Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

NOMIFENSINE

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Nomifensine is a short-acting tetrahydroisoquinoline antidepressant, structurally distinct from other antidepressants, which inhibits the pre-synaptic uptake of dopamine and noradrenaline.

Specific Substances

    1) 8-Amino-2-methyl-4-phenyl-1,2,3,4-
    2) tetrahydroiso-quinoline maleate
    3) HOE 984
    4) CAS 24526-64-5
    5) CAS 32795-47-4 (maleate)

Available Forms Sources

    A) FORMS
    1) Nomifensine was withdrawn from the market in 1986 because of an unusually high incidence of hypersensitivity reactions (notably immune complex hemolytic anemia) associated with the drug, both with therapeutic use and after acute overdose (Coccaro & Siever, 1985; Habibi et al, 1981).
    2) Nomifensine was marketed as 25 and 50 mg capsules under the trade names Merital(R), Alival(R), Anametrin(R), Hostalival(R), Merival(R) and Psicronizer(R).
    B) USES
    1) Nomifensine is effective in the treatment of endogenous and reactive depression. It is of doubtful usefulness in distinguishing tumoral from non-tumoral (idiopathic) hyperprolactinemia.

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 THERAPEUTIC USE
    1) Nomifensine is a short-acting tetrahydroisoquinoline antidepressant, structurally distinct from cyclic antidepressants and MAO inhibitors. Sinus tachycardia and drowsiness are the primary toxic effects. Symptoms usually resolve within 24 hours.
    B) WITH POISONING/EXPOSURE
    1) Nomifensine is a short-acting tetrahydroisoquinoline antidepressant, structurally distinct from cyclic antidepressants and MAO inhibitors. Sinus tachycardia and drowsiness are the primary toxic effects. Symptoms usually resolve within 24 hours.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Sinus tachycardia is the most consistent cardiovascular adverse effect.
    B) WITH POISONING/EXPOSURE
    1) Sinus tachycardia is common in overdose.
    2) Transient hypertension may be noted.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) Drowsiness is common, and rarely progresses to coma. Seizures may occur, but are uncommon.
    0.2.8) GASTROINTESTINAL
    A) WITH POISONING/EXPOSURE
    1) Nausea, vomiting, or abdominal pain may be noted.
    0.2.9) HEPATIC
    A) WITH THERAPEUTIC USE
    1) Granulomatous hepatitis and elevated hepatic enzymes have been reported.
    0.2.10) GENITOURINARY
    A) WITH THERAPEUTIC USE
    1) Immune intravascular hemolysis and acute tubular necrosis are uncommon hypersensitivity reactions; each of the two reactions has been noted following both therapeutic and toxic doses.
    B) WITH POISONING/EXPOSURE
    1) Immune intravascular hemolysis and acute tubular necrosis are uncommon hypersensitivity reactions; each of the two reactions has been noted following both therapeutic and toxic doses.
    0.2.18) PSYCHIATRIC
    A) WITH THERAPEUTIC USE
    1) Paranoid symptoms have been noted following therapeutic doses.

Laboratory Monitoring

    A) Blood level determination may be erratic due to difficulty in assay method and inability to distinguish between free and conjugated nomifensine. Plasma should be immediately deep frozen if accurate free nomifensine levels are desired.

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) 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.
    D) REFRACTORY SEIZURES -
    1) In seizures or myoclonus accompanied by signs and symptoms of anticholinergic toxicity, physostigmine may be indicated.
    2) PHYSOSTIGMINE
    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). It is most often used diagnostically to distinguish anticholinergic delirium from other causes of altered mental status. CAUTION: If tricyclic antidepressants are coingested, physostigmine may precipitate seizures and dysrhythmias.
    b) ADULT: 2 mg IV at a slow controlled rate, no more than 1 mg/min. May repeat doses at intervals of 10 to 30 min if severe symptoms recur. For patients with prolonged anticholinergic delirium consider a continuous infusion, start at 2 mg/hr and titrate to effect. CHILD: 0.02 mg/kg by slow IV injection, at a rate no more than 0.5 mg/minute. Repeat dosage at 5 to 10 minute intervals as long as the toxic effect persists and there is no sign of cholinergic effects. MAXIMUM DOSAGE: 2 mg total.
    3) It is unknown if this non-cyclic antidepressant has the same effect.
    E) SUPRAVENTRICULAR ARRHYTHMIAS - Usually do not require treatment unless heart rate exceeds 160 beats/min and/or signs of hemodynamic instability develop.
    F) CONDUCTION DEFECTS - Serious conduction defects (prolonged PR interval, prolonged QT interval, widened QRS complex) may be managed with phenytoin: LOADING DOSE (ADULT and CHILD) - administer 15 mg/kg up to 1.0 gram IV not to exceed a rate of 0.5 mg/kg/minute.
    1) Dysrhythmias and QRS widening may respond to alkalinization of the serum using sodium bicarbonate boluses. A reasonable starting dose is 1 to 2 milliequivalents/kilogram repeated as needed to achieve a serum pH of 7.45-7.55. Monitor blood gases and ECG frequently.
    G) MONITOR VITAL SIGNS including EKG for 24 hours in symptomatic patients. Nomifensine has a short half-life and cardiovascular/neurological symptoms generally resolve within 24 hours.

