ANTIHISTAMINES

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

1) Alkylamines
2) Ethylenediamine derivatives
3) Ethanolamine derivatives
4) Piperazine derivatives
5) Phenothiazine derivatives
6) Miscellaneous peripherally selective H1 antagonists

Specific Substances

1) CAS 91-75-8
2) CAS 2508-72-7 (antazoline hydrochloride)
3) CAS 3131-32-6 (antazoline mesylate)
4) CAS 154-68-7 (antazoline phosphate)
5) CAS 24359-81-7 (antazoline sulfate, anhydrous)

1) CAS 3964-81-6
2) CAS 3978-86-7 (azatadine maleate)

1) CAS 86-22-6
2) CAS 980-71-2 (brompheniramine maleate)

1) CAS 82-95-1
2) CAS 129-74-8 (buclizine hydrochloride)

1) CAS 82-93-9
2) CAS 1620-21-9 (chlorcyclizine hydrochloride)

1) CAS 132-22-9
2) CAS 113-92-8 (chlorpheniramine maleate)

1) CAS 15686-51-8
2) CAS 14976-57-9 (clemastine fumarate)

1) CAS 82-92-8
2) CAS 303-25-3 (cyclizine hydrochloride)
3) CAS 5897-19-8 (cyclizine lactate)

1) CAS 129-03-3
2) CAS 969-33-5 (cyproheptadine hydrochloride, anhydrous)
3) CAS 41354-29-4 (cyproheptadine hydrochloride, sesquihydrate)

1) CAS 132-21-8
2) CAS 2391-03-9 (dexbrompheniramine maleate)

1) CAS 25523-97-1
2) CAS 2438-32-6 (dexchlorpheniramine maleate)

1) CAS 5636-83-9
2) CAS 3614-69-5 (dimethindene maleate)

1) CAS 147-20-6
2) CAS 132-18-3 (diphenylpyraline hydrochloride)

1) CAS 469-21-6
2) CAS 562-10-7 (doxylamine succinate)

1) LAS-W-090
2) CAS 90729-43-4

1) CAS 87233-61-2

1) CAS 68-88-2
2) CAS 10246-75-0 (hydroxyzine embonate)
3) CAS 2192-20-3 (hydroxyzine hydrochloride)

1) CAS 524-81-2

1) CAS 569-65-3
2) CAS 1104-22-9 (meclizine hydrochloride, anhydrous)
3) CAS 31884-77-2 (meclizine hydrochloride monohydrate)

1) CAS 91-80-5
2) CAS 33032-12-1 (methapyrilene fumarate)
3) CAS 135-23-9 (methapyrilene hydrochloride)

1) CAS 1982-37-2
2) CAS 1229-35-2 (methdilazine hydrochloride)

1) CAS 27367-90-4

1) ALO 4943A
2) KW 4679

1) CAS 82-88-2
2) CAS 569-59-5 (phenindamine tartrate)

1) CAS 86-21-5
2) CAS 3269-83-8 (pheniramine aminosalicylate)
3) CAS 132-20-7 (pheniramine maleate)

1) CAS 92-12-6
2) CAS 1176-08-5 (phenyltoloxamine citrate)

1) Pizotyline
2) CAS 15574-96-6 (pizotifen)
3) CAS 5189-11-7 (pizotifen malate)

1) CAS 60-87-7
2) CAS 58-33-3 (promethazine hydrochloride)

1) CAS 91-84-9
2) CAS 59-33-6 (pyrilamine maleate)

1) CAS 135-31-9 (pyrobutamine phosphate)
2) CAS 91-82-7

1) CAS 91-79-2
2) CAS 958-93-0 (thenyldiamine hydrochloride)

1) CAS 84-96-8
2) CAS 4330-99-8 (trimeprazine tartrate)

1) CAS 486-12-4
2) CAS 550-70-9 (triprolidine hydrochloride, anhydrous)
3) CAS 6138-79-0 (triprolidine hydrochloride,
4) monohydrate)

1) CAS 91-81-6
2) CAS 6138-56-3 (tripelennamine citrate)
3) CAS 154-69-8 (tripelennamine hydrochloride)

1) Antihistamine

Available Forms Sources

1) AZATADINE MALEATE

1) No longer available in the US

2) AZELASTINE HYDROCHLORIDE

1) Refer to AZELASTINE document for more information.

3) BROMPHENIRAMINE MALEATE

1) Injection solution: 10 mg/mL
2) Oral capsule: 4 mg
3) Oral capsule, extended release: 12 mg
4) Oral elixir: 2 mg/5 mL
5) Oral liquid: 2 mg/5 mL
6) Oral solution: 2 mg/5 mL
7) Oral tablet: 4 mg
8) Oral tablet, extended release: 6 mg, 8 mg, 12 mg

4) BUCLIZINE

1) No longer available in the US

5) CARBINOXAMINE MALEATE

1) Refer to CARBINOXAMINE MALEATE document for more information.

6) CETIRIZINE HYDROCHLORIDE

1) Refer to CETIRIZINE document for more information.

7) CHLORPHENIRAMINE MALEATE

1) Injection: 10 mg/mL
2) Oral capsule, extended release: 6 mg, 8 mg, 12 mg
3) Oral liquid: 2 mg/5 mL
4) Oral syrup: 2 mg/5 mL
5) Oral tablet: 2 mg, 4 mg
6) Oral tablet, chewable: 2 mg
7) Oral tablet, extended release: 8 mg, 12 mg, 16 mg

8) CLEMASTINE FUMARATE

1) Oral syrup: 0.5 mg/5 mL
2) Oral tablet: 1.34 mg, 2.68 mg

9) CYCLIZINE LACTATE

1) No longer available in the US

10) CYPROHEPTADINE HCL

1) Oral syrup: 2 mg/5 mL
2) Oral tablet: 4 mg

11) DESLORATADINE

1) Refer to LORATADINE AND RELATED AGENTS document for more information.

12) DEXCHLORPHENIRAMINE MALEATE

1) Oral syrup: 2 mg/5 mL
2) Oral tablet: 2 mg
3) Oral tablet, extended release: 4 mg, 6 mg

13) DIMENHYDRINATE

1) Refer to DIPHENHYDRAMINE AND RELATED AGENTS for more information.

14) DIPHENYLPYRALINE HCL

1) No longer available in the US

15) DOXYLAMINE SUCCINATE

1) Oral tablet: 25 mg

16) EMEDASTINE DIFUMARATE

1) Ophthalmic solution: 0.05% in 5 mL, 10 mL, and 15 mL bottles

17) HYDROXYZINE HCL

1) Intramuscular solution: 25 mg/mL, 50 mg/mL
2) Oral syrup: 10 mg/5 mL
3) Oral tablet: 10 mg, 25 mg, 50 mg, 100 mg

18) HYDROXYZINE PAMOATE

1) Oral capsule: 25 mg, 50 mg, 100 mg
2) Oral suspension: 25 mg/5 mL

19) LORATADINE

1) Refer to LORATADINE AND RELATED AGENTS document for more information.

20) MECLIZINE

1) Oral capsule: 15 mg, 25 mg, and 30 mg
2) Oral tablet: 12.5 mg, 25 mg, 30 mg, 32 mg, 50 mg
3) Oral tablet, chewable: 25 mg

21) METHDILAZINE

1) No longer available in the US

22) OLOPATADINE HCL

1) Ophthalmic solution: 0.1%

23) PHENINDAMINE TARTRATE

1) Not available in the US

24) PYRILAMINE MALEATE

1) No longer available in the US

25) TRIMEPRAZINE TARTRATE

1) No longer available in the US

26) TRIPELENNAMINE HCL

1) No longer available in the US

27) TRIPROLIDINE HCL

1) Oral solution: 1.25 mg/5 mL
2) Oral syrup: 1.25 mg/5 mL

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Antihistamines are used primarily to treat allergic reactions. Also used to treat pruritus, peripheral vertigo, and as a sleep aid. Occasionally used as a drug of abuse for their hallucinogenic effects, primarily by adolescents.
B) EPIDEMIOLOGY: Poisoning is common but rarely severe. May occur via oral, parenteral, or dermal (patches or cream) routes.
C) PHARMACOLOGY: Competitive antagonist of histamine (H1 and H2) receptors. Second generation antihistamines tend to be less sedating as they do not cross the blood-brain barrier as readily as the first generation antihistamines.
D) TOXICOLOGY: Anticholinergic (primarily antimuscarinic) effects develop in overdose due to antagonism of central H1 receptors. Large overdoses of H1 blockers, particularly diphenhydramine, may cause sodium channel antagonism.
E) WITH THERAPEUTIC USE

1) ADVERSE EFFECTS: COMMON: Mild sedation, dizziness, impaired coordination, and mild anticholinergic effects. Paradoxical excitation can develop in some patients.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE POISONING: Somnolence, anticholinergic effects (ie, mydriasis, flushing, fever, dry mouth, and decreased bowel sounds), tachycardia, mild hypertension, and nausea and vomiting are common after overdose. Agitation, confusion, and hallucinations may develop with moderate poisoning.
2) SEVERE POISONING: Severe effects may include agitated delirium, psychosis, seizures, coma, hypotension, QRS widening, and ventricular dysrhythmias, including torsade de pointe but are generally only reported in adults after very large, deliberate ingestions. Rhabdomyolysis and renal failure may rarely develop in patients with prolonged agitation, coma, or seizures.
3) Refer to: ASTEMIZOLE, AZELASTINE, CARBINOXAMINE, CETIRIZINE, DESLORATADINE, DIPHENHYDRAMINE, LORATADINE, FEXOFENADINE, TERFENADINE, or PROMETHAZINE for information specific to those agents.

0.2.3)

A) Tachycardia is common. Hyperthermia, hypotension, and hypertension have been reported.

0.2.20)

A) Most antihistamines are classified as FDA pregnancy category B or C. The manufacturer has classified doxylamine succinate/pyridoxine hydrochloride as FDA pregnancy category A. In general, there have been few reported teratogenic effects in humans, although animal studies have suggested that certain antihistamines have teratogenic potential. Pyloric stenosis has occurred in infants following maternal use of antihistamines. Small amounts of antihistamines are excreted in breast milk.

0.2.21)

A) OLOPATADINE HYDROCHLORIDE: At the time of this review, the manufacturer does not report any carcinogenic potential.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) The majority of antihistamine overdoses requires only supportive care; give activated charcoal if patient presents shortly after ingestion; sedate 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 a diagnosis, it may also help avoid an invasive, costly work-up, but should only be given in a setting where intensive monitoring and resuscitation are available. It should NOT be given if there is a history or ECG (QRS widening) evidence that suggests a tricyclic antidepressant poisoning.

B) MANAGEMENT OF SEVERE TOXICITY

1) Orotracheal intubation for airway protection should be performed early. Gastric lavage may be of benefit, if the patient presents soon after a large ingestion; administer activated charcoal as well. 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 rarely 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. Monitor core temperature and treat hyperthermia with aggressive benzodiazepine sedation to control agitation and external cooling. Clinical manifestations may be prolonged due to delayed absorption in the setting of an anticholinergic ileus.

C) DECONTAMINATION

1) PREHOSPITAL: Not recommended because of the potential for somnolence and seizures. For dermal exposure, remove patches and wash skin thoroughly.
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, but first protect the airway.

D) AIRWAY MANAGEMENT

1) Perform early in patients with severe intoxication (i.e., seizures, dysrhythmias, severe delirium or hyperthermia).

E) ANTIDOTE

1) Physostigmine is indicated to reverse the CNS effects caused by clinical or toxic dosages of agents capable of producing anticholinergic syndrome; however, long lasting reversal of anticholinergic signs and symptoms is generally not achieved because of the relatively short duration of action of physostigmine (45 to 60 minutes). It is most often used diagnostically to distinguish anticholinergic delirium from other causes of altered mental status. CAUTION: If tricyclic antidepressants are coingested, physostigmine may precipitate seizures and dysrhythmias. DOSES: ADULT: 2 mg IV at a slow controlled rate, no more than 1 mg/min. May repeat doses at intervals of 10 to 30 min if severe symptoms recur. For patients with prolonged anticholinergic delirium consider a continuous infusion, start at 2 mg/hr and titrate to effect. CHILD: 0.02 mg/kg by slow IV injection, at a rate no more than 0.5 mg/minute. Repeat dosage at 5 to 10 minute intervals as long as the toxic effect persists and there is no sign of cholinergic effects. MAXIMUM DOSAGE: 2 mg total.

F) DYSRHYTHMIAS

1) QRS widening or ventricular tachycardia may respond to sodium bicarbonate. A reasonable starting dose is 1 to 2 mEq/kg bolus; repeat as needed. Endpoints include resolution of dysrhythmias, narrowing of QRS complex and blood pH 7.45 to 7.55. Use lidocaine if sodium bicarbonate is not successful.

G) SEIZURES

1) Most seizures are self-limited or respond to intravenous benzodiazepines. Patients with recurrent or recalcitrant seizures should be treated with propofol or barbiturate

H) HYPERTHERMIA

1) Control agitation with benzodiazepines, initiate aggressive external cooling measures (i.e., remove patient clothing, cover with a wet sheet or keep skin damp and direct fans at the patient's skin to enhance evaporation).

I) DELIRIUM

1) Sedate patient with benzodiazepines until the patient is sleepy. Large doses (greater than 10 mg of lorazepam) may be required.

J) ENHANCED ELIMINATION

1) Hemodialysis or hemoperfusion are of no value.

K) PATIENT DISPOSITION

1) HOME CRITERIA: Asymptomatic children (other than mild drowsiness or stimulation) with acute inadvertent ingestions may be monitored at home.
2) OBSERVATION CRITERIA: Patients with deliberate ingestions and symptomatic patients should be sent to a health care facility for observation for 6 to 8 hours.
3) ADMISSION CRITERIA: Patients with significant persistent central nervous system toxicity (i.e., 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 assistance in managing patients with severe toxicity (i.e., seizures, dysrhythmias, severe delirium, coma) or in whom the diagnosis is not clear.

L) PITFALLS

1) Physostigmine is generally not advised for long term management as anticholinergic effects generally recur 30 to 45 minutes after physostigmine administration. Toxicity may be delayed and prolonged secondary to prolonged absorption due to anticholinergic ileus.

