Dofetilide (Tikosyn) is an orally available Class III anti-arrhythmic drug marketed by Pfizer in various strengths (125 ugs, 250 ugs, and 500 ugs).

Dofetilide (Tikosyn) Uses:

• Atrial fibrillation and 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.

• Off Label Use of Dofetilide in Adults:

  • Atrial fibrillation in patients with hypertrophic cardiomyopathy
  • Supraventricular tachycardia

Dofetilide (Tikosyn) Dose in Adults

Note:

• CrCl and QTc (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 renal impairment).
• Dofetilide may be initiated at lower doses than recommended based on physician discretion; however, if the lower dose is increased, the patient will require rehospitalization for 3 days.

Dofetilide (Tikosyn) Dose in the treatment of Atrial fibrillation and atrial flutter:

• Oral: Initial: 500 mcg twice a day (maximum dose: 500 mcg twice daily)

Dofetilide (Tikosyn) Dose in the treatment of Supraventricular tachycardia:

• Oral: Initial: 500 mcg every 12 hours.

• Modification of dosage in response to the initial dose:

  • QTc interval should be measured 2 to 3 hours after the initial dose.
  • If the QTc 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 a day, then reduce to 250 mcg twice a day.
  • If the starting dose was 250 mcg twice a day, then reduce to 125 mcg twice a day.
  • If the starting dose was 125 mcg twice a day, then reduce to 125 mcg once a day.
  • 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), dofetilide should be discontinued.

• Maintenance therapy:

  • No further lowering of dose based on QTc is recommended following modification of the initial dose.
  • Renal function and QTc should be monitored every 3 months or as medically warranted. If QTc >500 msec (>550 msec in patients with ventricular conduction abnormalities) discontinue therapy.
  • If renal function deteriorates, adjust dose as described in Dosage adjustment in renal impairment.

Dofetilide (Tikosyn) Dose in Childrens

Not recommended for use in children.

Pregnancy Risk Factor C

• Animal reproduction studies have seen adverse events.

Dofetilide use during breastfeeding:

• It is unknown if dofetilide can be found in breast milk.
• The manufacturer does not recommend breast-feeding.

Dofetilide (Tikosyn) Dose in Kidney disease:

Note:

• Using the Modification of Diet in Renal Disease (MDRD) equation and subsequent eGFR to determine dose may lead to overestimation of CrCl and overdose of medication; use only the Cockcroft-Gault equation to estimate CrCl.
• Use actual body weight when using the Cockcroft-Gault equation to calculate CrCl (weight range of patients enrolled in clinical trials: 40 to 134 kg).

• CrCl >60 mL/minute:

  • Initial: No dosage adjustment necessary.

• CrCl 40 to 60 mL/minute:

  • Initial: 250 mcg twice daily.

• CrCl 20 to 39 mL/minute:

  • Initial: 125 mcg twice daily.

• CrCl <20 mL/minute:

  • Use is contraindicated.

Dofetilide (Tikosyn) Dose in Liver disease:

• Mild or moderate hepatic impairment (Child-Pugh class A or B):

  • No dosage adjustment is 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.

Common Side Effects of Dofetilide (Tikosyn):

• Cardiovascular:

  • Torsades De Pointes

• Central Nervous System:

  • Headache

Less Common Side Effects Of Dofetilide (Tikosyn):

• Cardiovascular:

  • Chest Pain
  • Ventricular Fibrillation
  • Ventricular Tachycardia
  • Bradycardia
  • Cardiac Arrest
  • Cerebral Ischemia
  • Cerebrovascular Accident
  • Edema
  • Myocardial Infarction
  • Syncope
  • Atrioventricular Block
  • Heart Block

• Central Nervous System:

  • Dizziness
  • Insomnia
  • Facial Paralysis
  • Flaccid Paralysis
  • Migraine
  • Paralysis
  • Paresthesia

• Dermatologic:

  • Skin Rash

• Gastrointestinal:

  • Nausea
  • Abdominal Pain
  • Diarrhea

• Hepatic:

  • Hepatotoxicity
  • Hepatic Injury

• Hypersensitivity:

  • Angioedema

• Neuromuscular & Skeletal:

  • Back Pain

• Respiratory:

  • Respiratory Tract Infection
  • Dyspnea
  • Flu-Like Symptoms
  • Increased Cough
  • Cough

• Miscellaneous:

  • Accidental Injury
  • Surgery

Contraindications to Dofetilide (Tikosyn):

