DIPHENHYDRAMINE AND RELATED AGENTS

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) 2-Benz-hydryloxy-NN-Dimethylethylamine
2) 2-(Benzhydryloxy),-N,N-Dimethylethylamine
3) 2(Diphenylmethoxy)-N,N-Dimethylethylamine
4) Alpha-(2-Dimethylaminoethoxy)diphenylmethane
5) Benzhydraminum
6) Beta-dimethylaminoethanol diphenylmethyl ether
7) Dimedrolum
8) DPH
9) O-Benzhydryldimethylaminoethanol
10) CAS 58-73-1

1) diphenhydrAMINE theoclate
2) Chloranautine
3) Diphenhydramini teoclas

1.2.1) MOLECULAR FORMULA
1) DIMENHYDRINATE: C17H21NO-C7H7ClN4O2
2) DIPHENHYDRAMINE HYDROCHLORIDE: C17H21NO-HCl

Available Forms Sources

1) DIPHENHYDRAMINE is available in the following dosage forms:

a) 25 mg or 50 mg capsules, tablets, gelcaps or liquicaps (Prod Info UNISOM(R) SLEEPGELS(R) oral gelcaps, 2006; Prod Info BENADRYL(R) ALLERGY oral capsules, 2006).
b) 12.5 mg chewable tablets (Prod Info BENADRYL(R) chewable tablets, 2006).
c) 25 mg orally dissolving strip (approximately 10 strips per box) (McNeil Consumer Healthcare, 2010).
d) 12.5 mg/5 mL elixir or syrup (Prod Info CHILDREN'S BENADRYL(R) ALLEGY oral liquid, 2006).
e) 10 mg or 50 mg/mL injection (Prod Info diphenhydramine hcl injection, 2006).
f) 1% or 2% cream in a 30 gram tube (Prod Info BENADRYL(R) extra strength cream, 2006).
g) 2% topical spray in 7.7 mL or 60 mL container (Prod Info Benadryl(R) Itch Stopping Spray Original Strength, 2004; McNeil Consumer Healthcare, 2010).
h) DiphenhydrAMINE is also available in combination products containing acetaminophen, ibuprofen, phenylephrine, dextromethorphan or hydrocodone (Prod Info ADVIL(R) PM oral liquid filled capsules, 2005; Prod Info Tylenol(R) PM,, 2004; Prod Info DYTAN-DM(TM) oral suspension, 2006; Prod Info D-TANN chewable oral tablets, 2006; Prod Info HYDRO-DP oral syrup, 2005).

2) DIMENHYDRINATE is available as 50 mg tablets, 50 mg chewable tablets, 12.5 mg/5 mL, and 50 mg/mL injection (Prod Info DRAMAMINE(R) chewable oral tablets, 2006; Prod Info dimenhydrinate IM, IV injection, 2008).

1) DIPHENHYDRAMINE

a) DiphenhydrAMINE is used to treat symptoms of upper respiratory allergies or common cold. It is also used to treat insomnia, motion sickness, parkinsonism symptoms, and allergic reactions to blood or blood plasma (Prod Info diphenhydramine hcl injection, 2006a; Prod Info BENADRYL(R) ALLERGY oral capsules, 2006; Prod Info CHILDREN'S BENADRYL(R) ALLERGY dissolving oral tablets, 2006; Prod Info UNISOM(R) SLEEPGELS(R) oral gelcaps, 2006). Topical diphenhydrAMINE is used as an anti-itch product (Prod Info Benadryl(R) Itch Stopping Cream Extra Strength, 2004; Prod Info Benadryl(R) Itch Stopping Gel Original Strength, 2004; Prod Info Benadryl(R) Itch Stopping Spray Original Strength, 2004; McNeil Consumer Healthcare, 2010).

2) DIMENHYDRINATE

a) DimenhyDRINATE is used to prevent and treat symptoms (nausea, vomiting, dizziness) associated with motion sickness (Prod Info DRAMAMINE(R) chewable oral tablets, 2006; Prod Info dimenhydrinate IM, IV injection, 2008).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: DiphenhydrAMINE and dimenhyDRINATE are sedating antihistamines used to treat allergic conditions, motion sickness and are used as a sleep aid. Occasionally used as a drug of abuse.
B) PHARMACOLOGY: Competitive antagonist of histamine at the H1 receptor.
C) TOXICOLOGY: Anticholinergic (primarily antimuscarinic) effects develop in overdose. DimenhyDRINATE toxicity is similar in nature to diphenhydrAMINE toxicity.
D) EPIDEMIOLOGY: Poisoning is common but rarely severe. May occur via oral, parenteral or dermal route.
E) WITH THERAPEUTIC USE

1) ADVERSE EFFECTS: Mild sedation, dizziness, impaired coordination, and mild anticholinergic effects are common, paradoxical excitation develops in some patients.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE POISONING: Somnolence, anticholinergic effects (mydriasis, flushing, fever, dry mouth, urinary retention, decreased bowel sounds), tachycardia, mild hypertension, nausea and vomiting are common after overdose. Agitation, confusion and hallucinations may develop with moderate poisoning.
2) SEVERE POISONING: Effects may include delirium, psychosis, seizures, coma, hypotension, QRS widening, and ventricular dysrhythmias, including torsades de pointe, but are generally only reported in adults after ingestions of one gram or more of diphenhydrAMINE. Rhabdomyolysis and renal failure may rarely develop in patients with prolonged agitation, coma or seizures.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Tachycardia is common. Tachypnea, hypotension, and bradycardia may rarely occur.

0.2.20)

A) DiphenhydrAMINE and dimenhyDRINATE have been classified as FDA pregnancy category B. Teratogenicity is variable and unconfirmed There was evidence of congenital anomalies following maternal use of diphenhydrAMINE in various studies; however, causality could not be established in all cases and other studies have refuted an association between diphenhydrAMINE use and fetal malformations. Excretion into breast milk is minimal. However, because of the potential risk of antihistamines to nursing infants, diphenhydrAMINE is CONTRAINDICATED for use in nursing mothers. It should be noted, however, that both diphenhydrAMINE and dimenhyDRINATE are CONTRAINDICATED in neonates and premature infants.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) The vast majority of diphenhydrAMINE overdoses require only supportive care; activated charcoal if patients present shortly after ingestion, and sedation with benzodiazepines for agitation and delirium. Hypertension and tachycardia are generally mild and well tolerated, and do not require specific treatment. Physostigmine can be used to establish the diagnosis if it may help avoid an invasive, costly work up, but should only be given in a setting where intensive monitoring and resuscitation is possible, and should NOT be given if the history or ECG (QRS widening) suggest tricyclic antidepressant poisoning.

B) MANAGEMENT OF SEVERE TOXICITY

1) Orotracheal intubation for airway protection should be performed early. May benefit from gastric lavage if patient presents soon after a large (more than 1 gram) ingestion; administer activated charcoal (GI decontamination should be performed only in patients who can protect their airway or who are intubated). Severe delirium may develop and require large doses of benzodiazepines for sedation. Seizures (may progress to status epilepticus) may require aggressive use of benzodiazepines, propofol and/or barbiturates. Monitor for QRS widening and ventricular dysrhythmias; treat with intravenous sodium bicarbonate (1 to 2 mEq/kg IV bolus starting dose, titrate to blood pH 7.45 to 7.55), or lidocaine if sodium bicarbonate unsuccessful. Consider intravenous lipid therapy early for patients with ventricular dysrhythmias or hypotension. Monitor core temperature and treat hyperthermia with aggressive benzodiazepine sedation to control agitation, and external cooling. Clinical manifestations may be prolonged due to prolonged absorption in the setting of anticholinergic ileus.

C) DECONTAMINATION

1) PREHOSPITAL: Not recommended because of potential for somnolence and seizures.
2) HOSPITAL: Activated charcoal if recent, substantial ingestion, and patient able to protect airway. Consider gastric lavage in recent, large (greater than 1 g) ingestion, protect airway first.

D) AIRWAY MANAGEMENT

1) Perform early in patients with severe toxicity (coma, seizures, dysrhythmias, severe delirium).

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) DELIRIUM

1) Sedate patient with benzodiazepines; large doses may be required.

G) DYSRHYTHMIAS

1) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Sodium bicarbonate is generally first-line therapy for QRS widening and ventricular dysrhythmias, administer 1 to 2 mEq/kg, repeat as needed to maintain blood pH between 7.45 and 7.55. In patients unresponsive to bicarbonate, consider lidocaine.

H) LIPID EMULSION

1) Limited anecdotal evidence suggest that lipid emulsion may be useful in patients with severe cardiac toxicity. Administer 1.5 mL/kg of 20% lipid emulsion over 2 to 3 minutes as an IV bolus, followed by an infusion of 0.25 mL/kg/min. Evaluate the patient's response after 3 minutes at this infusion rate. The infusion rate may be decreased to 0.025 mL/kg/min (ie, 1/10 the initial rate) in patients with a significant response. This recommendation has been proposed because of possible adverse effects from very high cumulative rates of lipid infusion. Monitor blood pressure, heart rate, and other hemodynamic parameters every 15 minutes during the infusion. If there is an initial response to the bolus followed by the re-emergence of hemodynamic instability during the lowest-dose infusion, the infusion rate may be increased back to 0.25 mL/kg/min or, in severe cases, the bolus could be repeated. A maximum dose of 10 mL/kg has been recommended by some sources. Where possible, lipid resuscitation therapy should be terminated after 1 hour or less, if the patient's clinical status permits. In cases where the patient's stability is dependent on continued lipid infusion, longer treatment may be appropriate.

I) SEIZURES

1) Intravenous benzodiazepines, propofol or barbiturates.

J) HYPERTHERMIA

1) Control agitation with benzodiazepines; initiate aggressive external cooling measures.

K) ENHANCED ELIMINATION

1) Hemodialysis and hemoperfusion are not of value because of the large volume of distribution.

L) PHARMACOKINETICS

1) At therapeutic doses: Onset 15 to 60 min; duration 4 to 6 hours; protein binding 76 to 85%; half-life 4 to 8 hours; elimination via hepatic metabolism; volume of distribution 4 to 8 L/kg.

M) PATIENT DISPOSITION

1) HOME CRITERIA: Asymptomatic (other than mild drowsiness or stimulation) children less than 6 years of age with acute inadvertent ingestion of less than 7.5 mg/kg may be monitored at home. Asymptomatic patients 6 years of age and older with acute inadvertent ingestions of less than 7.5 mg/kg or 300 mg (whichever is less) may be monitored at home. Patients with inadvertent ingestions who are asymptomatic at the time of the call, and more than 4 hours have elapsed since the ingestion, can be managed at home, as can asymptomatic excessive dermal exposures where more than 8 hours have elapsed since exposure and the skin has been washed.
2) OBSERVATION CRITERIA: Children less than 6 years of age with ingestions of at least 7.5 mg/kg should be sent to a healthcare facility. Patients 6 years of age and older with deliberate ingestions or those with ingestions of at least 7.5 mg/kg or 300 mg total or more (whichever is less), and symptomatic patients should be sent to a healthcare facility for observation for 6 to 8 hours. Patients who manifest more than mild sedation or stimulation at the end of this period should be admitted to the hospital.
3) ADMISSION CRITERIA: Patients with significant persistent central nervous system toxicity (hallucinations, somnolence, delirium, coma), or persistent tachycardia should be admitted. Patients with coma, seizures, dysrhythmias, or delirium should be admitted to an intensive care setting.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for patients with severe toxicity (seizures, dysrhythmias, coma, severe delirium) or in whom the diagnosis is not clear.

N) PITFALLS

1) Physostigmine is generally not advised for long term management, as anticholinergic effects generally recur within an hour after physostigmine administration. Toxicity may be prolonged secondary to prolonged absorption due to anticholinergic effects.

0.4.5)

A) OVERVIEW

1) Systemic toxicity has been described after topical exposure.
2) 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).

Range Of Toxicity

Clinical Effects

Summary Of Exposure

1) ADVERSE EFFECTS: Mild sedation, dizziness, impaired coordination, and mild anticholinergic effects are common, paradoxical excitation develops in some patients.

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Tachycardia is common. Tachypnea, hypotension, and bradycardia may rarely occur.

3.3.2)

A) WITH POISONING/EXPOSURE

1) CASE REPORT: Tachypnea (32 breaths/minute) was reported in a 17-year-old boy who ingested 2000 mg diphenhydrAMINE in a suicide attempt (Thakur et al, 2005).

