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DOFETILIDE AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Dofetilide is a class III antiarrhythmic agent. By inhibiting a component of the time-dependent potassium current, dofetilide increases the effective refractory period and action potential without effecting the conduction velocity. Dofetilide is indicated in adults for the conversion of atrial fibrillation/atrial flutter to normal sinus rhythm and the maintenance of normal sinus rhythm in patients with highly symptomatic atrial fibrillation/atrial flutter of greater than one week's duration, who have been converted to normal sinus rhythm.
    B) Azimilide is a class III antiarrhythmic which blocks slow/fast components of delayed rectifier outward potassium current. Further clinical studies are indicated to determine its role in the treatment of ventricular arrhythmias.
    C) Sematilide is a pure class III antiarrhythmic. Limited clinical data is available to evaluate its efficacy in the treatment of ventricular arrhythmias.

Specific Substances

    A) AZIMILIDE
    1) NE-10064
    DOFETILIDE
    1) UK-68798
    2) CAS 115256-11-6
    SEMATILIDE
    1) CK 1752
    2) CK 1752A
    3) ZK 110,516

    1.2.1) MOLECULAR FORMULA
    1) DOFETILIDE: C19H27N3O5S2

Available Forms Sources

    A) FORMS
    1) DOFETILIDE is available as 0.125 mg, 0.25 mg and 0.5 mg capsules (Prod Info TIKOSYN(R) oral capsules, 2016).
    B) USES
    1) Dofetilide is indicated in adults for the conversion of atrial fibrillation/atrial flutter to normal sinus rhythm and the maintenance of normal sinus rhythm in patients with highly symptomatic atrial fibrillation/atrial flutter of greater than one week's duration, who have been converted to normal sinus rhythm (Prod Info TIKOSYN(R) oral capsules, 2016).
    2) Azimilide has been shown to have a high degree of efficacy for the treatment of ventricular arrhythmias in animal studies only. Sematilide prolongs the action potential duration and has shown efficacy in the treatment of ventricular arrhythmias. These agents are not available in the United States.

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: Dofetilide is indicated in adults for the conversion of atrial fibrillation/atrial flutter to normal sinus rhythm and the maintenance of normal sinus rhythm in patients with highly symptomatic atrial fibrillation/atrial flutter of greater than one week's duration, who have been converted to normal sinus rhythm. Azimilide and sematilide are also class III antiarrhythmics, but they are not available in the US.
    B) PHARMACOLOGY: Dofetilide is a class III antiarrhythmic agent. By inhibiting a component of the time-dependent potassium current, dofetilide increases the effective refractory period and action potential without effecting the conduction velocity.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Dofetilide may induce or worsen ventricular dysrhythmias, producing life threatening polymorphic ventricular tachycardia. Patients with a history of torsade de pointes, prolonged QTc (greater than 440 milliseconds), hypomagnesemia or serum potassium below 4.0 mEq/L are at increased risk of developing ventricular dysrhythmias. Other adverse effects that may occur dofetilide administration include chest pain, nausea, abdominal pain, flatulence, diarrhea, headache, dizziness, and fatigue.
