AHFS Class:

• Methemoglobinemia antidote 91:04.16

Generic Name(s):

• Methylene Blue

Methylene blue, an oxidation-reduction agent, is a thiazine dye that accelerates conversion of methemoglobin to hemoglobin.9,113,115,200

Methemoglobinemia

Methylene blue is used for the treatment of acquired methemoglobinemia1,200 and has been designated an orphan drug by the US Food and Drug Administration (FDA) for this use.201 Because methylene blue was introduced into the US market before 1962 without an approved new drug application (NDA), some commercially available preparations of the drug may not be FDA-labeled.1,113,205

The accelerated approval of methylene blue (Provayblue^®) for the treatment of acquired methemoglobinemia is based on data from retrospective chart reviews and case reports demonstrating a reduction of at least 50% in methemoglobin within 1 hour following IV administration of Provayblue^® or a bioequivalent formulation.200 Continued FDA approval of Provayblue^® for this indication may be contingent upon verification of clinical benefits in future clinical studies.200

Methylene blue has been used for methemoglobinemia associated with certain drugs (e.g., dapsone, benzocaine, lidocaine),117,118 occupational or other exposures to toxic chemicals (e.g., hydrazine, aniline and other amine-substituted benzenes, chloronitrobenzene and other 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 an 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

Methylene blue will not reverse methemoglobinemia in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency,9,113,115,117 and may induce or exacerbate hemolysis in these patients.113,115 Due to the risk of hemolytic anemia, methylene blue is contraindicated in patients with G-6-PD deficiency.200 (See Cautions: Adverse Effects and also see Cautions: Precautions and Contraindications.)

Methylene blue has been used for the treatment of cyanosis in patients with congenital methemoglobinemia† related to cytochrome b₅ reductase deficiency,115,117,129,130,131 but is ineffective in patients with hemoglobin M (abnormal hemoglobin molecules).115,117,131 Methylene blue has been designated an orphan drug by FDA for the treatment of congenital methemoglobinemia.201

Methylene blue is not effective for the treatment of sulfhemoglobinemia.115,131

Ifosfamide-induced Encephalopathy

Methylene blue has been used in the management of ifosfamide-induced encephalopathy†.102 Although methylene blue has resulted in rapid improvement in CNS function in some patients, beneficial effects have not been consistently reported and further clinical studies are needed to establish the role of the drug in the management of ifosfamide-induced encephalopathy.102 Methylene blue does not appear to be effective when used prophylactically in an attempt to prevent ifosfamide-associated encephalopathy.102,103

Use as a Dye

Methylene blue is used as a bacteriologic stain, as an indicator dye, and for surgical and medical marking.

Methylene blue has been administered by local injection or instillation† as a 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 gastroesophageal reflux disease (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

Although further study is needed to evaluate safety and efficacy, methylene blue has been used topically† as a photosensitizer for photodynamic therapy† (PDT) in the 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

Although methylene blue was used in the past as an antidote for cyanide poisoning†,113 it is no longer recommended for this use.9 Cyanide poisoning usually is treated with an antidote regimen consisting of amyl nitrite, sodium nitrite, and sodium thiosulfate or with hydroxocobalamin.115,119 When sodium nitrite is used for cyanide poisoning, methylene blue should not be used in an attempt to treat excessive methemoglobinemia induced by the antidote because reduced cyanide binding and increased toxicity occurs.9

Methylene blue is of no value in the treatment of carbon monoxide poisoning.

Cystitis and Urethritis

Methylene blue was used in the past as a mild urinary antiseptic and stimulant to mucous surfaces in the treatment of cystitis and urethritis†, but is no longer recommended for this use.

Urolithiasis

Methylene blue has been used alone and in combination with ascorbic acid for the management of chronic urolithiasis†. Although methylene blue appears to have some inhibitory effect on the formation of calcium oxalate and calcium phosphate crystals in some patients, the drug is not currently recommended for this use and is ineffective in dissolving previously formed stones.

