Tikosyn

— THERAPEUTIC CATEGORIES —
  • CHF and arrhythmias
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Tikosyn Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Dofetilide 125mcg, 250mcg, 500mcg; caps.

    Pharmacological Class

    Class III antiarrhythmic.

    How Supplied

    Caps—14, 60

    How Supplied

    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. All strengths are available in 14- and 60-count bottles as well as 40-count unit-dose packaging.

    Storage

    Store at controlled room temperature, 15° to 30°C (59° to 86°F). Protect from moisture and humidity.

    Manufacturer

    Pfizer Inc.

    Tikosyn Indications

    Indications

    Maintenance of normal sinus rhythm in patients with atrial fibrillation or atrial flutter of >1 week duration who were converted to normal sinus rhythm (use only for highly symptomatic patients). Conversion of atrial fibrillation and atrial flutter to normal sinus rhythm.

    Tikosyn Dosage and Administration

    Prior to Treatment Evaluations

    • Serum potassium should be maintained within normal range before treatment is initiated and should be maintained within normal range during treatment. 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.

    Adult

    ≥18yrs: see full labeling. Initiate only in appropriate clinical setting and continue to be monitored for a minimum of 3 days.

    Adult

    Dosage and Administration

    • 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. Continue monitoring patients in this way for a minimum of 3 days. Do not discharge patients within 12 hours of electrical or pharmacological conversion to normal sinus rhythm.

    • Individual dose of Tikosyn based on 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.)

    • Usual recommended dose: 500 mcg twice daily.

     

    Instructions for Individualized Dose Initiation

    Initiation of Tikosyn Therapy

    • Step 1 – Electrocardiographic assessment: Prior to administration of the first dose, the QTc or QT must be checked using an average of 5–10 beats. If the QTc or QT 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. Proceed to Step 2 if the QTc or QT is 440 msec. 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] x actual body weight in kg) ÷ (72 x serum creatinine [mg/dL])

      • Creatinine clearance (female) = ([140-age] x actual body weight in kg x 0.85) ÷ (72 x 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:

      • 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 to 3 hours after administering the first dose of Tikosyn, determine the QTc or QT (if heart rate is <60 beats per minute). If the QTc or QT is less than or equal to 15% compared to the baseline established in Step 1, continue the current dose. If the QTc or QT has increased by >15% compared to the baseline established in Step 1 OR if the QTc or QT is >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 to 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.

    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 3 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

    • 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 >60 mL/min is 500 mcg BID; doses >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: 

      • Consider electrical conversion if patients do not convert to normal sinus rhythm within 24 hours of initiation of Tikosyn therapy. 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. 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.

    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). 

    Children

    <18yrs: not recommended.

    Tikosyn Contraindications

    Contraindications

    Long QT syndromes. Baseline QT interval or QTc >440msec (500msec in ventricular conduction abnormalities). Severe renal impairment (CrCl <20mL/min). Concomitant hydrochlorothiazide, verapamil, trimethoprim, cimetidine, ketoconazole, or other inhibitors of renal cationic secretion (eg, prochlorperazine, megestrol, dolutegravir).

    Tikosyn Boxed Warnings

    Boxed Warning

    Must be initiated or re-initiated in a facility that can provide ECG monitoring and management of ventricular arrhythmias.

    Tikosyn Warnings/Precautions

    Warnings/Precautions

    Monitor QTc, renal function (do baseline CrCl) at least every 3 months, and all concomitant drugs (including OTC drugs, herbs, supplements). Paroxysmal atrial fibrillation. Heart rate <50 beats/min. Sick sinus syndrome. 2nd or 3rd degree heart block, unless paced. Renal or severe hepatic impairment. Maintain normal potassium, magnesium levels. Conditions affecting electrolyte levels. Pregnancy (Cat.C). Nursing mothers: not recommended.

    Warnings/Precautions

    Ventricular Arrhythmia

    • May 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. 

    • May reduce the risk of TdP by controlling the plasma concentration through adjustment of the initial dose based on creatinine clearance and ECG monitoring.

    • Only initiate treatment with dofetilide in patients placed for a minimum of 3 days in a facility that can provide ECG monitoring and with personnel trained in managing serious ventricular arrhythmias.

