Dofetilide - Tikosyn Flashcards
Antiarrhythmic class
Class III
Mechanism of action
- Blocks IKr (delayed rectifier potassium current)
* ↑ action potential and refractory period
Indications
• 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
Oral Dosing Strengths
• 125 mcg, 250 mcg, 500 mcg (ie, 0.125 mg, 0.25 mg, 0.5 mg)
Dosing
• 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
Treatment setting
• Start in appropriate facility with ECG monitoring and personnel trained in the management of serious VAs
Monitoring requirements at initiation
Continuous ECG monitoring during initiation (3-day minimum)
Pharmacokinetics
• Dose proportional
Bioavailability/ absorption
- Oral dofetilide is >90% with Cmax of 2–3 hours
- Food/antacid does not affect absorption
- Steady state within 2–3 days
Half-life
10 hrs.
Protein binding
60-70%
Metabolism
- ~80% unchanged
* N-oxidation and N-dealkylation, some by CYP3A4
Major active metabolite
- Minimally active metabolites in urine
* None identified in plasma
Route of elimination
• ~80% renal excretion
Overdosage
- No known antidote; treat according to symptoms
- Initiate cardiac monitoring
- May ↑ QT interval
Contraindications
• 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
Boxed Warning
• 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
Warnings(except boxed warning—see above)
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
Precautions
• 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
Drug interactions
• 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
Adverse Reactions
• 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
