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TERFENADINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Terfenadine is a selective peripheral H1-receptor antagonist (antihistamine) without anticholinergic, antiserotonergic, or antiadrenergic properties.

Specific Substances

    1) RMI-9918
    2) 1-(4-tert-butyl-phenyl)-4-(4-(a-hydroxy-
    3) benzohydryl)piperidino) butan-l-ol
    4) CAS 50679-08-8

Available Forms Sources

    A) FORMS
    1) Terfenadine has been available in 60 mg tablets in the United States as Seldane(R) and in other countries as Teldane(R) or Triludan(R).
    2) On January 13, 1997, the Food and Drug Administration (FDA) announced it will withdraw approval for terfenadine in the United States due to the number of arrhythmias as a result of terfenadine drug interactions. In December of 1997 the US manufacturer of Seldane(R) announced it will voluntarily withdraw Seldane(R) and Seldane-D(R) from the marketplace (Anon, 1997). Terfenadine has also been withdrawn from the marketplace in France (Lindquist & Edwards, 1997).

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) Experience in overdose is limited. Cardiotoxicity with QT prolongation associated with torsade de pointes ventricular tachycardia may occur. Onset of cardiac toxicity may be delayed as long as 22 hours after ingestion. Syncope, asymptomatic hypotension, and sedation are possible.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Ingestion of 1500 mg in an adult produced hypotension that resolved spontaneously.
    2) Ingestion of 3360 mg has resulted in torsade de pointes progressing to ventricular fibrillation.
    3) Cardiotoxicity with QT prolongation associated with torsade de pointes ventricular tachycardia may occur.
    4) Syncope may occur as a result of ventricular dysrhythmias.
    0.2.7) NEUROLOGIC
    A) ANIMAL STUDIES
    1) Sedation and ataxia have occurred in animals receiving 80 to 500 mg/kg.
    2) Seizures and tremor occur in animals receiving 80 to 500 mg/kg.
    B) WITH THERAPEUTIC USE
    1) Seizures and tremor have rarely been reported in humans.
    C) WITH POISONING/EXPOSURE
    1) Seizures and syncope have been seen in human overdose.
    2) Sedation and ataxia have not been seen in human overdose.
    0.2.9) HEPATIC
    A) WITH THERAPEUTIC USE
    1) Hepatitis and jaundice have been reported but are rare.
    0.2.10) GENITOURINARY
    A) WITH THERAPEUTIC USE
    1) Urinary retention is a rare event.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Rashes, pruritus, urticaria, and alopecia have been noted but are rare.
    0.2.18) PSYCHIATRIC
    A) WITH THERAPEUTIC USE
    1) Anxiety reactions with autonomic symptoms have been reported but are rare.
    0.2.20) REPRODUCTIVE
    A) Terfenadine is not teratogenic in rats; teratogenicity was not noted in humans in a multicenter, prospective study.

Laboratory Monitoring

    A) Due to one reported case of ventricular arrhythmias 15 hours after an ingestion of 3360 mg, the manufacturer recommends cardiac monitoring for 24 hours following overdose, however, 8 to 12 hours may be sufficient in smaller ingestions.
    B) A prolonged QT has been associated with ventricular fibrillation following overdose and in certain clinical situations such as drug interactions at therapeutic doses. Patients should then be monitored until their QT interval returns to normal.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Treatment is supportive and directed at signs and symptoms of CNS depression, hypotension, ventricular dysrhythmias, and potential seizures.
    B) 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.
    C) 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.
    D) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    E) CAUTION: If VENTRICULAR DYSRHYTHMIAS occur, decrease rate of administration of dopamine or norepinephrine.
    F) VENTRICULAR DYSRHYTHMIAS SUMMARY
    1) 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.
    G) 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).
    H) 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.

Range Of Toxicity

    A) Terfenadine is no longer available in the United States.
    B) Single doses up to 600 mg in adults and up to 300 mg in children aged 1 to 5 years have produced no adverse effects. Ingestion of 1500 mg in an adult resulted in asymptomatic hypotension of short duration. Ingestion of 360 mg resulted in ventricular dysrhythmias.

