Methylene Blue (Monograph)

Brand name: ProvayBlue
Drug class: Antidotes
VA class: AD900
Molecular formula: C₁₆H₁₈CIN₃S.3H₂O
CAS number: 7220-79-3

Medically reviewed by Drugs.com on Feb 8, 2024. Written by ASHP.

Introduction

Oxidation-reduction agent, thiazine dye; accelerates conversion of methemoglobin to hemoglobin.^{9 113 115 200}

Uses for Methylene Blue

Methemoglobinemia

Treatment of acquired methemoglobinemia.^{1 200} Designated orphan drug by FDA for this use.²⁰¹

Accelerated approval of methylene blue for this indication based on reduction (≥50%) in methemoglobin within 1 hour following IV administration of the drug in patients with methemoglobinemia; continued FDA approval for this indication may be contingent upon verification of clinical benefits in future clinical studies.²⁰⁰

Used for methemoglobinemia associated with certain drugs (e.g., dapsone, benzocaine, lidocaine),^{117 118} occupational or other exposures to toxic chemicals (e.g., hydrazine, amine-substituted benzenes, nitro-substituted benzenes, nitrates, nitrites),^{111 113 115} or substance abuse (e.g., inhalation or ingestion of volatile nitrites).^{110 111 112 115} Methemoglobinemia may not resolve or may rebound after initial response to therapy with methylene blue in patients with methemoglobinemia associated with aryl amines (e.g., aniline) or sulfa drugs (e.g., dapsone).²⁰⁰

Does not reverse methemoglobinemia in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency;^{9 113 115 117} may induce or exacerbate hemolysis in these patients.^{2 113 115} Methylene blue is contraindicated in patients with G-6-PD deficiency due to risk of hemolytic anemia.²⁰⁰ (See Contraindications and also see Hematologic Effects, under Cautions.)

Has been used for treatment of cyanosis in patients with congenital methemoglobinemia^{† [off-label]} related to cytochrome b₅ reductase deficiency;^{115 117 129 130 131} ineffective in patients with hemoglobin M (abnormal hemoglobin molecules).^{115 117 131} Designated orphan drug by FDA for treatment of congenital methemoglobinemia.²⁰¹

Not effective for treatment of sulfhemoglobinemia.^{115 131}

Ifosfamide-induced Encephalopathy

Management of ifosfamide-induced encephalopathy^{† [off-label]};¹⁰² may be beneficial in some patients, but additional study needed.¹⁰²

Has been ineffective when used prophylactically in an attempt to prevent ifosfamide-associated encephalopathy.^{102 103}

Use as a Dye

Has been used as a bacteriologic stain, as an indicator dye, and for surgical and medical marking.^a

Has been used as diagnostic (visualizing) dye^{† [off-label]} in a variety of procedures, including sentinel lymph node biopsy in cancer patients (e.g., breast cancer patients),^{9 120 123} endoscopic evaluation of lesions in patients with GERD or Barrett's esophagus,¹²¹ urologic evaluation in patients with ureteral or renal pelvis injury,¹²² and thoroscopic procedures in patients with pulmonary nodules.¹²⁴

Photodynamic Therapy

Has been used as a photosensitizer for photodynamic therapy^{† [off-label]} (PDT) for topical treatment of dermatologic or mucocutaneous infections (e.g., herpes labialis, eczema herpeticum, oral candidiasis, cutaneous leishmaniasis, chromoblastomycosis)^{26 127 128 134 135} or chronic dermatologic or mucocutaneous conditions (e.g., plaque psoriasis, oral lichen planus).^{125 126}

Cyanide and Carbon Monoxide Poisoning

Was used in the past as an antidote for cyanide poisoning^{† [off-label]};¹¹³ no longer recommended for this use.⁹ Cyanide poisoning usually treated with antidote regimen consisting of amyl nitrite, sodium nitrite, and sodium thiosulfate or with hydroxocobalamin.^{115 119}

When sodium nitrite is used for cyanide poisoning, do not use methylene blue in an attempt to treat excessive methemoglobinemia induced by the antidote because reduced cyanide binding and increased toxicity occurs.⁹

Not effective for treatment of carbon monoxide poisoning.^a

Cystitis and Urethritis

Was used in the past as a mild urinary antiseptic and stimulant to mucous surfaces in the treatment of cystitis and urethritis^†; no longer recommended for this use.^a

