus injection
    2) PEDIATRIC LORAZEPAM DOSE: 0.05 mg/kg by IV bolus injection
    2) If physostigmine is used to control agitation or delirium, symptoms will likely recur as the duration of action of physostigmine is 45 to 60 minutes (Prod Info physostigmine salicylate injection, 2006).
    G) DRUG-INDUCED DYSTONIA
    1) ADULT
    a) BENZTROPINE: 1 to 4 mg once or twice daily intravenously or intramuscularly; maximum dose: 6 mg/day; 1 to 2 mg of the injection will usually provide quick relief in emergency situations (Prod Info benztropine mesylate IV, IM injection, 2009).
    b) DIPHENHYDRAMINE: 10 to 50 mg intravenously at a rate not exceeding 25 mg/minute or deep intramuscularly; maximum dose: 100 mg/dose; 400 mg/day (Prod Info diphenhydramine hcl injection, 2006).
    2) CHILDREN
    a) DIPHENHYDRAMINE: 5 mg/kg/day or 150 mg/m(2)/day intravenously divided into 4 doses at a rate not to exceed 25 mg/min, or deep intramuscularly; maximum dose: 300 mg/day. Not recommended in premature infants and neonates (Prod Info diphenhydramine hcl injection, 2006).
    H) CARDIOGENIC SHOCK
    1) Rarely occurs and may require use of an intraaortic balloon pump (Freedberg et al, 1987).
    I) FLUMAZENIL
    1) Flumazenil 0.5 mg IV was associated with reversal of CNS depression in a patient who inadvertently received 200 mg of promethazine intravenously (Plant & MacLeod, 1994). Routine use is NOT recommended.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) Promethazine can cause systemic toxicity by the dermal route.
    B) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) LACK OF EFFECT
    1) Based on limited experience, dialysis appears to have little utility (Prod Info promethazine HCl oral tablets, 2009). The high protein binding and large volume of distribution of promethazine make it a poor candidate for removal by hemodialysis or hemoperfusion.

Abstracts

Case Reports

    A) ROUTE OF EXPOSURE
    1) DERMAL
    a) INFANT: Application of 26 mg/kg of promethazine to 30% of total body surface area to a 16-month-old boy resulted in drowsiness within 30 minutes. Upon awakening, 2 hours after application, he was irritable and ataxic. Signs and symptoms on admission 8 hours after exposure included irritability, drowsiness, agitation, and tachycardia. All manifestations resolved by 18 hours postexposure. A urine specimen taken 10 hours postexposure did not contain promethazine (Shawn & McGuigan, 1984).
    b) PEDIATRIC: Topical application of 12.9 to 19.4 mg/kg of promethazine to 13% of total body surface area to a 44-month-old girl resulted in visual hallucinations 3 hours later. Some peripheral anticholinergic signs were also present (dry mucous membranes, mydriasis, urinary retention). Screaming, hallucinations, and excitomotor symptoms persisted until 12 hours after admission. Promethazine was identified qualitatively in the urine (Shawn & McGuigan, 1984).
    c) ADULT: A 14-year-old boy presented unconscious five hours after topical application of 90 grams of 2% promethazine cream to the entire body. Signs and symptoms on admission included disorientation, agitation, myoclonus, and dry mouth. The EKG showed a series of preventricular contractions. Blood and urine specimens on admission showed 140 ng/mL and 80 ng/mL, respectively. All manifestations resolved within 24 hours (Pan et al, 1989).
    2) ORAL
    a) PEDIATRIC: A two-year-old child ingested up to 200 mg of promethazine tablets. He was admitted after a 2-hour history of rigidity and alternate tightening and loosening of the hands. On admission, manifestations included restlessness, irritability, purposeless limb movements, and blocked nasal airways. Gastric lavage was performed 2.5 hours after admission, with no return of tablets. Three hours after this procedure, he was found in respiratory failure, and could not be resuscitated. An autopsy showed tablet fragments in the stomach (Dominikovich, 1962).
    b) A 5-year-old girl ingested 500 mg (28 mg/kg) of promethazine tablets. On admission, she was noted to have hallucinations, choreoathetoid movements, slurred speech, and ataxia. Sinus tachycardia and extensor plantar reflexes were present. She was given a single IV dose of physostigmine, and became quiet and oriented, with an uncomplicated course (Cleghorn & Bourke, 1980).
    c) A 6-year-old girl ingested 200 mg (20 mg/kg) of promethazine tablets and became delirious, hyperactive, disoriented, ataxic, and hypertonic. She received physostigmine 0.5 mg IV and improved, with discharge 24 hours after admission (Cleghorn & Bourke, 1980).
    d) An 11-year-old girl ingested 500 mg (12.5 mg/kg) of promethazine tablets, along with imipramine 375 mg. Within 6 hours she was noted to have irritability, extensor plantar reflexes, mydriasis, and tachycardia. One hour later, she was in coma, responding slowly to pain. She improved within 5 minutes of a single 2 mg dose of physostigmine IV. Eight hours after the dose, and 24 hours postingestion, hallucinations and choreoathetoid movements were noted. Improvement was noted after a second dose of physostigmine 0.5 mg (Cleghorn & Bourke, 1980).
    e) A 12-year-old boy developed delirium and hallucinations four hours after ingestion of 200 mg of promethazine. Hallucinations were both visual and tactile (hyperaesthesia, hyperalgesia). Slurred speech, restlessness, violent activity, agitation, and sinus tachycardia were also present. Other anticholinergic findings included dry mouth and stuffy nose. Hallucinations and extensor plantar reflexes resolved 22 hours after onset (Leak & Carroll, 1967).
    f) ADULT: A 40-year-old woman ingested an unknown amount of promethazine, and was admitted in coma, responding slightly to pain, with mydriasis and extensor plantar reflexes. Six hours after admission, she was arousable, but restless and aggressive. Examination 24 hours after admission showed confusion, disorientation, and visual hallucinations. A 0.5 mg dose of physostigmine IM resolved the delirium within 15 minutes. Confusion and drowsiness returned after 2 hours. By the following day, all symptoms had resolved (Cowen, 1979).