    • Relation of QT interval to dose:

      • The QT interval increases linearly with increasing Tikosyn dose. 

    • Frequency of Torsade de Pointes:

      • In the supraventricular arrhythmia population (patients with AF and other supraventricular arrhythmias), the overall incidence of Torsade de Pointes was 0.8%. There were no cases of TdP on placebo. The majority of the episodes of TdP occurred within the first three days of Tikosyn therapy.

    • Mortality:

      • 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.

    Pregnancy Considerations

    There are no adequate and well controlled studies in pregnant women. Therefore, dofetilide should only be administered to pregnant women where the benefit to the patient justifies the potential risk to the fetus.

    Nursing Mother Considerations

    There is no information on the presence of dofetilide in breast milk. Patients should be advised not to breast-feed an infant if they are taking Tikosyn.

    Pediatric Considerations

    The safety and effectiveness of Tikosyn in children (<18 years old) has not been established. 

    Geriatric Considerations

    No overall differences in safety, effect on QTc, or effectiveness were observed between elderly and younger patients. Because elderly patients are more likely to have decreased renal function with a reduced creatinine clearance, care must be taken in dose selection.

    Renal Impairment Considerations

    The overall systemic clearance of dofetilide is decreased and plasma concentration increased with decreasing creatinine clearance. The dose of Tikosyn must be adjusted based on creatinine clearance.

    Patients undergoing dialysis were not included in clinical studies, and appropriate dosing recommendations for these patients are unknown.

    Hepatic Impairment Considerations

    No additional dose adjustment is required for patients with mild or moderate hepatic impairment after adjustment for creatinine clearance.

    Use caution in patients with severe hepatic impairment.

    Other Considerations for Specific Populations

    Use in Women

    • As with other drugs that cause Torsade de Pointes, Tikosyn was associated with a greater risk of Torsade de Pointes in female patients than in male patients.

    • During the Tikosyn clinical development program, the risk of Torsade de Pointes in females was approximately 3 times the risk in males. Unlike Torsade de Pointes, the incidence of other ventricular arrhythmias was similar in female patients receiving Tikosyn and patients receiving placebo. Although no study specifically investigated this risk, in post-hoc analyses, no increased mortality was observed in females on Tikosyn compared to females on placebo.

    Carcinogenesis, Mutagenesis, Impairment of Fertility 

    • Dofetilide had no genotoxic effects, with or without metabolic activation, based on the bacterial mutation assay and tests of cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes. 

    • There was no effect on mating or fertility when dofetilide was administered to male and female rats at doses as high as 1.0 mg/kg/day, a dose that would be expected to provide a mean dofetilide AUC(0–24hr) about 3 times the maximum likely human AUC. Increased incidences of testicular atrophy and epididymal oligospermia and a reduction in testicular weight were, however, observed in other studies in rats. Reduced testicular weight and increased incidence of testicular atrophy were also consistent findings in dogs and mice.

    Tikosyn Pharmacokinetics

    Absorption

    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.

    Distribution

    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. 

    Metabolism

    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. 

    Elimination

    The terminal half-life of dofetilide 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.

    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, ketoconazole and dolutegravir).

    Tikosyn Interactions

    Interactions

    See Contraindications. Stop dofetilide for at least 2 days before starting an interacting drug. Drugs that prolong QT interval (eg, phenothiazines, cisapride, bepridil, tricyclic antidepressants, some macrolides and fluoroquinolones): not recommended. Caution with drugs that undergo renal cationic secretion (eg, triamterene, metformin, amiloride) and with CYP3A4 inhibitors (eg, macrolides, azole antifungals, protease inhibitors, SSRIs, amiodarone, cannabinoids, diltiazem, grapefruit juice, nefazodone, norfloxacin, quinine, zafirlukast); these may increase dofetilide levels. Allow at least 3 half-lives to elapse and monitor when withdrawing Class I or III antiarrhythmics before giving 1st dose of dofetilide (see full labeling); reduce serum amiodarone levels to <0.3mg/L or withdraw at least 3 months before starting dofetilide. Potassium-depleting diuretics, digoxin may increase risk of torsade de pointes.

    Tikosyn Adverse Reactions

    Adverse Reactions

    Headache, chest pain, dizziness, respiratory tract infection, dyspnea, nausea, flu syndrome, insomnia, back pain, diarrhea, rash, abdominal pain, torsade de pointes (esp. in females), serious ventricular arrhythmias, sudden death, conduction disturbances.