M) PHARMACOKINETICS

1) Depends on the specific antihistamine, though onset of action for most is between 15 to 60 minutes with variable duration of effect and half-life. Most are highly protein binding with primarily hepatic metabolism for elimination. The volume of distribution tends to be large (e.g., 4 to 8 L/kg for diphenhydramine).

N) DIFFERENTIAL DIAGNOSIS

1) Anticholinergic poisoning from other substances, sympathomimetic poisoning (should have less mydriasis, usually no visual hallucinations, usually have moist skin), CNS infection, ethanol/benzodiazepine/barbiturate withdrawal.

0.4.4)

A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.

0.4.5)

A) OVERVIEW

1) 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: COMMON: Mild sedation, dizziness, impaired coordination, and mild anticholinergic effects. Paradoxical excitation can develop in some patients.

Vital Signs

3.3.1)

A) Tachycardia is common. Hyperthermia, hypotension, and hypertension have been reported.

3.3.3)

A) Hyperthermia, most often in children, has been reported following overdose (Bharucha et al, 1987; Magera et al, 1981; Wyngaarden & Seevers, 1951; Waldman & Pelner, 1950). Death attributed to severe hyperthermia has been reported (Wyngaarden & Seevers, 1951a).
B) PIZOTIFEN/CASE REPORT: A 16-year-old girl, with a 3-year history of migraine and 1-year history of depression, ingested 60 0.5-mg pizotifen tablets 4 hours before presenting to the emergency department. At presentation, the patient experienced blurred vision and abdominal pain. Examination revealed drowsiness, flushing, hyperpyrexia (38 degrees C), dilated pupils, and tachycardia. Gastric lavage did not produce any tablets. The patient's pyrexia and tachycardia persisted for approximately 10 hours before resolving spontaneously (Griffiths et al, 1987).

3.3.4)

A) HYDROXYZINE/CASE SERIES: The circulatory effects of hydrOXYzine in volunteers and geriatric patients were reported in a study. Two young subjects developed marked hypotension after receiving 0.75 to 1 mg of IV hydrOXYzine (Lauria et al, 1968).
B) Hypertension has been reported in several cases as an overdose effect (Frankel et al, 1993; Mendoza et al, 1987; Waldman & Pelner, 1950).

3.3.5)

A) Tachycardia is a very common occurrence in overdose ingestions (Scott et al, 2007; Frankel et al, 1993; Bharucha et al, 1987; Richmond & Seger, 1985).

Heent

3.4.3)

A) Anticholinergic effects, including fixed and dilated pupils, visual disturbances, blurred vision, and diplopia, have been reported (Scott et al, 2007; Spiller et al, 2001; Frankel et al, 1993; Mendoza et al, 1987)
B) WITH POISONING/EXPOSURE

1) DOXYLAMINE: According to a review of patient records documenting the occurrence of seizures following doxylamine overdose ingestions (11 of 146 patients developed seizures), mydriasis was reported in 36.4% of patients. The mean amount of doxylamine ingested was 2425 mg (range, 750 to 4750 mg) (Kim et al, 2010).
2) PIZOTIFEN/CASE REPORT: A 16-year-old girl, with a 3-year history of migraine and 1-year history of depression, ingested 60 0.5-mg pizotifen tablets 4 hours before presenting to the emergency department. At presentation, the patient experienced blurred vision and abdominal pain. Examination revealed drowsiness, flushing, hyperpyrexia (38 degrees C), dilated pupils, and tachycardia. Gastric lavage did not produce any tablets. The patient's pyrexia and tachycardia persisted for approximately 10 hours before resolving spontaneously (Griffiths et al, 1987).

3.4.4)

A) Tinnitus and acute labyrinthitis have been reported (Wyngaarden & Seevers, 1951).

3.4.5)

A) Nasal dryness and stuffiness can develop as an anticholinergic effect (Wyngaarden & Seevers, 1951a). The incidence of anticholinergic effects vary according to the class of antihistamines.

3.4.6)

A) Mouth and throat dryness have occurred as a result of anticholinergic effects (Scott et al, 2007; Wyngaarden & Seevers, 1951). The incidence of anticholinergic effects vary according to the class of antihistamines.

Cardiovascular

3.5.2)

A) HYPERTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) There have been several reports of hypertension occurring following overdose of antihistamines (Spiller et al, 2001; Frankel et al, 1993; Mendoza et al, 1987; Waldman & Pelner, 1950).

B) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) PYRILAMINE MALEATE/CASE REPORT: An adult developed cardiogenic shock several hours after ingesting 10 grams of pyrilamine maleate in a suicide attempt. Intraaortic balloon counterpulsation was used to reverse the cardiogenic shock (Freedberg et al, 1987a).

C) ELECTROCARDIOGRAM ABNORMAL

1) WITH POISONING/EXPOSURE

a) Several cases of prolonged QTc and QRS intervals and nonspecific ST and T wave changes were reported following antihistamine overdoses. The widened QTc and QRS intervals appeared to be related to seizure activity (Donovan et al, 1992).
b) PYRILAMINE: A 15-year-old girl presented to the emergency department approximately 2 hours after intentionally ingesting 30 tablets of a combination product containing acetaminophen 500 mg (375 mg/kg), caffeine 60 mg (32 mg/kg), and pyrilamine 15 mg (32 mg/kg), as well as ingesting 1200 mg ibuprofen and 6 g acetaminophen separately. The patient was tachycardic (124 beats/min) with normal heart sounds; however, an ECG showed a prolonged QTc interval (0.62 seconds). Laboratory analysis indicated liver enzymes were within normal limits. With supportive care, including acetylcysteine administration and cardiac monitoring, the patient remained hemodynamically stable with normal liver enzymes. A repeat ECG, obtained 2 days later, indicated normalization of the QTc interval (Paudel et al, 2011).

D) TACHYARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) Tachycardia is a very common occurrence in overdose ingestions (Scott et al, 2007; Kirages et al, 2003; Leybishkis et al, 2001; Spiller et al, 2001; Bangh & Roberts, 1997; Frankel et al, 1993; Bharucha et al, 1987; Richmond & Seger, 1985).
b) PROLONGED TACHYCARDIA/CYCLIZINE: Persistent sinus tachycardia was reported in a 32-year-old woman following an overdose ingestion of 500 mg cyclizine. At admission, her heart rate was 160 beats/min (bpm) and continued to fluctuate over the next 72 hours between 88 and 110 bpm. She also experienced three episodes of transient supraventricular tachycardia at 47 hours, 49 hours, and 52 hours post-ingestion, with each episode lasting less than a minute. Seventy-two hours post admission, the patient decided to discharge herself against medical advice, despite a heart-rate of 103 bpm (Kamour et al, 2013).
c) PIZOTIFEN/CASE REPORT: A 16-year-old girl, with a 3-year history of migraine and 1-year history of depression, ingested 60 0.5-mg pizotifen tablets 4 hours before presenting to the emergency department. At presentation, the patient experienced blurred vision and abdominal pain. Examination revealed drowsiness, flushing, hyperpyrexia (38 degrees C), dilated pupils, and tachycardia. Gastric lavage did not produce any tablets. The patient's pyrexia and tachycardia persisted for approximately 10 hours before resolving spontaneously (Griffiths et al, 1987).
d) DOXYLAMINE: An observational case series was conducted that collected data retrospectively from a poison system database for all single substance doxylamine ingestions in pediatric patients (5 years and younger) from 1997 to 2012. There were 140 cases identified (ages ranging from 6 months to 5 years), of which 137 were due to unintentional self-administration and 3 were due to therapeutic error. Signs and symptoms were reported in 22 patients with drowsiness/lethargy, tachycardia, and agitation/hyperactivity as the most frequently reported symptoms, occurring in 17 patients, 12 patients, and 4 patients, respectively. The exact amount ingested was documented in 30 cases, ranging from 6.25 to 50 mg (median, 12.5 mg) and a maximum weight based dose of 6.2 mg/kg. The smallest reported weight based dose resulting in symptoms (drowsiness) was 1.5 mg/kg (Cantrell et al, 2015).

E) VENTRICULAR ARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) METHAPYRILENE/CASE REPORT (CHILD): A 2-month-old infant developed ventricular dysrhythmias several hours after administration of copious amounts of an ointment used to treat seborrheic dermatitis. The ointment contained cyclomethycaine (0.5%) and methapyrilene hydrochloride (2%). The dysrhythmias resolved 11 hours after emergency department admission (Tenley & Friedman, 1966).
b) PHENIRAMINE/CASE REPORT (ADULT): A 27-year-old man developed supraventricular and ventricular dysrhythmias several hours after an overdose ingestion of pheniramine (Bobik & McLean, 1976).

F) CARDIAC ARREST

1) WITH POISONING/EXPOSURE

a) DOXYLAMINE/CASE REPORT (CHILD): A 3-year-old boy ingested approximately 100 tablets of a combination drug containing 10 mg of dicyclomine hydrochloride and 10 mg of doxylamine hydrochloride. He developed restlessness, disorientation, and ataxia which developed into generalized tonic-clonic seizures and a series of cardiac arrests and died 18 hours following ingestion (Bayley et al, 1975).

G) HYPOTENSIVE EPISODE

1) HYDROXYZINE/CASE SERIES: The circulatory effects of hydrOXYzine in volunteers and geriatric patients was evaluated. Two young subjects developed marked hypotension after receiving 0.75 to 1 mg of hydrOXYzine IV (Lauria et al, 1968).

H) MYOCARDIAL INFARCTION

1) PENTAZOCINE AND TRIPELENNAMINE/CASE REPORT: A 27-year-old man began experiencing severe chest pain 15 to 30 minutes after the injection of a mixture of pentazocine and tripelennamine. An ECG indicated the development of an acute Q-wave anteroseptal myocardial infarction with associated lateral ischemia (McGwier et al, 1992).

Respiratory

3.6.2)

A) PNEUMONITIS

1) WITH THERAPEUTIC USE

a) ANTAZOLINE/CASE REPORT: A 35-year-old woman developed acute interstitial pneumonitis after administration of antazoline 400 mg daily for 2 days. Two days later, the patient improved following supportive care in the hospital.

1) One month later, the patient was challenged with 50 mg antazoline. Eight hours after the first dose, the patient complained of mild dyspnea. Seven hours after the second dose, dyspnea increased and a fever and rash appeared. She improved rapidly after methylprednisolone administration (Pahissa et al, 1979).

B) BRONCHOSPASM

1) WITH THERAPEUTIC USE

a) BROMPHENIRAMINE/CASE SERIES: Brompheniramine given to 10 asthmatic children not concomitantly using bronchodilators caused chest tightness and a decrease FEV1 (Schuller, 1983).
b) CASE SERIES: Five asthmatic children were challenged with several different antihistamines from other classes to determine the spectrum of response. FEV1 decreased when any antihistamine was given (Schuller, 1983a).
c) HYDROXYZINE PAMOATE/CASE REPORT: A 15-year-old boy with a past medical history of extrinsic asthma and allergies was admitted to the hospital for a possible bowel obstruction. He was given hydrOXYzine pamoate 50 mg intramuscularly preoperatively. Within 10 minutes, he complained of chest tightness, became dyspneic, and began to wheeze. The reaction subsided after administration of epinephrine and aminophylline.

1) Three days later, he was rechallenged with hydrOXYzine pamoate intramuscularly. Within 10 minutes, he developed chest tightness and wheezing (Massoud, 1978).
2) CASE REPORT: A patient with multiple allergies developed chest tightness and wheezing while hydrOXYzine was being administered intravenously (Lauria et al, 1968). The reaction subsided rapidly when the hydrOXYzine administration stopped and returned on rechallenge.

Neurologic

3.7.2)

A) DEPRESSIVE DISORDER

1) WITH THERAPEUTIC USE

a) CYPROHEPTADINE/CASE REPORT: Zubieta (1992) reported that a patient who had a past history of depression developed a recurrence of depression after 3 days of cyproheptadine administration of 4 mg/day. Discontinuation of cyproheptadine promptly reduced his depressive symptoms.

B) DELIRIUM

1) WITH THERAPEUTIC USE

a) CYPROHEPTADINE/CASE REPORT: A 9-year-old child experienced confusion, agitation, and visual hallucinations approximately 2 weeks after beginning cyproheptadine therapy of 4 mg twice daily for migraine prophylaxis. Following the discontinuation of the cyproheptadine, the patient's agitation and hallucinations gradually disappeared within 24 hours after onset of symptoms (Watemberg et al, 1999).
b) PYRILAMINE/CASE SERIES: There have been several cases reported of children younger than 5 years who developed toxic encephalopathy following administration of an antiemetic combination of pentobarbital and pyrilamine maleate (Schwartz & Patterson, 1978). Toxic encephalopathy is characterized by a decreased level of consciousness, irritability, and ataxia.
c) A 5-year-old girl became agitated and developed hallucinations after ingesting a sustained release antihistamine/decongestant preparation nightly for 4 days prior to admission. The product was a sustained-release tablet, containing carbinoxamine maleate 8 mg and pseudoephedrine 120 mg. The patient immediately responded to a test dose of physostigmine (Cockrell, 1987).

2) WITH POISONING/EXPOSURE

a) CYPROHEPTADINE: Cyproheptadine has been reported to cause toxic psychosis following overdose ingestions in children. Toxic psychosis is characterized by agitation, disorientation, and hallucinations (Blaustein et al, 1995; Bharucha et al, 1987; Richmond & Seger, 1985).
b) CYPROHEPTADINE/PROMETHAZINE: A 14-year-old girl intentionally ingested 200 mg of cyproheptadine and 1150 mg of promethazine and subsequently developed depressed consciousness (Glasgow Coma Scale of 8) and prolonged delirium, consisting of agitation, confusion, disorientation, rapid and unintelligible speech, and visual hallucinations. With supportive care, the delirium gradually resolved over a 7-day period. In conjunction with the overdose, the patient had also been taking fluvoxamine at a dose of 150 mg daily. It is speculated that concurrent administration of promethazine, predominantly metabolized by CYP2D6, and fluvoxamine, a CYP2D6 inhibitor, may have contributed to the development of the prolonged delirium (Scott et al, 2007).
c) PROPHENPYRIDAMINE/CASE SERIES: Two cases of toxic psychosis due to prophenpyridamine overdoses were reported. Both patients eventually recovered, following discontinuation of the medication (Waldman & Pelner, 1950).
d) CARBINOXAMINE/DEXCHLORPHENIRAMINE/PHENIRAMINE: Hallucinations, anxiety, restlessness, and agitation have been reported following overdoses of carbinoxamine (Cockrell, 1987), dexchlorpheniramine (Soleymanikashi & Weiss, 1970), pheniramine (Csillag & Landauer, 1973; Jones et al, 1973), and tripelennamine (Hays et al, 1980; Schipior, 1967). Discontinuation of the medications led to the disappearance of the symptoms.
e) DIPHENHYDRAMINE AND DOXYLAMINE/CASE REPORT: A 20-year-old woman, 36 weeks pregnant, presented to the emergency department with confusion, hallucinations, and incoherent speech approximately 3 hours after ingesting an unknown amount of sleep medications containing diphenhydramine and doxylamine. The patient completely recovered within 24 hours after decontamination and administration of physostigmine (Bangh & Roberts, 1997).
f) CHLORPHENIRAMINE: Toxic psychosis with hallucinations developed in a 4-year-old boy who accidentally ingested a single 12 mg oral dose of chlorpheniramine. Subsequently, the patient became agitated, restless, and grossly ataxic and experienced auditory and visual hallucinations. The patient picked at his clothes and demonstrated incoherent speech. Treatment with chloral hydrate resulted in improvement of the patient's condition (Jones et al, 1973a).

