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INDALPINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Indalpine is an antidepressant medication which specifically inhibits serotonin reuptake (Naylor & Martin, 1985).

Specific Substances

    1) 3-(2-(4-piperidyl)ethyl)-indole
    2) Indalpine
    3) ((Indolyl-3)-2-ethyl)-4-piperidine
    4) LM-5008
    5) Upstene(R) (France)
    6) CAS 63758-79-2

Available Forms Sources

    A) FORMS
    1) Indalpine was available in France under the trade name of Upstene(R) (Laboratoire Fournier Freres) as 50 milligram blue tablets dispensed in boxes of 30 tablets.
    B) SOURCES
    1) Indalpine was retired by the manufacturer in June 1985 because it was reported that it induced severe, life threatening agranulocytosis in some patients (Castot & Efthymiou, 1985).
    2) In the United States, Rorer Laboratories holds a license for the development of indalpine (FDC Reports, 1984), but because of reports of adverse reactions (agranulocytosis) by French authors, does not plan further development or marketing in America (Pers Comm, Rorer Lab, 1987).
    3) Currently, further development or marketing of indalpine in other countries has been discontinued.

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Agitation, confusion, or coma may occur. Central nervous system depression may lead to respiratory insufficiency.
    B) Initial tachycardia and hypertension have been observed, but serious hypotension has also occurred. Cardiac conduction disturbances and refractory seizures may occur.
    C) As of 2000, no new information has been obtained on this agent. Based on reports of severe agranulocytosis no further development of this agent has occurred since the mid- to late-1980's.
    0.2.3) VITAL SIGNS
    A) Initial tachycardia and hypertension have been observed, but serious hypotension has also occurred. Hyperthermia may be present.
    0.2.4) HEENT
    A) Either mydriasis or miosis may be seen.
    B) Tinnitus and auditory hallucinations have been reported.
    0.2.5) CARDIOVASCULAR
    A) Moderate hypertension with a narrowed pulse pressure, hypotension and shock, sinus tachycardia, and cardiac conduction disturbances (including right bundle branch block) have been described.
    0.2.6) RESPIRATORY
    A) Respiratory insufficiency may necessitate intubation. Noncardiogenic pulmonary edema has occurred.
    0.2.7) NEUROLOGIC
    A) Mental confusion, delirium with agitation, coma, seizures (may be refractory), extrapyramidal syndrome with muscle hypertonia, cerebellar syndrome, auditory or visual hallucinations, and headache have been reported.
    0.2.8) GASTROINTESTINAL
    A) Vomiting and abdominal distension may occur after overdose; pancreatitis was associated with chronic therapeutic use.
    0.2.10) GENITOURINARY
    A) Urinary retention and ejaculatory dysfunction have been reported.
    0.2.13) HEMATOLOGIC
    A) Agranulocytosis, leukopenia, or anemia may occur during chronic indalpine therapy.
    0.2.20) REPRODUCTIVE
    A) No teratogenic effects or effects on fertility were noted in animal studies. No effects during breast feeding were noted in experimental animals.

Laboratory Monitoring

    A) Plasma indalpine levels may be assayed by HPLC. Plasma levels greater than 1,000 ng/mL more than 3 hours after ingestion, or greater than 2,000 ng/mL less than 3 hours after ingestion, have been associated with significant toxicity.
    B) Liver function tests and serum amylase may be useful monitoring parameters in chronic administration. Although agranulocytosis has only been reported during chronic therapy, it may be advisable to obtain a baseline CBC after overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) EMESIS: Ipecac-induced emesis is not recommended because of the potential for 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) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    F) REFRACTORY SEIZURES: Consider continuous infusion of midazolam, propofol, and/or pentobarbital. Hyperthermia, lactic acidosis and muscle destruction may necessitate use of neuromuscular blocking agents with continuous EEG monitoring.
    G) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.

