FDA Drug Safety Communication: Serious CNS reactions possible when linezolid (Zyvox) is given to patients taking certain psychiatric medications

The FDA has issued new information about this safety issue, see the FDA Drug Safety Communication issued 10-20-2011.

Safety Announcement
Additional Information for Patients
Additional Information for Healthcare Professionals
Data Summary
References

Safety Announcement

[07-26-2011] The U.S. Food and Drug Administration (FDA) has received reports of serious central nervous system (CNS) reactions when the antibacterial drug linezolid (marketed as Zyvox) 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 linezolid can be found here.

Facts about Linezolid (Zyvox)

Used to treat infections, including pneumonia, infections of the skin, and infections caused by a resistant bacterium (Enterococcus faecium).
Is a reversible monoamine oxidase inhibitor (MAOI).

Although the exact mechanism of this drug interaction is unknown, linezolid inhibits the action of monoamine oxidase A—an enzyme responsible for breaking down serotonin in the brain. It is believed that when linezolid 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.

Healthcare professionals and patients may not realize that linezolid has monoamine oxidase inhibitor (MAOI) properties. Linezolid 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 linezolid such as when:

Linezolid is used to treat vancomycin-resistant Enterococcus faecium (VRE) infections.
Linezolid is used to treat infections such as nosocomial pneumonia and complicated skin and skin structure infections, including cases caused by methicillin-resistant Staphylococcus aureus (MRSA).

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 and linezolid (Zyvox). (See Additional Information for Healthcare Professionals)

A separate Drug Safety Communication (DSC) is being released today for methylene blue due to similar potential drug interactions with serotonergic psychiatric medications and includes drug usage recommendations.

Additional Information for Patients

You may need to temporarily stop taking your serotonergic psychiatric medication if it becomes necessary for you to take linezolid in certain situations. Your healthcare provider will tell you when to start linezolid after stopping your serotonergic psychiatric medication.
Do not stop taking your serotonergic psychiatric medicine without first talking to a healthcare professional.
Make sure your healthcare professional knows about all the medications you are taking. It is helpful to keep a list of all your current medications in your wallet or another location where it is easily retrieved.
Contact your healthcare professional immediately if you are taking a serotonergic psychiatric medication and develop any of the following symptoms: mental changes (confusion, hyperactivity, memory problems), muscle twitching, excessive sweating, shivering or shaking, diarrhea, trouble with coordination, and/or fever.
Discuss any questions or concerns about linezolid or serotonergic psychiatric medications with your healthcare professional.
Report any serious side effects you experience to the FDA MedWatch program using the information in the "Contact Us" box at the bottom of the page.

Additional Information for Healthcare Professionals

Linezolid (Zyvox) can interact with serotonergic psychiatric medications and cause serious CNS toxicity.
In emergency situations requiring life-threatening or urgent treatment with linezolid (as described above), the availability of alternative interventions should be considered and the benefit of linezolid treatment should be weighed against the risk of serotonin toxicity. If linezolid must be administered to a patient receiving a serotonergic drug, the serotonergic drug must be immediately stopped and the patient should be closely monitored for emergent symptoms of CNS toxicity for two weeks (five weeks if fluoxetine [Prozac] was taken), or until 24 hours after the last dose of linezolid, whichever comes first.
In non-emergency situations when non-urgent treatment with linezolid is contemplated and planned, the serotonergic psychiatric medication should be stopped, to allow its activity in the brain to dissipate. Most serotonergic psychiatric drugs should be stopped at least 2 weeks in advance of linezolid treatment. Fluoxetine (Prozac), which has a longer half-life compared to similar drugs, should be stopped at least 5 weeks in advance.
Treatment with the serotonergic psychiatric medication may be resumed 24 hours after the last dose of linezolid.
Serotonergic psychiatric medications should not be started in a patient receiving linezolid. Wait until 24 hours after the last dose of linezolid before starting the antidepressant.
Educate your patients to recognize the symptoms of serotonin toxicity or CNS toxicity and advise them to contact a healthcare professional immediately if they experience any symptoms while taking serotonergic psychiatric medications or linezolid.
Report adverse events involving linezolid or serotonergic psychiatric medications to the FDA MedWatch program, using the information in the "Contact Us" box at the bottom of the page.

Data Summary

FDA has received adverse event reports from the FDA Adverse Event Reporting System (AERS) database involving cases in which serotonin syndrome was associated with the concomitant administration of linezolid and a serotonergic psychiatric medication. Some deaths were reported. The literature search identified additional case reports, including at least 1 case with a fatal outcome.¹

Based on the available information provided in the AERS cases and literature, FDA has concluded that the concomitant administration of a serotonergic psychiatric medication with linezolid has the potential for a drug interaction causing serotonin syndrome. It appears this potential drug interaction can also occur following the discontinuation of serotonergic psychiatric medications with long half-lives. As a result, linezolid should generally not be given to patients taking serotonergic drugs unless the benefit is deemed to outweigh the risk.

References

Clark DB, Andrus MR, Byrd DC. Drug interactions between linezolid and selective serotonin reuptake inhibitors: case report involving sertraline and review of the literature. Pharmacotherapy. 2006;26:269-76.

Tables -Psychiatric medications with serotonergic activity

Selective Serotonin Reuptake Inhibitors (SSRIs)

Generic name	Found in Brand name(s)
paroxetine	Paxil, Paxil CR, Pexeva
fluvoxamine	Luvox, Luvox CR
fluoxetine	Prozac, Sarafem, Symbyax
sertraline	Zoloft
citalopram	Celexa
escitalopram	Lexapro

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

Generic name	Found in Brand name(s)
venlafaxine	Effexor, Effexor XR
desvenlafaxine	Pristiq
duloxetine	Cymbalta

Tricyclic Antidepressants (TCAs)

Generic name	Found in Brand name(s)
amitriptyline	Amitid, Amitril, Elavil, Endep, Etrafon, Limbitrol, Triavil
desipramine	Norpramin, Pertofrane
clomipramine	Anafranil
imipramine	Tofranil, Tofranil PM, Janimine, Pramine, Presamine
nortriptyline	Pamelor, Aventyl hydrochloride
protriptyline	Vivactil
doxepin	Sinequan, Zonalon, Silenor
trimipramine	Surmontil

Monoamine Oxidase Inhibitors (MAOIs)

Generic name	Found in Brand name(s)
Isocarboxazid	Marplan
Phenelzine	Nardil
Selegiline	Emsam, Eldepryl, Zelapar
Tranylcypromine	Parnate

Other Psychiatric Medications

Generic name	Found in Brand name(s)
amoxapine	Asendin
maprotiline	Ludiomil
nefazodone	Serzone
trazodone	Desyrel, Oleptro, Trialodine
bupropion	Wellbutrin, Wellbutrin SR, Wellbutrin XL, Zyban, Aplenzin
buspirone	Buspar
vilazodone	Viibryd
mirtazapine	Remeron, Remeron Soltab

Related Information