View source for Dofetilide

{{DrugProjectFormSinglePage
|authorTag={{SS}}
|genericName=Dofetilide
|drugClass=Antiarrhythmic
|indication=Maintenance of Normal Sinus Rhythm (Delay in AF/AFl Recurrence), Conversion of Atrial Fibrillation/Flutter
|hasBlackBoxWarning=Yes
|adverseReactions=chest pain, dizziness , headache
|blackBoxWarningBody=To minimize the risk of induced arrhythmia, patients initiated or re-initiated on TIKOSYN should be placed for a minimum of 3 days in a facility that can provide calculations of creatinine clearance, continuous electrocardiographic monitoring, and cardiac resuscitation. For detailed instructions regarding dose selection, see DOSAGE AND ADMINISTRATION. TIKOSYN is available only to hospitals and prescribers who have received appropriate TIKOSYN dosing and treatment initiation education; see DOSAGE AND ADMINISTRATION.
|fdaLIADAdult=&lt;h4&gt;Condition 1&lt;/h4&gt;

* Dosing Information

:: (Dosage)
|contraindications=TIKOSYN is contraindicated in patients with congenital or acquired long QT syndromes. TIKOSYN should not be used in patients with a baseline QT interval or QTc >440 msec (500 msec in patients with ventricular conduction abnormalities). TIKOSYN is also contraindicated in patients with severe renal impairment (calculated creatinine clearance <20 mL/min).
The concomitant use of [[verapamil]] or the cation transport system inhibitors [[cimetidine]], [[trimethoprim]] (alone or in combination with [[sulfamethoxazole]]), or [[ketoconazole]] with TIKOSYN is contraindicated (see WARNINGS and PRECAUTIONS, Drug-Drug Interactions), as each of these drugs cause a substantial increase in dofetilide plasma concentrations. In addition, other known inhibitors of the renal cation transport system such as [[prochlorperazine]], [[dolutegravir]] and [[megestrol]] should not be used in patients on TIKOSYN.
The concomitant use of [[hydrochlorothiazide]] (alone or in combinations such as with [[triamterene]]) with TIKOSYN is contraindicated (see PRECAUTIONS, Drug-Drug Interactions) because this has been shown to significantly increase dofetilide plasma concentrations and QT interval prolongation.
TIKOSYN is also contraindicated in patients with a known hypersensitivity to the drug.
|warnings=Ventricular Arrhythmia
TIKOSYN (dofetilide) can cause serious ventricular arrhythmias, primarily Torsade de Pointes (TdP) type ventricular tachycardia, a polymorphic ventricular tachycardia associated with QT interval prolongation. QT interval prolongation is directly related to dofetilide plasma concentration. Factors such as reduced creatinine clearance or certain dofetilide drug interactions will increase dofetilide plasma concentration. The risk of TdP can be reduced by controlling the plasma concentration through adjustment of the initial dofetilide dose according to creatinine clearance and by monitoring the ECG for excessive increases in the QT interval.
Treatment with dofetilide must therefore be started only in patients placed for a minimum of three days in a facility that can provide electrocardiographic monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. Calculation of the creatinine clearance for all patients must precede administration of the first dose of dofetilide. For detailed instructions regarding dose selection, see DOSAGE AND ADMINISTRATION.
The risk of dofetilide induced ventricular arrhythmia was assessed in three ways in clinical studies: 1) by description of the QT interval and its relation to the dose and plasma concentration of dofetilide; 2) by observing the frequency of TdP in TIKOSYN-treated patients according to dose; 3) by observing the overall mortality rate in patients with atrial fibrillation and in patients with structural heart disease.
Relation of QT Interval to Dose
The QT interval increases linearly with increasing TIKOSYN dose (see Figures 1 and 2 in CLINICAL PHARMACOLOGY and Dose-Response and Concentration Response for Increase in QT Interval).
Frequency of Torsade de Pointes
In the [[supraventricular arrhythmia]] population (patients with AF and other [[supraventricular arrhythmia]]s), the overall incidence of Torsade de Pointes was 0.8%. The frequency of TdP by dose is shown in Table 4. There were no cases of TdP on placebo.

