FDA Updates Warnings on Methylene Blue, Linezolid, and Serotonergics

Disclosures

October 21, 2011

October 21, 2011 — The US Food and Drug Administration (FDA) has fine-tuned a warning issued in July to avoid prescribing either methylene blue or linezolid (Zyvox, Pfizer) in combination with serotonergic agents because of the potential to cause serotonin syndrome.

Today, the FDA announced that the risk for this harmful interaction appears to be confined, in general, to 2 specific types of serotonergic drugs: selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors.

Methylene blue is a dye used in diagnostic procedures and in the treatment of conditions ranging from cyanide poisoning to methemoglobinemia. Linezolid is an antibacterial agent. Both drugs inhibit the action of monoamine oxidase A, an enzyme that breaks down serotonin. This allows the levels of the neurotransmitter to rise.

When serotonin builds up to excessive levels in patients taking serotonergic agents, the result can be serotonin syndrome. Its signs and symptoms include confusion, hyperactivity, memory problems, and other mental changes; muscle twitching, excessive sweating, shivering, or shaking; diarrhea; trouble with coordination; and fever.

In July, the FDA announced that its Adverse Event Reporting System database had received reports of cases of serotonin syndrome in patients taking serotonergic drugs together with linezolid or methylene blue. In a few cases involving linezolid, the patient died.

In 2 separate but similarly worded announcements issued today regarding linezolid and methylene blue, the FDA retreated from the earlier blanket warning about serotonergics. The agency stated that not all such agents "have an equal capacity to cause serontonin syndrome" in combination with the 2 other drugs. Most Adverse Event Reporting System reports of serontonin syndrome involving linezolid, the FDA stated, occurred in patients taking either a selective serotonin reuptake inhibitor or a serotonin-norepinephrine reuptake inhibitor.

Likewise, the cases involving methylene blue happened with patients receiving these same drugs as well as clomipramine, a tricyclic antidepressant. The agency noted that most of these patients had received methylene blue intravenously in the course of parathyroid surgery.

The FDA stated that it is not clear whether the combination of either linezolid or methylene blue with psychiatric drugs of lesser degrees of serotonergic activity poses "a comparable risk." Such drugs with an unclear risk consist of most tricyclic antidepressants, monoamine oxidase inhibitors, and several others: amoxapine, maprotiline, nefazodone, trazodone, bupropion, buspirone, and mirtazapine.

In addition, the agency said that because methylene blue is an unapproved drug with little data about its use in various settings, it does not know whether administering it orally or by injection, as opposed to intravenously, to patients receiving a serotonergic runs the risk for serotonin syndrome. The same uncertainty applies to intravenous doses of methylene blue lower than 1 mg/kg.

More information about the FDA announcements on linezolid and methylene blue is available on the agency's Web site.

To report adverse events related to methylene blue or linezolid, contact MedWatch, the FDA's Safety Information and Adverse Event Reporting System, by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/Safety/MedWatch/default.htm, or by mail to MedWatch, FDA, 5600 Fishers Lane, Rockville, Maryland 20852-9787.

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