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TERODILINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Terodiline is a unique agent for the treatment of urge incontinence as it possesses combined anticholinergic and calcium antagonist properties, each of which has been demonstrated clinically useful in these patients.
    B) An oral preparation of terodiline was investigational in the USA (Forest), however clinical trials have been put on hold at the request of the FDA. In 1991, Kabi Pharmacia discontinued sales of terodiline (Micturin(R)) worldwide due to reports of polymorphic ventricular tachycardia.

Specific Substances

    1) 2-N-tert-butyl-4,4-diphenyl butylamine
    2) N-tert-butyl-1-methyl-3,3-diphenylpropylamine

Available Forms Sources

    A) FORMS
    1) An oral preparation of terodiline was investigational in the USA (Forest), however clinical trials have been put on hold at the request of the FDA. In 1991, Kabi Pharmacia discontinued sales of terodiline (Micturin(R)) worldwide due to reports of polymorphic ventricular tachycardia.
    B) USES
    1) Terodiline was undergoing evaluation in the treatment of patients with urinary incontinence, but was withdrawn during clinical trials.

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) Few overdoses have been reported. Symptoms should be primarily anticholinergic: ventricular tachycardia, confusion, blurred vision, and tremor are possible.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Tachycardia may be present. Mild hypertension is seen with therapy and may be present in overdose.
    0.2.4) HEENT
    A) WITH THERAPEUTIC USE
    1) Blurred vision occurs in about 20% of the cases. Mydriasis may be present.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Tachycardia may be seen. Ventricular tachycardia has been seen with therapy.
    2) Bradycardia is occasionally seen early in therapy.
    3) Mild cases of hypertension have been reported.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Tremors occur with some frequency with therapy. Insomnia, restlessness, irritability, confusion, and paresthesias may also be seen.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Dry mouth occurs frequently in therapy. Abdominal pain, nausea, and both diarrhea and constipation have also been reported.
    B) WITH POISONING/EXPOSURE
    1) Vomiting has been seen in overdose.
    0.2.10) GENITOURINARY
    A) WITH THERAPEUTIC USE
    1) Urinary retention is seen in therapeutic use. There is some evidence that the drug may be nephrotoxic.
    B) WITH POISONING/EXPOSURE
    1) Urinary retention may occur, as it is seen in therapeutic use. There is some evidence that the drug may be nephrotoxic; renal function should be monitored in overdose.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Rashes have been seen with therapeutic use.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Laboratory Monitoring

    A) Monitor kidney function tests.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression and 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) 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) Minimum lethal human exposure is unknown.
    B) In one apparent fatality, serum and urine levels were greater than 10 mg/liter.

Clinical Effects

Summary Of Exposure

    A) WITH POISONING/EXPOSURE
    1) Few overdoses have been reported. Symptoms should be primarily anticholinergic: ventricular tachycardia, confusion, blurred vision, and tremor are possible.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Tachycardia may be present. Mild hypertension is seen with therapy and may be present in overdose.
    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) Mild hypertension has been seen with therapy (Fischer-Rasmussen & The Multicentre Study Group, 1984; Klarskov et al, 1986).
    B) WITH POISONING/EXPOSURE
    1) Monitor for hypertension during overdose; mild hypertension has been seen with therapy.
    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) Tachycardia may be occur with terodiline therapy (Klarskov et al, 1986) Anderson et al, 1988).

Heent

    3.4.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Blurred vision occurs in about 20% of the cases. Mydriasis may be present.
    3.4.3) EYES
    A) BLURRED VISION
    1) WITH THERAPEUTIC USE
    a) Blurred vision is a relatively common side effect of terodiline, occurring in about 15% to 28% of cases. It is secondary to the anticholinergic properties of the drug (Tapp et al, 1989; Petersen & Jakobsen, 1987; Fischer-Rasmussen & The Multicentre Study Group, 1984; Peters & The Multicentre Study Group, 1984).
    B) MYDRIASIS
    1) WITH THERAPEUTIC USE
    a) Mydriasis may occur.