C) SEIZURE

1) WITH POISONING/EXPOSURE

a) Antihistamines may precipitate epileptiform seizures in patients with preexisting focal lesions of the CNS (Fink, 1969; Reilly et al, 1968) and have produced generalized seizures after overdose ingestions (Bangh & Roberts, 1997; Frankel et al, 1993; Soto et al, 1993; Magera et al, 1981; Bayley et al, 1975a; Wyngaarden & Seevers, 1951), especially in children.
b) METHAPYRILENE/CASE REPORT (CHILD): A 2-month-old infant experienced brief clonic seizures several hours after administration of copious amounts of an ointment containing cyclomethycaine (0.5%) and methapyrilene hydrochloride (2%) (Tenley & Friedman, 1966).
c) TRIPELENNAMINE AND ANTAZOLINE/CASE REPORT: A case of a 3-year-old girl who ingested 750 mg tripelennamine and 1500 mg antazoline and subsequently developed tonic-clonic seizures was reported. The patient died 22 hours after onset of the seizures (Oberst, 1955).
d) PHENIRAMINE: According to a study, generalized seizures were more likely to occur in pheniramine overdose ingestions (30% of patients) than with other antihistamine overdose ingestions (Buckley et al, 1994).
e) DOXYLAMINE: According to a review of patient records documenting doxylamine overdose ingestions (n=146), seizures occurred in 11 patients. The mean amount of doxylamine ingested was 2425 mg (range, 750 to 4750 mg) and the mean time of seizure onset was 188 minutes postingestion (range, 60 to 480 minutes) (Kim et al, 2010).

D) COMA

1) WITH POISONING/EXPOSURE

a) CASE SERIES: In a series of 30 antihistamine overdoses, grade 3 or 4 coma was reported in 15 cases. The duration of the coma was an average of 3.9 hours (range, 1 to 14 hours) (Jacobsen et al, 1984).
b) METHAPYRILENE/CASE REPORT: An 18-year-old man ingested an unknown amount of methapyrilene and presented to the emergency department in a semiconscious state. A neurological examination revealed a stuporous, somnolent patient who reacted to painful stimuli. The patient recovered after treatment with forced diuresis (Soleymanikashi & Weiss, 1970).

E) CHOREOATHETOSIS

1) WITH POISONING/EXPOSURE

a) CYPROHEPTADINE/CASE REPORT: A 17-year-old girl developed choreoathetoid movements of all 4 extremities following an ingestion of cyproheptadine 280 mg. Movements resolved after gastric lavage and supportive measures (Samie & Ashton, 1989).

F) CEREBRAL EDEMA

1) WITH POISONING/EXPOSURE

a) METHAPYRILENE/CASE REPORT (CHILD): A 16-month-old girl developed hyperthermia and cerebral edema following ingestion of methapyrilene 100 mg. The patient died 15 hours after ingestion (Wyngaarden & Seevers, 1951).

G) DROWSY

1) WITH THERAPEUTIC USE

a) EMEDASTINE: Somnolence and malaise were reported following daily oral administration of emedastine (Prod Info Emadine(R), emedastine difumarate, 1997).
b) DOXYLAMINE/CASE REPORT: A 13-month-old child was found dead approximately 20 hours after being given 3.5 mL of an over-the-counter sleep aid containing doxylamine 250 mg/100 mL. Autopsy revealed that she aspirated gastric contents, likely secondary to severe sedation due to doxylamine ingestion (Turk & Ewald, 2012).

2) WITH POISONING/EXPOSURE

a) DOXYLAMINE: An observational case series was conducted that collected data retrospectively from a poison system database for all single substance doxylamine ingestions in pediatric patients (5 years and younger) from 1997 to 2012. There were 140 cases identified (ages ranging from 6 months to 5 years), of which 137 were due to unintentional self-administration and 3 were due to therapeutic error. Signs and symptoms were reported in 22 patients with drowsiness/lethargy, tachycardia, and agitation/hyperactivity as the most frequently reported symptoms, occurring in 17 patients, 12 patients, and 4 patients, respectively. The exact amount ingested was documented in 30 cases, ranging from 6.25 to 50 mg (median, 12.5 mg) and a maximum weight based dose of 6.2 mg/kg. The smallest reported weight based dose resulting in symptoms (drowsiness) was 1.5 mg/kg (Cantrell et al, 2015).

H) CLOUDED CONSCIOUSNESS

1) WITH THERAPEUTIC USE

a) MECLIZINE/CASE REPORT: An 85-year-old woman experienced increasing memory impairment, confusion, disorientation, and paranoia while taking meclizine for 3 years. Upon discontinuation of the meclizine, the patient's condition improved. However, after the meclizine was restarted, the patient's condition deteriorated with a worsening of the disorientation, confusion, and agitation (Molloy, 1987).

I) DYSTONIA

1) WITH THERAPEUTIC USE

a) Acute dystonic reactions have been reported following recommended doses of chlorpheniramine, diphenhydramine, and other antihistamines (Lavenstein & Cantor, 1976).

J) DYSKINESIA

1) WITH THERAPEUTIC USE

a) Acute dyskinesia was reported after therapeutic use of cyclizine (Klawans & Moskovitz, 1977), dexbrompheniramine (Barone & Raniolo, 1980), and doxylamine (Favis, 1976). Delayed onset of blepharospasm, facial dyskinesia, and involuntary head, face, and tongue movements have been described after chronic ingestion of brompheniramine (Thach et al, 1975), chlorpheniramine (Davis, 1976; Thach et al, 1975), and hydrOXYzine (Clark et al, 1982).

K) DISTURBANCE IN THINKING

1) Several investigators have evaluated the performance of subjects while under the influence of antihistamines and found that these agents decreased skills (Meltzer, 1990).
2) CHLORPHENIRAMINE: A Japanese study using chlorpheniramine measured EEG, eye movements, coarse steering adjustments, and sleepiness scores. Six of the 10 subjects experienced impaired driving performance (Aso & Sakai, 1989).
3) TRIPROLIDINE: The British studied driving ability under the influence of triprolidine and found subjects took longer to complete the course, struck obstacles, and made more mistakes like stalling and going the wrong way (Betts et al, 1984).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH THERAPEUTIC USE

a) Nausea, vomiting, loss of appetite, and abdominal distress accompanied by diarrhea or constipation may occur with antihistamine therapy (Cirillo & Tempero, 1976).

2) WITH POISONING/EXPOSURE

a) DOXYLAMINE: According to a review of patient records documenting the occurrence of seizures following doxylamine overdose ingestions (11 of 146 patients developed seizures), vomiting was reported in 45.5% of patients. The mean amount of doxylamine ingested was 2425 mg (range, 750 to 4750 mg) (Kim et al, 2010).

Hepatic

3.9.2)

A) CHOLESTATIC HEPATITIS

1) WITH THERAPEUTIC USE

a) CYPROHEPTADINE/CASE REPORT: A 25-year-old woman developed cholestatic jaundice 1 month after beginning cyproheptadine 12 mg daily for intermittent pruritus. A wedge biopsy of the liver appeared to be typical of drug-induced cholestasis, similar to that associated with the phenothiazines.

1) Two months after switching to chlorpheniramine 16 mg daily, the patient was well and anicteric. Bilirubin and alkaline phosphatase concentrations returned to normal, but minor elevations of SGOT (70 units/L) and SGPT (90 units/L) persisted (Henry et al, 1978).

b) MEBHYDROLIN/CASE REPORT: Cholestasis developed in a patient 12 hours after the initiation of mebhydrolin therapy of 50 mg 3 times daily. Bilirubin and liver enzyme levels were elevated. Liver function tests returned to normal 3 weeks after discontinuing the medication (McKenna & McMillan, 1993).
c) CASE REPORT: A 59-year-old man with a history of alcoholism developed jaundice and increased liver enzyme levels following administration of imipramine pamoate and cyproheptadine for 28 days. Prior to that time, liver function was normal after 10 days on cyproheptadine alone. All symptoms subsided rapidly after discontinuation of both medications (Karkalas & Lal, 1971).

B) DRUG-INDUCED LIVER DISEASE

1) WITH THERAPEUTIC USE

a) CYCLIZINE/CASE REPORT (CHILD): An 8-year-old girl developed hepatitis 8 days after beginning cyclizine hydrochloride therapy, 25 mg daily for 5 days, to prevent motion sickness. Signs and symptoms resolved a month and a half later.

1) The hepatitis recurred 1 day after the patient had been given 25 mg cyclizine to prevent motion sickness. The serum bilirubin level was markedly elevated. The bilirubin level returned to normal after 16 weeks (Kew et al, 1973).

b) CYPROHEPTADINE/CASE REPORT: A patient developed acute hepatitis after therapeutic administration of cyproheptadine. The hepatitis was followed by prolonged anicteric cholestasis. The cholestasis was present 31 months after the onset of the drug-induced acute hepatitis, despite discontinuation of the drug (Larrey et al, 1987).

2) WITH POISONING/EXPOSURE

a) DOXYLAMINE: According to a review of patient records documenting the occurrence of seizures following doxylamine overdose ingestions (11 of 146 patients developed seizures), drug-induced hepatitis was reported in 6 patients (54.5%). The mean amount of doxylamine ingested was 2425 mg (range, 750 to 4750 mg) (Kim et al, 2010).

Genitourinary

3.10.2)

A) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) Acute renal failure has been reported in patients who developed rhabdomyolysis after overdose (Frankel et al, 1993; Koppel et al, 1987; Koppel et al, 1987a)

B) RETENTION OF URINE

1) WITH THERAPEUTIC USE

a) Urinary retention has been reported as an anticholinergic effect of antihistamines. Discontinuation of the antihistamine usually resolves the urinary retention (Wyngaarden & Seevers, 1951).

2) WITH POISONING/EXPOSURE

a) Acute urinary retention has been reported after overdose (Kirages et al, 2003)

Hematologic

3.13.2)

A) HEMOLYTIC ANEMIA

1) WITH THERAPEUTIC USE

a) DEXCHLORPHENIRAMINE AND TRIPELENNAMINE: Hemolytic anemia is a rare adverse effect that has been reported following the therapeutic use of dexchlorpheniramine and tripelennamine. The anemia usually resolved following discontinuation of the medications (Duran-Suarez et al, 1981; Crumbley, 1950).

B) THROMBOCYTOPENIC DISORDER

1) WITH THERAPEUTIC USE

a) ANTAZOLINE/CHLORPHENIRAMINE/MEBHYDROLIN: Thrombocytopenia has been reported following administration of antazoline (Nielsen et al, 1981), chlorpheniramine (Deringer & Maniatis, 1976; Eisner et al, 1975), and mebhydrolin (McKenna & McMillan, 1993). Thrombocytopenia usually resolved with prednisone therapy and after discontinuation of the causative agent.

C) AGRANULOCYTOSIS

1) Drug-induced agranulocytosis, a rare adverse effect, has been associated with ingestions of brompheniramine (Hardin & Padilla, 1978), chlorpheniramine (Hardin, 1988), methaphenilene (Drake, 1950), thenalidine (Adams & Perry, 1958), and tripelennamine (Martland & Guck, 1950; Cahan et al, 1949).

Dermatologic

3.14.2)

A) CONTACT DERMATITIS

1) Contact dermatitis is associated with topical antihistamines, in particular the alkylamine class of antihistamines (Valsecchi et al, 1994; Santucci et al, 1992; Tosti et al, 1990; Cusano et al, 1989). The dermatitis resolved upon discontinuation of the topical agent.
2) ANTAZOLINE/CASE REPORT: A 53-year-old woman developed contact dermatitis after administration of antazoline eyedrops. The contact dermatitis slowly resolved after discontinuation of the medication (Mosko & Peterson, 1950).

B) ERUPTION DUE TO DRUG

1) CYCLIZINE/CASE REPORT: A fixed drug eruption due to cyclizine was reported. The patient experienced soreness and erythematous inflamed patches of the penile skin after ingesting cyclizine 50 mg for travel sickness. The eruption cleared following topical administration of betamethasone valerate ointment and discontinuation of the cyclizine. Fixed drug eruptions due to antihistamines are rare occurrences (Griffiths & Peachey, 1970).

C) PSORIASIS

1) MEBHYDROLIN/CASE SERIES: Two patients with past medical histories of psoriasis experienced an exacerbation of their psoriasis following administration of mebhydrolin for the treatment of pruritus. Discontinuation of mebhydrolin led to the subsequent dermal improvement (McKenna & McMillan, 1993).

D) PHLEBITIS AFTER INFUSION

1) HYDROXYZINE: One study showed a high incidence of phlebitis, associated with a burning sensation at the injection site, after IV administration of hydrOXYzine (Lauria et al, 1968).

