Methylene Blue

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Injection:

Generic: 1% (1 mL, 10 mL)

Solution, Intravenous:

ProvayBlue: 50 mg/10 mL (10 mL)

Pharmacology

Mechanism of Action

Methylene blue, in low concentrations, hastens the conversion of methemoglobin to hemoglobin; has opposite effect at high concentrations by converting ferrous ion of reduced hemoglobin to ferric ion to form methemoglobin; in cyanide toxicity, it combines with cyanide to form cyanmethemoglobin preventing the interference of cyanide with the cytochrome system

In the treatment of vasoplegia syndrome, methylene blue may be able to restore vascular tone by a direct inhibitory effect on endothelial nitric oxide synthase (eNOS), and probably inducible NOS (iNOS), by oxidation of enzyme-bound ferrous iron. Methylene blue also blocks the formation of cyclic guanosine monophosphate (cGMP) by inhibiting the guanylate cyclase enzyme through binding to iron in the heme complex and subsequently reducing vasorelaxation (Lenglet 2011).

Pharmacokinetics/Pharmacodynamics

Absorption

Oral: 53% to 97% (Clifton 2003)

Distribution

255 L ± 58 L

Metabolism

Likely undergoes first pass metabolism or distribution; peripheral reduction to leukomethylene blue (Peter 2000)

Excretion

Generic: In bile, feces, and urine (~33% as leukomethylene blue) (Clifton 2003; Peter 2000)

ProvayBlue: Urine (~40% unchanged)

Onset of Action

Reduction of methemoglobin: IV: 30 to 60 minutes (Clifton 2003)

Time to Peak

Oral: 1 to 2 hours (Peter 2000)); IV: 30 minutes (Clifton 2003)

Half-Life Elimination

Not well-defined: 5 to 6.5 hours (Peter 2000); ProvayBlue: ~24 hours

Protein Binding

94%

Use: Labeled Indications

Methemoglobinemia (acquired) (Provayblue only): Treatment of pediatric and adult patients with acquired methemoglobinemia

Methemoglobinemia (drug induced) (generic only): Treatment of drug-induced methemoglobinemia

Use: Off Label

Chromoendoscopy (diagnostic aid)byes

Data from a limited number of patients studied suggest that methylene blue may be beneficial for enhancing diagnostic views during chromoendoscopic procedures (eg, esophageal, gastric, colon) Areia 2008, Ichimasa 2014, Kaminski 2014, Ngamruengphong 2009.

Based on the European Society of Gastrointestinal Endoscopy guidelines for advanced imaging for detection and differentiation of colorectal neoplasia, methylene blue used for enhancing diagnostic views in detection and differentiation of colorectal neoplasia is recommended for the diagnosis of this condition.

Ifosfamide-induced encephalopathy (treatment and prevention)c

Data from a limited number of patients studied suggest that methylene blue may be beneficial for treatment and prevention of ifosfamide-induced encephalopathy Patel 2006, Turner 2003. Additional data may be necessary to further define the role of methylene blue in this condition.

Sentinel lymph node mapping in breast cancer surgeryc

Data from a limited number of patients studied suggest that methylene blue may be beneficial for mapping of sentinel lymph nodes in breast cancer surgery Simmons 2001, Simmons 2003, Thevarajah 2005.

Toenail onychomycosisc

Data from a limited number of patients studied suggest that methylene blue, in conjunction with photodynamic therapy, may be beneficial in the treatment of toenail onychomycosis Figueiredo Souza 2014. Additional data may be necessary to further define the role of methylene blue in this condition.

Vasoplegia syndrome associated with cardiac surgeryb

Data from two prospective clinical trials (one placebo-controlled) in patients with refractory vasoplegia syndrome after cardiopulmonary bypass supports the use of methylene blue for the treatment of vasoplegia syndrome associated with cardiac surgery Leyh 2003, Levin 2004. In the placebo-controlled clinical trial, the use of methylene blue demonstrated a reduction in mortality and morbidity Levin 2004. Of note, in one retrospective single center study, the use of methylene blue (initial bolus, then continuous infusion) was associated with an increase in major morbidity; however, selection bias may have influenced the results Weiner 2013. Additional trials may be necessary to further define the role of methylene blue in the treatment of this condition.

