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ENCAINIDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Encainide is a class 1C antiarrhythmic agent with some local anesthetic activity. It is a benzanilide derivative, not structurally related to other antiarrhythmic agents.

Specific Substances

    1) Encainide
    2) MJ 9067-1
    3) 4-Methoxy-2(2-(1-methyl-2-piperidyl)ethyl)-
    4) benzanilide hydrochloride
    5) Molecular Formula: C22-H28-N2-O2
    6) CAS 37612-13-8 (encainide)
    7) CAS 66778-36-7 (encainide)
    8) CAS 66794-74-9 (encainide hydrochloride)

Available Forms Sources

    A) FORMS
    1) Effective December 16, 1991, encainide was voluntarily withdrawn from the market. For patients started on encainide before this date, they may obtain the drug through their physicians via the Continuing Patient Access Program (800) 527-6741 (Personal Communication, 1991). Encainide hydrochloride is available in 25, 35, and 50 mg capsules as Enkaid(R) (Prod Info Enkaid(R), encainide, 1992).
    B) USES
    1) Encainide is used in the treatment of ventricular and supraventricular arrhythmias (Prod Info Enkaid(R), encainide, 1992).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH POISONING/EXPOSURE
    1) Cardiac and CNS effects have occurred in overdose, including seizures, bradycardia, hypotension, ventricular tachycardias and ECG changes (prolonged QRS, QTc, and PR intervals). These effects have occurred within 2 hours after ingestion. ECG changes may persist for more than 2 days.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Bradycardia, tachycardia and hypotension may occur.
    0.2.4) HEENT
    A) WITH THERAPEUTIC USE
    1) Blurred vision is a common adverse effect.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONIG/EXPOSURE
    1) Overdose effects may include bradycardia, tachycardia, and hypotension, ECG signs of conduction disturbance (prolonged QRS, PR, and QTc intervals) and ventricular dysrhythmias.
    B) WITH THERAPEUTIC USE
    1) Proarrhythmic events have occurred after therapeutic doses.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) Seizures and CNS depression may develop after overdose.
    0.2.11) ACID-BASE
    A) WITH POISONING/EXPOSURE
    1) Metabolic acidosis may occur secondary to seizures or hypotension.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) A dose related rash and angioedema may occur.
    0.2.16) ENDOCRINE
    A) WITH THERAPEUTIC USE
    1) Hyperglycemia has been reported during therapeutic use.
    0.2.20) REPRODUCTIVE
    A) Encainide is pregnancy category B. Reproductive studies in rats and rabbits have not demonstrated fetal harm. Encainide and its active metabolite are excreted in human milk.

Laboratory Monitoring

    A) Monitor blood glucose.
    B) Continuous cardiac monitoring is recommended.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) 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.
    B) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    C) CONDUCTION DEFECTS - Bolus intravenous injection of hypertonic sodium bicarbonate, 1 to 2 mEq/kg, has been successful in improving cardiac rhythm and hypotension. Monitor blood gases and serum electrolytes closely. Target blood pH is 7.45 to 7.55.
    D) PRECAUTIONS - Avoid type IA antiarrhythmic agents (quinidine, procainamide, disopyramide).
    E) VENTRICULAR DYSRHYTHMIAS - Standard supportive care for ventricular dysrhythmias should be instituted, including cardioversion and cardiopulmonary resuscitation, if necessary.
    1) Magnesium sulfate intravenously was anecdotally reported successful in a patient with arrhythmias resistant to other standard treatment.
    2) Usual adult dose is 2 grams of magnesium sulfate intravenously, repeated as necessary with clinical and laboratory monitoring for hypermagnesemia (depression of muscle stretch reflexes).
    F) VENTRICULAR DYSRHYTHMIAS/SUMMARY: Institute continuous cardiac monitoring, obtain an ECG, and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders. Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.

Range Of Toxicity

    A) Single "extra" therapeutic doses in patients receiving encainide for dysrhythmias have provoked serious proarrhythmic events.
    B) A young healthy man ingested 3 to 3.5 grams and developed serious toxicity, but survived.

