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Methylene blue: Pediatric drug information

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

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

Methylene blue 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.

Brand Names: US
  • ProvayBlue
Therapeutic Category
  • Antidote, Cyanide;
  • Antidote, Drug-induced Methemoglobinemia
Dosing: Neonatal

Note: Systemic doses as low as 2 mg/kg have been associated with hemolytic anemia and skin desquamation (Ref). Products are available in multiple concentrations (0.5% and 1%); use extra precaution when calculating dose volumes.

Methemoglobinemia, acquired

Methemoglobinemia, acquired (including drug-induced): I.O., IV: 1 mg/kg over 5 to 30 minutes; 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). In preterm neonates, a lower range of 0.3 to 1 mg/kg has been recommended based on a prospective screening study (n=13, GA: 25 to 30 weeks) (Ref).

Shock with hypotension unresponsive to fluid resuscitation, exogenous catecholamines and corticosteroids

Shock (vasodilatory) with hypotension unresponsive to fluid resuscitation, exogenous catecholamines and corticosteroids: Limited data available: IV: 1 mg/kg/dose; dosing based on a case series of five neonates (preterm: n=4, GA: 23 to 30 weeks; term: n=1, GA: 40 weeks) with presumed septic shock (Ref).

Dosing: Pediatric

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: Hepatic Impairment: Pediatric

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

Dosing: Adult

(For additional information see "Methylene blue: Drug information")

Chromoendoscopy

Chromoendoscopy (off-label use): Topical: 0.1% to 1% solution sprayed via catheter or directly applied onto GI mucosa during procedure (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 over 5 to 30 minutes (maximum single dose: 100 mg, using actual body weight; however, maximum dose has not been established (Ref)); may repeat dose 1 hour later if methemoglobin level remains above 30% or symptoms persist.

Note: If resolution does not occur after 2 doses, consider alternative therapy and consulting with a poison control center, as high doses 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).

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

Generic: 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.

Dosing: Hepatic 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.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults.

>10%:

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

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

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

Nervous system: Dizziness (16%), feeling hot (17%)

Neuromuscular & skeletal: Limb pain (84%)

1% to 10%:

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

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

Gastrointestinal: Decreased appetite (4%), diarrhea (2%), oral discomfort (2%), oral hypoesthesia (2%), oral paresthesia (9%), vomiting (2%)

Local: Discomfort at injection site (2%), infusion-site pain (6%), local discomfort (2%; limb)

Nervous system: Anxiety (4%), chills (2%), headache (10%), malaise (2%), paresthesia (9%), sensation of cold (6%)

Neuromuscular & skeletal: Arthralgia (2%), back pain (2%), muscle spasm (2%), musculoskeletal pain (9%)

Respiratory: Dyspnea (2%), flu-like symptoms (4%)

Frequency not defined:

Cardiovascular: Hypertension, palpitations, swelling of extremities, tachycardia

Dermatologic: Papule of skin

Endocrine & metabolic: Increased thirst

Gastrointestinal: Flatulence, glossalgia, lower abdominal pain, 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

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)

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.

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).

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 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 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.

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: 1% (1 mL [DSC], 10 mL [DSC])

Solution, Intravenous [preservative free]:

ProvayBlue: 50 mg/10 mL (10 mL)

Generic: 1% (10 mL)

Generic Equivalent Available: US

Yes

Pricing: US

Solution (ProvayBlue Intravenous)

50 mg/10 mL (per mL): $31.25

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: 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).

Administration: Adult

IV:

Generic: 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 (off label), spray or directly apply solution to the affected mucosa; methylene blue is used in conjunction with other preparatory methods (procedure-dependent) (Ref). 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.

Storage/Stability

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).

Pharmacy supply of emergency antidotes: Guidelines suggest that at least 400 to 600 mg of methylene blue be stocked. Suggested amount is stated to be a sufficient quantity to treat 1 patient weighing 100 kg for an initial 8- to 24-hour period (Dart 2018); actual amount to be stocked should take into account site-specific and population-specific needs.

Use

Treatment of acquired methemoglobinemia including drug-induced (FDA approved in pediatric patients [age not specified] and adults); has also been used for refractory vasodilatory shock in neonates

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 that have a heightened risk of causing significant patient harm when used in error.

