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GALANTAMINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Galantamine hydrobromide, a tertiary alkaloid, in the phenanthrene group, which has been obtained from the Caucasian snowdrop (Voronov's snowdrop), Galanthus woronowii (Amaryllidaceae), and related species. It is a reversible, competitive acetylcholinesterase inhibitor, a parasympathomimetic agent, and is used in mild to moderately severe Alzheimer's disease.

Specific Substances

    1) Galantamin
    2) Galantamine hydrobromide
    3) Galanthamine
    4) Galanthamine hydrobromide
    5) Galanthamini hydrobromidum
    6) Galantone
    7) Jilkon
    8) Lycoremin
    9) Lycoremine
    10) Nivalin
    11) Molecular Formula: C17-H21-N-O3, HBr
    12) CAS 357-70-0 (galantamine)
    13) CAS 1953-04-4 (galantamine hydrobromide)

Available Forms Sources

    A) FORMS
    1) ORAL SOLUTION: Available as a 4 mg/mL oral solution in a clear colorless solution in 100 mL bottles (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).
    2) TABLET: Available as a 4 mg, 8 mg, and 12 mg tablet (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).
    3) EXTENDED RELEASE: Available as an extended release capsule of 8 mg, 16 mg, and 24 mg (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).
    B) USES
    1) Galantamine is a reversible, competitive and long-acting inhibitor of cholinesterase activity and is used in mild to moderately severe dementia of the Alzheimer's type (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Galantamine is used to treat mild to moderately severe dementia of the Alzheimer's type.
    B) PHARMACOLOGY: Galantamine, a tertiary alkaloid, is a reversible, competitive and long-acting inhibitor of cholinesterase activity.
    C) TOXICOLOGY: Galantamine can produce cholinomimetic effects. Overdose effects of cholinergic agonists generally involve the central nervous system, the parasympathetic nervous system, and the neuromuscular junction.
    D) EPIDEMIOLOGY: Overdose is uncommon.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: Nausea, diarrhea, anorexia, weight loss and sleep disturbances were the most frequent adverse events. SEVERE: Bradyarrhythmia, cardiac dysrhythmia, heart failure, esophageal perforation, gastrointestinal hemorrhage, rectal hemorrhage, thrombocytopenia, and death may develop.
    F) WITH POISONING/EXPOSURE
    1) OVERDOSE: Limited data. Due to the cholinomimetic activity of galantamine, an overdose may be expected to result in muscarinic actions consisting of miosis, vomiting, salivation, lacrimation, increased bronchial secretions, involuntary urination and/or defecation, sweating, flushing, bradycardia, hypotension, respiratory depression and/or seizures.
    2) MILD TO MODERATE TOXICITY: Bradycardia, sweating, and vomiting have been reported after acute overdose.
    3) SEVERE TOXICITY: Near-syncope, QT prolongation, torsades de pointes, and ventricular tachycardia have been reported after acute overdose. Cholinergic crisis may be characterized by severe cardiovascular events (bradycardia, hypotension, various dysrhythmias including torsades de pointes). A fatal overdose may result from respiratory muscle weakness with respiratory failure.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Blood pressure and pulse may be decreased following an overdose.
    0.2.4) HEENT
    A) WITH POISONING/EXPOSURE
    1) Miosis, salivation, and lacrimation are common systemic effects of cholinergic agonists and may occur with galantamine in overdose.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Hypotension and bradycardia may occur at high doses or in overdose. Decreased cardiac contractility, shock, cardiac arrest, atrial fibrillation, and heart block may occur as a result of cholinergic crisis.
    0.2.6) RESPIRATORY
    A) WITH THERAPEUTIC USE
    1) Dyspnea and bronchospasm may occur, especially in asthmatic patients.
    B) WITH POISONING/EXPOSURE
    1) Cholinergic crisis may result in bronchospasm, tachypnea, increased pulmonary secretions, pulmonary edema, and respiratory paralysis.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) Seizures, vertigo, tremors, agitation, lethargy, and coma may occur following an overdose.
    0.2.10) GENITOURINARY
    A) WITH POISONING/EXPOSURE
    1) Increased micturition may occur due to cholinergic effects of galantamine.
    0.2.12) FLUID-ELECTROLYTE
    A) WITH POISONING/EXPOSURE
    1) Fluid depletion may occur through bronchorrhea, vomiting and diarrhea, polyuria, and sweating.
    0.2.14) DERMATOLOGIC
    A) WITH POISONING/EXPOSURE
    1) Diaphoresis may occur in galantamine overdose.
    0.2.15) MUSCULOSKELETAL
    A) WITH POISONING/EXPOSURE
    1) Tremors and fasciculations may occur following overdoses. Muscle weakness is expected following substantial acute overdoses, and may result in respiratory depression.
    0.2.20) REPRODUCTIVE
    A) Galantamine is in FDA Pregnancy Category C. Teratogenic effects included decreased pup weights and small increases in skeletal and visceral malformations in rats and rabbits. It is unknown whether or not galantamine is excreted into breast milk.