3.3.3)

A) WITH POISONING/EXPOSURE

1) HYPERTHERMIA was reported in one fatal case (Hausmann et al, 1983), in a massive overdose (Rinder et al, 1988), and in 6 patients (mean age 5 years) with diphenhydrAMINE toxicity following multiple drug applications of Caladryl(R) lotion on entire body surface (Goetz & Krenzelok, 1989).
2) CASE REPORT: Two 1-month-old twins were found with irregular breathing and cyanosis 6 hours after being given a 40 mg (13 mg/kg) dimenhyDRINATE suppository. At the hospital, the infants were irritable and hyperthermic with tachycardia (180 bpm). Both infants required intubation, but made a full recovery 48 hours after admission (Wolf et al, 2002).

3.3.4)

A) WITH POISONING/EXPOSURE

1) HYPOTENSION

a) Hypotension has occurred in one case following ingestion of 5000 mg dimenhyDRINATE (Winn & McDonnell, 1993).
b) A 17-year-old developed hypotension (systolic blood pressure 80 mmHg) after ingesting 2000 mg diphenhydrAMINE in a suicide attempt. The patient's blood pressure improved following administration of IV fluids (Thakur et al, 2005).

3.3.5)

A) WITH POISONING/EXPOSURE

1) TACHYCARDIA is common (Thakur et al, 2005; Zavitz et al, 1989). Tachycardia occurred in 36% to 44% of patients with diphenhydrAMINE overdose in two series (Radovanovic et al, 2000).
2) BRADYCARDIA occurred in one case following ingestion of 5000 mg dimenhyDRINATE (Winn & McDonnell, 1993).

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) MYDRIASIS: Dilated pupils are common (Abdelmalek et al, 2014; Rinder et al, 1988; Zavitz et al, 1989).

a) In one prospective study of 184 cases of diphenhydrAMINE or dimenhyDRINATE ingestions in children 18 years of age or less (mean age 5.2 years), mydriasis was present in 26% (Zavitz et al, 1989).

2) TEARING: Decreased tear production was noted to be the cause of filamentary keratitis in a 38-year-old woman with keratoconjunctivitis sicca (Seedor et al, 1986).
3) BLURRED VISION may occur due to the anticholinergic effects (Ellenhorn, 1997).

a) Accommodation for near vision may be impaired because of the atropine-like effect of 0.5% diphenhydrAMINE ophthalmic aqueous solution and systemic preparations (Grant & Schuman, 1993).

4) BLINDNESS occurred with deafness, seizures, and fixed mydriasis in an 18-month-old baby who swallowed 350 mg diphenhydrAMINE; recovery was complete over several months (Grant & Schuman, 1993).
5) NYSTAGMUS: Vertical/horizontal nystagmus were reported in a 29-year-old who overdosed on a preparation containing diphenhydrAMINE (Payne et al, 1991). The nystagmus may have been due to complications including status epilepticus and a small subarachnoid hemorrhage.

Cardiovascular

3.5.2)

A) TACHYARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) Tachycardia is the most common cardiovascular finding. In one prospective study of 184 cases of diphenhydrAMINE or dimenhyDRINATE ingestions in children 18 years of age or less (mean age 5.2 years), tachycardia was noted in 42% (Zavitz et al, 1989).
b) A report described two series of adults with diphenhydrAMINE overdose, 232 patients in a retrospective series and 50 patients in a prospective series; the incidence of tachycardia was 44% and 36%, respectively (Radovanovic et al, 2000).
c) CASE REPORT (PEDIATRIC): Two children presented to the emergency department with tachycardia (140 bpm) and other anticholinergic effects, including altered mental status, hallucinations, dry mouth, and dilated pupils. The children's symptoms resolved following supportive care (Zavitz et al, 1989).

1) Although routine urine and serum toxicology screenings were negative, a serum diphenhydrAMINE level of one of the patients was reported to be elevated at 760 ng/mL. The frozen serum of the other patient was then tested for diphenhydrAMINE and the level was reported to be 2800 ng/mL. One of the children confirmed that his mother had been giving him "little green pills" that were later identified as a diphenhydrAMINE product.

d) A retrospective chart review was conducted, identifying 198 cases of single substance diphenhydrAMINE ingestions that were reported to the three poison control centers of the Florida Poison Information Center Network from January, 2010 through October, 2014. Of the 198 cases, 66% were acute, intentional ingestions. The mean patient age was 26 +/- 15.9 years (ages ranging from 9 months to 84 years). Of all of the cardiotoxic events reported, tachycardia was the most commonly reported cardiovascular finding, at 96% (n=190) (Bohnenberger et al, 2015).

B) WIDE QRS COMPLEX

1) WITH POISONING/EXPOSURE

a) CASE REPORT (PEDIATRIC): A 13-month-old infant presented with tachycardia (200 bpm), tachypnea (41 breaths per minute), nystagmus, agitation alternating with lethargy, and dry, flushed skin after an unintentional suspected maximal ingestion of 24 25-mg diphenhydrAMINE tablets (50 mg/kg). Prior to presentation, the patient had also experienced a tonic-clonic seizure. An initial ECG indicated a wide complex tachycardia with a heart rate of 180 bpm, a QRS duration of 130 ms and a prolonged QTc interval of 506 ms. With supportive care, including a single intravenous bolus dose of sodium bicarbonate, the patient recovered and was discharged within 24 hours without sequelae. A repeat ECG, obtained prior to discharge, indicated normal sinus rhythm of 109 bpm with QRS and QTc durations of 65 and 437 ms, respectively (Cole et al, 2011).
b) CASE REPORT: A 17-year-old who reported ingesting 750 mg exhibited a normal narrow complex sinus tachycardia (QRS 92 msec) initially, but after a seizure developed a wide complex tachycardia (QRS 140 msec) which narrowed within minutes after the administration of 44 mEq of sodium bicarbonate (Clark & Vance, 1992).
c) CASE SERIES: A report described 3 cases of wide complex tachycardia (QRS range 102 to 162 msec) following intentional diphenhydrAMINE overdoses. One patient expired as a result of his ingestion, and the other two had successful narrowing of their QRS with administration of sodium bicarbonate (Sharma et al, 2003).
d) CASE REPORT: A 35-year-old woman deliberately ingested 16 grams of diphenhydrAMINE and subsequently developed QRS and QTc prolongation. The patient's ECG gradually returned to baseline following vasopressor therapy and administration of charcoal hemoperfusion with hemodialysis (Mullins et al, 1999).
e) CASE REPORT: A 30-year-old woman developed hypotension, seizures, several episodes of wide complex tachycardia (QRS range 98 to 112), successfully cardioverted each time, and cardiac arrest, with successful resuscitation, following an intentional ingestion of an unknown amount of diphenydrAMINE. Serum diphenhydrAMINE concentration, obtained in the emergency department at presentation, was 19,000 ng/mL (reference range 100 to 1000 ng/mL). Due to continued hemodynamic instability, despite vasopressor infusion and sodium bicarbonate administration, intravenous lipid emulsion (ILE) therapy was initiated. Approximately 19 minutes after beginning ILE therapy, the patient's blood pressure improved and vasopressor therapy was weaned, with complete cessation 4 hours after ILE administration (Abdelmalek et al, 2014).

C) TORSADES DE POINTES

1) WITH POISONING/EXPOSURE

a) Torsade de pointes is rare following diphenhydrAMINE overdose because tachycardia caused by anticholinergic and hypotensive effects of diphenhydrAMINE seems to protect against torsade de pointes (Sypc & Khan, 2005).
b) CASE REPORT: A 26-year-old man ingested 50 50-mg diphenhydrAMINE hydrochloride tablets (tox screening of the blood and urine were negative for other agents). An initial ECG (approximately 2 hours after ingestion) showed sinus rhythm with a PR interval of 220 msec and the QTc interval was 404 msec. Approximately 5.5 hours after admission, the patient had a generalized seizure, shortly followed by polymorphic ventricular tachycardia that was successfully terminated with cardioversion (200 joules); however, the QTc interval remained prolonged (500 msec) over the next 2 days. Subsequently, the patient developed metabolic acidosis (pH 7.16) and hypokalemia (K 3.2 mEq/L). The patient gradually improved following supportive care and made a complete recovery; 5 days after exposure an echocardiogram was normal. The authors suggested that the development of both hypokalemia and acidosis (induced by the seizure), as well as the lack of sinus tachycardia (a protective effect) may have precipitated the cardiac events observed in this case (Joshi et al, 2004).
c) CASE REPORT (PEDIATRIC): A 2-year-old developed status epilepticus, ventricular tachycardia and torsade de pointes that responded to conventional PALS protocols after ingesting an acetaminophen/diphenhydrAMINE combination product (Lynton et al, 2001).

D) BRADYCARDIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Bradycardia occurred in one case following ingestion of 5000 mg dimenhyDRINATE (Winn & McDonnell, 1993).

E) HYPERTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypertension may occur following massive exposure (Jones et al, 1986; Wyngaarden & Seevers, 1951).
b) CASE SERIES (PEDIATRIC): Hypertension was present in 18% of patients in a prospective study of 184 cases of diphenhydrAMINE or dimenhyDRINATE ingestions in children 18 years of age or less (mean age 5.2 years) (Zavitz et al, 1989).

F) HYPOTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) Postural hypotension may occur with use of antihistamines (Krenzelok et al, 1982).

2) WITH POISONING/EXPOSURE

a) Hypotension has been reported following diphenhydrAMINE overdose (Abdelmalek et al, 2014; Lopez-Barbeito et al, 2005; Winn & McDonnell, 1993; Mullins et al, 1999).
b) CASE REPORT: Hypotension has occurred in a case following ingestion of 5000 mg dimenhyDRINATE (Winn & McDonnell, 1993).
c) CASE REPORT: A 35-year-old woman became hypotensive (78/64 mm Hg) following activated charcoal with cathartic administration to remove 16 grams of diphenhydrAMINE ingested in a suicide attempt (Mullins et al, 1999).
d) CASE REPORT: A 17-year-old boy developed hypotension (systolic blood pressure 80 mmHg) after intentionally ingesting 2000 mg of diphenhydrAMINE in a suicide attempt. The patient's blood pressure improved with administration of IV fluids (Thakur et al, 2005).

G) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

a) Following massive overdose, ventricular tachycardia, ventricular fibrillation, electromechanical dissociation and cardiac arrest have been noted (Abdelmalek et al, 2014; Baselt, 2000; Ellenhorn, 1997; Hausmann et al, 1983; Winn & McDonnell, 1993; Zareba et al, 1997).
b) CASE REPORT: A 23-year-old man presented to the emergency department hypotensive (73/32 mmHg) and tachycardic (145 beats/min) after ingesting 2000 to 2500 mg of diphenhydrAMINE. Prior to presentation, emergency responders witnessed a generalized tonic clonic seizure and obtundation of the patient, necessitating ventilation. His initial ECG revealed sinus tachycardia with intraventricular conduction delay, with a QRS width of 172 msec, and a prolonged QTc interval of 577 msec. A venous blood gas analysis indicated metabolic acidosis, and laboratory data revealed a serum diphenhydrAMINE level of 4100 ng/mL (therapeutic range 50 to 100 ng/mL). Treatment included 2 cardioversions for wide complex tachycardia, IV sodium bicarbonate, magnesium sulfate, calcium gluconate, and 2 IV boluses of 20% lipid emulsion, each at a dose of 1.5 mL/kg, administered 20 minutes apart. Within 5 minutes after the second lipid emulsion bolus dose, the patient's QRS width narrowed to 106 msec and his wide complex tachycardia resolved, returning to sinus rhythm with a heart rate of 115 beats/minute. He was extubated on hospital day 3 and, other than development of an elevated lipase level, he recovered uneventfully (Abdi et al, 2014).

H) ELECTROCARDIOGRAM ABNORMAL

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 38-year-old man developed ECG changes typical of the Brugada syndrome (coved ST elevation in V1 and V2) after receiving 50 mg dimenhyDRINATE infused over 25 to 30 minutes. He was asymptomatic and ECG changes resolved within 24 hours. Echocardiogram, MRI and holter monitoring were normal, but the ECG changes recurred after he received 2 mg/kg flecainide over 10 minutes (Pastor et al, 2001).

