Dofetilide and Cimetidine: Why This Drug Pair Can Trigger Deadly Heart Rhythms

Feb, 20 2026

Imagine taking a medication to control your irregular heartbeat, only to unknowingly add something that turns that treatment into a ticking time bomb. That’s exactly what happens when dofetilide and cimetidine are taken together. This isn’t a rare edge case. It’s a well-documented, life-threatening interaction that has sent patients to the ICU - and even killed them - because it’s so predictable, yet still slips through the cracks.

What Dofetilide Does - and Why It’s So Sensitive

Dofetilide, sold under the brand name Tikosyn, is a powerful antiarrhythmic drug used to restore and maintain a normal heart rhythm in people with atrial fibrillation or atrial flutter. It works by blocking specific electrical channels in heart cells, slowing down abnormal signals. But here’s the catch: it has an extremely narrow safety window. Too little, and it doesn’t work. Too much, and it can trigger a chaotic, deadly heart rhythm called torsades de pointes.

This drug is eliminated almost entirely by the kidneys - about 80% of it leaves the body unchanged through a specific transport system called the renal cation exchange pathway. That’s why dosing is based on kidney function. If your creatinine clearance drops below 20 mL/min, you shouldn’t take it at all. But even if your kidneys are fine, something else can still overload your system.

Cimetidine: The Silent Saboteur

Cimetidine, known as Tagamet, was once one of the most common heartburn medications. It blocks stomach acid production by targeting H2 receptors. But unlike newer alternatives like famotidine (Pepcid) or proton pump inhibitors like omeprazole, cimetidine has a dangerous side effect: it shuts down that same kidney transport system that clears dofetilide.

Studies show cimetidine can increase dofetilide levels in the blood by 50% to 100% within just 24 hours. That’s not a small bump - it’s a massive spike. The FDA-approved prescribing info for Tikosyn says this interaction raises the risk of dangerous QT prolongation from 3-5% with dofetilide alone to 12-18% when cimetidine is added. QT prolongation means your heart takes longer than normal to recharge between beats. When it gets too long, it can spiral into torsades de pointes - a form of ventricular tachycardia that looks like a twisting pattern on an EKG and often leads to sudden cardiac arrest.

The Numbers Don’t Lie

The evidence isn’t theoretical. A 2021 study in Circulation: Arrhythmia and Electrophysiology analyzed over 12,000 patients and found the risk of QT prolongation was more than four times higher with cimetidine than without. The FDA’s own adverse event database recorded 23 confirmed cases of torsades de pointes directly linked to this combo between 2010 and 2022. That’s not an outlier - it’s a pattern.

One case from the Journal of Cardiovascular Electrophysiology involved a 72-year-old man on stable dofetilide who started cimetidine for heartburn. Three days later, he went into torsades de pointes and needed emergency cardioversion. Another case, published in Mayo Clinic Proceedings, described a 65-year-old woman who fainted after taking a single 300 mg dose of cimetidine. She had no prior history of heart problems - just dofetilide and a quick fix for acid reflux.

Why Famotidine Is Safe - And Cimetidine Isn’t

This is where it gets critical: not all acid blockers are equal. Famotidine (Pepcid) and ranitidine (Zantac, now largely off the market) do not interfere with the kidney’s cation transport system. Clinical trials (DOF-30001 and DOF-30002) showed that famotidine caused no meaningful change in dofetilide levels. That’s why experts say: if you need acid suppression while on dofetilide, use famotidine or a PPI like omeprazole. Not cimetidine. Ever.

The American College of Cardiology and the European Heart Rhythm Association both list this combination as contraindicated. Dr. Jonathan Piccini from Duke University called it “one of the clearest contraindications in clinical cardiology.” Dr. Bruce Wilkoff from Cleveland Clinic said its occurrence today is a “systems failure.” In other words: if this happens, someone dropped the ball.

How This Interaction Slips Through

Here’s the scary part: many patients don’t even realize they’re taking cimetidine. It’s sold over-the-counter. Someone might grab a bottle for “a little heartburn” without telling their cardiologist. Or a nurse in a nursing home might give it because it’s cheap and available. Elderly patients, especially those on multiple medications, are at highest risk.

A 2022 survey of 47 academic medical centers found that 12-15% of unexpected torsades de pointes cases in dofetilide patients involved unrecognized cimetidine use. Even short-term exposure - as little as 48 hours - can be enough. Dr. Anne Curtis warned that “even brief use can precipitate life-threatening arrhythmias.”

What Should You Do?

If you’re on dofetilide:

• Never take cimetidine (Tagamet) - even once.
• Check all your medications - including OTC ones. Look for “cimetidine” on the label.
• Switch to famotidine (Pepcid), omeprazole (Prilosec), or another PPI for acid reflux.
• Ask your pharmacist to run a drug interaction check before starting any new medication.
• Get your QT interval checked before starting dofetilide and again if you start a new drug.
• Keep potassium levels between 4.0 and 5.0 mmol/L. Low potassium makes the risk even worse.

If you’re a clinician:

• Screen for cimetidine use before prescribing dofetilide.
• Use electronic health record alerts - most major systems (Epic, Cerner) now block this combo.
• Document the switch to a safer acid suppressant in the patient’s plan.
• Remember: this isn’t just about avoiding a side effect - it’s about preventing sudden death.

The Bigger Picture

This interaction isn’t just about two drugs. It’s a window into how dangerous polypharmacy can be. The average patient with atrial fibrillation takes nearly seven prescription medications. Each one adds risk. The American Heart Association estimates that avoiding just this one interaction saves about $47,500 per case in emergency care, hospitalization, and long-term complications.

Since 2015, automatic EHR alerts have cut inappropriate co-prescribing from 8.7% to just 1.2%. That’s progress. But it’s not enough. AI systems now predict this interaction with 94.7% accuracy 72 hours before it happens - giving doctors time to intervene. Still, the American Geriatrics Society lists this combo as one of the most inappropriate for older adults.

The takeaway? This isn’t a theoretical warning. It’s a hard rule: dofetilide and cimetidine must never be used together. There’s no safe dose. No safe duration. No exception. The science is clear. The deaths are real. And the fix? Simple: switch to something else.