Laboratory Monitoring

    A) Signs and symptoms of cholinesterase inhibitor poisoning should be monitored. Cholinesterase activity may be depressed and should be monitored in plasma (pseudocholinesterase) and red blood cells.
    B) Monitor ECG following significant exposures. Overdoses may be associated with bradycardia.
    C) Monitor pulse oximetry and/or arterial blood gases and obtain a chest radiograph in patients with pulmonary symptoms.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Signs and symptoms of overdose are anticipated to be due to cholinomimetic effects (eg, nausea, vomiting, diarrhea, salivation, lacrimation, defecation). ATROPINE: ADULT: 1 to 2 mg IV, repeat every 3 to 60 min as needed to control symptoms, then as needed for 24 to 48 hr. CHILD: 0.05 mg/kg IM or IV (up to 4 mg) repeat every 10 to 30 min as necessary. CARDIOVASCULAR: Monitor vital signs and institute continuous cardiac monitoring; bradycardia, hypotension and QT prolongation have been observed. HYPOTENSION: IV 0.9% NaCl at 10 mL to 20 mL/kg, dopamine, norepinephrine.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Due to its cholinomimetic action, severe toxicity may produce cardiac dysrhythmias, seizures, bronchospasm, respiratory depression, and acute lung injury. Immediate assessment and evaluation. Airway management may be necessary. ANTIDOTE: Administer atropine for muscarinic manifestations (e.g. salivation, diarrhea, bronchorrhea). Initially treat seizures with benzodiazepines. TORSADES DE POINTES: Immediate electrical cardioversion, if hemodynamically unstable. Treatment with magnesium; atrial overdrive pacing is also indicated. Correct electrolyte abnormalities. RESPIRATORY DEPRESSION. Muscle weakness may lead to respiratory failure.
    C) DECONTAMINATION
    1) PREHOSPITAL: Activated charcoal may be considered after a potentially toxic ingestion, if the patient is alert and able to protect their airway.
    2) HOSPITAL: Administer activated charcoal after a potentially toxic ingestion and if the patient is able to maintain airway or if airway is protected.
    D) AIRWAY MANAGEMENT
    1) Assess airway and respiratory function. Administer oxygen. Endotracheal intubation and mechanical ventilation may be necessary because of respiratory muscle weakness or bronchorrhea.
    E) ANTIDOTE
    1) Atropine may be used as an antidote for overdosage. ADULT: 1 to 2 mg IV, repeated every 3 to 60 minutes as needed to control symptoms, then as needed for 24 to 48 hours. CHILD: 0.05 mg/kg IM or IV (up to 4 mg) repeated every 10 to 30 minutes as necessary.
    F) SEIZURE
    1) IV benzodiazepines are indicated for seizures or agitation, diazepam 5 to 10 mg IV, lorazepam 2 to 4 mg IV, repeat as needed.
    G) BRONCHOSPASM
    1) Administer beta2 adrenergic agonists. Consider use of inhaled corticosteroids and ipratropium. Monitor peak expiratory flow rate, monitor for hypoxia and respiratory failure, and administer oxygen as necessary.
    H) ACUTE LUNG INJURY
    1) Maintain adequate ventilation and oxygenation; frequently monitor ABGs and pulse oximetry. Mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: An asymptomatic child with a minor ingestion (ie a single immediate release tablet) can likely be monitored at home with adult supervision. An adult that has taken an inadvertent extra dose is not likely to develop symptoms.
    2) OBSERVATION CRITERIA: Patients with deliberate ingestions, adults with symptoms or ingestions of more than the therapeutic dose, or a pediatric ingestion should be sent to a healthcare facility for evaluation and treatment. IMMEDIATE RELEASE: Monitor for at least 3 to 6 hours. EXTENDED RELEASE: Patients ingesting extended release preparations should be observed for at least 7 to 12 hours (Tmax is 4.5 to 5 hours at a therapeutic dose) and admitted if symptoms develop; effects may be delayed and prolonged.
    3) ADMISSION CRITERIA: All intentional ingestions should be initially managed as a severe exposure. Patients who develop signs or symptoms of cholinergic toxicity (muscarinic, nicotinic or central) should be admitted to an intensive care setting.
    4) CONSULT CRITERIA: Consult a medical toxicologist or poison center for assistance with any patient with moderate to severe cholinergic manifestations.
    J) PREDISPOSING FACTORS
    1) Other drugs that are potent inhibitors for CYP2D6 or CYP3A4 may increase the AUC of galantamine (ie, ketoconazole and paroxetine increased AUC of galantamine by 30% and 40%, respectively). Hepatic and renal impairment would be anticipated to increase exposure.
    K) PHARMACOKINETICS
    1) TABLETS and ORAL SOLUTION: IMMEDIATE RELEASE: Absorption is rapid and complete with time to peak concentration about 1 hour following a single oral dose of galantamine. It has an oral bioavailability of approximately 90%. Plasma protein binding is 18%. The mean volume of distribution is 175 L. It has a half-life of about 7 hours and the kinetics are linear with doses of 8 to 32 mg/day. Galantamine is metabolized by hepatic cytochrome P450 enzymes. In vitro studies showed that CYP2D6 and CYP3A4 were the major cytochrome P450 isoenzymes that metabolized galantamine, and inhibitors of both pathways can increase oral bioavailability of galantamine modestly. EXTENDED RELEASE: A 24 mg ER tablet was bioequivalent to galantamine 12 mg tablets twice daily for AUC and Cmin; however, Cmax (about 25% lower) and Tmax (occurred about 4.5 to 5 hours after dosing) were lower and occurred later. CYP2D6 poor metabolizers had drug exposures that were approximately 50% higher than for extensive metabolizers.
    L) DIFFERENTIAL DIAGNOSIS
    1) Other drugs that may produce cholinergic excess.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established. Ingestion of 160 mg resulted in sweating, vomiting, bradycardia, and near-syncope in an adult. A dose of 32 mg/day in an adult who had been taking 4 mg daily for one week caused vomiting, bradycardia, QT prolongation, ventricular tachycardia, and torsades de pointes.
    B) THERAPEUTIC: ADULT: Doses must be slowly titrated up to a maximum daily dose. IMMEDIATE RELEASE: Doses of up to 32 mg/day divided in 2 doses may be used therapeutically. EXTENDED RELEASE: Doses of up to 24 mg taken once daily may be used therapeutically. PEDIATRIC: Galantamine is not recommended for use in children.