2) WITH POISONING/EXPOSURE

a) Prolonged QRS and QT intervals, first degree AV block, nonspecific ST-T segment changes, left and right bundle branch blocks have been reported (Abdelmalek et al, 2014; Radovanovic et al, 2000; Hestand & Teske, 1977; Huxtable & Landwirth, 1963; Rinder et al, 1988; Payne et al, 1991; Clark & Vance, 1992; Zareba et al, 1997).
b) CASE REPORT: A 17-year-old boy presented to the emergency department with tachycardia (150 bpm) and tachypnea (32 breaths/min) after being found unresponsive in a park with an empty bottle of diphenhydrAMINE (which would have contained 40 tablets of 50 mg diphenhydrAMINE). An ECG showed bundle branch block and QT interval prolongation at 522 msec. The patient also exhibited seizure-like activity which was controlled with intravenous administration of benzodiazepines. With supportive care, his cardiac dysrhythmias and ECG abnormalities resolved (Thakur et al, 2005).
c) CASE REPORT: A 40-year-old woman developed sinus tachycardia with prolonged QT interval (QTc 588 msec) with broad, biphasic T waves in V4 and V5, following the ingestion of 25 tablets of a preparation containing diphenhydrAMINE and acetaminophen (total ingested dose, 625 mg of diphenhydrAMINE and 12.5 grams of acetaminophen). She never developed dysrhythmias and recovered without further sequelae (Sypc & Khan, 2005).
d) CASE REPORT: A 39-year-old man presented to the emergency department with hypotension and hyperkalemia (potassium 8.3 mEq/L) after being found comatose (3 points at Glasgow coma score) at home following an overdose of diphenhydrAMINE. An ECG revealed a marked coved-type ST-segment elevation in leads V2-V3 and a QT prolongation of 0.57 seconds. Intensive treatment of the hyperkalemia or the intravenous infusion of isoproterenol did not normalize the ECG abnormalities. However, after regaining consciousness, his ECG normalized. A negative intravenous flecainide test (2 mg/kg over a 10 minute period) ruled out the Brugada syndrome (Lopez-Barbeito et al, 2005).
e) A retrospective chart review was conducted, identifying 198 cases of single substance diphenhydrAMINE ingestions that were reported to the three poison control centers of the Florida Poison Information Center Network from January, 2010 through October, 2014. Of the 198 cases, 66% were acute, intentional ingestions. The mean patient age was 26 +/- 15.9 years (ages ranging from 9 months to 84 years). Of all of the cardiotoxic events reported, conduction disturbances were the one of the most commonly reported cardiovascular findings, at 30.3% (n=60), with a prolonged QTc interval being the most common conduction disturbance reported, at 86.7% (n=60). The mean QTc was 461 +/- 58.4 msec (Bohnenberger et al, 2015).

I) GANGRENOUS DISORDER

1) WITH THERAPEUTIC USE

a) After injection of 1.2 mL diphenhydrAMINE (50 mg/mL) for anesthetic purposes, gangrene was noted and attributed to either vasoconstrictive effects or direct tissue injury (Ramsdell, 1989). No such adverse effects were reported with 1% diphenhydrAMINE solutions (10 mg/mL) (Pollack & Swindle, 1989).

Respiratory

3.6.2)

A) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) Hemorrhagic pulmonary edema occurred in a fatal diphenhydrAMINE overdose (Hausmann et al, 1983). Multiple cardiac arrests, CPR, vigorous fluid and chemical resuscitation and possible aspiration complicated the clinical course.
b) Pulmonary edema was reported on autopsy in four diphenhydrAMINE overdose ingestions (Karch, 1998).

B) SPUTUM ABNORMAL - AMOUNT

1) WITH POISONING/EXPOSURE

a) Thickened bronchial secretions may occur due to the anticholinergic effects (Ellenhorn, 1997).

C) IRREGULAR BREATHING

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Two 1-month-old twins were found with irregular breathing and cyanosis 6 hours after being given a 40 mg (13 mg/kg) dimenhyDRINATE suppository. At the hospital, the infants were irritable and hyperthermic with tachycardia (180 bpm). Intermittent apneas were observed with oxygen saturations dropping to 30%. Both infants required intubation, but made a full recovery 48 hours after admission (Wolf et al, 2002).

1) The dimenhyDRINATE blood concentration was reported to be 100 ng/mL 18 hours after administration, but there are no data available on toxic serum concentrations in children.

Neurologic

3.7.2)

A) CENTRAL STIMULANT ADVERSE REACTION

1) WITH POISONING/EXPOSURE

a) In children and young adults, CNS stimulation manifested by excitement, tremors, hyperactivity, hallucinations, hyperpyrexia, tonic clonic seizures (Tanaka et al, 2011; Hestand & Teske, 1977; Wyngaarden & Seevers, 1951a; Filloux, 1986; Goetz et al, 1990) and signs and symptoms of anticholinergic toxicity may be more common than CNS depression.
b) CASE SERIES: CNS stimulation was noted in 18% of patients in a prospective study of 184 cases of diphenhydrAMINE or dimenhyDRINATE ingestions in children 18 years of age or less (mean age 5.2 years) (Zavitz et al, 1989).
c) One report described 2 series of adults with diphenhydrAMINE overdose, 232 patients in a retrospective series and 50 patients in a prospective series; agitation was reported in 3% and 4%, respectively, confusion in 11% and 12%, respectively and hallucinations in 11% and 4%, respectively(Radovanovic et al, 2000). Delirium/psychosis were only reported in patients ingesting 1 gram or more of diphenhydrAMINE, and they developed in 7% of the retrospective series and 6% of the prospective series.
d) Headache, blurred vision, tinnitus, and irritability may occur (Baselt, 2000; Ellenhorn, 1997) Gilman et al, 1990; (Tomlinson et al, 1987; Wyngaarden & Seevers, 1951).

B) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH POISONING/EXPOSURE

a) In adults, CNS depression is common but prominent anticholinergic psychosis is not unusual.
b) CASE SERIES (PEDIATRIC): CNS depression was noted in 56% of patients in a prospective study of 184 cases of diphenhydrAMINE or dimenhyDRINATE ingestions in children 18 years of age or less (mean age 5.2 years) (Zavitz et al, 1989).
c) A report described two series of adults with diphenhydrAMINE overdose, 232 patients in a retrospective series and 50 patients in a prospective series; the incidence of somnolence was 48% and 42%, respectively (Radovanovic et al, 2000). Coma was only reported in patients who ingested one gram or more of diphenhydrAMINE, and it developed in 3% of patients in the retrospective series and 2% of patients in the prospective series.
d) CASE REPORT: A 35-year-old woman became lethargic with a Glasgow Coma Scale score of 8 following a massive overdose ingestion of 16 grams diphenhydrAMINE (Mullins et al, 1999).
e) TOPICAL: Topical administration of diphenhydrAMINE cream lead to vomiting, unresponsiveness, and death in a 17-month-old boy. The child had an active case of eczema over his entire back, bilateral shins, bilateral cheeks, and bilateral popliteal fossae. The parents indicated they purchased a tube of diphenhydrAMINE cream and applied some of it to his eczema three days prior and the morning of death. Further investigation revealed the diphenhydrAMINE had been applied to the areas of eczema after a warm bath the morning of his death. Upon autopsy, petechial hemorrhages of the thymus, heart and lungs were reported and the plasma diphenhydrAMINE level, measured by gas chromatography, was 1.03 mg/L. The authors suspected three factors were responsible for the child's death: the administration of the medication after a warm bath, which lead to increased absorption of the medication from the skin; application of the medication to eczema, which impaired the normal dermal barrier; and excessive application to the large surface area of the rash (Turner, 2009).

C) SEIZURE

1) WITH POISONING/EXPOSURE

a) The seizures of intermittent tonic-clonic type, sometimes heralded by muscular tremors and athetosis, may be difficult to control (Abdelmalek et al, 2014; Rinder et al, 1988; Payne et al, 1991).
b) Status epilepticus refractory to standard therapy has been reported (Lynton et al, 2001; Goetz et al, 1990; Payne et al, 1991; Winn & McDonnell, 1993).
c) A report described two series of adults with diphenhydrAMINE overdose, 232 patients in a retrospective series and 50 patients in a prospective series(Radovanovic et al, 2000). Seizures only developed in patients ingesting one gram or more of diphenhydrAMINE. Seizures were reported in 8% of patients in the retrospective series and 6% of patients in the prospective series.
d) CASE REPORT (PEDIATRIC): An 8-year-old child presented to the emergency department with tachycardia, altered mental status, and hallucinations, and 16 days after admission, experienced a single grand mal seizure.
e) CASE REPORT: A 35-year-old woman developed generalized seizures following an intentional ingestion of 16 grams of diphenhydrAMINE (Mullins et al, 1999).
f) CASE REPORT: A 17-year-old boy exhibited tonic-clonic seizure-like activity following an intentional ingestion of 40 50-mg diphenhydrAMINE tablets. The seizures resolved following intravenous administration of benzodiazepines (Thakur et al, 2005).

D) CATATONIC REACTION

1) WITH POISONING/EXPOSURE

a) A review of 136 cases of diphenhydrAMINE overdose concluded that impairment of consciousness was the most common effect reported and that it is occasionally accompanied by catatonic stupor (Koppel et al, 1987).

E) CHOREOATHETOSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Severe choreoathetoid movements of both upper and lower extremities and writhing movements of the trunk and pelvis were noted in a 50-year-old chronic schizophrenic patient, stable on haloperidol, who ingested 6 Sominex(R) tablets (containing 25 mg of diphenhydrAMINE each) within 20 minutes (Jones & Lal, 1985).

1) Tardive dyskinesia precipitated by diphenhydrAMINE was diagnosed and treated with haloperidol 5 mg. Three days later all signs of dyskinesia were absent.

F) DYSTONIA

1) WITH THERAPEUTIC USE

a) Dystonic posturing, restlessness, torticollis, and trismus have been noted in children and adolescents following the oral and intramuscular administration of diphenhydrAMINE for an allergic reaction (Brait & Zagerman, 1977; Lavenstein & Cantor, 1976).
b) CASE REPORT: A 66-year-old woman developed acute dystonia associated with an intravenous injection of diphenhydrAMINE 50 mg given over 2 minutes (Roila et al, 1989).

1) Symptoms included a burning sensation along the injected vein, general malaise, tachycardia, mental confusion, diffuse tremors, and dyskinesia including trismus, swallowing difficulties, dysarthria, rigidity, and motor incoordination. She had no psychiatric or central nervous system disturbances and had tolerated the same dose of diphenhydrAMINE on 2 previous occasions.

c) CASE REPORT: Protrusion of the tongue and lips, difficulty in speaking, involuntary limb stiffening, and mild extensor neck posturing were reported 30 to 45 minutes after ingestion of 50 mg of diphenhydrAMINE by a 28-year-old woman. Spontaneous resolution occurred within 30 to 60 minutes (Santora et al, 1989).

G) DISTURBANCE IN THINKING

1) WITH THERAPEUTIC USE

a) 50 mg of diphenhydrAMINE produced drowsiness and significantly longer reaction times during simulated driving compared to cetirizine and placebo (2.01 seconds vs 0.85 to 1.81 seconds) (Gengo et al, 1990).
b) Following 50 mg of diphenhydrAMINE, driving performance on the IOWA driving simulator was significantly more impaired than with alcohol (0.1% blood alcohol concentration) in 40 licensed drivers in a randomized, double-blind, crossover trial. Drowsiness was not a good predictor of impairment (Weiler et al, 2000).

H) TOXIC ENCEPHALOPATHY

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Moderate encephalopathy requiring hospitalization was reported 11 months after ingestion of 5 grams of dimenhyDRINATE by a 22-year-old woman (Rinder et al, 1988). The patient was in status epilepticus for 3 hours, which probably contributed to the poor outcome.
b) CASE REPORT: Acute hypoxic brain injury was reported in a woman who developed status epilepticus and cardiac arrest after ingesting 5000 mg of dimenhyDRINATE (Winn & McDonnell, 1993).

I) NEUROLEPTIC MALIGNANT SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 39-year-old man ingested approximately 2.4 grams of diphenhydrAMINE and 1.5 grams of diprophyllin in a suicide attempt and, 24 hours later, presented to the emergency department with hyperthermia, hyperhidrosis, and gait disturbance. A neurologic examination revealed muscle rigidity, tremor of the head and extremities, and akinesia. The patient's consciousness subsequently decreased and upon the third day after admission, he developed akinetic mutism prompting a diagnosis of neuroleptic malignant syndrome. Following fluid replacement and administration of bromocriptine and dantrolene, the patient's signs and symptoms gradually resolved (Park-Matsumoto & Tazawa, 1999).

Gastrointestinal

3.8.2)

A) GASTRITIS

1) WITH POISONING/EXPOSURE

a) Dry mouth, nausea, vomiting, diarrhea or constipation may occur (Ellenhorn, 1997).

