FDA Drug Safety Communication: Warning against use of Xyrem (sodium oxybate) with alcohol or drugs causing respiratory depression

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

Safety Announcement

[12-17-2012] The U.S. Food and Drug Administration (FDA) is reminding healthcare professionals and patients that the combined use of Xyrem (sodium oxybate) with alcohol or central nervous system (CNS) depressant drugs can markedly impair consciousness and may lead to severe breathing problems (respiratory depression). The use of alcohol with Xyrem is a new contraindication (FDA warns against combined use) added to the Xyrem label, which already contraindicates its use with insomnia drugs. The use of Xyrem with other CNS depressant drugs (drugs that affect the CNS and may lead to breathing problems) such as opioid analgesics, benzodiazepines, sedating antidepressants or antipsychotics, general anesthetics, and muscle relaxants should generally be avoided.

Facts about Xyrem (sodium oxybate)

Approved to reduce attacks of muscle weakness (cataplexy) and treat daytime sleepiness in patients with narcolepsy.
Sodium oxybate, the active ingredient of Xyrem, is also known as gamma-hydroxybutyrate (GHB). GHB is a known drug of abuse that has been associated with central nervous system (CNS) adverse events, including death. Even at recommended doses, Xyrem can cause confusion, depression, and other neuropsychiatric events.
Important CNS adverse events caused by abuse of GHB include seizures, respiratory depression, and profound decreases in level of consciousness, sometimes leading to coma and death.
Xyrem is available only through the Xyrem Success Program, which provides for restricted distribution of the drug through a central mail-order pharmacy.

FDA recently evaluated reports of patients who died while taking Xyrem along with alcohol or other CNS depressants. The cause of these deaths is not clear because the reports contained incomplete information and did not adequately address confounding factors, such as pre-existing sleep apnea and/or chronic obstructive lung disease (COPD) (see Data Summary). Given some of the circumstances noted in the deaths, however, FDA determined that the recommendations in the Xyrem drug label should be strengthened to more strongly remind healthcare professionals and patients of the risks when using Xyrem with CNS depressant drugs or alcohol.
Healthcare professionals are urged to follow the dosing recommendations, contraindications, and boxed warning in the updated Xyrem drug label (PDF - 566KB) and to avoid drug combinations that raise the risk of respiratory depression and death. Patients taking Xyrem should not drink alcohol or take insomnia drugs. The use of Xyrem along with these products or other CNS depressants increases the risk of breathing problems that may lead to loss of consciousness, coma, and death.
The Xyrem drug label (PDF - 566KB) is being revised as follows:

The addition of the statement: “Patients should not drink alcohol when using Xyrem.” (Contraindications section)
The addition of a statement recommending that, when concomitant use of Xyrem with a central nervous system depressant is required, a reduction in dose or discontinuation of one or more central nervous system depressants (including Xyrem) should be considered; and a further recommendation that, if short-term opioid treatment is required, interruption of Xyrem treatment should be considered (Warnings and Precautions section)
The addition of a sentence stating that Xyrem may be dispensed only to patients enrolled in the Xyrem Success Program(Indications and Usage section)
The addition of an updated summary of risks; a description of the components of the Xyrem Success Program; and details of the website and phone number where further information about Xyrem can be obtained (Warnings and Precautions section)

Additional Information for Patients

Patients who drink alcohol or take CNS depressant drugs while they are taking Xyrem are at increased risk of depressed breathing, loss of consciousness, coma, and death.
Alcohol or drugs for insomnia should not be used with Xyrem, and treatment with other CNS depressant drugs should generally be avoided.
Xyrem itself can depress breathing.
If you already have a medical condition that affects your breathing, such as a lung condition or sleep apnea (a condition where you stop breathing for short periods when you are asleep), you may have a higher risk of serious side effects (such as depressed breathing, loss of consciousness, coma, and death) when you take Xyrem. Talk to your healthcare professional to make sure Xyrem is still right for you.
Tell your healthcare professional if you develop a medical condition that affects your breathing.
Do not stop taking Xyrem without talking to your healthcare professional.
Discuss any questions you have about Xyrem with your healthcare professional.
Report any side effects you experience to the FDA MedWatch program using the information in the “Contact FDA” box at the bottom of the page.

Additional Information for Healthcare Professionals

Remind patients not to drink alcohol or take insomnia drugs when taking Xyrem; be mindful of the increased risk of respiratory depression, loss of consciousness, coma, and death with such combined use. The concurrent use of Xyrem with other CNS depressants may also increase the risk of respiratory depression, hypotension, profound sedation, syncope, and death. Follow the updated information in the Xyrem drug labeling (PDF - 566KB).
Xyrem should be used cautiously, if at all, in patients with respiratory issues such as sleep apnea or COPD because of the risk of respiratory depression.
Report adverse events involving Xyrem to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of the page.

Data Summary

Using information from postmarket adverse event reports submitted to FDA's Adverse Event Reporting System (AERS) or to Xyrem’s manufacturer (Jazz Pharmaceuticals), FDA evaluated reports of patients who died while taking Xyrem. The case descriptions were reviewed to determine whether Xyrem caused the deaths.
Many of the reports of death were poorly documented or incomplete, making it impossible for FDA to determine if patient deaths could be attributed to Xyrem.
A number of deaths occurred in patients who were reported to be concomitantly taking one or more medications that could depress the CNS. Such drugs included neuroleptics, benzodiazepines, opioids, and others; in a few patients, many such medications were being used concurrently. Other patients were reported to have ingested alcohol while taking Xyrem. A number of deaths occurred in patients who were prescribed Xyrem at doses that exceeded the recommended maximum dose or who underwent more rapid dose titration than recommended in the product label. Many of the deaths occurred in patients who were prescribed Xyrem for unapproved uses such as fibromyalgia, insomnia, or migraine. Some deaths were ascribed to drowning, suicide, or unknown causes.
Many of the deaths occurred in patients prescribed Xyrem who also had serious psychiatric disorders such as depression and substance abuse. A variety of concomitant illnesses were also present that may have predisposed some patients to the CNS and respiratory depressant effects of Xyrem.
FDA reminds healthcare professionals to follow the information in the updated Xyrem drug label to ensure safe use of Xyrem.