Dosing and uses of Tikosyn (dofetilide)
Adult dosage forms and strengths
capsule
- 125mcg
- 250mcg
- 500mcg
Conversion of Atrial Fibrillation/Flutter to Normal Sinus Rhythm
QTc must be <440 msec (or <500 msec with ventricular conduction abnormalities) before initiating first dose; contraindicated if >440 msec (or >500 msec with ventricular conduction abnormalities)
Initial dose
- CrCl >60 mL/min: 500 mcg PO q12hr
- CrCl 40-60 mL/min: 250 mcg PO q12hr
- CrCl 20-40 mL/min: 125 mcg PO q12hr
- CrCl <20 mL/min: Contraindicated
Sinus Rhythm Maintenance After Conversion
- Post initial dose adjustment based on QTc (2-3 hours after initial dose)
- If QTc increases <15% of baseline, continue current dose
- If QTc increases >15% or >500 msec (550 msec with ventricular conduction abnormalities) decrease dose as follows:
- If initial dose 500 mcg q12hr, decrease to 250 mcg q12hr
- If initial dose 250 mcg q12hr, decrease to 125 mcg q12hr
- If initial dose 125 mcg q12hr, decrease to 125 mcg qDay
Monitoring
Must be hospitalized to initiate
Measure QTc 2-3 hours after first 5 doses during inpatient stay
Discontinue dofetilide if at any time after second dose, QTC >500 msec (550 msec with ventricular conduction abnormalities)
Pediatric dosage forms and strengths
Not recommended
Tikosyn (dofetilide) adverse (side) effects
>10%
Headache (11%)
1-10%
Chest pain (10%)
Dizziness (8%)
Insomnia (4%)
Respiratory tract infection (7%)
Dyspnea (6%)
Rash (3%)
Flu-like syndrome (4%)
Back pain (3%)
Ventricular tachycardia (3-4%)
Torsade de pointes (3% in HF patients and 0.9% in patients with recent MI)
Nausea (5%)
Diarrhea (3%)
Frequency not defined
AV block, QTc interval prolongation, torsades de pointes, ventricular arrhythmias
Difficulty sleeping
Liver damage
Cough
Paresthesia
Angioedema
Warnings
Black box warnings
Hospitalize minimum of 3 days during initiation or reinitiation to minimize risk of induced arrhythmia
Facility must provide CrCl calculations, continuous ECG monitoring, and resuscitation for at least 3 days when initiating or restarting therapy
Experienced personnel who manage serious arrhythmias & setting required
Monitoring
- Baseline & continuous ECG during therapy
- Do not initiate if baseline QTc >440 msec (500 msec in patients w/ ventricular conduction problems)
- Do not initiate if heart rate <60 bpm
- Baseline CrCl determines initial dosage; dosage adjustments determined by QTc changes
- Reevaluate renal function and QTc q3mth or more often if medically required
Contraindications
Hypersensitivity
Congenital or acquired long QT syndromes; do not use with baseline QTc >440 msec (500 msec with ventricular conduction abnormalities)
Concomitant use of cation transport system inhibitors (eg, verapamil, cimetidine, trimethoprim, ketoconazole, prochlorperazine, dolutegravir and megestrol); each of these drugs cause a substantial increase in dofetilide plasma concentrations
Severe renal impairment: CrCl <20 mL/min
Cautions
Atrioventricular block, bradycardia, electrolyte imbalance, patients taking potassium-depleting diuretics, moderate QT interval prolongation prior to treatment, proarrhythmic events, liver disease, renal impairment
Coadministration of drugs that prolong QT interval and other antiarrhythmic agents: phenothiazines, cisapride, bepridil, TCAs, oral macrolides, class I or class III antiarrhythmics & amiodarone
Grapefruit juice may increase levels; avoid concurrent use
Magnesium and potassium serum levels should be maintained within normal range to avoid QTc prolongation
Pregnancy and lactation
Pregnancy category: C
Lactation: excretion in milk unknown/not recommended
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Tikosyn (dofetilide)
Mechanism of action
Blocks channels carrying delayed rectifier potassium currents, IKr
Markedly prolongs action potential as a result of delayed repolarization
Absorption
Bioavailability: >90%
Peak Plasma Time: 2-3 hr
Onset: 2 hr
Duration: 4 hr
Distribution
Protein Bound: 60-70%
Vd: 3-4 L/kg
Metabolism
50% of absorbed dose metabolized in liver by CYP3A4 to inactive metabolites
Metabolites: No quantifiable metabolites found in plasma, 5 metabolites identified in urine
Elimination
Half-Life: 10 hr
Excretion: 80% urine; <10% feces