Administration

Methylene blue is administered by slow IV injection over a period of several minutes (e.g., 5-30 minutes);200 high local concentrations of the drug should be avoided.1 (See Cautions: Adverse Effects.) Methylene blue also has been given by IV infusion†.9,113,115,118 The manufacturer of the commercially available 5-mg/mL solution for IV use (Provayblue^®) states that the drug may be diluted, if desired, in 50 mL of 5% dextrose injection to avoid local pain, particularly in pediatric patients.200 While methylene blue has been diluted in 0.9% sodium chloride injection,9,113 some manufacturers recommend against this because chloride reduces the solubility of methylene blue.200 Methylene blue IV solutions should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.200 The diluted solution of the drug should be used immediately after preparation.200

Methylene blue has been administered orally†,9,102,113,117,139 but oral preparations are no longer commercially available in the US. It has been suggested that an oral solution can be 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

When used as a diagnostic (visualizing) dye†, methylene blue has been administered by local instillation or injection†.9,104,105,120,121,122,123,124 In addition, methylene blue has been administered topically† for photodynamic therapy† (PDT).9,125,126,127,128,134,135 (See Cautions: Adverse Effects.)

Methylene blue should not be administered by subcutaneous, intrathecal, or intraspinal injection.1,200 (See Cautions: Precautions and Contraindications.)

Vital signs, electrocardiogram (ECG), and methemoglobin concentrations should be monitored during treatment with methylene blue and through resolution of methemoglobinemia.200

Dosage

Acquired Methemoglobinemia

For the treatment of methemoglobinemia in adults or children, the recommended dosage of methylene blue is 1 mg/kg administered by IV injection over 5-30 minutes.200 Alternatively, dosages of 1-2 mg/kg given by slow IV injection over a few minutes (usually 3-10 minutes) have been used.1,9,113,115,116,117 Symptomatic improvement usually occurs within 30 minutes.113,115 The recommended IV dose may be repeated after 1 hour, if required (i.e., methemoglobin concentration remains greater than 30% or clinical manifestations of methemoglobinemia persist).9,113,116,200 Alternatively, some clinicians state that a repeat dose may be administered after 30 minutes, if required.9,115,117

Some manufacturers state that if methemoglobinemia does not resolve after 2 doses of methylene blue, or if methemoglobinemia rebounds after a response, alternative treatment should be considered.200

Some manufacturers recommend a maximum IV dosage of 2 mg/kg of methylene blue.1 Additionally, some experts recommend a maximum total dose of 5-7 mg/kg during the first few hours of treatment.9,115

Ifosfamide-induced Encephalopathy

For the management of ifosfamide-induced encephalopathy†, 50 mg of methylene blue has been given by slow IV injection over at least 5 minutes; 1-6 doses have been given daily until symptoms resolved.102

Adverse Effects

Adverse effects reported in at least 10% of healthy individuals who received a single 2-mg/kg IV dose of the FDA-labeled methylene blue preparation include pain in extremity,200 chromaturia,200 dysgeusia,200 feeling hot,200 dizziness,200 hyperhidrosis,200 nausea,200 skin discoloration,200 and headache.200

Adverse effects reported in patients receiving large IV doses of methylene blue include 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 and mental confusion.1,200 Urinary tract irritation also may occur with large IV doses.9

Methylene blue is a potent inhibitor of monoamine oxidase (MAO),2,109 and may cause potentially fatal serotonin toxicity (serotonin syndrome) if used concomitantly with serotonergic drugs (e.g., selective serotonin-reuptake inhibitors [SSRIs], selective serotonin- and norepinephrine-reuptake inhibitors [SNRIs], MAO inhibitors).100,101,200 Additionally, in vitro studies cannot rule out the inhibition of cytochrome P-450 (CYP) isoenzyme 2D6 by methylene blue as a possible contributor to serotonin syndrome.200 Manifestations of serotonin syndrome may include mental changes (e.g., confusion, hyperactivity, memory problems, agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, 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 Patients who receive treatment with methylene blue should be monitored for the emergence of serotonin syndrome; methylene blue should be discontinued and supportive treatment initiated if such a reaction occurs.200 (See Drug Interactions: Serotonergic Drugs.)

