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Methylene blue: Drug information

Methylene blue: Drug information
2025© UpToDate, Inc. and its affiliates and/or licensors. All Rights Reserved.
For additional information see "Methylene blue: Patient drug information" and "Methylene blue: Pediatric drug information"

For abbreviations, symbols, and age group definitions show table
ALERT: US Boxed Warning
Serotonin syndrome with concomitant use of serotonergic drugs and opioids (IV formulations):

Methylene blue may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs and opioids. Avoid concomitant use of methylene blue with selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, and opioids.

Brand Names: US
  • ProvayBlue
Pharmacologic Category
  • Antidote;
  • Diagnostic Agent;
  • Phenothiazine Derivative
Dosing: Adult
Chromoendoscopy

Chromoendoscopy: Topical: 0.5% solution (VueBlu [FDA-approved formulation]) or 0.1% to 1% solution (using IV formulation [off-label use]) sprayed via catheter, injected, or directly applied onto GI mucosa during procedure, depending on formulation (Ref).

Ifosfamide-induced encephalopathy

Ifosfamide-induced encephalopathy (off-label use): Note: Treatment may not be necessary; encephalopathy may improve spontaneously (Ref):

Treatment: Oral, IV: 50 mg as a single dose or every 4 to 8 hours until symptoms resolve (Ref).

Prophylaxis (secondary): Oral, IV: 50 mg every 6 to 8 hours; Note: Prophylaxis has been described as beginning on the day prior to or on the day of subsequent courses of ifosfamide (Ref).

Methemoglobinemia

Methemoglobinemia (acquired):

IV: 1 to 2 mg/kg (using actual body weight (Ref)) over 5 to 30 minutes; may repeat dose 1 hour later if methemoglobin level remains above 30% or symptoms persist.

Note: Consultation with a clinical toxicologist or poison center is recommended if resolution of symptoms does not occur after 2 doses; alternative therapy may be recommended. High cumulative doses (eg, >7 mg/kg) may result in hemolysis or paradoxical methemoglobinemia, especially in patients with glucose-6-phosphate dehydrogenase deficiency (Ref). Repeat dosing may be required in patients who have ingested a long-acting oxidant drug or toxin (eg, dapsone) (Ref).

Onychomycosis

Onychomycosis (off-label use): Topical: 2% solution applied to affected area(s) at ~2-week intervals for 4 to 6 months; used in conjunction with photodynamic therapy (Ref).

Sentinel node mapping in breast cancer surgery

Sentinel node mapping in breast cancer surgery (off-label use): Intraparenchymal: 5 mL of a 1% solution injected in a subareolar or peritumoral area once during procedure (Ref).

Septic shock

Septic shock (adjunctive agent ): Routine use is not recommended but may be considered to reduce vasopressor requirements (Ref). Optimal dose and regimens are not well defined; refer to institutional protocols.

IV: 100 mg once daily administered over 6 hours for 3 days (Ref) or 2 mg/kg administered over 15 minutes followed 2 hours later by an infusion with successive increases over a 4-hour period; initiate infusion at 0.25 mg/kg/hour for 1 hour, then 0.5 mg/kg/hour for 1 hour, then 1 mg/kg/hour for 1 hour, and then 2 mg/kg/hour for 1 hour (Ref).

Shock, beta-blocker or calcium channel blocker overdose

Shock, beta-blocker or calcium channel blocker overdose (off-label use): Note: Dose based on use in vasoplegia syndrome associated with cardiac surgery:

IV: 1 to 2 mg/kg over 20 to 60 minutes administered once (Ref). Note: Improvement of shock (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 (Ref).

Vasoplegia syndrome associated with cardiac surgery

Vasoplegia syndrome associated with cardiac surgery (off-label use): IV: 1 to 2 mg/kg over 20 to 60 minutes administered once (Ref). If administered during cardiopulmonary bypass, may consider a higher dose (2 to 3 mg/kg) due to increased Vd during bypass (Ref). 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 (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

Methylene blue 1%: There are no dosage adjustments provided in the manufacturer's labeling. However, use with caution in severe renal impairment.

ProvayBlue:

eGFR 60 to 80 mL/min/1.73 m2: No dosage adjustment is necessary.

eGFR 15 to 59 mL/min/1.73 m2: 1 mg/kg as a single dose; consider alternative treatment if methemoglobin level remains >30% or if clinical symptoms persist 1 hour after dosing.

VueBlu: There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Liver Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling; however, methylene blue is extensively metabolized in the liver. Monitor for toxicities for an extended period of time following methylene blue treatment in patients with hepatic impairment.

