MOBILE VIEW  | 

MORICIZINE

Classification   |    Detailed evidence-based information

Therapeutic Toxic Class

    A) Moricizine is a Class 1 antiarrhythmic with potent local anesthetic activity and myocardial membrane stabilizing effects. Moricizine also reduces the fast inward current carried by sodium ions.

Specific Substances

    1) 10-(3-morpholinopropionyl) phenothiazine-2-carbamic
    2) acid ethyl ester hydrochloride
    3) Athmoxin
    4) Ethyl [10-(3-morpholinopropionyl)phenothiazin
    5) -2-yl]carbamate hydrochloride
    6) EN-313
    7) Ethmosine
    8) Ethmozine
    9) Etmozin
    10) G 214
    11) Moracizine
    12) Moricizine
    13) Molecular Formula: C22-H25-N3-O4-S
    14) CAS 31883-05-3 (moracizine)
    15) CAS 29560-58-5 (moracizine hydrochloride)

Available Forms Sources

    A) USES
    1) Moricizine is indicated for the treatment of documented ventricular dysrhythmias, such as sustained ventricular tachycardia, that, in the judgement of physicians are life-threatening (Prod Info ETHMOZINE(R) oral tablets, 2002).

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) ANIMAL STUDIES - Death was usually preceded by tremors, convulsions and respiratory depression in monkeys, dogs, rats and mice.
    B) WITH THERAPEUTIC USE
    1) The most serious adverse reaction reported for moricizine is proarrhythmia (3.7% to 15%).
    2) Dizziness (15.1%; N=1072) is dose dependent.
    3) Nausea (9.6%), headache (8.0%), palpitations (5.8%) and dyspnea (5.7%) were reported in 1072 patients during pre-marketing studies.
    C) WITH POISONING/EXPOSURE
    1) Deaths have occurred after accidental or intentional overdoses of 2,250 and 10,000 milligrams of moricizine hydrochloride.
    2) Overdose with moricizine may provoke a proarrhythmic effect (including junctional bradycardia, ventricular tachycardia (VT), ventricular fibrillation (VF), and asystole). Additional effects may include respiratory failure, coma, syncope, hypotension, conduction disturbances, exacerbation of congestive heart failure (CHF), myocardial infarction, sinus arrest, emesis and lethargy.
    0.2.20) REPRODUCTIVE
    A) No teratogenic effects have been seen in rats and rabbits at doses above the maximum recommended daily human dose.
    B) Moricizine is excreted in human breast milk.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    B) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.
    1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.
    C) Use special care to avoid aspiration as accidental introduction of moricizine into the lungs of monkeys resulted in RAPID arryhthmic death.
    D) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Sodium bicarbonate is generally first line therapy for QRS widening and ventricular dysrhythmias, administer 1 to 2 mEq/kg, repeat as needed to maintain blood pH between 7.45 and 7.55. In patients unresponsive to bicarbonate, consider lidocaine.
    E) LIDOCAINE: ADULT: LOADING DOSE: 1 to 1.5 milligram/kilogram via IV push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram. Only bolus therapy is recommended during cardiac arrest. INFUSION: Once circulation is restored begin an infusion of 1 to 4 mg/min. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute). PEDIATRIC: LOADING DOSE: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute. Monitor ECG continuously.
    F) CONTRAINDICATIONS
    1) Avoid Class 1A (disopyramide, procainamide, quinidine) because they act by similar mechanisms.
    G) TORSADES DE POINTES: Hemodynamically unstable patients require electrical cardioversion. Treat stable patients with magnesium (first-line agent) and/or atrial overdrive pacing. Correct electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia) and hypoxia, if present.
    1) MAGNESIUM SULFATE/DOSE: ADULT: 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes. An optimal dose has not been established. Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram/hour, if dysrhythmias recur. CHILDREN: 25 to 50 mg/kg diluted to 10 mg/mL; infuse IV over 5 to 15 minutes.
    2) OVERDRIVE PACING: Begin at 130 to 150 beats per minute, decrease as tolerated.
    3) Avoid class Ia (eg, quinidine, disopyramide, procainamide), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol).
    H) 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.
    I) 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.
    J) 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.

