Antiarrhythmic

Dofetilide

Approved 10 Apr 2018OralCapsule

The FDA lists this product in 36 strengths and forms.

Indications

Maintenance of Normal Sinus Rhythm (Delay in AF/AFl Recurrence) Dofetilide capsules are 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 dofetilide 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 (see CLINICAL STUDIES ). Conversion of Atrial Fibrillation/Flutter Dofetilide capsules are indicated for the conversion of atrial fibrillation and atrial flutter to normal sinus rhythm. Dofetilide has not been shown to be effective in patients with paroxysmal atrial fibrillation.

Contraindications

Dofetilide is contraindicated in patients with congenital or acquired long QT syndromes. Dofetilide should not be used in patients with a baseline QT interval or QTc > 440 msec (500 msec in patients with ventricular conduction abnormalities). Dofetilide is also contraindicated in patients with severe renal impairment (calculated creatinine clearance < 20 mL/min). The concomitant use of verapamil or the cation transport system inhibitors cimetidine, trimethoprim (alone or in combination with sulfamethoxazole), or ketoconazole with dofetilide is contraindicated (see WARNINGS and PRECAUTIONS, Drug-Drug Interactions ), as each of these drugs cause a substantial increase in dofetilide plasma concentrations.

In addition, other known inhibitors of the renal cation transport system such as prochlorperazine, dolutegravir and megestrol should not be used in patients on dofetilide. The concomitant use of hydrochlorothiazide (alone or in combinations such as with triamterene) with dofetilide is contraindicated (see PRECAUTIONS, Drug-Drug Interactions ) because this has been shown to significantly increase dofetilide plasma concentrations and QT interval prolongation.

Dofetilide is also contraindicated in patients with a known hypersensitivity to the drug.

Warnings and precautions

Ventricular Arrhythmia: Dofetilide can 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.

At a glance

Brand name: Dofetilide
Pharmacologic class: Antiarrhythmic
Route: Oral
Dosage form: Capsule
Applicant: Bionpharma
Status: Prescription
FDA approval: 10 Apr 2018
Application: ANDA208625-003

Indications

Contraindications

Dofetilide is also contraindicated in patients with a known hypersensitivity to the drug.

Warnings and precautions

Adverse reactions

The dofetilide clinical program involved approximately 8,600 patients in 130 clinical studies of normal volunteers and patients with supraventricular and ventricular arrhythmias. Dofetilide was administered to 5,194 patients, including two large, placebo-controlled mortality trials (DIAMOND CHF and DIAMOND MI) in which 1,511 patients received dofetilide 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 dofetilide 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 dofetilide treatment. It did not occur in placebo treated patients. The incidence of Torsade de Pointes in patients with supraventricular arrhythmias was 0.8% (11/1,346) (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 Dofetilide Dose Placebo Arrhythmia event: < 250 mcg BID N = 217 250 mcg BID N = 388 > 250-500 mcg BID N = 703 > 500 mcg BID N = 38 N = 677 Ventricular Arrhythmias 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. 3.7 % 2.6 % 3.4 % 15.8 % 2.7 % Ventricular fibrillation 0 0.3 % 0.4 % 2.6 % 0.1 % Ventricular tachycardia † 3.7 % 2.6 % 3.3 % 13.2 % 2.5 % Torsade de Pointes 0 0.3 % 0.9 % 10.5 % 0 Various forms of block AV block 0.9 % 1.5 % 0.4 % 0 0.3 % (Left) bundle branch block 0 0.5 % 0.1 % 0 0.1 % Heart block 0 0.5 % 0.1 % 0 0.1 % In the DIAMOND trials, a total of 1,511 patients were exposed to dofetilide for 1,757 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 Dofetilide Placebo N = 249 N = 257 Ventricular arrhythmias 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. 14.5 % 13.6 % Ventricular fibrillation 4.8 % 3.1 % Ventricular tachycardia † 12.4 % 11.3 % Torsade de Pointes 1.6 % 0 Various forms of block AV block 0.8 % 2.7 % (Left) bundle branch block 0 0.4 % Heart block 1.2 % 0.8 % Other Adverse Reactions: Table 8 presents other adverse events reported with a frequency of > 2% on dofetilide and reported numerically more frequently on dofetilide than on placebo in the studies of patients with supraventricular arrhythmias.

Table 8: Frequency of Adverse Events Occurring at > 2% on Dofetilide, and Numerically More Frequently on Dofetilide than Placebo in Patients with Supraventricular Arrhythmias Dofetilide 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 dofetilide 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 dofetilide 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 dofetilide 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.

Dofetilide

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

Dofetilide

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

Pregnancy and breastfeeding

Adverse reactions

Composition

Strengths and forms

Official product information