Clinical Effects

Summary Of Exposure

    A) WITH POISONING/EXPOSURE
    1) Experience in overdose is limited. Cardiotoxicity with QT prolongation associated with torsade de pointes ventricular tachycardia may occur. Onset of cardiac toxicity may be delayed as long as 22 hours after ingestion. Syncope, asymptomatic hypotension, and sedation are possible.

Vital Signs

    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) Hypotension may be noted.

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Ingestion of 1500 mg in an adult produced hypotension that resolved spontaneously.
    2) Ingestion of 3360 mg has resulted in torsade de pointes progressing to ventricular fibrillation.
    3) Cardiotoxicity with QT prolongation associated with torsade de pointes ventricular tachycardia may occur.
    4) Syncope may occur as a result of ventricular dysrhythmias.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Ingestion of 1500 mg in an adult produced asymptomatic hypotension (90/50 mmHg) which did not require treatment (Prod Info Seldane(R), 1990).
    B) TORSADES DE POINTES
    1) WITH THERAPEUTIC USE
    a) FDA's Spontaneous Reporting System for Adverse Drug Reactions covering May 1985 - April 1, 1992 found 25 cases of torsade de pointes in patients using terfenadine (Woosley, 1993). The manufacturer has reported QTc interval prolongation/ventricular dysrhythmia with overdoses, including single doses as low as 360 mg in adults (Prod Info Seldane(R), terfenadine, 1998).
    1) An increased risk of life-threatening ventricular events was seen in patients taking terfenadine and ketoconazole and a trend was seen with terfenadine and erythromycin as well as in patients taking terfenadine who had hepatic disease in an observational cohort study (Pratt et al, 1994).
    2) Subsequent studies have confirmed the risk of elevated terfenadine levels in patients concomitantly taking ketoconazole, itraconazole, and erythromycin (Monahan et al, 1990) Pohjola-Sintonen et al, Crane & Shih, 1993).
    b) Factors that are associated with the development of torsade de pointes include: acute overdose, ingestion of doses higher than 120 milligrams/day, coingestion of drugs known to inhibit terfenadine metabolism (ketoconazole, itraconazole, erythromycin, troleandomycin, possibly clarithromycin), hepatic disease (cirrhosis, ethanol abuse), and factors known to predispose to drug-induced torsade de pointes (congenital prolonged QT interval, drugs that prolong the QT interval, bradycardia, heart disease, and hypokalemia) (Prod Info Seldane(R), terfenadine, 1998; Woosley et al, 1993). There is also experimental evidence that suggests that grapefruit juice contains flavonoids that could inhibit terfenadine metabolism.
    c) CASE REPORT - Torsade de pointes was associated with the use of terfenadine in a patient who was taking the recommended prescribed dose of 60 mg orally twice daily in addition to cefaclor, ketoconazole, and medroxyprogesterone (Monahan et al, 1990). June & Nasr (1997) reported another patient, with no risk factors, who took therapeutic doses (60 mg twice a day for one day) and developed torsades de pointes.
    1) Elevated levels of unchanged terfenadine and its principle metabolite (carboxy terfenadine) were noted (Mathews et al, 1991).
    2) Inhibition of terfenadine metabolism by the hepatic enzyme P450 may result in elevated terfenadine concentrations. This appears to be the mechanism of terfenadine-induced torsade de pointes and QT prolongation following interactions with drugs such as macrolide antibiotic and fungicides.
    d) A 45-year-old woman developed torsades de pointes associated with the use of terfenadine 360 mg per day over two weeks (MacConnell & Stanners, 1991). Discontinuation of terfenadine use resulted in normalization of her QT interval.
    e) CASE SERIES (CHILDREN) - A series of 10 children, aged 5 to 12 years, were given terfenadine (1 mg/kg orally bid) with erythromycin. Slightly prolonged QT intervals (mean pretreatment and posttreatment values 0.32s and 0.34s, respectively) were shown in this group of children. However, no significant differences were seen in the QTc interval in this same group (Delgado et al, 1998).
    2) WITH POISONING/EXPOSURE
    a) The manufacturer has reported QTc interval prolongation/ventricular dysrhythmia with overdoses, including single doses as low as 360 mg in adults (Prod Info Seldane(R), terfenadine, 1998).
    b) CASE REPORT - Ingestion of 3360 mg of terfenadine in combination with 7 grams of cephalexin and 1200 mg of ibuprofen by a 16-year-old male resulted in torsade de pointes 15 hours postingestion.
    1) This progressed to ventricular fibrillation which responded to defibrillation and lidocaine (Prod Info Seldane(R), 1990).
    c) CASE SERIES (CHILDREN) - Of 39 children, aged 15 years or younger, who ingested 600 mg or more, only one child developed QT prolongation, which resolved spontaneously (Personal Communication, 1990).
    C) VENTRICULAR ARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) CASE SERIES - Ventricular dysrhythmias occurred in 17 of 25 cardiac reactions seen with terfenadine therapy or overdose (over 900 mg). Prolonged QTc times were also seen (Anon, 1991).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES - Ventricular dysrhythmias occurred in 17 of 25 cardiac reactions seen with terfenadine therapy or overdose (over 900 mg). Prolonged QTc times were also seen (Anon, 1991).
    1) A series of five overdoses (dose ranges of 540 mg to 4800 mg) were associated with QT prolongation and ventricular fibrillation on ECG. It is noteworthy that in two of the cases symptoms did not develop until 15 to 22 hours after ingestion. No fatalities were noted (Myrenfors & Feychting, 1993).