[[FileDofetilide_warning_table_01.jpg|thumb|none|400px]]

As shown in Table 5, the rate of TdP was reduced when patients were dosed according to their renal function (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations, Renal Impairment and DOSAGE AND ADMINISTRATION).

[[FileDofetilide_warning_table_02.jpg|thumb|none|400px]]

The majority of the episodes of TdP occurred within the first three days of TIKOSYN therapy (10/11 events in the studies of patients with [[supraventricular arrhythmia]]s; 19/25 and 4/7 events in DIAMOND CHF and DIAMOND MI, respectively; 2/4 events in the DIAMOND AF subpopulation).

=====Mortality=====

In a pooled survival analysis of patients in the [[supraventricular arrhythmia]] population (low prevalence of structural heart disease), deaths occurred in 0.9% (12/1346) of patients receiving TIKOSYN and 0.4% (3/677) in the placebo group. Adjusted for duration of therapy, primary diagnosis, age, gender, and prevalence of structural heart disease, the point estimate of the hazard ratio for the pooled studies (TIKOSYN/placebo) was 1.1 (95% CI: 0.3, 4.3). The DIAMOND CHF and MI trials examined mortality in patients with structural heart disease (ejection fraction ≤35%). In these large, double-blind studies, deaths occurred in 36% (541/1511) of TIKOSYN patients and 37% (560/1517) of placebo patients. In an analysis of 506 DIAMOND patients with atrial fibrillation/flutter at baseline, one year mortality on TIKOSYN was 31% vs. 32% on placebo (see CLINICAL STUDIES).
Because of the small number of events, an excess mortality due to TIKOSYN cannot be ruled out with confidence in the pooled survival analysis of placebo-controlled trials in patients with [[supraventricular arrhythmia]]s. However, it is reassuring that in two large placebo-controlled mortality studies in patients with significant heart disease (DIAMOND CHF/MI), there were no more deaths in TIKOSYN-treated patients than in patients given placebo (see CLINICAL STUDIES).

=====Drug-Drug Interactions=====

(see CONTRAINDICATIONS)
Because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant drugs that interfere with the metabolism or renal elimination of dofetilide may increase the risk of [[arrhythmia]](Torsade de Pointes). TIKOSYN is metabolized to a small degree by the CYP3A4 [[isoenzyme]] of the [[cytochrome]] P450 system and an inhibitor of this system could increase systemic dofetilide exposure. More important, dofetilide is eliminated by cationic renal secretion, and three inhibitors of this process have been shown to increase systemic dofetilide exposure. The magnitude of the effect on renal elimination by [[cimetidine]], [[trimethoprim]], and [[ketoconazole]] (all contraindicated concomitant uses with dofetilide) suggests that all renal cation transport inhibitors should be contraindicated.

=====Hypokalemia and Potassium-Depleting Diuretics=====
[[Hypokalemia]] or [[hypomagnesemia]] may occur with administration of potassium-depleting [[diuretics]], increasing the potential for Torsade de Pointes. Potassium levels should be within the normal range prior to administration of TIKOSYN and maintained in the normal range during administration of TIKOSYN (see DOSAGE AND ADMINISTRATION).

=====Use with Drugs that Prolong QT Interval and Antiarrhythmic Agents=====

The use of TIKOSYN in conjunction with other drugs that prolong the QT interval has not been studied and is not recommended. Such drugs include [[phenothiazines]], [[cisapride]], [[bepridil]], [[tricyclic antidepressants]], certain oral [[macrolides]], and certain fluoroquinolones. Class I or Class III antiarrhythmic agents should be withheld for at least three half-lives prior to dosing with TIKOSYN. In clinical trials, TIKOSYN was administered to patients previously treated with oral [[amiodarone]] only if serum [[amiodarone]] levels were below 0.3 mg/L or amiodarone had been withdrawn for at least three months.
|clinicalTrials=The TIKOSYN clinical program involved approximately 8,600 patients in 130 clinical studies of normal volunteers and patients with supraventricular and [[ventricular arrhythmias]]. TIKOSYN was administered to 5,194 patients, including two large, placebo-controlled mortality trials (DIAMOND CHF and DIAMOND MI) in which 1,511 patients received TIKOSYN for up to three years.
In the following section, adverse reaction data for cardiac arrhythmias and non-cardiac adverse reactions are presented separately for patients included in the [[supraventricular arrhythmia]] development program and for patients included in the DIAMOND CHF and MI mortality trials (see CLINICAL STUDIES, Safety in Patients with Structural Heart Disease, DIAMOND Studies, for a description of these trials).
In studies of patients with [[supraventricular arrhythmias]], a total of 1,346 and 677 patients were exposed to TIKOSYN and placebo for 551 and 207 patient years, respectively. A total of 8.7% of patients in the dofetilide groups were discontinued from clinical trials due to adverse events compared to 8.0% in the placebo groups. The most frequent reason for discontinuation (>1%) was [[ventricular tachycardia]] (2.0% on dofetilide vs. 1.3% on placebo). The most frequent adverse events were [[headache]], [[chest pain]], and [[dizziness]]
.
=====Serious Arrhythmias and Conduction Disturbances=====