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Tachycardia may be seen. Ventricular tachycardia has been seen with therapy.
    2) Bradycardia is occasionally seen early in therapy.
    3) Mild cases of hypertension have been reported.
    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia has been reported in some patients treated with terodiline (Andersen et al, 1988; Klarskov et al, 1986). An incidence of 4.2% has been reported (Fischer-Rasmussen & The Multicentre Study Group, 1984).
    b) Terodiline's association with polymorphic VENTRICULAR TACHYCARDIA resulted in the drug's withdrawal in Germany and Austria in August, 1991. As a result of Swedish regulatory action against the drug, Kabi Pharmacia has temporarily discontinued sales of terodiline worldwide (p 53).
    B) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) Transient bradycardia has also been described (Hallen et al, 1989; Petersen & Jakobsen, 1987).
    C) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) In some studies, mild increases in blood pressure have been reported with therapeutic use (Klarskov et al, 1986; Fischer-Rasmussen & The Multicentre Study Group, 1984).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Tremors occur with some frequency with therapy. Insomnia, restlessness, irritability, confusion, and paresthesias may also be seen.
    3.7.2) CLINICAL EFFECTS
    A) TREMOR
    1) WITH THERAPEUTIC USE
    a) Tremor has been described in 10% to 15% of terodiline treated patients (Tapp et al, 1989; Andersen et al, 1988; Peters & The Multicentre Study Group, 1984).
    B) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Other adverse central nervous system effects have included headache, insomnia, paresthesias, restless legs syndrome, confusion, and tiredness (Hallen et al, 1989; Klarskov et al, 1986; Sole & Arkell, 1984). The incidence of these adverse effects is undetermined.

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Dry mouth occurs frequently in therapy. Abdominal pain, nausea, and both diarrhea and constipation have also been reported.
    B) WITH POISONING/EXPOSURE
    1) Vomiting has been seen in overdose.
    3.8.2) CLINICAL EFFECTS
    A) APTYALISM
    1) WITH THERAPEUTIC USE
    a) Dry mouth occurs in 25% to 50% of patients treated and is secondary to the anticholinergic effects of the drug (Tapp et al, 1989; Andersen et al, 1988; Petersen & Jakobsen, 1987).
    B) GASTROENTERITIS
    1) WITH THERAPEUTIC USE
    a) Nausea, indigestion, constipation, abdominal pain, and diarrhea have been reported with terodiline therapy (Tapp et al, 1989; Hallen et al, 1989; Andersen et al, 1988).
    C) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation was observed in 23% of patients treated in one study (Tapp et al, 1989).
    D) VOMITING
    1) WITH POISONING/EXPOSURE
    a) Vomiting may be seen in overdose (Cattini et al, 1989).

Genitourinary

    3.10.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Urinary retention is seen in therapeutic use. There is some evidence that the drug may be nephrotoxic.
    B) WITH POISONING/EXPOSURE
    1) Urinary retention may occur, as it is seen in therapeutic use. There is some evidence that the drug may be nephrotoxic; renal function should be monitored in overdose.
    3.10.2) CLINICAL EFFECTS
    A) RETENTION OF URINE
    1) WITH THERAPEUTIC USE
    a) Urinary retention was described in 24% of patients with detrusor hyperreflexia receiving terodiline 25 mg twice daily (Petersen & Jakobsen, 1987).
    B) SERUM CREATININE RAISED
    1) WITH THERAPEUTIC USE
    a) Mild elevations in serum creatinine have been reported during terodiline administration (Klarskov et al, 1986; Fischer-Rasmussen & The Multicentre Study Group, 1984).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Rashes have been seen with therapeutic use.
    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Skin rash has been reported rarely during terodiline administration (Peters & The Multicentre Study Group, 1984).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor kidney function tests.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Mild elevations in serum creatinine have been reported during terodiline administration (Klarskov et al, 1986; Fischer-Rasmussen & The Multicentre Study Group, 1984).
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Heart rate, blood pressure, renal function tests, and body weight should be monitored periodically during terodiline therapy.