Neurologic

    3.7.1) SUMMARY
    A) ANIMAL STUDIES
    1) Sedation and ataxia have occurred in animals receiving 80 to 500 mg/kg.
    2) Seizures and tremor occur in animals receiving 80 to 500 mg/kg.
    B) WITH THERAPEUTIC USE
    1) Seizures and tremor have rarely been reported in humans.
    C) WITH POISONING/EXPOSURE
    1) Seizures and syncope have been seen in human overdose.
    2) Sedation and ataxia have not been seen in human overdose.
    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) WITH THERAPEUTIC USE
    a) Sedation occurred in 12.6% of 965 patients in clinical trials with doses of 120 mg daily (Barlow et al, 1982). However, no effect was detected on driving performance, CNS activity, or EEG activity with terfenadine 60 mg bid in a driving test that did show impairment following chlorpheniramine use (Aso & Sakai).
    2) ANIMAL STUDIES - SEDATION has been noted in high doses in animals.
    B) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures have been possibly associated with terfenadine use in patients with a predisposition to seizures or those taking more than 120 mg/day (Tidswell & Fonseca, 1992).
    2) WITH POISONING/EXPOSURE
    a) Seizures and syncope have been reported following overdoses of 360 mg or more in adults (Prod Info Seldane(R), terfenadine, 1998).
    C) TREMOR
    1) WITH THERAPEUTIC USE
    a) A case of tremor was reported in a mother and son taking terfenadine 120 mg/day (Soto et al, 1993).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) TREMOR
    a) Tremors and ataxia occurred after single daily doses of 80 mg/kg in dogs (Gibson et al, 1982).
    2) SEIZURES
    a) Seizures occurred in dogs receiving 500 mg/kg/day (Gibson et al, 1982).

Hepatic

    3.9.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Hepatitis and jaundice have been reported but are rare.
    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - Hepatitis with jaundice was observed in one patient after 17 months of therapy. Symptoms resolved when the drug was discontinued (JEF Reynolds , 1990) Sahai & Velleneuve, 1996).

Genitourinary

    3.10.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Urinary retention is a rare event.
    3.10.2) CLINICAL EFFECTS
    A) RETENTION OF URINE
    1) WITH THERAPEUTIC USE
    a) Urinary retention has been reported but is rare (Seggev & Fink, 1994).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Rashes, pruritus, urticaria, and alopecia have been noted but are rare.
    3.14.2) CLINICAL EFFECTS
    A) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Alopecia was reported in one case; regrowth occurred when treatment was discontinued (JEF Reynolds , 1990).
    B) URTICARIA
    1) WITH THERAPEUTIC USE
    a) Rash, pruritus, and urticaria have been seen with therapeutic use (Anon, 1988).

