Full Prescribing Information Important Safety Information Medication Guide

Tolerance, Withdrawal & Dependence

  • In the clinical trial experience with Xyrem in narcolepsy/cataplexy patients at therapeutic 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.
  • Tolerance to Xyrem has not been systematically studied in controlled clinical trials.

Withdrawal

  • The discontinuation effects of Xyrem have not been systematically evaluated in controlled clinical trials.
  • 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 therapeutic dose 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.

Dependence

  • The discontinuation effects of sodium oxybate have not been systematically evaluated in controlled clinical trials. Of the 398 Xyrem-treated patient 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 began during the first weeks of treatment.

WARNINGS AND PRECAUTIONS

Central Nervous System Depression

Xyrem is a central nervous system (CNS) depressant. Alcohol and sedative hypnotics are contraindicated in patients using Xyrem. The concurrent use of Xyrem with other CNS depressants, including but not limited to opioid analgesics, benzodiazepines, sedating antidepressants or antipsychotics, 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 airplaines, 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.

Abuse and Misuse

Xyrem is a Schedule III controlled substance. The active ingredient of Xyrem, sodium oxybate or gammahydroxybutyrate (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). 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).

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. 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. 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. 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.

Parasomnias

Sleepwalking 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. Five 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 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.

Adverse Reactions

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.

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%).

Dose-Response Information: In clinical trials in narcolepsy, 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 narcolepsy, discontinuations of treatment due to adverse reactions were greater at higher doses of Xyrem.

Drug interactions

Xyrem should not be used in combination with alcohol or sedative hypnotics. Use of other CNS depressants may potentiate the CNS-depressant effects of Xyrem.

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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

To report an adverse event please call: 1-800-520-5568

 

 

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