Range Of Toxicity

Summary

    A) TOXICITY: ADULT: In adults, there is a 55% incidence of delirium at doses of 1 g. PEDIATRIC: A fatality occurred in a 2-year-old patient (unknown weight) who ingested up to 200 mg of promethazine. Anticholinergic effects have been reported in children after ingestions of 200 to 500 mg of promethazine.
    B) THERAPEUTIC DOSE: ADULTS: Varies by indication; range, 12.5 to 50 mg. Rectal dosing ranges from 6.25 to 25 mg/dose. Elderly: 6.25 to 12.5 mg. IV or IM: Up to 75 mg/dose; MAX: 100 mg/24 hours. CHILDREN: Promethazine is contraindicated in children less than 2 years of age. PARENTERAL: 1.1 mg/kg IM or IV and is expected to cause sedation. ORAL OR RECTAL: 6.25 to 25 mg as once daily or divided doses OR 0.5 mg/pound of body weight.

Therapeutic Dose

    7.2.1) ADULT
    A) PROMETHAZINE
    1) ORAL: Varies by indication; the recommended dose is 12.5 to 50 mg as once daily or divided doses (Prod Info promethazine HCl oral tablets, 2013).
    2) RECTAL: Varies by indication; the recommended dose is 12.5 to 25 mg/dose or every 4 to 6 hours as needed OR up to 50 mg/dose postoperatively or for presurgical/obstetrical sedation (Prod Info PHENERGAN(TM) rectal suppositories, 2014).
    3) PARENTERAL: Varies by indication: (obstetric) 25 to 75 mg (mean dose, 50 mg) IM or IV (in combination with reduced dose analgesic); may repeat once or twice at 4-hour intervals during the course of the labor; MAX 100 mg/24 hours; for IV, MAX concentration is 25 mg/mL and MAX infusion rate is 25 mg/min (Prod Info Promethazine Hydrochloride IM, IV injection, 2009)
    4) Inadvertent intraarterial injection can result in gangrene of the affected extremity. SubQ injections are contraindicated as they can result in tissue necrosis (Prod Info Phenergan(R) intramuscular intravenous injection, 2012).
    B) PROMETHAZINE IN COMBINATION WITH OTHER AGENTS
    1) The recommended dose is 5 mL every 4 to 6 hours. MAX DOSE: 30 mL in 24 hours (Prod Info promethazine HCl codeine phosphate oral solution, 2013; Prod Info Promethazine HCl Phenylephrine HCl Codeine Phosphate oral solution, 2013; Prod Info PROMETHAZINE WITH DEXTROMETHORPHAN COUGH SYRUP oral syrup, 2010; Prod Info promethazine HCl phenylephrine HCl oral syrup, 2009).
    7.2.2) PEDIATRIC
    A) Promethazine is contraindicated in children less than 2 years of age (Prod Info PHENERGAN(TM) rectal suppositories, 2014; Prod Info promethazine HCl oral tablets, 2013).
    B) PROMETHAZINE
    1) ORAL OR RECTAL: CHILDREN OVER 2 YEARS OF AGE: 6.25 to 25 mg as once daily or divided doses OR 0.5 mg/pound of body weight (Prod Info PHENERGAN(TM) rectal suppositories, 2014; Prod Info promethazine HCl oral tablets, 2009).
    2) PARENTERAL: CHILDREN OVER 2 YEARS OF AGE: 1.1 mg/kg of body weight IM or IV. In children 2 years of age and older, the dose should not exceed half that of the suggested adult dose (Prod Info PHENERGAN intramuscular intravenous injection, 2011).
    3) Inadvertent intraarterial injection can result in gangrene of the affected extremity. SubQ injections are contraindicated as it can result in tissue necrosis (Prod Info PHENERGAN intramuscular intravenous injection, 2011).
    C) PROMETHAZINE AND CODEINE ORAL SOLUTION
