Dofetilide (Tikosyn)

A pure IKr blocker for AF/flutter. The most protocol-bound antiarrhythmic we use — mandatory in-hospital initiation with QT checks and renal-based dosing.

Indication

Maintenance of sinus rhythm and pharmacologic conversion in AF and atrial flutter

Typical dose

125–500 mcg PO twice daily, dosed by CrCl and QT; mandatory ~3-day inpatient telemetry initiation

Why we use it

Dofetilide maintains sinus rhythm (and can pharmacologically convert) AF and atrial flutter, and unlike many alternatives it has no negative inotropy — so it is usable in patients with heart failure and reduced EF (DIAMOND data). The price of that is the most demanding safety protocol of any oral antiarrhythmic.

Mechanism

Dofetilide is a pure, selective blocker of the rapid delayed-rectifier potassium current (IKr). It prolongs the action potential and the QT with no effect on conduction velocity, heart rate, or contractility. Its effect shows reverse use-dependence — more QT prolongation at slower rates — which is exactly why early, resting torsades is the danger.

The mandatory initiation protocol

This is the defining feature. Dofetilide must be started in hospital under a REMS-style protocol:

Admit for ≥3 days of continuous ECG/telemetry.
Baseline CrCl and QTc (use QTc; if QRS > 120 ms, use a JT-based correction). Do not start if baseline QTc > 440 ms (500 ms with conduction disease) or CrCl < 20.
Starting dose by CrCl: 500 mcg BID (CrCl > 60), 250 mcg BID (40–60), 125 mcg BID (20–40), contraindicated < 20.
QTc 2–3 hours after the first dose: if it increased > 15% or above 500 ms (550 with conduction disease), reduce the next dose; if it exceeds those limits again, stop the drug.
Continue per-dose QT surveillance through the inpatient run-in.

Renal dosing and interactions

Dosed strictly by creatinine clearance; recheck renal function on follow-up and re-evaluate dose.
Absolutely contraindicated with drugs that raise dofetilide levels or independently prolong QT: verapamil, cimetidine, hydrochlorothiazide, ketoconazole, trimethoprim (incl. TMP-SMX), prochlorperazine, megestrol, dolutegravir, and other QT-prolonging agents.

Monitoring

Continuous telemetry during initiation; QTc with each early dose.
Renal function and electrolytes (keep K⁺ and Mg²⁺ replete) on every follow-up.
Re-hospitalize for re-initiation if the drug is interrupted for more than a couple of doses or if renal function/interacting meds change materially.

Common pitfalls

Starting or restarting it outside the hospital.
Missing an interacting drug on the med list (the contraindicated list is long and includes very common agents).
Failing to re-dose for a falling CrCl.
Letting K⁺/Mg²⁺ drift low and unmasking torsades.