Range Of Toxicity

    A) Doses of 1 gram have been associated with drowsiness and tachycardia in adults. Higher doses (more than 2 grams) have produced seizures, coma, and conduction defects.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) Nomifensine is a short-acting tetrahydroisoquinoline antidepressant, structurally distinct from cyclic antidepressants and MAO inhibitors. Sinus tachycardia and drowsiness are the primary toxic effects. Symptoms usually resolve within 24 hours.
    B) WITH POISONING/EXPOSURE
    1) Nomifensine is a short-acting tetrahydroisoquinoline antidepressant, structurally distinct from cyclic antidepressants and MAO inhibitors. Sinus tachycardia and drowsiness are the primary toxic effects. Symptoms usually resolve within 24 hours.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) FEVER may occur.

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Sinus tachycardia is the most consistent cardiovascular adverse effect.
    B) WITH POISONING/EXPOSURE
    1) Sinus tachycardia is common in overdose.
    2) Transient hypertension may be noted.
    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) Sinus tachycardia is the most consistent cardiovascular effect. In patients ingesting therapeutic amounts (75 mg/day), 70% demonstrated increased heart rate (Bethge et al, 1982).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT - Tachycardia (140 beats/min) was reported in a 28-year-old female following acute ingestion of 1.5 grams (Montgomery et al, 1978). In a series of 12 pure nomifensine overdoses (mean dose 1.15 grams), one patient developed tachycardia (Dawling et al, 1979).
    B) VENTRICULAR ARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) Doses as large as 3.5 grams have been ingested without development of ventricular dysrhythmias or conduction defects (Vohra et al, 1978).
    C) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - Poussel et al (1983) reported a case of a 43-year-old female who ingested 2.25 grams and developed bradycardia, junctional rhythm, bigeminy, and conduction defects within 1 hour of ingestion. This resolved spontaneously without treatment over the next 24 hours.
    D) ECTOPIC BEATS
    1) WITH POISONING/EXPOSURE
    a) Ventricular extrasystoles were reported in 1 of 35 cases of pure nomifensine ingestion (Garnier et al, 1982).
    E) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Transient hypertension may occur following an overdose (Dawling et al, 1979).

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Drowsiness is common, and rarely progresses to coma. Seizures may occur, but are uncommon.
    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) WITH POISONING/EXPOSURE
    a) Drowsiness is common, occurring in 13 of 28 pure nomifensine overdoses in one series; coma was reported in 1 of 28 (Ali & Crome, 1984).
    B) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Seizures may occur, but are not common. No seizures occurred in a series of 28 pure nomifensine overdoses (Ali & Crome, 1984). One patient is described who developed coma and generalized seizures following ingestion of 2.25 grams (Poussel et al, 1983).
    C) TREMOR
    1) WITH POISONING/EXPOSURE
    a) Tremor or slurred speech may occur following an overdose (Baselt, 2000).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Nausea, vomiting, or abdominal pain may be noted.
    3.8.2) CLINICAL EFFECTS
    A) GASTRITIS
    1) WITH POISONING/EXPOSURE
    a) Nausea, vomiting, or abdominal pain may occur after an overdose (Baselt, 2000).

Hepatic

    3.9.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Granulomatous hepatitis and elevated hepatic enzymes have been reported.
    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Abnormal liver function tests have been noted with chronic therapeutic doses.
    B) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) CASE SERIES - Granulomatous hepatitis was described in 4 patients after 4 to 6 weeks of nomifensine treatment. All abnormalities disappeared within 6 to 10 weeks after discontinuing the drug (Kummer et al, 1985).