Clinical Effects

Summary Of Exposure

    A) USES: Galantamine is used to treat mild to moderately severe dementia of the Alzheimer's type.
    B) PHARMACOLOGY: Galantamine, a tertiary alkaloid, is a reversible, competitive and long-acting inhibitor of cholinesterase activity.
    C) TOXICOLOGY: Galantamine can produce cholinomimetic effects. Overdose effects of cholinergic agonists generally involve the central nervous system, the parasympathetic nervous system, and the neuromuscular junction.
    D) EPIDEMIOLOGY: Overdose is uncommon.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: Nausea, diarrhea, anorexia, weight loss and sleep disturbances were the most frequent adverse events. SEVERE: Bradyarrhythmia, cardiac dysrhythmia, heart failure, esophageal perforation, gastrointestinal hemorrhage, rectal hemorrhage, thrombocytopenia, and death may develop.
    F) WITH POISONING/EXPOSURE
    1) OVERDOSE: Limited data. Due to the cholinomimetic activity of galantamine, an overdose may be expected to result in muscarinic actions consisting of miosis, vomiting, salivation, lacrimation, increased bronchial secretions, involuntary urination and/or defecation, sweating, flushing, bradycardia, hypotension, respiratory depression and/or seizures.
    2) MILD TO MODERATE TOXICITY: Bradycardia, sweating, and vomiting have been reported after acute overdose.
    3) SEVERE TOXICITY: Near-syncope, QT prolongation, torsades de pointes, and ventricular tachycardia have been reported after acute overdose. Cholinergic crisis may be characterized by severe cardiovascular events (bradycardia, hypotension, various dysrhythmias including torsades de pointes). A fatal overdose may result from respiratory muscle weakness with respiratory failure.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Blood pressure and pulse may be decreased following an overdose.
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) Hypotension and syncope may occur in an overdose due to muscarinic cholinergic effects of galantamine (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).
    3.3.5) PULSE
    A) WITH POISONING/EXPOSURE
    1) Decreased pulse rate may occur due to vagotonic cholinergic effects of galantamine (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).

Heent

    3.4.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Miosis, salivation, and lacrimation are common systemic effects of cholinergic agonists and may occur with galantamine in overdose.
    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) An overdose may result in a muscarinic effect of miosis (Prod Info Reminyl(R), galantamine tablets and oral solution, 2001).
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) Therapeutic doses greater than 30 mg may be associated with hypersalivation (Riemann et al, 1994).
    B) WITH POISONING/EXPOSURE
    1) Salivation may occur with systemic poisonings (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Hypotension and bradycardia may occur at high doses or in overdose. Decreased cardiac contractility, shock, cardiac arrest, atrial fibrillation, and heart block may occur as a result of cholinergic crisis.
    3.5.2) CLINICAL EFFECTS
    A) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) Bradycardia was reported more often (2% to 3%) in galantamine-treated patients (up to 24 mg/day) than in patients given placebo (less than 1%) during randomized controlled trials. This rarely led to discontinuation (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).
    b) Galantamine 20 mg produced a minor reduction in mean pulse rate, from 71 beats/min (bpm) to 69 bpm, and had a negligible effect on blood pressure. However, 6 patients experienced a pulse less than 55 bpm, which was associated with minor dysrhythmias (Harvey, 1995). Doses greater than 30 mg have been associated with bradycardia (Riemann et al, 1994).
    2) WITH POISONING/EXPOSURE
    a) Overdose may cause a cholinergic crisis which may be characterized by bradycardia as well as hypotension (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).
    b) CASE REPORT: A 10-fold overdose occurred in a man who was taking 16 mg/day of the oral solution. He inadvertently ingested 160 mg. One hour after the ingestion he experienced sweating, vomiting, bradycardia, and near-syncope. Symptoms resolved within 24 hours with supportive care (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).
    c) CASE REPORT: Bradycardia, QT prolongation, ventricular tachycardia, and torsades de pointes occurred in a woman who ingested 32 mg in a single day. She had been taking galantamine 4 mg daily for one week prior. She was treated with supportive care (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).
    B) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Therapeutic doses may also result in a hypotensive episode as a result of cholinergic muscarinic effects (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).
    2) WITH POISONING/EXPOSURE
    a) Hypotension, which may be accompanied by reflex tachycardia, may initially occur as a sign of cholinergic crisis. Hypotension following overdose could be severe, leading to cardiovascular collapse or shock (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).
    C) SYNCOPE
    1) WITH THERAPEUTIC USE
    a) A dose-related increase in risk of syncope has been reported (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).
    D) HEART BLOCK
    1) WITH POISONING/EXPOSURE
    a) Various dysrhythmias, primarily heart block, may theoretically occur because of the cholinergic effects of galantamine (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).
    E) TORSADES DE POINTES
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Bradycardia, QT prolongation, ventricular tachycardia, and torsades de pointes occurred in a woman who ingested 32 mg in a single day. She had been taking galantamine 4 mg daily for one week prior. She was treated with supportive care (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).