    1) CHILDREN 12 YEARS AND OLDER: The recommended dose is 5 mL every 4 to 6 hours. MAX DOSE: 30 mL in 24 hours. Note: Each 5 mL contains 6.25 mg of promethazine hydrochloride and 10 mg of codeine phosphate (Prod Info promethazine HCl and codeine phosphate oral solution, 2008).
    2) CHILDREN 6 TO UNDER 12 YEARS OF AGE: The recommended dose is 2.5 mL to 5 mL every 4 to 6 hours. MAX DOSE: 30 mL in 24 hours. Note: Each 5 mL contains 6.25 mg of promethazine hydrochloride and 10 mg of codeine phosphate (Prod Info promethazine HCl codeine phosphate oral solution, 2013).
    D) PROMETHAZINE, CODEINE, AND PHENYLEPHRINE ORAL SOLUTION
    1) CHILDREN 12 YEARS AND OLDER: The recommended dose is 5 mL every 4 to 6 hours. MAX DOSE: 30 mL in 24 hours. Note: Each 5 mL contains 6.25 mg of promethazine hydrochloride, 5 mg of phenylephrine hydrochloride, and 10 mg of codeine phosphate (Prod Info Promethazine HCl Phenylephrine HCl Codeine Phosphate oral solution, 2013).
    2) CHILDREN 6 TO UNDER 12 YEARS OF AGE: The recommended dose is 2.5 mL to 5 mL every 4 to 6 hours. MAX DOSE: 30 mL in 24 hours. Note: Each 5 mL contains 6.25 mg of promethazine hydrochloride, 5 mg of phenylephrine hydrochloride, and 10 mg of codeine phosphate (Prod Info Promethazine HCl Phenylephrine HCl Codeine Phosphate oral solution, 2013).
    E) PROMETHAZINE AND DEXTROMETHORPHAN ORAL SYRUP
    1) CHILDREN 12 YEARS AND OLDER: The recommended dose is 5 mL every 4 to 6 hours. MAX DOSE: 30 mL in 24 hours. Note: Each 5 mL contains 15 mg of dextromethorphan hydrobromide and 6.25 mg of promethazine hydrochloride (Prod Info PROMETHAZINE WITH DEXTROMETHORPHAN COUGH SYRUP oral syrup, 2010).
    2) CHILDREN 6 TO UNDER 12 YEARS OF AGE: The recommended dose is 2.5 mL to 5 mL every 4 to 6 hours. MAX DOSE: 20 mL in 24 hours. Note: Each 5 mL contains 15 mg of dextromethorphan hydrobromide and 6.25 mg of promethazine hydrochloride (Prod Info PROMETHAZINE WITH DEXTROMETHORPHAN COUGH SYRUP oral syrup, 2010).
    3) CHILDREN 2 TO UNDER 6 YEARS OF AGE: The recommended dose is 1.25 to 2.5 mL to 5 mL every 4 to 6 hours. MAX DOSE: 10 mL in 24 hours. Note: Each 5 mL contains 15 mg of dextromethorphan hydrobromide and 6.25 mg of promethazine hydrochloride (Prod Info PROMETHAZINE WITH DEXTROMETHORPHAN COUGH SYRUP oral syrup, 2010).
    F) PROMETHAZINE AND PHENYLEPHRINE ORAL SYRUP
    1) CHILDREN 12 YEARS AND OLDER: The recommended dose is 5 mL every 4 to 6 hours. MAX DOSE; 30 mL in 24 hours. Note: Each 5 mL contains 6.25 mg of promethazine hydrochloride and 5 mg of phenylephrine hydrochloride (Prod Info promethazine HCl phenylephrine HCl oral syrup, 2009).
    2) CHILDREN 6 TO UNDER 12 YEARS OF AGE: The recommended dose is 2.5 mL to 5 mL every 4 to 6 hours. MAX DOSE: 30 mL in 24 hours. Note: Each 5 mL contains 6.25 mg of promethazine hydrochloride and 5 mg of phenylephrine hydrochloride (Prod Info promethazine HCl phenylephrine HCl oral syrup, 2009).
    3) CHILDREN 2 TO UNDER 6 YEARS OF AGE: The recommended dose is 1.25 to 2.5 mL to 5 mL every 4 to 6 hours. Note: Each 5 mL contains 6.25 mg of promethazine hydrochloride and 5 mg of phenylephrine hydrochloride (Prod Info promethazine HCl phenylephrine HCl oral syrup, 2009).