    E) WITH POISONING/EXPOSURE
    1) Overdose experience is limited. Effects reported include QT prolongation, torsade de pointes and complete heart block.
    0.2.20) REPRODUCTIVE
    A) Dofetilide is classified as FDA pregnancy category C. In animal studies, there was evidence of teratogenicity, decreased fetal weights, and decreased fetal survival. There were increased incidences of testicular atrophy and epididymal oligospermia and a reduction in testicular weight in animals exposed to dofetilide.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of dofetilide in humans.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Obtain an ECG, and institute continuous cardiac monitoring. Monitoring should be continued until the QT interval normalizes or returns to baseline. Monitor serum electrolytes, including potassium and magnesium in patients with significant overdose.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF TOXICITY
    1) Treatment is symptomatic and supportive. Obtain an ECG, and institute continuous cardiac monitoring. Therapeutic doses of dofetilide may cause prolongation of the QT interval. In patients with QT prolongation, monitor serum electrolytes, including potassium and magnesium in patients with significant overdose.
    B) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway. In healthy volunteers, activated charcoal was shown to be effective in decreasing both absorption, and the adverse effects associated with dofetilide.
    C) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with life-threatening cardiac dysrhythmias.
    D) ANTIDOTE
    1) None.
    E) VENTRICULAR DYSRHYTHMIAS
    1) Cardioversion if unstable. Administer lidocaine. Correct underlying electrolyte abnormalities. Avoid Class 1A (disopyramide, procainamide, quinidine), Class 1C (encainide, flecainide, lorcainide), sotalol and amiodarone because they may further prolong the QT interval and predispose to torsades de pointes.
    F) TORSADES DE POINTES
    1) Hemodynamically unstable patients require electrical cardioversion. Emergent treatment with magnesium or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities.
    G) ENHANCED ELIMINATION
    1) Hemodialysis is unlikely to remove significant amounts of dofetilide due to its large volume of distribution.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    I) PITFALLS
    1) When managing a suspected overdose, the possibility of multidrug involvement should be considered.
    J) PHARMACOKINETICS
    1) Oral absorption: About 100%. Tmax: 2 to 3 hours. Protein binding: 60% to 70%. Vd: 3.1 to 4.0 L/kg. Metabolism: 50% of dofetilide is metabolized in the liver into inactive metabolites. Excretion: Renal: About 80% of a single dose of dofetilide is excreted in urine with 80% as unchanged drug and the remaining 20% consisting of inactive or minimally active metabolites. Elimination half-life: 4.8 to 13.5 hours.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause dysrhythmias. Patients with underlying cardiac dysrhythmias or electrolyte imbalance may develop more severe symptoms.