Musculoskeletal

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) DOXYLAMINE

1) Several cases of rhabdomyolysis occurring after doxylamine overdose have been reported. Most patients had a history of prolonged coma or increased muscle activity associated with agitation and subsequently developed a decrease in urinary output and an increase in CPK levels. Patients generally recover with aggressive intravenous hydration; alkalinization of the urine using sodium bicarbonate and diuresis with furosemide have also been used (Khosla et al, 2003; Leybishkis et al, 2001; Frankel et al, 1993; Soto et al, 1993; Mendoza et al, 1987).
2) Rhabdomyolysis secondary to doxylamine overdose has been seen in 7 of 442 cases referred to 1 poison center. Secondary causes of rhabdomyolysis (eg, compression, shock, seizures, or hypokalemia) were not seen in any of these 7 patients (Koppel et al, 1987).
3) A case of rhabdomyolysis was reported in an 18-year-old man after ingestion of 2.25 g doxylamine. The rhabdomyolysis was associated with transitory impairment of renal function (Koppel et al, 1987aa).
4) According to a review of patient records documenting the occurrence of seizures following doxylamine overdose ingestions (11 of 146 patients developed seizures), rhabdomyolysis was reported in 7 patients (63.6%). The mean amount of doxylamine ingested was 2425 mg (range, 750 to 4750 mg) (Kim et al, 2010).
5) ASSOCIATED FACTORS: A review of medical records involving patients who were admitted after intentional doxylamine overdose and who had normal creatine phosphokinase (CPK) concentrations at admission was conducted in order to determine factors related to the development of delayed-onset rhabdomyolysis. Of 169 patients with doxylamine overdose and normal CPK at admission, 35 patients (21%) developed rhabdomyolysis (CPK greater than 1000 units/L). Multivariate logistic regression analysis of potential associated factors, including amount of doxylamine ingested, heart rate, initial value of ALT, and creatinine, was conducted. The amount of doxylamine ingested (at least 13 mg/kg; odds ratio (OR) 5.476; 95% CI, 1.716 to 17.475) and heart rate (at least 100 bpm; OR 4.885; 95% CI, 2.014 to 11.849) were determined to be the only significant factors associated with the development of delayed-onset rhabdomyolysis secondary to doxylamine overdose (Kim et al, 2011).

B) MYOCLONUS

1) WITH POISONING/EXPOSURE

a) A 14-year-old girl developed myoclonus after ingesting 200 mg of cyproheptadine and 1150 mg of promethazine. The myoclonus resolved following IV administration of benztropine 0.8 mg (Scott et al, 2007).

Reproductive

3.20.1)

3.20.2)

A) CONGENITAL ANOMALY

1) BROMPHENIRAMINE

a) Brompheniramine maleate has been associated with an increased frequency of congenital malformations in humans. This association was not observed with other common antihistamines (ie, diphenhydramine, chlorpheniramine, hydrOXYzine, or cetirizine) (Heinonen et al, 1977a; Einarson et al, 1997).

2) DOXYLAMINE/PYRIDOXINE

a) A study was conducted to show the prevalence of congenital disorders with first trimester drug use. The prevalence of any congenital disorder in doxylamine/pyridoxine combined drug users (30 of 1580; 1.9%) was slightly higher than that of nonusers (75 of 4929; 1.5%) (Aselton et al, 1985a).

B) PYLORIC STENOSIS

1) Infantile pyloric stenosis has been reported to be associated with the maternal use of antihistamines. The most common antihistamine implicated is doxylamine, an antihistamine that is used in an antiemetic combination drug (Aselton & Jick, 1985a; Eskenazi & Bracken, 1982; Eskenazi & Bracken, 1985).
2) DICYCLOMINE/DOXYLAMINE/PYRIDOXINE

a) One study showed a significant association between the occurrence of pyloric stenosis in the infant and exposure in utero to a combination drug, containing doxylamine, dicyclomine, and pyridoxine (odds ratio, 4.33). This same study also associated this combination drug with a 3-fold increase of risk for defective heart valves in the offspring (Eskenazi & Bracken, 1982).

3) DIPHENHYDRAMINE/TRIPROLIDINE

a) A study indicated that triprolidine and diphenhydramine are also associated with the development of infantile pyloric stenosis (Aselton & Jick, 1985a).

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 vs 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) CHLORPHENIRAMINE

a) There was no significant increase in the incidence of congenital abnormalities overall in the offspring of 1070 mothers who were exposed to chlorpheniramine during the first trimester of pregnancy nor among 3931 offspring exposed anytime during pregnancy (Heinonen et al, 1977). However, eye and ear abnormalities were significantly associated with first trimester use (relative risk, 2.89), although this would not be suggestive of a major teratogen. The incidence of congenital malformations observed in 275 infants exposed to chlorpheniramine during the first trimester was not increased as reported in the Boston Collaborative Drug Surveillance Program (Jick et al, 1982; Aselton et al, 1985).

3) DOXYLAMINE/PYRIDOXINE

a) The combination product doxylamine succinate/pyridoxine hydrochloride is approved for use in pregnant women. Epidemiological studies have reported no increased risk in malformations due to in utero exposure to doxylamine succinate/pyridoxine hydrochloride. A relationship between fetal abnormalities and exposure has not been established (Prod Info DICLEGIS(R) oral delayed-release tablets, 2013).
b) A study examined the relationship between doxylamine/pyridoxine combination drug and the occurrence of human congenital malformations, and concluded that there is no increase in the overall malformations (Shiono & Klebanoff, 1989).
c) An observational cohort study showed that prenatal exposure to the doxylamine succinate and pyridoxine hydrochloride combination product does not appear to adversely affect fetal brain development. The cohorts studied included 3 groups of mother-child pairs: 1) mothers with nausea and vomiting during pregnancy (NVP) treated with the doxylamine succinate and pyridoxine hydrochloride combination (n=45), 2) maternal NVP not treated with the combination (n=47), and 3) no NVP (n=29). When the children were between the ages of 3 and 7 years, they were assessed with a comprehensive battery of intelligence and neurocognitive tests. All children from the 3 groups scored within the normal range for IQ, with children from group 1 scoring significantly higher on Performance IQ than children from group 2 (P=0.01) or group 3 (P=0.002). Children from group 3 (no NVP) had significantly lower scores on the neuropsychology (NEPSY) test for verbal fluency compared with group 1 (P=0.013) or group 2 (P=0.047). Children from group 3 also had significantly lower scores on the McCarthy Numerical Memory Forward test compared with group 1 (P=0.004) or group 2 (P=0.018). While children from group 3 scored significantly lower on the NEPSY Phonological Processing test than children in group 1 (P=0.033), there was no difference in scores compared with group 2. A linear regression analysis determined that severity of NVP and maternal IQ were predictors of higher scores in children. Limitations of this study include its potential for recall bias due to its retrospective nature, cohort selectivity limited to 1 database, the use of different versions of assessment tests, and the broad range in ages of the children (Nulman et al, 2009).
d) Ecological analyses of population results showed no evidence of teratogenic effects from the use of the doxylamine succinate and pyridoxine hydrochloride combination with or without dicyclomine hydrochloride (Bendectin, the product was reformulated in 1976 to remove the dicyclomine component). Specific birth defect data for the period from 1970 to 1992 obtained from the CDC's nationwide Birth Defect Monitoring Program were compared graphically to the annual sales in the United States (US) of the combination product for the treatment of nausea and vomiting during pregnancy (NVP) and annual US rates for hospitalization for NVP. None of the specific birth defects, including CNS, cardiac, facial cleft, gastrointestinal, genital, limb, genetic, and third trimester malformation, examined for the time from 1970 to 1992 show changes in temporal trends in prevalence rates that reflect the decline in Bendectin use from 1980 to 1984 (the manufacturer ceased production in June 1983). The rate of hospitalizations for NVP doubled from 7 per 1000 live births in the period from 1974 to 1980 to 15 or 16 per 1000 live births from 1980 to 1987. The lack of any evidence for decreased incidence of birth defects contemporaneously with decreased Bendectin use suggest an association between the product and teratogenic effects does not exist (Kutcher et al, 2003).
e) Meta-analyses of 16 cohort and 11 case-control studies during pregnancy showed no significant difference in the relative risk of birth defects in infants whose mothers received the dicyclomine hydrochloride, doxylamine succinate, and pyridoxine hydrochloride combination product during the first trimester of pregnancy as compared with those infants whose mothers had not received the combination. The pooled estimate of the odds ratio (OR) for any malformation associated with exposure to the combination product during the first trimester was 0.95 (95% CI, 0.88 to 1.04). No evidence of heterogeneity was found among the studies included in the meta-analyses, which is consistent with the assumption that all the studies were measuring the same relative risk. A separate meta-analysis was conducted on each specific category of defect. The pooled OR for cardiac defects was 0.9 (95% CI, 0.77 to 1.05); for CNS malformations, it was 1.0 (95% CI, 0.83 to 1.2); for neural tube defects, 0.99 (95% CI, 0.76 to 1.29); for limb reduction defects, 1.12 (95% CI, 0.83 to 1.48); for genital tract defects, 0.98 (95% CI, 0.79 to 1.22); for oral cleft defects, 0.81 (95% CI, 0.64 to 1.03); and for pyloric stenosis, 1.04 (95% CI, 0.85 to 1.29). The test for heterogeneity showed no significant heterogeneity for each category of malformation, except for oral clefts and for pyloric stenosis, which showed significant heterogeneity (P=0.009 and P=0.004, respectively). The authors concluded that the therapeutic use of the combination product was unlikely the cause of human birth defects, because as a group, the studies showed no difference in the risk of birth defects for those infants who were exposed to the combination prenatally and those infants who were not exposed (McKeigue et al, 1994).

4) LORATADINE

a) No increase in the rate of fetal abnormalities was found in women who took loratadine during pregnancy compared with women who took other antihistamines and a control group with unexposed infants in a prospective cohort study. The incidence of malformation was 2.3% for loratadine, 4% for other antihistamines and 3% for the control group (p=0.553). This corresponds to a relative risk (RR) for the loratadine group of 0.77 (95% confidence interval (CI), 0.27 to 2.19) compared with the control group and an RR of 0.56 (95% CI, 0.18 to 1.77) compared with the other antihistamine group. When analyzing only those infants exposed to antihistamines during the first trimester, the malformation rates were 0.8% for loratadine, 4.8% for others, and 3% for the control group (p=0.152; loratadine vs control: RR, 0.27; 95% CI 0.04 to 1.94; loratadine vs others: RR, 0.17; 95% CI 0.02 to 1.33). The loratadine group had a higher incidence of miscarriage (11.4% vs others: 4.9% and vs control: 7.2%), but the women using loratadine had a significantly higher maternal age than those in the other groups (31.5 years vs. 30 years in other two groups, p=0.005). In this study, 68 patients (25.5%) took chlorpheniramine (Diav-Citrin et al, 2003).

5) MECLIZINE

a) A study was conducted to evaluate the teratogenic effects of meclizine given during the first trimester of pregnancy. The study showed that there were no teratogenic effects based on the dose used and the number of patients studied (Yerushalmy & Milkovich, 1965).

D) ANIMAL STUDIES

1) ALCAFTADINE

a) RATS, RABBITS: There was no evidence of fetal harm when rats and rabbits were given oral alcaftadine doses of 20 mg/kg/day and 80 mg/kg/day (approximately 200 and 9000 times the plasma exposure at the recommended human ocular dose) (Prod Info LASTACAFT(TM) ophthalmic solution, 2010).

2) DOXYLAMINE

a) Animal studies have suggested a relationship between the use of doxylamine during early pregnancy and diaphragmatic hernias and other birth defects (USPDI, 1993).

3) MECLIZINE

a) RATS: Animal reproduction studies have revealed an increased risk of cleft palate in rats administered meclizine doses approximately 25 to 50 times the human dose (Prod Info ANTIVERT(R) oral tablets, 2012; Prod Info ANTIVERT(R)/25 oral tablets, 2012; Prod Info ANTIVERT(R)/50 oral tablets, 2012).

4) OTOPATADINE

a) RATS: Cleft palate occurred in rat offspring with organogenesis exposures 1080 times the maximum recommended human ophthalmic dose (Prod Info PAZEO(TM) ophthalmic solution, 2015).
b) RATS, RABBITS: No teratogenic effects occurred in rat or rabbit offspring exposed to olopatadine during organogenesis (Prod Info Olopatadine HCl nasal spray, 2014; Prod Info PATADAY(TM) ophthalmic solution, 2010; Prod Info Patanol(R) 0.1% ophthalmic solution, 2007).

3.20.3)

A) WITHDRAWAL SYNDROME

1) HYDROXYZINE HYDROCHLORIDE

a) A neonatal withdrawal syndrome (jitteriness, tachypnea, clonic movements, shrill cry) was associated with maternal use of hydrOXYzine hydrochloride, 150 mg 4 times daily, throughout the pregnancy (Prenner, 1977).

B) BIRTH PREMATURE

1) PENTAZOCINE/TRIPELENNAMINE

a) CASE REPORT: A 24-year-old woman gave birth to an infant with an estimated age of 6 months gestation who survived for 11 hours. The mother had received no prenatal care. After toxicologic examinations revealed the presence of pentazocine and tripelennamine in the infant, the mother admitted to abusing this combination intravenously 9 hours prior to admission (Schaffer et al, 1983).

