XYREM is a sodium oxybate treatment for 2 key narcolepsy symptoms¹

Contraindications

XYWAV and XYREM are contraindicated for use in:

• combination with sedative hypnotics or alcohol
• patients with succinic semialdehyde dehydrogenase deficiency.

Warnings and Precautions

Central Nervous System Depression

The concurrent use of XYWAV or 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 XYWAV or XYREM is required, dose reduction or discontinuation of one or more CNS depressants (including XYWAV or XYREM) should be considered. In addition, if short-term use of an opioid (eg, post- or perioperative) is required, interruption of treatment with XYWAV or XYREM should be considered.

After first initiating treatment and until certain that XYWAV or 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 XYWAV or XYREM. Patients should be queried about CNS depression-related events upon initiation of XYWAV or XYREM therapy and periodically thereafter.

Abuse and Misuse

XYWAV and XYREM are Schedule III controlled substances. The active moiety of XYWAV and XYREM is oxybate, also known as gamma-hydroxybutyrate (GHB), 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 GHB, 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.

XYWAV and XYREM REMS

• Because of the risks of central nervous system depression and abuse/misuse, XYWAV and XYREM are available only through a restricted distribution program called the XYWAV and XYREM REMS.

Notable requirements of the XYWAV and XYREM REMS include the following:

• Healthcare Providers who prescribe XYWAV or XYREM are specially certified
• XYWAV and XYREM will be dispensed only by the central pharmacy that is specially certified
• XYWAV and 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.

Respiratory Depression and Sleep-Disordered Breathing

XYWAV and XYREM may impair respiratory drive, especially in patients with compromised respiratory function. In overdoses of oxybate and with illicit use of GHB, life-threatening respiratory depression has been reported. Increased apnea and reduced oxygenation may occur with XYWAV or XYREM administration in adult and pediatric patients. A significant increase in the number of central apneas and clinically significant oxygen desaturation may occur in patients with obstructive sleep apnea treated with XYWAV or XYREM. 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.

Depression and Suicidality

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 (<1%) discontinuing because of depression. In most cases, no change in XYREM treatment was required. In the pediatric clinical trial in patients with narcolepsy (n=104), one patient experienced suicidal ideation and two patients reported depression while taking XYREM.

In Study 1, the randomized-withdrawal clinical trial in adult patients with narcolepsy (n=201), depression and depressed mood were reported in 3% and 4%, respectively, of patients treated with XYWAV. Two patients (1%) discontinued XYWAV because of depression. In most cases, no change in XYWAV treatment was required.

The emergence of depression in patients treated with XYWAV or XYREM requires careful and immediate evaluation. Monitor patients for the emergence of increased depressive symptoms and/or suicidality while taking XYWAV or XYREM.

Other Behavioral or Psychiatric Adverse Reactions

During adult clinical trials in narcolepsy, 3% of 781 patients treated with XYREM experienced confusion, with incidence generally increasing with dose. In a controlled trial in adults 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 adult clinical trials in patients with narcolepsy, confusion resolved either soon after termination of dosing or with continued treatment.

Anxiety occurred in 5.8% of the 874 patients receiving XYREM in adult clinical trials in another population. Other neuropsychiatric reactions reported in adult XYREM clinical trials in patients with narcolepsy and the post-marketing setting included hallucinations, paranoia, psychosis, aggression, and agitation. In the pediatric clinical trial in patients with narcolepsy, neuropsychiatric reactions, including acute psychosis, confusion, and anxiety, were reported while taking XYREM.

In Study 1, the randomized-withdrawal pivotal clinical trial in adults with narcolepsy, confusion and anxiety occurred in 1% and 5% of patients treated with XYWAV, respectively. One patient experienced visual hallucinations and confusion after ingesting approximately 9 grams of XYWAV.

The emergence or increase of behavioral or psychiatric events in adult and pediatric patients taking XYWAV or XYREM should be carefully monitored.

Parasomnias

Parasomnias can occur in patients taking XYWAV or XYREM.

Instances of significant injury or potential injury were associated with sleepwalking during a clinical trial of XYREM in adult patients with narcolepsy. Parasomnias, including sleepwalking, also have been reported in the pediatric clinical trial and in postmarketing experience with XYREM.

In Study 1, the randomized-withdrawal pivotal clinical trial in adults with narcolepsy, parasomnias, including sleepwalking were reported in 6% of adult patients treated with XYWAV.

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 (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 adult clinical trials in patients with narcolepsy, the most common adverse reactions (incidence ≥5% and twice the rate seen with placebo) in XYREM-treated patients were nausea, dizziness, vomiting, somnolence, enuresis, and tremor.

In Study 1, the most common adverse reactions (incidence ≥5% of XYWAV-treated patients with narcolepsy) were headache, nausea, dizziness, decreased appetite, parasomnia, diarrhea, hyperhidrosis, anxiety, and vomiting.

In the pediatric clinical trial in pediatric patients 7 years of age and older with narcolepsy, the most common adverse reactions (≥5%) were nausea (20%), enuresis (19%), vomiting (18%), headache (17%), weight decreased (13%), decreased appetite (9%), dizziness (8%) and sleepwalking (6%). The overall adverse reaction profile of XYREM in the pediatric clinical trial was similar to that seen in the adult clinical trial program. The safety profile in pediatric patients with XYWAV is expected to be similar to that of adult patients treated with XYWAV and to that of pediatric patients treated with XYREM.