Range Of Toxicity

    A) TOXICITY: Toxic manifestations are usually an extension of the pharmacological activity (torsade de pointes). Oral dofetilide doses of 500 mcg twice daily have been associated with an increased risk of developing torsades de pointes; sudden death has been reported in one patient. A patient received two 500 mcg dofetilide doses one hour apart and developed ventricular fibrillation and cardiac arrest 2 hours after the second dose. During a clinical study, one subject ingested 28 500 mcg capsules, and was treated with gastric lavage within 30 minutes of exposure. No adverse effects were reported.
    B) THERAPEUTIC DOSE: ADULT: Dofetilide dosing is based on creatinine clearance - (CrCl > 60 mL/min) 500 mcg twice daily; (CrCl 40 - 60 mL/min) 250 mcg twice daily; (CrCl 20 - <40 mL/min) 125 mcg twice daily; (CrCl < 20 mL/min) contraindicated. PEDIATRIC: Safety and efficacy have not been established in children.

Clinical Effects

Summary Of Exposure

    A) USES: Dofetilide is indicated in adults for the conversion of atrial fibrillation/atrial flutter to normal sinus rhythm and the maintenance of normal sinus rhythm in patients with highly symptomatic atrial fibrillation/atrial flutter of greater than one week's duration, who have been converted to normal sinus rhythm. Azimilide and sematilide are also class III antiarrhythmics, but they are not available in the US.
    B) PHARMACOLOGY: Dofetilide is a class III antiarrhythmic agent. By inhibiting a component of the time-dependent potassium current, dofetilide increases the effective refractory period and action potential without effecting the conduction velocity.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Dofetilide may induce or worsen ventricular dysrhythmias, producing life threatening polymorphic ventricular tachycardia. Patients with a history of torsade de pointes, prolonged QTc (greater than 440 milliseconds), hypomagnesemia or serum potassium below 4.0 mEq/L are at increased risk of developing ventricular dysrhythmias. Other adverse effects that may occur dofetilide administration include chest pain, nausea, abdominal pain, flatulence, diarrhea, headache, dizziness, and fatigue.
    E) WITH POISONING/EXPOSURE
    1) Overdose experience is limited. Effects reported include QT prolongation, torsade de pointes and complete heart block.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Dofetilide can cause serious ventricular arrhythmias, primarily ventricular tachycardia, and torsade de pointes in association with QT interval prolongation. The incidence of ventricular arrhythmias was 2.6% to 14.5% (Prod Info TIKOSYN(R) oral capsules, 2016).
    b) Proarrhythmic effects, including torsade de pointes, have occurred in some patients (Tran et al, 1995a; Tham et al, 1993; Falk et al, 1997). Dofetilide produces significant prolongation of the QT interval which may enhance dysrhythmic activity with either oral or intravenous use (Falk et al, 1997). Higher doses (8 mcg/kg or more) may induce proarrhythmic effects (Falk et al, 1997).
    c) The greatest risk of proarrhythmic effects with dofetilide is during the first few days of therapy (Tran et al, 1995a; Prod Info TIKOSYN(R) oral capsules, 2006).
    d) INCIDENCE: The incidence of torsade de pointes, in limited studies, ranges from 3% to 4% (Tran et al, 1995a; Falk et al, 1997).
    1) The incidence of ventricular dysrhythmias (includes all cases of torsades de pointes) has ranged from 2.6% (250 mcg twice daily) to 15.8% (>500 mcg twice daily) by the manufacturer (Prod Info TIKOSYN(R) oral capsules, 2016).
    e) Torsade de pointes was reported in 4 of 38 patients (10.5%) who received dofetilide at doses of 750 mcg twice daily (Prod Info TIKOSYN(R) oral capsules, 2016).
    B) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) The ability of dofetilide to simultaneously slow heart rate and prolong the ventricular effective refractory period may INCREASE the risk of proarrhythmic activity of dofetilide compared with amiodarone (Tran et al, 1995a).
    b) As a class III antiarrhythmic, dofetilide appears to selectively prolong the QTc interval without effecting the PR interval or QRS duration (Falk et al, 1997; Gemmill et al, 1991a).