Dosing: Obesity: Adult

IV: Use of lean body weight has been recommended to determine the dose for treatment of methemoglobinemia (Ref); applicability to other indications has not been determined.

Dosing: Adjustment for Toxicity: Adult

Hemolysis, severe: Discontinue and consider alternative treatment.

Serotonin syndrome: Discontinue treatment and initiate supportive treatment if signs/symptoms arise.

Dosing: Older Adult

Refer to adult dosing.

Dosing: Pediatric

(For additional information see "Methylene blue: Pediatric drug information")

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

Methemoglobinemia, acquired

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) (Ref); consider alternative treatment if no resolution after 2 doses. Intraosseous administration has been reported (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling; however, use with caution in patients with severe renal impairment. Monitor for toxicity and drug interactions.

Dosing: Liver Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling. Monitor for toxicity and drug interactions.

Adverse Reactions

The following adverse drug reactions are derived from product labeling unless otherwise specified.

Frequency not defined:

Cardiovascular: Hypertension, palpitations, swelling of extremities, tachycardia

Dermatologic: Papule of skin

Endocrine & metabolic: Hypokalemia, hypomagnesemia, increased thirst

Gastrointestinal: Diarrhea, flatulence, glossalgia, lower abdominal pain, nausea, tongue rash, xerostomia

Genitourinary: Dysuria

Hematologic & oncologic: Hemolysis

Hepatic: Increased liver enzymes

Local: Induration at injection site, injection-site pruritus, swelling at injection site, urticaria at injection site

Nervous system: Headache, myoclonus, seizure-like activity

Neuromuscular & skeletal: Myalgia

Ophthalmic: Blurred vision, eye pruritus, ocular hyperemia

Respiratory: Nasal congestion, oropharyngeal pain, rhinorrhea, sneezing

Miscellaneous: Ulcer (necrotic)

Postmarketing:

Dermatologic: Phototoxicity (Maguire 2017), skin discoloration (Denshaw-Burke 2020)

Genitourinary: Urine discoloration (green or greenish-blue) (Howland 2019)

Hematologic & oncologic: Hemolytic anemia (Vincer 1987), methemoglobinemia (McRobb 2008)

Hepatic: Hyperbilirubinemia (Vincer 1987)

Hypersensitivity: Anaphylactic shock (Dewachter 2005), anaphylaxis (Giladi 2012)

Contraindications

Hypersensitivity to methylene blue or any component of the formulation.

Additional product-specific contraindications:

Methylene blue 1%: 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).

VueBlu: GI obstruction or perforation; G6PD deficiency; pregnancy; breastfeeding; pediatric use.

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.

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 renal impairment; dosage adjustments may be needed.

Special populations:

• Cyanide-poisoned patients: Patients with cyanide toxicity may receive nitrites to induce methemoglobinemia. Methylene blue should not be used to reverse nitrite-induced methemoglobinemia in this scenario because methylene blue will release free cyanide from methemoglobin (Mokhlesi 2003).

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

Other warnings/precautions:

• Administration: IV: 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.

• Appropriate use: VueBlu: For use as a tissue marker only. Do not use for the treatment of methemoglobinemia.

• 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.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Intravenous:

ProvayBlue: 50 mg/10 mL (10 mL)

Generic: 50 mg/10 mL (10 mL); 1% (1 mL [DSC], 10 mL [DSC])

Solution, Intravenous [preservative free]:

ProvayBlue: 50 mg/10 mL (10 mL)

Generic: 50 mg/10 mL (10 mL); 1% (10 mL)

Solution Prefilled Syringe, Intravenous [preservative free]:

Generic: 20 mg/2 mL (2 mL)

Generic Equivalent Available: US

Yes

Pricing: US

Solution (Methylene Blue (Antidote) Intravenous)

1% (per mL): $25.00

Solution (ProvayBlue Intravenous)

50 mg/10 mL (per mL): $28.13

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

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

Solution, Injection:

Generic: 1% (25 mL)

Solution, Intravenous:

Generic: 1% (1 mL, 5 mL)

Administration: Adult

IV:

Methylene blue 1%: Administer undiluted by direct IV injection slowly over several minutes. If a prolonged or continuous infusion is employed, administration via central line is recommended due to the risk of extravasation injury (Ref).

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; leave cannula/needle in place temporarily but do NOT flush the line; gently aspirate extravasated solution, then remove needle/cannula; elevate extremity; apply dry warm compresses (based on mechanism of extravasation injury) proximal to the injection site (Ref).

Optimal treatments for methylene blue extravasations are unknown (Ref):

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

Phentolamine: SUBQ: Dilute 5 to 10 mg in 10 mL NS and administer into extravasation site as soon as possible after extravasation; if IV catheter remains in place, administer initial dose IV through the infiltrated catheter; may repeat in 60 minutes if patient remains symptomatic (Ref).

