Dofetilide (Page 8 of 10)

OVERDOSAGE

There is no known antidote to dofetilide; treatment of overdose should therefore be symptomatic and supportive. The most prominent manifestation of overdosage is likely to be excessive prolongation of the QT interval.

In cases of overdose, cardiac monitoring should be initiated. Charcoal slurry may be given soon after overdosing but has been useful only when given within 15 minutes of dofetilide administration. Treatment of Torsade de Pointes or overdose may include administration of isoproterenol infusion, with or without cardiac pacing. Administration of intravenous magnesium sulfate may be effective in the management of Torsade de Pointes. Close medical monitoring and supervision should continue until the QT interval returns to normal levels.

Isoproterenol infusion into anesthetized dogs with cardiac pacing rapidly attenuates the dofetilide-induced prolongation of atrial and ventricular effective refractory periods in a dose-dependent manner. Magnesium sulfate, administered prophylactically either intravenously or orally in a dog model, was effective in the prevention of dofetilide-induced Torsade de Pointes ventricular tachycardia. Similarly, in man, intravenous magnesium sulfate may terminate Torsade de Pointes, irrespective of cause.

Dofetilide overdose was rare in clinical studies; there were two reported cases of dofetilide overdose in the oral clinical program. One patient received very high multiples of the recommended dose (28 capsules), was treated with gastric aspiration 30 minutes later, and experienced no events. One patient inadvertently received two 500 mcg doses one hour apart and experienced ventricular fibrillation and cardiac arrest 2 hours after the second dose.

In the supraventricular arrhythmia population, only 38 patients received doses greater than 500 mcg BID, all of whom received 750 mcg BID irrespective of creatinine clearance. In this very small patient population, the incidence of Torsade de Pointes was 10.5% (4/38 patients), and the incidence of new ventricular fibrillation was 2.6% (1/38 patients).

DOSAGE AND ADMINISTRATION

  • Therapy with dofetilide capsules must be initiated (and, if necessary, re-initiated) in a setting that provides continuous electrocardiographic (ECG) monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. Patients should continue to be monitored in this way for a minimum of three days. Additionally, patients should not be discharged within 12 hours of electrical or pharmacological conversion to normal sinus rhythm.
  • The dose of dofetilide capsules must be individualized according to calculated creatinine clearance and QTc. (QT interval should be used if the heart rate is <60 beats per minute. There are no data on use of dofetilide capsules when the heart rate is <50 beats per minute.) The usual recommended dose of dofetilide capsules is 500 mcg BID, as modified by the dosing algorithm described below. For consideration of a lower dose, see Special Considerations below.
  • Serum potassium should be maintained within the normal range before dofetilide capsules treatment is initiated and should be maintained within the normal range while the patient remains on dofetilide capsules therapy. (See WARNINGS, Hypokalemia and Potassium-Depleting Diuretics). In clinical trials, potassium levels were generally maintained above 3.6–4.0 mEq/L.
  • Patients with atrial fibrillation should be anticoagulated according to usual medical practice prior to electrical or pharmacological cardioversion. Anticoagulant therapy may be continued after cardioversion according to usual medical practice for the treatment of people with AF. Hypokalemia should be corrected before initiation of dofetilide capsules therapy (see WARNINGS, Ventricular Arrhythmia).
  • Patients to be discharged on dofetilide capsules therapy from an inpatient setting as described above must have an adequate supply of dofetilide capsules, at the patient’s individualized dose, to allow uninterrupted dosing until the patient can fill a dofetilide capsules prescription.

Instructions for Individualized Dose Initiation

Initiation of Dofetilide Capsules Therapy

Step 1. Electrocardiographic assessment: Prior to administration of the first dose, the QTc must be determined using an average of 5-10 beats. If the QTc is greater than 440 msec (500 msec in patients with ventricular conduction abnormalities), dofetilide is contraindicated. If heart rate is less than 60 beats per minute, QT interval should be used. Patients with heart rates <50 beats per minute have not been studied.

Step 2. Calculation of creatinine clearance: Prior to the administration of the first dose, the patient’s creatinine clearance must be calculated using the following formula:

creatinine clearance (male) = (140-age) × actual body weight in kg
72 × serum creatinine (mg/dL)

creatinine clearance (female) = (140-age) × actual body weight in kg × 0.85 72 × serum creatinine (mg/dL)

When serum creatinine is given in µmol/L, divide the value by 88.4 (1 mg/dL = 88.4 µmol/L).

Step 3. Starting Dose: The starting dose of dofetilide capsules is determined as follows:

Calculated Creatinine ClearanceDofetilide Capsules Dose
>60 mL/min500 mcg twice daily
40-60 mL/min 250 mcg twice daily
20-<40 mL/min 125 mcg twice daily
<20 mL/min

Dofetilide is contraindicated

in these patients

Step 4. Administer the adjusted dofetilide capsules dose and begin continuous ECG monitoring.

Step 5. At 2-3 hours after administering the first dose of dofetilide capsules, determine the QTc. If the QTc has increased by greater than 15% compared to the baseline established in Step 1 OR if the QTc is greater than 500 msec (550 msec in patients with ventricular conduction abnormalities), subsequent dosing should be adjusted as follows:

If the Starting Dose Based on Creatinine Clearance is:Then the Adjusted Dose(for QTc Prolongation) is:
500 mcg twice daily250 mcg twice daily
250 mcg twice daily125 mcg twice daily
125 mcg twice daily125 mcg once a day

Step 6. At 2–3 hours after each subsequent dose of dofetilide capsules, determine the QTc (for in-hospital doses 2–5). No further down titration of dofetilide capsules based on QTc is recommended.

NOTE: If at any time after the second dose of dofetilide capsules is given the QTc is greater than 500 msec (550 msec in patients with ventricular conduction abnormalities), dofetilide capsules should be discontinued.

Step 7. Patients are to be continuously monitored by ECG for a minimum of three days, or for a minimum of 12 hours after electrical or pharmacological conversion to normal sinus rhythm, whichever is greater.

The steps described above are summarized in the following diagram:

flow chart
(click image for full-size original)

Maintenance of Dofetilide Capsules Therapy

Renal function and QTc should be re-evaluated every three months or as medically warranted. If QTc exceeds 500 milliseconds (550 msec in patients with ventricular conduction abnormalities), dofetilide capsules therapy should be discontinued and patients should be carefully monitored until QTc returns to baseline levels. If renal function deteriorates, adjust dose as described in Initiation of Dofetilide Capsules Therapy, Step 3.

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