Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/40
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Tikosyn (Capsule)
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Instructions for Individualized Dose Initiation:<br/>Initiation of TIKOSYN 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), TIKOSYN 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 kg72��serum creatinine (mg/dL) creatinine clearance (female) = (140-age)��actual body weight in kg��0.8572��serum creatinine (mg/dL) When serum creatinine is given in��mol/L, divide the value by 88.4 (1 mg/dL = 88.4��mol/L). Step 3. Starting Dose: The starting dose of TIKOSYN is determined as follows: 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. 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: Step 6. At 2���3 hours after each subsequent dose of TIKOSYN, determine the QTc (for in-hospital doses 2���5). No further down titration of TIKOSYN based on QTc is recommended. NOTE: If at any time after the second dose of TIKOSYN is given, the QTc 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:<br/>Maintenance of TIKOSYN 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), TIKOSYN 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 TIKOSYN Therapy, Step 3.<br/>Special Considerations:<br/>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 , 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 . 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.<br/>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.<br/>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. Because of the unpredictable pharmacokinetics of amiodarone, TIKOSYN should not be initiated following amiodarone therapy until amiodarone plasma levels are below 0.3 mcg/mL or until amiodarone has been withdrawn for at least three months.<br/>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).
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TIKOSYN (dofetilide) is an antiarrhythmic drug with Class III (cardiac action potential duration prolonging) properties. Its empirical formula is CHNOSand it has a molecular weight of 441.6. The structural formula is The chemical name for dofetilide is N-[4-[2-[methyl[2-[4-[(methylsulfonyl)amino]phenoxy]ethyl]amino]ethyl]phenyl]-methanesulfonamide. Dofetilide is a white to off-white powder. It is very slightly soluble in water and propan-2-ol and is soluble in 0.1M aqueous sodium hydroxide, acetone and aqueous 0.1M hydrochloric acid. TIKOSYN capsules contain the following inactive ingredients: microcrystalline cellulose, corn starch, colloidal silicon dioxide and magnesium stearate. TIKOSYN is supplied for oral administration in three dosage strengths: 125 mcg (0.125 mg) orange and white capsules, 250 mcg (0.25 mg) peach capsules, and 500 mcg (0.5 mg) peach and white capsules.
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Mechanism of Action: TIKOSYN (dofetilide) shows Vaughan Williams Class III antiarrhythmic activity. The mechanism of action is blockade of the cardiac ion channel carrying the rapid component of the delayed rectifier potassium current, I. At concentrations covering several orders of magnitude, dofetilide blocks only Iwith no relevant block of the other repolarizing potassium currents (e.g., I, I). At clinically relevant concentrations, dofetilide has no effect on sodium channels (associated with Class I effect), adrenergic alpha-receptors, or adrenergic beta-receptors.<br/>Electrophysiology: TIKOSYN (dofetilide) increases the monophasic action potential duration in a predictable, concentration-dependent manner, primarily due to delayed repolarization. This effect, and the related increase in effective refractory period, is observed in the atria and ventricles in both resting and paced electrophysiology studies. The increase in QT interval observed on the surface ECG is a result of prolongation of both effective and functional refractory periods in the His-Purkinje system and the ventricles. Dofetilide did not influence cardiac conduction velocity and sinus node function in a variety of studies in patients with or without structural heart disease. This is consistent with a lack of effect of dofetilide on the PR interval and QRS width in patients with pre-existing heart block and/or sick sinus syndrome. In patients, dofetilide terminates induced re-entrant tachyarrhythmias (e.g., atrial fibrillation/flutter and ventricular tachycardia) and prevents their re-induction. TIKOSYN does not increase the electrical energy required to convert electrically-induced ventricular fibrillation, and it significantly reduces the defibrillation threshold in patients with ventricular tachycardia and ventricular fibrillation undergoing implantation of a cardioverter-defibrillator device.<br/>Hemodynamic Effects: In hemodynamic studies, TIKOSYN had no effect on cardiac output, cardiac index, stroke volume index, or systemic vascular resistance in patients with ventricular tachycardia, mild to moderate congestive heart failure or angina and either normal or low left ventricular ejection fraction. There was no evidence of a negative inotropic effect related to TIKOSYN therapy in patients with atrial fibrillation. There was no increase in heart failure in patients with significantleft ventricular dysfunction (see Safety in Patients with Structural Heart Disease: DIAMOND Studies). In the overall clinical program, TIKOSYN did not affect blood pressure. Heart rate was decreased by 4-6 bpm in studies in patients.<br/>Pharmacokinetics, General:<br/>Absorption and Distribution: The oral bioavailability of dofetilide is>90%, with maximal plasma concentrations occurring at about 2���3 hours in the fasted state. Oral bioavailability is unaffected by food or antacid. The terminal half life of TIKOSYN is approximately 10 hours; steady state plasma concentrations are attained within 2���3 days, with an accumulation index of 1.5 to 2.0. Plasma concentrations are dose proportional. Plasma protein binding of dofetilide is 60���70%, is independent of plasma concentration, and is unaffected by renal impairment. Volume of distribution is 3 L/kg.<br/>Metabolism and Excretion: Approximately 80% of a single dose of dofetilide is excreted in urine, of which approximately 80% is excreted as unchanged dofetilide with the remaining 20% consisting of inactive or minimally active metabolites. Renal elimination involves both glomerular filtration and active tubular secretion (via the cation transport system, a process that can be inhibited by cimetidine, trimethoprim, prochlorperazine, megestrol and ketoconazole). In vitro studies with human liver microsomes show that dofetilide can be metabolized by CYP3A4, but it has a low affinity for this isoenzyme. Metabolites are formed by N-dealkylation and N-oxidation. There are no quantifiable metabolites circulating in plasma, but 5 metabolites have been identified in urine.