Torsade de Pointes is the only [[arrhythmia]] that showed a dose-response relationship to TIKOSYN treatment. It did not occur in placebo treated patients. The incidence of Torsade de Pointes in patients with [[supraventricular arrhythmias]] was 0.8% (11/1346) (see WARNINGS). The incidence of Torsade de Pointes in patients who were dosed according to the recommended dosing regimen (see DOSAGE AND ADMINISTRATION) was 0.8% (4/525). Table 6 shows the frequency by randomized dose of serious [[arrhythmias]] and conduction disturbances reported as adverse events in patients with [[supraventricular arrhythmias]].

[[File:Dofetilide_adverse_table_01.jpg|thumb|none|400px]]

In the DIAMOND trials, a total of 1,511 patients were exposed to TIKOSYN for 1757 patient years. The incidence of Torsade de Pointes was 3.3% in CHF patients and 0.9% in patients with a recent [[MI]].
Table 7 shows the incidence of serious [[arrhythmias]] and conduction disturbances reported as adverse events in the DIAMOND subpopulation that had AF at entry to these trials.

[[File:Dofetilide_adverse_table_02.jpg|thumb|none|400px]]

=====Other Adverse Reactions=====

Table 8 presents other adverse events reported with a frequency of >2% on TIKOSYN and reported numerically more frequently on TIKOSYN than on placebo in the studies of patients with [[supraventricular arrhythmias]].

[[File:Dofetilide_adverse_table_03.jpg|thumb|none|400px]]

Adverse events reported at a rate >2% but no more frequently on TIKOSYN than on placebo were: [[angina pectoris]], [[anxiety]], [[arthralgia]], [[asthenia]], [[atrial fibrillation]], complications (application, injection, incision, insertion, or device), [[hypertension]], pain, [[palpitation]], [[peripheral edema]], [[supraventricular tachycardia]], [[sweating]], [[urinary tract infection]], [[ventricular tachycardia]].
The following adverse events have been reported with a frequency of ≤2% and numerically more frequently with TIKOSYN than placebo in patients with [[supraventricular arrhythmias]]: [[angioedema]], [[bradycardia]], [[cerebral ischemia]], cerebrovascular accident, [[edema]], [[facial paralysis]], [[flaccid paralysis]], heart arrest, increased cough, liver damage, [[migraine]], [[myocardial infarct]], [[paralysis]], [[paresthesia]], sudden death, and [[syncope]].
The incidences of clinically significant laboratory test abnormalities in patients with [[supraventricular arrhythmias]] were similar for patients on TIKOSYN and those on placebo. No clinically relevant effects were noted in serum alkaline phosphatase, serum GGT, LDH, AST, ALT, total bilirubin, total protein, blood urea nitrogen, creatinine, serum electrolytes (calcium, chloride, glucose, magnesium, potassium, sodium), or creatine kinase. Similarly, no clinically relevant effects were observed in hematologic parameters.
In the DIAMOND population, adverse events other than those related to the post-infarction and heart failure patient population were generally similar to those seen in the [[supraventricular arrhythmia]] groups.
|drugInteractions======[[Cimetidine]]=====