Reproductive

    3.20.1) SUMMARY
    A) Terfenadine is not teratogenic in rats; teratogenicity was not noted in humans in a multicenter, prospective study.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) No teratogenicity was observed in rats given 63 and 125 times the daily human dose (Prod Info Seldane(R), 1990).
    2) In a multicenter, prospective controlled study of 118 women, pregnancy outcome after gestational exposure to terfenadine was determined. In women exposed during the first trimester (n=65), rates of major malformations did not differ from rates in the matched control group (no terfenadine exposure). Although birth weights of the newborns were significantly lower in the terfenadine exposed group, no differences were noted in rates of birth weight below 2500 g and birth weight below the 10th percentile for the 2 groups (Loebstein et al, 1999).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    TERFENADINEC
    Reference: Briggs et al, 1998
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Effects in humans during breast feeding are unknown. Rats given 63 and 125 times the daily human dose throughout pregnancy and lactation had decreased pup survival and weight gain. The carboxylic acid metabolite has been detected in human milk, thus the drug is not recommended for use in lactating women (Prod Info Seldane(R), terfenadine, 1998).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Due to one reported case of ventricular arrhythmias 15 hours after an ingestion of 3360 mg, the manufacturer recommends cardiac monitoring for 24 hours following overdose, however, 8 to 12 hours may be sufficient in smaller ingestions.
    B) A prolonged QT has been associated with ventricular fibrillation following overdose and in certain clinical situations such as drug interactions at therapeutic doses. Patients should then be monitored until their QT interval returns to normal.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) No specific lab work (CBC, electrolytes) is needed unless otherwise clinically indicated.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Due to one reported case of ventricular arrhythmia 15 hours after an ingestion of 3360 mg, the manufacturer recommends CARDIAC MONITORING for at least 24 hours following overdose (Prod Info, 1989), however 8 to 12 hours may be sufficient in smaller ingestions.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.2) HOME CRITERIA/ORAL
    A) Preliminary data in a series of 24 children who ingested 120 milligrams or less suggest that no treatment and monitoring at home may be safe for children aged 1 to 5 years, if no other drug with potential drug interaction with terfenadine has been ingested.
    1) Younger children or those with suspected ingestion of larger amounts should be referred to a health care facility.
    2) Consider referral for patients who cannot be followed by telephone or who develop signs or symptoms (Spiller et al, 1989).
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Due to one reported case of ventricular arrhythmia 15 hours after an ingestion of 3360 milligrams, the manufacturer recommends cardiac monitoring for at least 24 hours following overdose (Prod Info, 1989), however 8 to 12 hours may be sufficient for smaller ingestions.

Monitoring

    A) Due to one reported case of ventricular arrhythmias 15 hours after an ingestion of 3360 mg, the manufacturer recommends cardiac monitoring for 24 hours following overdose, however, 8 to 12 hours may be sufficient in smaller ingestions.
    B) A prolonged QT has been associated with ventricular fibrillation following overdose and in certain clinical situations such as drug interactions at therapeutic doses. Patients should then be monitored until their QT interval returns to normal.

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) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    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) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    4) CAUTION: If VENTRICULAR DYSRHYTHMIAS occur, decrease rate of administration.
    B) 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/INDICATIONS
    a) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    3) LIDOCAINE/DOSE
    a) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    1) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    b) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    4) LIDOCAINE/MAJOR ADVERSE REACTIONS
    a) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    5) LIDOCAINE/MONITORING PARAMETERS
    a) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    C) 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.
    D) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Abstracts

Case Reports

    A) ADULT
    1) The manufacturer has a report of one case of overdose in a 16-year-old female who ingested 25 tablets. She recovered uneventfully following gastric lavage (Prod Info, 1989).
    2) Ingestion of 3360 mg of terfenadine in combination with 7 grams of cephalexin and 1200 mg of ibuprofen resulted in torsade de pointes 15 hours postingestion. This progressed to ventricular fibrillation which responded to defibrillation and lidocaine (Prod Info, 1989).