Clinical Effects

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HYPOPROTEINEMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - Possible encainide-induced hypoproteinemia has been noted in a post-myocardial infarct patient receiving encainide therapy for 3 months. Signs and symptoms resolved after discontinuing encainide therapy; however, total protein or albumin levels were not evaluated after discontinuation (Perry & Oszko, 1990).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) A dose related rash and angioedema may occur.
    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Periorbital edema and rash occur at a frequency of less than 1%, but at doses greater than 200 mg daily, rash is reported to occur at a frequency of 4% (Sun et al, 1994).

Endocrine

    3.16.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Hyperglycemia has been reported during therapeutic use.
    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) CASE SERIES - Four patients treated therapeutically with encainide were reported to develop episodes of marked hyperglycemia. Several patients appeared to have preexisting borderline hyperglycemia (Salerno et al, 1988).
    b) CASE REPORT - Symptomatic hyperglycemia occurred in a patient with a history of type II diabetes after receiving encainide 25 milligrams 3 times daily for 6 months.
    1) Encainide therapy was discontinued and the patient was instructed to follow the American Diabetes Association 1800 calorie diet and to monitor glucose levels.
    2) One week later the patient was asymptomatic for diabetes mellitus (Mason & Riger, 1989).
    c) CASE REPORT - Onset of type II diabetes mellitus occurred in a 65-year-old non-obese male after 4 months of encainide therapy. Two months after the first onset of glycosuria, glycosuria and fasting hyperglycemia persisted, with no ketonuria detected. Five months following discontinuation of encainide, euglycemia was achieved (Winter et al, 1992).

Reproductive

    3.20.1) SUMMARY
    A) Encainide is pregnancy category B. Reproductive studies in rats and rabbits have not demonstrated fetal harm. Encainide and its active metabolite are excreted in human milk.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) Reproductive studies in rats and rabbits given up to 13 and 9 times the average human dose (28 mg/kg/day and 19 mg/kg/day), respectively, have not demonstrated fetal harm (Prod Info, 1988).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    ENCAINIDEB
    Reference: Briggs et al, 1998
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Encainide and its active metabolite are excreted in human milk. One woman receiving encainide 50 milligrams four times daily had encainide and O-demethyl-encainide milk levels of 200 to 400 ng/mL and 100 to 200 ng/mL, respectively (Briggs et al, 1998).

Summary Of Exposure

    A) WITH POISONING/EXPOSURE
    1) Cardiac and CNS effects have occurred in overdose, including seizures, bradycardia, hypotension, ventricular tachycardias and ECG changes (prolonged QRS, QTc, and PR intervals). These effects have occurred within 2 hours after ingestion. ECG changes may persist for more than 2 days.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Bradycardia, tachycardia and hypotension may occur.
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) Hypotension has been described after overdose (Pentel et al, 1986; Mortensen et al, 1992).
    3.3.5) PULSE
    A) WITH POISONING/EXPOSURE
    1) Bradycardia has been described after overdose (Pentel et al, 1986).
    2) Tachycardia has been reported after overdose (Mortensen et al, 1992).

