Ciclosporin × Dabigatran

Dabigatran etexilate is a substrate of the efflux transporter P-glycoprotein (P-gp). Ciclosporin inhibits this transporter, so dabigatran plasma concentrations rise (dabigatran and ciclosporin labels). There are no clinical studies of the pair (ciclosporin label, US Food and Drug Administration, FDA). Based on in vitro data, the dabigatran manufacturer expects an effect similar to that of ketoconazole. Ketoconazole 400 mg increased the dabigatran area under the concentration–time curve (AUC) 2.38-fold after a single dose and 2.53-fold after multiple once-daily doses (dabigatran label, European Medicines Agency, EMA). The kidneys clear dabigatran mainly unchanged, and ciclosporin often raises serum creatinine and urea (dabigatran and ciclosporin labels). According to the FDA dabigatran label, P-gp inhibition and impaired renal function are the major independent factors that increase dabigatran exposure. Together, they are expected to raise it more than either factor alone.

The main risk is bleeding from the nose, stomach and gut, rectum and haemorrhoids, and the urinary and genital tract, with blood in the urine. Bleeding into the skin and joints, bruising, coughing up blood and, less often, intracranial haemorrhage can also occur (dabigatran label). Bleeding can present as weakness, pallor, dizziness, headache, shortness of breath, or unexplained swelling or shock (dabigatran label). An unexplained fall in haemoglobin, haematocrit or blood pressure points to hidden bleeding (dabigatran label).

The combination is contraindicated. The dabigatran label lists ciclosporin among its contraindications (European Medicines Agency, EMA). The ciclosporin label lists dabigatran among its contraindications (Spanish Agency of Medicines and Medical Devices, AEMPS). The ciclosporin label of the US Food and Drug Administration (FDA) says the combination should be avoided. The table of the European Heart Rhythm Association (EHRA 2021) marks the pair red, meaning contraindicated or not advisable because dabigatran levels rise. If a patient taking ciclosporin needs an oral anticoagulant, the same table marks apixaban and rivaroxaban with ciclosporin yellow with hatching (caution required, no clinical or pharmacokinetic data). For edoxaban, it gives a dose reduction to 30 mg once daily according to the edoxaban label (EHRA 2021). If the two drugs have already been taken together, watch closely for signs of bleeding or anaemia. Look for the bleeding site if haemoglobin, haematocrit or blood pressure falls without explanation (dabigatran label, EMA). The international normalised ratio (INR) is unreliable with dabigatran and should not be measured. Diluted thrombin time, ecarin clotting time and activated partial thromboplastin time can help detect excess dabigatran (dabigatran label, EMA). Check renal function often during ciclosporin treatment (ciclosporin label, AEMPS). Stop dabigatran if acute kidney failure develops (dabigatran label, EMA). In severe bleeding, stop dabigatran and find the cause. In adults, the specific reversal agent idarucizumab can be considered, and haemodialysis can remove dabigatran (dabigatran label, EMA).