Contraindications

Hypersensitivity to methylene blue or any component of the formulation.

Methylene blue (generic): Pregnancy; women who are or may become pregnant; intraspinal injection and SubQ injection

Provayblue: Hypersensitivity to any other thiazine dye; patients with glucose-6-phosphate dehydrogenase deficiency (G6PD).

Dosage and Administration

Dosing: Adult

Methemoglobinemia (acquired): IV: 1 mg/kg over 5 to 30 minutes, may repeat dose 1 hour later if methemoglobin level remains above 30% or symptoms persist; consider alternative therapy if resolution does not occur after 2 doses

Methemoglobinemia (drug induced): IV: 1 to 2 mg/kg or 25 to 50 mg/m² over several minutes; may be repeated in 1 hour if necessary

Chromoendoscopy (off label use): Topical: 0.1 % to 1% solution sprayed via catheter or directly applied onto gastrointestinal mucosa during procedure (Areia 2008; Ichimasa 2014; Kaminski 2014; Ngamruengphong 2009)

Ifosfamide-induced encephalopathy (off-label use): Oral, IV: Note: Treatment may not be necessary; encephalopathy may improve spontaneously (Patel 2006):

Prevention: 50 mg every 6 to 8 hours (Turner 2003). Additional data may be necessary to further define the role of methylene blue in this condition.

Treatment: 50 mg as a single dose or every 4 to 8 hours until symptoms resolve (Patel 2006; Turner 2003).

Onychomycosis (toenail; off-label use): Topical: 2% solution applied to affected area(s) at 15 day intervals for 6 months; used in conjunction with photodynamic therapy (Figueiredo Souza 2014).

Sentinel node mapping in breast cancer surgery (off-label use): Intraparenchymal: 5 mL of a 1% solution administered once during procedure (Simmons 2001; Simmons 2003; Thevarajah 2005).

Vasoplegia syndrome associated with cardiac surgery (off-label use): IV: 1.5 to 2 mg/kg over 20 to 60 minutes administered once (Levin 2004; Leyh 2003). Note: Improvement of vasoplegia (eg, increased systemic vascular resistance, reduced vasopressor dosage) has been observed within 1 to 2 hours following methylene blue administration. Some have employed the use of continuous infusion (0.5 to 1 mg/kg/hour) after administration of the bolus dose; however, prospective clinical trials are necessary to validate this dosing schema (Grayling 2003; Omar 2014; Weiner 2013).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Products are available in multiple concentrations (0.5% and 1%); use extra precaution when calculating dose volumes.

Methemoglobinemia, acquired (including drug-induced): Infants, Children, and Adolescents: I.O., IV: 1 to 2 mg/kg may be repeated every 30 to 60 minutes if necessary (eg, methemoglobin level >30% or signs and symptoms persist) (Kliegman 2016); consider alternative treatment if no resolution after 2 doses. Intraosseous administration has been reported (Herman 1999; Howland 2015).

Reconstitution

ProvayBlue: Dilution not required. In order to avoid local pain (especially in pediatric patients), may be diluted in 50 mL of D5W. Do not dilute in NS (the solubility of methylene blue is reduced).

Generic: Dilution not required.

For the treatment of ifosfamide-induced encephalopathy treatment (off-label use), case reports cite administering the dose undiluted, diluted in 50 mL NS or D5W, or diluted in 250 mL of D5W to allow for infusions over a longer duration (Patel 2006). However, use caution if diluting in NS due to the potential for precipitation (refer to specific product labeling or a compatibility reference); the manufacturer’s labeling for Provayblue specifically states to avoid diluting in NS because of reduced solubility of methylene blue due to chloride.

Administration

IV:

Generic: Administer undiluted by direct IV injection slowly over several minutes.

ProvayBlue: Administer IV over 5 to 30 minutes; do not administer subcutaneously. May be diluted (in D5W only) prior to administration to avoid pain on injection.

Vesicant; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation.

Extravasation management: If extravasation occurs, stop infusion immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity. Apply dry warm compresses (based on mechanism of extravasation injury) proximal to the injection site (Reynolds 2014).

