VA Class: AD200
Molecular Formula: C16H18CIN3S.3H2O
CAS Number: 7220-79-3
Uses for Methylene Blue
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
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 (See Hematologic Effects under Cautions.)
Has been used for treatment of cyanosis in patients with congenital methemoglobinemia† related to cytochrome b5 reductase deficiency;115 117 129 130 131 ineffective in patients with hemoglobin M (abnormal hemoglobin molecules).115 117 131
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† 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
Has been used as a photosensitizer for photodynamic therapy† (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†;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
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
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
Rate of Administration
Cautions for Methylene Blue
Known hypersensitivity to methylene blue.2
Women who are or may become pregnant.2 (See Fetal/Neonatal Morbidity under Warnings/Precautions.)
Contraindicated in women who are or may become pregnant; if used during pregnancy or if patient becomes pregnant, apprise patient of potential fetal hazard.2
Serotonin syndrome reported in patients receiving methylene blue concomitantly with serotonergic drugs.2 100 101 Signs and symptoms of serotonin syndrome include mental changes (confusion, hyperactivity, memory problems), muscle twitching, excessive sweating, shivering, shaking, diarrhea, loss of coordination, and/or fever.100
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.2 100 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.100 (See Serotonergic Drugs under Interactions.)
High IV dosage or high local concentrations may cause formation of methemoglobin and cyanosis.1 2 9 113 115 To prevent local high concentrations and production of additional methemoglobin, give IV injections slowly and do not exceed recommended dosage.1 2 (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
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 (See Contraindications under Cautions.)
Hypersensitivity, manifested as wheal and flare reactions at injection site, reported.114
Epinephrine and other appropriate agents and equipment should be available for immediate use in case anaphylactic reaction occurs.105
Category X.2 (See Fetal/Neonatal Morbidity under Cautions.)
Use with caution in patients with severe renal impairment.2 (See Renal Impairment under Dosage and Administration.)
Common Adverse Effects
Interactions for Methylene Blue
Artemisinin, artemether, or artesunate: In vitro evidence of synergistic antimalarial effects against Plasmodium falciparum138
Mefloquine or quinine: In vitro evidence of additive antimalarial effects against P. falciparum138
Chloroquine or pyrimethamine: In vitro evidence of antagonistic antimalarial effects against P. falciparum138
Clinical importance unclear138
MAO inhibitors (isocarboxazid, phenelzine, transdermal selegiline, tranylcypromine)
Serotonergic drugs (SSRIs, SNRIs, tricyclic antidepressants, amoxapine, bupropion, buspirone, maprotiline, mirtazapine, nefazodone, trazodone, vilazodone)
Do not use concurrently;2 100 in certain emergency situations that necessitate immediate use of methylene blue (e.g., methemoglobinemia, ifosfamide-induced encephalopathy†) in patient receiving a serotonergic drug, consider availability of alternative interventions and weigh benefits of methylene blue against risk of serotonin syndrome100
If emergency use of methylene blue is considered necessary, immediately discontinue the serotonergic drug; monitor closely for symptoms of CNS toxicity (e.g., mental changes, muscle twitching, excessive sweating, shivering/shaking, diarrhea, loss of coordination, fever) for 2 weeks (5 weeks if patient was receiving fluoxetine) or until 24 hours after last methylene blue dose, whichever comes first100
If nonemergency use of methylene blue is planned, withhold the serotonergic drug for at least 2 weeks (5 weeks if patient was receiving fluoxetine) prior to administering methylene blue;100 serotonergic drug may be resumed 24 hours after last methylene blue dose100
Do not initiate serotonergic drug in patient receiving methylene blue; when necessary, initiate 24 hours after last methylene blue dose100
Methylene Blue Pharmacokinetics
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
Following distribution into tissues, rapidly reduced to leukomethylene blue (leucomethylthioninium chloride).9
Metabolism to leucomethylene blue may be less efficient in neonates than in older individuals.9
On exposure to air, urine turns green or blue due to presence of oxidation product methylene azure (methylene blue sulfone).a
Some unchanged drug also excreted in urine.a
Solution for IV Use
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 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 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
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.a
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Injection, for IV use
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2013, Selected Revisions April 20, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
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a. AHFS Drug Information 2013. McEvoy GK, ed. Methylene Blue. Bethesda, MD: American Society of Health-System Pharmacists; 2013: .
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