Range Of Toxicity

Summary

    A) Terfenadine is no longer available in the United States.
    B) Single doses up to 600 mg in adults and up to 300 mg in children aged 1 to 5 years have produced no adverse effects. Ingestion of 1500 mg in an adult resulted in asymptomatic hypotension of short duration. Ingestion of 360 mg resulted in ventricular dysrhythmias.

Therapeutic Dose

    7.2.1) ADULT
    A) SUMMARY
    1) DRUG WITHDRAWAL: On January 13, 1997, the US Food and Drug Administration (FDA) announced it will withdraw approval for terfenadine in the United States due to the number of arrhythmias as a result of terfenadine drug interactions. In December of 1997 the US manufacturer of Seldane(R) announced it will voluntarily withdraw Seldane(R) and Seldane-D(R) from the marketplace (Anon, 1997). Terfenadine has also been withdrawn from the marketplace in France (Lindquist & Edwards, 1997).
    2) The following adult dosing is for historical purposes only. ADULT: 60 mg orally twice a day .

Maximum Tolerated Exposure

    A) ADULT
    1) Single therapeutic doses of up to 600 milligrams, and 200 milligrams three times daily have produced no adverse effects in clinical trials (Prod Info Seldane(R), terfenadine, 1998).
    2) Ingestion of 1500 milligrams in an adult resulted in asymptomatic hypotension (90/50 mmHg) which resolved without treatment (Prod Info Seldane(R), terfenadine, 1989).
    3) Terfenadine used at a dose of 360 milligrams daily caused prolongation of the QT interval resulting in torsades de pointes and syncope in a 45-year-old woman (MacConnell & Stanners, 1991).
    4) A single oral dose as low as 360 milligrams has resulted in ventricular dysrhythmias. Overdoses of 360 milligrams or more have been reported to result in ventricular dysrhythmias, including torsades de pointes and QTc prolongation, and occur more frequently at doses exceeding 600 milligrams. QTc prolongation of up to 30% has been reported with a dosage of 300 milligrams twice a day. Seizures and syncope have also been reported at these doses (Prod Info Seldane(R), terfenadine, 1998).
    5) Two days after taking terfenadine 60 milligrams twice a day for one day, a 59-year-old male was admitted to the ED with shortness of breath and dizziness. A cardiac monitor revealed 3 episodes of torsades de pointes. Resolution of the dysrhythmia was reported following 2 grams of magnesium (June & Nasr, 1997).
    B) PEDIATRIC
    1) In a retrospective chart review of 28 cases of accidental ingestion of terfenadine by children aged 1 to 5, 24 cases had a history of ingestion of 60 to 120 milligrams and remained asymptomatic, as assessed by home follow-up.
    a) Three children who ingested 120, 180, and 300 milligrams also remained asymptomatic. A 2-year-old child who ingested 900 milligrams received activated charcoal and sorbitol and was discharged from the hospital 6 hours postingestion (Spiller et al, 1989).
    2) Among 39 children, aged 15 years or younger, who ingested 600 milligrams or more, only one child developed QT prolongation, which resolved spontaneously (Personal Communication, 1990).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) A plasma terfenadine concentration drawn 12 hours after the last dose was 471 nanograms/milliliter (metabolite 1 only) in a 45-year-old woman who developed torsades de pointes associated with a terfenadine daily dose of 360 milligrams (MacConnell & Stanners, 1991).
    b) An association between increased levels of unchanged terfenadine and prolongation of the corrected QT interval has been suggested (unchanged drug is normally undetectable in the plasma) (Mathews et al, 1991).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (ORAL)MOUSE:
    a) 5 g/kg (RTECS, 2000)
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) >4500 mg/kg (RTECS, 2000)
    3) LD50- (ORAL)RAT:
    a) 5 g/kg (RTECS, 2000)
    4) LD50- (SUBCUTANEOUS)RAT:
    a) >1250 mg/kg (RTECS, 2000)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Terfenadine is equipotent to quinidine to block the delayed rectifier potassium current (IK). The duration of the QT interval is primarily controlled by IK. There is a uniform association between drugs that block the delayed rectifier and their clinical propensity to induce torsade de pointes (Woosley, 1993).
    B) Terfenadine binds to peripheral H1-receptors and only weakly to muscarinic, alpha and beta-adrenergic receptors. Once bound to the receptor the antagonism is noncompetitive and very slowly dissociates.
    1) Central nervous system effects were only evident in mice when high doses (10 mg/kg) were used.
    C) The apparent explanation for its non-sedating properties is its low ability to cross the blood-brain barrier. However, the relative influence of lipid solubility, molecular weight, electrostatic charge, and serum protein binding is not known (Woodward, 1988).
    D) Other studies suggest that terfenadine binds preferentially to peripheral rather than central histamine (H1) receptors (JEF Reynolds , 1990).

