xyrem

Important safety information

CNS depression: Use caution when considering the concurrent use of Xyrem with other CNS depressants ( 5.1 ). • Caution patients against hazardous activities requiring complete mental alertness or motor coordination within the first 6 hours of dosing or after first initiating treatment until certain that Xyrem does not affect them adversely ( 5.1 ). • Depression and suicidality: Monitor patients for emergent or increased depression and suicidality ( 5.5 ). • Confusion/Anxiety: Monitor for impaired motor/cognitive function ( 5.6 ). • Parasomnias: Evaluate episodes of sleepwalking ( 5.7 ). • High sodium content in Xyrem: Monitor patients with heart failure, hypertension, or impaired renal function ( 5.8 ). 5.1 Central Nervous System Depression Xyrem is a central nervous system (CNS) depressant. In adult clinical trials at recommended doses, obtundation and clinically significant respiratory depression occurred in patients treated with Xyrem. Xyrem is contraindicated in combination with alcohol and sedative hypnotics. 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 (e.g., post- or perioperative) is required, interruption of treatment with Xyrem should be considered. Healthcare providers should caution patients about operating hazardous machinery, including automobiles or airplanes, until they are reasonably certain that Xyrem does not affect them adversely (e.g., impair judgment, thinking, or motor skills). Patients should not engage in hazardous occupations or activities requiring complete mental alertness or motor coordination, such as operating machinery or a motor vehicle or flying an airplane, 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 available only through a restricted program under a REMS [see Warnings and Precautions ( 5.3 )] . 5.2 Abuse and Misuse 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 (e.g., assault victim). Because illicit use and abuse of GHB have been reported, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of GHB (e.g., increase in size or frequency of dosing, drug-seeking behavior, feigned cataplexy) [see Drug Abuse and Dependence ( 9.2 )]. Xyrem is available only through a restricted program under a REMS [see Warnings and Precautions ( 5.3 )] . 5.3 XYWAV and XYREM REMS Xyrem is available only through a restricted distribution program called the XYWAV and XYREM REMS because of the risks of central nervous system depression and abuse and misuse [see Warnings and Precautions ( 5.1 , 5.2 )] . Notable requirements of the XYWAV and XYREM REMS include the following: • 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 XYWAV and XYREM REMS with documentation of safe use Further information is available at www.XYWAVXYREMREMS.com or 1-866-997-3688. 5.4 Respiratory Depression and Sleep-Disordered Breathing Xyrem may impair respiratory drive, especially in patients with compromised respiratory function. In overdoses, life-threatening respiratory depression has been reported [see Overdosage ( 10 )]. In an adult study assessing the respiratory-depressant effects of Xyrem at doses up to 9 g per night in 21 patients with narcolepsy, no dose-related changes in oxygen saturation were demonstrated in the group as a whole. One of the four patients with preexisting, moderate-to-severe sleep apnea had significant worsening of the apnea/hypopnea index during treatment. In an adult study assessing the effects of Xyrem 9 g per night in 50 patients with obstructive sleep apnea, Xyrem did not increase the severity of sleep-disordered breathing and did not adversely affect the average duration and severity of oxygen desaturation overall. However, there was a significant increase in the number of central apneas in patients taking Xyrem, and clinically significant oxygen desaturation (≤55%) was measured in three patients (6%) after Xyrem administration, with one patient withdrawing from the study and two continuing after single brief instances of desaturation. During polysomnographic evaluation (PSG), central sleep apnea and oxygen desaturation were observed in pediatric patients with narcolepsy treated with Xyrem. Prescribers should be aware that increased central apneas and clinically relevant desaturation events have been observed with Xyrem administration in adult and pediatric patients. In adult clinical trials in 128 patients with narcolepsy, two subjects had profound CNS depression, which resolved after supportive respiratory intervention. Two other patients discontinued sodium oxybate because of severe difficulty breathing and an increase in obstructive sleep apnea. In two controlled trials assessing PSG measures in adult patients with narcolepsy, 40 of 477 patients were included with a baseline apnea/hypopnea index of 16 to 67 events per hour, indicative of mild to severe sleep-disordered breathing. None of the 40 patients had a clinically significant worsening of respiratory function as measured by apnea/hypopnea index and pulse oximetry at doses of 4.5 g to 9 g per night. 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. 5.5 Depression and Suicidality In adult clinical trials in patients with narcolepsy (n=781), there were two suicides and two attempted suicides in patients treated with Xyrem, 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 patients treated with Xyrem, with four patients (<1%) discontinuing because of depression. In most cases, no change in Xyrem treatment was required. In a controlled adult trial, with patients randomized to fixed doses of 3 g, 6 g, or 9 g per night Xyrem or placebo, there was a single event of depression at the 3 g per night dose. In another adult controlled trial, with patients titrated from an initial 4.5 g per night starting dose, the incidences of depression were 1 (1.7%), 1 (1.5%), 2 (3.2%), and 2 (3.6%) for the placebo, 4.5 g, 6 g, and 9 g per night doses, respectively. In the pediatric clinical trial in patients with narcolepsy (n=104), one patient experienced suicidal ideation and two patients reported depression while taking Xyrem. The emergence of depression in patients treated with Xyrem requires careful and immediate evaluation. Patients with a previous history of a depressive…