Genitourinary

    3.10.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Immune intravascular hemolysis and acute tubular necrosis are uncommon hypersensitivity reactions; each of the two reactions has been noted following both therapeutic and toxic doses.
    B) WITH POISONING/EXPOSURE
    1) Immune intravascular hemolysis and acute tubular necrosis are uncommon hypersensitivity reactions; each of the two reactions has been noted following both therapeutic and toxic doses.
    3.10.2) CLINICAL EFFECTS
    A) CRUSH SYNDROME
    1) WITH THERAPEUTIC USE
    a) Intravascular hemolysis and acute tubular necrosis have been seen with therapeutic doses (Habibi et al, 1981).
    2) WITH POISONING/EXPOSURE
    a) Intravascular hemolysis and acute tubular necrosis have been seen with toxic doses (Habibi et al, 1981).
    B) RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) Renal failure has been reported following therapeutic use of nomifensine (Baselt, 2000; JEF Reynolds , 2000).
    2) WITH POISONING/EXPOSURE
    a) Renal failure has been reported following overdoses of nomifensine (Baselt, 2000; JEF Reynolds , 2000).
    b) CASE REPORT - Oliguria, proteinuria, and hemoglobinuria were noted 2 days after acute overdose of 2 grams in a 25-year-old female. Anuria ensued and persisted for 6 days (Prescott et al, 1980).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMOLYSIS
    1) WITH THERAPEUTIC USE
    a) Acute, immune intravascular hemolysis has been described following intermittent, therapeutic dosing (Habibi et al, 1981; Coccaro & Siever, 1985; Fulton et al, 1986; Bloomfield & Wilson, 1986).
    2) WITH POISONING/EXPOSURE
    a) Acute, immune intravascular hemolysis has been described following overdose (Habibi et al, 1981; Coccaro & Siever, 1985; Fulton et al, 1986; Bloomfield & Wilson, 1986).
    B) BLOOD IN URINE
    1) WITH POISONING/EXPOSURE
    a) Symptoms of pain, oliguria, and hematuria occurred 2 days following overdose; thrombocytopenia was noted after 3 days (Prescott et al, 1980).
    C) DISSEMINATED INTRAVASCULAR COAGULATION
    1) WITH THERAPEUTIC USE
    a) Disseminated intravascular coagulopathy has been noted following therapeutic dosing (Lylloff et al, 1982).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Fever, alone or in association with rash or joint pain, has been described following chronic therapeutic doses (Garcia-Morteo, 1983).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Blood level determination may be erratic due to difficulty in assay method and inability to distinguish between free and conjugated nomifensine. Plasma should be immediately deep frozen if accurate free nomifensine levels are desired.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Blood level determination may be erratic due to difficulty in assay method and inability to distinguish between free and conjugated nomifensine. Plasma should be immediately deep frozen if accurate free nomifensine levels are desired.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT RECOMMENDED -
    1) Emesis is not recommended due to potential CNS depression or 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) 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).
    B) TACHYARRHYTHMIA
    1) The vast majority of patients who develop supraventricular tachycardia do not need treatment aimed at slowing the heart rate.
    a) Supraventricular tachyarrhythmias may require treatment if the rate exceeds 160 beats per minute and/or the patient demonstrates signs and symptoms of hemodynamic instability.
    2) In those patients demonstrating life-threatening hemodynamic instability associated with tachycardia physostigmine may be considered.
    a) PHYSOSTIGMINE/INDICATIONS
    1) Physostigmine is indicated to reverse the CNS effects caused by clinical or toxic dosages of agents capable of producing anticholinergic syndrome; however, long lasting reversal of anticholinergic signs and symptoms is generally not achieved because of the relatively short duration of action of physostigmine (45 to 60 minutes) (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).
    2) 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).
    b) DOSE
    1) 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)
    2) 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).
    3) 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).
    c) CAUTIONS
    1) 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).
    2) 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).
    d) ATROPINE FOR PHYSOSTIGMINE TOXICITY
    1) 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).
    C) WIDE QRS COMPLEX
    1) SODIUM BICARBONATE
    a) Dysrhythmias and QRS widening may respond to alkalinization of the serum using sodium bicarbonate boluses. A reasonable starting dose is 1 to 2 milliequivalents/kilogram repeated as needed to achieve a serum pH of 7.45-7.55. Monitor blood gases and ECG frequently.
    D) MONITORING OF PATIENT
    1) Monitor vital signs including EKG for 24 hours in symptomatic patients. Nomifensine has a short half-life and cardiovascular/neurological symptoms generally resolve within 24 hours.
    2) Delayed immune hemolysis and renal failure may occur rarely within 2 to 3 days following overdose.
    E) HEMOLYSIS
    1) Furosemide-induced diuresis, blood transfusions, and corticosteroids have been used successfully in anemic/oliguric patients. Hemodialysis may be required in the event of renal failure.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Nomifensine does not appear to be removed by hemodialysis. Plasma concentrations were unchanged after 3 hours of dialysis in 3 patients with renal failure (Ringoir et al, 1977).