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 (Ref).

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

Topical: When used as a diagnostic aid, spray, inject, or directly apply solution to the affected mucosa (method depends on formulation); methylene blue is used in conjunction with other preparatory methods (procedure-dependent) (Ref); if using the commercially available formulation, VueBlu, select a suitable spray catheter (for superficial tissue marking) or an injection needle (for submucosal marking) with a Luer lock connection and prime the catheter or injection needle prior to use. 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 (Ref).

Intraparenchymal (off-label route): When used for sentinel node mapping in breast cancer surgery (off label), administer as an injection either in a subareolar or peritumoral area directly into nodal tissue (Ref).

Do NOT administer subcutaneously or intrathecally.

Administration: Pediatric

Parenteral: Administer IV; may be administered intraosseously if necessary (Ref). Do not inject intrathecally or subcutaneously.

Provay blue (0.5% solution): Administer diluted (to lessen local pain) or undiluted over 5 to 30 minutes; if administered undiluted, follow with a flush (eg, 15 to 30 mL) (Ref).

Generic (1% solution): Administer undiluted or diluted by direct IV injection over 5 to 10 minutes; may follow with a flush (eg, 15 to 30 mL) to lessen local pain (Ref).

Vesicant; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation. 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 (Ref). Initiate nitroglycerin (topical) antidote (See Management of Drug Extravasations for details).

Use: Labeled Indications

Chromoendoscopy (diagnostic aid) (VueBlu): Temporary endoscopic marking of tissue in the GI tract to aid tissue visualization in patients ≥18 years of age. Note: Products indicated for IV administration have also been utilized for chromoendoscopic procedures (see "Use: Off-Label").

Methemoglobinemia (acquired) (IV formulations only): Treatment of pediatric and adult patients with acquired methemoglobinemia.

Use: Off-Label: Adult

Chromoendoscopy (diagnostic aid); Ifosfamide-induced encephalopathy (treatment and secondary prophylaxis); Onychomycosis; Sentinel lymph node mapping in breast cancer surgery; Septic shock; Shock, beta-blocker or calcium channel blocker overdose; Vasoplegia syndrome associated with cardiac surgery

Medication Safety Issues
Sound-alike/look-alike issues:

Methylene Blue may be confused with VisionBlue

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs (contraindicated in pregnancy [methylene blue 1%; VueBlu]) that have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Community/Ambulatory Care Settings).

Other safety concerns:

Due to the potential for dosing errors between mg and mL of methylene blue, prescribing and dosing should only be expressed in terms of mg of methylene blue (and not as mL)

Due to potential toxicity (hemolytic anemia), do not use methylene blue to color enteral feedings to detect aspiration.

Metabolism/Transport Effects

Substrate of CYP1A2 (Minor), CYP2C19 (Minor), CYP2D6 (Minor), UGT1A4, UGT1A9; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits Monoamine Oxidase;

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.

Agents with Blood Glucose Lowering Effects: Monoamine Oxidase Inhibitors may increase hypoglycemic effects of Agents with Blood Glucose Lowering Effects. Risk C: Monitor

Alcohol (Ethyl): May increase adverse/toxic effects of Monoamine Oxidase Inhibitors. Risk X: Avoid

Alosetron: May increase serotonergic effects 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. Risk C: Monitor

Alpha-/Beta-Agonists (Indirect-Acting): Monoamine Oxidase Inhibitors may increase hypertensive effects 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. Risk X: Avoid

Alpha1-Agonists: Monoamine Oxidase Inhibitors may increase hypertensive effects 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. Risk X: Avoid

Amifampridine: Agents With Seizure Threshold Lowering Potential may increase neuroexcitatory and/or seizure-potentiating effects of Amifampridine. Risk C: Monitor

Amisulpride (Oral): Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Amisulpride (Oral). Specifically, the risk of seizures may be increased. Risk C: Monitor

Amphetamines: Monoamine Oxidase Inhibitors may increase hypertensive effects 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. Risk X: Avoid

Antiemetics (5HT3 Antagonists): May increase serotonergic effects 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. Risk C: Monitor

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

Apraclonidine: Monoamine Oxidase Inhibitors may increase adverse/toxic effects of Apraclonidine. Monoamine Oxidase Inhibitors may increase serum concentration of Apraclonidine. Risk X: Avoid

ARIPiprazole Lauroxil: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of ARIPiprazole Lauroxil. Specifically, the risk of seizures may be increased. Risk C: Monitor

ARIPiprazole: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of ARIPiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor

Asenapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Asenapine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Atomoxetine: Monoamine Oxidase Inhibitors may increase neurotoxic (central) effects of Atomoxetine. Risk X: Avoid

Atropine (Ophthalmic): Monoamine Oxidase Inhibitors may increase hypertensive effects of Atropine (Ophthalmic). Risk X: Avoid

Avocado: May increase hypertensive effects of Monoamine Oxidase Inhibitors. Risk C: Monitor

Benperidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Benperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor

Benzhydrocodone: May increase serotonergic effects 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. If coadministration is required, use test doses and frequent titration of small benzhydrocodone. Risk D: Consider Therapy Modification

Beta2-Agonists: Monoamine Oxidase Inhibitors may increase adverse/toxic effects of Beta2-Agonists. Risk C: Monitor

Betahistine: Monoamine Oxidase Inhibitors may increase serum concentration of Betahistine. Risk C: Monitor

Bezafibrate: Monoamine Oxidase Inhibitors may increase adverse/toxic effects of Bezafibrate. Risk X: Avoid

Blonanserin: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Blonanserin. Specifically, the risk of seizures may be increased. Risk C: Monitor

Bornaprine: May increase adverse/toxic effects of Monoamine Oxidase Inhibitors. Risk C: Monitor

Brexpiprazole: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Brexpiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor

Brimonidine (Ophthalmic): Monoamine Oxidase Inhibitors may increase adverse/toxic effects of Brimonidine (Ophthalmic). Monoamine Oxidase Inhibitors may increase serum concentration of Brimonidine (Ophthalmic). Risk C: Monitor

Brimonidine (Topical): Monoamine Oxidase Inhibitors may increase adverse/toxic effects of Brimonidine (Topical). Monoamine Oxidase Inhibitors may increase serum concentration of Brimonidine (Topical). Risk C: Monitor

Bromperidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Bromperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor

Buprenorphine: May increase adverse/toxic effects of Monoamine Oxidase Inhibitors. Risk X: Avoid

BuPROPion: Monoamine Oxidase Inhibitors may increase hypertensive effects of BuPROPion. Risk X: Avoid

BusPIRone: May increase serotonergic effects of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid

Butorphanol: May increase serotonergic effects of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Risk X: Avoid

CarBAMazepine: May increase adverse/toxic effects of Monoamine Oxidase Inhibitors. Management: Do not use carbamazepine during, or within 14 days of discontinuing, treatment with a monoamine oxidase inhibitor. Risk X: Avoid

Carbinoxamine: Monoamine Oxidase Inhibitors may increase adverse/toxic effects of Carbinoxamine. Specifically, the anticholinergic effects of carbinoxamine may be enhanced and prolonged. Risk X: Avoid

Cariprazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Cariprazine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Cerebrolysin: May increase adverse/toxic effects of Monoamine Oxidase Inhibitors. Risk C: Monitor

Chlorphenesin Carbamate: May increase adverse/toxic effects of Monoamine Oxidase Inhibitors. Risk C: Monitor

ChlorproMAZINE: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of ChlorproMAZINE. Specifically, the risk of seizures may be increased. Risk C: Monitor

Clemastine: Monoamine Oxidase Inhibitors may increase anticholinergic effects of Clemastine. Risk C: Monitor

Clothiapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Clothiapine. Specifically, the risk of seizures may be increased. Risk C: Monitor

CloZAPine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of CloZAPine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Cocaine (Topical): May increase adverse/toxic effects of Monoamine Oxidase Inhibitors. Risk C: Monitor

Codeine: Monoamine Oxidase Inhibitors may increase adverse/toxic effects of Codeine. Risk X: Avoid

COMT Inhibitors: May increase adverse/toxic effects of Monoamine Oxidase Inhibitors. Management: Avoid coadministration of COMT inhibitors and nonselective monoamine oxidase inhibitors (MAOIs) (eg, isocarboxazid, phenelzine, tranylcypromine, linezolid, methylene blue) whenever possible. Risk D: Consider Therapy Modification

Cyclobenzaprine: May increase serotonergic effects of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Risk X: Avoid

Cyproheptadine: May decrease serotonergic effects of Monoamine Oxidase Inhibitors. Monoamine Oxidase Inhibitors may increase anticholinergic effects of Cyproheptadine. Risk X: Avoid

Dapoxetine: May increase serotonergic effects 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. Risk X: Avoid

Deutetrabenazine: Monoamine Oxidase Inhibitors may increase adverse/toxic effects of Deutetrabenazine. Risk X: Avoid

Dexmethylphenidate: Monoamine Oxidase Inhibitors may increase hypertensive effects of Dexmethylphenidate. Risk X: Avoid