Minimum Lethal Exposure

    A) INFANT
    1) Death was reported in a 2-year-old with a history of ingesting up to 200 mg of promethazine tablets (Dominikovich, 1962).

Maximum Tolerated Exposure

    A) ADULT
    1) In adults, there is a 55% incidence of delirium at doses of 1 g (Page et al, 2009).
    B) PEDIATRIC
    1) CNS toxicity (delirium, coma, hallucinations) with survival has been described in children aged 5 to 12 years after accidental ingestion of 200 to 500 milligrams of promethazine (12.5 to 28 milligrams/kilogram) (Leak & Carroll, 1967; Cleghorn & Bourke, 1980).
    2) Prolonged delirium occurred in a 14-year-old girl following intentional ingestion of 200 mg of cyproheptadine and 1150 mg of promethazine while she was taking fluvoxamine 150 mg/day (Scott et al, 2007).
    3) Ingestion of 575 mg by a 20-month-old child resulted in agitation alternated by somnolence, tachycardia, hallucinations, and hematuria with recovery by 15 hours after ingestion (Cliche, 1961).
    4) INFANT
    a) A 6-week-old developed symptoms of irritability and abdominal tenderness after receiving promethazine 3/4 to 1 teaspoon every 6 hours for colic on the previous day. A serum concentration of 166 ng/mL was reported; the patient was treated with supportive care with no permanent sequelae reported (Gesell & Stephan, 1996).
    C) OTHER
    1) Dystonic reactions have occurred after therapeutic use (DeGrandi & Simon, 1987; Schwinghammer et al, 1984a; Cohen et al, 1982; Swaiman, 1960):
    AGE(YR)DOSE(MG)DOSE(MG/KG)REFERENCE
    1512.5 X 3 PR0.6DeGrandi,1987
    2250 (syrup) PO0.6Schwinghammer,1984a
    36.875 IM0.48Cohen,1979
    59.375 IM0.625Cohen,1979
    512.5 IM Swaiman,1960

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORTS
    a) Adverse effects after IM administration were associated with plasma concentrations of 48 ng/mL(Schwinghammer et al, 1984).
    b) Toxicity was seen in a patient with a blood concentration of 140 ng/mL after topical application (Pan et al, 1989).
    c) Death was reported in an infant with a postmortem blood concentration of 156 ng/mL (Degouffe & Rice, 1982).
    d) A 6-week-old infant had a promethazine blood concentration of 166 ng/mL (obtained more than 7 hours after the last dose (peak concentration usually 2-3 hours after oral dosing); no permanent sequelae were reported (Gesell & Stephan, 1996). In a previously reported case, a 14-month-old died with a serum concentration of 156 ng/mL.