B) VASCULAR INSUFFICIENCY OF INTESTINE

1) WITH POISONING/EXPOSURE

a) Ischemic bowel injury developed during the hospitalization of a toxic ingestion of 5000 mg dimenhyDRINATE (Winn & McDonnell, 1993). Surgery was required.

Hepatic

3.9.2)

A) LIVER ENZYMES ABNORMAL

1) WITH POISONING/EXPOSURE

a) Elevated aminotransferase levels were reported in an infant who developed seizures after diphenhydrAMINE overdose (Hestand & Teske, 1977).
b) CASE REPORT: A 39-year-old man developed elevated liver enzyme levels following ingestion of approximately 2.4 grams of diphenhydrAMINE and 1.5 grams of diprophyllin in a suicide attempt (Park-Matsumoto & Tazawa, 1999).

Genitourinary

3.10.2)

A) RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) Renal failure has been reported, but was most likely secondary to shock or rhabdomyolysis rather than diphenhydrAMINE (Lopez-Barbeito et al, 2005; Haas et al, 2003; Hausmann et al, 1983; Frankel et al, 1993).

B) RETENTION OF URINE

1) WITH POISONING/EXPOSURE

a) Urinary retention may occur due to the anticholinergic effects of diphenhydrAMINE (Ellenhorn, 1997).

C) ABNORMAL RENAL FUNCTION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Elevated levels of BUN (35 mg/dL), serum creatinine (1.6 mg/dL), myoglobin (1069 ng/mL), and creatinine phosphokinase (14,770 International Units/L) were reported in a 39-year-old man following a deliberate ingestion of approximately 2.4 grams of diphenhydrAMINE and 1.5 grams of diprophyllin in a suicide attempt. Macroscopic urinalysis also showed gross hematuria. The patient's renal function returned to normal following supportive care (Park-Matsumoto & Tazawa, 1999).
b) A similar case was described in a 21-year-old who ingested an unknown amount of diphenhydrAMINE and alcohol and developed rhabdomyolysis, acute renal failure and myoglobinuria. Renal function returned to normal with supportive care and 4 sessions of hemodialysis (Haas et al, 2003).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Metabolic acidosis occurred in a case following ingestion of 5000 mg dimenhyDRINATE (Winn & McDonnell, 1993).
b) CASE REPORT: Metabolic acidosis (pH 7.19, HCO3 20 mEq/L, anion gap of 18) was reported in a 30-year-old woman following an intentional ingestion of an unknown amount of diphenhydrAMINE (Abdelmalek et al, 2014).
c) CASE REPORT: Metabolic acidosis (pH 6.83, pCO2 57 mmHg, HCO3 10 mmol/L, anion gap 19) was reported in a 23-year-old man who ingested 2000 to 2500 mg of diphenhydrAMINE (Abdi et al, 2014).

Hematologic

3.13.2)

A) DISSEMINATED INTRAVASCULAR COAGULATION

1) WITH POISONING/EXPOSURE

a) The hospital course of one case involving ingestion of 5000 mg dimenhyDRINATE was complicated by disseminated intravascular coagulation (Winn & McDonnell, 1993).

Dermatologic

3.14.2)

A) SYSTEMIC DISEASE

1) WITH POISONING/EXPOSURE

a) DERMAL ABSORPTION: CNS and peripheral anticholinergic toxicity has been described from absorption of diphenhydrAMINE following topical exposure (Savchak, 1982; Patranella, 1986; Filloux, 1986; Schunk & Svendsen, 1988; Tomlinson et al, 1987; Woodward & Baldassano, 1988; McGann et al, 1992).

B) FIXED DRUG ERUPTION

1) WITH THERAPEUTIC USE

a) Burning and vesiculation with postinflammatory pigmentation of the distal shaft of the penis was noted with intake of dimenhyDRINATE (Hogan & Rooney, 1989) and pigmented patches on face and extremities with diphenhydrAMINE (Dwyer & Dick, 1993).

Musculoskeletal

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) SUMMARY: Rhabdomyolysis may develop, usually in patients with prolonged agitation, seizures or coma (Lopez-Barbeito et al, 2005; Khosla et al, 2003).
b) CASE REPORT: Rhabdomyolysis occurred in a case following ingestion of 5000 mg dimenhyDRINATE (Winn & McDonnell, 1993) and following ingestions of 1450 to 2400 mg diphenhydrAMINE (Vearrier & Curtis, 2011; Park-Matsumoto & Tazawa, 1999).
c) CASE REPORT: Rhabdomyolysis developed in 2 men with status epilepticus after ingesting overdoses of doxylamine and diphenhydrAMINE (Frankel et al, 1993).
d) CASE REPORT: Rhabdomyolysis and acute renal failure were reported in a 21-year-old man, with a history of depression and binge drinking, who ingested an unknown amount of diphenhydrAMINE (urine tox screen was positive) and "3/4 of a bottle of gin". Approximately, 24 hours after ingestion, the patient became extremely agitated and required 4-point restraints. CK peaked at 223,570 Units/mL and urine screening was positive for myoglobin. The patient gradually improved with supportive care which included hemodialysis(Haas et al, 2003).

1) The use of restraints in the setting of severe agitation was likely responsible for the rhabdomyolysis; the patient's clinical course was likely further complicated by acute alcohol withdrawal (Mycyk, 2003).

e) CASE REPORT: Mild rhabdomyolysis (peak CK 4505 Units/L) developed in a 23-month-old who developed an anticholinergic syndrome including mild agitation after ingesting diphenhydrAMINE. The child never exhibited seizure activity and did not require restraints (Stuka et al, 2001).

B) COMPARTMENT SYNDROME

1) WITH POISONING/EXPOSURE

a) A 28-year-old woman developed rhabdomyolysis and compartment syndrome after she intentionally ingested 100 mL of vodka with 29 capsules of an over the counter sleep aid containing 1450 mg of diphenhydrAMINE (22 mg/kg). She was found wandering aimlessly in her home and was taken to the emergency department approximately 9 hours after the ingestion. She reported numbness and tingling to her bilateral legs and feet as well as an inability to control her leg muscles and weakness. Mottling was noted to the anterior aspects of both legs. Upon examination, strength, sensation, and capillary refill were normal. Palpable dorsalis pedis (DP) and posterior tibialis (PT) pulses were noted to both legs. Laboratory analysis confirmed rhabdomyolysis with a creatine kinase (CK) of 10,605 U/L (peak CK 233,900 U/L). Initial treatment included normal saline infusions, analgesics, and telemetry monitoring. Eighteen hours after presentation, worsening leg pain persisted and reexamination showed absent bilateral PT and DP pulses and limited or absent mobility to her feet. She was diagnosed with compartment syndrome and underwent fasciotomies to the left thigh and bilateral legs. Circulation and mobility were restored after surgery; however, decreased sensation to her left foot resolved gradually during her hospital admission. A delayed primary closure of the 3 fasciotomies was performed on postoperative day 11. She was discharged to inpatient psychiatric care 15 days after admission (Vearrier & Curtis, 2011).

Immunologic

3.19.2)

A) ANAPHYLACTOID REACTION

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 32-year-old black woman was treated with a single 25 mg IV dose of diphenhydrAMINE. She presented with dizziness, weakness, tightness in chest, severe shortness of breath, cough productive of frothy red sputum, blood pressure of 150/90 mm Hg, a pulse of 120 bpm, shallow respirations at 28/minute, and rales on both lungs (Lauderdale, 1964).

1) Tanned cell hemagglutination tests suggest that diphenhydrAMINE hydrochloride was the allergenic cause.

B) ACUTE ALLERGIC REACTION

1) WITH THERAPEUTIC USE

a) CASE REPORT: A patient, previously sensitized to Caladryl(R) lotion, presented with reversible pruritic eczematous swollen plaques and positive patch test to diphenhydrAMINE (Shelley & Bennett, 1972).

Reproductive

3.20.1)

3.20.2)

A) LACK OF INFORMATION

1) At the time of this review, no data were available to assess the teratogenic potential of dimenhyDRINATE or diphenhydrAMINE (Prod Info dimenhydrinate IM, IV injection, 2008; Prod Info Diphenhydramine Hydrochloride oral solution, 2008; Prod Info diphenhydramine hcl injection, 2006).

B) CONGENITAL ANOMALY

1) DIPHENHYDRAMINE

a) The Collaborative Perinatal Project monitored 50,282 mother child pairs, 595 of which had first trimester exposure to diphenhydrAMINE; 2948 reported an exposure at some time during pregnancy (Heinonen et al, 1977b). No relationship was found between diphenhydrAMINE exposure and large categories of major and minor malformations.
b) Although the statistical significance is unknown, several possible associations with individual malformations were found (genitourinary, hypospadia, eye and ear defects, inguinal hernia, club foot, ventricular septal defect, malformation of the diaphragm) (Heinonen et al, 1977b).
c) Cleft palate and diphenhydrAMINE use in the first trimester were statistically associated in a 1974 study (Saxen, 1974).
d) Positive associations between diphenhydrAMINE and congenital malformations have been refuted in other studies (Kullander & Kallen, 1976; Mellin, 1964; Winberg, 1964; Jick et al, 1981; Aselton et al, 1985).

2) CARDIAC DEFECT

a) DIMENHYDRINATE

1) A weak association between dimenhyDRINATE exposure and cardiovascular defects and inguinal hernia was suggested, but any causality could not be determined from the data (Mellin & Katzenstein, 1963).

b) DIPHENHYDRAMINE

1) In one study, there were 20 first trimester exposures to diphenhydrAMINE among 599 children with oral clefts compared with 6 exposures among 590 children without clefts indicating that there was an association between use of diphenhydrAMINE in the first trimester and cleft palate (Saxen, 1974a). These results have not been confirmed by other studies.

3) CLEFT PALATE

a) DIMENHYDRINATE

1) One retrospective study linked dimenhyDRINATE use to cleft palate (Conover, 2002).

C) LACK OF EFFECT

1) Analysis of 17,776 pregnancies in the Swedish Medical Birth Registry found that infants born to mothers who used antihistamines during pregnancy had a malformation rate equal to that normally expected (3.17% for antihistamine use compared with 3.16% in the general population). A slightly reduced rate of cardiovascular defects was also seen in the offspring of women using antihistamines during pregnancy. Reduced risks of premature births, low birth weight, and small size for gestational age were also seen with use of antihistamines. The most common antihistamines used by women in this study were clemastine, promethazine, cyclizine, meclizine, cetirizine, terfenadine, and loratadine (Kallen, 2002).
2) A review of the H1 receptor blockers showed that they are effective in decreasing nausea and vomiting in pregnant women (relative risk, 0.34; 95% confidence interval (CI), 0.27 to 0.43). In an analysis of over 200,000 drug exposures during the first trimester of pregnancy, use of antihistamines was also associated with a low risk for major and minor fetal malformations (odds ratio, 0.76; 95% CI, 0.6 to 0.94) (Magee et al, 2002).
3) DIMENHYDRINATE

a) In the Collaborative Perinatal Project, frequencies of congenital malformations were similar to that normally expected in the infants of 319 women who took dimenhyDRINATE during the first four months of pregnancy and among 697 women who took dimenhyDRINATE anytime during pregnancy (Heinonen et al, 1977).
b) Maternal use of dimenhyDRINATE was not associated with birth defects in another case-control study of 266 infants (Mellin & Katzenstein, 1963).

4) DIPHENHYDRAMINE

a) No increase in the incidence of congenital abnormalities was found among the offspring of 595 mothers exposed to diphenhydrAMINE during the first trimester nor among 2948 offspring exposed anytime during pregnancy (Heinonen et al, 1977a).
b) In another study, of 361 women who took diphenhydrAMINE during the first trimester, only 1 delivered an infant with a congenital defect (an incidence of 0.28% which is below the incidence for the general population) (Jick et al, 1982).

D) ANIMAL STUDIES

1) DIMENHYDRINATE

a) RATS, RABBITS: There was no evidence of fetal harm when rats and rabbits were given dimenhyDRINATE at doses that were up to 20 and 25 times the human dose, respectively (Prod Info dimenhydrinate IM, IV injection, 2008).

2) DIPHENHYDRAMINE

a) RATS, RABBITS: There was no evidence of fetal harm when rats and rabbits were given diphenhydrAMINE at doses that were up to 5 times the human dose (Prod Info Diphenhydramine Hydrochloride oral solution, 2008; Prod Info diphenhydramine hcl injection, 2006).

