Class: Antidotes
VA Class: AD200
CAS Number: 7220-79-3
Special Alerts:
[UPDATED 10/21/2011] FDA updated healthcare professionals and the public on the potential drug interaction between methylene blue and serotonergic psychiatric medications. Most cases from the FDA's Adverse Event Reporting System (AERS) of serotonin syndrome in patients given serotonergic psychiatric medications and methylene blue occurred in the context of parathyroid surgery, which involved the intravenous administration of methylene blue as a visualizing agent. Methylene blue doses ranged from 1 mg/kg to 8 mg/kg.
Because methylene blue is not an FDA-approved drug at this time, and limited data exist regarding its use in various settings, it is not known whether there is a risk of serotonin syndrome in patients taking serotonergic psychiatric medications who are given methylene blue by other routes (e.g., orally or by local tissue injection) or at intravenous doses lower than 1 mg/kg.
In addition, not all serotonergic psychiatric drugs have an equal capacity to cause serotonin syndrome with methylene blue. The cases of serotonin syndrome with methylene blue occurred in patients taking specific serotonergic psychiatric drugs, namely a selective serotonin reuptake inhibitor (SSRI), a serotonin norepinephrine reuptake inhibitor (SNRI), or clomipramine. It is unclear at this time whether intravenous methylene blue administration in patients receiving other psychiatric drugs with lesser degrees of serotonergic activity poses a comparable risk.
FDA will update the public when new information is available. For more information visit the FDA website at: and .
[Posted 07/26/2011] ISSUE: FDA has received reports of serious central nervous system (CNS) reactions when the drug methylene blue is given to patients taking psychiatric medications that work through the serotonin system of the brain (serotonergic psychiatric medications). A list of the serotonergic psychiatric medications that can interact with methylene blue can be found in the Drug Safety Communication. Safety information about this potential drug interaction and important drug usage recommendations for emergency and non-emergency situations are being added to the drug labels for serotonergic psychiatric medications.
BACKGROUND: Methylene blue is used to treat methemoglobinemia, vasoplegic syndrome, ifosfamide-induced encephalopathy, and cyanide poisoning. It is also used as a dye in therapeutic and diagnostic applications. Methylene blue is a potent, reversible monoamine oxidase inhibitor (MAOI). Although the exact mechanism of this drug interaction is unknown, methylene blue inhibits the action of monoamine oxidase A — an enzyme responsible for breaking down serotonin in the brain. It is believed that when methylene blue is given to patients taking serotonergic psychiatric medications, high levels of serotonin can build up in the brain, causing toxicity. This is referred to as Serotonin Syndrome — signs and symptoms include mental changes (confusion, hyperactivity, memory problems), muscle twitching, excessive sweating, shivering or shaking, diarrhea, trouble with coordination and/or fever.
RECOMMENDATION: Methylene blue should generally not be given to patients taking serotonergic drugs. However, there are some conditions that may be life-threatening or require urgent treatment with methylene blue such as when it is used in the emergency treatment of methemoglobinemia, ifosfamide-induced encephalopathy, or cyanide poisoning.
Patients should not stop taking their serotonergic psychiatric medicine without first talking to a healthcare professional. Read the Drug Safety Communication at: for other specific recommendations for Healthcare Professionals and for Patients. For more information visit the FDA website at: and .
