Methylene Blue

Methylene blue (methylthioninium chloride) is a thiazine dye with redox activity. The only FDA-approved product is ProvayBlue (methylene blue injection) 0.5%, for intravenous use. Methylene blue is also used as a bulk drug substance in compounded oral capsules and rapid-dissolve tablets, and as a diagnostic and surgical dye.

ProvayBlue is indicated for pediatric and adult patients with acquired methemoglobinemia. Labeled dosing, as prescribed, is 1 mg/kg intravenously over 5 to 30 minutes; the labeling permits a repeat dose if methemoglobinemia persists.

No oral methylene blue product is FDA approved, and no FDA-labeled oral dose exists; oral dosing is individualized by the prescriber. Prescribers use compounded oral methylene blue for off-label purposes they determine. Intravenous methylene blue is also used off label in hospitals, for example in vasoplegia and ifosfamide-associated encephalopathy. Oral preparations are not used to treat acute acquired methemoglobinemia.

At low concentrations, methylene blue is reduced by NADPH-dependent methemoglobin reductase to leucomethylene blue, which reduces methemoglobin (Fe3+) back to hemoglobin (Fe2+). The pathway needs NADPH from the pentose phosphate pathway, which depends on G6PD; in G6PD deficiency the drug may not work and can cause hemolysis. At high concentrations methylene blue can itself oxidize hemoglobin and cause methemoglobinemia.

Methylene blue is a potent, reversible inhibitor of monoamine oxidase A, the basis of its serotonin-syndrome risk. It also inhibits nitric oxide synthase and soluble guanylate cyclase. In preclinical studies it can act as an alternative electron carrier in mitochondria; this is a hypothesis, and clinical benefit in humans has not been established.

After intravenous dosing, methylene blue distributes widely and is reduced to leucomethylene blue; ProvayBlue labeling reports a prolonged terminal half-life. Oral doses are absorbed, with bioavailability reported around 70% in healthy volunteers and wide variability. Methylene blue, leucomethylene blue and metabolites are eliminated in urine and bile, coloring urine and feces blue-green; renal elimination is substantial. In vitro, methylene blue inhibits several CYP enzymes and drug transporters; clinical relevance for chronic oral use is not well defined.

• Severe hypersensitivity to methylene blue or any other thiazine dye, or to any component of the preparation.
• G6PD deficiency, because of the risk of hemolytic anemia.

• Serotonin syndrome: see Boxed Warning. Signs include mental status changes, autonomic instability and neuromuscular symptoms; discontinue and treat supportively.
• Hemolytic anemia: methylene blue is contraindicated in G6PD deficiency; screen at-risk patients and monitor hemoglobin.
• Hypersensitivity, including anaphylaxis, angioedema, urticaria and bronchospasm.
• Methemoglobinemia: high doses can cause methemoglobinemia, and acquired methemoglobinemia may not respond in G6PD or NADPH reductase deficiency.
• Interference with pulse oximetry: methylene blue can falsely lower SpO2 readings; use arterial blood gas or co-oximetry when oxygenation must be measured.
• CNS effects: dizziness, confusion and visual disturbance can impair driving or operating machinery.
• Renal impairment: use caution; avoid in severe renal impairment.

• Serotonergic drugs: SSRIs, SNRIs, MAO inhibitors including linezolid, clomipramine and other tricyclics, bupropion, buspirone, mirtazapine, triptans, lithium, St. John's wort and tryptophan. Avoid; see Boxed Warning.
• Opioids, especially those with serotonergic activity such as tramadol, meperidine, methadone, fentanyl and tapentadol: avoid concomitant use.
• CYP and transporter substrates with a narrow therapeutic index: in vitro inhibition data exist; monitor when used together.

Reactions reported with ProvayBlue include pain in the extremity, blue-green urine (chromaturia), altered taste, feeling hot, dizziness, sweating, nausea, skin discoloration and headache. Other reported effects include vomiting, abdominal pain, diarrhea, dysuria and bladder irritation, anxiety, confusion, tremor, chest pain, hypertension, hemolysis and blue discoloration of skin and mucous membranes. Larger doses raise the risk of hemolysis, methemoglobinemia and CNS toxicity.

Pregnancy: ProvayBlue labeling states that methylene blue may cause fetal harm. Intra-amniotic injection in the second trimester has been associated with neonatal intestinal atresia and fetal death, and animal studies showed adverse developmental effects. Avoid use in pregnancy unless the prescriber judges that the benefit outweighs the risk; methemoglobinemia in pregnancy is itself a risk to mother and fetus.

Lactation: there is no information on methylene blue in human milk. Because of the potential for serious adverse reactions, including genotoxicity, ProvayBlue labeling advises discontinuing breastfeeding during treatment and for up to 8 days after the last dose.

• Before therapy: full medication review for serotonergic drugs and opioids, G6PD status in at-risk patients, and pregnancy status.
• During therapy: signs of serotonin syndrome, CNS effects, hemolysis and hypersensitivity. Pulse oximetry is unreliable; use co-oximetry or arterial blood gas when oxygenation must be measured.
• Renal function in patients with renal impairment.

• ProvayBlue (methylene blue injection) 0.5% Prescribing Information, Provepharm.
• FDA Drug Safety Communication: Serious CNS reactions possible when methylene blue is given to patients taking certain psychiatric medications (2011).