Toxicologic Mechanism

    A) Terfenadine is equipotent to quinidine in blocking the delayed rectifier potassium current (IK). The duration of the QT interval is primarily controlled by IK. There is a uniform association between drugs that block the delayed rectifier and their clinical propensity to induce torsade de pointes (Lindquist & Edwards, 1997) Woosley, 1993).

Physicochemical

Molecular Weight

    A) 471.69 (Budavari, 1989)

Animal Toxicology

Clinical Effects

    11.1.3) CANINE/DOG
    A) Poisoning (1800 mg) in a dog has resulted in hyperthermia (rectal temperature of 41.4 degrees C), tachycardia with PVCs, agitation, vomiting, mydriasis, weakness and ataxia (Otto & Greentree, 1994).
    1) Vomiting is a prevalent symptom, usually occurring about 4 hours after ingestion.
    2) Lethargy has been commonly reported in canine terfenadine poisonings.
    3) Other less commonly reported signs/symptoms include: disorientation, shock, polydipsia, anorexia, polyuria, hyperpnea, salivation, hyperesthesia, and extensor rigidity.
    4) CNS excitation in a dog may lead to seizures, with signs of hallucinations, ataxia and incoordination, as well as fixed and dilated pupils.
    B) Weight loss, emesis and central nervous system effects were noted in some dogs receiving 80 milligrams/kilogram (Gibson et al, 1982). Tremors, ataxia, and seizures were seen at 100 milligrams/kilogram/day or more. Emesis was a consistent effect at 150 milligrams/kilogram/day.

Treatment

    11.2.2) LIFE SUPPORT
    A) GENERAL
    1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.
    11.2.4) DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) GENERAL TREATMENT
    a) Minimize absorption (canine) with gastric lavage, activated charcoal, and cathartics. Spontaneous vomiting may occur. Repeated administration of charcoal and cathartics may be indicated, due to a potential for enterohepatic cycling. Use of diuresis and cathartics may maximize excretion (Otto & Greentree, 1994).
    11.2.5) TREATMENT
    A) DOGS/CATS
    1) Maintain vital functions: as 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 anesthesia or heavy sedation. Administer pentobarbital to DOGS & CATS at a dose of 3 to 15 milligrams/kilogram intravenously slowly to effect. May need to repeat in 4 to 8 hours. Be sure to protect the airway.

Continuing Care

    11.4.2) DECONTAMINATION
    11.4.2.2) GASTRIC DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) GENERAL TREATMENT
    a) Minimize absorption (canine) with gastric lavage, activated charcoal, and cathartics. Spontaneous vomiting may occur. Repeated administration of charcoal and cathartics may be indicated, due to a potential for enterohepatic cycling. Use of diuresis and cathartics may maximize excretion (Otto & Greentree, 1994).
    11.4.3) TREATMENT
    11.4.3.4) PHARMACOLOGIC INTERVENTION
    A) GENERAL TREATMENT
    1) No antidote is available. Treatment is supportive. Monitor cardiac function and treat arrhythmias as needed. Hyperthermia may be treated with cooling blankets or alcohol bath. Diazepam may be administered to treat agitation. Treat seizures as above.
    11.4.3.5) SUPPORTIVE CARE
    A) GENERAL
    1) Ongoing treatment is symptomatic and supportive.

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