3.20.3)

A) LACK OF INFORMATION

1) At the time of this review, no data were available to assess the potential effects of exposure to dimenhyDRINATE or diphenhydrAMINE during pregnancy in humans (Prod Info dimenhydrinate IM, IV injection, 2008; Prod Info Diphenhydramine Hydrochloride oral solution, 2008; Prod Info diphenhydramine hcl injection, 2006).

B) PREMATURE LABOR

1) DimenhyDRINATE and diphenhydrAMINE may cause an increased level of uterine activity and its use may result in premature labor (Conover, 2002).

C) WITHDRAWAL SYNDROME

1) DIPHENHYDRAMINE

a) CASE REPORT: A syndrome (diarrhea and tremors) has been reported in a neonate of a mother who had used diphenhydrAMINE 150 mg/day for an unspecified period of time during pregnancy (Parkin, 1974).

D) PREGNANCY CATEGORY

1) The manufacturers have classified dimenhyDRINATE and diphenhydrAMINE as FDA pregnancy category B (Prod Info dimenhydrinate IM, IV injection, 2008; Prod Info Diphenhydramine Hydrochloride oral solution, 2008; Prod Info diphenhydramine hcl injection, 2006).

3.20.4)

A) LACK OF INFORMATION

1) At the time of this review, no data were available to assess the potential effects of exposure to dimenhyDRINATE or diphenhydrAMINE during lactation in humans. However, it should be noted that dimenhyDRINATE and diphenhydrAMINE are CONTRAINDICATED in neonates or premature infants (Prod Info dimenhydrinate IM, IV injection, 2008; Prod Info Diphenhydramine Hydrochloride oral solution, 2008; Prod Info diphenhydramine hcl injection, 2006).

B) BREAST MILK

1) Theoretically, due to their anticholinergic effects, antihistamines may reduce milk production. DimenhyDRINATE, like other H1 antagonists, is most likely excreted in breast milk in measurable concentrations. In general, antihistamines are relatively safe for administration in the breast feeding period (Beeley, 1981)(Catz & Giacoia, 1972).
2) DIMENHYDRINATE

a) DimenhyDRINATE has been shown to be excreted in human breast milk in small amounts (Prod Info dimenhydrinate IM, IV injection, 2008).

3) DIPHENHYDRAMINE

a) Excretion of diphenhydrAMINE into the breast milk is reported to be minimal and use in lactating mothers has not resulted in adverse effects in the breast fed infants (White & White, 1980; O'Brien, 1974).

3.20.5)

A) LACK OF INFORMATION

1) At the time of this review, no data were available to assess the potential effects on fertility from exposure to dimenhyDRINATE or diphenhydrAMINE (Prod Info dimenhydrinate IM, IV injection, 2008; Prod Info Diphenhydramine Hydrochloride oral solution, 2008; Prod Info diphenhydramine hcl injection, 2006).

B) ANIMAL STUDIES

1) DIMENHYDRINATE

a) RATS, RABBITS: There was no evidence of impaired fertility when rats and rabbits were given dimenhyDRINATE at doses that were up to 20 and 25 times the human dose, respectively (Prod Info dimenhydrinate IM, IV injection, 2008).

2) DIPHENHYDRAMINE

a) RATS, RABBITS: There was no evidence of impaired fertility when rats and rabbits were given diphenhydrAMINE at doses that were up to 5 times the human dose (Prod Info Diphenhydramine Hydrochloride oral solution, 2008; Prod Info diphenhydramine hcl injection, 2006).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS58-73-1 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs and mental status.
B) DiphenhydrAMINE plasma levels are not clinically useful or readily available.
C) No specific lab work is needed in most patients. Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (agitation, delirium, seizures, coma, hypotension). Monitor creatinine phosphokinase in patients with prolonged agitation, seizures or coma; monitor renal function and urine output in patients with rhabdomyolysis.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Renal and hepatic function tests, a white blood cell count and serum electrolytes and glucose may be necessary if the diagnosis is in question or to guide supportive therapy. Elevated LDH has been reported up to 10 weeks after an overdose (Hestand & Teske, 1977).
2) Interpretation of blood levels of diphenhydrAMINE should be made with caution since pulmonary and femoral blood levels may differ significantly (Roettger, 1990).

4.1.4)

A) OTHER

1) ECG

a) ECG changes that may occur include a wandering pacemaker, prolonged QRS and QT intervals, non-specific ST-T wave changes, and left bundle branch block that resolve with recovery (Hestand & Teske, 1977; Huxtable & Landwirth, 1963).
b) ECG monitoring should be done until EKG is normal and remains so for at least 12 to 24 hours (Ellenhorn & Barceloux, 1988).

2) EEG

a) Neurological evaluations and EEG monitoring have been conducted in order to assess adverse brain effects (Winn & McDonnell, 1993).
b) EEG may show general cerebral arrhythmia and diffuse delta wave activity (Huxtable & Landwirth, 1963). Burst suppression may be noted (Winn & McDonnell, 1993).

3) HAIR ANALYSIS

a) Liquid chromatography, mass spectroscopy of a hair sample was used to confirm the use of diphenhydrAMINE in a drug facilitated sexual assault (Kintz et al, 2007).

4) IMMUNOASSAY INTERFERENCE

a) DiphenhydrAMINE has been reported to cross-react with the EMIT II immunoassay for propoxyphene (Schneider & Wennig, 1999).
b) DiphenhydrAMINE may cross react with methadone on urine immunoassay. A 9-year-old boy who was being treated with diphenhydrAMINE for nasal congestion and difficulty sleeping, presented with an altered level of consciousness. An immunoassay toxicological screen was positive for methadone, however, his parents denied any risk of drug or toxin exposure except for the diphenhydrAMINE. Gas chromatography/mass spectrometry of the patient's urine did not show the presence of methadone (Rogers et al, 2010).

Methods

1) DiphenhydrAMINE can be measured using gas chromatography, ultraviolet spectrophotometry, liquid chromatography-mass spectrometry, and fluorescence dye technique (Abernethy & Greenblatt, 1983; Albert et al, 1974; Backer et al, 1977; Bilzer & Gundert-Remy, 1973; Blyden et al, 1986; Glazko et al, 1974; Wallace et al, 1966; Yoo et al, 1986; Kintz et al, 2007).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with significant persistent central nervous system toxicity (hallucinations, somnolence, delirium, coma) should be admitted. Patients with coma, seizures, dysrhythmias, or delirium should be admitted to an intensive care setting.

6.3.1.2) HOME CRITERIA/ORAL

A) Asymptomatic (other than mild drowsiness or stimulation) children less than 6 years of age with acute inadvertent ingestion of less than 7.5 mg/kg may be monitored at home. Asymptomatic patients 6 years of age and older with acute inadvertent ingestions of less than 7.5 mg/kg or 300 mg (whichever is less) may be monitored at home (Scharman et al, 2006).
B) Patients with inadvertent ingestions who are asymptomatic at the time of the call, and more than 4 hours have elapsed since the ingestion, can be managed at home, as can asymptomatic excessive dermal exposures where more than 8 hours have elapsed since exposure and the skin has been washed (Scharman et al, 2006).

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for patients with severe toxicity (seizures, dysrhythmias, coma, severe delirium) or in whom the diagnosis is not clear.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Children less than 6 years of age with ingestions of at least 7.5 mg/kg should be sent to a healthcare facility. Patients 6 years of age and older with deliberate ingestions or those with ingestions of at least 7.5 mg/kg or 300 mg total or more (whichever is less), and symptomatic patients should be sent to a healthcare facility for observation for 6 to 8 hours. Patients who manifest more than mild sedation or stimulation at the end of this period should be admitted to the hospital (Scharman et al, 2006).

Monitoring

Oral Exposure

6.5.1)

A) Prehospital gastrointestinal decontamination is not recommended because of potential for somnolence and seizures.

6.5.2)

A) SUMMARY

1) Activated charcoal is sufficient decontamination for most patients. However, the patient should be awake and able to protect his/her airway. Gastrointestinal decontamination may be of benefit even several hours after ingestion because of anticholinergic decreased GI motility. The practitioner should only administer activated charcoal in cases where there is potential benefit to the patient and minimal risk.

B) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.3)

A) VENTRICULAR ARRHYTHMIA

1) SODIUM BICARBONATE

a) Sodium bicarbonate has been used for treatment of dysrhythmias in diphenhydrAMINE toxicity. A reasonable starting dose is 1 to 2 mEq/kg. Monitor ECG continuously and monitor serum electrolytes and arterial blood gases. Repeat as needed; endpoints include cessation of dysrhythmias, normalization of QRS complexes and a blood pH of 7.45 to 7.55.
b) CASE REPORT: A 4-month-old infant presented with a diphenhydrAMINE blood level of 4.8 mcg/mL 6 hours after ingesting contaminated juice.

1) Effects included blood pH 6.94, status epilepticus, coma, and severe ventricular dysrhythmias with widened QRS and left bundle branch block. Intubation, mechanical ventilation and a sodium bicarbonate bolus (5 mEq) increased the blood pH to 7.49.
2) Infusion of sodium bicarbonate (100 mEq/L) in D5W was initiated, and 25 minutes later the dysrhythmias stopped, QRS interval narrowed to normal, and he reverted to normal sinus rhythm (blood pH was 7.55 at this time).
3) While therapy included administration of diazepam, phenytoin, phenobarbital, lorazepam, and respiratory and other support, the authors attributed the infant's successful recovery to the sodium bicarbonate (Farrell et al, 1991).

c) Sodium bicarbonate bolus was associated with narrowing the QRS complex in a 17-year-old girl who developed a wide-complex tachycardia postictally after diphenhydrAMINE overdose (Clark & Vance, 1992).
d) In 3 patients who developed wide complex tachycardia after diphenhydrAMINE overdose, use of IV sodium bicarbonate (50 mL of 89.2 mEq NaHCO3 in 2 cases and 25 mL of 44.6 mEq NaHCO3 in 1 case) was associated with narrowing of the QRS complex (Sharma et al, 2003).

2) LIDOCAINE

a) LIDOCAINE/DOSE

1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.

a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).

2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).

b) LIDOCAINE/MAJOR ADVERSE REACTIONS

1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).

c) LIDOCAINE/MONITORING PARAMETERS

1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).

B) FAT EMULSION

1) Intravenous lipid emulsion (ILE) has been effective in reversing severe cardiovascular toxicity from local anesthetic overdose in animal studies and human case reports. Several animal studies and human case reports have also evaluated the use of ILE for patients following exposure to other drugs. Although the results of these studies are mixed, there is increasing evidence that it can rapidly reverse cardiovascular toxicity and improve mental function for a wide variety of lipid soluble drugs. It may be reasonable to consider ILE in patients with severe symptoms who are failing standard resuscitative measures (Lavonas et al, 2015).
2) The American College of Medical Toxicology has issued the following guidelines for lipid resuscitation therapy (LRT) in the management of overdose in cases involving a highly lipid soluble xenobiotic where the patient is hemodynamically unstable, unresponsive to standard resuscitation measures (ie, fluid replacement, inotropes and pressors). The decision to use LRT is based on the judgement of the treating physician. When possible, it is recommended these therapies be administered with the consultation of a medical toxicologist (American College of Medical Toxicology, 2016; American College of Medical Toxicology, 2011):

a) Initial intravenous bolus of 1.5 mL/kg 20% lipid emulsion (eg, Intralipid) over 2 to 3 minutes. Asystolic patients or patients with pulseless electrical activity may have a repeat dose, if there is no response to the initial bolus.
b) Follow with an intravenous infusion of 0.25 mL/kg/min of 20% lipid emulsion (eg, Intralipid). Evaluate the patient's response after 3 minutes at this infusion rate. The infusion rate may be decreased to 0.025 mL/kg/min (ie, 1/10 the initial rate) in patients with a significant response. This recommendation has been proposed because of possible adverse effects from very high cumulative rates of lipid infusion. Monitor blood pressure, heart rate, and other hemodynamic parameters every 15 minutes during the infusion.
c) If there is an initial response to the bolus followed by the re-emergence of hemodynamic instability during the lowest-dose infusion, the infusion rate may be increased back to 0.25 mL/kg/min or, in severe cases, the bolus could be repeated. A maximum dose of 10 mL/kg has been recommended by some sources.
d) Where possible, LRT should be terminated after 1 hour or less, if the patient's clinical status permits. In cases where the patient's stability is dependent on continued lipid infusion, longer treatment may be appropriate.