Dextromethorphan: May increase serotonergic effects of Monoamine Oxidase Inhibitors. This may cause serotonin syndrome. Risk X: Avoid

Diamorphine: Monoamine Oxidase Inhibitors may increase adverse/toxic effects of Diamorphine. Risk X: Avoid

Diethylpropion: Monoamine Oxidase Inhibitors may increase hypertensive effects of Diethylpropion. Risk X: Avoid

Difenoxin: May increase hypertensive effects of Monoamine Oxidase Inhibitors. Risk C: Monitor

Dihydrocodeine: May increase adverse/toxic effects of Monoamine Oxidase Inhibitors. Management: Consider avoiding use of dihydrocodeine while the patient is taking monoamine oxidase inhibitors (MAOIs) and for 2 weeks after MAOI discontinuation. Risk D: Consider Therapy Modification

Diphenoxylate: May increase hypertensive effects of Monoamine Oxidase Inhibitors. Risk X: Avoid

Domperidone: Monoamine Oxidase Inhibitors may increase adverse/toxic effects of Domperidone. Monoamine Oxidase Inhibitors may decrease therapeutic effects of Domperidone. Domperidone may decrease therapeutic effects of Monoamine Oxidase Inhibitors. Risk C: Monitor

DOPamine: Monoamine Oxidase Inhibitors may increase hypertensive effects 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. Risk D: Consider Therapy Modification

Doxapram: Monoamine Oxidase Inhibitors may increase hypertensive effects of Doxapram. Risk C: Monitor

Doxylamine: Monoamine Oxidase Inhibitors may increase anticholinergic effects of Doxylamine. Risk X: Avoid

DroPERidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of DroPERidol. Specifically, the risk of seizures may be increased. Risk C: Monitor

Droxidopa: Monoamine Oxidase Inhibitors may increase hypertensive effects of Droxidopa. Risk X: Avoid

EPINEPHrine (Oral Inhalation): Monoamine Oxidase Inhibitors may increase hypertensive effects of EPINEPHrine (Oral Inhalation). Risk X: Avoid

Ergot Derivatives: May increase serotonergic effects 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. Risk C: Monitor

Esketamine (Nasal): May increase hypertensive effects of Monoamine Oxidase Inhibitors. Risk C: Monitor

Fenfluramine: May increase serotonergic effects of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid

FentaNYL: Methylene Blue may increase serotonergic effects of FentaNYL. This could result in serotonin syndrome. Risk X: Avoid

Flupentixol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Flupentixol. Specifically, the risk of seizures may be increased. Risk C: Monitor

FluPHENAZine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of FluPHENAZine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Gepirone: May increase serotonergic effects of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid

Guanethidine: May increase adverse/toxic effects of Monoamine Oxidase Inhibitors. Risk X: Avoid

Haloperidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Haloperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor

HYDROcodone: May increase serotonergic effects of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Monoamine Oxidase Inhibitors may increase adverse/toxic effects of HYDROcodone. Management: Consider alternatives to this combination when possible. If coadministration is required, use test doses, titrate small doses frequently, and monitor patients closely for evidence of serotonergic and opioid toxicities. Risk D: Consider Therapy Modification

HYDROmorphone: Monoamine Oxidase Inhibitors may increase adverse/toxic effects of HYDROmorphone. Management: Coadministration of hydromorphone and monoamine oxidase (MAO) inhibitors (or within 14 days of stopping an MAO inhibitor) is not recommended. If required, use test doses, titrate small doses frequently, and monitor for CNS and respitatory depression. Risk D: Consider Therapy Modification

Iloperidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iloperidone. Specifically, the risk of seizures may be increased. Risk C: Monitor

Indoramin: Monoamine Oxidase Inhibitors may increase hypotensive effects of Indoramin. Risk X: Avoid

Iobenguane Radiopharmaceutical Products: Monoamine Oxidase Inhibitors may decrease therapeutic effects 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. Risk X: Avoid

Iohexol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects 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 antiseizure drugs. Risk D: Consider Therapy Modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects 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 antiseizure drugs. Risk D: Consider Therapy Modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects 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 antiseizure drugs. Risk D: Consider Therapy Modification

Isoproterenol: Monoamine Oxidase Inhibitors may increase therapeutic effects of Isoproterenol. Risk C: Monitor

Lasmiditan: May increase serotonergic effects 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. Risk C: Monitor

Levodopa-Foslevodopa: May increase adverse/toxic effects of Monoamine Oxidase Inhibitors. Of particular concern is the development of hypertensive reactions when levodopa is used with nonselective MAOI. Risk X: Avoid

Levomethadone: May increase adverse/toxic effects of Monoamine Oxidase Inhibitors. Risk X: Avoid

