Tikosyn (Page 7 of 9)

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.

OVERDOSAGE

There is no known antidote to TIKOSYN; 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 TIKOSYN 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.

TIKOSYN overdose was rare in clinical studies; there were two reported cases of TIKOSYN 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 TIKOSYN 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 TIKOSYN 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 TIKOSYN when the heart rate is <50 beats per minute.) The usual recommended dose of TIKOSYN 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 TIKOSYN treatment is initiated and should be maintained within the normal range while the patient remains on TIKOSYN 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 TIKOSYN therapy (see WARNINGS, Ventricular Arrhythmia).
  • Patients to be discharged on TIKOSYN therapy from an inpatient setting as described above must have an adequate supply of TIKOSYN, at the patient’s individualized dose, to allow uninterrupted dosing until the patient can fill a TIKOSYN prescription.

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