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 GHB have been reported. There have been case reports of dependence after illicit use of GHB at frequent repeated doses (18 to 250 g/day), in excess of the therapeutic dose range.[1]

References:

^ XYREM® (sodium oxybate) [prescribing information]. Palo Alto, Calif: Jazz Pharmaceuticals; 2005.
^ The US XYREM® Multicenter Study Group. The abrupt cessation of therapeutically administered sodium oxybate (GHB) does not cause withdrawal symptoms. J Toxicol Clin Toxicol. 2003;41:131–135.
^ The US XYREM® Multicenter Study Group. Sodium oxybate demonstrates long-term efficacy for the treatment of cataplexy in patients with narcolepsy. Sleep Med. 2004;5:119–123.

Important Safety Information

1. XYREM^® is a controlled substance. Controlled substances are medicines that, if abused, may lead to varying degrees of physical or psychological dependence. XYREM is a Schedule III drug — which means that it has a moderate dependence liability. If you sell, distribute, or give your XYREM to anyone else or use it for purposes other than what it was prescribed for, you may be punished under federal and state law by jail and fines.

2. It is very important to keep XYREM out of reach of children and pets.

3. XYREM can cause serious side effects including trouble breathing while asleep, confusion, abnormal thinking, depression and loss of consciousness. Tell your doctor if you have any of these problems while taking XYREM.

BOXED WARNING:

!Warning

Central Nervous System Depressant with Abuse Potential. Should not be used with alcohol or other CNS depressants. Sodium oxybate is a form of GHB, a known drug of abuse. Abuse has been associated with some important central nervous system (CNS) adverse events (including death). Even at recommended doses, use has been associated with confusion, depression, and other neuropsychiatric events. Reports of respiratory depression occurred in clinical trials. Almost all of the patients who received sodium oxybate during clinical trials were receiving CNS stimulants.

Important CNS adverse events associated with abuse of GHB include seizure, respiratory depression and profound decreases in level of consciousness, with instances of coma and death. For events that occurred outside of clinical trials, in people taking GHB for recreational purposes, the circumstances surrounding the events are often unclear (e.g., dose of GHB taken, the nature and amount of alcohol or any concomitant drugs).

XYREM is available through the XYREM Success Program^®, using a centralized pharmacy 1-866-XYREM88^® (1-866-997-3688). The Success Program provides educational materials to the prescriber and the patient explaining the risks and proper use of sodium oxybate, and the required prescription form. Once it is documented that the patient has read and/or understood the materials, the drug will be shipped to the patient. The XYREM Success Program also recommends patient follow-up every 3 months. Physicians are expected to report all serious adverse events to the manufacturer.