Version May 2024
To minimize the risk of induced arrhythmia, patients initiated or re-initiated on dofetilide 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.
Note: CrCl and QTc interval (or QT interval if heart rate is <60 beats/minute) must be determined prior to first dose. If QTc >440 msec (>500 msec in patients with ventricular conduction abnormalities), dofetilide is contraindicated. Adjust initial dosage in patients with estimated CrCl <60 mL/minute (see dosage adjustment in "Dosing: Renal Impairment"). Dofetilide may be initiated at lower doses than recommended based on physician discretion; however, if the dose is increased, the patient will require rehospitalization for 3 days. Maintain potassium and magnesium in the normal range prior to initiation and during therapy.
Atrial fibrillation/flutter: Oral: Initial: 500 mcg twice daily (maximum dose: 500 mcg twice daily).
Supraventricular tachycardia (ongoing management) (off-label use): Oral: Initial: 500 mcg every 12 hours (Ref).
Modification of dosage in response to initial dose: QTc interval should be measured 2 to 3 hours after the initial dose. If the QTc interval increases to more than 15% above baseline QTc or if the QTc is >500 msec (>550 msec in patients with ventricular conduction abnormalities), dofetilide dose should be reduced by 50%. If the starting dose was 500 mcg twice daily, then reduce to 250 mcg twice daily. If the starting dose was 250 mcg twice daily, then reduce to 125 mcg twice daily. If the starting dose was 125 mcg twice daily, then reduce to 125 mcg once daily. QTc interval should be measured 2 to 3 hours after each subsequent dose (in-hospital doses 2 through 5). If at any time after the second dose the QTc is >500 msec (>550 msec in patients with ventricular conduction abnormalities), the manufacturer recommends discontinuing therapy.
Maintenance therapy: No further down titration of dose based on QTc is recommended following modification of initial dose. However, if QTc >500 msec (>550 msec in patients with ventricular conduction abnormalities), the manufacturer recommends discontinuing therapy. Renal function and QTc should be re-evaluated every 3 months or as medically warranted. If renal function deteriorates, adjust dose as described in dosage adjustment in renal impairment (see "Dosing: Renal Impairment").
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function:
Note: CrCl should only be calculated using the Cockcroft-Gault equation using actual body weight (weight range of patients enrolled in clinical trials: 40 to 134 kg). Use of other methods to assess kidney function (eg, modification of diet in renal disease) may result in overdose of dofetilide due to an overestimation of CrCl (Denetclaw 2011). For patients established on dofetilide therapy that experience a change in kidney function, the dofetilide dose should be adjusted based on the newly calculated CrCl range (eg, if a patient with an initial CrCl of 70 mL/minute experiences a decline in CrCl to 45 mL/minute then reduce dose by 50%).
CrCl >60 mL/minute: Oral: Initial: 500 mcg twice daily. Measure QTc interval 2 to 3 hours after the initial dose. If the QTc interval increases to more than 15% above baseline QTc or if the QTc is >500 msec (>550 msec in patients with ventricular conduction abnormalities), reduce dose to 250 mcg twice daily. QTc interval should be measured 2 to 3 hours after each subsequent dose (in-hospital doses 2 through 5). If at any time after the second dose the QTc is >500 msec (>550 msec in patients with ventricular conduction abnormalities), the manufacturer recommends discontinuing therapy.
CrCl 40 to 60 mL/minute: Oral: Initial: 250 mcg twice daily. Measure QTc interval 2 to 3 hours after the initial dose. If the QTc interval increases to more than 15% above baseline QTc or if the QTc is >500 msec (>550 msec in patients with ventricular conduction abnormalities), reduce dose to 125 mcg twice daily. QTc interval should be measured 2 to 3 hours after each subsequent dose (in-hospital doses 2 through 5). If at any time after the second dose the QTc is >500 msec (>550 msec in patients with ventricular conduction abnormalities), the manufacturer recommends discontinuing therapy.