(see WARNINGS, CONTRAINDICATIONS) Concomitant use of [[cimetidine]] is contraindicated. [[cimetidine]] at 400 mg BID (the usual prescription dose) co-administered with TIKOSYN (500 mcg BID) for 7 days has been shown to increase dofetilide plasma levels by 58%. [[cimetidine]] at doses of 100 mg BID (OTC dose) resulted in a 13% increase in dofetilide plasma levels (500 mcg single dose). No studies have been conducted at intermediate doses of [[cimetidine]]. If a patient requires TIKOSYN and anti-ulcer therapy, it is suggested that [[omeprazole]], [[ranitidine]], or [[antacids]] (aluminum and magnesium hydroxides) be used as alternatives to [[cimetidine]], as these agents have no effect on the pharmacokinetic profile of TIKOSYN.

=====Verapamil=====

(see CONTRAINDICATIONS) Concomitant use of [[verapamil ]]is contraindicated. Co-administration of TIKOSYN with [[verapamil ]]resulted in increases in dofetilide peak plasma levels of 42%, although overall exposure to dofetilide was not significantly increased. In an analysis of the [[supraventricular arrhythmia]] and DIAMOND patient populations, the concomitant administration of [[verapamil ]]with dofetilide was associated with a higher occurrence of Torsade de Pointes.

=====Ketoconazole=====

(see WARNINGS, CONTRAINDICATIONS) Concomitant use of [[ketoconazole]]is contraindicated. [[ketoconazole]]at 400 mg daily (the maximum approved prescription dose) co-administered with TIKOSYN (500 mcg BID) for 7 days has been shown to increase dofetilide Cmax by 53% in males and 97% in females, and AUC by 41% in males and 69% in females.

=====[[trimethoprim]]Alone or in Combination with Sulfamethoxazole=====

(see WARNINGS, CONTRAINDICATIONS) Concomitant use of [[trimethoprim]]alone or in combination with [[sulfamethoxazole]] is contraindicated. [[trimethoprim]]160 mg in combination with 800 mg [[sulfamethoxazole]] co-administered BID with TIKOSYN (500 mcg BID) for 4 days has been shown to increase dofetilide AUC by 103% and Cmax by 93%.

=====Hydrochlorothiazide (HCTZ) Alone or in Combination with Triamterene=====

(see CONTRAINDICATIONS) Concomitant use of HCTZ alone or in combination with [[triamterene]]is contraindicated. HCTZ 50 mg QD or HCTZ/[[triamterene]]50/100 mg QD was co-administered with TIKOSYN (500 mcg BID) for 5 days (following 2 days of diuretic use at half dose). In patients receiving HCTZ alone, dofetilide AUC increased by 27% and Cmax by 21%. However, the pharmacodynamic effect increased by 197% (QTc increase over time) and by 95% (maximum QTc increase). In patients receiving HCTZ in combination with [[triamterene]], dofetilide AUC increased by 30% and Cmax by 16%. However, the pharmacodynamic effect increased by 190% (QTc increase over time) and by 84% (maximum QTc increase). The pharmacodynamic effects can be explained by a combination of the increase in dofetilide exposure and the reductions in serum potassium. In the DIAMOND trials, 1252 patients were treated with TIKOSYN and diuretics concomitantly, of whom 493 died compared to 508 deaths among the 1248 patients receiving placebo and [[diuretics]]. Of the 229 patients who had potassium depleting [[diuretics]] added to their concomitant medications in the DIAMOND trials, the patients on TIKOSYN had a non-significantly reduced relative risk for death of 0.68 (95% CI: 0.376, 1.230).

===Potential Drug Interactions===

Dofetilide is eliminated in the kidney by cationic secretion. Inhibitors of renal cationic secretion are contraindicated with TIKOSYN. In addition, drugs that are actively secreted via this route (e.g., [[triamterene]], [[metformin]], and [[amiloride]]) should be co-administered with care as they might increase dofetilide levels.
Dofetilide is metabolized to a small extent by the CYP3A4 [[isoenzyme]] of the [[cytochrome]]P450 system. Inhibitors of the CYP3A4 [[isoenzyme]] could increase systemic dofetilide exposure. Inhibitors of this [[isoenzyme]] (e.g., [[macrolide]] [[antibiotics]], [[azole]] antifungal agents, [[protease inhibitors]], [[serotonin reuptake inhibitors]], [[amiodarone]], [[cannabinoids]], [[diltiazem]], grapefruit juice, [[nefazadone]], [[norfloxacin]], [[quinine]], [[zafirlukast]]) should be cautiously co-administered with TIKOSYN as they can potentially increase dofetilide levels. Dofetilide is not an inhibitor of CYP3A4 nor of other [[cytochrome]]P450 [[isoenzyme]]s (e.g., CYP2C9, CYP2D6) and is not expected to increase levels of drugs metabolized by CYP3A4.

