DRUG INTERACTIONS Drug Interactions
Interactions between sodium oxybate and three drugs commonly used in patients with narcolepsy (zolpidem tartrate, protriptyline HCl, and modafinil) have been evaluated in formal studies. Sodium oxybate, in combination with these drugs, produced no significant pharmacokinetic changes for either drug (see Pharmacokinetics). However, pharmacodynamic interactions cannot be ruled out. Nonetheless, sodium oxybate should not be used in combination with sedative hypnotics or other CNS depressants. Alteration of gastric pH with omeprazole produced no significant change in the oxybate kinetics.
|
OVERDOSAGE
Human Experience
Information regarding overdose with sodium oxybate is derived largely from reports in the medical literature that describe symptoms and signs in individuals who have ingested GHB illicitly. In these circumstances the co-ingestion of other drugs and alcohol is common, and may influence the presentation and severity of clinical manifestations of overdose. In addition, overdose with GHB may be indistinguishable from overdose with other drugs, or from several other medical conditions that result in similar symptoms.
In clinical trials two cases of overdose with Xyrem were reported. In the first case, an estimated dose of 150 g, more than 15 times the maximum recommended dose, caused a patient to be unresponsive with brief periods of apnea and to be incontinent of urine and feces. This individual recovered without sequelae. In the second case, death was reported following a multiple drug overdose consisting of Xyrem and numerous other drugs.
Signs and Symptoms
Information about signs and symptoms associated with overdosage with sodium oxybate derives from reports of its illicit use. Patient presentation following overdose is influenced by the dose ingested, the time since ingestion, the co-ingestion of other drugs and alcohol, and the fed or fasted state. Patients have exhibited varying degrees of depressed consciousness that may fluctuate rapidly between a confusional, agitated combative state with ataxia and coma. Emesis (even when obtunded), diaphoresis, headache, and impaired psychomotor skills may be observed. No typical pupillary changes have been described to assist in diagnosis; pupillary reactivity to light is maintained. Blurred vision has been reported. An increasing depth of coma has been observed at higher doses. Myoclonus and tonic-clonic seizures have been reported. Respiration may be unaffected or compromised in rate and depth. Cheyne-Stokes respiration and apnea have been observed. Bradycardia and hypothermia may accompany unconsciousness, as well as muscular hypotonia, but tendon reflexes remain intact.
Recommended Treatment of Overdose
General symptomatic and supportive care should be instituted immediately, and gastric decontamination may be considered if co-ingestants are suspected. Because emesis may occur in the presence of obtundation, appropriate posture (left lateral recumbent position) and protection of the airway by intubation may be warranted. Although the gag reflex may be absent in deeply comatose patients, even unconscious patients may become combative to intubation, and rapid-sequence induction (without the use of sedative) should be considered. Vital signs and consciousness should be closely monitored. The bradycardia reported with GHB overdose has been responsive to atropine intravenous administration. No reversal of the central depressant effects of sodium oxybate can be expected from naloxone or flumazenil administration. The use of hemodialysis and other forms of extracorporeal drug removal have not been studied in GHB overdose. However, due to the rapid metabolism of sodium oxybate, these measures are not warranted.
Poison Control Center
As with the management of all cases of drug overdosage, the possibility of multiple drug ingestion should be considered. The physician is encouraged to collect urine and blood samples for routine toxicologic screening, and to consult with a regional poison control center (1‑800‑222‑1222) for current treatment recommendations.
|
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
Xyrem is classified as a Schedule III controlled substance by Federal law. The active ingredient, sodium oxybate or gamma-hydroxybutyrate (GHB), is listed in the most restrictive schedule of the Controlled Substances Act (Schedule I). Thus, non-medical uses of sodium oxybate (Xyrem or GHB) are classified under Schedule I.
Abuse, Dependence, and Tolerance
Abuse
See applicable directions for use under HANDLING AND DISPOSAL below. Although sodium oxybate (also known as GHB) has not been systematically studied in clinical trials for its potential for abuse, illicit use and abuse have been reported. Sodium oxybate is a psychoactive drug that produces a wide range of pharmacological effects. It is a sedative-hypnotic that produces dose and concentration dependent central nervous system effects in humans. The onset of effect is rapid, enhancing its desirability as a drug of abuse or misuse.
The rapid onset of sedation, coupled with the amnestic features of sodium oxybate, particularly when combined with alcohol, has proven to be dangerous for the voluntary and involuntary (assault victim) user.
GHB is abused in social settings primarily by young adults. GHB has some commonalties with ethanol over a limited dose range and some cross tolerance with ethanol has been reported as well. Cases of severe dependence and craving for GHB have been reported. Dependence is indicated by the use of increasingly large doses, increased frequency of use, and continued use despite adverse consequences. Some of the doses reported abused in the "rave" setting have been similar to the dose range studied for therapeutic treatment of cataplexy.
Hospital emergency department reports increased 100-fold from 1992 to 1999 (source: Substance Abuse Mental Health Services Administration, Drug Abuse Warning Network [DAWN]). Sixty percent of the ED reports involved individuals 25 years and younger. Numerous deaths had been reported over that period of time, typically involving GHB in combination with alcohol and other drugs, including five in the DAWN system in which GHB was the only drug that could be identified. However, the incidence of hospital emergency department reports of events involving GHB and GHB-related analogs has decreased by about 33% since 2000, and reports to the American Association of Poison Control Centers of GHB exposures has decreased from 1916 (involving 6 deaths) in 2001 to 800 (without any deaths) in 2003.
Dependence
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. In these cases, the signs and symptoms of abrupt discontinuation included an abstinence syndrome consisting of insomnia, restlessness, anxiety, psychosis, lethargy, nausea, tremor, sweating, muscle cramps, and tachycardia. These symptoms generally abated in 3 to 14 days. 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. Although the clinical trial experience with sodium oxybate in narcolepsy/cataplexy patients at therapeutic doses does not show clear evidence of a withdrawal syndrome, 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
Tolerance to sodium oxybate has not been systematically studied in controlled clinical trials. Open-label, long-term (≥6 months) clinical trials did not demonstrate development of tolerance. There have been some case reports of symptoms of tolerance developing after illicit use at dosages far in excess of the recommended Xyrem dosage regimen. Clinical studies of sodium oxybate in the treatment of alcohol withdrawal suggest a potential cross-tolerance with alcohol. 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). Physicians should document the diagnosis and indication for Xyrem, being alert to drug-seeking behavior and/or feigned cataplexy.
|
