(dofetilide)
TIKOSYN (dofetilide) can cause serious ventricular arrhythmias, primarily Torsade de Pointes (TdP) type ventricular tachycardia, a polymorphic ventricular tachycardia associated with QT interval prolongation. QT interval prolongation is directly related to dofetilide plasma concentration. Factors such as reduced creatinine clearance or certain dofetilide drug interactions will increase dofetilide plasma concentration. The risk of TdP can be reduced by controlling the plasma concentration through adjustment of the initial dofetilide dose according to creatinine clearance and by monitoring the ECG for excessive increases in the QT interval.
Treatment with dofetilide must therefore be started only in patients placed for a minimum of three days in a facility that can provide electrocardiographic monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. Calculation of the creatinine clearance for all patients must precede administration of the first dose of dofetilide. For detailed instructions regarding dose selection, see DOSAGE AND ADMINISTRATION.
The risk of dofetilide induced ventricular arrhythmia was assessed in three ways in clinical studies: 1) by description of the QT interval and its relation to the dose and plasma concentration of dofetilide; 2) by observing the frequency of TdP in TIKOSYN-treated patients according to dose; 3) by observing the overall mortality rate in patients with atrial fibrillation and in patients with structural heart disease.
The QT interval increases linearly with increasing TIKOSYN dose (see Figures 1 and 2 in CLINICAL PHARMACOLOGY and Dose-Response and Concentration Response for Increase in QT Interval).
In the supraventricular arrhythmia population (patients with AF and other supraventricular arrhythmias), the overall incidence of Torsade de Pointes was 0.8%. The frequency of TdP by dose is shown in Table 4. There were no cases of TdP on placebo.
| TIKOSYN Dose | |||||
|---|---|---|---|---|---|
| <250 mcg BID | 250 mcg BID | >250–500 mcg BID | >500 mcg BID | All Doses | |
Number of Patients | 217 | 388 | 703 | 38 | 1346 |
Torsade de Pointes | 0 | 1 (0.3%) | 6 (0.9%) | 4 (10.5%) | 11 (0.8%) |
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).
| Population: | Total | Before | After |
|---|---|---|---|
| n/N % | n/N % | n/N % | |
Supraventricular Arrhythmias | 11/1346 (0.8%) | 6/193 (3.1%) | 5/1153 (0.4%) |
DIAMOND CHF | 25/762 (3.3%) | 7/148 (4.7%) | 18/614 (2.9%) |
DIAMOND MI | 7/749 (0.9%) | 3/101 (3.0%) | 4/648 (0.6%) |
DIAMOND AF | 4/249 (1.6%) | 0/43 (0%) | 4/206 (1.9%) |
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).
In a pooled survival analysis of patients in the supraventricular arrhythmia population (low prevalence of structural heart disease), deaths occurred in 0.9% (12/1346) of patients receiving TIKOSYN and 0.4% (3/677) in the placebo group. Adjusted for duration of therapy, primary diagnosis, age, gender, and prevalence of structural heart disease, the point estimate of the hazard ratio for the pooled studies (TIKOSYN/placebo) was 1.1 (95% CI: 0.3, 4.3). 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).
(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 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).
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. In clinical trials, TIKOSYN was administered to patients previously treated with oral amiodarone only if serum amiodarone levels were below 0.3 mg/L or amiodarone had been withdrawn for at least three months.
TIKOSYN® (Tee' ko sin)
(dofetilide) Capsules
Read the Medication Guide before you start taking TIKOSYN and each time you get a refill. This information does not take the place of talking with your doctor about your condition or treatment.
What is the most important information I should know about TIKOSYN?
TIKOSYN can cause serious side effects, including a type of abnormal heartbeat called Torsade de Pointes, which can lead to death.
To establish the right dose of TIKOSYN, treatment with TIKOSYN must be started in a hospital where your heart rate and kidney function will be checked for the first 3 days of treatment. It is important that when you go home, you take the exact dose of TIKOSYN that your doctor prescribed for you.
While you take TIKOSYN, always watch for signs of abnormal heartbeat.
Call your doctor and go to the hospital right away if you:
What is TIKOSYN?
TIKOSYN is a prescription medicine that is used to treat an irregular heartbeat (atrial fibrillation or atrial flutter).
It is not known if TIKOSYN is safe and effective in children under 18 years of age.
Who should not take TIKOSYN?
Do not take TIKOSYN if you:
What should I tell my doctor before taking TIKOSYN?
Before taking TIKOSYN, tell your doctor about all of your medical conditions including if you:
Especially tell your doctor if you take medicines to treat:
Ask your doctor if you are not sure about the medicines you take. Tell your doctor about all prescription and non-prescription medicines, vitamins, dietary supplements, and any natural or herbal remedies. TIKOSYN and other medicines may affect each other, causing serious side effects. If you take TIKOSYN with certain medicines, you will be more likely to have a different type of abnormal heartbeat. See "Who should not take TIKOSYN?"
Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine.
How should I take TIKOSYN?
What are the possible side effects of TIKOSYN?
TIKOSYN can cause serious side effects, including a type of abnormal heartbeat called Torsade de Pointes, which can lead to death. See "What is the most important information I should know about TIKOSYN?"
The most common side effects of TIKOSYN include:
Call your doctor right away if you have signs of electrolyte imbalance:
Tell your doctor if you have any side effects that bother you or do not go away.
These are not all the possible side effects of TIKOSYN. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store TIKOSYN?
General information about TIKOSYN
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TIKOSYN for a condition for which it was not prescribed. Do not give TIKOSYN to other people, even if they have the same symptoms you have. It may harm them.
This Medication Guide summarizes the most important information about TIKOSYN. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about TIKOSYN that is written for health professionals.
For more about TIKOSYN, go to www.tikosyn.com or call 1-877-TIKOSYN (1-877-845-6796).
What are the ingredients in TIKOSYN?
Active ingredient: dofetilide
Inactive ingredients:
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