Range Of Toxicity

    A) Deaths have been reported following ingestion of 2250 and 10000 milligrams.

Summary Of Exposure

    A) ANIMAL STUDIES - Death was usually preceded by tremors, convulsions and respiratory depression in monkeys, dogs, rats and mice.
    B) WITH THERAPEUTIC USE
    1) The most serious adverse reaction reported for moricizine is proarrhythmia (3.7% to 15%).
    2) Dizziness (15.1%; N=1072) is dose dependent.
    3) Nausea (9.6%), headache (8.0%), palpitations (5.8%) and dyspnea (5.7%) were reported in 1072 patients during pre-marketing studies.
    C) WITH POISONING/EXPOSURE
    1) Deaths have occurred after accidental or intentional overdoses of 2,250 and 10,000 milligrams of moricizine hydrochloride.
    2) Overdose with moricizine may provoke a proarrhythmic effect (including junctional bradycardia, ventricular tachycardia (VT), ventricular fibrillation (VF), and asystole). Additional effects may include respiratory failure, coma, syncope, hypotension, conduction disturbances, exacerbation of congestive heart failure (CHF), myocardial infarction, sinus arrest, emesis and lethargy.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) HYPERTHERMIA - Moricizine has been associated with 2 cases of fever of unknown origin (Miura et al, 1986). Both patients developed fevers greater than 40 C with shaking, chills, disorientation, elevated CPK, erythrocyte sedimentation rate and liver enzymes levels, and a positive antinuclear antibody.
    a) Due to moricizine's phenothiazine-like structure, these patients may have had neuroleptic malignant syndrome.
    b) Fever subsided within 48 hours of drug cessation. Fever recurred upon rechallenge with the patients becoming afebrile upon discontinuing moricizine.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Proarrhythmia is a relatively common adverse effect ranging from 3.2% to 15%, depending on study design and patient selection criteria (Morganroth & Pratt, 1989; Tschaidse et al, 1992). There does not appear to be a relationship between the dose of moricizine (milligrams/day) and the incidence of proarrhythmia (Morganroth & Pratt, 1989).
    b) Proarrhythmia occurred in patients with more conduction defects or structural heart disease at baseline; however, proarrhythmia was not related to moricizine dose or baseline frequency of ventricular premature complexes (Morganroth & Pratt, 1989).
    c) The majority of serious proarrhythmias occurred in patients with lethal or potentially lethal ventricular dysrhythmias (Morganroth & Pratt, 1989).
    d) All 29 proarrhythmic events occurred within 10 days, with 26 of 29 (90%) occurring within 7 days of initiating moricizine therapy (Morganroth & Pratt, 1989).
    e) Bhandari et al (1993) reported low efficacy rates with moricizine (16% as determined by electrophysiologic testing) in patients with clinically sustained VT/VF and a high rate of proarrhythmia (22%).
    f) Low ejection fraction (less than 40%), clinical congestive heart failure and previous episodes of proarrhythmia are predictive of a proarrhythmic event with moricizine (Tschaidse et al, 1992).
    g) TACHYCARDIA VENTRICULAR - The new onset (new morphologic features) of VT in 2 patients with chronic high-frequency ventricular dysrhythmias occurred following moricizine therapy (Singh et al, 1984).
    1) Each episode produced lightheadedness with spontaneous reversion to sinus rhythm.
    2) The rates of VT ranged from 168 to 200 beats/minute and lasted from 15 to 30 minutes.
    2) WITH POISONING/EXPOSURE
    a) Overdose has caused junctional bradycardia, ventricular tachycardia, ventricular fibrillation and asystole (Prod Info Ethmozine(R), moricizine hydrochloride, 2001).
    B) HEART FAILURE
    1) WITH THERAPEUTIC USE
    a) Moricizine may exacerbate CHF at therapeutic doses (O'Rangers & Kluger, 1992).
    b) CASE REPORT - A 61-year-old male with a history of CHF and ischemic heart disease developed progressive shortness of breath and pulmonary edema following five doses of moricizine (250 mg every 8 hours) (O'Rangers & Kluger, 1992). Moricizine was discontinued with diuretics added and the patient stabilized; however, he died 12 hours later after developing polymorphic VT which was unresponsive to resuscitation.
    c) Pratt et al (1990) reported recurrence of CHF in 48 of 374 patients (12.8%) with a history of CHF versus 1 of 546 patients (0.2%) without a history of CHF. Duration of therapy appears related to the development of CHF. Onset of CHF occurred within 1 month for the majority of patients.
    C) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) In a clinical study, Biollaz et al (1985) reported that one healthy volunteer experienced a drop in mean blood pressure of 15 mmHg 1 hour following a 500 mg dose and experienced concomitant dizziness and tingling hands.

