Flecainide × Ritonavir

The enzyme CYP2D6 breaks down a large part of flecainide. Ritonavir inhibits this enzyme and, even more strongly, the CYP3A enzymes. According to the ritonavir documents, flecainide blood levels rise, and with them the risk of arrhythmias and other serious adverse reactions. The documents give no figures for this pair. The US ritonavir label only says that the area under the curve (AUC) of drugs broken down by CYP2D6 can rise up to 2-fold. Flecainide lengthens the PR and QRS intervals on the electrocardiogram in a dose-related way. Ritonavir prolongs the PR interval on its own, and rare cases of second- or third-degree atrioventricular block have been reported with it.

When flecainide levels rise above the therapeutic range, adverse reactions become more likely, mainly cardiac ones. The electrocardiogram (ECG) shows a wider QRS complex and longer PR and QT intervals. Atrioventricular block, a slow heart rate, ventricular tachycardia or ventricular fibrillation can develop. The person may notice palpitations, dizziness, or double or blurred vision. Low blood pressure, fainting, and new or worsening heart failure with breathlessness and swelling can occur. In severe flecainide toxicity, seizures, cardiac arrest and death have been reported.

The combination is contraindicated (ritonavir prescribing information from the European Medicines Agency, EMA, and the US Food and Drug Administration, FDA). These documents set no dose condition for flecainide, so the contraindication also covers the low ritonavir doses used to boost other human immunodeficiency virus (HIV) protease inhibitors. When ritonavir boosts another protease inhibitor, check that drug's prescribing information for contraindications as well (ritonavir summary of product characteristics, EMA; ritonavir label, FDA). The flecainide prescribing information also says to avoid this combination (Spanish Agency of Medicines and Medical Devices, AEMPS). If a patient has taken both drugs, flecainide blood levels can be measured. Trough levels are usually 0.2–1.0 µg/mL, and adverse reactions, especially cardiac ones, become more likely above 0.7–1.0 µg/mL (flecainide prescribing information, AEMPS). Flecainide overdose is life-threatening. There is no specific antidote, and dialysis does not help. Treatment is supportive, and temporary transvenous pacing is considered for conduction block (flecainide prescribing information, AEMPS). Flecainide has a half-life of about 20 hours, so this treatment may be needed for a long time (flecainide prescribing information, AEMPS).