    Tikosyn Clinical Trials

    Clinical Trials

    Chronic Atrial Fibrillation and/or Atrial Flutter 

    Two randomized, parallel, double-blind, placebo-controlled, dose-response trials evaluated the ability of Tikosyn 1) to convert patients with atrial fibrillation or atrial flutter (AF/AFl) of more than 1 week duration to normal sinus rhythm (NSR) and 2) to maintain NSR (delay time to recurrence of AF/AFl) after drug-induced or electrical cardioversion. A total of 996 patients with a one week to two year history of atrial fibrillation/atrial flutter were enrolled. In both studies, patients were randomized to receive placebo or Tikosyn 125 mcg, 250 mcg, 500 mcg, or in one study a comparator drug, given twice a day (these doses were lowered based on calculated creatinine clearance and, in one of the studies, for QT interval or QTc). All patients were started on therapy in a hospital where their ECG was monitored.

    Patients were excluded from participation if they had had syncope within the past 6 months, AV block greater than first degree, MI or unstable angina within 1 month, cardiac surgery within 2 months, history of QT interval prolongation or polymorphic ventricular tachycardia associated with use of antiarrhythmic drugs, QT interval or QTc >440 msec, serum creatinine >2.5 mg/mL, significant diseases of other organ systems; used cimetidine; or used drugs known to prolong the QT interval. 

    The following results showed the proportion of patients treated with Tikosyn 125 mcg, 250 mcg, and 500 mcg twice daily who achieved acute conversion rates from atrial fibrillation/flutter to normal sinus rhythm (NSR) compared with placebo, respectively:

    • Study 1 – 6% (n=5/82), 10% (n=8/82), 30% (n=23/77) vs 1% (n=1/84)

    • Study 2 – 6% (n=8/135), 11% (n=14/133), 29% (n=38/129) vs 1% (n=2/137)

    • Among patients who converted pharmacologically, approximately 70% converted within 24 to 36 hours.

    Electrical cardioversion was administered to patients who did not convert to NSR with randomized therapy within 48 to 72 hours. Patients who remained in NSR after conversion in the hospital were continued on randomized therapy as outpatients for up to 1 year.

    Additionally, at 6 and 12 months, the following proportion of patients treated with Tikosyn 125 mcg, 250 mcg, and 500 mcg remained on treatment in NSR and withdrew due to recurrence of atrial fibrillation/flutter or adverse events compared with placebo, respectively: 

    • Study 1 – 6 months

      • Still on treatment in NSR: 38%, 44%, 52% vs 32%

      • D/C for recurrence: 55% , 49%, 33% vs 63%

      • D/C for AEs: 3%, 3%, 8% vs 4%

    • Study 1 – 12 months

      • Still on treatment in NSR: 32%, 26%, 46% vs 22%

      • D/C for recurrence: 58% , 57%, 36% vs 72%

      • D/C for AEs: 7%, 11%, 8% vs 6%

    • Study 2 – 6 months

      • Still on treatment in NSR: 41%, 49%, 57% vs 22%

      • D/C for recurrence: 48% , 42%, 27% vs 72%

      • D/C for AEs: 9%, 6%, 10% vs 4%

    • Study 2 – 12 months

      • Still on treatment in NSR: 25%, 42%, 49% vs 16%

      • D/C for recurrence: 59% , 47%, 32% vs 76%

      • D/C for AEs: 11%, 6%, 12% vs 5%

    The effectiveness of Tikosyn 125 mcg, 250 mcg, and 500 mcg twice daily in maintaining NSR using Kaplan Meier analysis showed the following P-values and median time to recurrence of atrial fibrillation/flutter compared with placebo, respectively: 

    • Study 1 

      • P =.21; P =.10; P <.001 

      • Median time to recurrence (days): 31; 179; >365 vs 27

    • Study 2

      • P =.006; P <.001; P <.001

      • Median time to recurrence (days): 182; >365; >365 vs 34

    The point estimates of the probabilities of remaining in NSR at 6 and 12 months were 62% and 58%, respectively, for Tikosyn 500 mcg BID; 50% and 37%, respectively, for Tikosyn 250 mcg BID; and 37%, and 25%, respectively, for placebo.

