Methylthioninium chloride (methylene blue)

Mechanism

Methylene blue (methylthioninium chloride) inhibits monoamine oxidase (MAO). The US Food and Drug Administration (FDA) amitriptyline label classes intravenous methylene blue as an MAO inhibitor, and the FDA methylene blue label cites literature describing it as a potent reversible inhibitor of this enzyme. Amitriptyline inhibits the reuptake of noradrenaline and serotonin (FDA amitriptyline label). Together they can cause severe, sometimes fatal serotonin syndrome (methylene blue labels). All reports that gave the route involved intravenous methylene blue at 1–8 mg/kg. There are no reports with oral tablets, local tissue injection or lower doses (FDA amitriptyline label).

Symptoms

Serotonin syndrome. Mental status changes: agitation, hallucinations, delirium, coma. Autonomic signs: tachycardia, labile blood pressure, dizziness, sweating, flushing, fever. Neuromuscular signs: tremor, rigidity, myoclonus, hyperreflexia, incoordination. Seizures, nausea, vomiting and diarrhoea may occur. Some reported cases were fatal (FDA methylene blue label). With tricyclic antidepressants and MAO inhibitors taken together, the FDA amitriptyline label reports hyperpyretic crises, severe convulsions and deaths.

Management

The combination is contraindicated: the US Food and Drug Administration (FDA) amitriptyline label says it should not be given with MAO inhibitors and should not be started in a patient receiving intravenous methylene blue. The methylene blue labels approved by the European Medicines Agency (EMA) and the FDA say to avoid it in patients taking drugs that enhance serotonergic transmission, antidepressants included. If a patient on amitriptyline needs methylene blue, stop amitriptyline before it is given (FDA amitriptyline label). When methylene blue cannot be avoided, give the lowest possible dose and observe the patient for nervous system effects for 4 hours (methylene blue labels). Monitor the ECG and blood pressure during and after the infusion (EMA methylene blue SmPC). If signs of serotonin syndrome appear, stop methylene blue and amitriptyline and start supportive treatment (FDA labels of both drugs). Restart amitriptyline no earlier than 14 days after the last methylene blue dose, cautiously and with gradual dose increases, as the FDA amitriptyline label requires after an MAO inhibitor.

Mechanism

IV methylene blue is a potent reversible MAO-A inhibitor. Bupropion inhibits dopamine and norepinephrine reuptake. Combined action raises monoamines sharply, risking hypertensive crisis and seizures.

Symptoms

Hypertension, tachycardia, tremor, agitation, headache. Seizures may occur (bupropion lowers seizure threshold). Serotonin syndrome is less common unless other serotonergics are involved.

Management

Avoid the combination. IV methylene blue is reserved for emergencies with bupropion withdrawn 14 days in advance. If unavoidable for methaemoglobinaemia on bupropion, give for life-threatening indications with blood pressure monitoring and anticonvulsants ready.

Mechanism

Methylene blue (methylthioninium chloride) inhibits monoamine oxidase (MAO). The US Food and Drug Administration (FDA) escitalopram label classes intravenous methylene blue as an MAO inhibitor, and the FDA methylene blue label cites literature describing it as a potent reversible inhibitor of this enzyme. Escitalopram blocks serotonin reuptake. Together they can cause severe, sometimes fatal serotonin syndrome (methylene blue labels). No reports involved other routes of methylene blue, such as oral tablets or local tissue injection (FDA escitalopram label).

Symptoms

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

Management

The combination is contraindicated: the US Food and Drug Administration (FDA) escitalopram label contraindicates escitalopram with MAO inhibitors and starting it in a patient who is receiving intravenous methylene blue. 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. If a patient on escitalopram needs methylene blue, stop escitalopram before it is given (FDA escitalopram label). When methylene blue cannot be avoided, give the lowest possible dose and observe the patient for nervous system effects for 4 hours (methylene blue labels). Monitor the ECG and blood pressure during and after the infusion (EMA methylene blue SmPC). If signs of serotonin syndrome appear, stop methylene blue and escitalopram and start supportive treatment (FDA labels of both drugs). Serotonergic drugs, escitalopram included, are not taken for 72 hours after the last methylene blue dose (FDA methylene blue label).

Mechanism

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).

Symptoms

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).

Management

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).

Mechanism

Linezolid is a reversible MAO inhibitor with antibacterial activity. IV methylene blue is a reversible MAO-A inhibitor. Two MAO inhibitors together raise the risk of hypertensive crisis and serotonin syndrome even without an SSRI on board.

Symptoms

Hypertensive crisis, tachycardia, severe headache, fever, agitation, confusion. With concomitant serotonergics (SSRI, SNRI, TCA, tramadol), full serotonin syndrome may develop with myoclonus, hyperreflexia, and rhabdomyolysis.

Management

Avoid the combination. For emergency methylene blue use in a patient on linezolid, give for life-threatening indications under ICU monitoring of blood pressure, pulse, and temperature. Pause linezolid if feasible; stop both at the first sign of hypertensive crisis.