C) PREGNANCY CATEGORY

1) The manufacturers have classified the following antihistamines as FDA pregnancy category C:

1) ANTAZOLINE (Briggs et al, 1998)
2) BROMDIPHENHYDRAMINE (Briggs et al, 1998)
3) BROMPHENIRAMINE (Prod Info B-VEX(R) suspension, 2005)
4) BUCLIZINE (Briggs et al, 1998)
5) CHLORCYCLIZINE (Briggs et al, 1998)
6) CHLORPHENIRAMINE (Prod Info P-TANN SUSPENSION oral suspension, 2006)
7) CHLORPHENIRAMINE/CODEINE (Prod Info TUZISTRA(TM) XR oral extended-release suspension, 2015)
8) CHLORPHENIRAMINE/HYDROCODONE (Prod Info TussiCaps(R) extended-release capsules, 2014; Prod Info VITUZ(R) oral solution, 2013; Prod Info Tussionex(R) Pennkinetic(R) oral extended-release suspension, 2011)
9) CYCLIZINE (Briggs et al, 1998)
10) DEXBROMPHENIRAMINE (Briggs et al, 1998)
11) DIMETHINDINE (Briggs et al, 1998)
12) DIMETHOTHIAZINE (Briggs et al, 1998)
13) HYDROXYZINE (Briggs et al, 1998)
14) METHDILAZINE (Briggs et al, 1998)
15) OLOPATADINE: (Prod Info Olopatadine HCl nasal spray, 2014)
16) PHENIRAMINE (Briggs et al, 1998)
17) PHENYLTOLOXAMINE
18) PROMETHAZINE (Prod Info Promethazine Hydrochloride IM, IV injection, 2009)
19) PYRILAMINE (Briggs et al, 1998)
20) TRIMEPRAZINE (Briggs et al, 1998)

2) The manufacturers have classified the following antihistamines as FDA pregnancy category B:

1) ALCAFTADINE (Prod Info LASTACAFT(TM) ophthalmic solution, 2010)
2) AZATADINE (Briggs et al, 1998)
3) CETIRIZINE (Prod Info ZYRTEC(R) oral tablets, chewable oral tablets, oral syrup, 2006)
4) CLEMASTINE (Prod Info clemastine fumarate oral syrup, 2003)
5) CYPROHEPTADINE (Prod Info cyproheptadine hcl oral tablets, 2005)
6) DEXCHLORPHENIRAMINE (Prod Info dexchlorpheniramine maleate extended release tablets, 1998)
7) DOXYLAMINE (Briggs et al, 1998)
8) EMEDASTINE (Prod Info EMADINE(R) ophthalmic solution, 2003)
9) MECLIZINE (Prod Info ANTIVERT(R) oral tablets, 2012; Prod Info ANTIVERT(R)/25 oral tablets, 2012; Prod Info ANTIVERT(R)/50 oral tablets, 2012)
10) TRIPELENNAMINE (Briggs et al, 1998)
11) TRIPROLIDINE (Prod Info ZYMINE(TM) LIQUID oral syrup, 2002)

3) The manufacturer has classified doxylamine succinate/pyridoxine hydrochloride as FDA pregnancy category A (Prod Info DICLEGIS(R) oral delayed-release tablets, 2013).

D) LACK OF EFFECT

1) DOXYLAMINE/PYRIDOXINE

E) ANIMAL STUDIES

1) CHLORPHENIRAMINE

a) Embryolethality was observed at chlorpheniramine doses approximately 9 times the maximum recommended human dose (MRHD) when administered throughout pregnancy and also when administered prior to mating. Decreased postnatal survival was observed at chlorpheniramine doses approximately 9 times the MRHD when administration continued after parturition (Prod Info TUZISTRA(TM) XR oral extended-release suspension, 2015).

3.20.4)

A) BREAST MILK

1) Antihistamines may be excreted into the breast milk in small amounts. Their use is not recommended in nursing mothers due to possible hyperactivity/irritability in infants (USPDI, 1999).
2) CHLORPHENIRAMINE

a) Chlorpheniramine is secreted in human breast milk and may suppress lactation if administered prior to nursing (Prod Info TUZISTRA(TM) XR oral extended-release suspension, 2015).

3) CLEMASTINE

a) CASE REPORT: Drowsiness, irritability, high-pitched crying, and anorexia were reported in a case report of a breastfed 10-week-old infant within 12 hours of maternal ingestion of clemastine 1 mg twice daily. Maternal plasma and corresponding breast milk levels were 20 and 5 to 10 mcg/L, with none detected in the infant. Symptoms resolved after discontinuation of the clemastine (Kok et al, 1982).

4) DOXYLAMINE/PYRIDOXINE

a) Pyridoxine hydrochloride is excreted into breast milk. It is unknown if doxylamine succinate is excreted into breast milk, however, the molecular weight is low enough that excretion can be expected. Nursing infants have developed excitement, irritability, and sedation following exposure to doxylamine succinate through breast milk. Infants with apnea or other respiratory syndromes may be at greater risk for sedative effects of doxylamine succinate/pyridoxine hydrochloride resulting in worsening of their apnea or respiratory conditions. Due to the lack of information regarding the combination product and the potential for adverse effects in nursing infants, the manufacturer does not recommend the use of doxylamine succinate/pyridoxine hydrochloride in women who intend to breastfeed (Prod Info DICLEGIS(R) oral delayed-release tablets, 2013).

5) MECLIZINE

a) Lactation studies with meclizine have not yet been conducted. It is not known whether meclizine is excreted into human breast milk (Prod Info ANTIVERT(R) oral tablets, 2012; Prod Info ANTIVERT(R)/25 oral tablets, 2012; Prod Info ANTIVERT(R)/50 oral tablets, 2012) and the potential for adverse effects in the nursing infant from exposure to the drug are unknown. It is not known if meclizine affects the quantity or composition of breastmilk. Given the short half-life of 2 to 3 hours, adverse effects for the nursing infant would not be expected. One source recommends meclizine as the antiemetic of choice during breastfeeding (Schaefer, 2001). Because many drugs are excreted in human breast milk, the manufacturer recommends using caution when administering meclizine to lactating women (Prod Info ANTIVERT(R) oral tablets, 2012; Prod Info ANTIVERT(R)/25 oral tablets, 2012; Prod Info ANTIVERT(R)/50 oral tablets, 2012).

B) ANIMAL STUDIES

1) OLOPATADINE

a) Olopatadine is excreted in the milk of nursing rats when given orally. It is not known if olopatadine is excreted into human breast milk following non-systemic ophthalmic or nasal use (Prod Info PAZEO(TM) ophthalmic solution, 2015; Prod Info Olopatadine HCl nasal spray, 2014; Prod Info PATADAY(TM) ophthalmic solution, 2010; Prod Info Patanol(R) 0.1% ophthalmic solution, 2007).

3.20.5)

A) ANIMAL STUDIES

1) OLOPATADINE

a) RATS: A decreased fertility index and reduced implantation rate occurred when male and female rats were administered olopatadine orally at doses approximately 7200 to 100,000 times the maximum recommended human ophthalmic dose or 680 times the maximum recommended human dose (Prod Info PAZEO(TM) ophthalmic solution, 2015; Prod Info Olopatadine HCl nasal spray, 2014; Prod Info PATADAY(TM) ophthalmic solution, 2010; Prod Info Patanol(R) 0.1% ophthalmic solution, 2007).

Carcinogenicity

3.21.2)

A) OLOPATADINE HYDROCHLORIDE: At the time of this review, the manufacturer does not report any carcinogenic potential.

3.21.4)

A) HEPATIC CARCINOMA

1) Methapyrilene has been shown to be a potent hepatocarcinogen in rats, but not in hamsters or guinea pigs (Mirsalis, 1987).

B) LACK OF EFFECT

1) OLOPATADINE HYDROCHLORIDE: There was no evidence of carcinogenicity in mice and rats administered oral olopatadine at doses up to 500 mg/kg/day and 200 mg/kg/day, respectively (Prod Info PAZEO(TM) ophthalmic solution, 2015; Prod Info Olopatadine HCl nasal spray, 2014; Prod Info PATADAY(TM) ophthalmic solution, 2010; Prod Info Patanol(R) 0.1% ophthalmic solution, 2007).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs (including temperature) and mental status.
B) Antihistamine 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 (i.e., agitation delirium, seizures, coma, and hypotension).
D) Monitor creatinine phosphokinase in patients with prolonged agitation, seizures or coma; monitor renal function urine output in patients with rhabdomyolysis.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Blood/serum/plasma concentrations are not generally useful for monitoring therapy, but may be helpful in confirming the diagnosis.
2) In cases of doxylamine overdoses, plasma CPK should be measured to rule out rhabdomyolysis (Koppel et al, 1987).
3) Many antihistamines are combined with acetaminophen or salicylates in cold and flu medications, therefore concurrent acetaminophen or salicylate ingestions should be excluded by performing serum acetaminophen and salicylate levels.
4) Monitor renal and liver function tests in symptomatic patients.

4.1.3)

A) OTHER

1) In doxylamine overdoses, or any antihistamine exposure involving significant agitation, check the urine for the signs of rhabdomyolysis (ie, dark urine color, presence of blood, absence of red blood cells).

4.1.4)

A) OTHER

1) ECG

a) Monitor ECG for tachycardia or dysrhythmias.

Methods

1) The most specific assay methods involve GLC, GC-MS, or HPLC. The HP-TLC method presents all metabolites and their relative quantities, and is used to complement the HPLC assay method (Fouda et al, 1979; Kintz et al, 1990; Siek & Dunn, 1993).
2) A hydrOXYzine assay using HPLC and reverse phase C(18) column was developed by Magera et al (1981). The assay is specific for hydrOXYzine and is capable of measuring a drug concentration of 40 mcg/ml or above.
3) Gas chromatography with basic liquid-liquid extraction was used for toxicologic analysis of chlorpheniramine following a fatal ingestion (Wogoman et al, 1999). The limits of detection and quantification for chlorpheniramine, using this method, was 0.02 mg/L and 0.05 mg/L, respectively.

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with significant persistent central nervous system toxicity (i.e., 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.

6.3.1.2) HOME CRITERIA/ORAL

A) Asymptomatic children (other than mild drowsiness or stimulation) with acute inadvertent ingestions may be monitored at home.

6.3.1.3) CONSULT CRITERIA/ORAL

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

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with deliberate ingestions and symptomatic patients should be sent to a health care facility for observation for 6 to 8 hours.

Monitoring

Oral Exposure

6.5.1)

A) DERMAL EXPOSURE

1) For dermal exposure, remove patches and wash skin thoroughly.

B) ACTIVATED CHARCOAL

1) Activated charcoal should NOT be administered at home or en route to the hospital due to the potential loss of consciousness or seizure.
2) Activated charcoal is recommended, in the hospital setting, if the patient is awake and able to protect their airway. The practitioner should only administer activated charcoal in cases where there is potential benefit to the patient and minimal risk.
3) CHARCOAL DOSE

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

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

b) ADVERSE EFFECTS/CONTRAINDICATIONS

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

6.5.2)

A) ACTIVATED CHARCOAL

1) Activated charcoal is recommended if the patient is awake and able to protect his/her airway. The practitioner should only administer activated charcoal in cases where there is potential benefit to the patient and minimal risk.
2) CHARCOAL ADMINISTRATION

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

3) CHARCOAL DOSE

b) ADVERSE EFFECTS/CONTRAINDICATIONS

4) For sustained-release preparations, a second dose of charcoal and whole bowel irrigation may be beneficial.

6.5.3)

A) MONITORING OF PATIENT

1) Monitor vital signs (including temperature) and mental status. No specific lab work is needed in most patients. Obtain an ECG and institute continuous cardiac monitoring in patients with significant toxicity (i.e., 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.

B) AIRWAY MANAGEMENT

1) Perform early in patients with severe intoxication (i.e., seizures, dysrhythmias, severe delirium or hyperthermia).

C) TACHYARRHYTHMIA

1) Sinus tachyarrhythmias rarely requires treatment. In agitated patients, sedation with benzodiazepines will generally control tachycardia. If severe tachycardia results in hemodynamic compromise or ischemia, beta blocking agents may be used as a temporizing measure. A short-acting cardioselective agent such as esmolol is preferred. Use with caution in patients with asthma or COPD.
2) TACHYCARDIA SUMMARY

a) Evaluate patient to be sure that tachycardia is not a physiologic response to dehydration, anemia, hypotension, fever, sepsis, or hypoxia. Sinus tachycardia does not generally require treatment unless hemodynamic compromise develops.
b) If therapy is required, a short acting, cardioselective agent such as esmolol is generally preferred (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
c) ESMOLOL/ADULT LOADING DOSE

1) Infuse 500 micrograms/kilogram (0.5 mg/kg) IV over 1 minute (Neumar et al, 2010).

d) ESMOLOL/ADULT MAINTENANCE DOSE

1) Follow loading dose with infusion of 50 mcg/kg per minute (0.05 mg/kg per minute) (Neumar et al, 2010).
2) EVALUATION OF RESPONSE: If response is inadequate, infuse second loading bolus of 0.5 mg/kg over 1 minute and increase the maintenance infusion to 100 mcg/kg (0.1 mg/kg) per minute. Reevaluate therapeutic effect, increase in the same manner if required to a maximum infusion rate of 300 mcg/kg (0.3 mg/kg) per minute (Neumar et al, 2010).
3) The manufacturer recommends that a maximum of 3 loading doses be used (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
4) END POINT OF THERAPY: As the desired heart rate or blood pressure is approached, omit loading dose and adjust maintenance infusion as required (Prod Info BREVIBLOC(TM) intravenous injection, 2012).

e) CAUTION

1) Esmolol is a short acting beta-adrenergic blocking agent with negative inotropic effects. Esmolol should be avoided in patients with asthma, obstructive airway disease, decompensated heart failure and pre-excited atrial fibrillation (wide complex irregular tachycardia) or atrial flutter (Neumar et al, 2010).

D) VENTRICULAR ARRHYTHMIA

1) Because some antihistamines have sodium blocking properties, dysrhythmias may respond to administration of sodium bicarbonate (Clark & Vance, 1992; Clark, 1993). An initial dose of 1 milliequivalent/kilogram is appropriate, repeated as needed with careful monitoring of blood pH. Target blood pH is 7.45 to 7.55.
2) Use lidocaine if sodium bicarbonate is not successful.

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).

3) Severe dysrhythmias caused by antihistamine intoxication may respond to physostigmine. If the overdose is mixed, or the etiology of the dysrhythmia is uncertain, administering physostigmine may worsen the dysrhythmia.

E) TORSADES DE POINTES

1) SUMMARY

a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).

2) MAGNESIUM SULFATE

a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).

3) OVERDRIVE PACING

a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).

4) POTASSIUM REPLETION

a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).

5) ISOPROTERENOL

a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

6) OTHER DRUGS

a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).

7) AVOID

a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

F) SEIZURE

1) SUMMARY

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

2) DIAZEPAM

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

3) NO INTRAVENOUS ACCESS

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

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).

5) PHENOBARBITAL

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

6) OTHER AGENTS

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

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

G) HYPOTENSIVE EPISODE

1) Administer isotonic intravenous fluid (1 to 2 liters in adults, 10 to 20 milliliters/kilogram in children) and place in Trendelenburg position. Patients with vasodilation secondary to severe overdose may require larger amounts of fluid. If the patient remains hypotensive, further fluid therapy should be guided by central venous pressure or pulmonary artery pressure monitoring to avoid volume overload. If the patient is unresponsive to these measures, administer dopamine (first choice) or norepinephrine (second choice).
2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

H) CARDIOGENIC SHOCK

1) Cardiogenic shock rarely occurs, but may require use of an intraaortic balloon pump (Freedberg et al, 1987).

I) HYPERTENSIVE EPISODE

1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
3) SODIUM NITROPRUSSIDE/INDICATIONS

a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.