3) CASE REPORT: A 30-year-old woman developed hypotension (range of 53/27 mmHg to 92/52 mmHg), seizures, several episodes of wide complex tachycardia (QRS range 98 to 112 msec), successfully cardioverted each time, and cardiac arrest, with successful resuscitation, following an intentional ingestion of an unknown amount of diphenydrAMINE. Serum diphenhydrAMINE concentration, obtained in the emergency department at presentation, was 19,000 ng/mL (reference range 100 to 1000 ng/mL). Due to continued hemodynamic instability, despite vasopressor infusion and sodium bicarbonate administration, 20% intravenous lipid emulsion (ILE) therapy was initiated at a dose of 1.5 mL/kg bolus, followed by an infusion of 0.25 mL/kg/min for a total of 8 mL/kg. Approximately 19 minutes after beginning ILE therapy, the patient's blood pressure improved (111/65 mmHg) and vasopressor therapy was weaned, with complete cessation 4 hours after ILE administration. Complications of ILE therapy included mottling of right arm with signs of phlebitis, occurring shortly after beginning infusion. Following central placement of lipids, the mottling improved; however, 2 weeks post-hospital discharge, the patient developed deep vein thrombosis in the brachial vein and a superficial thrombosis in the proximal basilic vein (Abdelmalek et al, 2014).
4) CASE REPORT: A 23-year-old man presented to the emergency department hypotensive (73/32 mmHg) and tachycardic (145 beats/min) after ingesting 2000 to 2500 mg of diphenhydrAMINE. Prior to presentation, emergency responders witnessed a generalized tonic clonic seizure and obtundation of the patient, necessitating ventilation. His initial ECG revealed sinus tachycardia with intraventricular conduction delay, with a QRS width of 172 msec, and a prolonged QTc interval of 577 msec. A venous blood gas analysis indicated metabolic acidosis, and laboratory data revealed a serum diphenhydrAMINE level of 4100 ng/mL (therapeutic range 50 to 100 ng/mL). Treatment included 2 cardioversions for wide complex tachycardia, IV sodium bicarbonate, magnesium sulfate, calcium gluconate, and 2 IV boluses of 20% lipid emulsion, each at a dose of 1.5 mL/kg, administered 20 minutes apart. Within 5 minutes after the second lipid emulsion bolus dose, the patient's QRS width narrowed to 106 msec and his wide complex tachycardia resolved, returning to sinus rhythm with a heart rate of 115 beats/minute. He was extubated on hospital day 3 and, other than development of an elevated lipase level, he recovered uneventfully (Abdi et al, 2014).

C) TACHYARRHYTHMIA

1) No treatment required if the patient is hemodynamically stable. Control agitation with benzodiazepine sedation. Beta blockers may be effective in severe cases, but are rarely if ever required. A short acting, titratable agent such as esmolol would be preferred.
2) May respond to physostigmine, but is likely to recur as physostigmine wears off, other treatment may be necessary.

D) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

7) RECURRING SEIZURES

a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:

1) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
2) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
3) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
4) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)

b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).

8) If severe anticholinergic effects exist, physostigmine may effective.
9) Mechanical ventilation may be necessary for respiratory depression in those patients with recurrent seizures.

E) DRUG-INDUCED DYSTONIA

1) Dystonic reactions to antihistamines may be treated with oral or intravenous diazepam (CHILD: 0.1 to 0.3 mg/kg slowly, ADULT: up to 10 mg, may be repeated as necessary).

F) HYPERTENSIVE EPISODE

1) Mild hypertension is fairly common but rarely requires treatment. Agitated patients may benefit from sedation with benzodiazepines.

G) 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).

5) A challenge dose of physostigmine may be warranted if the diagnosis of anticholinergic toxicity is in question and failure to prove the diagnosis may result in a more invasive and costly work-up. A diagnostic challenge with physostigmine should only be performed in a setting where intensive monitoring and resuscitative equipment is readily available.
6) The beneficial effects of physostigmine usually last only 30 to 60 minutes.
7) CASE REPORT/ADULT: A 31-year-old man presented to the emergency department after a car crash with altered mental status. He was tachycardic (140 bpm) with notably dry mucus membranes. Anticholinergic toxicity was suspected, and 2 mg physostigmine was given. Within 5 minutes, the patient was cognizant enough to report taking 750 mg diphenhydrAMINE daily for months. The patient required another 1 mg of physostigmine 90 minutes later when altered mental status returned, but made a full recovery in 6 hours (Padilla & Pollack, 2002).
8) CASE REPORT/CHILD: A 13-year-old girl presented with hallucinations, agitation, dry and flushed skin, tremors, hypertension, tachycardia (160 bpm), and hyperthermia (38 degrees C) following a polydrug overdose which included acetaminophen, bupropion, citalopram, diphenhydrAMINE, naproxen, and omeprazole. Two doses of physostigmine were administered (2-mg/dose approximately two hours apart), initially resulting in improvement in her hallucinations, agitation, and hyperthermia. However, approximately 1 hour after each dose, her signs and symptoms recurred. Because of her improvement following the physostigmine bolus doses, a physostigmine continuous infusion (0.02 mg/mL) was initiated at 2 mg/hour and continued for approximately 8 hours, when her heart rate had decreased to 90 to 100 beats/min. With the infusion and an additional 2-mg IV bolus dose during the infusion, the patient's agitation, hallucinations, dry and flushed skin, and hyperthermia completely resolved without recurrence (Phillips et al, 2014).

Dermal Exposure

6.9.1)

A) DERMAL DECONTAMINATION

1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

6.9.2)

A) SKIN ABSORPTION

1) CNS and peripheral anticholinergic toxicity has been described from absorption of diphenhydrAMINE following topical exposure (Savchak, 1982; Patranella, 1986; Filloux, 1986; Tomlinson et al, 1987; Woodward & Baldassano, 1988; Goetz & Krenzelok, 1989).

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

1) DiphenhydrAMINE has a large volume of distribution, high protein binding and rapid clearance from plasma, therefore dialysis and hemoperfusion are not expected to remove a significant amount of drug or enhance recovery.
2) CASE REPORT: A 35-year-old woman deliberately ingested 16 g of diphenhydrAMINE and subsequently developed QRS and QTc prolongation. The patient's ECG findings improved approximately 40 minutes after undergoing emergency charcoal hemoperfusion with in-line hemodialysis (Mullins et al, 1999). The patient's serum diphenhydrAMINE levels before and immediately following hemoperfusion were 3,300 ng/mL and 2,560 ng/mL, respectively. DiphenhydrAMINE clearance was not calculated.

1) A 15.5-month-old girl ingested an unknown amount of diphenhydrAMINE and was managed with exchange transfusion when her seizures were not controlled by subtherapeutic doses of anticonvulsants (50 mg phenytoin intravenously and 60 mg phenobarbital intramuscularly) (Huxtable & Landwirth, 1963).

a) Blood levels of diphenhydrAMINE before and after exchange transfusion were reported as 0.55 mg/100 mL and 0.32 mg/100 mL.

Abstracts

Case Reports

1) ADVERSE EFFECTS

a) Nigro (1968) reported a case of a 16-year-old woman who ingested approximately 500 mg of diphenhydrAMINE in an apparent suicide attempt(Nigro, 1968).

1) The patient was noted to be mumbling, giggling, and speaking nonsensically in structured sentences. She was observed to have mydriasis, open-mouthed immobility, poor judgment, loosened associations, and inappropriate, autistic, and mainly flat affect with intense staring. She was described, however, as oriented to person, place and time.
2) Blood pressure was 140/80 mmHg, heart rate was 146 bpm, pupils were dilated and fixed to light, and the tongue was noted to be parched and dry. Patient was treated supportively although the psychotic state continued with the patient exhibiting jerky, rapid, coherent but irrational speech, autism, blunted affect, and visual hallucinations. 29 hours after ingestion, she became cooperative, rational and amnesic of the episode. Dilated pupils and tachycardia persisted for 36 hours following hospitalization.

2) ACUTE EFFECTS

a) FATAL OVERDOSES (ADULT): Krenzelok et al (1982) presented the case of a 7.5 grams fatal diphenhydrAMINE overdose in a 14-year-old girl. The patient was found within 1 hour of ingestion experiencing a tonic-clonic seizure. This was followed by cardiac conduction and hemodynamic compromise.
b) Winn & McDonnell (1993) presented the fatal case of a 5000 mg dimenhyDRINATE overdose in a 19-year-old woman (Winn & McDonnell, 1993). Grand mal seizures were noted 30 minutes after ingestion. Hypotension, multiple cardiac arrhythmias, and metabolic acidosis occurred. Neurological evaluation and EEG suggested acute hypoxic brain injury.

1) Additional complications of the hospital course included rhabdomyolysis, hypocalcemia, ischemic bowel injury (surgery required), severe metabolic acidosis, disseminated intravascular coagulation, sepsis, and cessation of neurological activity.

3) CHRONIC EFFECTS

a) CHRONIC ABUSE: A report of chronic abuse of diphenhydrAMINE resulting in withdrawal symptoms was described (Feldman & Behar, 1986).

1) A 34-year-old schizophrenic had been ingesting approximately 800 mg diphenhydrAMINE twice daily for one month to achieve sedation and mild euphoria. DiphenhydrAMINE was tapered to 600 mg daily in divided doses over days 1 to 3 of hospitalization, and then was reduced more slowly with the last dose being given on the ninth day.
2) The patient developed recurrence of insomnia during the withdrawal period and increased daytime restlessness, irritability and excessive blinking; extrapyramidal symptoms and psychosis were absent.

a) A soft gel liquid preparation, Sleepia(R) (Pfizer) was found to be abused as a self-administered injection in the United Kingdom. The medication can be withdrawn from the gel capsule by needle (greater than or equal to 25 gauge) and syringe and then directly injected. The product is currently marketed over-the-counter in the United States and as a "pharmacist-only medicine" in Australia (Unisom(R) SleepGels) (Roberts et al, 1999).

4) ROUTE OF EXPOSURE

a) DERMAL

1) A 50-year-old man with chronic eczema applied 10% diphenhydrAMINE paste and became obtunded and irritable within 90 minutes(Savchak, 1982).

1) SUBSTANCE SPECIFIC

a) DIPHENHYDRAMINE

1) FATAL OVERDOSE: Topical administration of diphenhydrAMINE cream lead to vomiting, unresponsiveness, and death in a 17-month-old boy. The child had an active case of eczema over his entire back, bilateral shins, bilateral cheeks, and bilateral popliteal fossae. The parents indicated they purchased a tube of diphenhydrAMINE cream and applied some of it to his eczema three days prior and the morning of death. Further investigation revealed the diphenhydrAMINE had been applied to the areas of eczema after a warm bath the morning of his death. Upon autopsy, petechial hemorrhages of the thymus, heart and lungs were reported and the plasma diphenhydrAMINE level, measured by gas chromatography, was 1.03 mg/L. The authors suspected three factors were responsible for the child's death: the administration of the medication after a warm bath, which lead to increased absorption of the medication from the skin; application of the medication to eczema, which impaired the normal dermal barrier; and excessive application to the large surface area of the rash (Turner, 2009).

2) ROUTE OF EXPOSURE

a) DERMAL

1) A 5-year-old girl developed agitation, unsteady gait, trembling, and hallucinations following topical application of Caladryl(R) (calamine, camphor, alcohol, diphenhydrAMINE) for pruritic vesicular exanthem of chickenpox (Tomlinson et al, 1987).
2) Six patients (mean age 5 years) presented with ataxia, confusion, hallucinations, hyperactivity, dilated pupils, and hyperthermia following topical application of 2 to 6 ounces of Caladryl(R) lotion over a 24 to 48 hour period (Goetz & Krenzelok, 1989).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) SUBSTANCE SPECIFIC

1) DIMENHYDRINATE: PRESCRIPTION

a) INJECTION: The recommended dose is 50 to 100 mg every 4 hours (Prod Info dimenhydrinate IM, IV injection, 2008).

1) IM: Inject each mL (50 mg) as needed (Prod Info dimenhydrinate IM, IV injection, 2008).
2) IV: Dilute each mL (50 mg) in 10 mL of 0.9% sodium chloride. Then, inject over a 2-minute period (Prod Info dimenhydrinate IM, IV injection, 2008).

2) DIMENHYDRINATE: OVER-THE-COUNTER

a) TABLETS: The recommended dose is 50 mg to 100 mg every 4 to 6 hours with the first dose taken 30 minutes to an hour before starting activity. MAXIMUM DOSE: 400 mg in 24 hours (Prod Info DRAMAMINE(R) oral tablets, 2006).

