"The U.S. Food and Drug Administration today approved Hetlioz (tasimelteon), a melatonin receptor agonist, to treat non-24- hour sleep-wake disorder ("non-24") in totally blind individuals. Non-24 is a chronic circadian rhythm (body clock) disorde"...
Central Nervous System Depression
Xyrem is a central nervous system (CNS) depressant. Alcohol and sedative hypnotics are contraindicated in patients who are using Xyrem. 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 the second nightly dose of Xyrem. Patients should be queried about CNS depression-related events upon initiation of Xyrem therapy and periodically thereafter [see Xyrem Success Program].
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 Xyrem Success Program and Drug Abuse and Dependence].
Xyrem Success 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 Success Program.
Required components of the Xyrem Success Program are:
- Use of a centralized pharmacy
- Healthcare Providers who prescribe Xyrem must complete the enrollment forms and comply with the requirements.
- To receive Xyrem, patients must understand the risks and benefits of Xyrem. Further information is available at www.XYREM.com or 1-866-XYREM88® (1-866-997-3688).
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].
In a 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 a 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. Prescribers should be aware that increased central apneas and clinically relevant desaturation events have been observed with Xyrem administration.
In 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 polysomnographic (PSG) measures in 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 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.
In a controlled 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 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.
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.
Less than 1% of patients discontinued the drug because of confusion. Confusion was reported at all recommended doses from 6 g to 9 g per night. 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. In all cases in that controlled trial, the confusion resolved soon after termination of treatment. In Trial 3 where sodium oxybate was titrated from an initial 4.5 g per night dose, there was a single event of confusion in one patient at the 9 g per night dose. In the majority of cases in all clinical trials in narcolepsy, confusion resolved either soon after termination of dosing or with continued treatment. However, 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 included hallucinations, paranoia, psychosis, and agitation. The emergence of thought disorders and/or behavior abnormalities requires careful and immediate evaluation.
Sleepwalking, defined as confused behavior occurring at night and at times associated with wandering, was reported in 6% of 781 patients with narcolepsy treated with Xyrem in controlled and long-term open-label studies, with < 1% of patients discontinuing due to sleepwalking. Rates of sleepwalking were similar for patients taking placebo and patients taking Xyrem in controlled trials. It is unclear if some or all of the reported sleepwalking episodes correspond to true somnambulism, which is a parasomnia occurring during non-REM sleep, or to any other specific medical disorder. Five instances of significant injury or potential injury were associated with sleepwalking during a clinical trial of Xyrem in patients with narcolepsy.
Parasomnias including sleepwalking have been reported in postmarketing experience with Xyrem. Therefore, episodes of sleepwalking should be fully evaluated and appropriate interventions considered.
Use In Patients Sensitive To High Sodium Intake
Xyrem has a high salt content. In patients sensitive to salt intake (e.g., those with heart failure, hypertension, or renal impairment) consider the amount of daily sodium intake in each dose of Xyrem. Table 2 provides the approximate sodium content per Xyrem dose.
Table 2 : Approximate Sodium Content per Total Nightly
Dose of Xyrem (g = grams)
|Xyrem Dose||Sodium Content/Total Nightly Exposure|
|3 g per night||550 mg|
|4.5 g per night||820 mg|
|6 g per night||1100 mg|
|7.5 g per night||1400 mg|
|9 g per night||1640 mg|
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide).
Xyrem Success Program
Inform patients that Xyrem is available only through a restricted distribution program called the Xyrem Success Program.
The contents of the Xyrem Medication Guide and educational materials are reviewed with every patient before initiating treatment with Xyrem.
Patients must read and understand the materials in the Xyrem Success Program prior to initiating treatment. Inform the patient that they should be seen by the prescriber frequently to review dose titration, symptom response, and adverse reactions; a follow-up of every three months is recommended.
Discuss safe and proper use of Xyrem and dosing information with patients prior to the initiation of treatment. Instruct patients to store Xyrem bottles and Xyrem doses in a secure place, out of the reach of children and pets.
Alcohol or Sedative Hypnotics
Advise patients not to drink alcohol or take other sedative hypnotics if they are taking Xyrem.