• Hypersensitivity to dofetilide, or any component of its formulation.
• Congenital and acquired long QT syndromes
• Patients with QTc >440msec or a baseline QT interval (500msec for patients with ventricular conduction disorders);
• Grave renal impairment (CrCl 20 mg/minute);
• Concurrent use of cimetidine (alone and in combinations), hydrochlorothiazide, dolutegravir (alone and in combinations), itraconazole according to itraconazole prescribing Information), ketoconazole. Megestrol, megestrol. prochlorperazine. trimethoprim. (alone, in combination) or verapamil

Warnings and precautions

• Proarrhythmic effects

  • May cause serious ventricular arrhythmias, primarily torsades de pointes (TdP). Pay attention to proarrhythmic effects and monitor the dosage to avoid QTc prolongation. Dofetilide plasma concentrations will rise if there are reduced CrCl levels or dofetilide drug interactions.
  • TdP is more likely to occur if you take 500 mg twice daily.
  • TdP risk may be greater in certain patient groups (e.g., those with heart disease).
  • TdP episodes are most common within the first three days of therapy.

• Arrhythmias:

  • Use only for patients with severe symptoms of atrial fibrillation/atrial Flutter.
  • [US Boxed Warning]You must initiate (or reinitiate) the procedure in a way that provides continuous monitoring of CrCl, ECG monitoring, and cardiac resuscitation. The staff should be familiar with the treatment and recognition of life-threatening arrhythmias.
  • If the dose is increased, patients should be admitted again for continuous monitoring.

• Conduction disturbances:

  • Patients with sick sinus syndrome, second- or third-degree block of the heart and/or sick sinus syndrome should be cautious. These patients were not included on phase 3 clinical trials.
  • Patients with normal conduction and patients with first-degree block of the heart have no effect on AV Nodal Conduction.
  • The defibrillation threshold is reduced in patients with ventricular tachycardia or ventricular fibrillation undergoing implantation of a cardioverter-defibrillator device.

• Electrolyte imbalance:

  • Before and during therapy, correct electrolyte imbalances, particularly hypokalemia and hypomagnesemia.

• Hepatic impairment

  • Patients with severe hepatic impairment should be cautious (has not been researched).

• Renal impairment

  • Patients with impaired renal function should be cautious. Dofetilide's systemic clearance is reduced and plasma concentration increases with decreasing CrCl.
  • Patients with CrCl >=60 mL/minute will need to adjust their dose.

Dofetilide: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• ECG monitoring with attention to QT (if heart rate <60 beats per minute) or QTc and occurrence of ventricular arrhythmias,
• baseline serum creatinine and changes in serum creatinine.
• Upon initiation (or reinitiation) continuous ECG monitoring recommended for a minimum of 3 days, or for at least 12 hours after electrical or pharmacological conversion to normal sinus rhythm, whichever is greater.
• Monitor serum potassium and magnesium levels at baseline and throughout therapy.
• QT or QTc must be monitored at baseline prior to the first dose and 2 to 3 hours afterward.
• If at baseline, QTc >440 msec (>500 msec in patients with ventricular conduction abnormalities), use is contraindicated.
• If dofetilide is started, the QTc interval must be determined 2 to 3 hours after every subsequent dose of dofetilide for in-hospital doses 2 to 5.
• Thereafter, QT or 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), dofetilide should be discontinued.
• Consult individual institutional policies and procedures.

How to administer Dofetilide?

• Oral: Administer with or without fo

Mechanism of action of Dofetilide (Tikosyn):

• Vaughan Williams Class III antiarrhythmic activity.
• Inhibition of cardiac ion channels carrying the delayed rectifier potassium current's rapid component.
• Dofetilide does not affect sodium channels or adrenergic adrenergic Beta-receptors.
• Due to delayed repolarization, it prolongs monophasic action pot duration.
• The QT interval increases as a result of the prolongation of both functional and effective refractory times in the His-Purkinje and ventricles.
• Patients with and without structural heart disease have not reported any changes in their cardiac conduction velocity or sinus node function.
• Patients with preexisting heart disease or sick sinus syndrome will have their PR and QRS widths remain the same.

Absorption:

• Well absorbed

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, about 20% as inactive or minimally active metabolites); renal elimination is composed of glomerular filtration and active tubular secretion via the cationic transport system

International Brands of Dofetilide:

• Tikosyn

Dofetilide Brand Names in Pakistan:

No Brands Available in Pakistan.