Urolithiasis

Has been used alone and in combination with ascorbic acid for management of chronic urolithiasis^†.^a May inhibit formation of calcium oxalate and calcium phosphate crystals, but not currently recommended for this use and is ineffective in dissolving previously formed stones.^a

Methylene Blue Dosage and Administration

Administration

Administer by slow IV injection over several minutes.^{1 200} Has been given by IV infusion^†.^{9 113 115 118}

Has been administered orally^†,^{9 102 113 117 139} but oral preparations no longer commercially available in the US.^a Oral solutions have been prepared extemporaneously by diluting 5–10 mL of the commercially available 10-mg/mL solution for IV use in 100–200 mL of water.⁹

Has been administered by local instillation or injection^† for use as a diagnostic (visualizing) dye^†.^{9 104 105 120 121 122 123 124}

Has been administered topically^† for use as a photosensitizer in PDT^†.^{9 125 126 127 128 134 135} (See Administration Precautions under Cautions.)

Do not administer by sub-Q, intrathecal, or intraspinal injection.^{1 2} (See Administration Precautions under Cautions.)

IV Administration

Avoid high local concentrations.¹ (See Administration Precautions under Cautions.)

Dilution

The manufacturer of the commercially available 5-mg/mL solution (ProvayBlue) states that the drug may be diluted, if desired, in 50 mL of 5% dextrose injection.²⁰⁰ Use diluted solutions immediately after preparation.²⁰⁰

Rate of Administration

Inject slowly over several minutes (e.g., 5–30 minutes);^{1 9 200} alternatively, has been administered over 3–10 minutes.^{113 115 116 117}

Dosage

Pediatric Patients

Acquired Methemoglobinemia

IV

1 mg/kg by slow IV injection.²⁰⁰

Alternatively, dosages of 1–2 mg/kg given by slow IV injection have been used.^{1 9 113 115 116 117}

Symptomatic improvement usually occurs within 30 minutes.^{113 115} Repeat IV dose after 1 hour if required (i.e., methemoglobin concentration remains >30% or clinical manifestations of methemoglobinemia persist).^{9 113 116 200} Alternatively, repeat doses have been administered after 30 minutes, if required.^{9 115 117}

Adults

Acquired Methemoglobinemia

IV

1 mg/kg by slow IV injection.²⁰⁰

Alternatively, dosages of 1–2 mg/kg given by slow IV injection have been used.^{1 9 113 115 116 117}

Symptomatic improvement usually occurs within 30 minutes.^{113 115} Repeat IV dose after 1 hour if required (i.e., methemoglobin concentration remains >30% or clinical manifestations of methemoglobinemia persist).^{9 113 116 200} Alternatively, repeat doses have been administered after 30 minutes, if required.^{9 115 117}

Ifosfamide-induced Encephalopathy†

IV

50 mg by slow IV injection over ≥5 minutes;¹⁰² 1–6 doses daily until symptoms resolve.¹⁰²

Prescribing Limits

Pediatric Patients

Acquired Methemoglobinemia

IV

Maximum dosage 2 mg/kg.¹ Some experts recommend maximum total dose of 5–7 mg/kg during first few hours of treatment.^{9 115}

Adults

Acquired Methemoglobinemia

IV

Maximum dosage 2 mg/kg.¹ Some experts recommend maximum total dose of 5–7 mg/kg during first few hours of treatment.^{9 115}

Special Populations

Hepatic Impairment

No specific dosage recommendations.¹ Monitor patients for toxicities and potential drug interactions for an extended period of time following treatment with methylene blue.²⁰⁰

Renal Impairment

Monitor patients for toxicities and potential drug interactions for an extended period of time following treatment with methylene blue.²⁰⁰ Reduced initial dosage may not be necessary in patients with renal impairment,¹¹⁵ but consider Cl_cr if given by continuous IV infusion^†.¹¹⁵

Cautions for Methylene Blue

Contraindications

• Known hypersensitivity to methylene blue or any thiazine dye.²⁰⁰

• Women who are or may become pregnant.² (See Fetal/Neonatal Morbidity under Cautions.)

• Intraspinal injection.¹

• Known or suspected G-6-PD deficiency.²⁰⁰

Warnings/Precautions

Warnings

Serotonin Syndrome

Serotonin syndrome reported in patients receiving methylene blue concomitantly with serotonergic drugs.^{100 101 200} Avoid concomitant use of methylene blue and serotonergic drugs (e.g., SSRIs, SNRIs, MAO inhibitors, bupropion, buspirone, clomipramine, mirtazapine).^{100 101 200} (See Boxed Warning.)