Mechanism

Methylene blue (methylthioninium chloride) inhibits monoamine oxidase (MAO). The US Food and Drug Administration (FDA) mirtazapine label classes intravenous methylene blue as an MAO inhibitor, and the FDA methylene blue label cites literature describing it as a potent reversible inhibitor of this enzyme. Mirtazapine blocks presynaptic alpha-2 adrenergic receptors and enhances central noradrenergic and serotonergic transmission (mirtazapine labels). Together they can cause severe, sometimes fatal serotonin syndrome (methylene blue labels). No reports involved other routes of methylene blue, such as oral tablets or local tissue injection (FDA mirtazapine label).

Symptoms

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

Management

The combination is contraindicated: the US Food and Drug Administration (FDA) mirtazapine label contraindicates mirtazapine in patients taking MAO inhibitors, including intravenous methylene blue, or within 14 days of stopping them. The methylene blue labels approved by the European Medicines Agency (EMA) and the FDA name mirtazapine among the drugs to avoid with methylene blue. If a patient on mirtazapine needs methylene blue, stop mirtazapine before it is given (FDA mirtazapine label). When methylene blue cannot be avoided, give the lowest possible dose and observe the patient for nervous system effects for 4 hours (methylene blue labels). Monitor the ECG and blood pressure during and after the infusion (EMA methylene blue SmPC). If signs of serotonin syndrome appear, stop methylene blue and mirtazapine and start supportive treatment (FDA labels of both drugs). Restart mirtazapine no earlier than 14 days after the last methylene blue dose (FDA mirtazapine label).

Mechanism

Methylene blue (methylthioninium chloride) inhibits monoamine oxidase (MAO). The US Food and Drug Administration (FDA) sertraline label classes intravenous methylene blue as an MAO inhibitor, and the FDA methylene blue label cites literature describing it as a potent reversible inhibitor of this enzyme. Sertraline blocks serotonin reuptake. Together they can cause severe, sometimes fatal serotonin syndrome (methylene blue labels). The Spanish sertraline SmPC reports serious reactions, including deaths, also when sertraline was started soon after stopping an MAO inhibitor such as methylene blue, or an MAO inhibitor was started right after stopping sertraline. No reports involved other routes of methylene blue, such as oral tablets or local tissue injection (FDA sertraline label).

Symptoms

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

Management

The combination is contraindicated: the US Food and Drug Administration (FDA) sertraline label contraindicates sertraline in patients taking MAO inhibitors, including intravenous methylene blue, or within 14 days of stopping them. 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. If a patient on sertraline needs methylene blue, stop sertraline before it is given (FDA sertraline label). When methylene blue cannot be avoided, give the lowest possible dose and observe the patient for nervous system effects for 4 hours (methylene blue labels). Monitor the ECG and blood pressure during and after the infusion (EMA methylene blue SmPC). If signs of serotonin syndrome appear, stop methylene blue and sertraline and start supportive treatment (FDA labels of both drugs). Restart sertraline no earlier than 14 days after the last methylene blue dose (FDA sertraline label).

Mechanism

Methylene blue (methylthioninium chloride) inhibits monoamine oxidase (MAO). The US Food and Drug Administration (FDA) tramadol label classes intravenous methylene blue as an MAO inhibitor, and the FDA methylene blue label cites literature describing it as a potent reversible inhibitor of this enzyme. Tramadol is an opioid that inhibits noradrenaline reuptake and enhances serotonin release (tramadol SmPC). The FDA methylene blue label warns that use with opioids may cause serious or fatal serotonin syndrome. The FDA tramadol label adds that MAO inhibitor interactions with opioids may also present as opioid toxicity, and that MAO inhibitors raise the risk of seizures on tramadol.

Symptoms

Serotonin syndrome: agitation, hallucinations, coma, tachycardia, labile blood pressure, fever, hyperreflexia, incoordination, muscle rigidity, nausea, vomiting, diarrhoea. Symptoms usually start within several hours to a few days of combined use, but may appear later (US Food and Drug Administration, FDA, tramadol label). Some reported cases with methylene blue were fatal (FDA methylene blue label). Seizures may occur. The interaction can also present as opioid toxicity: respiratory depression up to coma (FDA tramadol label).

Management

The combination is contraindicated: the US Food and Drug Administration (FDA) tramadol label contraindicates tramadol with MAO inhibitors and within 14 days of their use, and the same label classes intravenous methylene blue as an MAO inhibitor. It also says not to start an MAO inhibitor while taking tramadol. The FDA methylene blue label says to avoid it in patients taking opioids, and the European Medicines Agency (EMA) label says to avoid it with drugs that enhance serotonergic transmission. When methylene blue cannot be avoided, give the lowest possible dose and observe the patient for nervous system effects for 4 hours (methylene blue labels). Monitor the ECG and blood pressure during and after the infusion (EMA methylene blue SmPC). If serotonin syndrome is suspected, stop tramadol at once (FDA tramadol label), stop methylene blue and start supportive treatment (methylene blue labels). Start tramadol no earlier than 14 days after the last methylene blue dose (FDA tramadol label).