CrCl 20 to <40 mL/minute: Oral: Initial: 125 mcg twice daily. Measure QTc interval 2 to 3 hours after the initial dose. If the QTc interval increases to more than 15% above baseline QTc or if the QTc is >500 msec (>550 msec in patients with ventricular conduction abnormalities), reduce dose to 125 mcg once daily. QTc interval should be measured 2 to 3 hours after each subsequent dose (in-hospital doses 2 through 5). If at any time after the second dose the QTc is >500 msec (>550 msec in patients with ventricular conduction abnormalities), the manufacturer recommends discontinuing therapy.
CrCl <20 mL/minute: Use is contraindicated.
Hemodialysis, intermittent (thrice weekly): Unlikely to be substantially dialyzable (large Vd, 60% to 70% protein bound) (Ref):
Oral: Use is contraindicated (Ref).
Peritoneal dialysis: Oral: Use is contraindicated (Ref).
CRRT: Oral: Avoid use (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): Oral: Avoid use (Ref).
Mild or moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustment necessary.
Severe hepatic impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution.
Refer to adult dosing. No specific dosage adjustments are recommended based on age; however, careful assessment of renal function is particularly important in this population.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%: Nervous system: Headache (11%)
1% to 10%:
Cardiovascular: Acute myocardial infarction (≤2%), atrioventricular block (2%), bradycardia (≤2%), chest pain (10%), edema (≤2%), heart block (1%), syncope (≤2%), torsades de pointes (≤3%), ventricular tachycardia (4%)
Dermatologic: Skin rash (3%)
Gastrointestinal: Abdominal pain (3%), diarrhea (3%), nausea (5%)
Hepatic: Hepatotoxicity (≤2%)
Hypersensitivity: Angioedema (≤2%)
Nervous system: Cerebral ischemia (≤2%), cerebrovascular accident (≤2%), dizziness (8%), facial nerve paralysis (≤2%), flaccid paralysis (≤2%), insomnia (4%), migraine (≤2%), paralysis (≤2%), paresthesia (≤2%)
Neuromuscular & skeletal: Back pain (3%)
Respiratory: Dyspnea (6%), flu-like symptoms (4%), increased cough (≤2%), respiratory tract infection (7%)
Postmarketing:
Cardiovascular: Prolonged QT interval on ECG (Aktas 2007)
Nervous system: Trigeminal neuralgia (Maluli 2015)
Hypersensitivity to dofetilide or any component of the formulation; congenital or acquired long QT syndromes; patients with baseline QT interval or QTc >440 msec (500 msec in patients with ventricular conduction abnormalities); severe renal impairment (CrCl <20 mL/minute); concurrent use with cimetidine, dolutegravir, hydrochlorothiazide (alone or in combinations), itraconazole (according to itraconazole prescribing information), ketoconazole, megestrol, prochlorperazine, trimethoprim (alone or in combination), verapamil, or Biktarvy (bictegravir, emtricitabine, and tenofovir) (Biktarvy prescribing information).
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• Proarrhythmic effects: May cause serious ventricular arrhythmias, primarily torsades de pointes (TdP). Watch for proarrhythmic effects; monitor and adjust dose to prevent QTc prolongation; reduced CrCl or certain dofetilide drug interactions will increase dofetilide plasma concentration. Risk of TdP significantly increases with doses greater than the maximum dose of 500 mcg twice daily. The risk of TdP may be higher in certain patient subgroups (eg, patients with heart failure). Most episodes of TdP occur within the first 3 days of therapy.
Disease-related concerns:
• Arrhythmias: Appropriate use: Reserve for patients who are highly symptomatic with atrial fibrillation/atrial flutter. [US Boxed Warning]: Must be initiated (or reinitiated) in a setting that can provide continuous monitoring of CrCl and ECG monitoring and cardiac resuscitation with staff familiar with the recognition and treatment of life-threatening arrhythmias for a minimum of 3 days, or for a minimum of 12 hours after electrical or pharmacological cardioversion to normal sinus rhythm, whichever is greater. Patients should be readmitted for continuous monitoring if dosage is later increased.