Range Of Toxicity

    A) One patient died after ingestion of 850 mg, although ingestions of 1,300 and 5,500 mg have been survived.

Clinical Effects

Summary Of Exposure

    A) Agitation, confusion, or coma may occur. Central nervous system depression may lead to respiratory insufficiency.
    B) Initial tachycardia and hypertension have been observed, but serious hypotension has also occurred. Cardiac conduction disturbances and refractory seizures may occur.
    C) As of 2000, no new information has been obtained on this agent. Based on reports of severe agranulocytosis no further development of this agent has occurred since the mid- to late-1980's.

Vital Signs

    3.3.1) SUMMARY
    A) Initial tachycardia and hypertension have been observed, but serious hypotension has also occurred. Hyperthermia may be present.
    3.3.3) TEMPERATURE
    A) Hyperthermia may occur (Djeghout et al, 1985).
    3.3.4) BLOOD PRESSURE
    A) CASE REPORT - Moderate hypertension with a narrowed pulse pressure has been described in a patient overdosed with indalpine (Furet et al, 1986).
    B) CASE REPORT - Hypotension and shock have also been reported in a patient with a serious indalpine overdose (Djeghout et al, 1985).

Heent

    3.4.1) SUMMARY
    A) Either mydriasis or miosis may be seen.
    B) Tinnitus and auditory hallucinations have been reported.
    3.4.2) HEAD
    A) Although one case with findings consistent with an anticholinergic poisoning has been reported (Furet et al, 1986), hypersalivation rather than dry mucous membranes may be noted (Djeghout et al, 1985).
    3.4.3) EYES
    A) CASE REPORT - Miosis has been reported in a patient overdosed with indalpine who had numerous symptoms consistent with an anticholinergic poisoning (Furet et al, 1986).
    B) A patient indalpine overdosed who did not present symptoms consistent with anticholinergic poisoning had mydriasis (Djeghout et al, 1985).
    3.4.4) EARS
    A) TINNITUS and auditory hallucinations have been described in overdose (Furet et al, 1986).

Cardiovascular

    3.5.1) SUMMARY
    A) Moderate hypertension with a narrowed pulse pressure, hypotension and shock, sinus tachycardia, and cardiac conduction disturbances (including right bundle branch block) have been described.
    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) CASE REPORT - Moderate hypertension with a narrowed pulse pressure has been described in a patient overdosed with indalpine (Furet et al, 1986).
    B) HYPOTENSIVE EPISODE
    1) CASE REPORT - Hypotension and shock have also been reported in one patient with a serious indalpine overdose (Djeghout et al, 1985).
    C) TACHYARRHYTHMIA
    1) CASE REPORT - Sinus tachycardia has occurred in one case of indalpine overdose in a patient presenting with symptoms consistent with an anticholinergic poisoning (Furet et al, 1986).
    D) BUNDLE BRANCH BLOCK
    1) Cardiac conduction disturbances including right bundle branch block have been noted (Djeghout et al, 1985).

Respiratory

    3.6.1) SUMMARY
    A) Respiratory insufficiency may necessitate intubation. Noncardiogenic pulmonary edema has occurred.
    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FAILURE
    1) Central nervous system depression may produce respiratory insufficiency necessitating intubation (Djeghout et al, 1985).
    B) ACUTE LUNG INJURY
    1) Noncardiogenic pulmonary edema has occurred in the course of indalpine poisoning (Djeghout et al, 1985).

