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dofetilide 125 mcg capsule generic tikosyn

In stock Manufacturer GREENSTONE LLC. 59762003702
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Uses

Supraventricular Tachyarrhythmias

Dofetilide is used for the maintenance of normal sinus rhythm in patients with atrial fibrillation/ atrial flutter of more than 1 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. Dofetilide also is used 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.

In 2 randomized, double-blind, dose-response studies, about 30% of patients with atrial fibrillation/ atrial flutter who received 500 mcg of dofetilide twice daily were successfully converted to normal sinus rhythm compared with about 10 or 6% of those receiving 250 or 125 mcg twice daily and 1% of those who received placebo. Approximately 70% of the patients who successfully achieved normal sinus rhythm did so within 24-36 hours of beginning dofetilide therapy. After 12 months of therapy, the probabilities of remaining in normal sinus rhythm were 58-66 or 25-21% in patients who had converted to normal sinus rhythm and were still receiving dofetilide (500 mcg twice daily) or placebo, respectively. In one of these studies, dofetilide also was more effective than sotalol (80 mg orally twice daily) in converting atrial fibrillation to normal sinus rhythm or maintaining normal sinus rhythm for up to 12 months. In a third study, dofetilide was effective in converting and preventing the recurrence of atrial fibrillation without affecting mortality in patients with congestive heart failure and reduced left ventricular function.

Dosage and Administration

Administration

Dofetilide is administered orally twice daily without regard to meals.

Restricted Distribution Program

Commercially available dofetilide must be obtained through a restricted distribution program. Clinicians and pharmacies in institutions must confirm their participation in a designated Tikosyn educational program before prescribing or ordering the drug; the drug is not available through community pharmacies. The status of clinicians who have participated in these programs may be verified on the internet (www.tikosynlist.com); for information regarding such educational programs, contact the manufacturer at 877-845-6796.

Dosage

The recommended adult dosage of dofetilide is 500 mcg twice daily, which is modified according to creatinine clearance and QTc interval. The risk of torsades de pointes is related to the dosage of dofetilide, and clinicians may elect to initiate therapy with lower dosages. Dosages exceeding 500 mcg twice daily have been associated with an increased incidence of torsades de pointes.

Because of the arrhythmogenic potential of dofetilide, the manufacturer recommends that both initiation of therapy with the drug and any subsequent increases in dosage be performed in a hospital setting where creatinine clearance calculations, continuous ECG monitoring, and cardiac resuscitation can be performed and where the patient can be monitored by personnel trained in the management of serious ventricular arrhythmias. Prior to initiation of dofetilide, the creatinine clearance must be calculated and QTc interval (or QT interval if the heart rate is less than 60 beats/minute) must be determined using an average of 5-10 beats. If the QTc interval exceeds 440 msec (500 msec in patients with ventricular conduction abnormalities), dofetilide is contraindicated. If creatinine clearance is less than 60 mL/minute, the initial dosage of dofetilide must be reduced.(See Dosage and Administration: Special Populations.) Serum potassium should be within the normal range (above 3.6-4 mEq/L) before initiation of dofetilide therapy and maintained in that range during therapy. Within 2-3 hours of administering the first dose of dofetilide, determine the QTc interval. If QTc interval has increased by more than 15% or exceeds 500 msec (550 msec in patients with ventricular conduction abnormalities), adjust subsequent dosages as indicated in Table 1.

Table 1.
Initial Dosage (Based on Creatinine Clearance) Adjusted Dosage (for QTc Prolongation)
500 mcg twice daily 250 mcg twice daily
250 mcg twice daily 125 mcg twice daily
125 mcg twice daily 125 mcg once daily

Within 2-3 hours after each subsequent dose of dofetilide (for in-hospital doses 2-5), determine the QTc interval. No further downward titration of dofetilide based on QTc is recommended. However, if at any time after the second dose of dofetilide is given the QTc exceeds 500 msec (550 msec in patients with ventricular conduction abnormalities), discontinue dofetilide. Continuous ECG monitoring should be performed for a minimum of 3 days or for a minimum of 12 hours after electrical or pharmacologic conversion to normal sinus rhythm, whichever is greater.