Heent

    3.4.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Blurred vision is a common adverse effect.
    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Blurred vision was a commonly reported side effect during oral therapeutic use, occurring in 19% of 1245 patients in one study (Soyka, 1986).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONIG/EXPOSURE
    1) Overdose effects may include bradycardia, tachycardia, and hypotension, ECG signs of conduction disturbance (prolonged QRS, PR, and QTc intervals) and ventricular dysrhythmias.
    B) WITH THERAPEUTIC USE
    1) Proarrhythmic events have occurred after therapeutic doses.
    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Paradoxical worsening of ventricular tachycardia or fibrillation has been noted during initiation of therapy in patients treated for cardiac dysrhythmias.
    1) The risk of precipitation of malignant tachydysrhythmia was 11% to 12% in patients with recurrent V-tach or V-fib and 2.2% to 2.8% in patients with chronic ventricular extrasystoles (Soyka, 1986; Winkle et al, 1981).
    2) This effect was more common when doses exceeded 200 mg/day.
    b) Proarrhythmic events are also more frequent in patients with cardiomyopathy (16%), congestive heart failure (17%), and myocardial infarction (10 to 11%) (Soyka, 1986).
    c) CASE SERIES - Two patients with recurrent V-tach had proarrhythmic events after single large doses (75 mg IV or PO), and one patient developed a cardiac arrest 1.5 hours after inadvertently receiving an extra 35 mg dose two hours after the previous dose.
    d) Ventricular tachycardia followed by fibrillation and death has been reported in a patient whose encainide therapy was discontinued. Hospitalization for select patients whose encainide therapy is to be discontinued may be necessary (Thomas, 1989).
    e) Encainide was associated with twice as many deaths from dysrhythmia as placebo in post-myocardial infarct patients, with asymptomatic ventricular dysrhythmias, in the Cardiac Dysrhythmia Suppression Trial (CAST).
    f) The manufacturer recommends use only for the treatment of life-threatening dysrhythmias, such as sustained ventricular tachycardia (Anon, 1989; CAST, 1989).
    1) CASE SERIES - Over the course of 1 year, 10% of patients receiving encainide or flecainide developed symptomatic atrial proarrhythmic effects requiring hospitalization and treatment (Feld et al, 1990). Withdrawal of the drug resulted in resolution of these, new or modified, atrial dysrhythmias in all patients.
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT - Wide-complex sinus tachycardia (QRS, 0.16 seconds) occurred, followed by acute decompensation and ventricular tachycardia, which progressed into ventricular fibrillation, in a 6-month-old infant within approximately 40 minutes of ingestion of a single 25 mg tablet (Mortensen et al, 1992).
    b) CASE REPORT - A patient with benign ventricular dysrhythmia developed right bundle branch block and sustained ventricular tachycardia after inadvertently taking an extra dose while receiving 300 mg/day (Soyka, 1986).
    B) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Encainide produces a dose-dependent increase in QRS, PR, and QTc intervals (Prod Info, 1986).
    2) WITH POISONING/EXPOSURE
    a) Dose-dependent increase in QRS, PR, and QTc intervals have been described after overdose (Pentel et al, 1986).
    C) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) Bradycardia occurs in about 1% of patients receiving therapeutic doses (Prod Info, 1988).
    2) WITH POISONING/EXPOSURE
    a) Bradycardia has been reported after overdose (Pentel et al, 1986).
    D) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypotension has been described after overdose (Mortensen et al, 1992; Pentel et al, 1986).
    E) DEAD - SUDDEN DEATH
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A patient treated for asymptomatic ventricular dysrhythmias developed sudden cardiac death after receiving encainide 25 milligrams 3 times daily for 7 days. The patient was resuscitated, and upon rechallenge, electrophysiology demonstrated sinus node dysfunction with sinus pauses and asystole (Lemery et al, 1989).
    F) ANGINA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A patient with dilated cardiomyopathy receiving encainide therapy developed ischemic symptoms, including substernal chest pain, dyspnea, diaphoresis, and nausea (Barron & Billhardt, 1989).
    1) Symptoms resolved upon withdrawal of the drug, but recurred with a re-challenge of encainide 36 hours later.
    2) The patient's signs and symptoms resolved within 10 minutes of administering sublingual nitroglycerin, suggesting an ischemic process.
    G) CARDIAC PACEMAKER SENSITIVITY PROBLEM
    1) WITH THERAPEUTIC USE
    a) Encainide has been reported to increase the pacemaker threshold at high therapeutic doses (more than 200 mg/day) (Prod Info, 1988).

