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ASTEMIZOLE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Astemizole is an antihistamine with specificity for the Histamine H1 receptor. Anticholinergic activity has not been reported.

Specific Substances

    1) R-43512
    2) CAS 68844-77-9

Available Forms Sources

    A) FORMS
    1) In June 1999, astemizole was voluntarily removed from the United States market and is no longer available in the U.S. Astemizole was available as Hismanal(R) 10 mg tablets from Janssen prior to the market removal (Kastrup, 1989).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH POISONING/EXPOSURE
    1) Overdose effects may include sedation, seizures and ventricular dysrhythmias, particularly torsades de pointes and prolonged QT intervals.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Ventricular dysrhythmias (torsades de pointes, ventricular tachycardia, ventricular fibrillation) have been reported following ingestion of 200 and 400 mg. QT prolongation and Mobitz type two heart block have also been associated with astemizole overdose.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) Drowsiness may be noted.
    2) Generalized seizures were associated with an ingestion of 200 to 250 mg of astemizole in a previously healthy 15-year-old female.
    0.2.20) REPRODUCTIVE
    A) Astemizole is classified as FDA pregnancy category C.
    B) It is not known whether or not astemizole is excreted in human breast milk.

Laboratory Monitoring

    A) Obtain an EKG and institute continuous cardiac monitoring in suspected overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    B) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.
    1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.
    C) VENTRICULAR DYSRHYTHMIAS: Institute continuous cardiac monitoring, obtain an ECG, and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders. Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Because astemizole can cause torsades de pointes and QTc prolongation, amiodarone should only be used with extreme caution. Unstable rhythms require immediate cardioversion.
    1) In one case report, ventricular tachyarrhythmias (not torsades de pointes) improved with administration of IV magnesium sulfate (2 gram bolus followed by a continuous infusion of 17 mg/min over the next 4 hours) after a man ingested 740 mg of astemizole. Two bolus doses of 100 mg of lidocaine were given, without effect, prior to administration of magnesium sulfate.
    D) TORSADES DE POINTES: Hemodynamically unstable patients require electrical cardioversion. Treat stable patients with magnesium (first-line agent) and/or atrial overdrive pacing. Correct electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia) and hypoxia, if present.
    1) MAGNESIUM SULFATE/DOSE: ADULT: 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes. An optimal dose has not been established. Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram/hour, if dysrhythmias recur. CHILDREN: 25 to 50 mg/kg diluted to 10 mg/mL; infuse IV over 5 to 15 minutes.
    2) OVERDRIVE PACING: Begin at 130 to 150 beats per minute, decrease as tolerated.
    3) Avoid class Ia (eg, quinidine, disopyramide, procainamide), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol).
    E) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 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) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 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).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    F) ALLERGIC REACTION: MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.

Range Of Toxicity

    A) Ingestion of 200 mg produced mild drowsiness in one case and severe ventricular dysrhythmias in another.
    B) Ventricular dysrhythmias have occurred in children ingesting 6 to 8 mg/kg.

Clinical Effects

Summary Of Exposure

    A) WITH POISONING/EXPOSURE
    1) Overdose effects may include sedation, seizures and ventricular dysrhythmias, particularly torsades de pointes and prolonged QT intervals.