Neurologic

    3.7.1) SUMMARY
    A) Mental confusion, delirium with agitation, coma, seizures (may be refractory), extrapyramidal syndrome with muscle hypertonia, cerebellar syndrome, auditory or visual hallucinations, and headache have been reported.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) Mental confusion, delirium with agitation, or coma may occur (Djeghout et al, 1985). Sedation has been noted at doses of 150 mg/day (Seppala et al, 1988).
    B) SEIZURE
    1) Seizures may occur, with or without prior onset of coma (Djeghout et al, 1985; Furet et al, 1986). Refractory seizures have been reported (Djeghout et al, 1985).
    C) EXTRAPYRAMIDAL DISEASE
    1) One case of indalpine overdose presenting with an extrapyramidal syndrome and muscular hypertonia has been reported (Furet et al, 1986).
    D) CEREBELLAR DISORDER
    1) CASE REPORT - A cerebellar syndrome and auditory hallucinations developed in an alcoholic patient receiving chronic indalpine therapy for depression (Maroy & Audoin, 1985).
    E) HALLUCINATIONS
    1) CASE REPORT - Auditory and visual hallucinations, headache, and multiple somatic complaints were noted in one indalpine overdosed patient who had symptoms consistent with an anticholinergic poisoning (Furet et al, 1986).

Gastrointestinal

    3.8.1) SUMMARY
    A) Vomiting and abdominal distension may occur after overdose; pancreatitis was associated with chronic therapeutic use.
    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) Vomiting and abdominal distension may occur (Djeghout et al, 1985).
    B) PANCREATITIS
    1) One case of acute pancreatitis associated with chronic indalpine treatment has been reported (Calmus et al, 1985).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) CASE SERIES - Two cases of hepatitis associated with chronic indalpine therapy have been reported. Elevated amylase levels were also reported in these two cases (Calmus et al, 1985).

Genitourinary

    3.10.1) SUMMARY
    A) Urinary retention and ejaculatory dysfunction have been reported.
    3.10.2) CLINICAL EFFECTS
    A) RETENTION OF URINE
    1) Urinary retention has been reported in overdose (Djeghout et al, 1985).
    B) ABNORMAL EJACULATION
    1) CASE SERIES - Ejaculatory dysfunction was reported in eight of 12 subjects (67%) receiving indalpine 150 mg/day in one study (Seppala et al, 1988).

Hematologic

    3.13.1) SUMMARY
    A) Agranulocytosis, leukopenia, or anemia may occur during chronic indalpine therapy.
    3.13.2) CLINICAL EFFECTS
    A) AGRANULOCYTOSIS
    1) Agranulocytosis or leukopenia may occur during chronic indalpine therapy (Naylor & Martin, 1985; Grosbois et al, 1985; Laaban et al, 1985; Castot & Efthymiou, 1985).
    2) CASE SERIES - Castot & Efthymiou (1985) reported 30 cases of hematologic side effects with 19 cases of severe agranulocytosis after chronic indalpine therapy. The incidence of agranulocytosis was estimated to be 1 case per 20,000 patients treated (information from the manufacturer).
    3) These side effects were observed during the first year following the marketing of indalpine in France. Side effects occurred mean 9 weeks after the onset of the treatment.
    4) Five patients died from septic shock or meningeal hemorrhage. Although occurrence of agranulocytosis was higher in the elderly, this side effect was also reported in younger adults.
    B) ANEMIA
    1) CASE SERIES - Castot & Efthymiou (1985) reported mild anemia in 10 cases and a regenerative anemia in 6 cases.

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) FLUSHING
    1) Indalpine overdose may produce a drug flush (Manigand et al, 1985).

Reproductive

    3.20.1) SUMMARY
    A) No teratogenic effects or effects on fertility were noted in animal studies. No effects during breast feeding were noted in experimental animals.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) No teratogenic effects or effects on fertility were noted in rat and rabbit experiments.
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF EFFECT
    1) No effects on pregnancy were noted in experimental animals.
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF EFFECT
    1) No effects during breast feeding were noted in experimental animals.

Carcinogenicity

    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 indalpine.

