Dofetilide - Tikosyn

Question 1

Antiarrhythmic class

Answer 1

Class III

Question 2

Mechanism of action

Answer 2

• Blocks IKr (delayed rectifier potassium current)

* ↑ action potential and refractory period

Question 3

Indications

Answer 3

• Maintenance of normal sinus rhythm in AF/AFL of >1 week after cardioversion
— Reserved for highly symptomatic AF/AFL
due to risk of VA
• Conversion of AF/AFL to sinus rhythm
— Not shown to be effective in paroxysmal AF

Question 4

Oral Dosing Strengths

Answer 4

• 125 mcg, 250 mcg, 500 mcg (ie, 0.125 mg, 0.25 mg, 0.5 mg)

Question 5

Dosing

Answer 5

• Must be initiated in a setting that provides continuous ECG and monitored for minimum of 3 days

• Individualize dose: 7-step instructions
1. Assess QTc interval
2. Calculate CrCl
3. Starting dose breakpoints for CrCl
>60 mL/min (500 mcg BID), 40-60 mL/min (250 mcg BID), 20 to 15% from baseline or if >500 ms; adjust
dose as directed in PI
6. For doses 2 to 5, if QTc >500 ms at any
time, discontinue
7. Monitor ECG for 3 days minimum or
12 hours after electrical cardioversion,
whichever is greater

• Reevaluate renal function and ECG every 3 months

Critical to adjust dose based on kidney function. No adjustment for mild to moderate hepatic insufficiency (HI); severe HI not studied

Question 6

Treatment setting

Answer 6

• Start in appropriate facility with ECG monitoring and personnel trained in the management of serious VAs

Question 7

Monitoring requirements at initiation

Answer 7

Continuous ECG monitoring during initiation (3-day minimum)

Question 8

Pharmacokinetics

Answer 8

• Dose proportional

Question 9

Bioavailability/ absorption

Answer 9

• Oral dofetilide is >90% with Cmax of 2–3 hours
• Food/antacid does not affect absorption
• Steady state within 2–3 days

Question 10

Half-life

Answer 10

10 hrs.

Question 11

Protein binding

Answer 11

60-70%

Question 12

Metabolism

Answer 12

• ~80% unchanged

* N-oxidation and N-dealkylation, some by CYP3A4

Question 13

Major active metabolite

Answer 13

• Minimally active metabolites in urine

* None identified in plasma

Question 14

Route of elimination

Answer 14

• ~80% renal excretion

Question 15

Overdosage

Answer 15

• No known antidote; treat according to symptoms
• Initiate cardiac monitoring
• May ↑ QT interval

Question 16

Contraindications

Answer 16

• Congenital/acquired long QT syndromes
• Baseline QT interval or QTc >440 ms (500 ms with ventricular conduction abnormalities)
• Severe renal impairment (CrCl <20 mL/ min)
• Concomitant use with
— Verapamil
— Known inhibitors of the renal cation transport system (cimetidine, trimethoprim, ketoconazole, prochlorperazine, megestrol)
— Hydrochlorothiazide
• Hypersensitivity to drug

Question 17

Boxed Warning

Answer 17

• To minimize risk of arrhythmias, treat in appropriate facility for 3 days (minimum). An appropriate facility is one that can provide cardiac resuscitation, continuous electrocardiographic monitoring, and CrCl calculations

Question 18

Warnings(except boxed warning—see above)

Answer 18

Bolded Warnings
• Can cause serious VA, primarily TdP
— QT interval prolongation related to
dofetilide plasma concentration, which is affected by ↓ CrCl or drug interactions
— Treatment must be started in facility with ECG and trained personnel for 3 days minimum
— Calculation of renal function must precede 1st dose

Warnings
• TdP occurred in 0.8% of patients with SVA; TdP rate reduced when dosing adjusted to CrCl
• Use of drugs that ↓ metabolism or renal elimination ↑ risk of TdP
• Patients with hypokalemia and use of potassium-depleting diuretics
• Use with drugs that prolong QT interval is not recommended
• Other AADs should be withheld for at least 3 half-lives

Question 19

Precautions

Answer 19

• Renal Impairment: Dosage must be adjusted based on CrCl
• Severe hepatic impairment: use with
caution
• Cardiac conduction disturbances:
patients with SSS or 2nd- or 3rd-degree heart block were not included in studies unless functioning pacemaker was present
• Advise patient to read PPI
— Assess medication history
— Report symptoms of electrolyte imbalance (prolonged diarrhea, sweating, vomiting, loss of appetite) to HCP
— Dosing schedule: do NOT double a dose

Question 20

Drug interactions

Answer 20

• Drugs that prolong QT interval have not been studied and are not recommended (phenothiazines, cisapride, bepridil, tricyclic antidepressants, certain oral macrolides, certain fluoroquinolones)
• Class I or III AADs should be withheld for 3 half-lives prior to Tikosyn dosing
• Drugs that ↑ dofetilide exposure and
are contraindicated:
— Cimetidine
— Verapamil
— Ketoconazole
— Trimethoprim alone or with sulfamethoxazole
— Hydrochlorothiazide alone or with triamterene
• Potential interaction with inhibitors of renal cationic secretion and drugs secreted via this route (triamterene, metformin, amiloride)
• Inhibitors of CYP3A4 may ↑ dofetilide levels:
— Macrolide antibiotics, azole antifungal agents, protease inhibitors, serotonin reuptake inhibitors, amiodarone, cannabinoids, diltiazem, grapefruit juice, nefazodone, norfloxacin, quinine, zafirlukast)
• Digoxin: higher incidence of TdP
• Thiazide diuretics

No interaction with warfarin, propranolol, phenytoin, theophylline, oral contraceptives, omeprazole, ranitidine, antacids, glyburide, amlodipine

Question 21

Adverse Reactions

Answer 21

• TdP is dose dependent: TdP occurred in 0.8% of 525 patients with SVAs and 1.6% of 249 patients with AF
• In 1511 patients given dofetilide in DIAMOND trials, TdP occurred in 3.3% with CHF and 0.9% with recent MI
• Safety evaluated in 1346 patients with SVA given Tikosyn; most common AEs (Tikosyn vs placebo) include
— Headache (11% vs 9%)
— Chest pain (10% vs 7%)
— Dizziness (8% vs 6%)
— Respiratory tract infections (7% vs 5%) — Dyspnea (6% vs 5%)
— Nausea (5% vs 4%)
— Flu (4% vs 2%)
— Insomnia (4% vs 3%)
• Other AEs ≤2% but more common with Tikosyn include angioedema, bradycardia, cerebral ischemia, cerebrovascular accident, edema, facial paralysis, heart arrest, increased cough, liver damage, migraine, MI, paralysis