TIKOSYN
Clinical safety rating
cautionComprehensive clinical and safety monograph for TIKOSYN (TIKOSYN).
Selective class III antiarrhythmic agent; blocks cardiac potassium channels (IKr), prolonging action potential duration and effective refractory period.
| Metabolism | Primarily metabolized by CYP3A4; also undergoes N-dealkylation and glucuronidation; renal excretion of unchanged drug (20-30%) and metabolites. |
| Excretion | Renal: 80% as unchanged drug; biliary/fecal: 20% (metabolites and minor parent drug). |
| Half-life | 10 hours (terminal) in patients with normal renal function; prolonged to up to 42 hours in severe renal impairment; clinically relevant for dosing interval adjustment. |
| Protein binding | 96% bound to plasma proteins (primarily albumin). |
| Volume of Distribution | 3 L/kg (range 2-4 L/kg), indicating extensive tissue distribution, particularly to cardiac tissue. |
| Bioavailability | >90% after oral administration (approximately 93% with low first-pass metabolism). |
| Onset of Action | Oral: 2-3 hours (reduction in heart rate, conversion of atrial fibrillation/flutter). IV: not available clinically, but onset within 30 minutes if used. |
| Duration of Action | Up to 12 hours after a single oral dose; continuous daily dosing maintains therapeutic levels. Duration is dependent on renal clearance. |
| Molecular Weight | 458.53 Da |
500 mcg orally twice daily for atrial fibrillation/flutter conversion and maintenance of sinus rhythm.
| Dosage form | CAPSULE |
| Renal impairment | CrCl > 60 mL/min: 500 mcg BID. CrCl 40-60 mL/min: 250 mcg BID. CrCl < 40 mL/min: contraindicated. |
| Liver impairment | No formal Child-Pugh based adjustment; use caution in severe hepatic impairment due to limited data. |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | Adjust based on renal function per CrCl; monitor QTc interval closely due to increased risk of toxicity. |
| 1st trimester | No adequate studies in pregnant women; animal studies not available; potential benefit may warrant use despite potential risks. |
| 2nd trimester | No adequate studies in pregnant women; teratogenic effects unknown; use only if clearly needed. |
| 3rd trimester | Risk of fetal bradycardia and QT prolongation; monitor fetal heart rate; use only if benefit outweighs risk. |
Clinical note
Comprehensive clinical and safety monograph for TIKOSYN (TIKOSYN).
| Placental transfer | Unknown; molecular weight low enough to expect placental passage. |
| Breastfeeding | Excretion in human milk unknown; due to potential for serious adverse reactions in nursing infants, discontinue nursing or drug, taking into account importance of drug to mother. |
| Lactation Rating | L4 (Possibly Hazardous) |
| Teratogenic Risk | Pregnancy Category C. Animal studies have shown fetal toxicity (increased fetal loss, reduced fetal weight) at maternally toxic doses. No adequate and well-controlled studies in pregnant women. Potential fetal risks in all trimesters; use only if benefit justifies risk. |
| Fetal Monitoring | Monitor maternal ECG for QTc prolongation, baseline and during therapy. Assess renal function (CrCl) prior to and during treatment. Monitor electrolytes (K+, Mg2+). Fetal monitoring not specifically required, but consider fetal heart rate monitoring if used near term. |
| Fertility Effects | No human data on fertility effects. In animal studies, no adverse effects on fertility were observed at clinically relevant doses. |
■ FDA Black Box Warning
Tikosyn can cause life-threatening ventricular arrhythmias (e.g., torsade de pointes) and must be initiated in a hospital setting with continuous ECG monitoring and dose adjustment based on creatinine clearance and QTc interval.
| Serious Effects |
Hypersensitivity to dofetilide or any componentCreatinine clearance <20 mL/minQTc interval >440 msec (>500 msec with ventricular conduction abnormalities)Baseline QRS interval >200 msecConcomitant use of cimetidine, verapamil, ketoconazole, trimethoprim, prochlorperazine, megestrol, or hydrochlorothiazideConcurrent use of Class I or Class III antiarrhythmicsHypokalemia or hypomagnesemia
| Precautions | QTc prolongation; hypokalemia; hypomagnesemia; renal impairment; bradycardia; concurrent use of other QT-prolonging drugs; drug interactions with CYP3A4 inhibitors. |
| Food/Dietary | Grapefruit juice inhibits CYP3A4, increasing dofetilide levels and risk of arrhythmia; avoid grapefruit and grapefruit juice. High-potassium foods (e.g., bananas, oranges, spinach) are generally safe but must be consumed consistently to avoid electrolyte fluctuations. Avoid excessive licorice intake which can cause hypokalemia. |
| Clinical Pearls | TIKOSYN (dofetilide) is a class III antiarrhythmic indicated for maintenance of sinus rhythm in patients with atrial fibrillation/flutter. Requires inpatient initiation with continuous ECG monitoring due to risk of torsade de pointes. Dosing is based on creatinine clearance and QTc interval; must not exceed 500 mcg twice daily. Drug interactions via CYP3A4 and renal clearance are critical; avoid verapamil, cimetidine, ketoconazole, and trimethoprim. Hypokalemia and hypomagnesemia must be corrected before use. |
| Patient Advice | You must be hospitalized for the first 3 days of treatment to monitor your heart rhythm. · Do not take any new medications, including over-the-counter drugs or herbal supplements, without consulting your doctor. · Report any fainting, lightheadedness, or palpitations immediately. · Take your dose exactly as prescribed, usually twice daily with or without food. · Do not skip doses or double up if you miss a dose; call your doctor if you miss more than one dose. · Avoid grapefruit juice and grapefruit products while on this medication. · Your kidney function will be checked regularly; keep all lab appointments. · Inform all healthcare providers that you are taking TIKOSYN. |
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