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Seizures and CNS depression may develop after overdose.
    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - Several brief generalized seizures were reported two hours after ingestion of 3 to 3.5 grams in a healthy 46-year-old man (Pentel et al, 1986).
    B) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - An adult who took 3 to 3.5 grams was obtunded for 6 to 8 hours after ingestion (Pentel et al, 1986).
    2) ANIMAL STUDIES - Coma was reported in animal toxicology studies.
    C) TOXIC ENCEPHALOPATHY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A patient with chronic renal failure receiving encainide 25 milligrams every 8 hours for chronic ventricular dysrhythmias developed a drug-induced encephalopathic condition within 2 weeks of initiating therapy.
    1) Symptoms of confusion, memory impairment, and agitation improved 72 hours after discontinuance. Rechallenge demonstrated the same symptoms within 48 hours.
    b) Patients with renal impairment should receive one-third of the regularly prescribed dose (Tartini & Kesselbrenner, 1990).
    D) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) CASE SERIES - Dizziness was the most frequent noncardiac adverse reaction during therapeutic use, occurring in 26% of 1245 patients (Soyka, 1986).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) Encainide is reported to induce hepatitis with jaundice as a rare adverse effect following therapeutic use (Sun et al, 1994).

Acid-Base

    3.11.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Metabolic acidosis may occur secondary to seizures or hypotension.
    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - Acidosis (pH 7.26, bicarb 12 mEq/liter) was reported in a patient with seizures after encainide overdose (Pentel et al, 1986).

Laboratory Monitoring

Methods

    A) CHROMATOGRAPHY
    1) Encainide and its metabolites, O-demethyl encainide (ODE) and 3-methoxy-O-demethyl encainide (MODE), can be measured by high performance liquid chromatography (HPLC) (Mayol et al, 1981). Radioimmunoassay measures only the parent drug.

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor blood glucose.
    B) Continuous cardiac monitoring is recommended.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor blood glucose, especially in patients with preexisting diabetes.
    2) PLASMA DRUG CONCENTRATIONS - The value of monitoring encainide or its metabolite plasma concentrations has not been studied in overdose patients.
    a) Assessment of plasma concentrations is different for extensive versus poor metabolizers.
    b) Prolonged QRS interval correlated best with O-demethyl encainide (ODE) plasma concentrations (the primary active metabolite) in extensive metabolizers, and with encainide plasma concentrations in poor metabolizers (Carey et al, 1984).
    c) Phenotype can be determined by measuring an 8-hour urinary excretion. A ratio of encainide to O-demethyl encainide (ODE) of greater than 1 indicates a poor metabolizer (McAllister et al, 1986).
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Continuous ECG monitoring is recommended until ECG changes normalize. The QRS, PR, and QTc intervals normalized over 57 hours in one case (Pentel et al, 1986).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Monitor blood glucose.
    B) Continuous cardiac monitoring is recommended.