===Other Drug Interaction Information===

=====[[Digoxin]]=====

Studies in healthy volunteers have shown that TIKOSYN does not affect the pharmacokinetics of [[digoxin]]. In patients, the concomitant administration of [[digoxin]] with dofetilide was associated with a higher occurrence of Torsade de Pointes. It is not clear whether this represents an interaction with TIKOSYN or the presence of more severe structural heart disease in patients on [[digoxin]]; structural heart disease is a known risk factor for [[arrhythmia]]. No increase in mortality was observed in patients taking [[digoxin]] as concomitant medication.

=====Other Drugs=====

In healthy volunteers, [[amlodipine]], [[phenytoin]], [[glyburide]], [[ranitidine]], [[omeprazole]], [[hormone replacement therapy]] (a combination of conjugated [[estrogens]] and [[medroxyprogesterone]]), [[antacid]] (aluminum and magnesium hydroxides), and [[theophylline]] did not affect the pharmacokinetics of TIKOSYN. In addition, studies in healthy volunteers have shown that TIKOSYN does not affect the pharmacokinetics or pharmacodynamics of [[warfarin]], or the pharmacokinetics of propranolol (40 mg twice daily), [[phenytoin]], [[theophylline]], or oral [[contraceptives]].
Population pharmacokinetic analyses were conducted on plasma concentration data from 1445 patients in clinical trials to examine the effects of concomitant medications on clearance or volume of distribution of dofetilide. Concomitant medications were grouped as [[ACE inhibitors]], oral [[anticoagulants]], [[calcium channel blockers]], [[beta blockers]], [[cardiac glycosides]], inducers of CYP3A4, substrates and inhibitors of CYP3A4, substrates and inhibitors of P-glycoprotein, [[nitrates]], [[sulphonylureas]], [[loop diuretics]], potassium sparing [[diuretics]], [[thiazide diuretics]], substrates and inhibitors of tubular organic cation transport, and QTc-prolonging drugs. Differences in clearance between patients on these medications (at any occasion in the study) and those off medications varied between -16% and +3%. The mean clearances of dofetilide were 16% and 15% lower in patients on [[thiazide diuretics]] and inhibitors of tubular organic cation transport, respectively.
|FDAPregCat=C
|useInPregnancyFDA=Dofetilide had no genotoxic effects, with or without metabolic activation, based on the bacterial mutation assay and tests of cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes. Rats and mice treated with dofetilide in the diet for two years showed no evidence of an increased incidence of tumors compared to controls. The highest dofetilide dose administered for 24 months was 10 mg/kg/day to rats and 20 mg/kg/day to mice. Mean dofetilide AUCs(0–24hr) at these doses were about 26 and 10 times, respectively, the maximum likely human AUC.
There was no effect on mating or fertility when dofetilide was administered to male and female rats at doses as high as 1.0 mg/kg/day, a dose that would be expected to provide a mean dofetilide AUC(0–24hr) about 3 times the maximum likely human AUC. Increased incidences of [[testicular atrophy]] and [[epididymal oligospermia]] and a reduction in testicular weight were, however, observed in other studies in rats. Reduced testicular weight and increased incidence of [[testicular atrophy]] were also consistent findings in dogs and mice. The no effect doses for these findings in chronic administration studies in these 3 species (3, 0.1, and 6 mg/kg/day) were associated with mean dofetilide AUCs that were about 4, 1.3, and 3 times the maximum likely human AUC, respectively.
|useInNursing=There is no information on the presence of dofetilide in breast milk. Patients should be advised not to breast-feed an infant if they are taking TIKOSYN.
|useInPed=The safety and effectiveness of TIKOSYN in children (<18 years old) has not been established.