    The point estimates of the probabilities of remaining in NSR at 6 and 12 months were 71% and 66%, respectively, for Tikosyn 500 mcg BID; 56% and 51%, respectively, for Tikosyn 250 mcg BID; and 26% and 21%, respectively, for placebo.

    In both studies, there was a dose-related increase in the number of patients who received Tikosyn and maintained NSR at all time periods and delayed the time of recurrence of sustained AF. Data pooled from both studies show that there is a positive relationship between the probability of staying in NSR, Tikosyn dose, and increase in QTc.

    Analysis of pooled data for patients randomized to a Tikosyn dose of 500 mcg twice daily showed that maintenance of NSR was similar in both males and females, in both patients aged <65 years and patients 65 years of age, and in both patients with atrial flutter as a primary diagnosis and those with a primary diagnosis of atrial fibrillation. 

    During the period of in-hospital initiation of dosing, 23% of patients in Studies 1 and 2 had their dose adjusted downward on the basis of their calculated creatinine clearance, and 3% had their dose down-titrated due to increased QT interval or QTc. Increased QT interval or QTc led to discontinuation of therapy in 3% of patients. 

     

    Safety in Patients with Structural Heart Disease: DIAMOND Studies (The Danish Investigations of Arrhythmia and Mortality on Dofetilide)

    The two DIAMOND studies were 3-year trials comparing the effects of Tikosyn and placebo on mortality and morbidity in patients with impaired left ventricular function (ejection fraction  35%). Patients were treated for at least one year. One study was in patients with moderate to severe (60% NYHA Class III or IV) congestive heart failure (DIAMOND CHF) and the other was in patients with recent myocardial infarction (DIAMOND MI) (of whom 40% had NYHA Class III or IV heart failure). Both groups were at relatively high risk of sudden death. The DIAMOND trials were intended to determine whether Tikosyn could reduce that risk. In both trials, there was not a reduction in mortality, but they did provide reassurance that, when initiated carefully, in a hospital or equivalent setting, Tikosyn did not increase mortality in patients with structural heart disease, an important finding because other antiarrhythmics [notably the Class IC antiarrhythmics studied in the Cardiac Arrhythmia Suppression Trial (CAST) and a pure Class III antiarrhythmic, d-sotalol (SWORD)] have increased mortality in post-infarction populations. The DIAMOND trials therefore provide evidence of a method of safe use of Tikosyn in a population susceptible to ventricular arrhythmias. In addition, the subset of patients with AF in the DIAMOND trials provide further evidence of safety in a population of patients with structural heart disease accompanying the AF. Note, however, that this AF population was given a lower (250 mcg BID) dose.

    In both DIAMOND studies, patients were randomized to 500 mcg BID of Tikosyn, but this was reduced to 250 mcg BID if calculated creatinine clearance was 40–60 mL/min, if patients had AF, or if QT interval prolongation (>550 msec or >20% increase from baseline) occurred after dosing. Dose reductions for reduced calculated creatinine clearance occurred in 47% and 45% of DIAMOND CHF and MI patients, respectively. Dose reductions for increased QT interval or QTc occurred in 5% and 7% of DIAMOND CHF and MI patients, respectively. Increased QT interval or QTc (>550 msec or >20% increase from baseline) resulted in discontinuation of 1.8% of patients in DIAMOND CHF and 2.5% of patients in DIAMOND MI.

     

    In the DIAMOND studies, all patients were hospitalized for at least 3 days after treatment was initiated and monitored by telemetry. Patients with QTc >460 msec, second or third degree AV block (unless with pacemaker), resting heart rate <50 bpm, or prior history of polymorphic ventricular tachycardia were excluded.

    DIAMOND CHF included 1518 patients hospitalized with severe CHF who had confirmed impaired left ventricular function (ejection fraction 35%). Patients received a median duration of therapy of greater than one year. There were 311 deaths from all causes in patients randomized to Tikosyn (n=762) and 317 deaths in patients randomized to placebo (n=756). The probability of survival at one year was 73% (95% CI: 70% – 76%) in the Tikosyn group and 72% (95% CI: 69% – 75%) in the placebo group. Similar results were seen for cardiac deaths and arrhythmic deaths. Torsade de Pointes occurred in 25/762 patients (3.3%) receiving Tikosyn. The majority of cases (76%) occurred within the first 3 days of dosing. In all, 437/762 (57%) of patients on Tikosyn and 459/756 (61%) on placebo required hospitalization. Of these, 229/762 (30%) of patients on Tikosyn and 290/756 (38%) on placebo required hospitalization because of worsening heart failure. 