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) In clinical trials, dyspnea was reported in 5.7% (n=1072) of patients taking moricizine (S Sweetman , 2001; Prod Info Ethmozine(R), moricizine hydrochloride, 2001).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH THERAPEUTIC USE
    a) The most common central nervous system effects at therapeutic doses include dizziness, lightheadedness, anxiety, fatigue, headache, euphoria and perioral numbness (S Sweetman , 2001) Morganroth et al, 1987; (Pratt et al, 1983; Gear et al, 1986; Singh et al, 1984).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH THERAPEUTIC USE
    a) Although not common, nausea, diarrhea, dry mouth and abdominal discomfort have been reported at therapeutic doses (S Sweetman , 2001; Pratt et al, 1983; Gear et al, 1986; Singh et al, 1984).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) RATS - Zymbal's Gland Carcinoma and hepatocellular cholangioma (bile ductile cystadenoma or cystic hyperplasia) was reported in a 24-month study in which moricizine was administered at doses of 25, 50 and 100 mg/Kg/day (Prod Info Ethmozine(R), moricizine hydrochloride, 2001).
    2) Zymbal's Gland carcinoma was observed in one mid-dose and two high-dose males (Prod Info Ethmozine(R), moricizine hydrochloride, 2001).
    3) A dose-related increase in hepatocellular cholangioma was observed in both sexes (Prod Info Ethmozine(R), moricizine hydrochloride, 2001).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) A significant elevation in liver enzymes associated with severe pruritus and malaise developed in a patient on the second day of treatment with moricizine. Liver enzyme levels returned to normal after discontinuation of therapy (Geller et al, 2001).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) A severe rash developed in a patient receiving moricizine for atrial fibrillation. The rash resolved after discontinuation of therapy (Geller et al, 2001).

Reproductive

    3.20.1) SUMMARY
    A) No teratogenic effects have been seen in rats and rabbits at doses above the maximum recommended daily human dose.
    B) Moricizine is excreted in human breast milk.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) Teratology studies have been performed with moricizine in rats and rabbits at doses up to 6.7 and 4.7 times the maximum recommended human daily dose, respectively, with no evidence of harm to the fetus (Prod Info Ethmozine(R), moricizine hydrochloride, 2001).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) FDA Pregnancy Category B (Prod Info Ethmozine(R), moricizine hydrochloride, 2001)
    B) ANIMAL STUDIES
    1) Dose related decrease in pup weight observed when moricizine was administered to rats prior to mating, during mating and throughout gestation and lactation at doses as high as 6.7 times the maximum recommended human daily dose (Prod Info Ethmozine(R), moricizine hydrochloride, 2001).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Moricizine is excreted in human breast milk (Prod Info Ethmozine(R), moricizine hydrochloride, 2001).