Genotoxicity

    A) Indalpine was not mutagenic in the Ames test.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma indalpine levels may be assayed by HPLC. Plasma levels greater than 1,000 ng/mL more than 3 hours after ingestion, or greater than 2,000 ng/mL less than 3 hours after ingestion, have been associated with significant toxicity.
    B) Liver function tests and serum amylase may be useful monitoring parameters in chronic administration. Although agranulocytosis has only been reported during chronic therapy, it may be advisable to obtain a baseline CBC after overdose.
    4.1.2) SERUM/BLOOD
    A) TOXICITY
    1) In a series of 29 indalpine overdosed patients, severe poisoning was associated with indalpine plasma levels greater than 1,000 nanograms per milliliter more than three hours after ingestion, or with indalpine plasma levels greater than 2,000 nanograms per milliliter less than three hours after ingestion (Djeghout et al, 1985).
    B) BLOOD/SERUM CHEMISTRY
    1) Complete blood count, liver function tests, and serum amylase may be useful monitoring parameters in chronic administration.
    C) HEMATOLOGIC
    1) Complete blood count may be a useful monitoring parameter in chromic administration.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) If noncardiogenic pulmonary edema is suspected, a chest x-ray should be obtained.

Methods

    A) CHROMATOGRAPHY
    1) Indalpine and its inactive lactam metabolite can be quantitated in plasma by a high-performance liquid chromatographic assay (Jozefczak et al, 1982). Samples should be collected in heparinized tubes, centrifuged, and stored at -20 degrees C until assayed.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Plasma indalpine levels may be assayed by HPLC. Plasma levels greater than 1,000 ng/mL more than 3 hours after ingestion, or greater than 2,000 ng/mL less than 3 hours after ingestion, have been associated with significant toxicity.
    B) Liver function tests and serum amylase may be useful monitoring parameters in chronic administration. Although agranulocytosis has only been reported during chronic therapy, it may be advisable to obtain a baseline CBC after overdose.

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 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) EMESIS/NOT RECOMMENDED
    1) EMESIS: Ipecac-induced emesis is not recommended because of the potential for seizures.
    B) 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).
    C) 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) Continuous cardiac and frequent blood pressure monitoring should be instituted. Mild sinus tachycardia and hypertension usually do not require pharmacologic therapy.
    B) 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).
    C) AIRWAY MANAGEMENT
    1) Respiratory insufficiency may occur and necessitate intubation with assisted ventilation and supplemental oxygenation.
    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).
    7) RECURRING SEIZURES
    a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:
    1) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
    2) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
    3) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
    4) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)
    b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
    c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).
    E) DRUG-INDUCED DYSTONIA
    1) ADULT
    a) BENZTROPINE: 1 to 4 mg once or twice daily intravenously or intramuscularly; maximum dose: 6 mg/day; 1 to 2 mg of the injection will usually provide quick relief in emergency situations (Prod Info benztropine mesylate IV, IM injection, 2009).
    b) DIPHENHYDRAMINE: 10 to 50 mg intravenously at a rate not exceeding 25 mg/minute or deep intramuscularly; maximum dose: 100 mg/dose; 400 mg/day (Prod Info diphenhydramine hcl injection, 2006).
    2) CHILDREN
    a) DIPHENHYDRAMINE: 5 mg/kg/day or 150 mg/m(2)/day intravenously divided into 4 doses at a rate not to exceed 25 mg/min, or deep intramuscularly; maximum dose: 300 mg/day. Not recommended in premature infants and neonates (Prod Info diphenhydramine hcl injection, 2006).
    F) HYPERTENSIVE EPISODE
    1) Monitor vital signs regularly.
    2) For mild/moderate asymptomatic hypertension, pharmacologic intervention is seldom necessary and 4 to 6 hours of observation is usually adequate. Severe life-threatening hypertension has not been reported.
    G) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

Enhanced Elimination

    A) SUMMARY
    1) Neither hemodialysis nor charcoal hemoperfusion have been evaluated in the treatment of indalpine poisoning. As the agent has a large volume of distribution (Vd) (30.5 liters per kilogram), hemodialysis is unlikely to be of benefit.