    DIAMOND MI studied 1510 patients hospitalized with recent myocardial infarction (2–7 days) who had confirmed impaired left ventricular function (ejection fraction 35%). Patients received a median duration of therapy of greater than one year. There were 230 deaths in patients randomized to Tikosyn (n=749) and 243 deaths in patients randomized to placebo (n=761). The probability of survival at one year was 79% (95% CI: 76% – 82%) in the Tikosyn group and 77% (95% CI: 74% – 80%) in the placebo group. Cardiac and arrhythmic mortality showed a similar result. Torsade de Pointes occurred in 7/749 patients (0.9%) receiving Tikosyn. Of these, 4 cases occurred within the first 3 days of dosing and 3 cases occurred between Day 4 and the conclusion of the study. In all, 371/749 (50%) of patients on Tikosyn and 419/761 (55%) on placebo required hospitalization. Of these, 200/749 (27%) of patients on Tikosyn and 205/761 (27%) on placebo required hospitalization because of worsening heart failure.

    DIAMOND Patients with Atrial Fibrillation (the DIAMOND AF subpopulation). There were 506 patients in the two DIAMOND studies who had atrial fibrillation (AF) at entry to the studies (249 randomized to Tikosyn and 257 randomized to placebo). DIAMOND AF patients randomized to Tikosyn received 250 mcg BID; 65% of these patients had impaired renal function, so that 250 mcg BID represents the dose they would have received in the AF trials, which would give drug exposure similar to a person with normal renal function given 500 mcg BID. In the DIAMOND AF subpopulation, there were 111 deaths (45%) in the 249 patients in the Tikosyn group and 116 deaths (45%) in the 257 patients in the placebo group. Hospital readmission rates for any reason were 125/249 or 50% on Tikosyn and 156/257 or 61% for placebo. Of these, readmission rates for worsening heart failure were 73/249 or 29% on Tikosyn and 102/257 or 40% for placebo. Of the 506 patients in the DIAMOND studies who had atrial fibrillation or flutter at baseline, 12% of patients in the Tikosyn group and 2% of patients in the placebo group had converted to normal sinus rhythm after one month. In those patients converted to normal sinus rhythm, 79% of the Tikosyn group and 42% of the placebo group remained in normal sinus rhythm for one year. In the DIAMOND studies, although Torsade de Pointes occurred more frequently in the Tikosyn-treated patients, Tikosyn, given with an initial 3-day hospitalization and with dose modified for reduced creatinine clearance and increased QT interval, was not associated with an excess risk of mortality in these populations with structural heart disease in the individual studies or in an analysis of the combined studies. The presence of atrial fibrillation did not affect outcome.

    Tikosyn Note

    Notes

    This product is being made available only to those hospitals and prescribers who have received appropriate education from the manufacturer.

    Tikosyn Patient Counseling

    Patient Counseling

    • Prior to initiation of Tikosyn therapy, the patient should be advised to read the Medication Guide and reread it each time therapy is renewed in case the patient’s status has changed. 

    • The patient should be fully instructed on the need for compliance with the recommended dosing of Tikosyn and the potential for drug interactions, and the need for periodic monitoring of QTc and renal function to minimize the risk of serious abnormal rhythms.

    • Instruct patients to notify their health care providers of any change in over-the-counter, prescription, or supplement use. If a patient is hospitalized or is prescribed a new medication for any condition, the patient must inform the health care provider of ongoing Tikosyn therapy. Patients should also check with their health care provider and/or pharmacist prior to taking a new over-the-counter preparation. 

    • Patient should Immediately report any symptoms that may be associated with altered electrolyte balance, such as excessive or prolonged diarrhea, sweating, or vomiting or loss of appetite or thirst to their health care provider.

    • Instruct patients to not double the next dose if a dose is missed. The next dose should be taken at the usual time. 

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