Ketoconazole × Ritonavir

Dual potent CYP3A4 inhibition. Ketoconazole plasma levels may rise 3-fold. Hepatotoxicity and adrenal cortex suppression intensify.

Nausea, vomiting, abdominal pain and rising liver enzymes (ALT, AST); in severe cases jaundice and dark urine. Signs of adrenal insufficiency: weakness, fatigue, loss of appetite and weight, low blood pressure, low sodium and high potassium, low blood sugar. Ketoconazole itself prolongs the QT interval on the ECG.

Ketoconazole tablets authorised by the European Medicines Agency (EMA) are indicated for Cushing's syndrome. With ritonavir alone the combination is not contraindicated, but the ketoconazole dose is kept lower than usual. The US ritonavir label (FDA) does not recommend ketoconazole doses above 200 mg a day, and the European ritonavir and ketoconazole SmPCs advise considering a dose reduction. While both drugs are taken, watch closely for signs of adrenal insufficiency and adjust the ketoconazole dose to cortisol levels (ketoconazole SmPC, EMA). Check liver enzymes and bilirubin before starting, weekly in the first month, then monthly for six months, and weekly for a month after each dose increase. Record an ECG before ketoconazole starts and within the first week (ketoconazole SmPC, EMA). If ritonavir boosts saquinavir or is part of paritaprevir/ombitasvir, ketoconazole is contraindicated with that regimen (ketoconazole SmPC, EMA).