• Conduction disturbances: Use with caution in patients with second or third-degree heart block and/or sick sinus syndrome unless a functional pacemaker is in place; these patients were not included in phase 3 clinical trials. However, no effect on AV nodal conduction seen in patients with normal conduction and those with first-degree heart block. Defibrillation threshold is reduced in patients with ventricular tachycardia or ventricular fibrillation undergoing implantation of a cardioverter-defibrillator device.
• Electrolyte imbalance: Correct electrolyte disturbances, especially hypokalemia or hypomagnesemia, prior to use and throughout therapy.
• Hepatic impairment: Use with caution in patients with severe hepatic impairment (has not been studied).
• Renal impairment: Use with caution in patients with renal impairment; systemic clearance of dofetilide is decreased and plasma concentration increased with decreasing CrCl. Dose adjustment is required for patients with CrCl ≤60 mL/minute.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Tikosyn: 125 mcg, 250 mcg, 500 mcg [contains corn starch]
Generic: 125 mcg, 250 mcg, 500 mcg
Yes
Capsules (Dofetilide Oral)
125 mcg (per each): $8.16 - $9.74
250 mcg (per each): $8.16 - $9.74
500 mcg (per each): $8.16 - $9.74
Capsules (Tikosyn Oral)
125 mcg (per each): $13.30
250 mcg (per each): $13.30
500 mcg (per each): $13.30
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Oral: Administer with or without food.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020931s017lbl.pdf#page=27, must be dispensed with this medication.
Atrial fibrillation/atrial flutter: Maintenance of normal sinus rhythm in patients with chronic atrial fibrillation/atrial flutter of longer than 1-week duration who have been converted to normal sinus rhythm; conversion of atrial fibrillation and atrial flutter to normal sinus rhythm.
Supraventricular tachycardia
Dofetilide may be confused with defibrotide
Substrate of CYP3A4 (major), OCT2; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Aldesleukin: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
AMILoride: May increase the serum concentration of Dofetilide. Risk C: Monitor therapy
Amiodarone: QT-prolonging Class III Antiarrhythmics (Highest Risk) may enhance the QTc-prolonging effect of Amiodarone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Amisulpride (Oral): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Amisulpride (Oral). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even greater risk. Risk D: Consider therapy modification
Azithromycin (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Azithromycin (Systemic). Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
Bictegravir: May increase the serum concentration of Dofetilide. Risk X: Avoid combination
Carbetocin: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Ceritinib: QT-prolonging Class III Antiarrhythmics (Highest Risk) may enhance the QTc-prolonging effect of Ceritinib. Ceritinib may enhance the QTc-prolonging effect of QT-prolonging Class III Antiarrhythmics (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Chloroquine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Chloroquine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Cimetidine: May increase the serum concentration of Dofetilide. This is likely via inhibition of dofetilide renal tubular secretion (primarily) and inhibition of dofetilide metabolism. Risk X: Avoid combination
Citalopram: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Citalopram. Risk X: Avoid combination
Clarithromycin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Clarithromycin. Risk X: Avoid combination
Clofazimine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Clofazimine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
ClomiPRAMINE: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
CloZAPine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of CloZAPine. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Dofetilide. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Dofetilide. Risk C: Monitor therapy
CYP3A4 Inhibitors (Weak): May increase the serum concentration of Dofetilide. Risk C: Monitor therapy
Dabrafenib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Dasatinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Dasatinib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
Dolutegravir: May increase the serum concentration of Dofetilide. Risk X: Avoid combination
Domperidone: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Domperidone. Risk X: Avoid combination
Doxepin-Containing Products: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Doxepin-Containing Products. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
DroPERidol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of DroPERidol. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
Elranatamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Encorafenib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Entrectinib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Risk X: Avoid combination
Epcoritamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Erythromycin (Systemic): QT-prolonging Class III Antiarrhythmics (Highest Risk) may enhance the QTc-prolonging effect of Erythromycin (Systemic). Erythromycin (Systemic) may enhance the QTc-prolonging effect of QT-prolonging Class III Antiarrhythmics (Highest Risk). Management: Avoid concomitant use of erythromycin and class III antiarrhythmic agents. Use of erythromycin with dronedarone is specifically contraindicated. Risk X: Avoid combination
Escitalopram: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Escitalopram. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
Etelcalcetide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Fexinidazole: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Risk X: Avoid combination
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fingolimod: May enhance the QTc-prolonging effect of QT-prolonging Class III Antiarrhythmics (Highest Risk). Risk X: Avoid combination
Flecainide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Flecainide. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
Fluorouracil Products: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Fluorouracil Products. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Flupentixol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Flupentixol. Risk X: Avoid combination
Foslevodopa: May increase the serum concentration of MATE1/2-K Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Gadobenate Dimeglumine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Gadobenate Dimeglumine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Gemifloxacin: May enhance the QTc-prolonging effect of QT-prolonging Class III Antiarrhythmics (Highest Risk). Risk X: Avoid combination
Gilteritinib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this combination. If use is necessary, monitor for QTc interval prolongation and arrhythmias. Risk D: Consider therapy modification
Glofitamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Halofantrine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Halofantrine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Haloperidol: QT-prolonging Class III Antiarrhythmics (Highest Risk) may enhance the QTc-prolonging effect of Haloperidol. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
HydroCHLOROthiazide: May enhance the QTc-prolonging effect of Dofetilide. HydroCHLOROthiazide may increase the serum concentration of Dofetilide. Risk X: Avoid combination
HydrOXYzine: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Risk C: Monitor therapy
Imipramine: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Inotuzumab Ozogamicin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Inotuzumab Ozogamicin. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Itraconazole: May increase the serum concentration of Dofetilide. Risk X: Avoid combination
Ketoconazole (Systemic): May increase the serum concentration of Dofetilide. Risk X: Avoid combination
Lacosamide: Antiarrhythmic Agents (Class III) may enhance the adverse/toxic effect of Lacosamide. Specifically the risk for bradycardia, ventricular tachyarrhythmias, or a prolonged PR interval may be increased. Risk C: Monitor therapy
LamoTRIgine: May increase the serum concentration of Dofetilide. Risk X: Avoid combination
Landiolol: May enhance the adverse/toxic effect of QT-prolonging Class III Antiarrhythmics (Highest Risk). Risk C: Monitor therapy
Lefamulin: May enhance the QTc-prolonging effect of QT-prolonging CYP3A4 Substrates. Management: Do not use lefamulin tablets with QT-prolonging CYP3A4 substrates. Lefamulin prescribing information lists this combination as contraindicated. Risk X: Avoid combination
Levofloxacin-Containing Products (Systemic): May enhance the QTc-prolonging effect of QT-prolonging Class III Antiarrhythmics (Highest Risk). Risk X: Avoid combination
Levoketoconazole: QT-prolonging CYP3A4 Substrates may enhance the QTc-prolonging effect of Levoketoconazole. Levoketoconazole may increase the serum concentration of QT-prolonging CYP3A4 Substrates. Risk X: Avoid combination
Lofexidine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Lofexidine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Loop Diuretics: May enhance the QTc-prolonging effect of Dofetilide. Management: Monitor serum potassium and magnesium more closely when dofetilide is combined with loop diuretics. Electrolyte replacements will likely be required to maintain potassium and magnesium serum concentrations. Risk D: Consider therapy modification
MATE1/2-K Inhibitors: May increase the serum concentration of Dofetilide. Risk X: Avoid combination
Megestrol: May increase the serum concentration of Dofetilide. Risk X: Avoid combination
Meglumine Antimoniate: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
MetFORMIN: May increase the serum concentration of Dofetilide. Risk C: Monitor therapy
