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Special Alerts
Methylene Blue: Risk of Serotonin Syndrome when Administered in Combination with Serotonin Reuptake Inhibitors
February 2011
Health Canada has issued important safety information notifying practitioners of updates to the methylene blue Canadian prescribing information. These changes are a result of several case reports of serotonin toxicity in association with the use of injectable methylene blue in patients exposed to selective serotonin reuptake inhibitors (SSRIs) or other drugs with serotonin reuptake inhibition properties (eg, duloxetine, venlafaxine, clomipramine). Recent research has shown that methylene blue has structural properties similar to monoamine oxidase inhibitors (MAOI). Revisions to the prescribing information will include the following points:
- Serotonin syndrome (agitation or diaphoresis, or hypertonia accompanied with fever, and tremor, hyperreflexia, or clonus) has been reported when methylene blue was administered intravenously at doses as low as 1 mg/kg in patients also receiving other medications with serotonin reuptake inhibition properties. Several of these cases required admission to the intensive care unit.
- Carefully consider concurrent use of methylene blue with a serotonin reuptake inhibitor; allow a washout period of at least 4-5 half-lives of the serotonin reuptake inhibitor prior to intravenous methylene blue use.
For further detail regarding these changes, please refer to http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2011/methylene_blue-bleu_nth-aah-eng.php
Pronunciation
(METH i leen bloo)
Generic Available (U.S.)
Yes
Index Terms
Pharmacologic Category
Use: Labeled Indications
Antidote for cyanide poisoning and drug-induced methemoglobinemia, indicator dye
Use: Unlabeled/Investigational
Treatment/prevention of ifosfamide-induced encephalopathy; topically, in conjunction with polychromatic light to photoinactivate viruses such as herpes simplex; alone or in combination with vitamin C for the management of chronic urolithiasis
Pregnancy Risk Factor
C
Contraindications
Hypersensitivity to methylene blue or any component of the formulation; intraspinal injection; renal insufficiency
Warnings/Precautions
Concerns related to adverse effects:
• Anemia: Continued use can cause profound anemia.
• 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. Monitor methemoglobin concentrations regularly during administration.
Disease-related concerns:
• Renal impairment: Use with caution in patients with severe impairment.
Concurrent drug therapy issues:
• Serotonin modulators: Serotonin syndrome has been reported with concomitant administration of methylene blue and serotonin reuptake inhibitors (eg, SSRIs, SNRIs, tricyclic antidepressants); avoid concomitant use and allow a washout period of at least 4-5 half-lives of the serotonin reuptake inhibitor prior to intravenous methylene blue use.
Special populations:
• G6PD deficiency: Use with caution in patients with G6PD deficiency.
• Young patients: Use with caution in young patients.
Other warnings/precautions:
• Administration: Do not inject SubQ or intrathecally.
• Enteral feedings: Methylene blue should not be added to enteral feeding products (Durfee, 2006; Wessel, 2005). Safety and efficacy have not been established.
Adverse Reactions
Frequency not defined.
Cardiovascular: Hypertension, precordial pain
Central nervous system: Dizziness, headache, fever, mental confusion
Dermatologic: Staining of skin
Gastrointestinal: Abdominal pain, fecal discoloration (blue-green), nausea, vomiting
Genitourinary: Bladder irritation, discoloration of urine (blue-green)
Hematologic: Anemia, transient reduction in oxygen saturation as read by pulse oximetry
Miscellaneous: Diaphoresis
Postmarketing and/or case reports: Serotonin syndrome
Drug Interactions
Mirtazapine: May enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid combination
Nefazodone: May enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid combination
Selective Serotonin Reuptake Inhibitors: May enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. 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
TraZODone: May enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid combination
Tricyclic Antidepressants: May enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid combination
Mechanism of Action
Weak germicide in low concentrations, hastens the conversion of methemoglobin to hemoglobin; has opposite effect at high concentrations by converting ferrous ion of reduced hemoglobin to ferric ion to form methemoglobin; in cyanide toxicity, it combines with cyanide to form cyanmethemoglobin preventing the interference of cyanide with the cytochrome system
Pharmacodynamics/Kinetics
Onset of action: Reduction of methemoglobin: I.V.: 30-60 minutes
Absorption: Oral: 53% to 97%
Metabolism: Peripheral reduction to leukomethylene blue
Excretion: In bile, feces, and urine as leukomethylene blue
Dosage
Children and Adults: Methemoglobinemia: I.V.: 1-2 mg/kg or 25-50 mg/m2 over 5-10 minutes; may be repeated in 1 hour if necessary
Adults: Ifosfamide-induced encephalopathy (unlabeled use): Note: Treatment may not be necessary; encephalopathy may improve spontaneously: I.V.:
Prevention: 50 mg every 6-8 hours
Treatment: 50 mg as a single dose or every 4-8 hours until symptoms resolve
Dosage adjustment in renal impairment: No dosage adjustment recommendations available; however, caution should be used in severe renal impairment.
Administration: I.V.
