METHYLENE BLUE

Clinical safety rating: caution

Comprehensive clinical and safety monograph for METHYLENE BLUE (METHYLENE BLUE).

How it works

Methylene blue is a dye that acts as a redox agent, reducing methemoglobin to hemoglobin by activating the enzyme methemoglobin reductase. It also inhibits nitric oxide synthase and guanylate cyclase, causing vasoconstriction in septic shock.

What the body does with it

Metabolism	Reduced to leukomethylene blue by NADPH-dependent reductases (e.g., methemoglobin reductase) and other flavin reductases; subsequently metabolized by glucuronidation or sulfation in the liver; partially excreted unchanged in urine.
Excretion	Renal (80% as leukomethylene blue and unchanged drug); biliary/fecal minor
Half-life	Terminal elimination half-life approximately 12–24 hours; clinically, levels may persist for 2–3 days due to enterohepatic recycling
Protein binding	Approximately 50% bound to plasma proteins (albumin and others)
Volume of Distribution	0.7–1.2 L/kg; indicates extensive extravascular distribution including RBCs and tissues
Bioavailability	Oral: 53–73% (first-pass metabolism to leuko form); IV: 100%
Onset of Action	Oral: 30–60 minutes; Intravenous: seconds to minutes; Intramuscular: 15–30 minutes
Duration of Action	Methemoglobin reduction: 2–6 hours after single IV dose; optical staining effects may last 4–7 days; enterohepatic recycling may prolong effects

Classification & Brands

Dosing & administration

1-2 mg/kg IV over 5-30 minutes for methemoglobinemia; repeat after 1 hour if needed. Maximum dose: 7 mg/kg.

Dosage form	SOLUTION
Renal impairment	No specific GFR-based adjustment required; use with caution in severe impairment (eGFR <30 mL/min/1.73m²) due to potential accumulation.
Liver impairment	Child-Pugh A: no adjustment; Child-Pugh B or C: reduce dose by 50% or consider alternative due to risk of serotonin syndrome (drug affecting hepatic metabolism).
Pediatric use	1-2 mg/kg IV (maximum dose 7 mg/kg) for methemoglobinemia; repeat after 1 hour if necessary. Preferred concentration 1% solution.
Geriatric use	No specific dose adjustment; monitor for serotonin syndrome and renal function (age-related decreased clearance). Start at lower end of dosing range.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for METHYLENE BLUE (METHYLENE BLUE).

Breastfeeding	Methylene blue is excreted into breast milk; M/P ratio not established. Avoid breastfeeding during therapy due to potential for methemoglobinemia and hemolysis in infants, especially those with G6PD deficiency.
Teratogenic Risk	Methylene blue is contraindicated in the first trimester due to risk of fetal harm, including methemoglobinemia and hemolytic anemia. In second and third trimesters, use only if clearly needed; may cause fetal methemoglobinemia and hyperbilirubinemia.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

Serotonin syndrome: Methylene blue inhibits monoamine oxidase A (MAO-A), increasing serotonin levels. Life-threatening serotonin syndrome can occur when combined with serotonergic drugs (e.g., SSRIs, SNRIs, MAOIs). Avoid use in patients taking serotonergic agents, or discontinue serotonergic drugs at least 5 weeks before methylene blue administration.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Severe hypersensitivity to methylene blue or any component","Severe renal impairment (no established safety)","G6PD deficiency (risk of hemolytic anemia)","Use in patients taking serotonergic drugs (risk of serotonin syndrome)"]

Clinical Precautions

Precautions

["Risk of serotonin syndrome with serotonergic drugs; avoid concurrent use or discontinue serotonergic agents 5 weeks prior.","Hemolytic anemia in G6PD deficiency (may cause Heinz body formation).","Hypersensitivity reactions (rash, urticaria, anaphylaxis).","Interference with pulse oximetry readings (may cause falsely low SpO2)."]

Clinical Tips & Counseling

Drug interactions

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METHYLENE BLUE

Clinical safety rating: caution

Comprehensive clinical and safety monograph for METHYLENE BLUE (METHYLENE BLUE).

How it works

What the body does with it

Metabolism	Reduced to leukomethylene blue by NADPH-dependent reductases (e.g., methemoglobin reductase) and other flavin reductases; subsequently metabolized by glucuronidation or sulfation in the liver; partially excreted unchanged in urine.
Excretion	Renal (80% as leukomethylene blue and unchanged drug); biliary/fecal minor
Half-life	Terminal elimination half-life approximately 12–24 hours; clinically, levels may persist for 2–3 days due to enterohepatic recycling
Protein binding	Approximately 50% bound to plasma proteins (albumin and others)
Volume of Distribution	0.7–1.2 L/kg; indicates extensive extravascular distribution including RBCs and tissues
Bioavailability	Oral: 53–73% (first-pass metabolism to leuko form); IV: 100%
Onset of Action	Oral: 30–60 minutes; Intravenous: seconds to minutes; Intramuscular: 15–30 minutes
Duration of Action	Methemoglobin reduction: 2–6 hours after single IV dose; optical staining effects may last 4–7 days; enterohepatic recycling may prolong effects

Classification & Brands

Dosing & administration

1-2 mg/kg IV over 5-30 minutes for methemoglobinemia; repeat after 1 hour if needed. Maximum dose: 7 mg/kg.

Dosage form	SOLUTION
Renal impairment	No specific GFR-based adjustment required; use with caution in severe impairment (eGFR <30 mL/min/1.73m²) due to potential accumulation.
Liver impairment	Child-Pugh A: no adjustment; Child-Pugh B or C: reduce dose by 50% or consider alternative due to risk of serotonin syndrome (drug affecting hepatic metabolism).
Pediatric use	1-2 mg/kg IV (maximum dose 7 mg/kg) for methemoglobinemia; repeat after 1 hour if necessary. Preferred concentration 1% solution.
Geriatric use	No specific dose adjustment; monitor for serotonin syndrome and renal function (age-related decreased clearance). Start at lower end of dosing range.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for METHYLENE BLUE (METHYLENE BLUE).

Breastfeeding	Methylene blue is excreted into breast milk; M/P ratio not established. Avoid breastfeeding during therapy due to potential for methemoglobinemia and hemolysis in infants, especially those with G6PD deficiency.
Teratogenic Risk	Methylene blue is contraindicated in the first trimester due to risk of fetal harm, including methemoglobinemia and hemolytic anemia. In second and third trimesters, use only if clearly needed; may cause fetal methemoglobinemia and hyperbilirubinemia.
Fetal Monitoring