Methadone: QT-prolonging Class III Antiarrhythmics (Highest Risk) may enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Midostaurin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Midostaurin. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Mosunetuzumab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Moxifloxacin (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Moxifloxacin (Systemic). Risk X: Avoid combination
Nilotinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Nilotinib. Risk X: Avoid combination
Nirogacestat: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
OCT2 Inhibitors: May increase the serum concentration of Dofetilide. Risk X: Avoid combination
OLANZapine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of OLANZapine. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
Ondansetron: QT-prolonging Class III Antiarrhythmics (Highest Risk) may enhance the QTc-prolonging effect of Ondansetron. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Osimertinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Osimertinib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
Oxytocin: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Pacritinib: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
PAZOPanib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of PAZOPanib. Risk X: Avoid combination
Pentamidine (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pentamidine (Systemic). Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Pilsicainide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pilsicainide. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Pimozide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pimozide. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk X: Avoid combination
Piperaquine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Piperaquine. Risk X: Avoid combination
Posaconazole: May increase the serum concentration of QT-prolonging CYP3A4 Substrates. Such increases may lead to a greater risk for proarrhythmic effects and other similar toxicities. Risk X: Avoid combination
Probucol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Probucol. Risk X: Avoid combination
Prochlorperazine: May increase the serum concentration of Dofetilide. Risk X: Avoid combination
Propafenone: May enhance the QTc-prolonging effect of QT-prolonging Class III Antiarrhythmics (Highest Risk). Risk X: Avoid combination
Propofol: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
QT-prolonging Agents (Indeterminate Risk - Avoid): May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Agents (Indeterminate Risk - Caution): May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Class IA Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of QT-prolonging Class III Antiarrhythmics (Highest Risk). Risk X: Avoid combination
QT-prolonging Class III Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of other QT-prolonging Class III Antiarrhythmics (Highest Risk). Risk X: Avoid combination
QT-Prolonging Inhalational Anesthetics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
QT-prolonging Kinase Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of QT-prolonging Class III Antiarrhythmics (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
QT-prolonging Miscellaneous Agents (Highest Risk): QT-prolonging Class III Antiarrhythmics (Highest Risk) may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): QT-prolonging Class III Antiarrhythmics (Highest Risk) may enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Class III Antiarrhythmics (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of Dofetilide. QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk) may increase the serum concentration of Dofetilide. Management: Consider alternatives to this combination. If combined, monitor for increased dofetilide toxicities, including QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): QT-prolonging Class III Antiarrhythmics (Highest Risk) may enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Class III Antiarrhythmics (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
QUEtiapine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of QUEtiapine. Risk X: Avoid combination
Quizartinib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
Ribociclib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Ribociclib. Risk X: Avoid combination
Risdiplam: May increase the serum concentration of MATE1/2-K Substrates (Clinically Relevant with Inhibitors). Management: Avoid use of risdiplam with MATE substrates if possible. If the combination cannot be avoided, monitor closely for adverse effects. Consider a reduced dose of the MATE substrate according to that substrate's labeling if appropriate. Risk D: Consider therapy modification
RisperiDONE: QT-prolonging Agents (Highest Risk) may enhance the CNS depressant effect of RisperiDONE. QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of RisperiDONE. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Ritlecitinib: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Sertindole: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Risk X: Avoid combination
Sparfloxacin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Sparfloxacin. Risk X: Avoid combination