Administer undiluted by direct I.V. injection over 5-10 minutes. For the treatment of ifosfamide-induced encephalopathy, methylene blue may be administered either undiluted as a slow I.V. push over at least 5 minutes or diluted in 50 mL NS or D5W and infused over at least 5 minutes. Consider concomitant dextrose administration, especially in patients who are hypoglycemic, to ensure efficacy of methylene blue.
Monitoring Parameters
Arterial blood gases; cardiac monitoring (patients with pre-existing pulmonary and/or cardiac disease); CBC; methemoglobin levels (co-oximetry yields a direct and accurate measure of methemoglobin levels); pulse oximeter (will not provide accurate measurement of oxygenation when methemoglobin levels are >35%); renal function; signs and symptoms of methemoglobinemia such as pallor, cyanosis, nausea, muscle weakness, dizziness, confusion, agitation, dyspnea, and tachycardia; transcutaneous O2 saturation
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)
Additional Information
Skin stains may be removed using a hypochlorite solution.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause confusion or dizziness
Mental Health: Effects on Psychiatric Treatment
None reported
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution: 10 mg/mL (1 mL, 10 mL)
References
Albert M, Lessin MS, and Gilchrist BF, “Methylene Blue: Dangerous Dye for Neonates,” J Pediatr Surg, 2003, 38(8):1244-5.
Burnakis TG, “Inadvertent Substitution of Methylene Blue for Indigo Carmine to Detect Premature Rupture of Membranes,” Hosp Pharm, 1995, 30(4):336-8.
Clifton J 2nd and Leikin JB, “Methylene Blue,” Am J Ther, 2003, 10(4):289-91.
David KA and Picus J, “Evaluating Risk Factors for the Development of Ifosfamide Encephalopathy,” Am J Clin Oncol, 2005, 28(3):277-80.
Dawson AH and Whyte IM, “Management of Dapsone Poisoning Complicated by Methaemoglobinaemia,” Med Toxicol Adverse Drug Exp, 1989, 4(5):387-92.
DiSanto AR and Wagner JG, “Pharmacokinetics of Highly Ionized Drugs II: Methylene Blue - Absorption, Metabolism, and Excretion in Man and Dog After Oral Administration,” J Pharm Sci, 1972, 61(7):1086-90.
Durfee SM, Gallagher-Allred C, Pasquale JA, “Standards for Specialized Nutrition Support for Adult Residents of Long-Term Care Facilities,” Nutr Clin Pract, 2006, 21(1):96-104.
Harvey JW and Keitt AS, “Studies of the Efficacy and Potential Hazards of Methylene Blue Therapy in Aniline-Induced Methaemoglobinaemia,” Br J Haematol, 1983, 54(1):29-41.
Jahns BE, Rynn KO, and Paloucek FP, “Interference of Methylene Blue (MthB) in the Determination of Whole Blood Methemoglobin (MtHgb) Concentrations,” Vet Hum Toxicol, 1994, 36:342.
Maloney JP, Ryan TA, Brasel KJ, et al, “Food Dye Use in Enteral Feedings: A Review and a Call for a Moratorium,” Nutr Clin Pract, 2002, 17(3):169-81.
Mokhlesi B, Leikin JB, Murray P, et al, “Adult Toxicology in Critical Care: Part II: Specific Poisonings,” Chest, 2003, 123(3):897-922.
Patel PN, “Methylene Blue for Management of Ifosfamide-Induced Encephalopathy,” Ann Pharmacother, 2006, 40(2):299-303.
Pelgrims J, DeVos F, Van den Brande J, et al, “Methylene Blue in the Treatment and Prevention of Ifosfamide-Induced Encephalopathy: Report of 12 Cases and a Review of the Literature,” Br J Cancer, 2000, 82(2) 291-4.
Preiser JC, Lejeune P, Roman A, et al, “Methylene Blue Administration in Septic Shock: A Clinical Trial,” Crit Care Med, 1995, 23(2):259-64.
Sills M and Zinkham W, “Methylene Blue-Induced Heinz Body Hemolytic Anemia,” Arch Pediatr Adolesc Med, 1994, 148(3):306-10.
Turner AR, Duong CD, and Good DJ, “Methylene Blue for the Treatment and Prophylaxis of Ifosfamide-Induced Encephalopathy,” Clin Oncol (R Coll Radiol), 2003, 15(7):435-9.
Wessel J, Balint J, Crill C, et al, “Standards for Specialized Nutrition Support: Hospitalized Pediatric Patients,” Nutr Clin Pract, 2005, 20(1):103-116.
Wright RO, Lewander WJ, and Woolf AD, “Methemoglobinemia: Etiology, Pharmacology, and Clinical Management,” Ann Emerg Med, 1999, 34(5):646-56.
Zulian GB, Tullen E, and Maton B, “Methylene Blue for Ifosfamide-Associated Encephalopathy,” N Engl J Med, 1995, 332(18):1239-40.
Lexi-Comp.com
Last full review/revision June 2011
Content last modified June 2011
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