Levonordefrin: Monoamine Oxidase Inhibitors may increase hypertensive effects of Levonordefrin. Management: Avoid the use of levonordefrin during or within 2 weeks of treatment with a monoamine oxidase inhibitor whenever possible. If levonordefrin cannot be avoided during this period, monitor closely for enhanced or prolonged increases in blood pressure. Risk D: Consider Therapy Modification

Linezolid: Methylene Blue may increase serotonergic effects of Linezolid. This could result in serotonin syndrome. Risk X: Avoid

Lithium: Methylene Blue may increase serotonergic effects 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). Risk D: Consider Therapy Modification

Loxapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Loxapine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Lumateperone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Lumateperone. Specifically, the risk of seizures may be increased. Risk C: Monitor

Lurasidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Lurasidone. Specifically, the risk of seizures may be increased. Risk C: Monitor

Maprotiline: May increase hypertensive effects of Monoamine Oxidase Inhibitors. Risk X: Avoid

Meptazinol: Monoamine Oxidase Inhibitors may increase adverse/toxic effects of Meptazinol. Risk X: Avoid

Mequitazine: Monoamine Oxidase Inhibitors may increase anticholinergic effects of Mequitazine. Risk X: Avoid

Metaraminol: Monoamine Oxidase Inhibitors may increase hypertensive effects of Metaraminol. Risk C: Monitor

Metaxalone: May increase serotonergic effects 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. Risk C: Monitor

Methadone: May increase serotonergic effects of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Risk X: Avoid

Methotrimeprazine: Monoamine Oxidase Inhibitors may increase adverse/toxic effects of Methotrimeprazine. Specifically, monoamine oxidase inhibitors may enhance dopamine blockade, possible increasing the risk for neuroleptic malignant syndrome. Methotrimeprazine may increase serotonergic effects of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Risk X: Avoid

Methoxsalen (Systemic): Methylene Blue may increase photosensitizing effects of Methoxsalen (Systemic). Risk C: Monitor

Methyldopa: Monoamine Oxidase Inhibitors may increase adverse/toxic effects of Methyldopa. Risk X: Avoid

Methylphenidate: Monoamine Oxidase Inhibitors may increase hypertensive effects of Methylphenidate. Risk X: Avoid

Metoclopramide: May increase hypertensive effects of Monoamine Oxidase Inhibitors. Risk X: Avoid

Mianserin: Monoamine Oxidase Inhibitors may increase neurotoxic effects of Mianserin. Risk X: Avoid

Mivacurium: Monoamine Oxidase Inhibitors may increase serum concentration of Mivacurium. Risk C: Monitor

Molindone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Molindone. Specifically, the risk of seizures may be increased. Risk C: Monitor

Monoamine Oxidase Inhibitors (Antidepressant): May increase serotonergic effects of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid

Monoamine Oxidase Inhibitors (Type B): May increase serotonergic effects of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid

Morphine (Systemic): Monoamine Oxidase Inhibitors may increase adverse/toxic effects of Morphine (Systemic). Risk X: Avoid

Nalbuphine: Monoamine Oxidase Inhibitors may increase CNS depressant effects of Nalbuphine. Nalbuphine may increase serotonergic effects of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Nalbuphine may increase hypertensive effects of Monoamine Oxidase Inhibitors. Management: Use of nalbuphine is not recommended in patients taking MAOIs, or within 14 days of stopping MAOI therapy. If urgent nalbuphine use is needed, use test doses and frequent titration while monitoring blood pressure, CNS depression, and serotonergic toxicity Risk D: Consider Therapy Modification

Nefazodone: May increase serotonergic effects of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid

Nefopam: Monoamine Oxidase Inhibitors may increase adverse/toxic effects of Nefopam. Risk X: Avoid

Normethadone: Monoamine Oxidase Inhibitors may increase adverse/toxic effects of Normethadone. Risk X: Avoid

OLANZapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of OLANZapine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Ondansetron: May increase serotonergic effects 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. Risk C: Monitor

Opicapone: May increase adverse/toxic effects of Monoamine Oxidase Inhibitors. Risk X: Avoid

Opioid Agonists: May increase serotonergic effects of Monoamine Oxidase Inhibitors. 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. Risk C: Monitor

Opipramol: May increase serotonergic effects of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Risk X: Avoid

Opium: Monoamine Oxidase Inhibitors may increase adverse/toxic effects of Opium. Risk X: Avoid

Oxitriptan: Serotonergic Agents (High Risk) may increase serotonergic effects 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. Risk C: Monitor