Respiratory

    3.6.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Dyspnea and bronchospasm may occur, especially in asthmatic patients.
    B) WITH POISONING/EXPOSURE
    1) Cholinergic crisis may result in bronchospasm, tachypnea, increased pulmonary secretions, pulmonary edema, and respiratory paralysis.
    3.6.2) CLINICAL EFFECTS
    A) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) As a cholinomimetic, galantamine may cause dyspnea, increased pulmonary secretions, bronchospasm, pulmonary edema or aggravate preexisting severe asthma or obstructive pulmonary disease (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).
    B) SPUTUM ABNORMAL - AMOUNT
    1) WITH THERAPEUTIC USE
    a) Bronchial secretions may be increased secondary to cholinergic effects and bouts of coughing may occur (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).
    C) APNEA
    1) WITH POISONING/EXPOSURE
    a) Cholinergic crisis may result in muscle weakness which may cause a respiratory paralysis leading to apnea (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).
    D) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Cholinergic agonists can cause bronchorrhea and in severe cases of acute lung injury (Prod Info RAZADYNE(TM) oral solution, tablets, 2006).

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Seizures, vertigo, tremors, agitation, lethargy, and coma may occur following an overdose.
    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Therapeutic doses greater than 30 mg may be associated with seizures (Riemann et al, 1994).
    2) WITH POISONING/EXPOSURE
    a) Overdose may result in seizures, tremor, and vertigo from cholinergic toxicity to the CNS (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).
    B) COMA
    1) WITH POISONING/EXPOSURE
    a) Drowsiness and coma are uncommon events, but are effects that may occur on occasion with cholinergic drug overdoses (Prod Info Reminyl(R), galantamine tablets and oral solution, 2001).
    C) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Dizziness, headache, tremor, fatigue, depression, insomnia, and somnolence have developed following the administration of galantamine (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012; Wilcock et al, 2000). In one study using galantamine 20 mg, approximately 37% of the 40 patients experienced some degree of dizziness. The severity of dizziness was classified as mild in 11 patients and severe in four patients (Cozanitis, 1970).
    b) Agitation, irritation, and insomnia developed in 75% of patients receiving galantamine 15 mg 3 times daily for Alzheimer's disease (Thomsen & Kewitz, 1990). Excessive dreaming may occur following higher doses (Riemann et al, 1994).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) Nausea, vomiting, diarrhea, anorexia, abdominal pain, and dyspepsia are the most commonly reported adverse effects associated with galantamine (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012; Wilkinson & Murray, 2001; Wilcock et al, 2000; Fulton & Benfield, 1996; Riemann et al, 1994; Cozanitis et al, 1971).
    2) WITH POISONING/EXPOSURE
    a) Overdose may result in cholinergic signs and symptoms of gastroenteritis, including severe nausea and vomiting, abdominal pain, diarrhea, and increased salivation as a result of increased gastrointestinal motility (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).
    B) EXCESSIVE SALIVATION
    1) WITH THERAPEUTIC USE
    a) In one study, some degree of salivation occurred in all 40 patients who received galantamine 20 mg. Minimal salivation occurred in 11 (27.5%) patients compared to 6 (15%) patients who experienced maximal salivation. The remaining 23 patients experienced salivation that was classified between minimum and maximum (Cozanitis, 1970).
    b) Therapeutic doses greater than 30 mg may be associated with hypersalivation (Riemann et al, 1994).
    2) WITH POISONING/EXPOSURE
    a) Increased salivation is a parasympathetic effect and may be expected following an overdose of a cholinesterase inhibitor such as galantamine (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).
    C) VOMITING
    1) WITH POISONING/EXPOSURE
    a) Vomiting has been reported after overdose (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).
    b) CASE REPORT: A 10-fold overdose occurred in a man who was taking 16 mg/day of the oral solution. He inadvertently ingested 160 mg. One hour after the ingestion he experienced sweating, vomiting, bradycardia, and near-syncope. Symptoms resolved within 24 hours with supportive care (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INJURY OF LIVER
    1) WITH THERAPEUTIC USE
    a) LACK OF EFFECT: Hepatic enzyme elevations or other signs of liver toxicity have NOT been reported with galantamine use (Wilkinson & Murray, 2001) (Fulton & Benfield, 1996).