    c) ORAL: In a small study to evaluate oral dofetilide, prolongation (intervals exceeding 500 ms) of the QT interval appeared to be dose-dependent; doses of up to 2500 mcg/day were given (Allen et al, 2000). In another study using doses of 125 to 500 mcg, no dose-response relation for serious adverse events was reported (Singh et al, 2000).
    d) INCIDENCE: In a study of patients (n=325) with atrial fibrillation or atrial flutter, 10 of the 11 patients withdrawn from the study were due to the development QT or QTc prolongation (Singh et al, 2000).
    C) VENTRICULAR TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Wide QRS complex tachycardia (short runs) have occurred during intravenous dofetilide administration while the patients were still in atrial fibrillation. One patient had aberrantly conducted atrial fibrillation during an episode of nonsustained wide QRS complex dysrhythmia. Dysrhythmic activity did NOT result in hemodynamic deterioration in any patients despite significant cardiac risk factors (heart failure in 30 of 61 subjects) (Falk et al, 1997).
    1) INCIDENCE: An incidence of 2.6% (250 mcg twice daily) to 13.2% (>500 mcg twice daily) following oral administration has been reported (Prod Info TIKOSYN(R) oral capsules, 2016). Note: slight variations in rate may occur depending on the type of underlying dysrhythmia being treated.
    D) VENTRICULAR FIBRILLATION
    1) WITH THERAPEUTIC USE
    a) INCIDENCE: An incidence of 0.3% (250 mcg twice daily) to 2.6% (>500 mcg twice daily) following oral administration has been reported (Prod Info TIKOSYN(R) oral capsules, 2016). Note: slight variations in rate may occur depending on the type of underlying dysrhythmia being treated.
    2) WITH POISONING/EXPOSURE
    a) A patient inadvertently ingested two 500 mcg doses of dofetilide one hour apart and developed ventricular fibrillation and cardiac arrest 2 hours after the second dose (Prod Info TIKOSYN(R) oral capsules, 2016).
    E) HEART BLOCK
    1) WITH THERAPEUTIC USE
    a) Various forms of block (ie, AV block, bundle branch block and heart block) have occurred during oral dofetilide use. The following incidences have been reported and do NOT appear dose related (Prod Info TIKOSYN(R) oral capsules, 2016). Note: slight variations in rate may occur depending on the type of underlying dysrhythmia being treated):
    1) AV block: 0.9% (less than 250 mcg twice daily) to 1.5% (250 mcg twice daily) and 0% (>500 mcg twice daily)
    2) Bundle branch block: 0.1% (greater than 250 to 500 mcg twice daily) to 0.5% (250 mcg twice daily)
    3) Heart block: 0.1% (greater than 250 to 500 mcg twice daily) to 0.5% (250 mcg twice daily)
    F) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) No significant changes in blood pressure or heart rate have been observed following intravenous doses of dofetilide in most studies (Falk et al, 1997; Tran et al, 1995a; Suttorp et al, 1992; Gemmill et al, 1991a).
    b) Tham et al (1993) reported small but statistically significant reductions in supine heart rate 8 hours post-infusion and increases in standing systolic blood pressure at a 24 hour time point following intravenous dofetilide in healthy subjects. Decreases in supine and standing heart rate, as well as supine systolic pressure 4 hours after oral dosing with dofetilide also were reported (Tham et al, 1993).
    c) Syncope was reported in one patient after receiving a high (2500 mcg/daily) oral dose of dofetilide (Allen et al, 2000).
    G) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) INCIDENCE: Chest pain was reported in 10% of patients receiving oral dofetilide therapy (Prod Info TIKOSYN(R) oral capsules, 2016).
    H) VASODILATATION
    1) WITH THERAPEUTIC USE
    a) Vasodilatation was reported in one patient receiving a high (2500 mcg/daily) oral dose of dofetilide (Allen et al, 2000).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) BRADYCARDIA
    a) DOGS: Using an ischemic heart failure model in dogs (N=9), Mortensen et al (1992) reported a reduced spontaneous heart rate in dogs after administration of 10 and 25 micrograms/kilogram dofetilide. Dofetilide reduced the heart rate in open chest anesthetized dogs (N=5) in a dose dependent manner at doses greater than 3 microgram/kilogram (Gwilt et al, 1992). No change in the systolic or diastolic blood pressure compared with controls were observed in either of the above studies.
    1) No reductions in heart rate were observed in conscious dogs (Rasmussen et al, 1992). The relevance to humans is unknown.

