Fluoxetine × Methylthioninium chloride (methylene blue)

Methylene blue (methylthioninium chloride) inhibits monoamine oxidase: the fluoxetine SmPC lists it among MAO-A inhibitors, and the FDA methylene blue label cites literature describing it as a potent reversible inhibitor of this enzyme. Fluoxetine blocks serotonin reuptake. Together they can cause severe, sometimes fatal serotonin syndrome (labels of both drugs). Fluoxetine and its active metabolite norfluoxetine are eliminated slowly, so the risk persists after fluoxetine is stopped (fluoxetine labels).

Serotonin syndrome. Mental status changes: agitation, hallucinations, confusion, delirium, coma. Autonomic signs: tachycardia, labile blood pressure, dizziness, sweating, flushing, fever. Neuromuscular signs: tremor, rigidity, myoclonus, hyperreflexia, incoordination, seizures. Gastrointestinal: nausea, vomiting, diarrhoea. Some reported cases were fatal (FDA methylene blue label).

Starting fluoxetine in a patient receiving intravenous methylene blue is contraindicated in the FDA fluoxetine label. The methylene blue labels approved by the European Medicines Agency (EMA) and the FDA say to avoid it in patients taking selective serotonin reuptake inhibitors, and the Spanish fluoxetine SmPC lists the combination as not recommended. If a patient on fluoxetine urgently needs methylene blue and there is no acceptable alternative, stop fluoxetine promptly and give methylene blue (FDA fluoxetine label) at the lowest possible dose, then observe the patient for nervous system effects for 4 hours (methylene blue labels). Monitor for serotonin syndrome for 5 weeks or until 24 hours after the last methylene blue dose, whichever comes first (FDA fluoxetine label). The FDA fluoxetine label allows restarting fluoxetine 24 hours after the last methylene blue dose, while the FDA methylene blue label advises no serotonergic drugs for 72 hours after it. Monitor the ECG and blood pressure during and after methylene blue (EMA methylene blue SmPC). If serotonin syndrome develops, stop methylene blue and start supportive treatment (methylene blue labels).