Nitroglycerin 2% ointment (based on mechanism of extravasation injury): Apply a 1-inch strip of topical nitroglycerin 2% ointment to the site of ischemia (may repeat every 8 hours as necessary) (Reynolds 2014).

If a prolonged or continuous infusion is employed, administration via central line is recommended due to the risk of extravasation injury (Dumbarton 2012).

Ifosfamide-induced encephalopathy (off-label use):

IV: Methylene blue may be administered either undiluted as a slow IV push over at least 5 minutes or diluted and infused over 5 to 30 minutes. Consider concomitant dextrose administration, especially in patients who are hypoglycemic, to ensure efficacy of methylene blue (Patel 2006).

Oral: Administer mixed in fruit juice to mask the taste (Patel 2006).

Topical: When used as a diagnostic aid (off-label), spray or directly apply solution to the affected mucosa; methylene blue is used in conjunction with other preparatory methods (procedure-dependent) (Areia 2008; Ichimasa 2014; Kaminski 2014; Ngamruengphong 2009). When used for the treatment of onychomycosis (off-label), apply to affected area and wait 3 minutes for the solution to soak in followed by photodynamic therapy (Figueiredo Souza 2014).

Intraparenchymal (off-label route): Administer as an injection directly into nodal tissue (Simmons 2001; Simmons 2003; Thevarajah 2005).

Do NOT administer subcutaneously or intrathecally.

Storage

ProvayBlue: Store at 20°C to 25°C (68°F to 77°F); do not refrigerate or freeze. Store in original package to protect from light. Solutions diluted in D5W should be used immediately after preparation.

Generic: Store at 20°C to 25°C (68°F to 77°F).

Drug Interactions

Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy

Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Alcohol (Ethyl): May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Avoid combination

Alosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Alpha-/Beta-Agonists (Indirect-Acting): Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Alpha-/Beta-Agonists (Indirect-Acting). While linezolid is expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to linezolid specific monographs for details. Avoid combination

Alpha1-Agonists: Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Alpha1-Agonists. While linezolid is expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to linezolid specific monographs for details. Avoid combination

Amantadine: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. Monitor therapy

Amphetamines: Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Amphetamines. While linezolid and tedizolid may interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Avoid combination

Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Monitor therapy

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Exceptions: Alosetron; Ondansetron; Ramosetron. Monitor therapy

Antipsychotic Agents: Serotonergic Agents (High Risk) may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Monitor therapy

Apraclonidine: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Apraclonidine. Monoamine Oxidase Inhibitors may increase the serum concentration of Apraclonidine. Avoid combination

AtoMOXetine: Monoamine Oxidase Inhibitors may enhance the neurotoxic (central) effect of AtoMOXetine. Avoid combination

Atropine (Ophthalmic): Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Atropine (Ophthalmic). Avoid combination

Benzhydrocodone: May enhance the serotonergic effect of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Management: The use of benzhydrocodone is not recommended for patients taking monoamine oxidase inhibitors (MAOIs) or within 14 days of MAOI discontinuation. Consider therapy modification

Beta2-Agonists: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Beta2-Agonists. Monitor therapy

Betahistine: Monoamine Oxidase Inhibitors may increase the serum concentration of Betahistine. Monitor therapy

Bezafibrate: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Bezafibrate. Avoid combination

Blood Glucose Lowering Agents: Monoamine Oxidase Inhibitors may enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Botulinum Toxin-Containing Products: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

Brimonidine (Ophthalmic): Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Brimonidine (Ophthalmic). Monoamine Oxidase Inhibitors may increase the serum concentration of Brimonidine (Ophthalmic). Monitor therapy

Brimonidine (Topical): Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Brimonidine (Topical). Monoamine Oxidase Inhibitors may increase the serum concentration of Brimonidine (Topical). Monitor therapy

Buprenorphine: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Avoid combination

BuPROPion: Monoamine Oxidase Inhibitors may enhance the hypertensive effect of BuPROPion. Avoid combination

BusPIRone: May enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Avoid combination

Cannabinoid-Containing Products: Anticholinergic Agents may enhance the tachycardic effect of Cannabinoid-Containing Products. Exceptions: Cannabidiol. Monitor therapy