Genitourinary

    3.10.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Increased micturition may occur due to cholinergic effects of galantamine.
    3.10.2) CLINICAL EFFECTS
    A) INCREASED FREQUENCY OF URINATION
    1) WITH THERAPEUTIC USE
    a) Urinary frequency and stimulation of the urinary bladder may occur, with resultant involuntary urination as a result of cholinergic effects of galantamine, especially at higher doses (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).
    b) Urinary incontinence, a peripheral cholinergic side effect, has been reported following therapy with galantamine (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).
    2) WITH POISONING/EXPOSURE
    a) Urinary frequency and stimulation of the urinary bladder may occur, with resultant involuntary urination as a result of cholinergic effects of galantamine, especially at higher doses or overdoses (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).

Dermatologic

    3.14.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Diaphoresis may occur in galantamine overdose.
    3.14.2) CLINICAL EFFECTS
    A) EXCESSIVE SWEATING
    1) WITH THERAPEUTIC USE
    a) Therapeutic doses greater than 30 mg are reported to occasionally result in hyperhidrosis (Riemann et al, 1994).
    2) WITH POISONING/EXPOSURE
    a) Overdosage may result in a cholinergic crisis which can cause increased sweating and flushing (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).
    b) CASE REPORT: A 10-fold overdose occurred in a man who was taking 16 mg/day of the oral solution. He inadvertently ingested 160 mg. One hour after the ingestion he experienced sweating, vomiting, bradycardia, and near-syncope. Symptoms resolved within 24 hours with supportive care (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).

Musculoskeletal

    3.15.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Tremors and fasciculations may occur following overdoses. Muscle weakness is expected following substantial acute overdoses, and may result in respiratory depression.
    3.15.2) CLINICAL EFFECTS
    A) TREMOR
    1) WITH POISONING/EXPOSURE
    a) Tremors and fasciculations may occur following cholinergic stimulation in overdoses of galantamine (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).
    B) MUSCLE WEAKNESS
    1) WITH POISONING/EXPOSURE
    a) Substantial overdoses are expected to result in muscle weakness. In severe cases, muscle weakness leading to respiratory depression may occur as a result of cholinergic crisis (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).

Reproductive

    3.20.1) SUMMARY
    A) Galantamine is in FDA Pregnancy Category C. Teratogenic effects included decreased pup weights and small increases in skeletal and visceral malformations in rats and rabbits. It is unknown whether or not galantamine is excreted into breast milk.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) In animal studies, rats given galantamine 8 mg/kg/day and 16 mg/kg/day prior to mating through organogenesis produced pups with an increased incidence of skeletal malformations. Galantamine 8 or 16 mg/kg/day exposure from organogenesis through postpartum day 21 resulted in decreased pup weights. The no-effect dose for both studies approximated the maximum recommended human dose. In rabbits, galantamine 48 mg/kg/day administered through organ formation resulted in small increases in visceral and skeletal malformations in offspring; the no-effect dose (28 mg/kg/day) was approximately 20 times the maximum recommended human dose (Prod Info RAZADYNE(R) ER oral extended release capsules, 2013; Prod Info RAZADYNE(R) oral tablets, oral solution, 2013).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) U.S. Food and Drug Administration's Pregnancy Category C (Prod Info RAZADYNE(R) ER oral extended release capsules, 2013; Prod Info RAZADYNE(R) oral tablets, oral solution, 2013).
    2) There are no adequate or well-controlled studies of galantamine use in pregnant women (Prod Info RAZADYNE(R) ER oral extended release capsules, 2013; Prod Info RAZADYNE(R) oral tablets, oral solution, 2013).
    B) ANIMAL STUDIES
    1) In animal studies, rats given galantamine 8 mg/kg/day and 16 mg/kg/day prior to mating through organogenesis produced pups with an increased incidence of skeletal malformations. Galantamine 8 or 16 mg/kg/day exposure from organogenesis through postpartum day 21 resulted in decreased pup weights. The no-effect dose for both studies approximated the maximum recommended human dose. In rabbits, galantamine 48 mg/kg/day administered through organ formation resulted in small increases in visceral and skeletal malformations in offspring; the no-effect dose (28 mg/kg/day) was approximately 20 times the maximum recommended human dose (Prod Info RAZADYNE(R) ER oral extended release capsules, 2013; Prod Info RAZADYNE(R) oral tablets, oral solution, 2013).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown whether or not galantamine is excreted into human breast milk (Prod Info RAZADYNE(R) ER oral extended release capsules, 2013; Prod Info RAZADYNE(R) oral tablets, oral solution, 2013).
    3.20.5) FERTILITY
    A) LACK OF EFFECT
    1) RATS: No fertility effects were observed in rats administered up to 16 mg/kg/day of galantamine (about 7 times the maximum recommended human dose) for 14 or 60 days before mating in female and male rats, respectively (Prod Info RAZADYNE(R) ER oral extended release capsules, 2013; Prod Info RAZADYNE(R) oral tablets, oral solution, 2013).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) ENDOMETRIAL CARCINOMA
    1) A slight increase in endometrial adenocarcinomas was reported in a 24-month oral carcinogenicity study in rats at doses of 10 mg/kg/day. No carcinogenicity was reported in a 24-month oral study in mice given up to 10 mg/kg/day (Prod Info Reminyl(R), galantamine tablets and oral solution, 2001).