4) SODIUM NITROPRUSSIDE/DOSE

a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).

5) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION

a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

6) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS

a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

7) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS

a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

8) NITROGLYCERIN/INDICATIONS

a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).

9) NITROGLYCERIN/ADULT DOSE

a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).

10) NITROGLYCERIN/PEDIATRIC DOSE

a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).

J) DRUG-INDUCED DYSTONIA

1) DIAZEPAM: Acute dystonic reactions to antihistamines may be treated with oral or intravenous diazepam (CHILD: 0.1 to 0.3 milligram/kilogram slowly, ADULT: up to 10 milligrams, may be repeated as necessary).

K) DELIRIUM

1) SUMMARY

a) Sedate patient with benzodiazepines until the patient is sleepy. Large doses (greater than 10 mg of lorazepam) may be required.

2) DIAZEPAM

a) If severe, treat with small incremental doses of intravenous diazepam (adult: 2 to 10 milligrams slowly, repeat if necessary; child: 0.1 milligram/ kilogram).

3) LORAZEPAM

a) ADULT LORAZEPAM DOSE: 2 to 4 milligrams by intravenous bolus injection.
b) PEDIATRIC LORAZEPAM DOSE: 0.05 milligrams/kilogram by intravenous bolus injection.

L) BODY TEMPERATURE ABOVE REFERENCE RANGE

1) Hyperthermia due to agitation and delirium is generally responsive to sedation with benzodiazepines and external cooling measures. If severe hyperthermia develops (core temperature 42 degrees Celsius or greater), neuromuscular paralysis may be necessary. Sponge patient with tepid water, and use fans to maximize evaporative heat loss. Avoid phenothiazines.

M) RHABDOMYOLYSIS

1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).

N) PHYSOSTIGMINE

1) A diagnostic trial with physostigmine (see physostigmine dosing below), when indicated for life-threatening complications, may be initiated without waiting for laboratory confirmation of poisoning.

a) Reversal within minutes of coma, arrhythmias, hallucinations, and other findings can be expected if the diagnosis is correct and the patient has not suffered anoxia or other insult or ingested a combination preparation.
b) Avoid in cases where tricyclic antidepressants may also be involved, or in patients with cardiac conduction defects.

2) 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).

3) 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).

4) 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).

5) 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).

6) CASE REPORT - A 20-year-old female, 36 weeks pregnant, presented to the ED with tachycardia (166 bpm), confusion, hallucinations, and incoherent speech approximately 3 hours after ingesting an unknown amount of sleep medications containing diphenhydramine and doxylamine. The fetal heart rate was 200 to 210 beats per minute. Following decontamination and intravenous administration of a 1 milligram test dose of physostigmine given over 5 minutes, the patient's heart rate decreased to 121 bpm. She became coherent, and could answer questions appropriately within 5 minutes of receiving the injection. The fetal heart rate also decreased to 182 bpm within 10 minutes of the physostigmine injection, and was slowed to 150 to 160 bpm within an hour, indicating that physostigmine crosses the placenta (Bangh & Roberts, 1997).

O) FLUMAZENIL

1) CASE REPORT - A 7-month-old infant presented to the hospital with drowsiness (GCS 10/15) and dilated pupils. After an extensive evaluation was not diagnostic, he received 0.1 mg flumazenil for possible benzodiazepine poisoning, and that dose was repeated 1 minute later. The infant woke up within one minute to GCS 14 to 15/15. Urine and serum toxicology screens revealed trimeprazine, nortrimeprazine and diphenhydramine but were negative for other substances including benzodiazepines (Lassaletta et al, 2004).

Enhanced Elimination

1) Hemodialysis or hemoperfusion are of no value in this setting.

1) Urinary excretion of chlorpheniramine is increased when the pH of the urine is acidic (Paton & Webster, 1985), however, acid diuresis is not recommended to enhance elimination in overdose.

Abstracts

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) SPECIFIC SUBSTANCE

1) Refer to "Astemizole", "Azelastine", "Cetirizine", "Fexofenadine", "Terfenadine", "Diphenhydramine", "Carbinoxamine", or "Promethazine" documents for more information.
2) BROMPHENIRAMINE MALEATE

a) ALL INDICATIONS: : 4 milligrams orally every 4-6 hours or 8 milligrams sustained-release (SR) tablet orally every 8-12 hours or 12 milligrams SR tablet orally every 12 hours (Druce et al, 1998; Prod Info Dimetane(R), 1989)
b) ALL INDICATIONS: : 5-20 milligrams Intramuscularly, Intravenously, or SubQ divided twice daily; MAX dose 40 milligrams/24 hours (Sifton, 1999).

3) CHLORPHENIRAMINE MALEATE

a) ALLERGIC RHINITIS: 4 milligrams orally every 4-6 hours; maximum dose: 24 milligrams/day (Prod Info Chlor-Trimeton(R), 1999).
b) ALLERGIC RHINITIS: sustained-release, 8 or 12 milligrams orally every 8-12 hours; maximum dose: 24 milligrams/day (Prod Info Chlor-Trimeton(R), 1999).
c) ALLERGIC RHINITIS: 5-40 milligrams Intramuscularly, Intravenously, SubQ as a single dose; maximum dose: 40 milligrams/day (Trissel, 1988).

4) CHLORPHENIRAMINE/HYDROCODONE

a) EXTENDED-RELEASE ORAL SOLUTION

1) 5 mL (hydrocodone bitartrate 5mg/chlorpheniramine maleate 4 mg) orally every 4 to 6 hours as needed; MAX, 4 doses (20 mL) in 24 hours (Prod Info VITUZ(R) oral solution, 2013).

b) ORAL CAPSULES

1) 1 full-strength capsule (hydrocodone polistirex equivalent to 10 mg of hydrocodone bitartrate and chlorpheniramine polistirex equivalent to 8 mg of chlorpheniramine maleate) every 12 hours; MAX: 2 capsules in 24 hours (Prod Info TussiCaps(R) extended-release capsules, 2014)

5) CHLORPHENIRAMINE POLISTIREX/CODEINE POLISTIREX

a) The usual dose is 10 mL (equivalent to codeine phosphate 40 mg/chlorpheniramine maleate 8 mg) orally every 12 hours; MAX 20 mL/day (Prod Info TUZISTRA(TM) XR oral extended-release suspension, 2015)

6) CLEMASTINE FUMARATE

a) The maximum recommended clemastine dose is 2.68 milligrams (2 milligrams clemastine base) orally three times daily. The recommended dose for the combination product (ie, clemastine 1.34 milligrams/phenylpropanolamine 75 milligrams) is 1 tablet twice daily not to exceed 2 tablets in 24 hours (Prod Info Tavist-D(R), 1999).

7) CYPROHEPTADINE

a) The therapeutic dosage of cyproheptadine is 4 to 20 milligrams/day orally with the majority of patients requiring 12 to 16 milligrams/day. The total daily dose in adults should not exceed 0.5 milligram/kilogram/day. The dose should be initiated with 4 milligrams (1 tablet or 2 teaspoons) three times daily and adjusted according to the size and response of the patient. As much as 32 milligrams/day for adequate relief may be required by some patients (Prod Info Periactin(R), 1999).

8) DEXCHLORPHENIRAMINE MALEATE

a) ALLERGIC RHINITIS: 2 milligrams orally every 4-6 hours (Prod Info Polaramine(R), 1990)
b) ALLERGIC RHINITIS: repeat action tablet (Polaramine(R) Repetabs), 4-6 milligrams orally at bedtime or every 8-10 hours (Prod Info Polaramine(R), 1990)

9) DOXYLAMINE SUCCINATE

a) COLD SYMPTOMS: The recommended dose of doxylamine is 7.5 to 12.5 milligrams every 4 to 6 hours, not to exceed 75 milligrams/24 hours (Feldman, 1990).
b) INSOMNIA: 25 milligrams taken 30 minutes before retiring (Prod Info Unisom(R), 1997). Not to be used for insomnia over 2 weeks.

10) DOXYLAMINE SUCCINATE/PYRIDOXINE HYDROCHLORIDE

a) The initial recommended dose is 2 tablets orally before bed (each tablet contains doxylamine succinate 10 mg/pyridoxine hydrochloride 10 mg). If this dose is not sufficient, increase to 3 tablets orally (one tablet in the morning and two tablets at bedtime) and continue to increase as needed. MAX dose: 4 tablets (one tablet in the morning, one mid-afternoon, and 2 before bed) (Prod Info DICLEGIS(R) oral delayed-release tablets, 2013).

11) EMEDASTINE DIFUMARATE

a) ALLERGIC CONJUNCTIVITIS: 1 drop 0.05% ophthalmic solution in affected EYE(s) up to four times daily (Prod Info Emadine(TM), 1998).

12) HYDROXYZINE

a) ADMINISTRATION OF MEDICATION; ADJUNCT - POSTOPERATIVE CARE: 50-100 milligrams orally or 25-100 milligrams Intramuscularly (Prod Info Atarax(R), 1999)
b) ALCOHOL WITHDRAWAL SYNDROME: 50-100 milligrams Intramuscularly immediately, then every 4-6 hours as needed (Prod Info Vistaril(R), 2004)
c) ANXIETY: 50-100 milligrams orally four times daily (Prod Info Atarax(R), 1999)
d) MENTAL DISORDER, EMERGENCIES: 50-100 milligrams Intramuscularly immediately, then every 4-6 hours as needed (Prod Info Vistaril(R), 2004)
e) PREGNANCY, CHILDBIRTH AND PUERPERIUM FINDING; ADJUNCT: 25-100 milligrams Intramuscularly (Prod Info Vistaril(R), 2004)
f) PREMEDICATION FOR PROCEDURE; ADJUNCT: 50-100 milligrams orally or 25-100 milligrams Intramuscularly (Prod Info Atarax(R), 1999)
g) PRURITUS: 25 milligrams orally 3-4 times daily (Prod Info Atarax(R), 1999)
h) VOMITING: excluding nausea and vomiting of pregnancy, 25-100 milligrams Intramuscularly (Prod Info Atarax(R), 1999)

13) MECLIZINE HYDROCHLORIDE

a) MOTION SICKNESS: 25-50 milligrams orally 1 hour before departure; repeat, if necessary at 24-hour intervals (Prod Info ANTIVERT(R) oral tablets, 1996).
b) PERIPHERAL VERTIGO: 25-100 milligrams a day orally as needed, in divided doses (Prod Info ANTIVERT(R) oral tablets, 1996).

14) OLOPATADINE HYDROCHLORIDE

a) OPHTHALMIC SOLUTION

1) ALLERGIC CONJUNCTIVITIS: The recommended dose of topical ophthalmic olopatadine in adults and children 2 years of age or greater is one drop of a 0.2% or 0.7% solution instilled into each affected eye once daily (Prod Info PAZEO(TM) ophthalmic solution, 2015; Prod Info PATADAY(TM) ophthalmic solution, 2010).
2) ALLERGIC CONJUNCTIVITIS: The recommended dose of topical ophthalmic olopatadine in adults and children 3 years of age or greater is one drop of a 0.1% solution instilled into each affected eye twice a day at 6- to 8-hour intervals (Prod Info Patanol(R) 0.1% ophthalmic solution, 2007).

b) NASAL SPRAY

1) ALLERGIC RHINITIS: The recommended dose for adults and adolescents aged 12 years and older is 2 intranasal sprays per nostril (665 mcg per spray) twice daily (Prod Info Olopatadine HCl nasal spray, 2014).

15) PHENIRAMINE

a) ALLERGIC CONJUNCTIVITIS; RHINITIS: 1-2 drops 0.3% ophthalmic solution into each EYE every 3-4 hours (with 0.025% naphazoline) (Prod Info Naphcon-A(R), 1993); 1 to 2 drops in the affected eye up to 4 times a day (Prod Info Visine AC(R), 1994).

16) TRIPROLIDINE

a) ALLERGIC RHINITIS; COMMON COLD: (alone or in combination with pseudoephedrine) 2.5 milligrams orally every 4-6 hours; maximum dose: 10 milligrams/day (Prod Info ZYMINE(TM) LIQUID oral syrup, 2002; Prod Info Actifed(R), 1988)
b) ALLERGIC RHINITIS; COMMON COLD: (in combination with pseudoephedrine) sustained release, 5 milligrams orally every 12 hours; maximum dose: 10 milligrams/day (Prod Info Actifed(R), 1988)

7.2.2)

A) SPECIFIC SUBSTANCE

1) BROMPHENIRAMINE MALEATE

a) 6 to 12 years: 1 teaspoonful (2 mg) four times daily (Prod Info VAZOL oral liquid, 2007).
b) 2 to 6 years: 1/2 teaspoonful (1 mg) four times daily (Prod Info VAZOL oral liquid, 2007).
c) Less than 2 years of age: 0.5 mg/kg/day in equally divided doses, four times daily (Prod Info VAZOL oral liquid, 2007).

2) CARBINOXAMINE

a) ORAL SOLUTION

1) Greater than 6 years of age: 1 to 1.5 teaspoonfuls (4 to 6 mg) 3 or 4 times daily (Prod Info PALGIC(R) oral tablets, oral solution, 2006).
2) 3 to 6 years: 1/2 to 1 teaspoonful (2 to 4 mg) 3 or 4 times daily (Prod Info PALGIC(R) oral tablets, oral solution, 2006).
3) 2 to 3 years: 1/2 teaspoonful (2 mg) 3 or 4 times daily (Prod Info PALGIC(R) oral tablets, oral solution, 2006).

b) TABLETS

1) Greater than 6 years of age: 1 to 1.5 tablets (4 to 6 mg) 3 or 4 times daily (Prod Info PALGIC(R) oral tablets, oral solution, 2006).