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAMUSCULAR)MOUSE:
    a) 175 mg/kg (RTECS , 2000)
    2) LD50- (INTRAPERITONEAL)MOUSE:
    a) 124 mg/kg (RTECS , 2000)
    3) LD50- (ORAL)MOUSE:
    a) 326 mg/kg (RTECS , 2000)
    4) LD50- (SUBCUTANEOUS)MOUSE:
    a) 225 mg/kg (RTECS , 2000)
    5) LD50- (INTRAMUSCULAR)RAT:
    a) 169 mg/kg (RTECS , 2000)
    6) LD50- (SUBCUTANEOUS)RAT:
    a) 700 mg/kg (RTECS , 2000)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Promethazine is a competitive inhibitor at histamine type 1 (H1) receptors. The drug has sedative, antiemetic, and anticholinergic effects but has no dopaminergic action (Prod Info PHENERGAN intramuscular intravenous injection, 2011; Prod Info promethazine HCl oral tablets, 2009).

Toxicologic Mechanism

    A) The toxicity of promethazine is primarily related to its anticholinergic (antimuscarinic) activity. The action of acetylcholine at muscarinic receptors is blocked.

Physicochemical

Ph

    A) A white or faintly yellow crystalline powder; essentially no odor. Following prolonged exposure to air it slowly oxidizes and turns blue in color (S Sweetman , 2000).

Molecular Weight

    A) 320.9 (S Sweetman , 2000)

Animal Toxicology

Clinical Effects

    11.1.3) CANINE/DOG
    A) A 7-month-old Doberman Pinscher was admitted with profound hypotension, a weak and rapid pulse, dilated and unresponsive pupils, and severe abdominal pain following the symptomatic use of promethazine suppositories for vomiting. The animal made a complete recovery following supportive care (Staley & Staley, 1995).

Treatment

    11.2.2) LIFE SUPPORT
    A) A 7-month-old Doberman Pinscher in near cardiac collapse following a promethazine overdose was initially given atropine and intravenous fluids. Treatment with atropine was begun before the causative agent was known; no arrhythmias were reported (Staley & Staley, 1995).