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.
    6.5.3) TREATMENT
    A) CONTRAINDICATED TREATMENT
    1) Avoid type IA antiarrhythmic agents (i.e., quinidine, procainamide, disopyramide), that have similar effects as encainide on depolarization.
    2) In one patient, administration of procainamide was associated with abrupt worsening of dysrhythmias and multiple cardiac arrests (Winkle et al, 1981).
    B) WIDE QRS COMPLEX
    1) SODIUM BICARBONATE
    a) Administer intravenous bolus of sodium bicarbonate (initial dose 1 to 2 milliequivalents/kilogram repeated as necessary). Target blood pH is 7.45 to 7.55.
    b) CASE REPORT: Bolus intravenous injection of hypertonic sodium bicarbonate given over several minutes was effective in improving cardiac rhythm and hypotension in one patient who overdosed on encainide. Subsequent bolus injections produced transient decreases in QRS duration (Pentel et al, 1986).
    2) PHENYTOIN: Has been effective in the treatment of conduction defects due to other drugs with similar ECG effects and may be considered in patients with conduction defects due to encainide overdose, particularly in patients with seizures. Phenytoin loading can be administered concurrently with sodium bicarbonate boluses.
    a) PHENYTOIN LOADING DOSE (ADULT and CHILD): Administer 15 milligrams/kilogram up to 1.0 gram intravenously not to exceed a rate of 0.5 milligram/kilogram/minute or 50 milligrams per minute with ECG monitoring.
    b) PHENYTOIN MAINTENANCE DOSE: ADULT - administer 2 milligrams/kilogram intravenously every 12 hours as needed; CHILD - administer 2 milligrams/kilogram intravenously every 8 hours as needed.
    c) MONITOR
    1) SERUM PHENYTOIN LEVELS just prior to initiating and during maintenance therapy to assure therapeutic levels of 10 to 20 micrograms/milliliter.
    C) VENTRICULAR ARRHYTHMIA
    1) SODIUM BICARBONATE
    a) Administer intravenous bolus of sodium bicarbonate (initial dose 1 to 2 milliequivalents/kilogram repeated as necessary). Target blood pH is 7.45 to 7.55.
    b) CASE REPORT: Bolus intravenous injection of hypertonic sodium bicarbonate given over several minutes was effective in improving cardiac rhythm and hypotension in one patient who overdosed on encainide. Subsequent bolus injections produced transient decreases in QRS duration (Pentel et al, 1986).
    2) Standard supportive care for ventricular dysrhythmias should be instituted, including cardioversion and cardiopulmonary resuscitation, if necessary.
    3) CONTRAINDICATIONS
    a) Avoid type IA antiarrhythmic agents (i.e., quinidine, procainamide, disopyramide), that have similar effects as encainide on depolarization.
    1) In one patient, administration of procainamide was associated with abrupt worsening of dysrhythmias and multiple cardiac arrests (Winkle et al, 1981).
    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) AMIODARONE
    a) AMIODARONE/INDICATIONS
    1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).
    b) AMIODARONE/ADULT DOSE
    1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).
    c) AMIODARONE/PEDIATRIC DOSE
    1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).
    d) ADVERSE EFFECTS
    1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).
    6) MAGNESIUM SULFATE
    a) CASE REPORT: Intravenous magnesium sulfate was anecdotally successful in a patient with encainide-induced dysrhythmias resistant to other standard treatment (Winkle et al, 1981).
    b) Usual adult dose is 2 grams of magnesium sulfate intravenously, repeated as necessary with clinical and laboratory monitoring for hypermagnesemia (depression of muscle stretch reflexes).
    D) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis does not result in clinically significant removal of encainide or its metabolites (Halvorsen et al, 1991).
    2) The hemodialysis clearance of encainide, 3-methoxy O-demethyl encainide (MODE), and O-demethyl encainide (ODE) were less than 10 percent of the creatinine clearance of the dialyzer in a 31-year-old hemodialysis patient following a 25-milligram oral dose during an interdialytic period and a second 25-milligram oral dose 48 hours later (2 hours before hemodialysis).

Abstracts

Case Reports

    A) INFANT
    1) A near-fatal case of encainide toxicity occurred in a 6-month-old infant ingesting a single encainide 25-mg tablet. Sixty minutes after ingestion, serum encainide and encainide metabolite concentrations exceeded the adult therapeutic range (encainide concentration was 180 ng/mL) (Mortensen et al, 1992).
    a) Within 30 minutes, a wide-complex sinus tachycardia (QRS, 0.16 seconds) occurred followed by acute decompensation and ventricular tachycardia. Electroshock cardioversion was successfully performed; however, the ventricular tachycardia returned. Following intraosseous fluids, sodium bicarbonate, phenytoin, and defibrillation, the wide-complex tachyarrhythmia normalized.
    B) ADULT
    1) A 46-year-old previously healthy man ingested encainide 3 to 3.5 grams. Two hours later he was obtunded, had several brief seizures, and was hypotensive (50 mmHg systolic) and bradycardic (60 BPM). Shortly after presentation the heart rate abruptly decreased to 30 BPM with unmeasurable blood pressure. Administration of sodium bicarbonate 150 mEq was associated with normalization of heart rate and blood pressure.
    a) Transient decrease in QRS duration (from 0.157 to 0.13 seconds) was observed after a further dose of 100 mEq of sodium bicarbonate two hours after admission. CNS changes reversed within 6 hours of presentation and the QRS, PR, and QTc intervals were normal by 57 hours after ingestion (Pentel et al, 1986).

