Pfizer Tikosyn Roll-Out Tied To Hospital And Physician Training Program

Pfizer is developing a pilot training program in preparation for the launch of the anti-arrhythmic Tikosyn (dofetilide) in the first quarter of 2000.

Tikosyn cleared FDA Oct. 1 for use in patients with "highly symptomatic" atrial fibrillation/atrial flutter. Because of a risk of torsades de pointes associated with the drug, marketing will be tied to a training program designed to ensure appropriate dosing.

Pfizer plans to initiate the pilot program in select U.S. cities soon in order to have a fully vetted program ready for the early 2000 launch date.

Pfizer will offer the training program to any hospital that requests it and to any physician that intends to prescribe Tikosyn.

Tikosyn will be "distributed only to those hospitals and other appropriate institutions confirmed to have received applicable dosing and treatment initiation education programs," labeling states.

In addition, "inpatient and subsequent outpatient discharge and refill prescriptions are filled only upon confirmation that the prescribing physician has received applicable dosing and treatment initiation education programs," labeling continues.

"For this purpose, a list for use by pharmacists is maintained containing hospitals and physicians who have received one of the education programs," labeling adds.

The labeling for Tikosyn reflects the recommendations of FDA's Cardiovascular & Renal Drugs Advisory Committee, which supported approval of the drug provided that Pfizer develop a program to ensure that use of the product includes predosing creatinine measurement and subsequent QT measurement (¹ ).

Tikosyn labeling includes a boxed warning stating that "patients initiated or re-initiated on Tikosyn should be placed for a minimum of three days in a facility that can provide calculations of creatinine clearance, continuous electrocardiographic monitoring, and cardiac resuscitation."

In addition, the warning statement continues, "Tikosyn is available only to hospitals and prescribers who have received appropriate Tikosyn dosing and treatment initiation education."

The boxed warning refers prescribers to the unusually lengthy dosage and administration section of labeling, which outlines the treatment algorithm for Tikosyn.

Dosage must be individualized and will depend on calculated creatinine clearance and QTc. The usual recommended dose of 500 mcg b.i.d. should be modified according to the dosing algorithm, labeling says.

The seven-step dosing algorithm is depicted in a flowchart format in the drug label. It is initiated by an electrocardiographic assessment, prior to administration, in order to determine QTc using an average of 5-10 beats. Tikosyn is contraindicated in the case that QTc exceeds 440 msec (or 500 msec for patients with ventricular conduction abnormalities).

The patient's creatinine clearance is also calculated prior to administration of the first dose using a formula that takes into account age, gender, body weight and serum creatinine levels.

The starting dose is then determined based on the calculated creatinine clearance. The recommended dose of 500 mcg twice daily is only administered when the clearance level is greater than 60 ml/min. A dose of 250 mcg b.i.d. is recommended for creatinine levels between 40-60 mL/min. A dose of 125 mcg is recommended for patients below 40 ml/min, and the drug is contraindicated in patients with levels below 20 ml/min.

Once the first dose has been dispensed, the patient's ECG should be constantly monitored. The QTc is determined two to three hours after the initial dose. If QTc jumps by more than 15% or if it becomes greater than 500 msec, the starting dose should be cut in half, labeling states.

Two to three hours after each subsequent dose, labeling requires the physician to determine the QTc. "No further titration of Tikosyn based on QTc is recommended," labeling states. If at any time after the second dose of Tikosyn is given, the QTc interval exceeds recommended levels, "Tikosyn should be discontinued," labeling advises.

Finally, "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."

Labeling recommends consideration of electrical conversion if Tikosyn does not convert the patient to normal sinus rhythm within 24 hours of initiation of therapy.

Tikosyn is approved both for conversion of patients with atrial fibrillation and atrial flutter to normal sinus rhythm and for maintenance of normal sinus rhythm in patients with AF/AFl who have been converted to normal sinus rhythm.

For patients on maintenance therapy, labeling recommends re-evaluation every three months "or as medically warranted." Therapy should be discontinued if QTc exceeds recommended levels, "and patients should be carefully monitored until QTc returns to baseline levels."

The complex dosing and monitoring requirements pose a hurdle for Pfizer in reaching a wide patient population with Tikosyn. Pfizer estimates that as many as 2.2 mil. patients may be candidates for Tikosyn therapy.

Approval of Tikosyn was based on two randomized trials showing that dofetilide was more effective than placebo in converting patients to normal sinus rhythm and in maintaining normal rhythm after six months and one year.

In the two trials, Tikosyn converted 6%-30% of patients, depending on dose, compared to 1% of placebo patients. At six months, 38%-57% of Tikosyn patients remained on therapy and in normal sinus rhythm, compared to 22%-32% of placebo patients. At one year, 25%-49% of Tikosyn patients remained on therapy in normal rhythm, compared to 16%-22% of placebo patients.

In the second trial, 6%-29% of patients converted compared to 1% of placebo.

Pfizer also conducted two three-year trials designed to assess morbidity and mortality in patients with impaired left ventricular function (the DIAMOND trials).

The studies were designed to test whether Tikosyn would reduce the risk of sudden death in that patient population. "The trials did not demonstrate a reduction in mortality," labeling notes.

In the DIAMOND studies, deaths occurred in 36% (54/1,511) of Tikosyn patients and 37% (560/1,517) of placebo patients, labeling notes.

"However," labeling continues, the DIAMOND trials "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...have increased mortality in post-infarction populations."

Labeling also includes a section on mortality, reporting that "in a pooled survival analysis of patients in the supraventricular arrhythmia population (low prevalence of structural heart disease), deaths occurred in .9% (12/1,346) of patients receiving Tikosyn and .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 was 1.1" with a 95% confidence interval of .3-4.3, labeling notes.

"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," labeling comments.

Tikosyn is contraindicated for patients with congenital or acquired long QT syndromes, and patients with severe renal impairment (calculated creatinine clearance less than 20 mL/min).

Concomitant use of cimetidine, verapamil or ketoconazole with Tikosyn is also contraindicated because results in a substantial increase in dofetilide blood concentrations, labeling states.

In patients with supraventricular arrhythmias, the most frequent reason for discontinuation was ventricular tachycardia (2% dofetilide vs. 1.3% placebo), labeling notes. Headache, chest pain, and dizziness were the most common adverse events.

The dofetilide NDA 20-931 was submitted March 9, 1998 and received an "approvable" letter March 5. It was designated a "1S" drug, denoting a new molecular entity receiving a standard review.