References

General Bibliography

    1) ADRAC: Adverse Drug Reactions Advisory Committee. Seven case studies: antihistamines. ADRAC: Med J Aust 1982; 1:522.
    2) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    3) Adelman MH, Jacobson E, & Lief PA: Promethazine hydrochloride in surgery and obstetrics. JAMA 1959; 169:73-75.
    4) Baselt RC: Disposition of Toxic Drugs and Chemicals in Man, 5th ed, Chemical Toxicology Institute, Foster City, CA, 2000.
    5) Bergman J & Wallman P: Promethazine overdose: is it a "goodnight" after all?. NZ Med J 1998; 246-248.
    6) Borgstedt AD & Rosen MG: Medication during labor correlated with behavior and EEG of the newborn. Am J Dis Child 1986; 115:21-24.
    7) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    8) Buck ML & Blumer JL: Phenothiazine-associated apnea in two siblings. DICP 1991; 25:244-247.
    9) Burgess JL, Kirk M, Borron SW, et al: Emergency department hazardous materials protocol for contaminated patients. Ann Emerg Med 1999; 34(2):205-212.
    10) Cantu TG: Phenothiazines and sudden infant death syndrome. DICP 1989; 23:795-799.
    11) 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.
    12) 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.
    13) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    14) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    15) Cleghorn G & Bourke G: Physostigmine for promethazine poisoning (letter). Lancet 1980; 2:368-369.
    16) Cliche F: Intoxication au promethazine (Phenergan). L'Union Medicale du Canada 1961; 90:625-626.
    17) Cockfield: J EEC 1986; 29:C130.
    18) Cohen GH, Casta A, & Sapire DW: Decorticate posture following 'Cardiac Cocktail". Pediatr Cardiol 1982; 2:251-253.
    19) Corby DG & Schulman I: The effects of antenatal drug administration on aggregation of platelets of newborn infants. J Pediatr 1971; 79:307-313.
    20) Cowen PJ: Toxic psychosis with antihistamines reversed by physostigmine. Postgrad Med J 1979; 55:556-559.
    21) Darwish H, Grant R, & Haslam R: Promethazine-induced acute dystonic reactions. Am J Dis Child 1980; 134:990-991.
    22) Daunderer M: Physostigmine salicylate as an antidote. Int J Clin Pharmacol Ther Toxicol 1980; 18(12):523-535.
    23) DeGrandi T & Simon JE: Promethazine-induced dystonic reaction. Pediatr Emerg Care 1987; 3:91-92.
    24) Degouffe M & Rice J: Possible involvement of promethazine in a sudden unexpected infant death. Can Soc Forensic Sci J 1982; 15:166-168.
    25) DiGregorio GJ & Ruch E: Human whole blood and parotid saliva concentrations of oral and intramuscular promethazine. J Pharm Sci 1980; 69:1457-1459.
    26) Dollberg S, Hurvitz H, & Kerem E: Hallucinations and hyperthermia after promethazine ingestion. Acta Paediatr Scand 1989; 78:131-132.
    27) Dominikovich EG: Drug toxicity (letter). NZ Med J 1962; 61:467-469.
    28) El-Kadre D & Giordano C: The "lytic cocktail" induces recurrence of fits in the treatment of eclampsia (letter). Am J Obstet Gynecol 1985; 151:143-145.
    29) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    30) Eyer F, Jetzinger E, Pfab R, et al: Withdrawal from high-dose tranylcypromine. Clin Toxicol (Phila) 2008; 46(3):261-263.
    31) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    32) Fisher SE: Encephalitic reaction to promethazine (letter). J Pediatr 1972; 80:896-897.
    33) Foret AL , Bozeman AP , & Floyd WE : Necrosis caused by intra-arterial injection of promethazine: case report. J Hand Surg Am 2009; 34(5):919-923.
    34) Frascogna N: Physostigmine: is there a role for this antidote in pediatric poisonings?. Curr Opin Pediatr 2007; 19(2):201-205.
    35) Freedberg RS, Friedman GR, & Palu RN: Cardiogenic shock due to antihistamine overdose: reversal with intra-aortic balloon counterpulsation. JAMA 1987; 257:660-661.
    36) Gesell LB & Stephan M: Promethazine toxicity in a neonate treated for colic (abstract). Clin Toxicol 1996; 34:569.
    37) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    38) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    39) Hall PF: Use of promethazine (Phenergan) in labour. Can Med Assoc J 1987; 136:690-691.
    40) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    41) Heber R & Helmig L: Med Welt 1976; 27:2026.
    42) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    43) Hickson GB, Altemeier WA, & Martin ED: Parental administration of chemical agents: A cause of apparent life-threating events. Pediatrics 1989; 83:772-776.
    44) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    45) Jacobsen D, Frederichsen PS, & Knutsen KM: Clinical course in acute self-poisonings: a prospective study of 1125 consecutively hospitalised adults. Human Toxicol 1984; 3:107-116.