Genotoxicity

    A) No evidence of genotoxic potential was seen when galantamine was evaluated in the in vitro Ames S. typhimurium or E. coli reverse mutation assay, in vitro mouse lymphoma assay, in vivo micronucleus test in mice, or in vitro chromosome aberration assay in Chinese hamster ovary cells (Prod Info Reminyl(R), galantamine tablets and oral solution, 2001).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Signs and symptoms of cholinesterase inhibitor poisoning should be monitored. Cholinesterase activity may be depressed and should be monitored in plasma (pseudocholinesterase) and red blood cells.
    B) Monitor ECG following significant exposures. Overdoses may be associated with bradycardia.
    C) Monitor pulse oximetry and/or arterial blood gases and obtain a chest radiograph in patients with pulmonary symptoms.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor serum electrolytes and renal function tests in severe exposures.
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) ECG should be monitored for signs of cholinesterase inhibitor toxicity, such as bradycardia.
    2) OTHER
    a) Monitor bronchial secretions, aggressive pulmonary toilet may be indicated. Chest x-ray and monitoring or pulse oximetry and/or arterial blood gases may be indicated in patients with dyspnea or bronchospasm.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Obtain a chest radiograph in patients with pulmonary symptoms.

Methods

    A) CHROMATOGRAPHY
    1) Reversed-phase liquid chromatography has been used for quantification of galantamine and its major metabolites (epigalanthamine (II) and galanthaminone (III)) in plasma and urine. Detection limits of 0.05 mcg/mL in plasma and urine were reported (Tencheva et al, 1987). Mihailova et al (1989) described a reversed-phase high performance liquid chromatography method for determination of galantamine and its metabolites in plasma and urine.
    2) A high performance liquid chromatography (HPLC) assay, with fluorescence detection, has been performed to determine levels of galantamine and its metabolites in human plasma. Detection limits reported were: 1 ng/mL for galantamine and epigalanthamine and 15 ng/mL for galanthaminone. HPLC was used for urine analysis (Bickel et al, 1991). Westra et al (1986) have also reported using a HPLC assay for quantitation of galantamine in serum, urine and bile.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) All intentional ingestions should be initially managed as a severe exposure. Patients who develop signs or symptoms of cholinergic toxicity (muscarinic, nicotinic or central) should be admitted to an intensive care setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) An asymptomatic child with a minor ingestion (ie a single immediate release tablet) can likely be monitored at home with adult supervision. An adult that has taken an inadvertent extra dose (ie, immediate release formulation) is not likely to develop symptoms.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or poison center for assistance with any patient with moderate to severe cholinergic manifestations.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate ingestions, adults with symptoms or ingestions of more than the therapeutic dose, or a pediatric ingestion should be sent to a healthcare facility for evaluation and treatment.
    1) IMMEDIATE RELEASE: Monitor for at least 3 to 6 hours (time to peak concentration of galantamine immediate release is about 1 hour).
    2) EXTENDED RELEASE: Patients ingesting extended release preparations should be observed for at least 7 to 12 hours (Tmax is 4.5 to 5 hours at a therapeutic dose) and admitted if symptoms develop; effects may be delayed and prolonged.