Inform patients that after taking Xyrem they are likely to fall asleep quickly (often within 5 and usually within 15 minutes), but the time it takes to fall asleep can vary from night to night. The sudden onset of sleep, including in a standing position or while rising from bed, has led to falls complicated by injuries, in some cases requiring hospitalization. Instruct patients to remain in bed following ingestion of the first and second doses. Instruct patients not to take their second dose until 2.5 to 4 hours after the first dose.
Food Effects on Xyrem
Inform patients to take the first dose at least 2 hours after eating.
Inform patients that Xyrem can be associated with respiratory depression.
Operating Hazardous Machinery
Inform patients that until they are reasonably certain that Xyrem does not affect them adversely (e.g., impair judgment, thinking, or motor skills) they should not operate hazardous machinery, including automobiles or airplanes.
Instruct patients or families to contact a healthcare provider immediately if the patient develops depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, or suicidal ideation.
Instruct patients and their families that Xyrem has been associated with sleepwalking and to contact their healthcare provider if this occurs.
Instruct patients who are sensitive to salt intake (e.g., those with heart failure, hypertension, or renal impairment) that Xyrem contains a significant amount of sodium and they should limit their sodium intake.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Administration of sodium oxybate to rats at oral doses of up to 1,000 mg/kg/day for 83 (males) or 104 (females) weeks resulted in no increase in tumors. Plasma exposure (AUC) at the highest dose tested was 2 times that in humans at the maximum recommended human dose (MRHD) of 9 g per night.
The results of 2-year carcinogenicity studies in mouse and rat with gamma-butyrolactone, a compound that is metabolized to sodium oxybate in vivo, showed no clear evidence of carcinogenic activity. The plasma AUCs of sodium oxybate achieved at the highest doses tested in these studies were less than that in humans at the MRHD.
Sodium oxybate was negative in the in vitro bacterial gene mutation assay, an in vitro chromosomal aberration assay in mammalian cells, and in an in vivo rat micronucleus assay.
Impairment of Fertility
Oral administration of sodium oxybate (150, 350, or 1,000 mg/kg/day) to male and female rats prior to and throughout mating and continuing in females through early gestation resulted in no adverse effects on fertility. The highest dose tested is approximately equal to the MRHD on a mg/m² basis.
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. Xyrem should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Oral administration of sodium oxybate to pregnant rats (150, 350, or 1,000 mg/kg/day) or rabbits (300, 600, or 1,200 mg/kg/day) throughout organogenesis produced no clear evidence of developmental toxicity. The highest doses tested in rats and rabbits were approximately 1 and 3 times, respectively, the maximum recommended human dose (MRHD) of 9 g per night on a body surface area (mg/m²) basis.
Oral administration of sodium oxybate (150, 350, or 1,000 mg/kg/day) to rats throughout pregnancy and lactation resulted in increased stillbirths and decreased offspring postnatal viability and body weight gain at the highest dose tested. The no-effect dose for pre-and postnatal developmental toxicity in rats is less than the MRHD on a mg/m² basis.
Labor And Delivery
Xyrem has not been studied in labor or delivery. In obstetric anesthesia using an injectable formulation of sodium oxybate, newborns had stable cardiovascular and respiratory measures but were very sleepy, causing a slight decrease in Apgar scores. There was a fall in the rate of uterine contractions 20 minutes after injection. Placental transfer is rapid, but umbilical vein levels of sodium oxybate were no more than 25% of the maternal concentration. No sodium oxybate was detected in the infant's blood 30 minutes after delivery. Elimination curves of sodium oxybate between a 2-day-old infant and a 15-year-old patient were similar. Subsequent effects of sodium oxybate on later growth, development, and maturation in humans are unknown.
It is not known whether sodium oxybate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Xyrem is administered to a nursing woman.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of Xyrem in patients with narcolepsy did not include sufficient numbers of subjects age 65 years and older to determine whether they respond differently from younger subjects. In controlled trials in another population, 39 (5%) of 874 patients were 65 years or older. Discontinuations of treatment due to adverse reactions were increased in the elderly compared to younger adults (20.5% v. 18.9%). Frequency of headaches was markedly increased in the elderly (38.5% v. 18.9%). The most common adverse reactions were similar in both age categories. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Last reviewed on RxList: 4/28/2014
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