Introduction
Thiazine dye; increases conversion rate of methemoglobin to hemoglobin.a b c
Uses for Methylene Blue
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Methemoglobinemia
Treatment of idiopathic and drug-induced methemoglobinemia.a b c Does not reverse methemoglobinemia in glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.a
Cyanide Poisoning
Has been used as an antidote for cyanide poisoning;a c however, is inferior to sodium nitrite and amyl nitrite for this use.a
Urolithiasis
Has been used alone and in combination with ascorbic acid for the management of chronic urolithiasis.a May inhibit formation of calcium oxalate and calcium phosphate crystals; however, it is ineffective in dissolving previously formed stones.a
Cystitis and Urethritis
Has been used as a mild urinary antiseptic and stimulant to mucous surfaces in the treatment of cystitis and urethritis, but more effective agents have replaced its use in these conditions.a c
Use as a Dye
Has been used as a bacteriologic stain, as an indicator dye, and for surgical and medical marking.a c
Has also been used as a diagnostic agent in renal function tests and in vital nerve staining, but other agents are considered superior.a
Photoinactivation of Viruses
Has been used topically as a 0.1% solution in conjunction with polychromatic light for the photoinactivation of viruses† in the treatment of cutaneous viral infections† (e.g., herpes simplex).a
Gastroesophageal Reflux
Has been given via a nasogastric (NG) tube for the diagnosis of gastroesophageal reflux† in infants and children.a
Other Uses
Methylene blue is of novalue in the treatment of carbon monoxide poisoning.a
Methylene Blue Dosage and Administration
Administration
Administer orally or by IV injection;a b c however, oral preparation is no longer commercially available in the US.f g
IV administration usually preferred in treatment of acute methemoglobinemia due to more rapid onset of effect.a
Do not administer sub-Q.a b Necrotic abscesses may result from sub-Q administration.a
Do not administer intrathecally.a b Neural damage may result from intrathecal injection.a (See Contraindications under Cautions.)
Oral Administration
Administer after meals with a full glass of water.a c
NG Tube
For diagnosis of gastroesophageal reflux, administer 0.1% methylene blue solution containing hydrochloric acid into the fasting stomach via an NG tube†.a
Following withdrawal of the NG tube, pass a polyvinyl tube (2 mm in outer diameter) with several openings cut along its length and containing a cotton thread transnasally until tip is approximately in the lower part of the esophagus.a
Patient should lie supine for 2 hours; after patient sits up, rapidly withdraw tube and remove cotton thread.a Staining of the thread opposite the holes in the tube occurs in patients with reflux.a
IV Administration
Nacrotic abscesses may result if extravasation occurs.a
Rate of Administration
Inject slowly over several minutes.a b (See Increased Production of Methemoglobin under Cautions.)
Dosage
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Pediatric Patients
Methemoglobinemia
IV
Usually, 1–2 mg/kg.a b Alternatively, 25–50 mg/m2 has been administered.a Repeat dose after 1 hour if needed.a
Gastroesophageal Reflux
NG Tube
5 mL/kg into the fasting stomach.a (See Oral Administration: NG Tube, Under Dosage and Administration.)
Adults
Methemoglobinemia
Acute Methemoglobinemia
Oral
Usually, 65–130 mg 3 times daily.a
IV
Usually, 1–2 mg/kg.a b Alternatively, 25–50 mg/m2 has been administered.a Repeat dose after 1 hour if needed.a
Chronic Methemoglobinemia
Oral
Maintenance therapy: 100–300 mg daily has been recommended.a
Urolithiasis
Oral
Usually, 65 mg 3 times daily.a
Prescribing Limits
Pediatric Patients
Methemoglobinemia
IV
Maximum 2 mg/kg.a b (See Large IV Doses under Cautions.)
Adults
Methemoglobinemia
IV
Maximum 2 mg/kg.a b (See Large IV Doses under Cautions.)
Special Populations
Hepatic Impairment
No specific dosage recommendations at this time.a b c
Renal Impairment
No specific dosage recommendations at this time.a b c (See Contraindications under Cautions.)
Geriatric Patients
No specific dosage recommendations at this time.a b c
Cautions for Methylene Blue
Contraindications
Intrathecal injection.a b
Severe renal impairment.a c
Hypersensitivity to methylene blue or any ingredient in the formulation.a c
Warnings/Precautions
Warnings
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Route of Administration
Necrotic abscesses may result from sub-Q administration or if extravasation occurs.a
Neural damage may result from intrathecal injection.a (See Contraindications under Cautions.)
Major Toxicities
Large IV Doses
Large IV doses may cause precordial pain, dizziness, headache, hypertension, profuse sweating, mental confusion, the formation of methemoglobin, cyanosis, nausea, vomiting or abdominal pain.a b Do not exceed recommended IV dose.b (See Prescribing Limits under Dosage and Administration.)