High IV dosage or high local concentrations of methylene blue may cause formation of methemoglobin and cyanosis.1,9,113,115

Hemolysis and hemolytic anemia requiring red blood cell transfusions can occur with methylene blue therapy,9,113,200 especially in young infants9,115,142 and patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.113,115,200 (See Cautions: Precautions and Contraindications.) Laboratory data may show a negative Coombs' test but with Heinz body formation, elevated indirect bilirubin, and low haptoglobin.200 The lowest effective number of doses of methylene blue should be used during treatment; the onset of anemia may be delayed one or more days following treatment with methylene blue.200 Methylene blue should be discontinued and alternative treatment options considered if severe hemolysis occurs.200

Hypersensitivity, manifested as wheal and flare reactions at the injection site, has been reported.114 Severe hypersensitivity reactions, including anaphylaxis, generalized urticaria, and hypotension, tachycardia, and bronchospasm, have been reported following administration of methylene blue.104,105,114,200 The drug should be discontinued and appropriate supportive care initiated if anaphylaxis or other severe hypersensitivity reactions occur.200

Methylene blue imparts a blue-green color to saliva, urine, feces, and skin.9,115,200 Bluish skin discoloration from excessive methylene blue dosage can be mistaken for methemoglobinemia.115 Phototoxicity has been reported in patients receiving methylene blue.142,200,202

Methylene blue may cause confusion, dizziness, and visual disturbances.200 Patients should be advised to refrain from engaging in hazardous occupations or activities (e.g., operating heavy machinery, driving) until such adverse reactions resolve.200

IV administration of methylene blue has caused adverse local effects, including pain,113 burning sensation,9 rash,9 necrosis,9 abscess,9 ulceration,9 and thrombophlebitis;9 extravasation has caused tissue necrosis.113

Oral† administration of methylene blue has caused adverse GI effects and dysuria.9

Topical† application of methylene blue may stain the skin; skin stains may be removed by hypochlorite solution.9

Subcutaneous† or intradermal injection† of methylene blue has caused adverse skin and tissue reactions (e.g., erythematous macular lesions, superficial ulcers, abscess formation, skin and fat necrosis) at the injection site.107,108 (See Cautions: Precautions and Contraindications.)

Intrathecal† injection of the drug has caused neural damage.9 (See Cautions: Precautions and Contraindications.)

Precautions and Contraindications

To prevent local high concentrations of methylene blue and production of additional methemoglobin (see Cautions: Adverse Effects). IV injections must be made very slowly and recommended dosage should not be exceeded.1 (See Dosage and Administration.)

Long-term administration of methylene blue may result in marked anemia due to accelerated destruction of erythrocytes; hemoglobin concentrations should be checked frequently.

Patients with any degree of renal or hepatic impairment should be monitored for toxicities and potential drug interactions for an extended period of time following treatment with methylene blue.200 Some clinicians suggest that initial dosage may not need to be reduced when methylene blue is used for the treatment of methemoglobinemia in patients with renal impairment, but the patient's creatinine clearance should be considered if the drug is given by continuous IV infusion†.115

Some manufacturers state that additional treatment options should be considered in patients with methemoglobinemia caused by aryl amines (e.g., aniline) or sulfa drugs (e.g., dapsone) that does not resolve or that rebounds after initial response.200 (See Dosage and Administration: Dosage.)

Because of the risk of serotonin syndrome, methylene blue generally should not be used in patients receiving serotonergic drugs.100,200 (See Drug Interactions: Serotonergic Drugs.)