Additional Adverse Reactions

Additional adverse reactions that occurred in ≥2% of patients in any treatment group for three controlled adult 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, cataplexy, muscle spasms, extremity pain, attention disturbance, paresthesia, sleep paralysis, disorientation, irritability, sleepwalking, anxiety, and hyperhidrosis.

Additional adverse reactions that occurred in ≥2% of adult patients with narcolepsy treated with XYWAV in the Open Label Titration and Stable Dose Periods of Study 1 were fatigue, dry mouth, depressed mood, enuresis, irritability, paresthesia, depression, tremor, somnolence, and muscle spasms.

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 taking XYREM 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).

In Study 1, 9 of 201 XYWAV-treated patients with narcolepsy (4%) reported adverse reactions that led to withdrawal from the study (anxiety, decreased appetite, depressed mood, depression, fatigue, headache, irritability, nausea, pain in extremity, parasomnia, somnolence, and vomiting). The most common adverse reaction leading to discontinuation was nausea (1.5%). The majority of adverse reactions leading to discontinuation began during the first few weeks of treatment.

Dose-Response Information: In clinical trials in adult patients with narcolepsy treated with XYREM, a dose-response relationship was observed for nausea, vomiting, paresthesia, disorientation, irritability, disturbance in attention, feeling drunk, sleepwalking, and enuresis. The incidence of all these reactions was notably higher at 9 g per night. In controlled trials in adults with narcolepsy, discontinuations of treatment due to adverse reactions were greater at higher doses of XYREM.

Drug Interactions

XYWAV and XYREM are contraindicated for use in combination with alcohol or sedative hypnotics. Use of other CNS depressants may potentiate the CNS-depressant effects of XYWAV and XYREM.

Concomitant use of XYREM with divalproex sodium resulted in a 25% mean increase in systemic exposure to XYREM (AUC ratio range of 0.8 to 1.7) and in a greater impairment on some tests of attention and working memory. An initial dose reduction of XYREM at least 20% is recommended if divalproex sodium is prescribed to patients already taking XYREM. A similar increase in exposure is expected with concomitant use of XYWAV and divalproex sodium; therefore, an initial dose reduction of XYWAV is recommended when used concomitantly with divalproex sodium. Prescribers are advised to monitor patient response closely and adjust dose accordingly if concomitant use of XYWAV or XYREM and divalproex sodium is warranted.

Pregnancy and Lactation

There are no adequate data on the developmental risk associated with the use of XYWAV or XYREM in pregnant women. XYWAV or XYREM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. GHB is excreted in human milk after oral administration of sodium oxybate. There is insufficient information on the risk to a breastfed infant, and there is insufficient information on milk production in nursing mothers. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XYWAV or XYREM and any potential adverse effects on the breastfed infant from XYWAV or XYREM or from the underlying maternal condition.

Pediatric Use

Safety and effectiveness of XYWAV and XYREM in pediatric patients below the age of 7 years have not been established.

The safety and effectiveness of XYWAV for the treatment of cataplexy or excessive daytime sleepiness in pediatric patients 7 years of age and older with narcolepsy have been established. XYWAV has not been studied in a pediatric clinical trial for narcolepsy. Use of XYWAV in pediatric patients 7 years of age and older with narcolepsy is supported by evidence from an adequate and well controlled study of XYREM in pediatric patients 7 to 17 years of age, a study in adults showing a treatment effect of XYWAV similar to that observed with sodium oxybate, pharmacokinetic data of sodium oxybate from adult and pediatric patients, and pharmacokinetic data of XYWAV from healthy adult volunteers.

Geriatric Use

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.

Hepatic Impairment

The starting dose of XYWAV or XYREM should be reduced in patients with liver impairment.

Dosage Modification in Patients with Hepatic Impairment: The recommended starting dosage in patients with hepatic impairment is one-half of the original dosage per night, administered orally divided into two doses.

Dependence and Tolerance

There have been case reports of withdrawal, ranging from mild to severe, following discontinuation of illicit use of GHB at frequent repeated doses (18 g to 250 g per day) in excess of the recommended dosage range. Signs and symptoms of GHB withdrawal following abrupt discontinuation included insomnia, restlessness, anxiety, psychosis, lethargy, nausea, tremor, sweating, muscle cramps, tachycardia, headache, dizziness, rebound fatigue and sleepiness, confusion, and, particularly in the case of severe withdrawal, visual hallucinations, agitation, and delirium. These symptoms generally abated in 3 to 14 days. In cases of severe withdrawal, hospitalization may be required. The discontinuation effects of XYREM have not been systematically evaluated in controlled clinical trials.

In the clinical trial experience with XYREM in narcolepsy/cataplexy patients at recommended doses, two patients reported anxiety and one reported insomnia following abrupt discontinuation at the termination of the clinical trial; in the two patients with anxiety, the frequency of cataplexy had increased markedly at the same time. In the XYWAV clinical trial in adult narcolepsy/cataplexy patients at recommended doses, one patient reported insomnia following abrupt discontinuation of XYWAV.

Tolerance to XYWAV or XYREM has not been systematically studied in controlled clinical trials. There have been some case reports of symptoms of tolerance developing after illicit use at dosages far in excess of the recommended XYWAV or XYREM dosage regimen.

Please see full Prescribing Information, including BOXED Warning for XYREM.

Please see full Prescribing Information, including BOXED Warning for XYWAV.