3) CHLORPHENIRAMINE MALEATE

a) IMPORTANT NOTE

1) Chlorpheniramine may cause excitability in children. It is not recommended to give the 8-hour or 12-hour allergy tablets to children under 12 years of age or the 4-hour allergy tablets to children under 6 years of age (Prod Info Chlor-Trimeton(R) , 1999). Codeprex(TM) is not recommended for children under 6 years of age (Prod Info Codeprex(TM) Pennkinetic(R), 2004).

b) ORAL

1) The dose for children ages 6 to 11 years, using the 4-hour allergy tablet, is half of the recommended adult dose. Therefore, 2 milligrams (break the 4 milligrams tablet in half) every 4 to 6 hours up to 12 milligrams in 24 hours. The 8-hour and 12-hour allergy tablets are not recommended (Prod Info Chlor-Trimeton(R) , 1999).
2) For cough, allergic rhinitis, and hay fever in children 12 years and older: 2 teaspoonfuls of Codeprex(TM) (10 mL; equivalent to codeine 40 milligrams and chlorpheniramine maleate 8 milligrams) orally every 12 hours; maximum dose 4 teaspoonfuls in 24 hours (Prod Info Codeprex(TM) Pennkinetic(R), 2004).
3) For cough, allergic rhinitis, and hay fever in children 6 to 12 years of age: 1 teaspoonful of Codeprex(TM) (5 mL; equivalent to codeine 20 milligrams and chlorpheniramine maleate 4 milligrams) orally every 12 hours; maximum dose 2 teaspoonfuls in 24 hours (Prod Info Codeprex(TM) Pennkinetic(R), 2004).

c) MAXIMUM DOSE

1) The maximum recommended dose for oral chlorpheniramine in children 6 to 11 years old is 12 milligrams/day (Prod Info Chlor-Trimeton(R) , 1999).

4) CHLORPHENIRAMINE/HYDROCODONE

a) EXTENDED-RELEASE ORAL CAPSULES

1) UNDER 6 YEARS: Contraindicated (Prod Info TussiCaps(R) extended-release capsules, 2014).
2) 6 TO 11 YEARS: 1 half-strength capsule (hydrocodone polistirex equivalent to 5 mg of hydrocodone bitartrate and chlorpheniramine polistirex equivalent to 4 mg of chlorpheniramine maleate) every 12 hours; MAX: 2 capsules in 24 hours (Prod Info TussiCaps(R) extended-release capsules, 2014)
3) 12 YEARS AND OLDER: 1 full-strength capsule (hydrocodone polistirex equivalent to 10 mg of hydrocodone bitartrate and chlorpheniramine polistirex equivalent to 8 mg of chlorpheniramine maleate) every 12 hours; MAX: 2 capsules in 24 hours (Prod Info TussiCaps(R) extended-release capsules, 2014)

b) ORAL SOLUTION

1) The safety and efficacy in pediatric patients have not been established (Prod Info VITUZ(R) oral solution, 2013).

5) CHLORPHENIRAMINE POLISTIREX/CODEINE POLISTIREX

a) Safety and effectiveness have not been established in pediatric patients (Prod Info TUZISTRA(TM) XR oral extended-release suspension, 2015).

6) CLEMASTINE FUMARATE

a) 12 YEARS AND OLDER: 1/2 to 1 tablet (2.68 mg) ORALLY 1 to 3 times daily; maximum dose is 1 tablet (2.68 mg) 3 times daily (Prod Info clemastine fumarate tablets, 2004)
b) 6 TO 11 YEARS: 5 ml (0.5 mg) of syrup ORALLY twice daily, maximum dose: 3 mg/day (Prod Info clemastine fumarate oral syrup, 2003)
c) In infants and children up to 6 years of age have received 0.25 to 0.5 milligrams/day for various dermatologic conditions and 0.25 milligrams two to three times daily for various allergic conditions (Ghillione de Torviso, 1973; Lothaller, 1970; Kwiatowski, 1970).

7) CYPROHEPTADINE HYDROCHLORIDE

a) ALLERGIC CONJUNCTIVITIS; ALLERGIC REACTION; ALLERGIC RHINITIS; DERMATOGRAPHIC URTICARIA: (2-6 yrs) 2 milligrams orally two to three times daily; maximum dose: 12 milligrams/day (Prod Info Periactin(R), 1999).
b) ALLERGIC CONJUNCTIVITIS; ALLERGIC REACTION; ALLERGIC RHINITIS; DERMATOGRAPHIC URTICARIA: (7-14 yrs) 4 milligrams orally two to three times daily; maximum dose: 16 milligrams/day (Prod Info Periactin(R), 1999).

8) DEXCHLORPHENIRAMINE MALEATE

a) (syrup) ages 12 years and older, 2 mg ORALLY every 4 to 6 h; ages 6 to 11 years, 1 mg ORALLY every 4 to 6 h; ages 2 to 6 years, 0.5 mg ORALLY every 4 to 6 h (Prod Info dexchlorpheniramine maleate syrup, 2002)
b) (extended-release tablets) ages 12 years and older, 4 to 6 mg ORALLY at bedtime or every 8 to 10 h during the day; ages 6 to 12 years, 4 mg ORALLY once daily at bedtime (Prod Info dexchlorpheniramine maleate extended release tablets, 1998)

9) DOXYLAMINE SUCCINATE

a) INSOMNIA: 12 years and older, 25 to 50 mg ORALLY taken 30 min before bed (Prod Info UNISOM(R) SLEEPGELS(R) oral gelcaps, 2006).
b) Doxylamine is not recommended for use in children under 12 years of age (Prod Info Unisom(R), 1997), since children may be more prone than adults to paradoxical central nervous system stimulation rather than sedation (Covington, 1993).
c) Doxylamine doses of 1.9 to 3.125 milligrams every 4 to 6 hours have been used for children 2 to 6 years of age with cold or cough symptoms, and total doses should not exceed 18.75 milligrams in 24 hours (Feldman, 1990).
d) Doxylamine doses of 3.75 to 6.25 milligrams every 4 to 6 hours have been used for children 6 to 12 years of age with cold or cough symptoms, and total doses should not exceed 37.5 milligrams daily (Feldman, 1990).

10) DOXYLAMINE SUCCINATE/PYRIDOXINE HYDROCHLORIDE

a) Safety and efficacy has not been established (Prod Info DICLEGIS(R) oral delayed-release tablets, 2013).

11) EMEDASTINE DIFUMARATE

a) ALLERGIC CONJUNCTIVITIS: In children 3 years of age or older, use 1 drop of a 0.05% ophthalmic solution up to four times a day (Prod Info Emadine(TM), 1998).

12) HYDROXYZINE

a) ADMINISTRATION OF MEDICATION; ADJUNCT - POSTOPERATIVE CARE: 0.6 milligram/kilogram orally or 1.1 milligrams/kilogram of body weight Intramuscularly (Prod Info Vistaril(R), 2004; Prod Info Atarax(R), 1999)
b) ANXIETY: (over 6 years) 50-100 milligrams orally in divided doses (Prod Info Atarax(R), 1999)
c) ANXIETY: (under 6 years) 50 milligrams/day orally in divided doses (Prod Info Atarax(R), 1999)
d) PREMEDICATION FOR PROCEDURE; ADJUNCT: 0.6 milligram/kilogram orally or 1.1 milligrams/kilogram of body weight Intramuscularly (Prod Info Vistaril(R), 2004; Prod Info Atarax(R), 1999)
e) PRURITUS: (over 6 years) 50-100 milligrams/day orally in divided doses (Prod Info Atarax(R), 1999)
f) PRURITUS: (under 6 years) 50 milligrams/day orally in divided doses (Prod Info Atarax(R), 1999)
g) VOMITING: 1.1 milligrams/kilogram of body weight Intramuscularly (Prod Info Vistaril(R), 2004)

13) MECLIZINE HYDROCHLORIDE

a) Safety and efficacy in children, under 12 years of age, has not been established (Prod Info ANTIVERT(R) oral tablets, 1996).

14) OLOPATADINE HYDROCHLORIDE

a) 0.2% OR 0.7% OPHTHALMIC SOLUTION

1) ALLERGIC CONJUNCTIVITIS, AGED 2 YEARS AND OLDER: The recommended dose of topical ophthalmic olopatadine is one drop of a 0.2% or 0.7% solution instilled into each affected eye once daily (Prod Info PAZEO(TM) ophthalmic solution, 2015; Prod Info PATADAY(TM) ophthalmic solution, 2010).

b) 0.1% OPHTHALMIC SOLUTION

1) ALLERGIC CONJUNCTIVITIS, AGED 3 YEARS AND OLDER: The recommended dose of topical ophthalmic olopatadine in children 3 years of age or greater is one drop of a 0.1% solution instilled into each affected eye twice a day at 6- to 8-hour intervals (Prod Info Patanol(R) 0.1% ophthalmic solution, 2007).
2) ALLERGIC CONJUNCTIVITIS, UNDER 3 YEARS OF AGE: Safety and efficacy has not been established (Prod Info PATANOL(R) ophthalmic solution, 2003).

15) NASAL SPRAY

a) ALLERGIC RHINITIS: The recommended dose for children aged 6 to 11 years is 1 intranasal spray per nostril (665 mcg per spray) twice daily (Prod Info Olopatadine HCl nasal spray, 2014).

16) TRIPROLIDINE HYDROCHLORIDE

a) For children 6 to 12 years of age, the usual oral dose of triprolidine, either as a single entity or in combination with pseudoephedrine, is 1.25 milligrams every 4 to 6 hours, not exceeding 4 doses in 24 hours (Prod Info ZYMINE(TM) LIQUID oral syrup, 2002; Prod Info Actifed(R), 1988).

Minimum Lethal Exposure

1) ANTAZOLINE

a) ADULT: A 21-year-old man ingested antazoline 5000 mg. Seven hours later, he became drowsy, developed dilated pupils, nystagmus, hypotension, hypothermia, hallucinations, and cardiac arrest. The patient died 5 days after the ingestion following a series of cardiac arrests and resuscitations (Technical Information, 1982).
b) CHILD: A 3-year-old girl ingested 1500 mg of antazoline and 750 mg of tripelennamine and subsequently developed generalized tonic-clonic seizures. The patient died 22 hours after the onset of the seizures (Oberst, 1955).

2) DOXYLAMINE SUCCINATE

a) CHILD: Ingestion of 100 tablets, each tablet containing 10 mg doxylamine, 10 mg dicyclomine, and 10 mg pyridoxine, resulted in seizures followed by cardiac arrest in a 3-year-old boy (Bayley et al, 1975).
b) CHILD: A 13-month-old child was found unresponsive approximately 20 hours after being given 3.5 mL of an over-the-counter sleep aid containing doxylamine succinate 250 mg/100 mL. Several hours post-administration, after having been asleep, the child woke once, vomited and then fell asleep for several more hours. Approximately 17 hours post-ingestion, the father noted that the child was still breathing. At approximately 20 hours post-ingestion, a recheck of the child found her to be unresponsive. Emergency medical personnel could not successfully resuscitate the child. Post-mortem toxicologic analysis revealed a serum doxylamine concentration of 0.16 mg/L, considered to be within the upper therapeutic range for adults. Autopsy revealed severe acute over-inflation and atelectasis of the lungs, and the presence of stomach contents in the larger and smaller airways, indicating that the cause of death was aspiration of stomach contents, with severe sedation due to doxylamine ingestion as a contributing factor (Turk & Ewald, 2012).

3) METHAPYRILENE

a) CHILD: A 16-month-old girl died 15 hours after ingesting 100 mg. Hyperthermia and cerebral edema were present (Wyngaarden & Seevers, 1951).

4) TRIPELENNAMINE

a) ADULT: A 19-year-old man ingested an estimated 1000 mg of tripelennamine. Six hours later, he developed tonic-clonic seizures followed by cardiopulmonary arrest (Bayley et al, 1975a).
b) CHILD: A 3-year-old girl ingested 750 mg tripelennamine and 1500 mg antazoline and developed generalized tonic-clonic seizures. The patient subsequently died 22 hours after the onset of the seizures (Oberst, 1955).

Maximum Tolerated Exposure

1) CHLORPHENIRAMINE

a) An adult ingested 400 mg with no reported serious adverse effects (Wyngaarden & Seevers, 1951).
b) CHILD: Toxic psychosis was reported in a 4-year-old boy who ingested 12 mg (Jones et al, 1973).

2) CYCLIZINE

a) Persistent sinus tachycardia and 3 episodes of transient supraventricular tachycardia were reported in a 32-year-old woman following an overdose ingestion of 500 mg of cyclizine (Kamour et al, 2013).

3) CYPROHEPTADINE

a) CHILD: A 2-year-old boy developed classic signs and symptoms of anticholinergic toxicity following ingestion of 20 4-mg tablets (Richmond & Seger, 1985).
b) CHILD: A 3-year-old boy ingested 12 mg and developed toxic psychosis (Bharucha et al, 1987).
c) CHILD: Prolonged delirium occurred in a 14-year-old girl following intentional ingestion of 200 mg of cyproheptadine and 1150 mg of promethazine while she was taking fluvoxamine 150 mg/day (Scott et al, 2007).

4) DOXYLAMINE

a) According to a review of patient records documenting doxylamine overdose ingestions (n=146), seizures occurred in 11 patients. In combination with seizures, other effects that were reported included tachycardia, vomiting, mydriasis, hypertension, rhabdomyolysis, and hepatitis. The mean amount of doxylamine ingested was 2425 mg (range, 750 to 4750 mg) (Kim et al, 2010).
b) An observational case series was conducted that collected data retrospectively from a poison system database for all single substance doxylamine ingestions in pediatric patients (5 years and younger) from 1997 to 2012. There were 140 cases identified (ages ranging from 6 months to 5 years), of which 137 were due to unintentional self-administration and 3 were due to therapeutic error. Signs and symptoms were reported in 22 patients with drowsiness/lethargy, tachycardia, and agitation/hyperactivity as the most frequently reported symptoms, occurring in 17 patients, 12 patients, and 4 patients, respectively. The exact amount ingested was documented in 30 cases, ranging from 6.25 to 50 mg (median, 12.5 mg) and a maximum weight based dose of 6.2 mg/kg. The smallest reported weight based dose resulting in symptoms (drowsiness) was 1.5 mg/kg (Cantrell et al, 2015).

5) HYDROXYZINE

a) CHILD: Ingestion of 500 to 625 mg (45 to 57 mg/kg) in a 13-month-old girl produced coma and seizures (Magera et al, 1981).

6) METHAPYRILENE

a) ADULT: Two adults developed seizures after ingesting 800 to 1000 mg (Wyngaarden & Seevers, 1951).
b) CHILD: Seizures occurred in a 20-month-old boy who ingested 800 mg (Wyngaarden & Seevers, 1951).

7) PHENIRAMINE

a) Ingestion of 175 mg (10.7 mg/kg) by a 4-year-old child and 1500 mg (25 mg/kg) by an adult resulted in dry mouth, fever, mydriasis, and toxic psychosis (Wyngaarden & Seevers, 1951).
b) Abuse of pheniramine in doses of 500 to 1000 mg was reported to result in visual hallucinations (Csillag & Landauer, 1973).
c) Mendelson (1977) reported that 700 mg of pheniramine caused delirium, with choreiform movements, in a 16-year-old girl (Mendelson, 1977).