Some manufacturers state that methylene blue is contraindicated in women who are or may become pregnant.2 (See Pregnancy under Cautions: Pregnancy and Lactation.)

Because of the risk of paradoxical methemoglobinemia and hemolysis,200,203 methylene blue is contraindicated in patients with known or suspected G-6-PD deficiency.200

Methylene blue is contraindicated in patients with known hypersensitivity to the drug or any other thiazine dye.200 Epinephrine and other appropriate agents and equipment should be available for immediate use in case an anaphylactic reaction occurs.105

Intraspinal injection of methylene blue is contraindicated.1 Methylene blue also should not be administered by subcutaneous or intrathecal injection.1,200 (See Cautions: Adverse Effects.)

Pediatric Precautions

Safety and efficacy of methylene blue have been established by data from retrospective case series that included 14 pediatric patients who were treated for methemoglobinemia.200 The efficacy outcomes (i.e., reduction in methemoglobin by at least 50% within 1 hour after drug administration) in all pediatric age groups (neonates, infants, children, and adolescents) were similar to those seen in adults.200 However, use of methylene blue in neonates and young infants has caused hemolysis, hemolytic anemia, hyperbilirubinemia, and phototoxicity; fatalities have been reported.142

Geriatric Precautions

Analysis of a retrospective cases series that included 8 patients 65 years of age or older revealed similar efficacy of methylene blue among geriatric and younger individuals.200 Methylene blue is known to be substantially excreted by the kidneys and the risk of methylene blue-induced adverse effects may be increased in patients with impaired renal function.200 Because geriatric patients may have decreased renal function, use of methylene blue in these patients should employ the lowest number of doses needed to achieve a response.200

Pregnancy and Lactation

Pregnancy

Some manufacturers have stated that methylene blue is contraindicated in women who are or may become pregnant.2 There is epidemiologic evidence that methylene blue is a teratogen204 and can cause fetal harm if administered during pregnancy, especially during the second and third trimesters.9,141,143,144,145,146,200,207 Use of methylene blue 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 Intra-amniotic injection of methylene blue to detect ruptured membranes should be avoided.207

Use of methylene blue during pregnancy has resulted in hemolytic anemia, hyperbilirubinemia, methemoglobinemia, respiratory distress, skin staining, and phototoxicity in neonates.9,141,143,144,145,146,200 If methylene blue is administered to a pregnant woman at term, the neonate should be observed for such adverse effects and appropriate supportive care instituted if needed.200

If methylene blue is used during pregnancy or if the patient becomes pregnant, the patient should be apprised of the potential fetal hazard.200

Lactation

It is not known whether methylene blue is distributed into human milk.200 Because of the potential for serious adverse reactions in nursing infants to methylene blue, including genotoxicity, some manufacturers state that breast-feeding should be discontinued during and for up to 8 days following treatment with methylene blue.200

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Methylene blue is metabolized by cytochrome P-450 (CYP) isoenzymes 1A2, 2C19, and 2D6 in vitro, but the predominant in vitro metabolic pathway appears to be uridine diphosphate-glucuronosyltransferase (UGT)-mediated conjugation.200 (See Drug Interactions: Drugs Affecting or Affected by Uridine Diphosphate-glucuronosyltransferase.) Methylene blue is an inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, and 3A5.200 Pharmacokinetic interactions may be more pronounced with drugs having a narrow therapeutic index (e.g., alfentanil, cyclosporine, digoxin, dihydroergotamine, ergotamine, fentanyl, phenytoin, pimozide, quinidine, sirolimus, tacrolimus) that are metabolized by these enzymes.200 Methylene blue also induces CYP1A2, but does not induce CYP2B6 or 3A4 in vitro.200 The clinical relevance of these in vitro interactions is unknown.200

Drugs Affecting or Affected by P-glycoprotein Transport

Methylene blue is a substrate for P-glycoprotein (P-gp) ABCB1 and an inhibitor of P-gp.200 The clinical relevance of these findings is unknown; systemic exposure of drugs that are substrates of P-gp may be affected.200