Spironolactone: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
SUNItinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of SUNItinib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
Tafenoquine: May increase the serum concentration of MATE1/2-K Substrates (Clinically Relevant with Inhibitors). Management: Avoid use of MATE substrates with tafenoquine, and if the combination cannot be avoided, monitor closely for evidence of toxicity of the MATE substrate and consider a reduced dose of the MATE substrate according to that substrate's labeling. Risk D: Consider therapy modification
Tafenoquine: May increase the serum concentration of OCT2 Substrates (Clinically Relevant with Inhibitors). Management: Avoid use of OCT2 substrates with tafenoquine, and if the combination cannot be avoided, monitor closely for evidence of toxicity of the OCT2 substrate and consider a reduced dose of the OCT2 substrate according to that substrate's labeling. Risk D: Consider therapy modification
Talquetamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Teclistamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Terbutaline: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
Thiazide and Thiazide-Like Diuretics: May enhance the QTc-prolonging effect of Dofetilide. Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Dofetilide. Management: Although hydrochlorothiazide is specifically cited as a contraindication, the risk likely extends to all thiazide and thiazide-like diuretics and may be even greater with chlorthalidone or bendroflumethiazide. Consider alternatives when possible. Risk D: Consider therapy modification
Thioridazine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination
Toremifene: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Toremifene. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
Treosulfan: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Triamterene: May increase the serum concentration of Dofetilide. Risk C: Monitor therapy
Trimethoprim: May increase the serum concentration of Dofetilide. Risk X: Avoid combination
Trofinetide: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Vemurafenib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Vemurafenib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
Verapamil: May increase the serum concentration of Dofetilide. Risk X: Avoid combination
Adverse events have been observed in animal reproduction studies.
It is not known if dofetilide is present in breast milk. Breastfeeding is not recommended by the manufacturer.
ECG monitoring with attention to QTc interval (or QT interval if heart rate <60 beats per minute) and occurrence of ventricular arrhythmias, baseline serum creatinine and changes in serum creatinine, serum potassium and magnesium levels at baseline and throughout therapy.
Upon initiation (or reinitiation) continuous ECG monitoring is necessary for a minimum of 3 days, or for at least 12 hours after electrical or pharmacological conversion to normal sinus rhythm, whichever is greater. QTc must be monitored at baseline prior to the first dose and 2 to 3 hours after administration. If baseline QTc >440 msec (>500 msec in patients with ventricular conduction abnormalities), use is contraindicated. If dofetilide is initiated, QTc interval must be monitored 2 to 3 hours after each subsequent dose of dofetilide for in-hospital doses 2 to 5. Thereafter, QTc and CrCl should be evaluated every 3 months. If at any time during therapy after the second dose the measured QTc is >500 msec (>550 msec in patients with ventricular conduction abnormalities), the manufacturer recommends discontinuing therapy.
Consult individual institutional policies and procedures.
Vaughan Williams Class III antiarrhythmic activity. Blockade of the cardiac ion channel carrying the rapid component of the delayed rectifier potassium current. Dofetilide has no effect on sodium channels, adrenergic alpha-receptors, or adrenergic beta-receptors. It increases the monophasic action potential duration due to delayed repolarization. The increase in the QT interval is a function of prolongation of both effective and functional refractory periods in the His-Purkinje system and the ventricles. Changes in cardiac conduction velocity and sinus node function have not been observed in patients with or without structural heart disease. PR and QRS width remain the same in patients with preexisting heart block and or sick sinus syndrome.
Absorption: Well absorbed
Distribution: Vd: 3 L/kg
Protein binding: 60% to 70%
Metabolism: Hepatic via CYP3A4 (low affinity); metabolites formed by N-dealkylation and N-oxidation
Bioavailability: >90%
Half-life elimination: ~10 hours; prolonged with renal impairment
Time to peak, serum: Fasting: 2 to 3 hours
Excretion: Urine (80%; ~80% as unchanged drug, 20% as inactive or minimally active metabolites); renal elimination consists of glomerular filtration and active tubular secretion via cationic transport system
Altered kidney function: Clearance is decreased and half-life is prolonged with decreasing CrCl.
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