Reevaluate renal function and QTc interval every 3 months or as medically warranted. If QTc exceeds 500 msec (550 msec in patients with ventricular conduction abnormalities), discontinue dofetilide and carefully monitor the patient until QTc returns to baseline levels. If renal function deteriorates, adjust dosage as described in Dosage and Administration: Special Populations.

The manufacturer recommends that patients be hospitalized and closely monitored for 3 days (until steady-state plasma concentrations are obtained) whenever treatment is initiated or reinitiated or when dofetilide dosage is increased. Previously successful use of such dosages of dofetilide does not eliminate the need for rehospitalization when the dosage is increased.

Special Populations

In patients with impaired renal function, dosage of dofetilide must be modified according to the degree of impairment.Because increase in QT interval and the risk of ventricular arrhythmias are directly related to plasma dofetilide concentrations, dosage adjustment based on calculated creatinine clearance is essential. The patient's creatinine clearance (Ccr) can be estimated by using the following formulas:

Ccr male = [(140 - age) x weight (in kg)] / [72 x serum creatinine (in mg/dL)]Ccr female = 0.85 x Ccr male

The manufacturer recommends that patients receive the following dosage based on calculated creatinine clearance (see Table 2).

Table 2.
Calculated Creatinine Clearance (mL/minute) Dosage
>60 500 mcg twice daily
40-60 250 mcg twice daily
20 to <40 125 mcg twice daily
<20 Dofetilide is contraindicated

No dosage adjustment is required in patients with mild to moderate hepatic impairment (Child-Pugh class A or B). The pharmacokinetics of the drug have not been studied in patients with severe hepatic insufficiency (Child-Pugh class C) and such patients should be treated cautiously.

Cautions

Contraindications

Congenital or acquired long QT syndromes; baseline QT or QTc interval exceeding 440 msec (500 msec in patients with ventricular conduction abnormalities). Severe renal impairment (calculated creatinine clearance below 20 mL/minute). Concomitant use of verapamil or cation transport system inhibitors (e.g., cimetidine, ketoconazole, megestrol, prochlorperazine, trimethoprim [alone or in combination with sulfamethoxazole]). Concomitant use of hydrochlorothiazide (alone or in combination with triamterene).(See Drug Interactions.) Known hypersensitivity to dofetilide.

Warnings/Precautions

Warnings

Arrhythmogenic Effects

Dofetilide may cause serious ventricular arrhythmias, principally polymorphic ventricular tachycardia associated with QT interval prolongation (i.e., torsades de pointes). The risk of torsades de pointes can be reduced by controlling the plasma concentration (e.g., adjustment of initial dofetilide dosage according to creatinine clearance, avoiding certain drug interactions) and monitoring the ECG for excessive increases in the QT interval. In clinical trials, the overall incidence of torsades de pointes was 0.8% and was dose-related in patients with supraventricular arrhythmias. Most episodes of torsades de pointes occurred within the first 3 days of dofetilide therapy, and the risk was threefold greater in women than in men.

Drug Interactions

Because there is a linear relationship between plasma dofetilide concentration and QTc, drug interactions that increase plasma dofetilide concentrations either through decreased renal excretion (e.g., inhibitors of cationic renal secretion) or decreased metabolism (e.g., inhibitors of cytochrome P-450 [CYP] isoenzyme 3A4) may increase the risk of torsades de pointes. Use of dofetilide with other drugs that prolong the QT interval has not been studied, and concomitant use of dofetilide with such drugs is not recommended. Carefully screen patients' medication history, including all over-the-counter, prescription, and herbal/natural preparations with emphasis on those that may affect dofetilide pharmacokinetics. If dofetilide must be discontinued to permit administration of potentially interacting drug(s), allow a washout period of at least 2 days.(See Drug Interactions.)