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 Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

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

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

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

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

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

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

Amisulpride (Oral): Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Amisulpride (Oral). Specifically, the risk of seizures may be increased. Risk C: 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. Risk X: Avoid combination

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

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

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

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

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

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

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

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

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. If coadministration is required, use test doses and frequent titration of small benzhydrocodone. Risk D: Consider therapy modification

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

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

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

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

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

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

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

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

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

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

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

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

CarBAMazepine: May enhance the adverse/toxic effect 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 combination

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

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

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

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

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

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

Chlorprothixene: Anticholinergic Agents may enhance the anticholinergic effect of Chlorprothixene. Risk C: Monitor therapy

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

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

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

CloZAPine: Anticholinergic Agents may enhance the constipating effect of CloZAPine. Management: Consider alternatives to this combination whenever possible. If combined, monitor closely for signs and symptoms of gastrointestinal hypomotility and consider prophylactic laxative treatment. Risk D: Consider therapy modification

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

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

COMT Inhibitors: May enhance the adverse/toxic effect 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 enhance the serotonergic effect of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Risk X: Avoid combination

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

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

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

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

Diamorphine: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Diamorphine. Risk X: Avoid combination

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

Dihydrocodeine: May enhance the adverse/toxic effect 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 enhance the hypertensive effect of Monoamine Oxidase Inhibitors. Risk X: 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. Risk C: 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. Risk D: Consider therapy modification

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Indoramin: Monoamine Oxidase Inhibitors may enhance the hypotensive effect of Indoramin. Risk X: 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. Risk X: 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 antiseizure drugs. Risk D: 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 antiseizure drugs. Risk D: 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 antiseizure drugs. Risk D: Consider therapy modification

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

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

Isoproterenol: Monoamine Oxidase Inhibitors may enhance the therapeutic effect of Isoproterenol. Risk C: Monitor therapy

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

Levodopa-Foslevodopa: 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. Risk X: Avoid combination

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

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

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

Linezolid: Methylene Blue may enhance the serotonergic effect of Linezolid. This could result in serotonin syndrome. Risk X: 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). Risk D: Consider therapy modification

Lorcaserin (Withdrawn From US Market): 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. Risk C: Monitor therapy

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

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

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

Maprotiline: May enhance the hypertensive effect of Monoamine Oxidase Inhibitors. Risk X: Avoid combination

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

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

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

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

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

Methoxsalen (Systemic): Methylene Blue may enhance the photosensitizing effect of Methoxsalen (Systemic). Risk C: Monitor therapy

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

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

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

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

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

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

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

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

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

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

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

Nefopam: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Nefopam. Risk X: 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. Risk C: Monitor therapy

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

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

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

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. Risk C: Monitor therapy

Opicapone: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Risk X: Avoid combination

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. Risk C: Monitor therapy

Opioid Agonists: May enhance the serotonergic effect 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 therapy

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

Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: 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. Risk C: Monitor therapy

OxyCODONE: May enhance the serotonergic effect 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 enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Risk X: Avoid combination

Ozanimod: May enhance the hypertensive effect of Monoamine Oxidase Inhibitors. Risk X: Avoid combination

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

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

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

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

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

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

Pipamperone [INT]: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Pipamperone [INT]. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

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

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

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. Risk X: Avoid combination

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

Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Risk X: Avoid combination

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

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

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

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

Reboxetine: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Reboxetine. Risk X: 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. If coadministration is required, use test doses and titrate small doses of remifentanil frequently. Risk D: 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. Monitor closely for paradoxical effects of reserpine (eg, excitation, hypertension). Risk D: Consider therapy modification

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

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

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. Risk D: Consider therapy modification

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

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

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

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

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

Sodium Phosphates: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect 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 therapy

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

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

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. Risk C: 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. Risk X: Avoid combination

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

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

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

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

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

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

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

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

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

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

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

Tyrosine: May enhance the hypertensive effect of Monoamine Oxidase Inhibitors. Risk X: Avoid combination

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

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

Viloxazine: May enhance the hypertensive effect of Monoamine Oxidase Inhibitors. Risk X: Avoid combination

Ziprasidone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Ziprasidone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

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

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.

Monitoring Parameters

Vital signs; arterial blood gases; cardiac monitoring; 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

Reference Range

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

10% to 25%: Cyanosis

35% to 40%: Fatigue, dizziness, dyspnea, headache, tachycardia

60%: Lethargy, stupor

>70%: Death (adults)

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:

Generic: 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;
  • (CZ) Czech Republic: Methylthioniniumchlorid proveblue;
  • (DE) Germany: Methylenblau vitis | Methylthioniniumchlorid proveblue;
  • (EE) Estonia: Methylene Blue;
  • (FI) Finland: Methylthioninium chloride proveblue;
  • (GB) United Kingdom: Proveblue;
  • (GR) Greece: Methylthioninium chloride proveblue;
  • (HU) Hungary: Metilenkek pm;
  • (IE) Ireland: Methylthioninium chloride proveblue;
  • (IT) Italy: Metiltioninio bioindustria;
  • (KR) Korea, Republic of: Methylene Blue | Proveblue;
  • (KW) Kuwait: Proveblue;
  • (LT) Lithuania: Coloxyd | Methylenblau | Metiblo;
  • (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;
  • (RO) Romania: Proveblue;
  • (RU) Russian Federation: Methylenum Coeruleum;
  • (SE) Sweden: Methylthioninium chloride proveblue;
  • (SK) Slovakia: Methylthioninium chloride proveblue;
  • (TN) Tunisia: Bleu de methylene;
  • (TR) Turkey: Blumet;
  • (TW) Taiwan: Methylene Blue
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