Etoricoxib × Rivaroxaban

Rivaroxaban blocks coagulation factor Xa; etoricoxib selectively inhibits cyclooxygenase-2 (COX-2) and by itself causes upper gastrointestinal ulcers, perforations and bleeding, some of them fatal (etoricoxib SmPC, AEMPS, section 4.4). Etoricoxib has no antiplatelet effect (etoricoxib SmPC, 4.4), but it damages the mucosa, and on an anticoagulant such damage bleeds more. The rivaroxaban SmPC lists NSAIDs among drugs that affect haemostasis and asks for caution (EMA, 4.4 and 4.5). There is no kinetic conflict: etoricoxib does not affect CYP3A4 (etoricoxib SmPC, 4.5), the enzyme that clears rivaroxaban. Etoricoxib adds a second factor through the kidney: NSAIDs can impair renal function (etoricoxib SmPC, 4.4), and in renal impairment rivaroxaban concentrations rise (rivaroxaban SmPC, 4.4).

Above all gastrointestinal bleeding: black or bloody stools, vomiting blood, abdominal pain, weakness, a fall in haemoglobin. The rivaroxaban SmPC lists mucosal bleeding (nosebleeds, gums, gastrointestinal, genitourinary including heavier menstrual bleeding) and anaemia, and requires a search for the bleeding site after any unexplained fall in haemoglobin or blood pressure (EMA, 4.4). From etoricoxib separately: fluid retention, oedema, a rise in blood pressure, worsening renal function (etoricoxib SmPC, AEMPS, 4.4). Uncontrolled hypertension and renal impairment in a patient on rivaroxaban are also bleeding risk factors (rivaroxaban SmPC, 4.4).

The combination is acceptable with caution; no label forbids it. The rivaroxaban SmPC asks for caution with concomitant NSAIDs because of the bleeding risk (EMA, 4.4 and 4.5), and the etoricoxib SmPC asks for caution with warfarin and other oral anticoagulants (AEMPS, 4.4). The EHRA 2021 practical guide advises weighing such a combination against the expected benefit in each clinical situation. First check the etoricoxib contraindications: active peptic ulcer or gastrointestinal bleeding, uncontrolled hypertension above 140/90 mmHg, congestive heart failure, ischaemic heart disease, peripheral arterial or cerebrovascular disease, creatinine clearance below 30 mL/min (etoricoxib SmPC, 4.3). Rivaroxaban is also contraindicated with an active or recent ulcer (rivaroxaban SmPC, 4.3). Give etoricoxib at the lowest effective dose for the shortest possible time (etoricoxib SmPC, 4.4), and in patients at risk of ulcer disease consider prophylactic treatment (rivaroxaban SmPC, 4.4). Monitoring: watch for signs of bleeding and anaemia; haemoglobin and haematocrit help to detect occult bleeding (rivaroxaban SmPC, 4.4); promptly evaluate any sign of blood loss in a patient on an NSAID (rivaroxaban FDA label, 7.4). The etoricoxib requirement to monitor the INR closely is written for warfarin. The INR does not measure the effect of rivaroxaban, routine monitoring is not needed, and a calibrated anti-Xa assay is reserved for exceptional situations (rivaroxaban SmPC, EMA, 4.4; FDA, 5.2). Check blood pressure during the first two weeks of etoricoxib and periodically afterwards (etoricoxib SmPC, 4.4). If renal function worsens, use rivaroxaban with caution at creatinine clearance 15–29 mL/min and do not use it below 15 mL/min (rivaroxaban SmPC, 4.4). Stop rivaroxaban in case of severe bleeding (EMA, 4.4).