General Precautions

Effects on Cardiac Conduction

Animal and human studies have not shown any adverse effects of dofetilide on conduction velocity. No effect on AV nodal conduction following dofetilide treatment was noted in normal volunteers or in patients with first degree heart block. Dofetilide has been used safely in conjunction with pacemakers.

Drug Transfer

The manufacturer recommends a transition period for patients being transferred from another antiarrhythmic agent to dofetilide. Class I and class III antiarrhythmic agents should be withheld for at least 3 half-lives prior to initiating dofetilide. Amiodarone should be withheld for at least 3 months or until serum amiodarone concentration is less than 0.3 mcg/mL prior to administering dofetilide.(See Drug Interactions.)

Anticoagulants

Patients with atrial fibrillation should receive appropriate anticoagulant therapy.

Electrolyte Imbalance

Hypokalemia or hypomagnesemia may increase the risk of torsades de pointes in patients receiving dofetilide. Patients experiencing prolonged or excessive diarrhea, sweating, vomiting, loss of appetite, or thirst or receiving concomitant therapy with drugs that may increase the risk of such electrolyte imbalance (e.g., diuretics) should be closely monitored. Hypokalemia should be corrected before initiation of dofetilide.(See Drug Interactions.)

Specific Populations

Pregnancy

Category C.

Lactation

Not known whether dofetilide is distributed in milk. Patients should not breast-feed while receiving dofetilide.

Pediatric Use

Safety and efficacy not established in children younger than 18 years of age.

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults. Because geriatric patients may have decreased renal function, cautious dosage selection is advised.

Renal Impairment

Safety and efficacy not established in patients with creatinine clearance less than 20 mL/minute.(See Dosage and Administration: Special Populations.)

Hepatic Impairment

No dosage adjustment necessary in mild to moderate hepatic impairment. Use with caution in patients with severe hepatic impairment.(See Dosage and Administration: Special Populations.)

Common Adverse Effects

Adverse effects occurring in 2% or more of patients receiving dofetilide and more frequently than placebo include headache, chest pain, dizziness, respiratory tract infection, dyspnea, nausea, flu syndrome, insomnia, accidental injury, back pain, medical, surgical, or other health service procedure, diarrhea, rash, and abdominal pain.

Drug Interactions

Drugs Inhibiting Renal Tubular Cationic Transport

Pharmacokinetic interaction (decreased dofetilide excretion) when dofetilide is used with drugs inhibiting renal tubular cationic transport (e.g., cimetidine, ketoconazole, megestrol, prochlorperazine, trimethoprim [with or without sulfamethoxazole]).(See Cautions: Contraindications.)

Drugs Secreted by Renal Tubular Cationic Transport

Potential pharmacokinetic interaction (decreased dofetilide excretion and increased plasma concentration) when dofetilide is used with drugs secreted by renal tubular cationic transport (e.g., amiloride, metformin, triamterene).(See Cautions: Contraindications.)

Verapamil

Pharmacokinetic interaction (increased dofetilide concentrations).(See Cautions: Contraindications.)

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (decreased dofetilide metabolism and possible increased systemic exposure to dofetilide) with inhibitors of cytochrome P-450 (CYP) 3A4 isoenzyme (e.g., macrolide antibiotics, azole antifungal agents, protease inhibitors, serotonin reuptake inhibitors, amiodarone, cannabinoids, diltiazem, grapefruit juice, nefazodone, norfloxacin, quinine, zafirlukast).

Drugs that Prolong QT Interval

Potential pharmacodynamic interaction (increased toxicity) when dofetilide is used with drugs that prolong QT interval (e.g., class I or III antiarrhythmic agents, bepridil, cisapride, phenothiazines, tricyclic antidepressants, certain oral macrolides, hydrochlorothiazide-containing preparations).

Warfarin

Pharmacodynamic or pharmacokinetic interaction unlikely.

Potassium-depleting Diuretics

Potential pharmacodynamic interaction (increased dofetilide toxicity). Concomitant use with hydrochlorothiazide alone or in combination (e.g., with triamterene) is contraindicated.

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