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The TIKOSYN clinical program involved approximately 8,600 patients in 130 clinical studies of normal volunteers and patients with supraventricular and ventricular arrhythmias. TIKOSYN was administered to 5,194 patients, including two large, placebo-controlled mortality trials (DIAMOND CHF and DIAMOND MI) in which 1,511 patients received TIKOSYN for up to three years.

In the following section, adverse reaction data for cardiac arrhythmias and non-cardiac adverse reactions are presented separately for patients included in the supraventricular arrhythmia development program and for patients included in the DIAMOND CHF and MI mortality trials (see Clinical Studies, Safety in Patients with Structural Heart Disease, DIAMOND Studies, for a description of these trials).

In studies of patients with supraventricular arrhythmias, a total of 1,346 and 677 patients were exposed to TIKOSYN and placebo for 551 and 207 patient years, respectively. A total of 8.7% of patients in the dofetilide groups were discontinued from clinical trials due to adverse events compared to 8.0% in the placebo groups. The most frequent reason for discontinuation ( > 1%) was ventricular tachycardia (2.0% on dofetilide vs. 1.3% on placebo). The most frequent adverse events were headache, chest pain, and dizziness.

Serious Arrhythmias And Conduction Disturbances

Torsade de Pointes is the only arrhythmia that showed a dose-response relationship to TIKOSYN treatment. It did not occur in placebo treated patients. The incidence of Torsade de Pointes in patients with supraventricular arrhythmias was 0.8% (11/1346) (see WARNINGS). The incidence of Torsade de Pointes in patients who were dosed according to the recommended dosing regimen (see DOSAGE AND ADMINISTRATION) was 0.8% (4/525). Table 6 shows the frequency by randomized dose of serious arrhythmias and conduction disturbances reported as adverse events in patients with supraventricular arrhythmias.

Table 6: Incidence of Serious Arrhythmias and Conduction Disturbances in Patients with Supraventricular Arrhythmias

Arrhythmia event: TIKOSYN Dose Placebo
N=677
< 250 mcg BID
N=217
250 mcg BID
N=388
> 250–500 mcg BID
N=703
> 500 mcg BID
N=38
Ventricular arrhythmias* ^ 3.70% 2.60% 3.40% 15.80% 2.70%
  Ventricular fibrillation 0 0.30% 0.40% 2.60% 0.10%
  Ventricular tachycardia^ 3.70% 2.60% 3.30% 13.20% 2.50%
    Torsade de Pointes 0 0.30% 0.90% 10.50% 0
Various forms of block
  AV block 0.90% 1.50% 0.40% 0 0.30%
  Bundle branch block   0 0.50% 0.10% 0 0.10%
  Heart block 0 0.50% 0.10% 0 0.10%
* 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.

In the DIAMOND trials, a total of 1,511 patients were exposed to TIKOSYN for 1757 patient years. The incidence of Torsade de Pointes was 3.3% in CHF patients and 0.9% 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
N=249
Placebo
N=257
Ventricular arrhythmias* ^ 14.50% 13.60%
  Ventricular fibrillation    4.80% 3.10%
  Ventricular tachycardia^ 12.40% 11.30%
    Torsade de Pointes 1.60% 0
Various forms of block
  AV block 0.80% 2.70%
  (Left) bundle branch block 0 0.40%
  Heart block 1.20% 0.80%
* 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.

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

Adverse Event TIKOSYN
%
Placebo
%
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.