Methods

    A) CHROMATOGRAPHY
    1) Terodiline may be detected using thin-layer and gas-liquid chromatography and identified by gas chromatography/mass spectrometry (Cattini et al, 1989).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Monitor kidney function tests.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT RECOMMENDED -
    1) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression and seizures.
    B) 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) SUPPORT
    1) Symptoms are likely to be anticholinergic in nature. Treatment will be primarily decontamination and supportive.
    2) Although physostigmine will reverse anticholinergic symptoms, it should only be used to fight life-threatening seizures or cardiac arrhythmias.
    3) PHYSOSTIGMINE/INDICATIONS
    a) Physostigmine is indicated to reverse the CNS effects caused by clinical or toxic dosages of agents capable of producing anticholinergic syndrome; however, long lasting reversal of anticholinergic signs and symptoms is generally not achieved because of the relatively short duration of action of physostigmine (45 to 60 minutes) (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008). It is most often used diagnostically to distinguish anticholinergic delirium from other causes of altered mental status (Frascogna, 2007; Shannon, 1998).
    b) Physostigmine should not be used in patients with suspected tricyclic antidepressant overdose, or an ECG suggestive of tricyclic antidepressant overdose (eg, QRS widening). In the setting of tricyclic antidepressant overdose, use of physostigmine has precipitated seizures and intractable cardiac arrest (Stewart, 1979; Newton, 1975; Pentel & Peterson, 1980; Frascogna, 2007).
    4) DOSE
    a) ADULT: BOLUS: 2 mg IV at slow controlled rate, no more than 1 mg/min. May repeat doses at intervals of 10 to 30 min, if severe symptoms recur (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008). INFUSION: For patients with prolonged anticholinergic delirium, a continuous infusion of physostigmine may be considered. Starting dose is 2 mg/hr, titrate to effect (Eyer et al, 2008)
    b) CHILD: 0.02 mg/kg by slow IV injection, at a rate no more than 0.5 mg/minute. Repeat dosage at 5 to 10 minute intervals as long as the toxic effect persists and there is no sign of cholinergic effects. MAXIMUM DOSAGE: 2 mg total (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
    c) AVAILABILITY: Physostigmine salicylate is available in 2 mL ampules, each mL containing 1 mg of physostigmine salicylate in a vehicle containing sodium metabisulfite 0.1%, benzyl alcohol 2%, and water (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
    5) CAUTIONS
    a) Relative contraindications to the use of physostigmine are asthma, gangrene, diabetes, cardiovascular disease, intestinal or urogenital tract mechanical obstruction, peripheral vascular disease, cardiac conduction defects, atrioventricular block, and in patients receiving choline esters and depolarizing neuromuscular blocking agents (decamethonium, succinylcholine). It may cause anaphylactic symptoms and life-threatening or less severe asthmatic episodes in patients with sulfite sensitivity (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
    b) Too rapid IV administration of physostigmine has resulted in bradycardia, hypersalivation leading to respiratory difficulties, and possible seizures (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
    6) ATROPINE FOR PHYSOSTIGMINE TOXICITY
    a) Atropine should be available to reverse life-threatening physostigmine-induced, toxic cholinergic effects (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008; Frascogna, 2007). Atropine may be given at half the dose of previously given physostigmine dose (Daunderer, 1980).
    B) 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).

Enhanced Elimination

    A) SUMMARY
    1) No studies have addressed the utilization of extracorporeal elimination techniques in poisoning with this agent.

Range Of Toxicity

Summary

    A) Minimum lethal human exposure is unknown.
    B) In one apparent fatality, serum and urine levels were greater than 10 mg/liter.

Therapeutic Dose

    7.2.1) ADULT
    A) DISEASE STATE
    1) URGE INCONTINENCE -
    a) Effective doses in the treatment of motor or sensory urge incontinence have been 37.5 to 50 milligrams orally daily (Tapp et al, 1989; Andersen et al, 1988; Klarskov et al, 1986; Ulmsten et al, 1985).
    1) These doses have generally been administered in 2 divided doses (12.5 milligrams in the morning and 25 milligrams at night).
    2) Doses of 75 milligrams or 25 milligrams daily have been used in some patients with only mild or no adverse effects (Tapp et al, 1989).
    b) THERAPY DURATION - 3 to 4 weeks, sometimes as long as 3 years (Ulmsten et al, 1985; Fischer-Rasmussen & The Multicentre Study Group, 1984)
    c) ONCE DAILY ADMINISTRATION - Should be feasible due to the long half-life (Karlen et al, 1982).
    d) OPTIMAL DOSES - Have not been adequately established.
    e) WITHDRAWAL SCHEDULE - When switching patients to an alternate therapy, there should be a washout period of 2 weeks because of potential additive anticholinergic effects (Anon, 1991a).
    7.2.2) PEDIATRIC
    A) GENERAL
    1) Initial doses of 1 tablet (12.5 milligrams) orally daily for 1 week, followed by 2 tablets (25 milligrams) daily for 3 further weeks, was reported effective against urgency or urge INCONTINENCE in 6- to 14-year-old children (Hellstrom et al, 1989).
    2) The authors suggest that higher doses will be needed in some children.

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) The minimum lethal human dose to this agent has not been delineated.

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) The maximum tolerated human exposure to this agent has not been delineated.