CarBAMazepine: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Management: Avoid concurrent use of carbamazepine during, or within 14 days of discontinuing, treatment with a monoamine oxidase inhibitor. Avoid combination

Cerebrolysin: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Monitor therapy

Chloral Betaine: May enhance the adverse/toxic effect of Anticholinergic Agents. Monitor therapy

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Monitor therapy

Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Avoid combination

Clemastine: Monoamine Oxidase Inhibitors may enhance the anticholinergic effect of Clemastine. Monitor therapy

Cocaine (Topical): May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Monitor therapy

Codeine: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Codeine. Avoid combination

COMT Inhibitors: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Consider therapy modification

Cyclobenzaprine: May enhance the serotonergic effect of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Avoid combination

Cyproheptadine: Monoamine Oxidase Inhibitors may enhance the anticholinergic effect of Cyproheptadine. Cyproheptadine may diminish the serotonergic effect of Monoamine Oxidase Inhibitors. Avoid combination

Dapoxetine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Do not use serotonergic agents (high risk) with dapoxetine or within 7 days of serotonergic agent discontinuation. Do not use dapoxetine within 14 days of monoamine oxidase inhibitor use. Dapoxetine labeling lists this combination as contraindicated. Avoid combination

Deutetrabenazine: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Deutetrabenazine. Avoid combination

Dexmethylphenidate: Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Dexmethylphenidate. Avoid combination

Dextromethorphan: Monoamine Oxidase Inhibitors may enhance the serotonergic effect of Dextromethorphan. This may cause serotonin syndrome. Avoid combination

Diethylpropion: Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Diethylpropion. Avoid combination

Dihydrocodeine: May enhance the serotonergic effect of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Monitor therapy

Diphenoxylate: May enhance the hypertensive effect of Monoamine Oxidase Inhibitors. Avoid combination

Domperidone: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Domperidone. Monoamine Oxidase Inhibitors may diminish the therapeutic effect of Domperidone. Domperidone may diminish the therapeutic effect of Monoamine Oxidase Inhibitors. Monitor therapy

DOPamine: Monoamine Oxidase Inhibitors may enhance the hypertensive effect of DOPamine. Management: Initiate dopamine at no greater than one-tenth (1/10) of the usual dose in patients who are taking (or have taken within the last 2 to 3 weeks) monoamine oxidase inhibitors. Monitor for an exaggerated hypertensive response to dopamine. Consider therapy modification

Doxapram: Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Doxapram. Monitor therapy

Doxylamine: Monoamine Oxidase Inhibitors may enhance the anticholinergic effect of Doxylamine. Management: The US manufacturer of Diclegis (doxylamine/pyridoxine) and the manufacturers of Canadian doxylamine products specifically lists use with monoamine oxidase inhibitors as contraindicated. Monitor therapy

Droxidopa: Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Droxidopa. Avoid combination

Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Avoid combination

EPINEPHrine (Nasal): Monoamine Oxidase Inhibitors may enhance the hypertensive effect of EPINEPHrine (Nasal). Monitor therapy

EPINEPHrine (Oral Inhalation): Monoamine Oxidase Inhibitors may enhance the hypertensive effect of EPINEPHrine (Oral Inhalation). Avoid combination

Epinephrine (Racemic): Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Epinephrine (Racemic). Monitor therapy

EPINEPHrine (Systemic): Monoamine Oxidase Inhibitors may enhance the hypertensive effect of EPINEPHrine (Systemic). Monitor therapy

Ergot Derivatives: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Exceptions: Nicergoline. Monitor therapy

Esketamine: May enhance the hypertensive effect of Monoamine Oxidase Inhibitors. Monitor therapy

Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Monitor therapy

Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Avoid combination

Glycopyrronium (Topical): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Guanethidine: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Avoid combination

Heroin: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Heroin. Avoid combination

HYDROcodone: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of HYDROcodone. Management: Consider alternatives to this combination when possible. Consider therapy modification

HYDROmorphone: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of HYDROmorphone. Avoid combination

Indoramin: Monoamine Oxidase Inhibitors may enhance the hypotensive effect of Indoramin. Avoid combination

Iobenguane Radiopharmaceutical Products: Monoamine Oxidase Inhibitors may diminish the therapeutic effect of Iobenguane Radiopharmaceutical Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5 biological half-lives before iobenguane administration. Do not administer these drugs until at least 7 days after each iobenguane dose. Avoid combination

Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Isometheptene: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Isometheptene. Avoid combination

Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Monitor therapy

Lasmiditan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Levodopa-Containing Products: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Of particular concern is the development of hypertensive reactions when levodopa is used with nonselective MAOI. Avoid combination

Levomethadone: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Avoid combination

Levonordefrin: Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Levonordefrin. Avoid combination

Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Avoid combination

Linezolid: Methylene Blue may enhance the serotonergic effect of Linezolid. This could result in serotonin syndrome. Avoid combination

Lithium: Methylene Blue may enhance the serotonergic effect of Lithium. This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes). Consider therapy modification

Lorcaserin: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Maprotiline: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Avoid combination

Meptazinol: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Meptazinol. Avoid combination

Mequitazine: Monoamine Oxidase Inhibitors may enhance the anticholinergic effect of Mequitazine. Avoid combination

Metaraminol: Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Metaraminol. Monitor therapy

Metaxalone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Methadone: May enhance the serotonergic effect of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Avoid combination

Methyldopa: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Methyldopa. Avoid combination

Methylphenidate: Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Methylphenidate. Avoid combination

Metoclopramide: May enhance the hypertensive effect of Monoamine Oxidase Inhibitors. Avoid combination

Mianserin: Monoamine Oxidase Inhibitors may enhance the neurotoxic effect of Mianserin. Avoid combination

Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Monitor therapy

Monoamine Oxidase Inhibitors (Antidepressant): May enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Avoid combination

Monoamine Oxidase Inhibitors (Type B): May enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Avoid combination

Morphine (Systemic): Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Morphine (Systemic). Avoid combination

Nefazodone: May enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Avoid combination

Nefopam: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Nefopam. Avoid combination

Nitroglycerin: Anticholinergic Agents may decrease the absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Monitor therapy

Norepinephrine: Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Norepinephrine. Monitor therapy

Normethadone: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Normethadone. Avoid combination

Ondansetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Opioid Agonists: Anticholinergic Agents may enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Monitor therapy

Opioid Agonists: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Exceptions: FentaNYL; Meperidine; TraMADol. Monitor therapy

Opium: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Opium. Avoid combination

Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Oxitriptan: Serotonergic Agents (High Risk) may enhance the serotonergic effect of Oxitriptan. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

OxyCODONE: May enhance the serotonergic effect of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Avoid combination

OxyMORphone: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Avoid combination

Pheniramine: May enhance the anticholinergic effect of Monoamine Oxidase Inhibitors. Avoid combination

Pholcodine: May enhance the serotonergic effect of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Avoid combination

Pizotifen: Monoamine Oxidase Inhibitors may enhance the anticholinergic effect of Pizotifen. Avoid combination

Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Avoid combination

Potassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Citrate. Avoid combination

Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Consider therapy modification

Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Monitor therapy

Ramosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Reboxetine: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Reboxetine. Avoid combination

Remifentanil: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Remifentanil. Specifically, the risk for opioid toxicity (eg, respiratory depression) may be increased. Remifentanil may enhance the serotonergic effect of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Management: The use of remifentanil is not recommended for patients taking monoamine oxidase inhibitors (MAOIs) or within 14 days of MAOI discontinuation. Consider therapy modification

Reserpine: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Reserpine. Existing MAOI therapy can result in paradoxical effects of added reserpine (e.g., excitation, hypertension). Management: Monoamine oxidase inhibitors (MAOIs) should be avoided or used with great caution in patients who are also receiving reserpine. Consider therapy modification

Revefenacin: Anticholinergic Agents may enhance the anticholinergic effect of Revefenacin. Avoid combination

Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid concomitant use of anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration of secretin. Consider therapy modification

Selective Serotonin Reuptake Inhibitors: May enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Exceptions: Dapoxetine. Avoid combination

Serotonergic Non-Opioid CNS Depressants: May enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Avoid combination

Serotonergic Opioids (High Risk): Methylene Blue may enhance the serotonergic effect of Serotonergic Opioids (High Risk). This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes). Consider therapy modification