Manifestations of serotonin syndrome may include mental changes (e.g., confusion, hyperactivity, memory problems, agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile BP, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or GI symptoms (e.g., nausea, vomiting, diarrhea).^{100 200}

Most cases of serotonin syndrome occurred when methylene blue was used as a diagnostic (visualizing) dye^† (1–8 mg/kg IV) during parathyroid surgery in patients receiving a serotonergic drug; unclear whether there is a risk when methylene blue administered by other routes or in lower IV doses.¹⁰¹ Most cases occurred in patients receiving an SSRI (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), SNRI (e.g., desvenlafaxine, duloxetine, venlafaxine), or clomipramine.^{2 100 101} Not reported to date with concomitant use of vilazodone, but risk is considered comparable to that with SSRIs.¹⁰¹

FDA has not concluded whether concomitant use of methylene blue and other drugs with lesser degrees of serotonergic activity, including tricyclic antidepressants (amitriptyline, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine), MAO inhibitors (isocarboxazid, phenelzine, transdermal selegiline, tranylcypromine), amoxapine, bupropion, buspirone, maprotiline, mirtazapine, nefazodone, or trazodone, is associated with a risk of serotonin syndrome comparable to that reported when methylene blue is used concomitantly with SSRIs or SNRIs.¹⁰¹

Methylene blue generally should not be used in patients receiving serotonergic drugs.^{100 200} FDA states that certain emergency situations (e.g., methemoglobinemia, ifosfamide-induced encephalopathy^†) may necessitate immediate methylene blue treatment in a patient receiving a serotonergic drug.¹⁰⁰ In such situations, consider availability of alternative interventions and weigh benefits of methylene blue against risk of serotonin syndrome.¹⁰⁰ If methylene blue is initiated, immediately discontinue the serotonergic drug, use the lowest possible dose of methylene blue, and monitor the patient for CNS effects.^{100 200} (See Specific Drugs and Laboratory Tests under Interactions.)

Sensitivity Reactions

Hypersensitivity, manifested as wheal and flare reactions at injection site, reported.¹¹⁴

Severe hypersensitivity reactions (e.g., anaphylaxis, generalized urticaria, hypotension, tachycardia, bronchospasm) reported following administration of methylene blue.^{104 105 114 200}

Discontinue drug and initiate appropriate supportive care if anaphylaxis or other severe hypersensitivity reactions occur.²⁰⁰ Epinephrine and other appropriate agents and equipment should be available for immediate use in such cases.¹⁰⁵

Other Warnings and Precautions

Fetal/Neonatal Morbidity

Potentially teratogenic;²⁰⁴ may cause fetal harm if used during pregnancy, especially during second and third trimesters.^{9 141 143 144 145 146 200 207}

Use in amniocentesis has been associated with intestinal atresia (e.g., ileum and jejunum),^{200 204} ileal occlusion, and other adverse effects in neonates.^{9 200} (See Pediatric Use under Cautions.)

Contraindicated in women who are or may become pregnant;² if used during pregnancy or if patient becomes pregnant, apprise patient of potential fetal hazard.²⁰⁰

Hematologic Effects

Hemolysis and hemolytic anemia may occur,^{9 113 200} especially in young infants^{9 115 142} and patients with G-6-PD deficiency.^{113 115} Use lowest effective number of doses of methylene blue during treatment; onset of anemia may be delayed ≥1 days following treatment with methylene blue.²⁰⁰

Because of risk of paradoxical methemoglobinemia and hemolysis,^{200 203} contraindicated in patients with known or suspected G-6-PD deficiency.^{117 200}

High IV dosage or high local concentrations may cause formation of methemoglobin and cyanosis.^{1 9 113 115} To prevent local high concentrations and production of additional methemoglobin, give IV injections slowly and do not exceed recommended dosage.¹ (See Prescribing Limits under Dosage and Administration.)