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache and fatigue have occurred occasionally during intravenous administration of dofetilide (Tran et al, 1995a).
    b) Headache was also reported following a high (receiving 2500 micrograms/daily) oral dose of dofetilide (Allen et al, 2000).
    c) INCIDENCE: In clinical studies, 11% of patients developed headache after oral dofetilide administration (Prod Info TIKOSYN(R) oral capsules, 2016).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) INCIDENCE: Dizziness developed in 8% of patients receiving oral dofetilide (Prod Info TIKOSYN(R) oral capsules, 2016).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Flatulence and diarrhea have infrequently occurred with intravenous dofetilide (Sedgwick et al, 1991).
    b) INCIDENCE: Diarrhea was reported in 3% of patients receiving oral dofetilide (Prod Info TIKOSYN(R) oral capsules, 2016).
    B) NAUSEA
    1) WITH THERAPEUTIC USE
    a) INCIDENCE: Nausea occurred in 5% of patients during oral dofetilide therapy (Prod Info TIKOSYN(R) oral capsules, 2016).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) INCIDENCE: Abdominal pain developed in 3% of patients (Prod Info TIKOSYN(R) oral capsules, 2016).

Reproductive

    3.20.1) SUMMARY
    A) Dofetilide is classified as FDA pregnancy category C. In animal studies, there was evidence of teratogenicity, decreased fetal weights, and decreased fetal survival. There were increased incidences of testicular atrophy and epididymal oligospermia and a reduction in testicular weight in animals exposed to dofetilide.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of dofetilide (Prod Info TIKOSYN(R) oral capsules, 2006).
    B) ANIMAL STUDIES
    1) RATS, MICE: In utero growth and survival were adversely effected when rats and mice were given dofetilide at doses of 2 mg/kg/day or more during organogenesis. The adverse effects with the clearest association to amiodarone were cleft palate, adactyly, levocardia, dilation of cerebral ventricles, hydroureter, hydronephroses, and unossified metacarpal in rats and unossified calcaneum in mice. The no observed adverse effect dose was 0.5 mg/kg/day; the mean dofetilide AUC at this dose in rats and mice was about equal to and about half of the likely maximum human AUC, respectively. When the dose was less than 2 mg/kg/day, there was no evidence of structural anomalies in either species. In rats, there was an increased incidence of nonossified fifth metacarpal, hydroureter, and hydronephroses at doses as low as 1 mg/kg/day (Prod Info TIKOSYN(R) oral capsules, 2006).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to dofetilide during pregnancy in humans (Prod Info TIKOSYN(R) oral capsules, 2006).
    B) PREGNANCY CATEGORY
    1) The manufacturer has classified dofetilide as FDA pregnancy category C (Prod Info TIKOSYN(R) oral capsules, 2006).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to dofetilide during lactation in humans(Prod Info TIKOSYN(R) oral capsules, 2006).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS: There was no effect on mating or fertility when male and female rats were given dofetilide at doses as high as 1 mg/kg/day (a mean dofetilide AUC about 3 times the maximum likely human AUC). In other rat studies, there were increased incidences of testicular atrophy and epididymal oligospermia and a reduction in testicular weight (Prod Info TIKOSYN(R) oral capsules, 2006).
    2) DOGS, MICE: There was also reduced testicular weight and an increased incidence of testicular atrophy in dogs and mice exposed to dofetilide (Prod Info TIKOSYN(R) oral capsules, 2006).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of dofetilide in humans.
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) RATS, MICE: Compared with controls, there was no increased incidence of tumors when rats and mice were given dofetilide in the diet for 2 years. The highest doses given over the 2-year study were 10 and 20 mg/kg/day (mean AUC at these doses of approximately 26 and 10 times the maximum likely human AUC), in rats and mice, respectively (Prod Info TIKOSYN(R) oral capsules, 2006).

Genotoxicity

    A) There was no evidence of genotoxicity (with or without metabolic activation) in the following tests: bacterial mutation assay and tests of cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes (Prod Info TIKOSYN(R) oral capsules, 2006).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Obtain an ECG, and institute continuous cardiac monitoring. Monitoring should be continued until the QT interval normalizes or returns to baseline. Monitor serum electrolytes, including potassium and magnesium in patients with significant overdose.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