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Ventricular dysrhythmias (torsades de pointes, ventricular tachycardia, ventricular fibrillation) have been reported following ingestion of 200 and 400 mg. QT prolongation and Mobitz type two heart block have also been associated with astemizole overdose.
    3.5.2) CLINICAL EFFECTS
    A) TORSADES DE POINTES
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - Concomitant use of therapeutic doses of ketoconazole and astemizole resulted in elevated plasma concentrations of astemizole in a 63-year-old female, with resultant torsades de pointes and a prolonged QT interval (Tsai et al, 1997).
    b) CASE REPORT - A suspected drug interaction between cimetidine and astemizole resulted in toxic serum concentrations of astemizole (16 ng/mL, about 3 times normal) in a 77-year-old female. The patient was admitted to the hospital with vasospastic angina and later diagnosed with QT prolongation and torsades de pointes. Other factors predisposing to torsades de pointes were the patient's age, history of hepatitis, and use of another antihistamine (Ikeda et al, 1998).
    2) WITH POISONING/EXPOSURE
    a) Cardiotoxic effects, primarily ventricular conduction abnormalities and torsades de pointes have been described. Doses causing torsades de pointes have ranged from 20 to 300 mg in case reports. Taking the recommended dose of astemizole has not been reported to result in clinically significant cardiotoxic effects in either adults or children with no predisposing factors (Delgado et al, 1998; Kelloway et al, 1995). Rare cases of patients with underlying heart disease developing torsades de pointes have been described following ingestions of 2 to 3 times the recommended dose (Kelloway et al, 1995).
    b) CASE REPORT - A 16-year-old girl ingested 270 mg astemizole. Her initial QTc was 0.42 seconds. Seven hours later she developed torsade de pointes with a QTc of 0.62 seconds. Magnesium sulfate was started at 2 mg/minute. A repeat episode occurred 4 hours later. A 2 gram bolus of magnesium sulfate was given. Magnesium sulfate was continued at 2 mg/minute tapering over 36 hours. Recovery was uneventful (Hasan & Nolan, 1993).
    c) CASE REPORT - Ventricular tachycardia consistent with torsades de pointes, and a QTc interval of 0.65 seconds was reported 7 hours postingestion in a 16-year-old girl who ingested 200 mg (Craft, 1986).
    d) CASE REPORT - Another case of torsades de pointes with a QTc of 0.62 seconds was described in a patient with a plasma level 6 times the maximum therapeutic level (Snook et al, 1988).
    e) CASE REPORT - A 52-year-old woman developed torsades de pointes and ventricular fibrillation after gradually increasing her astemizole dose from 10 milligrams/day to 90 milligrams/day. She had been taking 90 milligrams/day for 3 days before developing symptoms (Burke & Mutnick, 1993).
    B) VENTRICULAR TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES - The Committee on Safety of Medicines in the UK reported 3 cases of ventricular tachycardia following acute ingestion of 200 and 400 mg in 2 cases, respectively, and of chronic intermittent ingestion of 20 mg/day for 2 to 3 years in another case (plasma concentration was 3 times the therapeutic range) (CSM, 1987).
    b) CASE REPORT (CHILD) - Ventricular tachycardia developed 3 hours postingestion in a 17-month-old who reportedly ingested 80 mg (6 mg/kg). The QTc was 0.52 at 3 hours and 0.43 on discharge (Wiley et al, 1991).
    C) HEART BLOCK
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT (ADOLESCENT) - A 15-year-old female developed QT prolongation, torsades de pointes ventricular tachycardia, and Mobitz type two block associated with an ingestion of 20 to 25 tablets of astemizole (200 to 250 mg) (Clark & Love, 1991).
    b) CASE REPORT (CHILD) - A 3-year-old girl who ingested 8 mg/kg astemizole experienced ECG changes including second degree heart block, right bundle branch block, intermittent axis shift, and prolongation QT interval.
    D) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) No ECG abnormalities were noted in six healthy volunteers given astemizole 10 mg three times daily for 3 days followed by 10 mg daily for 12 days (Craft et al, 1987).
    2) WITH POISONING/EXPOSURE
    a) ADULT - A 12-lead ECG revealed a QT interval of 0.36 second accompanied by prominent U waves (Q-TU interval 0.52s, QTc 0.58s) in a 22-year-old male following an ingestion of 740 mg of astemizole (Leor et al, 1991).
    b) PEDIATRIC - Prolongation of the corrected QT interval was reported in three children; one developed ventricular tachycardia and another developed second-degree AV block, ventricular bigeminy and right bundle branch block. QT intervals returned to normal in 1 to 3 days (Wiley et al, 1992).
    c) CASE REPORT (CHILD) - A 2.5-year-old girl who was thought to have ingested 8.1 to 12.2 mg/kg had a QTc of 0.52 five hours postingestion and 0.39 three days later (Wiley et al, 1991).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ECG ABNORMAL
    a) BEAGLE DOGS were anesthetized then administered a toxic dose of astemizole (3 mg/kg IV) which prolonged the repolarization and refractory period while decreasing the sinus automaticity, ventricular contraction, and conduction (Sugiyama et al, 1997).

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Drowsiness may be noted.
    2) Generalized seizures were associated with an ingestion of 200 to 250 mg of astemizole in a previously healthy 15-year-old female.
    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - Slight drowsiness lasting 12 hours was the only effect observed in a 14-year-old girl who ingested 200 mg (Kingswood et al, 1986).
    B) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT (ADOLESCENT) - A 15-year-old female developed seizures of 5 minutes duration that were associated with an ingestion of 20 to 25 tablets of astemizole (200 to 250 mg) (Clark & Love, 1991).
    1) This patient had no family history of blackouts or palpitations.
    2) The first seizure developed at four hours postingestion. A total of four generalized seizures were observed, and one seizure was reported three hours prior to admission.
    3) Urine and serum toxicology screen was negative.