Life Support

    A) Support respiratory and cardiovascular function.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    B) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6) Use special care to avoid aspiration as accidental introduction of moricizine into the lungs of monkeys resulted in RAPID arryhthmic death (Prod Info Ethmozine(R), moricizine hydrochloride, 1994).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Obtain baseline ECG and intermittent ECGs as indicated, continuous cardiac monitoring and vital signs.
    2) ELECTROLYTES: Monitor serum potassium and magnesium.
    B) VENTRICULAR ARRHYTHMIA
    1) SUMMARY: Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Sodium bicarbonate is generally first line therapy for QRS widening and ventricular dysrhythmias, administer 1 to 2 mEq/kg, repeat as needed to maintain blood pH between 7.45 and 7.55. In patients unresponsive to bicarbonate, consider lidocaine.
    2) SODIUM BICARBONATE
    a) Although not reported for moricizine, hypertonic sodium bicarbonate (100 mEq/mL) boluses have been used to reverse QRS widening and dysrhythmias after overdose with other agents with sodium channel blocking effects (flecainide, tricyclic antidepressants).
    b) A reasonable starting dose is 1 to 2 mEq/kg repeated as needed to maintain arterial pH 7.45-7.55.
    3) SODIUM LACTATE: Infusion of molar sodium lactate in high doses to 3 patients with flecainide intoxication (cardiovascular collapse, wide QRS) resulted in rapid clinical and electrocardiographic improvement. The molar sodium lactate may displace flecainide from its receptor sites or may alter the action of flecainide on the fast sodium channels. Patients received 500 mL of a 1 mEq/mL sodium lactate solution intravenously over 30 minutes with apparent shortening of the QRS duration. (Pentel et al, 1990).
    4) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    c) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    5) CONTRAINDICATIONS
    a) Avoid Class 1A (disopyramide, procainamide, quinidine) because they may act by similar mechanisms.
    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) 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).
    E) 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).
    F) 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).

Summary

    A) Deaths have been reported following ingestion of 2250 and 10000 milligrams.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) CAUTION -
    a) The dose of moricizine must be individualized on the basis of antiarrhythmic response and tolerance. The manufacturer recommends hospitalization with cardiac monitoring during the initiation of therapy (Prod Info Ethmozine(R), moricizine hydrochloride, 2001).
    2) USUAL DOSE -
    a) The usual adult dose is between 600 and 900 milligrams/day, given every 8 hours in three equally divided doses (Prod Info Ethmozine(R), moricizine hydrochloride, 2001).
    b) Within this range, the dose can be adjusted as tolerated, in increments of 150 milligrams/day at three day intervals, up to a total dose of 900 milligrams/day (USPDI, 2001; (Prod Info Ethmozine(R), moricizine hydrochloride, 2001).
    c) Patients with life-threatening arrhythmias who exhibit a beneficial response as judged by objective criteria (Holter monitoring, programmed electrical stimulation, exercise testing, etc) can be maintained on chronic moricizine (Prod Info Ethmozine(R), moricizine hydrochloride, 2001).
    d) Patients whose arrhythmias are well controlled on the every 8 hours regimen may be given the same total daily dose in a every 12 hour regimen to improve compliance and convenience (Prod Info Ethmozine(R), moricizine hydrochloride, 2001).
    e) When higher doses are used, patients may experience more dizziness and nausea on the every 12 hour regimen (Prod Info Ethmozine(R), moricizine hydrochloride, 2001).
    3) DOSE ADJUSTMENTS FOR HEPATIC OR RENAL IMPAIRMENT -
    a) Patients with hepatic disease or significant renal dysfunction should be started at 600 milligrams/day or lower and monitored closely, including measurement of ECG intervals, before dose adjustment (Prod Info Ethmozine(R), moricizine hydrochloride, 2001).

Minimum Lethal Exposure

    A) CASE REPORTS
    1) Six fatalities resulting from the use of 600 to 900 milligrams/day moricizine have occurred (Prod Info Ethmozine(R), moricizine hydrochloride, 2001).
    2) All six proarrhythmic deaths were in patients with coronary artery disease; 5 of the 6 each had documented acute myocardial infarct, congestive heart failure, and cardiomegaly.

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) The maximum reported dose of moricizine was 1500 milligrams/day or 16 milligrams/kilogram/day with no unanticipated adverse events (Pratt et al, 1983).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA

General Bibliography

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