Drugs Affecting or Affected by Uridine Diphosphate-glucuronosyltransferase

In vitro, methylene blue mainly undergoes conjugation by UGT enzymes including 1A4 and 1A9.200 Methylene blue inhibits UGT1A4 and 1A9 in vitro.200 The drug does not substantially inhibit UGT1A1, 1A3, 1A6, 2B7, or 2B15.200 The clinical relevance of these findings is unknown; systemic exposure of drugs that are substrates of UGT1A4 or 1A9 may be affected.200

Drugs Affecting or Affected by Other Membrane Transporters

Methylene blue is neither a substrate for, nor an inhibitor of, breast cancer resistance protein (BCRP).200 In vitro, the drug is not an inhibitor of organic anion transporter (OAT) 1, 3, 1B1, or 1B3.200

Methylene blue is not a substrate for organic cation transporter (OCT) 2 in vitro.200 Methylene blue inhibits OCT2, multidrug and toxin extrusion protein (MATE) 1, and MATE2-K in vitro.200 The clinical relevance of these findings is unknown; systemic exposure of drugs that are substrates of these transporters may be affected.200 The OCT2/MATE pathway for renal transport may have an important role in the elimination of several substances, including metformin, cimetidine, acyclovir, and creatinine.200

Antimalarial Agents

Although the clinical importance is unclear, in vitro studies indicate that the antimalarial effects of methylene blue and artemisinin, artemether, or artesunate are synergistic and the antimalarial effects of methylene blue and mefloquine or quinine are additive against Plasmodium falciparum .138 Antagonism occurred when methylene blue was used with chloroquine or pyrimethamine in vitro.138

Serotonergic Drugs

Concomitant use of methylene blue and serotonergic drugs (e.g., selective serotonin-reuptake inhibitors [SSRIs], selective serotonin- and norepinephrine-reuptake inhibitors [SNRIs], monoamine oxidase [MAO] inhibitors, bupropion, buspirone, clomipramine, mirtazapine) may result in serious adverse CNS effects, including serotonin syndrome, and should be avoided.100,101,200

There have been case reports of serotonin syndrome in patients who received methylene blue while receiving serotonergic drugs, including SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), SNRIs (e.g., desvenlafaxine, duloxetine, venlafaxine), and clomipramine; fatalities have been reported.100,101,200 Most of these cases occurred when methylene blue was used as a diagnostic (visualizing) dye† (1-8 mg/kg IV) during parathyroid surgery; it is unclear whether there is a risk of serotonin syndrome when methylene blue is administered by other routes or in lower IV doses in patients receiving serotonergic drugs.101 While FDA has not received reports of serotonin syndrome with concomitant use of methylene blue and vilazodone, the 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

Because of the risk of serotonin syndrome, 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 use of methylene blue in a patient receiving a serotonergic drug.100 In such emergency situations, the availability of alternative interventions should be considered and the benefits of methylene blue should be weighed against the risk of serotonin syndrome.100 If methylene blue is indicated in such emergency situations, the serotonergic drug must be immediately discontinued and the patient monitored 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 the patient was receiving fluoxetine) or until 24 hours after the last methylene blue dose, whichever comes first.100 Additionally, some manufacturers recommend that the lowest possible dose of methylene blue be used in such circumstances and that patients be closely monitored (i.e., inpatient setting) for CNS effects for up to 4 hours after the administration of methylene blue.200

If nonemergency use of methylene blue is being planned for a patient receiving a serotonergic drug, the serotonergic drug should be withheld for at least 2 weeks (5 weeks if the patient was receiving fluoxetine) prior to initiating methylene blue.100

Treatment with serotonergic drugs should not be used in a patient receiving methylene blue; when necessary, the serotonergic drug may be started or resumed 24 hours after the last methylene blue dose.100 However, some manufacturers recommend that serotonergic drugs not be used within 72 hours after the last dose of methylene blue.200