Serotonin 5-HT1D Receptor Agonists (Triptans): May enhance the serotonergic effect of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Monoamine Oxidase Inhibitors may increase the serum concentration of Serotonin 5-HT1D Receptor Agonists (Triptans). Avoid combination

Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Avoid combination

Solriamfetol: Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Solriamfetol. Avoid combination

St John's Wort: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. St John's Wort may decrease the serum concentration of Serotonergic Agents (High Risk). Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

SUFentanil: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Specifically, the risk for serotonin syndrome or opioid toxicities (eg, respiratory depression, coma) may be increased. Management: Sufentanil should not be used with monoamine oxidase (MAO) inhibitors (or within 14 days of stopping an MAO inhibitor) due to the potential for serotonin syndrome and/or excessive CNS depression. Avoid combination

Syrian Rue: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Tapentadol: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Specifically, the additive effects of norepinephrine may lead to adverse cardiovascular effects. Tapentadol may enhance the serotonergic effect of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Avoid combination

Tetrabenazine: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Avoid combination

Tetrahydrozoline (Nasal): Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Tetrahydrozoline (Nasal). Avoid combination

Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Tianeptine: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Avoid combination

Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Avoid combination

Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate. Monitor therapy

Tricyclic Antidepressants: May enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Avoid combination

Tryptophan: May enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Avoid combination

Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Valbenazine: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Avoid combination

Test Interactions

May interfere with the interpretation of any urine test that relies on a blue indicator (such as the dipstick for leucocyte esterase).

Adverse Reactions

>10%:

Central nervous system: Feeling hot (17%), dizziness (16%)

Dermatologic: Hyperhidrosis (13%), skin discoloration (13%)

Gastrointestinal: Dysgeusia (20%), nausea (13%)

Genitourinary: Urine discoloration (74%; blue-green)

Neuromuscular & skeletal: Limb pain (84%)

1% to 10%:

Cardiovascular: Chest discomfort (4%), syncope (4%), presyncope (2%)

Central nervous system: Headache (10%), paresthesia (9%), infusion-site pain (6%), sensation of cold (6%), anxiety (4%), chills (2%), discomfort at injection site (2%), local discomfort (2%; limb), malaise (2%), orthostatic dizziness (2%)

Dermatologic: Contact dermatitis (5%), pallor (5%), pruritus (4%), diaphoresis (2%), ecchymosis (2%), erythema (2%)

Gastrointestinal: Oral paresthesia (9%), decreased appetite (4%), diarrhea (2%), oral hypoesthesia (2%), vomiting (2%)

Local: Catheter pain (2%)

Neuromuscular & skeletal: Musculoskeletal pain (9%), arthralgia (2%), back pain (2%), muscle spasm (2%), oral discomfort (2%)

Respiratory: Flu-like symptoms (4%), dyspnea (2%)

Frequency not defined:

Cardiovascular: Hypertension, palpitations, peripheral edema, tachycardia

Central nervous system: Confusion

Dermatologic: Papule, phototoxicity, skin discoloration

Endocrine & metabolic: Increased thirst

Gastrointestinal: Abdominal pain, fecal discoloration (blue-green), flatulence, glossalgia, lower abdominal pain, tongue rash, xerostomia

Genitourinary: Dysuria

Hematologic & oncologic: Hemolysis, hemolytic anemia, methemoglobinemia

Hepatic: Hyperbilirubinemia, increased liver enzymes

Local: Extravasation, infusion site reaction (pruritus, urticaria, swelling, and induration)

Neuromuscular & skeletal: Myalgia

Ophthalmic: Blurred vision, eye pruritus, ocular hyperemia

Respiratory: Nasal congestion, oropharyngeal pain, rhinorrhea, sneezing

Miscellaneous: Ulcer (necrotic)