<br/>Pharmacokinetics in Special Populations:<br/>Renal Impairment: In volunteers with varying degrees of renal impairment and patients with arrhythmias, the clearance of dofetilide decreases with decreasing creatinine clearance. As a result, and as seen in clinical studies, the half-life of dofetilide is longer in patients with lower creatinine clearances. Because increase in QT interval and the risk of ventricular arrhythmias are directly related to plasma concentrations of dofetilide, dosage adjustment based on calculated creatinine clearance is critically important . Patients with severe renal impairment (creatinine clearance<20 mL/min) were not included in clinical or pharmacokinetic studies .<br/>Hepatic Impairment: There was no clinically significant alteration in the pharmacokinetics of dofetilide in volunteers with mild to moderate hepatic impairment (Child-Pugh class A and B) compared to age- and weight-matched healthy volunteers. Patients with severe hepatic impairment were not studied.<br/>Patients with Heart Disease: Population pharmacokinetic analyses indicate that the plasma concentration of dofetilide in patients with supraventricular and ventricular arrhythmias, ischemic heart disease, or congestive heart failure are similar to those of healthy volunteers, after adjusting for renal function.<br/>Elderly: After correction for renal function, clearance of dofetilide is not related to age.<br/>Women: A population pharmacokinetic analysis showed that women have approximately 12���18% lower dofetilide oral clearances than men (14���22% greater plasma dofetilide levels), after correction for weight and creatinine clearance. In females, as in males, renal function was the single most important factor influencing dofetilide clearance. In normal female volunteers, hormone replacement therapy (a combination of conjugated estrogens and medroxyprogesterone) did not increase dofetilide exposure.<br/>Drug-Drug Interactions:<br/>Dose-Response and Concentration Response for Increase in QT Interval: Increase in QT interval is directly related to dofetilide dose and plasma concentration. Figure 1 shows that the relationship in normal volunteers between dofetilide plasma concentrations and change in QTc is linear, with a positive slope of approximately 15���25 msec/(ng/mL) after the first dose and approximately 10���15 msec/(ng/mL) at Day 23 (reflecting a steady state of dosing). A linear relationship between mean QTc increase and dofetilide dose was also seen in patients with renal impairment, in patients with ischemic heart disease, and in patients with supraventricular and ventricular arrhythmias. Note: The range of dofetilide plasma concentrations achieved with the 500 mcg BID dose adjusted for creatinine clearance is 1���3.5 ng/mL. The relationship between dose, efficacy and the increase in QTc from baseline at steady state for the two randomized, placebo-controlled studies (described further below) is shown in Figure 2. The studies examined the effectiveness of TIKOSYN in conversion to sinus rhythm and maintenance of normal sinus rhythm after conversion in patients with atrial fibrillation/flutter of>1 week duration. As shown, both the probability of a patient's remaining in sinus rhythm at six months and the change in QTc from baseline at steady state of dosing increased in an approximately linear fashion with increasing dose of TIKOSYN. Note that in these studies doses were modified by results of creatinine clearance measurement and in-hospital QTc prolongation. Number of patients evaluated for maintenance of NSR: 503 TIKOSYN, 174 placebo.Number of patients evaluated for QTc change: 478 TIKOSYN, 167 placebo. Figure 2: Relationship Between TIKOSYN Dose, QTc Increase and Maintenance of NSR.
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TIKOSYN 125 mcg (0.125 mg) capsules are supplied as No. 4 capsules with a light orange cap and white body, printed with TKN 125 PFIZER, and are available in: TIKOSYN 250 mcg (0.25 mg) capsules are supplied as No. 4 capsules, peach cap and body, printed with TKN 250 PFIZER, and are available in: TIKOSYN 500 mcg (0.5 mg) capsules are supplied as No. 2 capsules, peach cap and white body, printed with TKN 500 PFIZER, and are available in: Store at controlled room temperature, 15��to 30��C (59��to 86��F). PROTECT FROM MOISTURE AND HUMIDITY. Dispense in tight containers (USP).
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To minimize the risk of induced arrhythmia, patients initiated or re-initiated on TIKOSYN should be placed for a minimum of 3 days in a facility that can provide calculations of creatinine clearance, continuous electrocardiographic monitoring, and cardiac resuscitation. For detailed instructions regarding dose selection, see DOSAGE AND ADMINISTRATION. TIKOSYN is available only to hospitals and prescribers who have received appropriate TIKOSYN dosing and treatment initiation education, see DOSAGE AND ADMINISTRATION.
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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).
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dofetilide
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Tikosyn (Capsule)
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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 . In studies of patients with supraventricular arrhythmias a total of 1346 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.<br/>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) . The incidence of torsade de pointes in patients who were dosed according to the recommended dosing regimen 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. In the DIAMOND trials a total of 1511 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.<br/>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. 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.
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Maintenance of Normal Sinus Rhythm (Delay in AF/AFl Recurrence): TIKOSYN is indicated for the maintenance of normal sinus rhythm (delay in time to recurrence of atrial fibrillation/atrial flutter [AF/AFl]) in patients with atrial fibrillation/atrial flutter of greater than one week duration who have been converted to normal sinus rhythm. Because TIKOSYN can cause life threatening ventricular arrhythmias, it should be reserved for patients in whom atrial fibrillation/atrial flutter is highly symptomatic. In general, antiarrhythmic therapy for atrial fibrillation/atrial flutter aims to prolong the time in normal sinus rhythm. Recurrence is expected in some patients.<br/>Conversion of Atrial Fibrillation/Flutter: TIKOSYN is indicated for the conversion of atrial fibrillation and atrial flutter to normal sinus rhythm. TIKOSYN has not been shown to be effective in patients with paroxysmal atrial fibrillation.
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Tikosyn
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