Long-term administration may result in marked anemia due to accelerated destruction of erythrocytes; frequently monitor hemoglobin concentrations.^a

Effects on Ability to Drive and Use Heavy Machinery

May cause confusion, dizziness, and visual disturbances.²⁰⁰ Advise patient to refrain from engaging in hazardous occupations or activities (e.g., operating heavy machinery, driving) until such effects resolve.²⁰⁰

Administration Precautions

Do not administer by sub-Q^† or intradermal^† injection; adverse skin and tissue reactions (e.g., erythematous macular lesions, superficial ulcers, abscess formation, skin and fat necrosis) at injection site reported.^{107 108}

Do not administer by intrathecal^† injection; neural damage reported.⁹

Imparts blue-green color to saliva, urine, feces, and skin;^{9 115 200} bluish skin discoloration from excessive dosage can be mistaken for methemoglobinemia.¹¹⁵

IV administration: Adverse local effects, including pain,¹¹³ burning sensation,⁹ rash,⁹ necrosis,⁹ abscess,⁹ ulceration,⁹ and thrombophlebitis⁹ reported; extravasation has caused tissue necrosis.¹¹³

Oral^†: Adverse GI effects and dysuria reported.⁹

Topical^† application: Skin may become stained; skin stains may be removed by hypochlorite solution.⁹

Specific Populations

Pregnancy

Epidemiologic evidence indicates that methylene blue is a teratogen,²⁰⁴ and the drug can cause fetal harm if administered during pregnancy, especially during the second and third trimesters.^{9 141 143 144 145 146 200 207} (See Fetal/Neonatal Morbidity under Cautions.)

Use during pregnancy has resulted in hemolytic anemia, hyperbilirubinemia, methemoglobinemia, respiratory distress, skin staining, and phototoxicity in neonates.^{9 141 143 144 145 146 200}

Lactation

Not known whether distributed into human milk.²⁰⁰ Due to potential serious adverse reactions in nursing infants, including genotoxicity, discontinue breast-feeding during and for up to 8 days following treatment with methylene blue.²⁰⁰

Pediatric Use

No difference in efficacy relative to adults.²⁰⁰ Hemolysis, hemolytic anemia, hyperbilirubinemia, and phototoxicity reported in neonates and young infants;¹⁴² fatalities reported.¹⁴²

Geriatric Use

No difference in efficacy relative to younger adults.²⁰⁰ Substantially eliminated by kidneys; geriatric patients may have decreased renal function.²⁰⁰ Use lowest number of doses needed to achieve a response.²⁰⁰

Hepatic Impairment

Monitor for toxicities and potential drug interactions for an extended period of time following treatment with methylene blue.²⁰⁰ (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Monitor for toxicities and potential drug interactions for an extended period of time following treatment with methylene blue.²⁰⁰ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Pain in extremity, chromaturia, dysgeusia, feeling hot, dizziness, hyperhidrosis, nausea, skin discoloration, headache.²⁰⁰

Large IV doses: Nausea,^{1 200} vomiting,^{9 200} abdominal pain,^{1 200} precordial pain,^{1 200} dizziness,^{1 200} headache,^{1 200} profuse sweating,¹ dyspnea,^{9 200} hypertension,⁹ mental confusion.^{1 200}

Drug Interactions

Metabolized by CYP1A2, 2C19, and 2D6.²⁰⁰ Inhibits CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, and 3A5.²⁰⁰ Induces CYP1A2, but does not induce CYP2B6 or 3A4 in vitro.²⁰⁰

Substrate for P-glycoprotein (P-gp) ABCB1; inhibitor of P-gp.²⁰⁰

In vitro, mainly undergoes conjugation by UGT enzymes including 1A4 and 1A9.²⁰⁰ Inhibits UGT1A9 and 1A4 in vitro.²⁰⁰ Does not substantially inhibit UGT1A1, 1A3, 1A6, 2B7, or 2B15.²⁰⁰

Not a substrate for or inhibitor of breast cancer resistance protein (BCRP).²⁰⁰ Not an inhibitor of organic anion transporter (OAT) 1, 3, 1B1, or 1B3 in vitro.²⁰⁰

Not a substrate for organic cation transporter (OCT) 2 in vitro.²⁰⁰ Inhibits OCT2, multidrug and toxin extrusion protein (MATE) 1, and MATE2-K in vitro.²⁰⁰

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, and 3A5: Pharmacokinetic interactions possible with drugs having a narrow therapeutic index.²⁰⁰ Data regarding clinical relevance of these in vitro interactions lacking.²⁰⁰