Monitoring

    A) Signs and symptoms of cholinesterase inhibitor poisoning should be monitored. Cholinesterase activity may be depressed and should be monitored in plasma (pseudocholinesterase) and red blood cells.
    B) Monitor ECG following significant exposures. Overdoses may be associated with bradycardia.
    C) Monitor pulse oximetry and/or arterial blood gases and obtain a chest radiograph in patients with pulmonary symptoms.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) Administer as an aqueous slurry. Cathartics should NOT be used as they will contribute to nausea and diarrhea.
    2) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. Monitor and support respiratory and cardiovascular function. Monitor for cholinomimetic effects. Atropine, a tertiary anticholinergic, may be used as an antidote for overdosage.
    B) ATROPINE
    1) ATROPINE sulfate is the drug of choice and will reverse actions at muscarinic receptors.
    2) DOSE: ADULT: Initial dose of 1 to 2 mg IV repeated every 3 to 60 minutes as needed to control muscarinic symptoms, then as needed for 24 to 48 hours. As much as 50 mg of atropine sulfate may be required in the first 24 hours.
    3) CHILD: Initial dose 0.05 mg/kg up to 4 mg (usual dose 1 mg), IM or IV every 10 to 30 minutes until muscarinic signs and symptoms subside, and repeat if they reappear.
    C) TORSADES DE POINTES
    1) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    2) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    3) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
    4) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    5) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    6) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    7) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.
    D) BRONCHOSPASM
    1) BRONCHOSPASM SUMMARY
    a) Administer beta2 adrenergic agonists. Consider use of inhaled ipratropium and systemic corticosteroids. Monitor peak expiratory flow rate, monitor for hypoxia and respiratory failure, and administer oxygen as necessary.
    2) ALBUTEROL/ADULT DOSE
    a) 2.5 to 5 milligrams diluted with 4 milliliters of 0.9% saline by nebulizer every 20 minutes for three doses. If incomplete response, administer 2.5 to 10 milligrams every 1 to 4 hours as needed OR administer 10 to 15 milligrams every hour by continuous nebulizer as needed. Consider adding ipratropium to the nebulized albuterol; DOSE: 0.5 milligram by nebulizer every 30 minutes for three doses then every 2 to 4 hours as needed, NOT administered as a single agent (National Heart,Lung,and Blood Institute, 2007).
    3) ALBUTEROL/PEDIATRIC DOSE
    a) 0.15 milligram/kilogram (minimum 2.5 milligrams) diluted with 4 milliliters of 0.9% saline by nebulizer every 20 minutes for three doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulizer as needed. Consider adding ipratropium to the nebulized albuterol; DOSE: 0.25 to 0.5 milligram by nebulizer every 20 minutes for three doses then every 2 to 4 hours as needed, NOT administered as a single agent (National Heart,Lung,and Blood Institute, 2007).
    4) ALBUTEROL/CAUTIONS
    a) The incidence of adverse effects of beta2-agonists may be increased in older patients, particularly those with pre-existing ischemic heart disease (National Asthma Education and Prevention Program, 2007). Monitor for tachycardia, tremors.
    5) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm. PREDNISONE: ADULT: 40 to 80 milligrams/day in 1 or 2 divided doses. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 or 2 divided doses (National Heart,Lung,and Blood Institute, 2007).
    E) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Overdoses may be expected to result in severe fluid losses. Monitor and replace fluids and electrolytes as needed.
    F) 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).
    G) 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).
    H) 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).
    I) BRADYCARDIA
    1) ATROPINE/DOSE
    a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    1) There is no minimum dose (de Caen et al, 2015).
    2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    J) CONTRAINDICATED TREATMENT
    1) Galantamine is a cholinesterase inhibitor; do NOT use concurrently with succinylcholine-type and similar neuromuscular blocking agents during anesthesia.

Enhanced Elimination

    A) HEMODIALYSIS
    1) It is unknown whether galantamine or its metabolites can be removed by hemodialysis, peritoneal dialysis, or hemofiltration. Galantamine has a relatively low plasma protein binding of 18% with a mean volume of distribution of 175 L. (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established. Ingestion of 160 mg resulted in sweating, vomiting, bradycardia, and near-syncope in an adult. A dose of 32 mg/day in an adult who had been taking 4 mg daily for one week caused vomiting, bradycardia, QT prolongation, ventricular tachycardia, and torsades de pointes.
    B) THERAPEUTIC: ADULT: Doses must be slowly titrated up to a maximum daily dose. IMMEDIATE RELEASE: Doses of up to 32 mg/day divided in 2 doses may be used therapeutically. EXTENDED RELEASE: Doses of up to 24 mg taken once daily may be used therapeutically. PEDIATRIC: Galantamine is not recommended for use in children.

Therapeutic Dose

    7.2.1) ADULT
    A) IMMEDIATE RELEASE TABLETS and ORAL SOLUTION: INITIAL: 4 mg twice daily (total 8 mg/day); preferably with morning and evening meals. MAINTENANCE: Increase dose initially to 8 mg twice daily (total 16 mg/day) after a minimum of 4 weeks of therapy. A further increase to 12 mg twice daily (total 24 mg/day) should be done after a minimum of 4 weeks at 8 mg twice daily (16 mg/day) (Prod Info RAZADYNE(R) oral tablets, oral solution, 2013).
    B) EXTENDED RELEASE: INITIAL: 8 mg/day; preferably with the morning meal. MAINTENANCE: After a minimum of 4 weeks of therapy, increase dose to 16 mg/day. A further increase to 24 mg/day should be done after a minimum of 4 weeks at 16 mg/day (Prod Info RAZADYNE(R) ER oral extended release capsules, 2013).
    7.2.2) PEDIATRIC
    A) Safety and efficacy of galantamine in pediatric and adolescent patients have not been established (Prod Info RAZADYNE(R) oral tablets, oral solution, 2013; Prod Info RAZADYNE(R) ER oral extended release capsules, 2013).
    B) ANTICHOLINERGIC SYNDROME: In Europe, doses of 0.25 to 1 mg in pediatric patients 1 to 2 years of age have been used. In patients 3 to 5 years of age, 0.5 to 5 mg have been recommended. Doses of 0.75 to 7.5 mg have been advised for those who are 6 to 8 years old. Children 9 to 11 years old have received 1 to 10 mg and those 12 to 15 years of age have received 1.25 to 12.5 mg (ABDA-Datenbank, 1996).

