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Special Alerts
Update on Serious CNS Reactions Reported with Specifically Implicated Serotonergic Psychiatric Medications Such as SSRIs, SNRIs and Clomipramine
October 2011
The U.S. Food and Drug Administration (FDA) has acknowledged that drugs used for psychiatric treatment possess differing degrees of pro-serotonergic activity. Therefore, the FDA is not explicitly implicating psychiatric medications outside of the SSRIs, SNRIs, and clomipramine (Anafranil®) at this time, as there appears to be insufficient evidence to define a comparable risk. Other medications belonging to the tricyclic and MAOI classes, as well as other psychiatric medications, are listed in the updated bulletin as a precautionary measure, but without explicit wording to avoid concomitant use.
An updated list of medications to avoid or exercise caution with can be found at http://www.fda.gov/Drugs/DrugSafety/ucm276119.htm.
Methylene Blue: Serious CNS Reactions Reported with Concomitant Use of Serotonergic Psychiatric Medications
July 2011
Similar to the previous safety notice issued by Health Canada, the U.S. Food and Drug Administration (FDA) has issued a safety announcement regarding the potential for serotonin syndrome to develop in patients receiving methylene blue and psychiatric medications with serotonergic effects including, SSRIs, SNRIs, tricyclic and MAOI antidepressants, and other medications with proserotonergic properties. For a complete list of medications not to be used with methylene blue, please refer to the link below.
The FDA has received reports of serious CNS reactions with these combinations, thus prompting additional warnings to be added to the labels of the respective psychiatric medications. Use of methylene blue in emergency situations (eg, methemoglobinemia, cyanide poisoning, ifosfamide-induced encephalopathy) should prompt immediate discontinuation of any serotonergic medication with close monitoring for CNS adverse effects for 2 weeks (5 weeks if discontinuing fluoxetine), or for 24 hours after the last methylene blue dose. For nonemergent use of methylene blue, discontinue serotonergic medication(s) at least 2 weeks (5 weeks with fluoxetine) prior to initiating methylene blue therapy. Serotonergic psychiatric medications should not be initiated in any patient on methylene blue, but can be started 24 hours after the last dose of methylene blue.
Patients should notify their healthcare provider if they are taking any serotonergic psychiatric medications and reminded not to discontinue these medications without advice from their healthcare practitioner. Patients should be instructed to recognize the signs of CNS toxicity (eg, mental changes, muscle twitching, shivering, incoordination) and to report these symptoms immediately to their healthcare provider.
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
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; vasoplegia syndrome associated with cardiac surgery
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: Angina, arrhythmia, 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
Metabolism/Transport Effects
None known.
Drug Interactions
Antipsychotics: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Risk C: Monitor therapy
BuPROPion: May enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid combination
BusPIRone: May enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid combination
MAO Inhibitors: May enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid combination
Maprotiline: May enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid combination
Metoclopramide: Serotonin Modulators may enhance the adverse/toxic effect of Metoclopramide. This may be manifest as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome. Risk C: Monitor therapy
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 Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Risk D: Consider therapy modification
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
Vasoplegia syndrome associated with cardiac surgery (unlabeled use): I.V.: 1.5-2 mg/kg over 20-60 minutes administered once (Levin, 2004; Leyh, 2003). Note: Improvement of vasoplegia (eg, increased systemic vascular resistance, reduced vasopressor dosage) has been in observed 1-2 hours following methylene blue administration.
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% 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
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.
Levin RL, Degrange MA, Bruno GF, et al, “Methylene Blue Reduces Mortality and Morbidity in Vasoplegic Patients After Cardiac Surgery,” Ann Thorac Surg, 2004, 77(2):496-9.
Leyh RG, Kofidis T, Strüber M, et al, “Methylene Blue: The Drug of Choice for Catecholamine-Refractory Vasoplegia After Cardiopulmonary Bypass?” J Thorac Cardiovasc Surg, 2003, 125(6):1426-31.
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.
Shanmugam G, "Vasoplegic Syndrome -- the Role of Methylene Blue," Eur J Cardiothorac Surg, 2005, 28(5):705-10.
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 February 2012
Content last modified February 2012
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