8) PIZOTIFEN

a) ADOLESCENT: A 16-year-old girl, with a 3-year history of migraine and 1-year history of depression, ingested 60 0.5-mg pizotifen tablets 4 hours before presenting to the emergency department. At presentation, the patient experienced blurred vision and abdominal pain. Examination revealed drowsiness, flushing, hyperpyrexia (38 degrees C), dilated pupils, and tachycardia. Gastric lavage did not produce any tablets. The patient's pyrexia and tachycardia persisted for approximately 10 hours before resolving spontaneously (Griffiths et al, 1987).

9) PYRILAMINE

a) ADULT: A 46-year-old woman ingested 10 g of pyrilamine, which resulted in cardiogenic shock refractory to pharmacologic intervention. The patient was mechanically supported with an intraaortic balloon pump for 7 days, after which time she regained normal cardiac function (Freedberg et al, 1987).
b) ADOLESCENT: A 15-year-old girl developed sinus tachycardia (124 beats/min) and a prolonged QTc interval after intentionally ingesting 30 tablets of a combination product containing acetaminophen 500 mg (375 mg/kg), caffeine 60 mg (32 mg/kg), and pyrilamine 15 mg (32 mg/kg), as well as ingesting 1200 mg ibuprofen and 6 g acetaminophen separately. With supportive care, the patient recovered with resolution of her ECG abnormality (Paudel et al, 2011).

10) TRIPELENNAMINE

a) ADULT: A 25-year-old woman was increasingly nervous, absent-minded, depressed, and suicidal, before ingesting 1250 mg of tripelennamine. After the ingestion, there was no added symptomatology (Technical Information, 1982a).
b) CHILD: A 5-year-old girl developed hallucinations following ingestion of the third dose of tripelennamine, 37.5 mg every 4 hours. The hallucinations resolved 3 days later (Hays et al, 1980).
c) CHILD: An 18-month-old boy ingested 375 mg of tripelennamine, developed vomiting, cyanosis, stupor, seizures, and coma, but recovered after receiving supportive care, including gastric lavage and sodium amobarbital (Technical Information, 1982a).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) DOXYLAMINE - Plasma levels are reported to be approximately 100 nanograms/milliliter (0.1 microgram/milliliter) after a therapeutic dose (Mendoza et al, 1987).

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CASE REPORTS

a) CYCLIZINE -

1) A massive overdose of cyclizine resulted in the death of a 17-year-old female. A post-mortem exam revealed a blood cyclizine concentration of 80 micrograms/milliliter (Backer et al, 1989).

b) DOXYLAMINE -

1) In a review of 109 cases, no correlation was found between the amounts ingested or plasma levels and the frequency and extent of symptoms (Koppel et al, 1987a).
2) Rhabdomyolysis was reported in a patient with a plasma level of 7.5 micrograms/milliliter (Mendoza et al, 1987).
3) Serum doxylamine concentrations of 140 mg/L and 100 mg/L were reported in two patients who were found dead following overdose ingestions of unknown amounts (Bockholdt et al, 2001). Carbon monoxide was also involved in one of these cases.

c) HYDROXYZINE -

1) Acute overdose in a 13-month-old child was associated with coma, seizures, and a plasma level of 102.7 micrograms/milliliter 8-1/2 hours postingestion (Magera et al, 1981).
2) The blood levels of a suspected hydrOXYzine overdose in a 46-year-old female was 1.1 milligrams/liter (Spiehler & Fukumoto, 1984).

d) MECLIZINE -

1) A serum levels of 10 nanograms/milliliter was reported 12 hours following an oral dose of 50 milligrams (Park et al, 1977).

e) METHAPYRILENE -

1) Winek et al (1977) reported 4 cases of methapyrilene toxicity, all resulting in death, where the blood methapyrilene concentrations were 1.2 to 3.0 milligram percent.
2) A post-mortem methapyrilene blood level of 0.9 milligrams/100 milliliters was detected following a fatal overdose by a 38-year-old female (Ainsworth & Biggs, 1977).

f) PYRILAMINE -

1) A pyrilamine blood concentration of 121 nanograms/milliliter was measured in a 46-year-old female after she ingested 10 grams of pyrilamine maleate (Freedberg et al, 1987).
2) A pyrilamine blood concentration of 11 milligrams/liter was measured in a 25-year-old female following a suspected fatal pyrilamine overdose (Johnson, 1981).

g) TRIPELENNAMINE -

1) A 19-year-old male died 7 hours after ingesting approximately 1000 milligrams of tripelennamine. A concentration of 1.0 milligrams/100 milliliters was found in the blood (Bayley et al, 1975a).

Toxicity Information

7.7.1)

A) CHLORPHENIRAMINE

1) LD50- (ORAL)MOUSE:

a) 162 mg/kg (Budavari, 1996)

B) CLEMASTINE FUMARATE

1) LD50- (ORAL)MOUSE:

a) 730 mg/kg (Budavari, 1996)

2) LD50- (ORAL)RAT:

a) 3550 mg/kg (Budavari, 1996)

C) CYCLIZINE

1) LD50- (ORAL)MOUSE:

a) 147 mg/kg (Budavari, 1996)

D) CYPROHEPTADINE

1) LD50- (ORAL)MOUSE:

a) 74.2 mg/kg (Budavari, 1996)

E) DOXYLAMINE

1) LD50- (ORAL)MOUSE:

a) 470 mg/kg (Budavari, 1996)

F) HYDROXYZINE

1) LD50- (INTRAPERITONEAL)RAT:

a) 126 mg/kg (Budavari, 1996)

2) LD50- (ORAL)RAT:

a) 950 mg/kg (Budavari, 1996)

G) PHENYLTOLOXAMINE DIHYDROGEN CITRATE

1) LD50- (ORAL)MOUSE:

a) 246 mg/kg (Hoekstra et al, 1953)

H) PHENYLTOLOXAMINE HYDROCHLORIDE

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 163 mg/kg (Hoekstra et al, 1953)

2) LD50- (ORAL)MOUSE:

a) 424 mg/kg (Hoekstra et al, 1953)

I) PYRILAMINE

1) LD50- (ORAL)MOUSE:

a) 312 mg/kg (Budavari, 1996)

J) TRIPELENNAMINE

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 47 mg/kg (Budavari, 1996)

Pharmacology Toxicology

Pharmacologic Mechanism

Toxicologic Mechanism

Physicochemical

Animal Toxicology

Clinical Effects

11.1.3)

A) ACUTE, LOW EXPOSURE causes signs including depression, drowsiness, salivation, and vomiting (Humphreys, 1988). The most common side effect seen around therapeutic doses is sedation; alternatively, hyperexcitability may occur (Medleau, 1990; Scott & Buerger, 1988).
B) CHLORPHENIRAMINE - In a study of 45 dogs given various antihistamines, chlorpheniramine maleate most consistently produced side effects (Scott & Buerger, 1988).

11.1.13)

A) OTHER

1) MEPYRAMINE - When injected intravenously, mepyramine may cause transient nervous signs, including incoordination and visual disturbances, in horses and cattle (Humphreys, 1988).
2) ACUTE, HIGH EXPOSURE could produce spasmolysis, an antifibrillatory action on the myocardium, excitement, and seizures (Humphreys, 1988).

Treatment

11.2.1)

A) GENERAL TREATMENT

1) Begin treatment immediately.
2) Keep animal warm and do not handle unnecessarily.
3) Sample vomitus, blood, urine, and feces for analysis.
4) ANIMAL POISON CONTROL CENTERS

a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.

11.2.2)

A) GENERAL

1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.

11.2.4)

A) GASTRIC DECONTAMINATION

1) DOGS/CATS

a) EMESIS AND LAVAGE - If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os.

1) Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.
2) Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
3) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1989).

b) ACTIVATED CHARCOAL - Administer activated charcoal, 2 grams/kilogram per os or via stomach tube.
c) CATHARTIC - Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.

2) HORSES/CATTLE

a) EMESIS - Do not attempt to induce emesis in ruminants (cattle) or equids (horses).
b) ACTIVATED CHARCOAL - Give 250 to 500 grams activated charcoal in a water slurry per os or via stomach tube.
c) CATHARTIC - Administer an oral cathartic:

1) Mineral oil (small ruminants and swine, 60 to 200 milliliters; equids and cattle, 0.5 to 1 gallon)
2) Magnesium sulfate (ruminants and swine, 1 to 2 grams/kilogram; equine, 0.2 to 0.9 gram/kilogram)
3) Milk of Magnesia (small ruminants, up to 0.25 gram/kilogram in 1 to 3 gallons warm water; adult cattle up to 1 gram/kilogram in 1 to 3 gallons warm water or 2 to 4 boluses MgOH per os).
4) Give these solutions via stomach tube and monitor for aspiration.

11.2.5)

A) DOGS/CATS

1) Maintain vital functions: Secure airway, supply oxygen and begin supportive fluid therapy if necessary.
2) DECONTAMINATE as specified above.
3) SEIZURES -

a) DIAZEPAM - Dose of diazepam for DOGS & CATS is 0.5 milligram/kilogram intravenous bolus; may repeat dose every ten minutes for four total doses. Give slowly over 1 to 2 minutes.
b) PHENOBARBITAL may be used as adjunct treatment at 5 to 30 milligrams/kilogram over 5 to 10 minutes intravenously.
c) REFRACTORY SEIZURES - Consider anaesthesia or heavy sedation. Administer pentobarbital to DOGS & CATS at a dose of 3 to 15 milligrams/kilogram intravenously slowly to effect. The dose may need to be repeated in 4 to 8 hours. Be sure to protect the airway.

B) RUMINANTS/HORSES/SWINE

1) MAINTAIN VITAL FUNCTIONS - Secure airway, supply oxygen and begin supportive fluid therapy if necessary.
2) DECONTAMINATE as specified above.
3) SEIZURES may be controlled with diazepam. Doses of diazepam, given slowly intravenously:

a) HORSES - 1 milligram/kilogram
b) CATTLE, SHEEP AND SWINE - 0.5 to 1.5 milligrams/kilogram

Range Of Toxicity

11.3.1)

A) DOG

1) INDICATIONS - ORAL antihistamines are commonly used in the treatment of canine atopy.
2) CHLORPHENIRAMINE - Dose for DOGS is 2 to 12 milligrams 2 to 3 times daily (Medleau, 1990).
3) CLEMASTINE - Dose for DOGS is 0.5 to 1.5 milligrams/kilogram every 12 hours (Merchant & Taboada, 1989).
4) DIPHENHYDRAMINE HCL - Dose for DOGS is 2 to 4 milligrams/ kilogram three times daily (Medleau, 1990).
5) TRIMEPRAZINE - Dose for DOGS is 1 to 2 milligrams/kilogram three times daily (Medleau, 1990).
6) CYPROHEPTADINE - Dose for DOGS is 0.3 to 2 milligrams/kilogram two times daily (Medleau, 1990).
7) HYDROXYZINE HCL - Dose for DOGS is 2 milligrams/kilogram three times daily (Medleau, 1990).
8) DIMENHYDRINATE - Dose for DOGS is 8 milligrams/kilogram every 8 hours (Merchant & Taboada, 1989).
9) TERFENADINE - Dose for DOGS is 4 to 10 milligrams/kilogram two times daily (Medleau, 1990).
10) TRIMETHOBENZAMIDE - INTRAMUSCULAR dose for DOGS is 3 milligrams/kilogram every 8 hours (Merchant & Taboada, 1989).

B) DOGS/CATS

1) DOXYLAMINE SUCCINATE - INJECTABLE dose for DOGS & CATS is 0.5 to 1 milligram/pound body weight two to three times daily (Prod Info, 1988).
2) DOXYLAMINE SUCCINATE - TABLETS - Oral dosage for DOGS & CATS is 1 to 2 milligrams/pound body weight per day, divided into 3 or 4 equal doses (Prod Info, 1988).

C) HORSE

1) DOXYLAMINE SUCCINATE - INJECTABLE dose for HORSES is 25 milligrams/100 pounds body weight (Prod Info, 1988).

11.3.2)

A) LACK OF INFORMATION

1) No specific information on a minimal toxic dose was available at the time of this review.

Continuing Care

11.4.1)

11.4.1.2) DECONTAMINATION/TREATMENT

A) GENERAL TREATMENT

1) Begin treatment immediately.
2) Keep animal warm and do not handle unnecessarily.
3) Sample vomitus, blood, urine, and feces for analysis.
4) ANIMAL POISON CONTROL CENTERS

11.4.2)

11.4.2.2) GASTRIC DECONTAMINATION

A) GASTRIC DECONTAMINATION

1) DOGS/CATS

a) EMESIS AND LAVAGE - If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os.

2) HORSES/CATTLE

Kinetics

11.5.1)

A) DOG

1) CHLORPHENIRAMINE - Absorption in dogs is rapid and complete from the gastrointestinal tract, reaching peak plasma concentrations 30 to 60 minutes after oral administration (Kamm et al, 1969).

11.5.4)

A) DOG

1) CHLORPHENIRAMINE - Plasma half-life in dogs is approximately 24 hours (Merchant & Taboada, 1989).

Sources

1) DOXYLAMINE SUCCINATE -

a) INJECTABLE - A product marketed as A-H Injection contains 11.36 milligrams doxylamine succinate and 5 milligrams chlorobutanol (preservative) per milliliter. It comes in vials of 250 milliliters (Prod Info, 1988).
b) TABLET - A-H Tablets contain 100 milligrams doxylamine succinate each and come in bottles of 50 tablets (Prod Info, 1988).

Other

1) GENERAL

a) TERATOGENICITY - Antihistamines, especially hydrOXYzine, may be teratogenic and should not be used in pregnant dogs (Medleau, 1990).

References

General Bibliography

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FeedBack

ANTIHISTAMINES

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

Hematologic

Dermatologic

Musculoskeletal

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Methods

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Patient Disposition

Monitoring

Oral Exposure

Enhanced Elimination

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Toxicity Information

Pharmacologic Mechanism

Toxicologic Mechanism

Clinical Effects

Treatment

Range Of Toxicity

Continuing Care

Kinetics

Sources

Other

General Bibliography