Cisapride × Ritonavir

Ritonavir strongly inhibits the liver enzyme CYP3A4 and slows the breakdown of drugs that depend on it. The US ritonavir label lists cisapride among drugs whose clearance depends heavily on CYP3A and whose raised plasma levels are linked to serious or life-threatening reactions. When the two are taken together, cisapride levels in the blood rise, but the documents give no study with numbers for this pair. With clarithromycin, another strong CYP3A4 inhibitor, the prescribing information reports raised cisapride levels in patients taking both drugs. This can prolong the QT interval on the electrocardiogram and cause ventricular arrhythmias.

The danger of the combination is serious heart rhythm disorders (ritonavir labels). They include QT interval prolongation on the electrocardiogram, ventricular tachycardia, ventricular fibrillation and torsade de pointes (clarithromycin prescribing information on its combination with cisapride). An attack shows as sudden strong palpitations, dizziness or fainting. Prolonged torsade de pointes can turn into ventricular fibrillation and cardiac arrest. Ritonavir itself causes a moderate, symptom-free prolongation of the PR interval in some healthy people. Rare cases of second- or third-degree atrioventricular block have been reported in people with structural heart disease and conduction abnormalities (ritonavir label, European Medicines Agency, EMA).

The combination is contraindicated (ritonavir label, European Medicines Agency, EMA; ritonavir label, US Food and Drug Administration, FDA). The same contraindication appears in the generic ritonavir label (Spanish Agency of Medicines and Medical Devices, AEMPS) and in the label of Paxlovid, where ritonavir is combined with nirmatrelvir (EMA). These documents set no dose condition for cisapride, so the contraindication also covers the low ritonavir doses used to boost other antiviral drugs, including in Paxlovid. When ritonavir boosts another protease inhibitor, also check the contraindications in that drug's label (ritonavir labels, EMA and FDA).