Tolerance, Withdrawal & Dependence

No development of tolerance with sustained use

• While tolerance was not systematically studied in controlled clinical trials, development of tolerance was not demonstrated in open-label, long-term (≥6 months) clinical trials.
• There have been some case reports of symptoms of tolerance developing after illicit use of dosages far in excess of the recommended XYREM^® dosage regimen.^[1][2]

No acute withdrawal symptoms

• Although not systematically evaluated in controlled clinical trials, no acute withdrawal symptoms were observed after 2 weeks of discontinuation following an average of 21 months of therapy (range: 7 to 44 months).
• In clinical trials, 2 patients reported anxiety and 1 patient reported insomnia following abrupt discontinuation of XYREM.^[2][3]

Dependence

• The discontinuation effects of sodium oxybate have not been systematically evaluated in controlled clinical trials.
• An abstinence syndrome has not been reported in clinical investigations.
• Cases of severe dependence and craving for γ-hydroxybutyrate have been reported. There have been case reports of dependence after illicit use of γ-hydroxybutyrate at frequent repeated doses (18 to 250 g/day), in excess of the therapeutic dose range.^[1]

Precautions

• Consider the sodium load in patients with heart failure, hypertension, or compromised renal function
• Hepatic insufficiency
  • Patients with compromised liver function will have an increased elimination half-life. The starting dose should therefore be decreased by one half in such patients, and response to dose increments should be monitored closely
• Drug interactions
  • Sodium oxybate did not produce pharmacokinetic interactions with
    • Modafinil (stimulant)
    • Zolpidem tartrate (hypnotic)
    • Protriptyline HCI (Tricyclic Antidepressants (TCA))
  • Pharmacodynamic interactions cannot be ruled out
• XYREM^® (sodium oxybate) should not be used in combination with sedative hypnotics or other CNS depressants
• Consider the sodium load in patients with heart failure, hypertension, or compromised renal function
• Nocturnal urinary incontinence
  • In 7% of patients treated with sodium oxybate in clinical trials
  • Has been reported at all doses tested
  • <1% of patients discontinued because of incontinence
• Sleepwalking
  • Observed in 4% of patients in clinical trials (n=717) with <1% discontinuation; 1% in controlled trials (n=655)
  • Episodes of sleepwalking should be fully evaluated and appropriate interventions considered
• Pregnancy Category B
  • There are no adequate and well-controlled studies in pregnant women
• Nursing mothers
  • It is not known whether sodium oxybate is excreted in human milk
• Pediatric use
  • Safety and effectiveness in patients under 16 years of age have not been established

© 2012 Jazz Pharmaceuticals Inc.