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) CASE REPORT: An adult inadvertently ingested 160 mg (a 10-fold overdose) of oral solution; daily dose was 16 mg/day. One hour after the ingestion he experienced sweating, vomiting, bradycardia, and near-syncope. Symptoms resolved within 24 hours with supportive care (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).
    2) CASE REPORT: Bradycardia, QT prolongation, ventricular tachycardia, and torsades de pointes occurred in a woman who ingested 32 mg in a single day. She had been taking galantamine 4 mg daily for one week prior. She was treated with supportive care (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) GALANTAMINE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 10 mg/kg (RTECS, 2002)
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) 14 mg/kg (RTECS, 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Galantamine hydrobromide is a reversible, competitive acetylcholinesterase inhibitor that has an unknown mechanism of action. However, it is suggested that the drug improves cholinergic function by increasing acetylcholine levels by reversibly inhibiting the neurotransmitter's hydrolysis by acetylcholinesterase. Galantamine hydrobromide does not alter the clinical course of dementia associated with advancing Alzheimer's disease (Prod Info RAZADYNE(R) ER extended release oral capsules, oral tablets, oral solution, 2007).
    B) Galantamine hydrobromide, extracted from the bulbs of the daffodil, Narcissus pseudonarcissus, is an alkaloid that was initially obtained from the Caucasian snowdrop (Voronov's snowdrop), Galanthus woronowii (Amaryllidaceae) and related species (Prod Info Reminyl(R), galantamine tablets and oral solution, 2001; Fulton & Benfield, 1996; Harvey, 1995). It has been hypothesized that the agent (called "moly" in the Homeric Odyssey) used by Odysseus and his men as an antidote to the sorceress Circe's drugs was a derivative of Galanthus nivalis, and thus that the anticholinesterase properties of the snowdrop were known as early as 3000 years ago (Plataikis & Duvoisin, 1983).
    C) Galantamine is a tertiary alkaloid with a dual mode of action: it competitively inhibits AchE and modulates the nicotinic receptor by allosterically potentiating submaximal nicotinic responses to Ach. This agent is a long-acting, reversible competitive inhibitor of cholinesterase activity which antagonizes muscular relaxation produced by nondepolarizing, curare-like, muscular relaxants. It is much less potent against butyrylcholinesterase activity (Prod Info Reminyl(R), galantamine tablets and oral solution, 2001; Harvey, 1995; Thomsen & Kewitz, 1990). It has no activity against depolarizing muscular relaxants.
    1) Galantamine inhibits acetylcholinesterase activity at the peripheral and central cholinergic synapses and in parasympathetic nervous systems (Fulton & Benfield, 1996; Thomsen & Kewitz, 1990; Tencheva et al, 1987; Cozanitis, 1977), but is much less potent against butyrylcholinesterase activity (Harvey, 1995; Fulton & Benfield, 1996; Thomsen & Kewitz, 1990). Galantamine is also known to allosterically modulate nicotinic receptors so as to potentiate the receptor response to acetylcholine (Raskind et al, 2000; Tariot et al, 2000). The affinity of acetylcholinesterase to galantamine is approximately 100 times the affinity of pseudocholinesterase (butyrylthiocholine substrate) to galantamine (Schuh, 1976). Studies involving neuromuscular transmission revealed that galantamine is approximately 10 to 20 times weaker than neostigmine regarding anticholinesterase activity (Harvey, 1995).
    2) Due to its mechanism as an anticholinesterase drug capable of penetrating the blood-brain barrier, galantamine has been used in the treatment of scopolamine overdose in patients exhibiting central effects of scopolamine. Galantamine is longer acting than physostigmine and has been used in anesthesia to reverse the nondepolarizing neuromuscular block (Cozanitis, 1977).
    D) Galantamine is a tertiary amine and phenanthrene derivative that crosses the blood-brain barrier (Harvey, 1995; Tencheva et al, 1987; Cozanitis & Toivakka, 1974). However, galantamine possesses greater cholinesterase inhibition in erythrocytes than in human brain tissue and it is unknown how effective this agent may prove to be. In vitro studies have demonstrated that the galantamine concentration required to produce 50% inhibition (IC50) of acetylcholinesterase was 0.35 mmol/L in erythrocytes compared to 2.8 mmol/L to 3.2 mmol/L for a study utilizing human brain tissue (Fulton & Benfield, 1996).
    E) Early clinical reports stated that galantamine had a minimal effect on the autonomic nervous system. However, some muscarinic adverse effects including nausea, blurred vision, electrocardiogram changes, and hypersalivation have suggested that parasympathetic stimulation appears to exist with galantamine (Harvey, 1995).

Toxicologic Mechanism

    A) Signs and symptoms of significant overdose is anticipated to be similar to other cholinomimetics (eg, nausea, vomiting, diarrhea, salivation, defecation, bronchorrhea and convulsions) (Prod Info RAZADYNE(R) oral tablets, oral solution, 2012).

Physicochemical

Physical Characteristics

    A) The hydrobromide salt of galantamine is a white to almost white powder with a bitter taste. Galantamine is sparingly soluble in water, but its hydrobromide salt is readily soluble in water (Prod Info Reminyl(R), galantamine tablets and oral solution, 2001) Cozantis, 1970).

Molecular Weight

    A) 368.27 (Galantamine hydrobromide)
    B) 287.39 (Galantamine)

References

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