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLAXIS
    1) WITH THERAPEUTIC USE
    a) The FDA has issued a warning concerning the possibility of anaphylaxis following ingestion of astemizole. Although this is a rare occurrence, it may result in potentially life-threatening reaction (Anon, 1998).

Reproductive

    3.20.1) SUMMARY
    A) Astemizole is classified as FDA pregnancy category C.
    B) It is not known whether or not astemizole is excreted in human breast milk.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    AstemizoleC
    Reference: Prod Info Hismanal(R), 1996
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) There are no human studies which quantitate the levelsof astemizole in breast milk. In animal studies, milk-plasma ratios of 4.4 and 4.6 have been reported for astemizole and desmethylastemizole, respectively (Richards et al, 1984).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Obtain an EKG and institute continuous cardiac monitoring in suspected overdose.

Methods

    A) CHROMATOGRAPHY
    1) Astemizole and desmethylastemizole have been quantitated by high pressure liquid chromatography (Woestenborghs et al, 1983).
    B) IMMUNOASSAY
    1) Radiommunoassay has been used to measure astemizole and related metabolites (detection limit 0.1 mcg/L) (Richards et al, 1984).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) In any suspected overdose, admission and continuous cardiac monitoring are recommended. The onset of ventricular dysrhythmias was 7 hours postingestion in one case (Kingswood et al, 1986).

Monitoring

    A) Obtain an EKG and institute continuous cardiac monitoring in suspected overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) Laine et al (1994) have shown that 85% of astemizole absorption from the gastrointestinal tract is effectively prevented with one dose of activated charcoal if administered immediately. Multiple doses of activated charcoal were not effective in shortening the elimination half-life of astemizole (Laine et al, 1994a).
    2) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    B) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) VENTRICULAR ARRHYTHMIA
    1) VENTRICULAR DYSRHYTHMIAS SUMMARY
    a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    2) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) 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).
    c) 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).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    3) AMIODARONE
    a) AMIODARONE/INDICATIONS
    1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).
    b) AMIODARONE/ADULT DOSE
    1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).
    c) AMIODARONE/PEDIATRIC DOSE
    1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).
    d) ADVERSE EFFECTS
    1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).
    4) Ventricular tachyarrhythmias (not torsades de pointes) improved with administration of intravenous magnesium sulfate (2 gram bolus followed by a continuous infusion of 17 milligrams/minute over the next 4 hours), as reported in a 22-year-old man who ingested 740 milligrams of astemizole. Two bolus doses of 100 milligrams of lidocaine were given, without effect, prior to administration of magnesium sulfate (Leor et al, 1991).
    5) Wiley & Henretig (1993) reported that QT prolongation in children will last from one to three days following overdoses with no specific therapy. They still recommend early use of magnesium sulfate in the treatment of torsades de pointes (Wiley & Henretig, 1993).
    6) ANIMAL STUDY: Beagle dogs were anesthetized then administered a toxic dose of astemizole (3 mg/kg IV) which prolonged the repolarization and refractory period while decreasing the sinus automaticity, ventricular contraction, and conduction. One hour later the dogs were given magnesium sulfate (100 mg/kg IV), which increased the AV conduction time, electrical vulnerability, and preload of the left ventricle, and decreased blood pressure and cardiac output. During astemizole overdose, magnesium acted as a calcium channel blocker, but did not antagonize the proarrhythmic effects of astemizole (Sugiyama et al, 1997).
    B) 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.
    C) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    D) ANAPHYLAXIS
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Richards et al (1984) indicated that dialysis does not decrease the plasma concentration of astemizole or desmethylastemizole (Richards et al, 1984).