|useInGeri=Of the total number of patients in clinical studies of TIKOSYN, 46% were 65 to 89 years old. No overall differences in safety, effect on QTc, or effectiveness were observed between elderly and younger patients. Because elderly patients are more likely to have decreased renal function with a reduced creatinine clearance, care must be taken in dose selection (see DOSAGE AND ADMINISTRATION).
|useInGender=Female patients constituted 32% of the patients in the placebo-controlled trials of TIKOSYN. As with other drugs that cause Torsade de Pointes, TIKOSYN was associated with a greater risk of Torsade de Pointes in female patients than in male patients. During the TIKOSYN clinical development program, the risk of Torsade de Pointes in females was approximately 3 times the risk in males. Unlike Torsade de Pointes, the incidence of other [[ventricular arrhythmias]] was similar in female patients receiving TIKOSYN and patients receiving placebo. Although no study specifically investigated this risk, in post-hoc analyses, no increased mortality was observed in females on TIKOSYN compared to females on placebo.
|useInRenalImpair=The overall systemic clearance of dofetilide is decreased and plasma concentration increased with decreasing creatinine clearance. The dose of TIKOSYN must be adjusted based on creatinine clearance (see DOSAGE AND ADMINISTRATION). Patients undergoing dialysis were not included in clinical studies, and appropriate dosing recommendations for these patients are unknown. There is no information about the effectiveness of [[hemodialysis]] in removing dofetilide from plasma.
|useInHepaticImpair=After adjustment for creatinine clearance, no additional dose adjustment is required for patients with mild or moderate hepatic impairment. Patients with severe hepatic impairment have not been studied. TIKOSYN should be used with particular caution in these patients.
|othersTitle=Cardiac Conduction Disturbances
|useInOthers=Animal and human studies have not shown any adverse effects of dofetilide on conduction velocity. No effect on AV nodal conduction following TIKOSYN treatment was noted in normal volunteers and in patients with 1st degree heart block. Patients with [[sick sinus syndrome]] or with 2nd or 3rd degree heart block were not included in the Phase 3 clinical trials unless a functioning pacemaker was present. TIKOSYN has been used safely in conjunction with [[pacemakers]] (53 patients in DIAMOND studies, 136 in trials in patients with ventricular and [[supraventricular arrhythmias]]).
}}
{{drugbox | IUPAC_name = N-[4-[2-[2-[4-(methanesulfonamido)phenoxy]ethyl-methyl-amino] ethyl]phenyl] methanesulfonamide | image = Dofetilide.png | CAS_number = 115256-11-6 | ATC_prefix = C01 | ATC_suffix = BD04 | ATC_supplemental = | PubChem = 71329 | DrugBank = APRD00367 | C=19 | H=27 | N=3 | O=5 | S=2 | molecular_weight = 441.567 g/mol | bioavailability = 96% (oral) | protein_bound = 60% -70% | metabolism = | elimination_half-life = 10 hours | pregnancy_category = | legal_status = | routes_of_administration = }}
{{SI}}
{{CMG}}



==[[Dofetilide (patient information)|For patient information, click here]]==

'''Dofetilide''' is a class III [[antiarrhythmic agents|antiarrhythmic agent]] that is approved by the [[Food and Drug Administration]] (FDA) for the maintenance of [[sinus rhythm]] in individuals prone to the formation of [[atrial fibrillation]] and [[atrial flutter|flutter]], and for the chemical [[cardioversion]] to sinus rhythm from [[atrial fibrillation]] and [[atrial flutter|flutter]].

The chemical name for dofetilide is
N-[4-(2-{2-[4-(methanesulphonamido) phenoxyl]-N-methylethylamino}ethyl)phenyl]-
methanesulphonamide.  It is marketed under the trade name '''Tikosyn<sup>®</sup>''' by [[Pfizer]], and is available in the United States in capsules containing 125, 250, and 500 µg of dofetilide.  Due to the pro-arrhythmic potential of dofetilide, it is only available by prescription by physicians who have undergone specific training in the risks of treatment with dofetilide.  In addition, it is only available by mail order or through specially trained local pharmacies to individuals who are prescribed dofetilide by a physician who is registered as being able to prescribe the pharmaceutical.

