Xyrem (sodium oxybate)
Xyrem (sodium oxybate) is a Central Nervous System (CNS) depressant. In clinical trials at recommended doses, obtundation and clinically significant respiratory depression occurred in XYREM-treated patients. Almost all of the patients who received XYREM during clinical trials in narcolepsy were receiving CNS stimulants.
Xyrem (sodium oxybate) is the sodium salt of gamma hydroxybutyrate (GHB). Abuse of 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, abuse, and misuse, XYREM is available only through a restricted distribution program called the XYREM REMS Program, using the central pharmacy that is specially certified. Prescribers and patients must enroll in the program
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 the second nightly dose. Patients should be queried about CNS depression-related events upon initiation of XYREM therapy and periodically thereafter.
Abuse and Misuse
Xyrem (sodium oxybate) 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 (sodium oxybate) REMS Program
Because of the risks of central nervous system depression and abuse/misuse, XYREM is available only through a restricted distribution program called the XYREM REMS Program.
Required components of the XYREM REMS Program include:
- Healthcare Providers who prescribe XYREM are specially certified
- XYREM will be dispensed only by the central pharmacy that is specially certified
- XYREM will be dispensed and shipped only to patients who are enrolled in the XYREM REMS Program with documentation of safe use
Respiratory Depression and Sleep-Disordered Breathing
Xyrem (sodium oxybate) 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 sleep-related breathing disorders tend to be more prevalent in obese patients and in postmenopausal women not on hormone replacement therapy as well as among patients with narcolepsy.
Depression and Suicidality
In 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 (<1%) discontinuing because of depression. In most cases, no change in XYREM treatment was required. The emergence of depression in patients treated with XYREM requires careful and immediate evaluation. Patients with a previous history of a depressive illness and/or suicide attempt should be monitored carefully for the emergence of depressive symptoms while taking XYREM.
Other Behavioral or Psychiatric Adverse Reactions
During clinical trials in narcolepsy, 3% of 781 patients treated with XYREM experienced confusion, with incidence generally increasing with dose. In a controlled trial where patients were randomized to fixed total daily doses of 3 g, 6 g, or 9 g per night or placebo, a dose-response relationship for confusion was demonstrated, with 17% of patients at 9 g per night experiencing confusion. Patients treated with XYREM who become confused should be evaluated fully, and appropriate intervention considered on an individual basis.
Anxiety occurred in 5.8% of the 874 patients receiving XYREM in clinical trials in another population. The emergence of or increase in anxiety in patients taking XYREM should be carefully monitored. Other neuropsychiatric reactions reported in XYREM clinical trials and the post-marketing setting included hallucinations, paranoia, psychosis, aggression, and agitation. The emergence of thought disorders and/or behavior abnormalities requires careful and immediate evaluation.
Instances of significant injury or potential injury were associated with sleepwalking during a clinical trial of XYREM in patients with narcolepsy. Episodes of sleepwalking should be fully evaluated and appropriate interventions considered.
Use in Patients Sensitive to High Sodium Intake
Xyrem (sodium oxybate) has a high salt content. In patients sensitive to salt intake (eg, those with heart failure, hypertension, or renal impairment), consider the amount of daily sodium intake in each dose of XYREM.
MOST COMMON ADVERSE REACTIONS
In three controlled clinical trials, the most common adverse reactions (incidence ≥5% and twice the rate seen with placebo) in XYREM-treated patients were nausea (20%), dizziness (15%), vomiting (11%), somnolence (8%), enuresis (7%), and tremor (5%).
ADDITIONAL ADVERSE REACTIONS
Additional adverse reactions that occurred in ≥2% of patients in any treatment group for three controlled trials and were more frequent in any XYREM treatment group than with placebo were diarrhea, upper abdominal pain, dry mouth, pain, feeling drunk, peripheral edema, extremity pain, cataplexy, muscle spasms, paresthesia, attention disturbance, sleep paralysis, disorientation, anxiety, irritability, sleepwalking, and hyperhidrosis.
Discontinuation: Of the 398 XYREM-treated 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.