3) DIPHENHYDRAMINE: PRESCRIPTION

a) INJECTION

1) The recommended dose is 10 mg to 50 mg intravenously at a rate generally not exceeding 25 mg/min; or 100 mg by deep intramuscular injection, if required. MAXIMUM DOSE: 400 mg/day (Prod Info diphenhydramine hcl injection, 2006).

b) ORAL SOLUTION

1) The recommended dose is 25 mg to 50 mg 3 or 4 times per day. As a nighttime sleep aid, the recommended dose is 50 mg at bedtime (Prod Info Diphenhydramine Hydrochloride oral solution, 2008).

4) DIPHENHYDRAMINE: OVER-THE-COUNTER

a) ORAL

1) ANTIHISTAMINE: The recommended dose is 25 mg to 50 mg every 4 to 6 hours. MAXIMUM DOSE: 150 mg in 24 hours (Prod Info BENADRYL(R) ALLERGY oral capsules, 2006).
2) SLEEP AID: The recommended dose is 50 mg at bedtime (Prod Info UNISOM(R) SLEEPGELS(R) oral gelcaps, 2006).

b) TOPICAL

1) ANTI-ITCH: Apply diphenhydrAMINE hydrochloride cream or spray to affected area not more than 3 or 4 times per day. Avoid using cream or spray on large areas of the body (Prod Info BENADRYL(R) extra strength cream, 2006; Prod Info Benadryl(R) Itch Stopping Spray Original Strength, 2004; McNeil Consumer Healthcare, 2010).

5) DIPHENHYDRAMINE: OVER-THE-COUNTER COMBINATIONS

a) DIPHENHYDRAMINE/ACETAMINOPHEN

1) The recommended dose is diphenhydrAMINE hydrochloride 50 mg/acetaminophen 1000 mg (2 caplets/geltabs or 2 tablespoons of oral liquid) at bedtime. MAXIMUM DOSE: 2 caplets/geltabs or 2 tablespoons of oral liquid in 24 hours (McNeil Consumer Healthcare, 2010).

b) DIPHENHYDRAMINE/IBUPROFEN

1) The recommended dose is 2 caplets (diphenhydrAMINE citrate 38 mg/ibuprofen 200 mg per caplet) at bedtime. MAXIMUM DOSE: 2 caplets in 24 hours (Prod Info Advil(R)PM oral caplets, 2010).

7.2.2)

A) GENERAL

1) DimenhyDRINATE and diphenhydrAMINE are CONTRAINDICATED in neonates and premature infants (Prod Info dimenhydrinate IM, IV injection, 2008; Prod Info Diphenhydramine Hydrochloride oral solution, 2008; Prod Info diphenhydramine hcl injection, 2006).

B) SUBSTANCE

1) DIMENHYDRINATE: PRESCRIPTION

a) CHILDREN (OTHER THAN NEONATES): The recommended IM dose is 1.25 mg/kg of body weight or 37.5 mg/m(2) of body surface area 4 times per day. MAXIMUM DOSE: 300 mg/day (Prod Info dimenhydrinate IM, IV injection, 2008).

2) DIMENHYDRINATE: OVER-THE-COUNTER

a) TABLETS

1) 2 TO 6 YEARS OF AGE: The recommended dose is 12.5 to 25 mg every 6 to 8 hours. MAXIMUM DOSE: 75 mg in 24 hours (Prod Info DRAMAMINE(R) oral tablets, 2006).
2) 6 TO 12 YEARS OF AGE: The recommended dose is 25 to 50 mg every 6 to 8 hours. MAXIMUM DOSE: 150 mg in 24 hours (Prod Info DRAMAMINE(R) oral tablets, 2006).
3) 12 TO 18 YEARS OF AGE: The recommended dose is 50 to 100 mg every 4 to 6 hours. MAXIMUM DOSE: 400 mg in 24 hours (Prod Info DRAMAMINE(R) oral tablets, 2006).

3) DIPHENHYDRAMINE: PRESCRIPTION

a) INJECTION

1) CHILDREN (OTHER THAN PREMATURE INFANTS AND NEONATES): The recommended dose is 5 mg/kg of body weight/24 hours or 150 mg/m(2) of body surface area/24 hours divided into 4 doses and administered intravenously at a rate generally not exceeding 25 mg/min, or deep intramuscularly. MAXIMUM DOSE: 300 mg/day (Prod Info diphenhydramine hcl injection, 2006).

b) ORAL SOLUTION

1) 12 YEARS AND OLDER: The recommended dose is 12.5 to 25 mg 3 or 4 times per day. On the basis of body weight or surface area, the recommended dose is 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. MAXIMUM DOSE: 300 mg/day (Prod Info Diphenhydramine Hydrochloride oral solution, 2008).
2) LESS THAN 12 YEARS: Data are not available for the use of diphenhydrAMINE as a nighttime sleep aid (Prod Info Diphenhydramine Hydrochloride oral solution, 2008).

c) DIPHENHYDRAMINE: OVER-THE-COUNTER

1) ORAL

a) ANTIHISTAMINE:

1) 12 YEARS AND OLDER: The recommended dose is 25 to 50 mg every 4 to 6 hours. MAXIMUM DOSE: 300 mg/day (Prod Info BENADRYL(R) ALLERGY oral capsules, 2006).
2) 6 TO 12 YEARS: The recommended dose is 12.5 to 25 mg every 4 to 6 hours. Capsule not available as 12.5 mg; do not break capsule. Do not exceed 6 doses in 24 hours (Prod Info BENADRYL(R) ALLERGY oral capsules, 2006).
3) LESS THAN 6 YEARS: Ask doctor before use (Prod Info BENADRYL(R) ALLERGY oral capsules, 2006).

b) SLEEP AID:

1) 12 YEARS AND OLDER: The recommended dose is 50 mg at bedtime (Prod Info UNISOM(R) SLEEPGELS(R) oral gelcaps, 2006).
2) LESS THAN 12 YEARS: Do not use (Prod Info UNISOM(R) SLEEPGELS(R) oral gelcaps, 2006).

2) TOPICAL

a) ANTI-ITCH:

1) 2 YEARS AND OLDER: Apply to affected area not more than 3 or 4 times per day. Avoid using on large areas of the body(Prod Info BENADRYL(R) extra strength cream, 2006; Prod Info Benadryl(R) Itch Stopping Spray Original Strength, 2004; McNeil Consumer Healthcare, 2010).
2) LESS THAN 2 YEARS: Ask doctor before use (Prod Info BENADRYL(R) extra strength cream, 2006; McNeil Consumer Healthcare, 2010; Prod Info Benadryl(R) Itch Stopping Spray Original Strength, 2004).

d) DIPHENHYDRAMINE: OVER-THE-COUNTER COMBINATIONS

1) DIPHENHYDRAMINE/ACETAMINOPHEN

a) 12 YEARS AND OLDER: The recommended dose is diphenhydrAMINE hydrochloride 50 mg/acetaminophen 1000 mg (2 caplets/geltabs or 2 tablespoons of oral liquid) at bedtime. MAXIMUM DOSE: 2 caplets/geltabs or 2 tablespoons of oral liquid in 24 hours (McNeil Consumer Healthcare, 2010).
b) LESS THAN 12 YEARS: Do not use (McNeil Consumer Healthcare, 2010).

2) DIPHENHYDRAMINE/IBUPROFEN

a) 12 YEARS AND OLDER: The recommended dose is 2 caplets (diphenhydrAMINE citrate 38 mg/ibuprofen 200 mg per caplet) at bedtime. MAXIMUM DOSE: 2 caplets in 24 hours (Prod Info Advil(R)PM oral caplets, 2010).
b) LESS THAN 12 YEARS: Do not use (Prod Info Advil(R)PM oral caplets, 2010).

Minimum Lethal Exposure

1) ADULT

a) Fatality was reported in an adult after ingestion of 25 mg/kg (Treibergs & Lovejoy, 1983).
b) A fatality was reported in an adult after ingestion of 5,000 mg dimenhyDRINATE (Winn & McDonnell, 1993).
c) Acute ingestion of 7.5 grams of diphenhydrAMINE in a 14-year-old girl resulted in grand mal seizures, hypotension, severe acidosis, and death (Krenzelok et al, 1982).
d) A 48-year-old woman ingested an unknown amount of guaifenesin, diphenhydrAMINE, and chlorpheniramine in overdose and was found dead. The diphenhydrAMINE blood concentration was 8.8 mg/L, approximately 100 times greater than the average peak plasma concentration following a single therapeutic dose. Elevated levels of guaifenesin (approximately 20 times the therapeutic dose) and chlorpheniramine (approximately 10 times the therapeutic dose) were also found and it is unclear whether a particular agent or a combination of these agents caused her death (Wogoman et al, 1999).

2) INFANT

a) An 18-month-old, 10-kg-infant developed grand mal seizures following rectal administration of 3 doses of 50 mg of pyrilamine maleate over 24 hours (Reyes-Jacanq & Wenzl, 1969).

1) DiphenhydrAMINE 30 mg was administered parenterally for initial control of seizures. Status epilepticus developed shortly thereafter. The child died 10 hours after hospitalization.

b) Ingestion of an estimated 495 mg (33 mg/kg) resulted in status epilepticus and death 7 days postingestion in a 15-month-old child (Goetz et al, 1990).
c) A 9-week-old 5.4 kg infant died after ingesting 62.5 mg diphenhydrAMINE(Baker et al, 2003).

Maximum Tolerated Exposure

1) Patients 6 years of age and older with acute ingestions of less than 7.5 mg/kg or 300 mg (whichever is less) re unlikely to develop significant toxicity (Scharman et al, 2006).
2) CASE REPORTS

a) A 35-year-old woman developed hypotension, lethargy, generalized seizures, and prolonged QRS and QTc intervals following a deliberate ingestion of 16 grams of diphenhydrAMINE in a suicide attempt (Mullins et al, 1999).

1) In a similar case, a healthy 26-year-old man ingested 25 g of diphenhydrAMINE and developed lethargy, coma, generalized seizures, and prolonged QRS and QTc interval. Torsades de pointes occurred approximately 6.5 hours after ingestion, and laboratory evidence of metabolic acidosis and hypokalemia were also observed (Joshi et al, 2004) .

b) A 39-year-old man ingested 2.4 grams of diphenhydrAMINE in a suicide attempt and subsequently developed hyperthermia, akinesia, rhabdomyolysis, and a decrease in consciousness (Park-Matsumoto & Tazawa, 1999).
c) A 22-year-old woman ingested 5 grams of diphenhydrAMINE, experienced severe toxicity, and survived with residual encephalopathy (Rinder et al, 1988).
d) DiphenhydrAMINE dependence with no apparent physical effects were reported in a 34-year-old man taking 1,600 mg daily (Feldman & Behar, 1986).
e) Severe toxicity (seizure, wide-complex tachycardia) was described in a 17-year-old after ingestion of 750 mg of diphenhydrAMINE (Clark & Vance, 1992).
f) A 17-year-old ingested 2,000 mg of diphenhydrAMINE in a suicide attempt, subsequently became unresponsive, and developed tachycardia, tachypnea, bundle branch block with QT interval prolongation, seizures, hypotension, and metabolic acidosis. The patient recovered with supportive care (Thakur et al, 2005).
g) A 23-year-old man presented to the emergency department hypotensive (73/32 mmHg) and tachycardic (145 beats/min) after ingesting 2000 to 2500 mg of diphenhydrAMINE. Prior to presentation, emergency responders witnessed a generalized tonic clonic seizure and obtundation of the patient, necessitating ventilation. His initial ECG revealed sinus tachycardia with intraventricular conduction delay, with a QRS width of 172 msec, and a prolonged QTc interval of 577 msec. A venous blood gas analysis indicated metabolic acidosis, and laboratory data revealed a serum diphenhydrAMINE level of 4100 ng/mL (therapeutic range 50 to 100 ng/mL). Treatment included 2 cardioversions for wide complex tachycardia, IV sodium bicarbonate, magnesium sulfate, calcium gluconate, and 2 IV boluses of 20% lipid emulsion, each at a dose of 1.5 mL/kg, administered 20 minutes apart. Within 5 minutes after the second lipid emulsion bolus dose, the patient's QRS width narrowed to 106 msec and his wide complex tachycardia resolved, returning to sinus rhythm with a heart rate of 115 beats/minute. He was extubated on hospital day 3 and, other than development of an elevated lipase level, he recovered uneventfully (Abdi et al, 2014).