Abstracts

Case Reports

    A) ADULT
    1) ORAL - Montgomery (1978) reported that a 28-year-old female patient ingested 1.5 grams nomifensine in a suicide attempt. The patient remained conscious; pulse, blood pressure, and respiration were normal. There were no abnormal neurological signs.
    a) The patient remained normal over the next 24 to 48 hours and recovered uneventfully.
    2) ORAL - Poussel et al (1983) reported cardiotoxicity (bradycardia, junctional rhythm, bigemini, and conduction defects) within 1 hour of ingestion of 2.25 grams in a 43-year-old female. Coma and seizures were also present.
    a) Cardiovascular signs resolved without treatment over the next 24 hours and neurological symptoms within 48 hours.

Range Of Toxicity

Summary

    A) Doses of 1 gram have been associated with drowsiness and tachycardia in adults. Higher doses (more than 2 grams) have produced seizures, coma, and conduction defects.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) 50 to 200 milligrams daily (JEF Reynolds , 2000). Nomifensine was withdrawn from the world market in 1996.
    7.2.2) PEDIATRIC
    A) GENERAL
    1) 1 to 2 milligrams/kilogram daily in children 5 to 15 years of age (Porath & Schreier, 1977). Nomifensine was withdrawn from the world market in 1996.

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) Doses of around 1 gram have been ingested in adults with minor effects consisting mainly of tachycardia (Dawling et al, 1979). More serious effects (seizures, ventricular arrhythmias) were seen in an adult female following ingestion of 2.25 grams (Poussel et al, 1983).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) Toxic blood levels have not been established. Levels of 2780 to 3710 nanograms/milliliter have been observed in overdoses of 1.5 to 3.5 grams of nomifensine (Montgomery et al, 1978) Vohra et al, 1978).
    b) A nomifensine plasma level of 16 milligrams/liter was reported 28 hours after ingestion of an unknown quantity in a 60-year-old man. He became comatose and developed renal failure, but recovered one week later following symptomatic therapy (Baselt, 2000).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 128 mg/kg (RTECS, 2000)
    2) LD50- (ORAL)MOUSE:
    a) 400 mg/kg (Budavari, 1996)
    b) 260 mg/kg (RTECS, 2000)
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 410 mg/kg (Budavari, 1996)
    4) LD50- (ORAL)RAT:
    a) 430 mg/kg (Budavari, 1996)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Nomifensine is a tetrahydroisoquinoline antidepressant which is structurally unrelated to tricyclic or tetracyclic antidepressants.
    B) It is a strong inhibitor of norepinephrine and dopamine reuptake but does not directly stimulate the receptors. In therapeutic doses, it does not inhibit serotonin reuptake (Brodgen et al, 1979).

Physicochemical

Molecular Weight

    A) 238.3 (RTECS , 2000)