Range Of Toxicity

Summary

    A) Single "extra" therapeutic doses in patients receiving encainide for dysrhythmias have provoked serious proarrhythmic events.
    B) A young healthy man ingested 3 to 3.5 grams and developed serious toxicity, but survived.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) INITIAL DOSE - 25 milligrams every 8 hours, three times a day (Prod Info Enkaid(R), encainide, 1988).
    2) MAINTENANCE DOSE - Increase dose gradually allowing 3 to 5 days to reach steady-state before additional increases in dose.
    3) Maximum - 50 milligrams every 8 hours (Prod Info Enkaid(R), encainide, 1988).
    7.2.2) PEDIATRIC
    A) GENERAL
    1) Encainide has been used in clinical trials in children aged 5 days to 19 years in doses of 60 to 120 milligrams/square meter/day (2 to 5.7 milligrams/kilogram/day) (Moak et al, 1987; Strasburger et al, 1986).

Maximum Tolerated Exposure

    A) ACUTE
    1) SINGLE EXTRA DOSES - Inadvertent therapeutic misadventures where single extra doses were given have resulted in malignant ventricular arrhythmias in patients with underlying cardiac disease (Soyka, 1986; Winkle et al, 1981).
    2) ADULT OVERDOSE -
    a) An acute overdose of 3 to 3.5 grams in a previously healthy adult resulted in serious toxicity, with full recovery (Pentel et al, 1986).
    3) RENAL FAILURE ADULT -
    a) A patient with chronic renal failure receiving encainide 25 milligrams every 8 hours for chronic ventricular arrhythmias developed a drug-induced encephalopathic condition within 2 weeks of initiating therapy.
    1) Symptoms of confusion, memory impairment, and agitation improved 72 hours after discontinuance. Rechallenge demonstrated the same symptoms within 48 hours.
    2) Appropriate dosing guidelines for encainide in patients with renal impairment is one third the normal dose (Tartini & Kesselbrenner, 1990).
    4) PEDIATRIC OVERDOSE -
    a) A near-fatal case of encainide toxicity occurred in a 6-month-old infant ingesting a single encainide 25 milligram tablet. Within 30 minutes of ingestion, a wide-complex sinus tachycardia (QRS, 0.16 seconds) occurred followed by acute decompensation and ventricular tachycardia (Mortensen et al, 1992).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) Assessment of plasma concentrations is different for extensive versus poor metabolizers.
    b) Prolonged QRS interval correlated best with ODE plasma concentrations (the primary active metabolite) in extensive metabolizers, and with encainide plasma concentrations in poor metabolizers (Carey et al, 1984).
    c) Sixty minutes after a 6-month-old infant ingested a single encainide 25-milligram tablet, serum encainide concentration was 180 nanograms/milliliter, and O-demethyl encainide and 3-methoxy-O-demethyl encainide concentrations were 464 and 126 nanograms/milliliter, respectively (Mortensen et al, 1992).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ENCAINIDE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 38100 mcg/kg (RTECS, 2000)
    2) LD50- (ORAL)MOUSE:
    a) 80 mg/kg (Prod Info Enkaid(R), 1988)
    3) LD50- (ORAL)RAT:
    a) 59 mg/kg (Prod Info Enkaid(R), 1988)
    B) MODE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 43.6 mg/kg (Gomoll et al, 1986)
    C) NDE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 81.1 mg/kg (Gomoll et al, 1986)
    D) ODE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 22.6 mg/kg (Gomoll et al, 1986)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) SODIUM CHANNEL INHIBITION - Encainide inhibits the fast sodium channel in Purkinje and myocardial cells, resulting in slowing of phase O depolarization. Unlike class 1A antiarrhythmics, encainide has little effect on action potential duration.

Toxicologic Mechanism

    A) HYPERGLYCEMIA - Encainide appears to induce a bihormonal type II diabetes disorder. C-peptide secretion has been measured in the normal range, but persistent hyperglycemia implicates a relative insulinopenia and concurrent insulin resistance playing a role in encainide-induced diabetes (Winter et al, 1992).

Physicochemical

Physical Characteristics

    A) White crystals (Budavari, 1996)

Molecular Weight

    A) ENCAINIDE: 352.52 (RTECS, 2000) ENCAINIDE HYDROCHLORIDE: 388.9 (JEF Reynolds , 2000)

References

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