    46) Kahn A & Blum D: Phenothiazines and sudden infant death syndrome. Pediatrics 1982; 70:75-78.
    47) Kahn A, Hasaerts D, & Blum D: Phenothiazine-induced sleep apneas in normal infants. Pediatrics 1985; 75:844-847.
    48) Kalikow KT & Kisco M: Drug-induced hallucinations (letter). J Am Acad Child Adolesc Psychiatr 1988; 27:141.
    49) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    50) Leak D & Carroll D: Promethazine poisoning: clinical and electorencephalographic observations. Br Med J 1967; 2:31-21.
    51) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    52) Malesker MA, Malone PM, & Cingle CM: Extravasation of i.v. promethazine. Am J Health-Syst Pharm 1999; 56:1742-1743.
    53) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    54) Mantz JM, Storck D, & Hamman B: Les intoxications aigues par le Phenergan: A propos de 12 observations (abstract). Sem Hop Paris 1964; 40:425-426.
    55) McAllister CJ, Scowden EB, & Stone WJ: Toxic psychosis induced by phenothiazine administration in patients with chronic renal failure. Clin Nephrol 1978; 10:191-195.
    56) Miller RR & Greenblatt DJ: Drugs effects in hospitalized patients, John Wiley & Son, New York, NY, 1976.
    57) Mills PJ: Anaphylactoid reaction to oral premedication with temazepam and promethazine (letter). Anaesthesia 1988; 43:66.
    58) Mostafavi H & Samimi M: Anesthesiology 1971; 25:645.
    59) Nahata MC, Clotz MA, & Krogg EA: Adverse effects of meperidine, promethazine and chlorpromazine for sedation in pediatric patients. Clin Pediatr 1985; 24:558-560.
    60) Newton RW: Physostigmine salicylate in the treatment of tricyclic antidepressant overdosage. JAMA 1975; 231:941-943.
    61) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    62) Owczuk R , Twardowski P , Dylczyk-Sommer A , et al: Influence of promethazine on cardiac repolarisation: a double-blind, midazolam-controlled study. Anaesthesia 2009; 64(6):609-614.
    63) Page CB, Duffull SB, Whyte IM, et al: Promethazine overdose: clinical effects, predicting delirium and the effect of charcoal. QJM 2009; 102(2):123-131.
    64) Pan CV, Quintela AG, & Anuncibay PG: Topical promethazine intoxication (letter). Drug Intell Clin Pharm 1989; 23:89.
    65) Patel RB & Welling PG: On-column reduction of promethazine metabolite during gas chromatography. Clin Chem 1981; 27:1780-1781.
    66) Paton D & Webster DR: Clinical pharmacokinetics of H1-receptor antagonists (the antihistamines). Clin Pharmacokinet 1985; 10:477-497.
    67) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    68) Pentel P & Peterson CD: Asystole complicating physostigmine treatment of tricyclic antidepressant overdose. Ann Emerg Med 1980; 9:588-590.
    69) Petik D, Acs N, Banhidy F, et al: A study of the potential teratogenic effect of large doses of promethazine used for a suicide attempt by 32 pregnant women. Toxicol Ind Health 2008; 24(1-2):87-96.
    70) Plant JR & MacLeod DB: Response of a promethazine-induced coma to flumazenil. Ann Emerg Med 1994; 24:979-982.
    71) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    72) Product Information: PHENERGAN intramuscular intravenous injection, promethazine HCl intramuscular intravenous injection. West-ward Pharmaceutical Corp. (per DailyMed), Eatontown, NJ, 2011.
    73) Product Information: PHENERGAN(TM) rectal suppositories, promethazine HCl rectal suppositories. Prestium Pharma, Inc. (per manufacturer), Newtown, PA, 2014.
    74) Product Information: PROMETHAZINE WITH DEXTROMETHORPHAN COUGH SYRUP oral syrup, promethazine HCl dextromethorphan hydrobromide oral syrup. Wockhardt USA, LLC (per DailyMed), Parsippany, NJ, 2010.
    75) Product Information: Phenergan(R) intramuscular intravenous injection, promethazine HCl intramuscular intravenous injection. West-Ward Pharmaceutical Corp. (per DailyMed), Eatontown, NJ, 2012.
    76) Product Information: Promethazine HCl Phenylephrine HCl Codeine Phosphate oral solution, promethazine HCl phenylephrine HCl codeine phosphate oral solution. BayPharma, Inc. (per FDA), Baltimore, MD, 2013.
    77) Product Information: Promethazine Hydrochloride IM, IV injection, Promethazine Hydrochloride IM, IV injection. Teva Parenteral Medicines, Inc., Irvine, CA, 2009.
    78) Product Information: benztropine mesylate IV, IM injection, benztropine mesylate IV, IM injection. West-ward Pharmaceutical Corp, Eatontown, NJ, 2009.
    79) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    80) Product Information: diphenhydramine hcl injection, diphenhydramine hcl injection. Bioniche Pharma USA,LLC, Lake Forest, IL, 2006.
    81) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    82) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    83) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    84) Product Information: physostigmine salicylate injection, physostigmine salicylate injection. Taylor Pharmaceuticals, Decatur, IL, 2006.