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    3) Ali C & Crome P: The clinical toxicology of nomifensine: An update, in L'Etaney HJC (Ed): International Congress and Symposium Series, Royal Society Medicine, London, 1984, pp 121-123.
    4) Baselt RC: Disposition of Toxic Drugs and Chemicals in Man, 5th ed, Chemical Toxicology Institute, Foster City, CA, 2000.
    5) Bethge K, Godt U, & Blanco-Cruz E: Incidence of cardiac arrhythmias during antidepressant therapy with maprotiline or nomifensine. J Cardiovasc Pharmacol 1982; 4:142-148.
    6) Bloomfield RJ & Wilson IJ: Nomifensine, acute hemolytic anemia, and renal failure (letter). Ann Intern Med 1986; 15:807.
    7) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    8) Caravati EM, Knight HH, & Linscott MS: Esophageal laceration and charcoal mediastinum complicating gastric lavage. J Emerg Med 2001; 20:273-276.
    9) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    10) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    11) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    12) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    13) Coccaro EF & Siever LJ: Second generation antidepressants: a comparative review. J Clin Pharmacol 1985; 25:241-260.
    14) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    15) Daunderer M: Physostigmine salicylate as an antidote. Int J Clin Pharmacol Ther Toxicol 1980; 18(12):523-535.
    16) Dawling S, Braithwaite R, & Crome P: Nomifensine overdose and plasma drug concentration. Lancet 1979; 1:56.
    17) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    18) Eyer F, Jetzinger E, Pfab R, et al: Withdrawal from high-dose tranylcypromine. Clin Toxicol (Phila) 2008; 46(3):261-263.
    19) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    20) Frascogna N: Physostigmine: is there a role for this antidote in pediatric poisonings?. Curr Opin Pediatr 2007; 19(2):201-205.
    21) Fulton JD, Briggs JD, & Dominiczak AF: Intravascular haemolysis and acute renal failure induced by nomifensine. Scott Med J 1986; 31:242-243.
    22) Garcia-Morteo O: Lupus-like syndrome during treatment with nomifensine. Arthr Rheumat 1983; 26:936.
    23) Garnier R, Delaby F, & Chabaux C: Acute poisoning by nomifensine. J Toxicol Med 1982; 2:141-144.
    24) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    25) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    26) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    27) Habibi B, Cartron JP, & Bretagne M: Anti-nomifensine antibody causing immune hemolytic anemia and renal failure. Vox Sang 1981; 40:79-84.
    28) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    29) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    30) Heptner W, Hornke I, & Cavagna F: Metabolism of nomifensine in man and animal species. Arzneim Forsch 1978; 28:58.
    31) Heptner W, Hornke I, & Uiohlein M: Kinetics and metabolism of nomifensine. J Clin Psychiatry 1984; 45:21-25.
    32) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    33) JEF Reynolds : Martindale: The Extra Pharmacopoeia (CD-ROM Version). The Pharmaceutical Press. London, UK (Internet Version). Edition expires 2000; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    34) Katona C: Paranoid symptoms after nomifensine. Lancet 1982; 2:384.
    35) Kummer H, Marti F, & Wegmann W: Granulomatose hepatitis auf nomifensin. Schweiz Med Wschr 1985; 115:1674-1678.
    36) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    37) Lylloff K, Jersild C, & Bacher T: Massive intravascular hemolysis during treatment with nomifensine. Lancet 1982; 2:41.
    38) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    39) Montgomery S, Crome P, & Braithwaite R: Nomifensine overdose. Lancet 1978; 1:828-829.
    40) Newton RW: Physostigmine salicylate in the treatment of tricyclic antidepressant overdosage. JAMA 1975; 231:941-943.
    41) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    42) Pentel P & Peterson CD: Asystole complicating physostigmine treatment of tricyclic antidepressant overdose. Ann Emerg Med 1980; 9:588-590.
    43) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    44) Porath U & Schreier K: On the use of nomifensine in depressive mood in children and young people. Paper presented at Alival(R) Symposium uber Ergebnissed der Experimentellen und Klinischen Prufung, Schattauer, Stuttgart, Germany, 1977, pp 39-45.
    45) Poussel JF, Artru F, & Riche H: Troubles cardiaques et nomifensine. J Toxicologie Medicale 1983; 3:187-189.
    46) Prescott LF, Illingworth RN, & Critchley JAJH: Acute hemolysis and renal failure after nomifensine overdosage. Br Med J 1980; 281:1392-1393.
    47) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    48) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    49) Product Information: physostigmine salicylate intravenous injection, intramuscular injection, physostigmine salicylate intravenous injection, intramuscular injection. Akorn, Inc. (per Manufacturer), Lake Forest, IL, 2008.
    50) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 2000; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    51) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    52) Scott R, Besag FMC, & Neville BGR: Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet 1999; 353:623-626.
    53) Shannon M: Toxicology reviews: physostigmine. Pediatr Emerg Care 1998; 14(3):224-226.
    54) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    55) Sreenath TG, Gupta P, Sharma KK, et al: Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: A randomized controlled trial. Eur J Paediatr Neurol 2009; Epub:Epub.
    56) Stewart GO: Convulsions after physostigmine (letter). Anaesth Intens Care 1979; 7:283.
    57) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    58) Vale JA, Kulig K, American Academy of Clinical Toxicology, et al: Position paper: Gastric lavage. J Toxicol Clin Toxicol 2004; 42:933-943.
    59) Vale JA: Position Statement: gastric lavage. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin Toxicol 1997; 35:711-719.
    60) Vereczkey L, Biachetti G, & Garattini S: Pharmacokinetics of nomifensine in man. Psychopharmacologia 1975; 45:225.