The elimination [[half-life]] of dofetilide is roughly 10 hours, however this is variable based on many physiologic factors (most significantly [[creatinine clearance]]), and ranges from 4.8 to 13.5 hours.

==Mechanism of action==
Dofetilide works by selectively blocking the rapid component of the delayed rectifier outward potassium current (I<sub>Kr</sub>).

This causes prolongation of the effective refractory period of accessory pathways (both anterograde and retrograde conduction in the accessory pathway).  It is this selective action on accessory pathways that makes dofetilide effective in the treatment of [[atrial fibrillation]] and [[atrial flutter|flutter]].

Dofetilide does not effect V<sub>max</sub> (The [[slope]] of the upstroke of phase 0 depolarization), conduction velocity, or the resting membrane potential.

There is a dose-dependent increase in the QT interval and the corrected QT interval (QTc).  Because of this, many practitioners will initiate dofetilide therapy only on individuals under telemetry monitoring or if serial EKG measurements of QT and QTc can be performed.

==Metabolism==
A steady-state plasma level of dofetilide is achieved in 2-3 days.

80% of dofetilide is excreted by the [[kidney]]s, so the dose of dofetilide should be adjusted in individuals with [[renal insufficiency]], based on [[creatinine clearance]].

In the kidneys, dofetilide is eliminated via cation exchange (secretion).  Agents that interfere with the renal cation exchange system, such as [[verapamil]], [[cimetidine]], [[hydrochlorothiazide]], [[itraconazole]], [[ketoconazole]], [[prochlorperazine]], and [[trimethoprim]] should not be administered to individuals taking dofetilide.

About 20 percent of dofetilide is metabolized in the liver via the [[CYP3A4]] isoenzyme of the [[cytochrome P450]] enzyme system.  Drugs that interfere with the activity of the [[CYP3A4]] isoenzyme can increase serum dofetilide levels.  If the renal cation exchange system is interfered with (as with the medications listed above), a larger percentage of dofetilide is cleared via the [[CYP3A4]] isoenzyme system.

==Side effects==
[[Torsades de pointes]] is the most serious side effect of dofetilide therapy.  The incidence of torsades de pointes is dose-related, and is 0.3-10.5%.  The risk appears to be dose-dependent, with an increased incidence of torsades de pointes associated with higher doses of dofetilide administered.

The risk of inducing torsades de pointes can be decreased by taking precautions when initiating therapy, such as hospitalizing individuals for a minimum of three days for serial [[creatinine]] measurement, continuous telemetry monitoring and availability of cardiac resuscitation.

==Clinical use==
Based on the results of the Danish Investigations of Arrhythmias and Mortality on Dofetilide (DIAMOND) study, dofetilide does not affect mortality in the treatment of patients post-[[myocardial infarction]] with [[left ventricle|left ventricular]] dysfunction.<sup>3</sup>  Because of the results of the DIAMOND study, many physicians use dofetilide in the suppression of atrial fibrillation in individuals with LV dysfunction.

==See also==
*[[Antiarrhythmic agents]]
*[[Cardiac action potential]]
*[[Electrocardiogram]]

==References==
#Thomas L. Lenz, Pharm.D., and Daniel E. Hilleman, Pharm.D., Department of Cardiology, Creighton University, Omaha, Nebraska. Dofetilide, a New Class III Antiarrhythmic Agent. Pharmacotherapy 20(7):776-786, 2000. ([http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10907968 Medline abstract])
#Lenz TL, Hilleman DE. Dofetilide: A new antiarrhythmic agent approved for conversion and/or maintenance of atrial fibrillation/atrial flutter. Drugs Today (Barc). 2000 Nov;36(11):759-71. ([http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12845335 Medline abstract])
#Torp-Pedersen C, Moller M, Bloch-Thomsen PE, Kober L, Sandoe E, Egstrup K, Agner E, Carlsen J, Videbaek J, Marchant B, Camm AJ. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. N Engl J Med. 1999 Sep 16;341(12):857-65. ([http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10486417 Medline abstract])


{{Antiarrhythmic agents}}

[[Category:Antiarrhythmic agents]]
[[Category:Drugs]]
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