OxyCODONE: May increase serotonergic effects of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Management: Use of oxycodone is not recommended for patients taking MAOIs or within 14 days of MAOI discontinuation. If combined, use test doses and frequent titration of small doses while monitoring blood pressure, CNS depression, and signs of serotonin syndrome. Risk D: Consider Therapy Modification

OxyMORphone: May increase adverse/toxic effects of Monoamine Oxidase Inhibitors. Risk X: Avoid

Ozanimod: May increase hypertensive effects of Monoamine Oxidase Inhibitors. Risk X: Avoid

Paliperidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Paliperidone. Specifically, the risk of seizures may be increased. Risk C: Monitor

Pegulicianine: Coadministration of Methylene Blue and Pegulicianine may alter diagnostic results. Risk X: Avoid

Periciazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Periciazine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Perphenazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Perphenazine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Pheniramine: May increase anticholinergic effects of Monoamine Oxidase Inhibitors. Risk X: Avoid

Pholcodine: May increase serotonergic effects of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Risk X: Avoid

Pimozide: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Pimozide. Specifically, the risk of seizures may be increased. Risk C: Monitor

Pipamperone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Pipamperone. Specifically, the risk of seizures may be increased. Risk X: Avoid

Pizotifen: Monoamine Oxidase Inhibitors may increase anticholinergic effects of Pizotifen. Risk X: Avoid

Polyethylene Glycol-Electrolyte Solution: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Polyethylene Glycol-Electrolyte Solution. Specifically, the risk of seizure may be increased. Risk C: Monitor

Prochlorperazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Prochlorperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Promazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Promazine. Specifically, the risk of seizures may be increased. Risk C: Monitor

QUEtiapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of QUEtiapine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Ramosetron: May increase serotonergic effects 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. Risk C: Monitor

Reboxetine: Monoamine Oxidase Inhibitors may increase adverse/toxic effects of Reboxetine. Risk X: Avoid

Remifentanil: May increase serotonergic effects of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Monoamine Oxidase Inhibitors may increase adverse/toxic effects of Remifentanil. Specifically, the risk for opioid toxicity (eg, respiratory depression) may be increased. Management: The use of remifentanil is not recommended for patients taking monoamine oxidase inhibitors (MAOIs) or within 14 days of MAOI discontinuation. If coadministration is required, use test doses and titrate small doses of remifentanil frequently. Risk D: Consider Therapy Modification

Reserpine: Monoamine Oxidase Inhibitors may increase adverse/toxic effects 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. Monitor closely for paradoxical effects of reserpine (eg, excitation, hypertension). Risk D: Consider Therapy Modification

RisperiDONE: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of RisperiDONE. Specifically, the risk of seizures may be increased. Risk C: Monitor

Selective Serotonin Reuptake Inhibitor: May increase serotonergic effects of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid

Serotonergic Non-Opioid CNS Depressants: May increase serotonergic effects of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid

Serotonergic Opioids (High Risk): Methylene Blue may increase serotonergic effects of Serotonergic Opioids (High Risk). This could result in serotonin syndrome. Risk X: Avoid

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

Serotonin/Norepinephrine Reuptake Inhibitor: May increase serotonergic effects of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid

Sertindole: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Sertindole. Specifically, the risk of seizures may be increased. Risk C: Monitor

Sevoflurane: Monoamine Oxidase Inhibitors may increase adverse/toxic effects of Sevoflurane. Specifically, the risk of hemodynamic instability may be increased. Risk C: Monitor

Sodium Phosphates: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Sodium Phosphates. Specifically, the risk of seizure or loss of consciousness may be increased in patients with significant sodium phosphate-induced fluid or electrolyte abnormalities. Risk C: Monitor

Solriamfetol: Monoamine Oxidase Inhibitors may increase hypertensive effects of Solriamfetol. Risk X: Avoid

St John's Wort: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. St John's Wort may decrease 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. Risk C: Monitor

SUFentanil: May increase adverse/toxic effects 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. Risk X: Avoid

Sulpiride: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Sulpiride. Specifically, the risk of seizures may be increased. Risk C: Monitor

Syrian Rue: May increase serotonergic effects 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. Risk C: Monitor

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

Tetrabenazine: May increase adverse/toxic effects of Monoamine Oxidase Inhibitors. Risk X: Avoid

Thioridazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Thioridazine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Thiothixene: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Thiothixene. Specifically, the risk of seizures may be increased. Risk C: Monitor

Tianeptine: May increase adverse/toxic effects of Monoamine Oxidase Inhibitors. Risk X: Avoid

Tilidine: May increase serotonergic effects 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. Risk C: Monitor

Tricyclic Antidepressants: May increase serotonergic effects of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid

Trifluoperazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Trifluoperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Tryptophan: May increase serotonergic effects of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid

Tyrosine: May increase hypertensive effects of Monoamine Oxidase Inhibitors. Risk X: Avoid

Valbenazine: May increase adverse/toxic effects of Monoamine Oxidase Inhibitors. Risk X: Avoid

Viloxazine: May increase hypertensive effects of Monoamine Oxidase Inhibitors. Risk X: Avoid

Ziprasidone: May increase serotonergic effects of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid

Zuclopenthixol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Zuclopenthixol. Specifically, the risk of seizures may be increased. Risk C: Monitor

Reproductive Considerations

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

Pregnancy Considerations

Use of some products may be contraindicated by the manufacturer in women who are 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.

Breastfeeding Considerations

It is not known if methylene blue is excreted in breast milk. One manufacturer recommends discontinuing breastfeeding during treatment and for up to 8 days after therapy is complete.

Monitoring Parameters

Arterial or venous 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; signs and symptoms of serotonin syndrome; transcutaneous O2 saturation; monitor infusion site.

Reference Range

Methemoglobin levels (Ludlow 2020): Note: The level of methemoglobin is expressed as a percent of total hemoglobin affected.

Generally asymptomatic.

15% to 30%: Skin color changes (pale, gray, blue) most commonly seen on mucus membranes; headache, dyspnea, anxiety due to increasing hypoxia.

30% to 50%: Weakness, tachypnea, palpitations, confusion.

50% to 70%: Metabolic acidosis, cardiac arrhythmias, seizures, coma.

>70%: Usually fatal.

Mechanism of Action

In the treatment of methemoglobinemia, methylene blue hastens the conversion of methemoglobin to hemoglobin in low concentrations; however, it has the opposite effect at high concentrations by converting ferrous ion of reduced hemoglobin to ferric ion to form methemoglobin. In cyanide toxicity, methemoglobin combines with cyanide to form cyanomethemoglobin 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 (Adult Data Unless Noted)

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

Absorption: Oral: 53% to 97% (Clifton 2003)

Distribution: 255 L ± 58 L

Protein binding: 94%

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

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

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

Excretion:

Methylene blue 1%: In bile, feces, and urine (~33% as leukomethylene blue) (Clifton 2003; Peter 2000)

ProvayBlue: Urine (~40% unchanged)

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AU) Australia: Proveblue;
  • (BE) Belgium: Methylthionium chloride proveblue | Metiblo;
  • (CO) Colombia: Azul de metileno;
  • (CZ) Czech Republic: Methylthioniniumchlorid proveblue;
  • (DE) Germany: Methylenblau vitis | Methylthioniniumchlorid proveblue;
  • (EE) Estonia: Methylene Blue;
  • (FI) Finland: Methylthioninium chloride proveblue;
  • (GB) United Kingdom: Methylthioninium chloride proveblue | Proveblue;
  • (GR) Greece: Methylthioninium chloride proveblue;
  • (HK) Hong Kong: Methylene Blue;
  • (HU) Hungary: Methylthioninium chloride proveblue | Metilenkek pm;
  • (IE) Ireland: Methylthioninium chloride proveblue;
  • (IN) India: Sam mb;
  • (IT) Italy: Metiltioninio bioindustria;
  • (KR) Korea, Republic of: Methylene Blue | Proveblue;
  • (KW) Kuwait: Blumet | Proveblue;
  • (LT) Lithuania: Coloxyd | Methylenblau | Metiblo | Sam mb;
  • (LV) Latvia: Coloxyd;
  • (MY) Malaysia: Methylene Blue;
  • (NL) Netherlands: Methylthioninium chloride proveblue;
  • (NO) Norway: Methylthioninium chloride proveblue;
  • (NZ) New Zealand: Methylene Blue | Proveblue;
  • (PL) Poland: Coloxyd | Methylene Blue | Methylthioninium chloride proveblue | Metiblo | Metiltioninio cloruro bioindustria;
  • (PR) Puerto Rico: Methylene Blue | Provayblue;
  • (PT) Portugal: Azul de metileno labesfal | Azul metileno | Cloreto de metiltionina proveblue | Proveblue;
  • (QA) Qatar: Blumet | Proveblue;
  • (RO) Romania: Proveblue;
  • (RU) Russian Federation: Methylenum Coeruleum;
  • (SE) Sweden: Methylthioninium chloride proveblue;
  • (SG) Singapore: Proveblue;
  • (SK) Slovakia: Methylthioninium chloride proveblue;
  • (TN) Tunisia: Bleu de methylene;
  • (TR) Turkey: Blumet;
  • (TW) Taiwan: Methylene Blue
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