Laboratory Test Interferences

Methylene blue passes freely into urine and may interfere with the interpretation of urine tests that rely on a blue indicator (e.g., dipstick test for leukocyte esterase).200

The presence of methylene blue in the blood may result in an underestimation of the oxygen saturation reading as determined by pulse oximetry.200 It is recommended that an arterial blood sample be obtained and tested by an alternative method if a measure of oxygen saturation is required during or shortly after administration of methylene blue.200

A decrease in the bispectral index (BIS) has been reported following the administration of methylene blue.200 Alternative methods for assessing depth of anesthesia should be used if methylene blue is administered during surgery.200

Pharmacology

Methylene blue can be reduced to a colorless form, leukomethylene blue; together, these compounds form a reversible oxidation-reduction system. In low concentrations, methylene blue accelerates conversion of methemoglobin to hemoglobin.1,200 In patients with methemoglobinemia, methylene blue is reduced to leukomethylene blue by methemoglobin reductases in erythrocytes; leukomethylene blue then reduces methemoglobin to hemoglobin. In high concentrations, methylene blue oxidizes the ferrous iron of reduced hemoglobin to the ferric state, thereby changing hemoglobin to methemoglobin.1

Although the exact mechanism of activity is unclear, methylene blue acts as a photosensitizer when used in conjunction with light (photodynamic therapy).126 When activated by specific wavelengths of light, the drug may act as a strong oxidizer to destroy targeted cells as the result of 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 Methylene blue appears to bind irreversibly to viral nucleic acid and cause disruption of the virus molecule upon exposure to light.

Although the clinical importance is unclear, methylene blue has in vitro activity against Plasmodium falciparum , including strains with reduced susceptibility to chloroquine, quinine, monodesethylamodiaquine (active metabolite of amodiaquine; not commercially available in the US), and mefloquine.136,137,138,140 (See Drug Interactions: Antimalarial Agents.)

Methylene blue posses weak urinary antiseptic properties. Methylene blue directly inhibits calcium binding by oxalate and by organic stone matrix. The drug also acts as a crystal poison at the interface, reducing the tendency of calcium oxalate particles to aggregate. In addition, it reverses intracellular acidosis (such as that in renal tubule acidosis), apparently by competing with diphosphopyridine nucleotide as a hydrogen receptor.

Pharmacokinetics

Absorption

Methylene blue is well absorbed from the GI tract, and peak plasma concentrations occur approximately 1-2 hours after an oral dose.9 Oral absorption is too slow and inconsistent for the treatment of severe methemoglobinemia; IV administration is necessary.113

Distribution

Methylene blue exhibits concentration-dependent partitioning into blood cells in vitro.200 Following distribution into tissues, methylene blue is rapidly reduced to leukomethylene blue (leukomethylthioninium chloride).9 Metabolism to leukomethylene blue may be less efficient in neonates than in older individuals.9

Elimination

Methylene blue is excreted in urine and bile.9 Approximately 40% of methylene blue is excreted into urine unchanged.200 On exposure to air, the urine turns green or blue due to the presence of the oxidation product methylene azure (methylene blue sulfone).

Following IV administration, the estimated half-life of methylene blue is approximately 5-24 hours.9,132,200,209,210

Chemistry and Stability

Chemistry

Methylene blue is a thiazine dye. The dye occurs as dark green crystals or a crystalline powder, having a bronze-like luster, and may have a slight odor. Methylene blue is soluble in water and sparingly soluble in alcohol, and forms deep blue solutions. Methylene blue injection has a pH of 3-4.5. The pK_a of the drug is reported to be between 0 and -1.

Stability

Commercially available methylene blue 5-mg/mL solution for IV use should be protected from light and stored in the original carton at 20-25°C; the solution should not be refrigerated or frozen.200 Commercially available methylene blue 10-mg/mL solution for IV use should be stored at 20-25°C.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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