Abstracts

Case Reports

    A) ADULT
    1) A 17-year-old man taking 20 mg/day chronically and denying acute overdose presented with syncope, palpitations, and lightheadedness. An EKG revealed multifocal ventricular ectopy and episodes of ventricular tachycardia. Three further episodes of ventricular tachycardia with characteristics of torsades de pointes occurred. Ventricular ectopy resolved over the next 12 hours. The QTc interval was 0.61 seconds and normalized over 5 days. The plasma astemizole concentration was 30 ng/mL (Snook et al, 1988).
    2) Ingestion of 200 mg by a 14-year-old girl resulted in slight drowsiness, lasting 12 hours. No other signs or symptoms occurred. Peak plasma concentrations were approximately 10 times greater than that seen after a single 20 mg dose (Kingswood et al, 1986).
    3) A 16-year-old girl who ingested 200 mg developed a cardiac arrest 7 hours postingestion. One hour later ventricular tachycardia, refractory to lidocaine, with a prolonged QTc interval (0.65 second), consistent with torsades de pointes, was observed. Isoprenaline (isopropyl analog of epinephrine) infusion controlled the dysrhythmia over the next 5 days (Craft, 1986).

Range Of Toxicity

Summary

    A) Ingestion of 200 mg produced mild drowsiness in one case and severe ventricular dysrhythmias in another.
    B) Ventricular dysrhythmias have occurred in children ingesting 6 to 8 mg/kg.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) Janssen Pharmaceutica voluntarily removed astemizole from the United States market on June 18, 1999. Its removal was based on reports of serious cardiovascular toxicities associated with the drug, as well as the availability of alternative agents (eg, fexofenadine), which do not appear to have the same potential for serious drug interactions such as reported with astemizole (Tech Info Hismanal(R), 1999; (Prod Info Hismanal(R), astemizole, 1998).
    7.2.2) PEDIATRIC
    A) ROUTE OF ADMINISTRATION
    1) Janssen Pharmaceutica voluntarily removed astemizole from the United States market on June 18, 1999. Its removal was based on reports of serious cardiovascular toxicities associated with the drug, as well as the availability of alternative agents (eg, fexofenadine), which do not appear to have the same potential for serious drug interactions such as reported with astemizole (Tech Info Hismanal(R), 1999; (Prod Info Hismanal(R), astemizole, 1998).

Maximum Tolerated Exposure

    A) ADULT
    1) Acute ingestion of 200 milligrams in a 16-year-old (Craft, 1986) and 200 milligrams in a 14-year-old (Kingswood et al, 1986) resulted in life-threatening toxicity and mild drowsiness only, respectively, both with full recovery.
    B) INFANT
    1) A reported ingested dose of 6 milligrams/kilogram in a 17-month-old produced stable ventricular tachycardia with a QTc of 0.52 at 3 hours postingestion (0.43 on discharge).
    C) PEDIATRIC
    1) A dose of 8.1 to 12.2 milligrams/kilogram in a 2.5-year-old produced a QTc of 0.52 five hours postingestion (0.39 three days later) (Wiley et al, 1992).
    2) Prolonged QTc interval was found in 5 children following ingestion of between 2.5 and 16.7 milligrams/kilogram of astemizole (Hoppu et al, 1991).
    a) Severe dysrhythmias were associated with ingestion of 16.7 milligrams/kilogram in a 2-year-old female.
    b) All 5 children had some type of gastrointestinal decontamination performed.

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION
    a) THERAPEUTIC -
    1) The plasma concentration obtained after therapeutic doses of 10 milligrams/day ranges from 2 to 5 nanograms/milliliter (Snook et al, 1988).
    b) TOXIC -
    1) A 26-year-old female ingested 200 mg astemizole, 750 mg hydroxyzine, and alcohol. Her 13 hour radioimmunoassay plasma concentration of astemizole & desmethylastemizole was 61.3 nanograms/milliliter. Torsade de pointes developed briefly with a QTc of 0.41s (baseline 0.35s) (Saviuc et al, 1993).
    2) A patient who developed ventricular tachycardia had a plasma concentration of 30 nanograms/milliliter (Snook et al, 1988).
    3) A 16-year-old female had the following concentrations of astemizole plus hydroxylated metabolites following a deliberate ingestion of 20 10-milligram tablets of astemizole (Craft et al, 1987) -
    Time in hours post overdoseConcentration (ng/mL)
    1079.9
    1781.7
    4340.9
    6834.4

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (ORAL)MOUSE:
    a) >2560 mg/kg (RTECS, 2001)
    2) LD50- (ORAL)RAT:
    a) 2560 mg/kg (RTECS, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Astemizole is a histamine H1 receptor antagonist with no apparent anticholinergic properties. Antihistamine effects persisting for as long as 32 days after treatment has been discontinued suggest irreversible binding to the H1 receptor (Krause & Shuster, 1985).

Physicochemical

Physical Characteristics

    A) Astemizole is an odorless, cream-colored crystalline powder

Molecular Weight

    A) 458.6

References

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