<1%, postmarketing, and/or case reports: Serotonin syndrome

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).
• Extravasation: Vesicant: If administering as a continuous infusion, ensure proper needle or catheter placement prior to and during infusion; avoid extravasation. Infuse via central line if possible; monitor IV site closely (Dumbarton 2012).
• Hypersensitivity: Discontinue use and initiate supportive treatment if severe hypersensitivity reactions or anaphylaxis occurs.
• Methemoglobinemia: At high doses or in patients with G6PD-deficiency and infants, methylene blue may catalyze the oxidation of ferrous iron in hemoglobin to ferric iron causing paradoxical methemoglobinemia and hemolysis; onset of anemia may be delayed 1or more days and may require red blood cell transfusions. Use the lowest effective number of doses during treatment; discontinue and consider alternative treatment if severe hemolysis occurs. Monitor methemoglobin concentrations regularly during administration.
• Serotonin syndrome: [US Boxed Warning]: May cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs; avoid concomitant use of methylene blue with selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOI). Monitor patients closely for signs of SS such as mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia); neuromuscular changes (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination); GI symptoms (eg, nausea, vomiting, diarrhea); and/or seizures. Discontinue treatment and initiate supportive treatment if signs/symptoms arise.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; monitor for drug toxicity.
• Renal impairment: Use with caution in patients with severe impairment; monitor for drug toxicity.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• G6PD deficiency: Use with caution in patients with G6PD deficiency (may result in severe hemolysis and anemia); use of Provayblue is contraindicated.

Other warnings/precautions:

• Administration: Inject slowly over a period of several minutes to prevent high local concentration from producing additional methemoglobin. Large IV doses produce nausea, abdominal and precordial pain, dizziness, headache, profuse sweating, mental confusion, and formation of methemoglobin. Do not inject subcutaneously or intrathecally.
• Appropriate use: Provayblue: If methemoglobinemia does not respond to 2 doses of methylene blue or if rebounds after a response, consider additional treatment options.
• Enteral feedings: Methylene blue should not be added to enteral feeding products (Durfee 2006; Wessel 2005). Safety and efficacy have not been established.
• Monitoring: Use methods other than pulse oximetry to assess oxygen saturation (presence of methylene blue in the blood may result in an underestimation of the oxygen saturation reading). A fall in the bispectral index has been reported following administration of methylene blue; use alternative methods for assessing the depth of anesthesia if administered during surgery.
• Skin and body fluid discoloration: May cause blue discoloration of the skin and body fluids.

Monitoring Parameters

Arterial blood gases; cardiac monitoring (patients with pre-existing pulmonary and/or cardiac disease); CBC; methemoglobin levels (co-oximetry yields a direct and accurate measure of methemoglobin levels); pulse oximeter (will not provide accurate measurement of oxygenation when methemoglobin levels are >35% or following methylene blue administration); renal function; signs and symptoms of methemoglobinemia such as pallor, cyanosis, nausea, muscle weakness, dizziness, confusion, agitation, dyspnea, and tachycardia; transcutaneous O₂ saturation; monitor infusion site.

Pregnancy

Pregnancy Risk Factor

X

Pregnancy Considerations

Use of some products may be contraindicated by the manufacturer in women who are or may become pregnant. In general, medications used as antidotes should take into consideration the health and prognosis of the mother (Bailey 2003).

Use during amniocentesis has shown evidence of fetal abnormalities (atresia of the ileum and jejunum, ileal occlusions); has been used orally without similar adverse events (Bailey 2003). Adverse events in the newborn following intra-amniotic injection near term also include hyperbilirubinemia, skin staining, and respiratory distress. In addition, hemolytic anemia, methemoglobinemia, and phototoxicity have been reported in neonates following in utero exposure (Burnakis 1995; Porat 1996; Vincer 1987). Based on studies in nonpregnant women, potential exposure to the fetus may be less when methylene blue is used for lymphatic mapping in breast cancer (Pruthi 2011). Monitor the newborn for adverse events if administered near term.

Patient Education

What is this drug used for?

• It is used to treat methemoglobinemia.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Diarrhea
• Abdominal pain
• Painful extremities
• Sensation of warmth
• Sensation of cold
• Change in taste
• Muscle pain
• Injection site pain
• Skin discoloration
• Urine or stool discoloration

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Dizziness
• Passing out
• Headache
• Severe nausea
• Severe vomiting
• Sweating a lot
• Arrhythmia
• Shortness of breath
• Chest pain
• Loss of strength and energy
• Pale skin
• Burning or numbness feeling
• Confusion
• Serotonin syndrome like dizziness, severe headache, agitation, sensing things that seem real but are not, fast heartbeat, arrhythmia, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea.
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.