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) THERAPEUTIC (CORRELATIONS WITH EFFECT) - There has been no significant correlation between serum concentrations of terodiline and clinical efficacy in incontinence (Hallen et al, 1988; Klarskov et al, 1986).
    b) STEADY STATE - Serum concentrations of 200 to 700 micrograms/liter are achieved at steady-state with oral doses of 37.5 milligrams daily (Andersson, 1984).
    c) PEAK SERUM LEVELS -
    1) Following oral administration of 12.5 milligrams terodiline to 6 healthy volunteers, peak serum levels of 17 to 61 micrograms/liter (mean, 32 micrograms/liter) were observed 4 hours post-administration. In 2 subjects, doses of 25 milligrams produced peak levels of approximately 100 micrograms/liter at 4 to 6 hours (Karlen et al, 1982).
    2) Peak serum levels following single oral doses and at steady-state are higher in elderly patients (Hallen et al, 1989; Hallen et al, 1988).
    3) In elderly patients with incontinence (mean age, 82 years), mean peak serum levels of 110 micrograms/liter were observed 4 hours following a single oral dose of terodiline 25 milligrams. Following oral doses of 12.5 milligrams orally twice daily, mean steady-state serum levels of 642 micrograms/liter were achieved in 2 to 5 weeks (Hallen et al, 1988).
    d) TOXIC -
    1) In one fatal overdose case, blood and urine levels were greater than 10 milligrams per liter. The patient had aspirated vomitus prior to death, so it is unknown if this level would have been fatal otherwise (Cattini et al, 1989).
    2) In available studies, no correlation has existed between adverse effects and serum levels of terodiline (Klarskov et al, 1986; Tapp et al, 1989).
    3) Some investigators suggest an increased incidence of adverse effects (anticholinergic and vasodilatory) can be expected with serum concentrations above 600 micrograms/liter (Hallen et al, 1989; Andersson, 1984).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)RAT:
    1) 465 mg /kg ((RTECS, 2000))
    B) LD50- (SUBCUTANEOUS)RAT:
    1) 370 mg/kg ((RTECS, 2000))
    C) LD50- (ORAL)MOUSE:
    1) 330 mg/kg ((RTECS, 2000))
    D) LD50- (SUBCUTANEOUS)MOUSE:
    1) 170 mg/kg ((RTECS, 2000))

Pharmacology Toxicology

Pharmacologic Mechanism

    A) ANTICHOLINERGIC/CALCIUM ANTAGONIST - In vitro studies have confirmed the anticholinergic and calcium antagonist actions of terodiline in various tissues (Andersson, 1984; Husted et al, 1980; Ostergaard et al, 1980).
    1) These effects generally occur within the same concentration range, however anticholinergic effects predominate at low concentrations with calcium antagonist activity being more prominent at higher concentrations (Andersson, 1988; Andersson, 1984).
    2) The anticholinergic potency of terodiline is less than that of propantheline, oxybutynin, emepronium, and dicyclomine; nifedipine is significantly more potent than terodiline as a calcium channel blocking agent (Anderson, 1984).
    3) Synergistic effects with combination calcium antagonist/anticholinergic agents have been observed in bladders of patients with detrusor instability (Sjogren et al, 1982).
    a) It was speculated that combining these pharmacologic effects may enhance therapeutic efficacy in incontinence as well as reduce adverse effects occurring with effective doses of anticholinergic and calcium antagonists agents (Andersson, 1984; Andersson & Ulmsten, 1980).
    B) LOCAL ANESTHETIC - Terodiline possesses local anesthetic actions (Andersson, 1984; Lecerof & Malmborg, 1969), being as active as lidocaine on a molar basis in some experimental models (Andersson, 1984).
    C) ANTIHISTAMINE - The drug also exhibits antihistaminic effects, although the clinical relevance of this effect is controversial (Andersson, 1984).
    D) BRONCHODILATOR - A bronchodilating effect has also been reported (Castenfors et al, 1975).
    E) VASODILATING EFFECTS -
    1) Increases in coronary blood flow and a reduction in systemic vascular resistance following terodiline administration have been observed in animal studies; these vasodilating effects were attributed to calcium channel blocking effects of the drug (Andersson, 1984).
    2) The coronary dilating properties of terodiline led to its initial use as an antianginal agent (Wibell, 1968).
    3) Digitalis-like positive inotropic effects have been reported with terodiline in patients with coronary artery disease (Lecerof & Malmborg, 1969); these effects may be secondary to peripheral vasodilation, resulting in reflex cardiac stimulation (Andersson, 1984).

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