    85) Product Information: physostigmine salicylate intravenous injection, intramuscular injection, physostigmine salicylate intravenous injection, intramuscular injection. Akorn, Inc. (per Manufacturer), Lake Forest, IL, 2008.
    86) Product Information: promethazine HCl and codeine phosphate oral solution, promethazine HCl and codeine phosphate oral solution. BayPharma, Baltimore, MD, 2008.
    87) Product Information: promethazine HCl codeine phosphate oral solution, promethazine HCl codeine phosphate oral solution. BayPharma, Inc. (per FDA), Baltimore, MD, 2013.
    88) Product Information: promethazine HCl oral tablets, promethazine HCl oral tablets. BluePoint Laboratories (per DailyMed), Columbus, OH, 2013.
    89) Product Information: promethazine HCl oral tablets, promethazine HCl oral tablets. Watson Pharma, Inc. (per DailyMed), Corona, CA, 2009.
    90) Product Information: promethazine HCl phenylephrine HCl oral syrup, promethazine HCl phenylephrine HCl oral syrup. Amneal Pharmaceuticals (per DailyMed), Glasgow, KY, 2009.
    91) Product Information: promethazine hcl injection, promethazine hcl injection. Hospira,Inc, Lake Forest, IL, 2006.
    92) Product Information: promethazine hcl oral tablets, promethazine hcl oral tablets. Sandoz,Inc, Princeton, NJ, 2006.
    93) Quinn J & Calvert R: The disposition of promethazine in man. J Pharm Pharmacol 1976; 28:59P.
    94) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 2000; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    95) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    96) S Sweetman : Martindale: The Complete Drug Reference (Internet version). The Pharmaceutical Press. London, UK (Internet Version). Edition expires 2000; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    97) Schwinghammer TL, Juhl RO, & Dittert LW: Comparison of the bioavailability of oral, rectal, and intramuscular promethazine. Biopharmaceut Drug Disp 1984; 5:185-194.
    98) Schwinghammer TL, Kroboth FJ, & Juhl RP: Extrapyramidal reaction secondary to oral promethazine. Clin Pharm 1984a; 3:83-85.
    99) Scott J, Pache D, Keane G, et al: Prolonged anticholinergic delirium following antihistamine overdose. Australas Psychiatry 2007; 15(3):242-244.
    100) 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.
    101) Shannon DC & Bergman A: Nosedrops and SIDS (letter). Pediatrics 1991; 88:418-419.
    102) Shannon M: Toxicology reviews: physostigmine. Pediatr Emerg Care 1998; 14(3):224-226.
    103) Shawn DH & McGuigan MA: Poisoning from dermal absorption of promethazine. Can Med Assoc J 1984; 130:1460-1461.
    104) 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.
    105) Staley EC & Staley EE: Promethazine toxicity in a seven-month-old doberman pinscher. Vet Human Toxicol 1995; 37:243-244.
    106) Stewart GO: Convulsions after physostigmine (letter). Anaesth Intens Care 1979; 7:283.
    107) Swaiman KF: Acute neurologic reaction to promethazine. N Engl J Med 1960; 263:747.
    108) Taylor G, Calvert RT, & Houston JB: Determination of promethazine in biological fluids. Anal Letters 1979; 12:1435-1442.
    109) Terndrup TE, Cantor RM, & Madden CM: Intramuscular meperidine, promethazine, and chlorpromazine: analysis of use and complications in 487 pediatric emergency department patients. Ann Emerg Med 1989; 18:528-533.
    110) Tsay ME, Procopio G, Anderson BD, et al: Abuse and intentional misuse of promethazine reported to US poison centers: 2002 to 2012. J Addict Med 2015; 9(3):233-237.
    111) VanSweden B & Dumon-Radermecker M: The EEG in chronic psychotropic drug intoxications. Clin Electroencephalogr 1982; 13:206-215.
    112) Wallace JE, Shimek EL Jr, & Harris SC: Determination of promethazine in serum by liquid chromatography. Clin Chem 1981; 27:253-255.
    113) Waterhouse RG: Epileptiform convulsions in children following premedication with Pamergan SP100. Br J Anaesth 1967; 39:268-270.
    114) Weaving EA, Berro VE, & Kew MC: Heat stroke during a 'run for fun'. S Afr Med J 1980; 57:753-754.
    115) Whaun JM, Smith GR, & Sochor VA: Effect of prenatal drug administration on maternal and neonatal platelet aggregation and PF-4 release. Haemostasis 1980; 9:226-237.
    116) Wood CD, Manno JE, & Manno BR: Side effects of antimotion sickness drugs. Aviation Space Environ Med 1984; 113-116.
    117) Yung CY: Case vignettes of movement disorders. Brain Res Bull 1983; 11:191-194.
    118) Zametkin AJ, Linnoila M, Karoun F, et al: Pemoline and urinary excretion of catecholamines and indoleamines in children with attention deficit disorder. Am J Psychiatry 1986; 143:359-362.