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) Patients with severe symptoms despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Obtain an ECG, and institute continuous cardiac monitoring. Monitoring should be continued until the QT interval normalizes or returns to baseline. Monitor serum electrolytes, including potassium and magnesium in patients with significant overdose.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) In healthy volunteers, activated charcoal was shown to be effective in decreasing both absorption, and the clinical effects associated with dofetilide (Boyer et al, 2001).
    2) 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).
    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).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) Activated charcoal has been shown to be an effective method of gastrointestinal decontamination when given rapidly after exposure. During an open label, randomized, three-way crossover study with healthy volunteers, there was a significant decrease in Cmax and AUC when activated charcoal was given 15 minutes after dofetilide administration, as compared to charcoal administration 4 hours after exposure. Also, there were fewer increases in the QT and QTc intervals for subjects given charcoal 15 minutes after the dofetilide administration (Boyer et al, 2001).
    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) MANAGEMENT OF TOXICITY
    a) Treatment is symptomatic and supportive. Obtain an ECG, and institute continuous cardiac monitoring. Therapeutic doses of dofetilide may cause prolongation of the QT interval. In patients with QT prolongation, monitor serum electrolytes, including potassium and magnesium in patients with significant overdose.
    B) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs and mental status.
    3) Obtain an ECG, and institute continuous cardiac monitoring. Monitoring should be continued until the QT interval normalizes or returns to baseline. Monitor serum electrolytes, including potassium and magnesium in patients with significant overdose.
    4) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) VENTRICULAR ARRHYTHMIA
    1) Follow standard ACLS guidelines for cardioversion.
    2) LIDOCAINE
    a) 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).
    b) 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).
    c) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    3) Avoid Class 1A (disopyramide, procainamide, quinidine) and Class 1C (encainide, flecainide, lorcainide) antiarrhythmics, and amiodarone and sotalol since they may further prolong the QT interval and predispose to torsade de pointes.
    D) 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.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Dialysis is unlikely to remove significant amounts of dofetilide due to its large volume of distribution.

Range Of Toxicity

Summary

    A) TOXICITY: Toxic manifestations are usually an extension of the pharmacological activity (torsade de pointes). Oral dofetilide doses of 500 mcg twice daily have been associated with an increased risk of developing torsades de pointes; sudden death has been reported in one patient. A patient received two 500 mcg dofetilide doses one hour apart and developed ventricular fibrillation and cardiac arrest 2 hours after the second dose. During a clinical study, one subject ingested 28 500 mcg capsules, and was treated with gastric lavage within 30 minutes of exposure. No adverse effects were reported.
    B) THERAPEUTIC DOSE: ADULT: Dofetilide dosing is based on creatinine clearance - (CrCl > 60 mL/min) 500 mcg twice daily; (CrCl 40 - 60 mL/min) 250 mcg twice daily; (CrCl 20 - <40 mL/min) 125 mcg twice daily; (CrCl < 20 mL/min) contraindicated. PEDIATRIC: Safety and efficacy have not been established in children.

Therapeutic Dose

    7.2.1) ADULT
    A) SUBSTANCE
    1) DOFETILIDE
    a) ECG Evaluation: Prior to administering the first dose, the QTc should be determined using an average of 5 to 10 beats. If the QTc is greater than 440 msec (500 msec in patients with ventricular conduction abnormalities, dofetilide is contraindicated. If the heart rate is less than 60 beats/min, QT interval should be used; no data is available on patients with heart rates less than 50 beats/min (Prod Info TIKOSYN(R) oral capsules, 2016).
    b) Initial dose is individualized, based on calculated creatinine clearance (CrCl) (Prod Info TIKOSYN(R) oral capsules, 2016):
    1) CrCl greater than 60 mL/min: 500 mcg orally twice daily
    2) CrCl 40 to 60 mL/min: 250 mcg orally twice daily
    3) CrCl 20 to less than 40 mL/min: 125 mcg orally twice daily
    4) CrCl less than 20 mL/min: Contraindicated in these patients.
    c) Any adjustments after the first dose is determined by the patient's QTc interval (Prod Info TIKOSYN(R) oral capsules, 2016).
    2) SEMATILIDE
    a) ORAL: Data are limited. Electrophysiologic study: 75 to 200 mg every 8 hours (mean, 130 mg every 8 hours) effective for inducible sustained ventricular tachycardia. Dose similar in responders/nonresponders (Sager et al, 1993).
    b) IV: Data are limited. 0.15 to 1.5 mg/kg (15-minute infusion) effective in suppressing premature ventricular contractions (Wong et al, 1992).
    7.2.2) PEDIATRIC
    A) DOFETILIDE
    1) Safety and effectiveness have not been established in pediatric patients (Prod Info TIKOSYN(R) oral capsules, 2016).

