Tikosyn

Starting Dose:

The starting dose of TIKOSYN is determined as follows: Calculated Creatinine Clearance TIKOSYN Dose >60 mL/min 500 mcg twice daily 40 to 60 mL/min 250 mcg twice daily 20 to <40 mL/min 125 mcg twice daily <20 mL/min Tikosyn is contraindicated in these patients Step 4.

Administer the adjusted TIKOSYN dose and begin continuous ECG monitoring. Step 5. At 2–3 hours after administering the first dose of Tikosyn, determine the QTc or QT (if heart rate is less than 60 beats per minute). If the QTc or QT has increased by greater than 15% compared to the baseline established in Step 1 OR if the QTc or QT 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 or QT Prolongation) is: 500 mcg twice daily 250 mcg twice daily 250 mcg twice daily 125 mcg twice daily 125 mcg twice daily 125 mcg once a day Step 6.

At 2–3 hours after each subsequent dose of Tikosyn, determine the QTc or QT (if heart rate is less than 60 beats per minute) (for in-hospital doses 2–5). No further down titration of Tikosyn based on QTc or QT is recommended.

NOTE:

If at any time after the second dose of Tikosyn is given the QTc or QT is greater than 500 msec (550 msec in patients with ventricular conduction abnormalities), Tikosyn 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 Maintenance of TIKOSYN Therapy Renal function and QTc or QT (if heart rate is less than 60 beats per minute) should be re-evaluated every three months or as medically warranted.

If QTc or QT exceeds 500 milliseconds (550 msec in patients with ventricular conduction abnormalities), TIKOSYN therapy should be discontinued and patients should be carefully monitored until QTc or QT returns to baseline levels. If renal function deteriorates, adjust dose as described in Initiation of TIKOSYN Therapy, Step 3.

Special Considerations Consideration of a Dose Lower than that Determined by the Algorithm: The dosing algorithm shown above should be used to determine the individualized dose of TIKOSYN. In clinical trials (see CLINICAL STUDIES ), the highest dose of 500 mcg BID of TIKOSYN as modified by the dosing algorithm led to greater effectiveness than lower doses of 125 or 250 mcg BID as modified by the dosing algorithm.

The risk of Torsade de Pointes, however, is related to dose as well as to patient characteristics (see WARNINGS ). Physicians, in consultation with their patients, may therefore in some cases choose doses lower than determined by the algorithm.

It is critically important that if at any time this lower dose is increased, the patient needs to be rehospitalized for three days. Previous toleration of higher doses does not eliminate the need for rehospitalization. The maximum recommended dose in patients with a calculated creatinine clearance greater than 60 mL/min is 500 mcg BID; doses greater than 500 mcg BID have been associated with an increased incidence of Torsade de Pointes.

A patient who misses a dose should NOT double the next dose. The next dose should be taken at the usual time.

Cardioversion:

If patients do not convert to normal sinus rhythm within 24 hours of initiation of TIKOSYN therapy, electrical conversion should be considered. Patients continuing on TIKOSYN after successful electrical cardioversion should continue to be monitored by electrocardiography for 12 hours post cardioversion, or a minimum of 3 days after initiation of TIKOSYN therapy, whichever is greater.

Switch to TIKOSYN from Class I or other Class III Antiarrhythmic Therapy Before initiating TIKOSYN therapy, previous antiarrhythmic therapy should be withdrawn under careful monitoring for a minimum of three (3) plasma half-lives. 3 mcg/mL or until amiodarone has been withdrawn for at least three months.

Stopping TIKOSYN Prior to Administration of Potentially Interacting Drugs If TIKOSYN needs to be discontinued to allow dosing of other potentially interacting drug(s), a washout period of at least two days should be followed before starting the other drug(s).

Ventricular arrhythmias and ventricular tachycardia include all cases of Torsade de Pointes. 1% In the DIAMOND trials, a total of 1,511 patients were exposed to TIKOSYN for 1757 patient years. 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.

Table 7:

Incidence of Serious Arrhythmias and Conduction Disturbances in Patients with AF at Entry to the DIAMOND Studies TIKOSYN Placebo N=249 N=257 Ventricular arrhythmias Patients with more than one arrhythmia are counted only once in this category.

Ventricular arrhythmias and ventricular tachycardia include all cases of Torsade de Pointes. 8% 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.

Table 8:

Frequency of Adverse Events Occurring at >2% on TIKOSYN, and Numerically More Frequently on TIKOSYN than Placebo in Patients with Supraventricular Arrhythmias TIKOSYN Placebo Adverse Event % % headache 11 9 chest pain 10 7 dizziness 8 6 respiratory tract infection 7 5 dyspnea 6 5 nausea 5 4 flu syndrome 4 2 insomnia 4 3 accidental injury 3 1 back pain 3 2 procedure (medical/surgical/health service) 3 2 diarrhea 3 2 rash 3 2 abdominal pain 3 2 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.

There were no cases of TdP on placebo. 8%) 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 ).

9%) 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 arrhythmias; 19/25 and 4/7 events in DIAMOND CHF and DIAMOND MI, respectively; 2/4 events in the DIAMOND AF subpopulation).

4% (3/677) in the placebo group. 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 arrhythmias.

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).

Dofetilide 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.

3 mg/L or amiodarone had been withdrawn for at least three months.