3) CASE SERIES

a) ADULT: In a large series of adult overdoses with diphenhydrAMINE alone (232 studied retrospectively and 50 studied prospectively) serious intoxication (delirium, psychosis, seizures, coma) only developed after ingestion of one gram or more (Radovanovic et al, 2000)

1) Children less than 6 years of age with acute ingestion of less than 7.5 mg/kg are unlikely to develop significant toxicity (Scharman et al, 2006).
2) GENERAL: Children, in particular infants tend to be more sensitive to the toxic effects of diphenhydrAMINE than adults.
3) In a review by Baker et al (2003) small doses of diphenhydrAMINE can produce severe toxicity in children. In one case a 34-month-old (11.5 kg) ingested only 50 mg of diphenhydrAMINE and developed ataxia, aphasia, and grand mal seizures; and a 13-month old (10 kg) ingested between 100 to 150 mg diphenhydrAMINE and developed respiratory arrest with left bundle branch block and seizures. Both recovered with supportive care. The authors concluded that children and, in particular, infants appear to develop more severe CNS stimulation (including seizures), as compared to adults with supratherapeutic blood diphenhydrAMINE levels; this appears to improve with age (Baker et al, 2003).
4) Acute ingestions in the range of 10 to 15 mg/kg have caused severe toxicity (seizures, respiratory arrest, dysrhythmias) in young children (Scharman et al, 2006).
5) CASE SERIES: In a prospective study of 184 cases of diphenhydrAMINE (n=131) or dimenhyDRINATE (n=53) ingestions in children 18 years of age or less, the mean age was 5.2 years, with a mean weight of 20.6 kg. A total of 50 cases (not specified as diphenhydrAMINE or dimenhyDRINATE) were symptomatic on presentation; CNS depression (56%), tachycardia (18%), and hypertension (18%) were observed. Of these cases, the mean age was 8.9 years with a mean ingested dose of 17.3 mg/kg (Zavitz et al, 1989).
6) CASE REPORT: Ingestion of 700 to 800 mg of diphenhydrAMINE (50 to 60 mg/kg) was not fatal to a three-year-old child (Dverfeldt, 1947).

1) SEIZURE: As little as 150 to 200 mg of diphenhydrAMINE in an 18-month-old child (Wyngaarden & Seevers, 1951) has resulted in seizures.
2) A 13-month-old infant developed wide complex tachycardia, prolonged QTc interval, tachypnea, nystagmus, agitation alternating with lethargy, a single tonic clonic seizure, and dry, flushed skin after an unintentional suspected maximal ingestion of 24 25-mg diphenhydrAMINE tablets (50 mg/kg). With supportive care, the patient recovered within 24 hours and was discharged without sequelae (Cole et al, 2011).

1) DERMAL EXPOSURE

a) In a 7-year retrospective study, 6 patients (mean age 5 years) were identified with diphenhydrAMINE toxicity following total body application of 2 to 6 ounces of Caladryl(R) lotion over 24 to 48 hours (Goetz & Krenzelok, 1989).
b) A 2.5-year-old boy presented with visual hallucinations following topical application of a warmed solution of calamine-diphenhydrAMINE hydrochloride to his entire body (Reilly & Weisse, 1990).
c) A 5-year-old boy developed bizarre behavior with visual hallucinations associated with administration of 3.6 mg/kg of oral diphenhydrAMINE over 36 hours and topical application of 3 ounces of calamine-diphenhydrAMINE lotion over 12 hours (Woodward & Baldassano, 1988).
d) A 9-year-old boy presented with agitation, confusion, hallucinations, and a serum diphenhydrAMINE concentration of 1.4 mg/liter after dermal application to treat skin eruptions (Filloux, 1986).
e) Psychotic symptoms usually appear with doses greater than 600 mg/day of dimenhyDRINATE (Craig & Mellor, 1990).

1) CASE REPORT: A 35-year-old schizophrenic man ingested 8 to 10 25-mg diphenhydrAMINE capsules daily over an 11-year period. Randomly measured plasma drug concentrations reflected an even higher intake. There were no signs of anticholinergic delirium. There was no attempt at withdrawal (Isabelle & Warner, 1999).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) SUMMARY

a) Based on a review of the medical literature and the Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System from 1983 through 2002 of diphenhydrAMINE monointoxication fatalities, 35 cases were identified that had drug levels obtained. The following describes the mean diphenhydrAMINE blood levels based on age:

1) Adults: 18 to 60 years (mean 34.3 years): mean drug level 16.14 mg/L (range 0.87 to 48.5 mg/L)
2) Pediatric: 1.25 to 17 years (mean 6.5 years): mean drug level 6.35 mg/L (range 0.69 to 13.7 mg/L)
3) Infants: 6 to 24 weeks (mean 12.4 weeks): mean drug level 1.51 mg/L (1.1 to 2.2 mg/L)

b) Based on a review of 55 diphenhydrAMINE fatalities, diphenhydrAMINE concentrations above 5 mcg/mL (5 mg/L) in venous blood were potentially lethal in overdoses involving diphenhydrAMINE alone. DiphenhydrAMINE concentrations ranged form 0.5 to 8.9 mcg/mL (0.5 to 8.9 mg/L) in nonfatal cases and from 0.3 to 119 mcg/mL (0.3 to 119 mg/L) in fatal cases (many cases involved mixed ingestions. DiphenhydrAMINE concentrations were much higher in heart blood as compared to venous blood in some cases (Pragst et al, 2006).
c) A review of 136 cases of diphenhydrAMINE overdose revealed a wide range of plasma levels (0.1 to 4.7 mcg/mL) which did not correlate with symptoms or signs (Koppel et al, 1987).
d) In infants, postmortem diphenhydrAMINE levels from 1.1 to 1.6 mg/L have been reported. DiphenhydrAMINE redistributes to blood post mortem. In one study the average central: peripheral blood ratio was 2.3 (range 0.8 to 21) (Baker et al, 2003).

2) CASE REPORTS

a) DIPHENHYDRAMINE

1) A fatal case had a diphenhydrAMINE plasma level of 5 mcg/mL and liver tissue level of about 34 micrograms/gram (Hausmann et al, 1983).
2) Death occurred in a 15-month-old child with a plasma level of 10 mcg/mL (Goetz et al, 1990).
3) An intentional overdose of a 4-month-old resulted in status epilepticus, coma, and a life-threatening dysrhythmia; serum diphenhydrAMINE level was 4.8 mcg/mL (Farrel et al, 1991).
4) TOPICAL MISUSE

a) A 17-month-old boy had postmortem blood and liver diphenhydrAMINE concentrations of 1.03 mg/L and 1.06 mg/L, respectively. The child had eczema on his entire back, bilateral shins, bilateral cheeks and bilateral popliteal fossae and was administered diphenhydrAMINE to these areas three days prior to death and after a warm bath on the morning of death (Turner, 2009)
b) A 2.5-year-old boy had serum and urine diphenhydrAMINE concentrations of 1958 nanograms/mL and 230 mcg/mL, respectively following topical application of a warmed solution of calamine-diphenhydrAMINE hydrochloride to his entire body (Reilly & Weisse, 1990).

b) Postmortem serum diphenhydrAMINE levels ranged from 14.7 to 35.0 mg/L in four fatal diphenhydrAMINE overdose ingestions (Karch, 1998).
c) Serum diphenhydrAMINE levels before and immediately following hemoperfusion were 3,300 ng/mL and 2,560 ng/mL, respectively, in a 35-year-old female who ingested 16 g of diphenhydrAMINE in a suicide attempt (Mullins et al, 1999).
d) The diphenhydrAMINE blood concentration, in a 48-year-old woman following a fatal ingestion of diphenhydrAMINE in an unknown amount, was 8.8 mg/L (approximately 100 times greater than the average peak plasma concentration following a single therapeutic dose) (Wogoman et al, 1999).
e) The plasma diphenhydrAMINE levels of a 35-year-old man, following ingestion of 8 to 10 25-mg capsules daily for 11 years, was 1272 ng/mL (normal plasma range is 25 to 50 nanograms/mL) (Isabelle & Warner, 1999).

3) CONCENTRATION LEVEL

a) Expected effects at given concentrations (Gilman et al, 1990):

1) Antihistaminic effect >25 nanograms/mL
2) Drowsiness 30 to 40 nanograms/mL
3) Mental impairment >60 nanograms/mL

Workplace Standards

1) Not Listed

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

1) Not Listed

Toxicity Information

7.7.1)

A) References: RTECS, 2000

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 56 mg/kg

2) LD50- (ORAL)MOUSE:

a) 160 mg/kg

3) LD50- (SUBCUTANEOUS)MOUSE:

a) 50 mg/kg

4) LD50- (INTRAPERITONEAL)RAT:

a) 280 mg/kg

5) LD50- (ORAL)RAT:

a) 390 mg/kg

6) LD50- (SUBCUTANEOUS)RAT:

a) 474 mg/kg

Pharmacology Toxicology

Pharmacologic Mechanism

1) DiphenhydrAMINE has the properties and uses of the antihistamines which do not inhibit histamine release, antibody production, nor antigen-antibody reaction but rather antagonize histamine effects on receptor sites (Ellenhorn & Barceloux, 1988).
2) It has anti-emetic, anti-cholinergic, antimotion-sickness, CNS anti-tussive, CNS excitation and depression, quinidine-like, and local anesthetic properties (Hardman et al, 1996).
3) The central antimuscarinic effects of diphenhydrAMINE blunt the excitatory action of the cholinergic system on the nigrostriatal pathways (Schreibman, 1990).
4) H1 antagonists inhibit both the vasoconstrictor effect of histamine and the more rapid vasodilator effects mediated by H1 receptors on endothelial cells (Hardman et al, 1996). Residual vasodilation reflects involvement of H2 receptors on smooth muscles.
5) DiphenhydrAMINE has antiparkinson effects. It suppresses tremulous jaw movements in the rat model of Parkinson's-like tremor through a mechanism that does not depend on antagonism of histamine H1 receptors (Carlson et al, 2000).

Toxicologic Mechanism

Physicochemical

Physical Characteristics

Ph

Molecular Weight

Animal Toxicology

References

General Bibliography

10)

11)

12)

13)

14)

15)

16)

17)

18)

19)

20)

21)

22)

23)

24)

25)

26)

27)

28)

29)

30)

31)

32)

33)

34)

35)

36)

37)

38)

39)

40)

41)

42)

43)

44)

45)

46)

47)

48)

49)

50)

51)

52)

53)

54)

55)

56)

57)

58)

59)

60)

61)

62)

63)

64)

65)

66)

67)

68)

69)

70)

71)

72)

73)

74)

75)

76)

77)

78)

79)

80)

81)

82)

83)

84)

85)

86)

87)

88)

89)

90)

91)

92)

93)

94)

95)

96)

97)

98)

99)

100)

101)

102)

103)

104)

105)

106)

107)

108)

109)

110)

111)

112)

113)

114)

115)

116)

117)

118)

119)

120)

121)

122)

123)

124)

125)

126)

127)

128)

129)

130)

131)

132)

133)

134)

135)

136)

137)

138)

139)

140)

141)

142)

143)

144)

145)

146)

147)

148)

149)

150)

151)

152)

153)

154)

155)

156)

157)

158)

159)

160)

161)

162)

163)

164)

165)

166)

167)

168)

169)

170)

171)

172)

173)

174)

175)

176)

177)

178)

179)

180)

181)

182)

183)

184)

185)

186)

187)

188)

189)

190)

191)

192)

193)

194)

195)

196)

197)

198)

199)

200)

201)

202)

203)

204)

205)

206)

207)

208)

209)

210)

211)

212)

213)

214)

215)

216)

217)

218)

219)

220)

221)

222)

223)

224)

225)

226)

227)

228)

229)

230)

231)

232)

233)

234)

235)

236)

237)

238)

239)

240)

241)

242)

243)

244)

245)

246)

247)

248)

249)

250)

251)

252)

253)

254)

255)

256)

257)

258)

259)

260)

261)

262)

263)

264)

265)

266)

267)

268)

269)

270)

271)

272)

273)

274)

275)

276)

277)

278)

279)

280)

281)

282)

283)

284)

285)

286)

287)

288)

289)

290)

291)

292)

293)

294)

295)

296)

297)

298)

299)

300)

301)

302)

303)

304)

305)

306)

307)

308)

309)

310)

311)

312)

313)

FeedBack

DIPHENHYDRAMINE AND RELATED AGENTS

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Acid-Base

Hematologic

Dermatologic

Musculoskeletal

Immunologic

Reproductive

Carcinogenicity

Monitoring Parameters Levels

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Dermal Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Pharmacologic Mechanism

Toxicologic Mechanism

Physical Characteristics

Ph

Molecular Weight

General Bibliography