The full contraindications for Xyrem recommended by the CHMP include patients with hypersensitivity to the active substance or to any of the excipients; patients with major depression; patients with succinic semialdehyde dehydrogenase deficiency and patients being treated with opioids or barbiturates.
[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. */
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.
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.
The Xywav and Xyrem REMS program is used to help decrease the risk of serious side effects of Xyrem, such as misuse and central nervous system (CNS) depression. This program limits how freely Xyrem is prescribed (as well as a similar drug called Xywav).
Xyrem can cause central nervous system (CNS) depression in some people. In fact, Xyrem belongs to a class of medications called CNS depressants. And Xyrem has a boxed warning from the FDA regarding the risk of CNS depression. A boxed warning is the strongest warning the FDA requires. It alerts doctors and patients about drug effects that may be dangerous.
With CNS depression, the function of your central nervous system is slowed down too much. Sometimes this can cause respiratory depression (slow, weak breathing), which can be life threatening. Other symptoms of CNS depression can include:
Taking other drugs that are CNS depressants along with Xyrem can increase your risk of respiratory depression. With respiratory depression, you have weak and slow breathing. In some cases, this condition can be fatal.
With CNS depression, you have slowed function of your brain. Symptoms of CNS depression can be severe and may include slow or weak breathing, low blood pressure, sleepiness, and passing out. And rarely, CNS depression may even lead to death.
Central nervous system depression. Xyrem is a central nervous system (CNS) depressant. This means that it works by relaxing your central nervous system, including muscles that help you breathe.
Dependence can lead to misuse (sometimes called abuse). Misuse is associated with seizures, respiratory depression, loss of consciousness, coma, and death. It is important to monitor people taking Xyrem for signs of dependence or misuse. The REMS program for Xyrem should be followed when prescribing and dispensing this drug.
WARNING: Taking XYREM with other Central Nervous System (CNS) depressants such as medicines used to make you or your child fall asleep, including opioid analgesics, benzodiazepines, sedating antidepressants, antipsychotics, sedating anti-epileptic medicines, general anesthetics, muscle relaxants, alcohol, or street drugs, may cause serious medical problems, including trouble breathing (respiratory depression), low blood pressure (hypotension), changes in alertness (drowsiness), fainting (syncope), and death.
The active ingredient of XYREM is a form of gamma hydroxybutyrate (GHB). Abuse or misuse of illegal GHB alone or with other CNS depressants (drugs that cause changes in alertness or consciousness) have caused serious side effects. These effects include seizures, trouble breathing (respiratory depression), changes in alertness (drowsiness), coma, and death. Call your doctor right away if you or your child has any of these serious side effects.
XYREM is a Central Nervous System (CNS) depressant. In clinical trials at recommended doses, obtundation and clinically significant respiratory depression occurred in adult patients treated with XYREM. Many patients who received XYREM during clinical trials in narcolepsy were receiving CNS stimulants.
XYREM is the sodium salt of gamma-hydroxybutyrate (GHB). Abuse or misuse of illicit GHB, either alone or in combination with other CNS depressants, is associated with CNS adverse reactions, including seizure, respiratory depression, decreases in the level of consciousness, coma, and death.
Because of the risks of CNS depression and abuse and misuse, XYREM is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the XYWAV and XYREM REMS.
The concurrent use of XYREM with other CNS depressants, including but not limited to opioid analgesics, benzodiazepines, sedating antidepressants or antipsychotics, sedating anti-epileptic drugs, general anesthetics, muscle relaxants, and/or illicit CNS depressants, may increase the risk of respiratory depression, hypotension, profound sedation, syncope, and death. If use of these CNS depressants in combination with XYREM is required, dose reduction or discontinuation of one or more CNS depressants (including XYREM) should be considered. In addition, if short-term use of an opioid (eg, post- or perioperative) is required, interruption of treatment with XYREM should be considered.
After first initiating treatment and until certain that XYREM does not affect them adversely (eg, impair judgment, thinking, or motor skills), caution patients against hazardous activities requiring complete mental alertness or motor coordination such as operating hazardous machinery, including automobiles or airplanes. Also caution patients against these hazardous activities for at least 6 hours after taking XYREM. Patients should be queried about CNS depression-related events upon initiation of XYREM therapy and periodically thereafter.
XYREM is a Schedule III controlled substance. The active ingredient of XYREM, sodium oxybate or gamma hydroxybutyrate (GHB), is a Schedule I controlled substance. Abuse of illicit GHB, either alone or in combination with other CNS depressants, is associated with CNS adverse reactions, including seizure, respiratory depression, decreases in the level of consciousness, coma, and death. The rapid onset of sedation, coupled with the amnestic features of XYREM, particularly when combined with alcohol, has proven to be dangerous for the voluntary and involuntary user (eg, assault victim). Physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely.
XYREM may impair respiratory drive, especially in patients with compromised respiratory function. In overdoses, life-threatening respiratory depression has been reported. Prescribers should be aware that increased central apneas and clinically relevant desaturation events have been observed with XYREM administration in adult and pediatric patients. Prescribers should be aware that sleep-related breathing disorders tend to be more prevalent in obese patients, in men, in postmenopausal women not on hormone replacement therapy and among patients with narcolepsy.
In adult clinical trials in patients with narcolepsy (n=781), there were two suicides and two attempted suicides in XYREM-treated patients, including three patients with a previous history of depressive psychiatric disorder. Of the two suicides, one patient used XYREM in conjunction with other drugs. XYREM was not involved in the second suicide. Adverse reactions of depression were reported by 7% of 781 XYREM-treated patients, with four patients (
Discontinuation: Of the 398 XYREM-treated adult patients with narcolepsy, 10.3% of patients discontinued because of adverse reactions compared with 2.8% of patients receiving placebo. The most common adverse reaction leading to discontinuation was nausea (2.8%). The majority of adverse reactions leading to discontinuation began during the first few weeks of treatment. In the pediatric clinical trial, 7 of 104 patients reported adverse reactions that led to withdrawal from the study (hallucination, tactile; suicidal ideation; weight decreased; sleep apnea syndrome; affect lability; anger, anxiety, depression; and headache). 153554b96e