General Precautions
Increased Production of Methemoglobin
Methemoglobin production may be increased if methylene blue is injected too rapidly; inject IV slowly over several minutes to prevent a local high concentration of methylene blue.a b
Dye Properties
Methylene blue may stain skin; a hypochlorite solution may remove skin stains.a
Methylene blue imparts a blue-green color to urine and sometimes feces.a c
Hematologic Effects
Long-term administration may result in marked anemia due to accelerated destruction of erythrocytes; monitor hemoglobin concentrations frequently.a
Possible hemolysis, especially in young infants and in patients with G-6-PD deficiency.a
Genitourinary Effects
Possible bladder irritation following oral administration.a c
Specific Populations
Pregnancy
Category C.d
Lactation
No data available.d e
Pediatric Use
Safety and efficacy not established.e
Possible increased risk of hemolysis in young infants.a
Geriatric Use
Safety and efficacy not established.e
Hepatic Impairment
Safety and efficacy not established.e
Renal Impairment
Safety and efficacy not established.e Contraindicated in patients with severe renal impairment.a c
Common Adverse Effects
High IV doses: Nausea, abdominal and precordial pain, dizziness, headache, profuse sweating, mental confusion, methemoglobin formation.b
Oral administration: Bladder irritation.c
Interactions for Methylene Blue
No formal drug interaction studies conducted.b c
Methylene Blue Pharmacokinetics
Absorption
Bioavailability
Well absorbed from the GI tract.a
Elimination
Metabolism
In tissues, rapidly reduced to leukomethylene blue, which is stabilized in some salt, complex, or combination form in urine but not in blood.a Some leukomethylene blue may be partially demethylated.a
Elimination Route
Excreted in the urine and bile.a About 75% of an oral dose is excreted in urine, primarily as stabilized colorless leukomethylene blue.a
On exposure to air, urine turns green or blue due to the presence of the oxidation product methylene azure (methylene blue sulfone).a
Some unchanged drug is also excreted in urine.a
Stability
Storage
Parenteral
Solution for Injection
20–25°C.b
Actions
Low concentrations increase the rate of conversion of methemoglobin to hemoglobin.a b
High concentrations convert ferrous iron of reduced hemoglobin to ferric iron, resulting in methemoglobin formation.a b In cyanide toxicity, methemoglobin combines with cyanide to form cyanmethemoglobin, thereby preventing the potentially lethal interference of cyanide with the cytochrome system vital to cellular respiration.a
Directly inhibits calcium binding by oxalate and by organic stone matrix.a
Acts as a crystal poison at the interface, reducing the tendency of calcium oxalate particles to aggregate.a In addition, it reverses intracellular acidosis (such as that in renal tubule acidosis), apparently by competing with diphosphopyridine nucleotide as a hydrogen receptor.a
Possesses weak antiseptic and tissue-staining properties and is reported to inhibit amine oxidase in tissues.a
Appears to bind irreversibly to viral nucleic acid and causes disruption of the virus molecule upon exposure to light.a
Advice to Patients
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Importance of informing patients that urine or feces may be discolored a blue-green hue.c a Skin may also be stained; a hypochlorite solution may remove the stain.a
Importance of advising patients to take oral dose after meals with a full glass of water.a c
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.a b
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.a
Importance of informing patients of other important precautionary information.b c (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Bulk | Powder* | |||
Parenteral | Injection, for IV use | 10 mg/mL* | Methylene Blue 1% Injection | Akorn, American Regent |
Methylene blue is also commercially available as reagent solutions and in combination with analgesics, anti-infectives, and antispasmodics.
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 24, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
References
a. AHFS Drug Information 2007. McEvoy GK, ed. Methylene Blue. Bethesda, MD: American Society of Health-System Pharmacists; 2007: 3664-3665.
b. Taylor Pharmaceuticals. Methylene Blue 1% injection prescribing information. Decatur, IL; 2006 Mar. Accessed 23 Sep 2007 from website.
c. Star Pharmaceuticals. Urolene Blue(methylene blue) tablets prescribing information. FL. Accessed 24 Sep 2007 from website.
d. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 7th edition. Philadelphia, PA: Lippincott, Williams, & Wilkins, 2005: 1050-51.
e. Akorn, Decatur, IL; Personal communication.
f. Star Pharmaceuticals, FL; Personal communication.
g. K A Manne Co Inc, Johns Island, SC; Personal communication.
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