Abstracts

Case Reports

    A) ACUTE EFFECTS
    1) A patient reported by Djeghout et al (1985) ingested an undetermined amount of indalpine in a mixed overdose with phenothiazines and benzodiazepines.
    2) Coma and electrocardiographic right bundle branch block were noted on admission. The patient later developed respiratory insufficiency and required intubation. Hypotension, shock, and seizures were noted, followed by pulmonary edema.
    3) The patient died twelve hours after admission despite intensive supportive therapy. Plasma indalpine levels were 1,713 nanograms per milliliter at one hour, 1,332 nanograms per milliliter at 3 hours, 784 nanograms per milliliter at 10 hours, and 762 nanograms per milliliter at 13 hours after ingestion.
    B) ADVERSE EFFECTS
    1) Furet et al (1986) reported the case of a patient receiving chronic indalpine therapy (150 milligrams per day for three weeks) who ingested about 1.3 grams in a suicide attempt.
    2) No other drugs were found on toxicology screening. This patient developed a marked extrapyramidal syndrome with muscular hypertonia and a sinus tachycardia of 120 beats per minute.
    3) The patient was conscious on admission and had a moderately elevated blood pressure of 150/110 millimeters of mercury. The patient remained conscious, but suddenly had a generalized seizure about 6 hours after ingestion.
    4) Complaints of headache, chills, muscular stiffness, tinnitus, and visual and auditory hallucinations persisted for about 24 hours, followed by full recovery.

Range Of Toxicity

Summary

    A) One patient died after ingestion of 850 mg, although ingestions of 1,300 and 5,500 mg have been survived.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) Since June 1985, this preparation has been retired by the manufacturer (Laboratories Fournier Freres), because it was reported that indalpine could induce severe agranulocytosis (Castot & Efthymiou, 1985).

Minimum Lethal Exposure

    A) SPECIFIC SUBSTANCE
    1) One patient who ingested 850 milligrams of indalpine developed cardiac arrest following seizures and died (Djeghout et al, 1985). Two other deaths have been reported following ingestion of 3,000 and 3,750 milligrams of indalpine (Djeghout et al, 1985).

Maximum Tolerated Exposure

    A) ACUTE
    1) A poor prognosis has been associated with ingestion of between 750 and 1,000 milligrams (Djeghout et al, 1985), although ingestions of 1,300 and 5,500 milligrams have been survived (Djeghout et al, 1985; Furet et al, 1986).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) Indalpine plasma levels of 1,000 nanograms per milliliter more than three hours after ingestion, or 2,000 nanograms per milliliter less than three hours after ingestion, have been associated with significant toxicity (Djeghout et al, 1985).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)MOUSE:
    1) 236-302 mg/kg
    B) LD50- (INTRAPERITONEAL)RAT:
    1) 21-30 mg/kg
    C) LD50- (ORAL)RAT:
    1) 605-857 mg/kg

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Indalpine's mechanism of action is a presynaptic inhibition of serotonin uptake. No experimental effects of indalpine on uptake of adrenaline, noradrenaline, choline, tryptophane, tyrosine, taurine, glycine, glutamate, aspartate, GABA, MAO-A, or MAO-B have been shown.

Toxicologic Mechanism

    A) Indalpine's toxicologic mechanism of action is most likely an exacerbation of its therapeutic pharmacologic effects.
    B) With the exception of hypersalivation rather than dry mucous membranes, one poisoning case presented clinical findings consistent with an anticholinergic syndrome (Furet et al, 1986).
    C) The exact mechanism of indalpine-induced agranulocytosis remains uncertain. Although agranulocytosis could not be reproduced in experimental studies (information from the manufacturer), clinical data are in favor of a toxic rather than an immunoallergic mechanism.

Physicochemical

Physical Characteristics

    A) Indalpine is a white powder.

Molecular Weight

    A) 228.34 (Budavari, 1996)

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