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) Higher doses have been reported to induce proarrhythmic effects including torsades de pointes (Lenz & Hilleman, 2000; Singh et al, 2000). Doses of greater than 500 mcg twice daily have been associated with an increased incidence of torsades de pointes (Prod Info TIKOSYN(R) oral capsules, 2004).
    2) Sudden death has been reported in one patient receiving oral dofetilide (Singh et al, 2000).
    B) CASE REPORTS
    1) A 69-year-old man died of sudden death following a treatment related proarrhythmic event after receiving 500 micrograms twice daily. The patient died 8 days after the start of treatment and death (unwitnessed) was presumed to be secondary to a sudden cardiac event (Singh et al, 2000).
    2) In a small number of patients, doses of 8 micrograms/kilogram were more likely to induce arrhythmic events (QT prolongation, short runs of wide QRS complex tachycardia and torsade de pointes); hemodynamic compromise was not reported in any of the patients (Falk et al, 1997).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) Maximum dose of dofetilide administered is 15 micrograms/kilogram (Bashir et al, 1995). Oral doses of 2500 micrograms/day have been given to a small number of patients (n=9) with one patient developing ventricular bigeminy and another experiencing headache, syncope and vasodilation (Allen et al, 2000).
    2) The manufacturer reported the following overdose with oral dofetilide during clinical studies. A patient received two 500-microgram doses one hour apart and developed ventricular fibrillation and cardiac arrest 2 hours after the second dose (Prod Info TIKOSYN(R) oral capsules, 2004).
    3) During a clinical study, one subject ingested 28 500-microgram capsules, and was treated with gastric lavage within 30 minutes of exposure. No other treatment was performed, and no adverse effects were reported (Prod Info TIKOSYN(R) oral capsules, 2004; Boyer et al, 2001).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) DOFETILIDE
    B) SEMATILIDE
    1) LD50- (ORAL)MOUSE:
    a) 1800 mg/kg (RTECS , 2001)
    2) LD50- (ORAL)RAT:
    a) 3200 mg/kg (RTECS , 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Class III antiarrhythmics characteristically prolong repolarization (resulting in an increase in cardiac action potential duration and effective refractory period) without affecting conduction velocity (Gemmill et al, 1991; Katritsis & Camm, 1993; Tham et al, 1993a; Singh, 1993). In vitro studies indicate these effects are secondary to blockade of one or more time-dependent potassium currents (Gemmill et al, 1991).
    B) Dofetilide, a methanesulfonanilide derivative, is a pure class III antiarrhythmic agent (Prod Info TIKOSYN(R) oral capsules, 2016; Singh, 1993; Katritsis & Camm, 1993). It is more potent and selective than other class III methanesulfonanilides, including d-sotalol and E-4031 (Tran et al, 1995; Katritsis & Camm, 1993). Specifically, dofetilide blocks only the rapid component of the delayed rectifier potassium current, with no relevant block of other potassium currents (Prod Info TIKOSYN(R) oral capsules, 2016). Chemically, dofetilide is essentially the non-beta-blocking moiety of the sotalol molecule.
    C) Dofetilide dose-dependently prolongs the action potential duration and atrial and ventricular effective refractory period, as well as the effective refractory period in the accessory pathway. Corresponding electrocardiographic changes include prolongation of the QT and QTc intervals, but no change in the QRS interval (reflecting lack of prolongation of ventricular conduction time) (Tran et al, 1995; Katritsis & Camm, 1993; Sedgwick et al, 1992).

Physicochemical

Physical Characteristics

    A) DOFETILIDE is a white to off-white powder that is soluble in 0.1M aqueous sodium hydroxide, acetone, and aqueous 0.1M hydrochloric acid and very slightly soluble in water and propan-2-ol (Prod Info TIKOSYN(R) oral capsules, 2006).

Molecular Weight

    A) DOFETILIDE: 441.6 (Prod Info TIKOSYN(R) oral capsules, 2006)

References

General Bibliography

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