Drugs Affected by P-glycoprotein Transport

Substrates of P-gp: Systemic exposure may be affected; clinical relevance unknown.²⁰⁰

Drugs Affected by UGT

Substrates of UGT1A9 and 1A4: Systemic exposure may be affected; clinical relevance unknown.²⁰⁰

Drugs Affected by Other Membrane Transporters

Substrates of OCT2, MATE1, and MATE2-K: Systemic exposure may be affected; clinical relevance unknown.²⁰⁰

Specific Drugs and Laboratory Tests

Methylene Blue Pharmacokinetics

Absorption

Bioavailability

Well absorbed from GI tract; peak plasma concentrations occur approximately 1–2 hours after an oral dose.⁹

Oral absorption may be too slow and inconsistent for treatment of severe methemoglobinemia; IV administration necessary.¹¹³

Elimination

Metabolism

Following distribution into tissues, rapidly reduced to leukomethylene blue (leukomethylthioninium chloride).⁹

Metabolism to leukomethylene blue may be less efficient in neonates than in older individuals.⁹

Elimination Route

Excreted in urine and bile.^a Approximately 40% of methylene blue is excreted into urine unchanged.²⁰⁰

On exposure to air, urine turns green or blue due to presence of oxidation product methylene azure (methylene blue sulfone).^a

Half-life

IV administration: Estimated half-life is 5–24 hours.^{9 132 200 209 210}

Stability

Storage

Parenteral

Solution for IV Use

20–25°C; do not refrigerate or freeze.^{1 200} Store in original carton to protect from light.²⁰⁰

Actions

• Low concentrations accelerate rate of conversion of methemoglobin to hemoglobin.^{1 2}

• High concentrations convert ferrous iron of reduced hemoglobin to ferric iron, resulting in methemoglobin formation.¹

• Acts as a photosensitizer when used in conjunction with light (photodynamic therapy);¹²⁶ exact mechanism unclear.¹²⁶ When activated by specific wavelengths of light, may act as a strong oxidizer to destroy targeted cells through cellular damage, altered membrane permeability, or protein inactivation.^{126 133} In vitro, exposure of Candida albicans to methylene blue and laser light resulted in increased membrane permeability and decreased yeast growth.¹³³ Appears to bind irreversibly to viral nucleic acid and cause disruption of the virus molecule upon exposure to light.^a

• Has in vitro activity against Plasmodium falciparum, including strains with reduced susceptibility to chloroquine, quinine, monodesethylamodiaquine (active metabolite of amodiaquine; not commercially available in US), and mefloquine;^{136 137 138 140} clinical importance unclear.^{136 137 138 140} (See Specific Drugs under Interactions.)

• Possesses weak antiseptic properties.^a

• Directly inhibits calcium binding by oxalate and by organic stone matrix.^a Acts as a crystal poison at the interface, reducing tendency of calcium oxalate particles to aggregate.^a In addition, reverses intracellular acidosis (such as that in renal tubule acidosis), apparently by competing with diphosphopyridine nucleotide as a hydrogen receptor.^a

Advice to Patients

• Advise patients of the potential risk of serotonin syndrome, particularly if methylene blue is used concomitantly with SSRIs, SNRIs, MAO inhibitors, tricyclic antidepressants, or other serotonergic drugs.^{100 200} Importance of immediately contacting clinician if signs or symptoms of serotonin syndrome develop (e.g., confusion, hyperactivity, memory problems, muscle twitching, excessive sweating, shivering, shaking, diarrhea, loss of coordination, fever).^{100 200} Importance of not discontinuing serotonergic drugs without first consulting clinician.¹⁰⁰

• Advise patients that saliva, urine, feces, and skin may have a blue-green discoloration.^{9 115} If administered by topical^† application, advise patients that skin may become stained; skin stains may be removed by hypochlorite solution.⁹

• Risk of phototoxicity.²⁰⁰ Advise patients to take protective measures against exposure to light.²⁰⁰

• Risk of confusion, dizziness, and vision disturbances.²⁰⁰ Advise patients to avoid driving and operating machinery during treatment with methylene blue.²⁰⁰

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 2} Advise pregnant women of risk to the fetus.²⁰⁰ (See Fetal/Neonatal Morbidity under Cautions.) Advise patients to discontinue breast-feeding for up to 8 days following treatment with methylene blue.²⁰⁰

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.^a

• Importance of informing patients of other important precautionary information.^{1 2} (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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