Sodium oxybate (patient information)
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
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Black Box Warning
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CENTRAL NERVOUS SYSTEM (CNS) DEPRESSION AND MISUSE AND ABUSE.
See full prescribing information for complete Boxed Warning.
Xyrem (sodium oxybate) is a CNS depressant. In clinical trials at recommended doses obtundation and clinically significant respiratory depression occurred in Xyrem-treated patients. Almost all of the patients who received Xyrem during clinical trials in narcolepsy were receiving central nervous system stimulants [see Warnings and Precautions (5.1)].
Xyrem® (sodium oxybate) is the sodium salt of gamma hydroxybutyrate (GHB). Abuse of 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 [see Warnings and Precautions (5.2)]. Because of the risks of CNS depression, abuse, and misuse, Xyrem is available only through a restricted distribution program called the Xyrem Success Program®, using a centralized pharmacy. Prescribers and patients must enroll in the program. For further information go to www.XYREM.com or call 1-866-XYREM88® (1-866-997-3688) [see Warnings and Precautions (5.3)]. |
Overview
Sodium oxybate (patient information) is {{{aOrAn}}} {{{drugClass}}} that is FDA approved for the treatment of ��cataplexy in narcolepsy and excessive daytime sleepiness (EDS) in narcolepsy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include {{{adverseReactions}}}.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
There is limited information regarding Sodium oxybate (patient information) FDA-Labeled Indications and Dosage (Adult) in the drug label.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sodium oxybate (patient information) in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sodium oxybate (patient information) in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Sodium oxybate (patient information) FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sodium oxybate (patient information) in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sodium oxybate (patient information) in pediatric patients.
Contraindications
- Xyrem is contraindicated in patients being treated with sedative hypnotic agents.
- Patients should not drink alcohol when using Xyrem.
- Xyrem is contraindicated in patients with succinic semialdehyde dehydrogenase deficiency. This is a rare disorder of inborn error of metabolism variably characterized by mental retardation, hypotonia, and ataxia.
Warnings
|
CENTRAL NERVOUS SYSTEM (CNS) DEPRESSION AND MISUSE AND ABUSE.
See full prescribing information for complete Boxed Warning.
Xyrem (sodium oxybate) is a CNS depressant. In clinical trials at recommended doses obtundation and clinically significant respiratory depression occurred in Xyrem-treated patients. Almost all of the patients who received Xyrem during clinical trials in narcolepsy were receiving central nervous system stimulants [see Warnings and Precautions (5.1)].
Xyrem® (sodium oxybate) is the sodium salt of gamma hydroxybutyrate (GHB). Abuse of 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 [see Warnings and Precautions (5.2)]. Because of the risks of CNS depression, abuse, and misuse, Xyrem is available only through a restricted distribution program called the Xyrem Success Program®, using a centralized pharmacy. Prescribers and patients must enroll in the program. For further information go to www.XYREM.com or call 1-866-XYREM88® (1-866-997-3688) [see Warnings and Precautions (5.3)]. |
Central Nervous System Depression
Xyrem is a central nervous system (CNS) depressant. Alcohol and sedative hypnotics are contraindicated in patients who are using Xyrem. The concurrent use of 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 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 airplanes, 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 [see Warnings and Precautions (5.3)].
Abuse and Misuse
Xyrem is a Schedule III controlled substance. The active ingredient of Xyrem, sodium oxybate or gamma-hydroxybutyrate (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). 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, feigned cataplexy) [see Warnings and Precautions (5.3) and Drug Abuse and Dependence (9.2)].
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 [see Overdosage (10)].
In a study assessing the respiratory-depressant effects of Xyrem at doses up to 9 g per night in 21 patients with narcolepsy, no dose-related changes in oxygen saturation were demonstrated in the group as a whole. One of the four patients with preexisting, moderate-to-severe sleep apnea had significant worsening of the apnea/hypopnea index during treatment.
In a study assessing the effects of Xyrem 9 g per night in 50 patients with obstructive sleep apnea, Xyrem did not increase the severity of sleep-disordered breathing and did not adversely affect the average duration and severity of oxygen desaturation overall. However, there was a significant increase in the number of central apneas in patients taking Xyrem, and clinically significant oxygen desaturation (≤55%) was measured in three patients (6%) after Xyrem administration, with one patient withdrawing from the study and two continuing after single brief instances of desaturation. Prescribers should be aware that increased central apneas and clinically relevant desaturation events have been observed with Xyrem administration.
In clinical trials in 128 patients with narcolepsy, two subjects had profound CNS depression, which resolved after supportive respiratory intervention. Two other patients discontinued sodium oxybate because of severe difficulty breathing and an increase in obstructive sleep apnea. In two controlled trials assessing polysomnographic (PSG) measures in patients with narcolepsy, 40 of 477 patients were included with a baseline apnea/hypopnea index of 16 to 67 events per hour, indicative of mild to severe sleep-disordered breathing. None of the 40 patients had a clinically significant worsening of respiratory function as measured by apnea/hypopnea index and pulse oximetry at doses of 4.5 g to 9 g per night.
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.
In a controlled trial, with patients randomized to fixed doses of 3 g, 6 g, or 9 g per night Xyrem or placebo, there was a single event of depression at the 3 g per night dose. In another controlled trial, with patients titrated from an initial 4.5 g per night starting dose, the incidences of depression were 1 (1.7%), 1 (1.5%), 2 (3.2%), and 2 (3.6%) for the placebo, 4.5 g, 6 g, and 9 g per night doses, respectively.
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 Psychiatic Adverse Reactions
During clinical trials in narcolepsy, 3% of 781 patients treated with Xyrem experienced confusion, with incidence generally increasing with dose.
Less than 1% of patients discontinued the drug because of confusion. 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. 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 clinical trials in narcolepsy, confusion resolved either soon after termination of dosing or with continued treatment. However, 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, defined as confused behavior occurring at night and at times associated with wandering, 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. Rates of sleepwalking were similar for patients taking placebo and patients taking Xyrem in controlled trials. It is unclear if some or all of the reported sleepwalking episodes correspond to true somnambulism, which is a parasomnia occurring during non-REM sleep, or to any other specific medical disorder. Five instances of significant injury or potential injury were associated with sleepwalking during a clinical trial of Xyrem in patients with narcolepsy.
Parasomnias including sleepwalking have been reported in postmarketing experience with Xyrem. Therefore, 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. Table 2 provides the approximate sodium content per Xyrem dose.
Adverse Reactions
Clinical Trials Experience
The following adverse reactions appear in other sections of the labeling:
- CNS depression
- Abuse and Misuse
- Respiratory Depression and Sleep-disordered Breathing
- Depression and Suicidality
- Other Behavioral or Psychiatric Adverse Reactions
- Parasomnias
- Use in Patients Sensitive to High Sodium Intake
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Xyrem was studied in three placebo-controlled clinical trials (Trials N1, N3, and N4, described in SECTIONS 14.1 and 14.2) in 611 patients with narcolepsy (398 subjects treated with Xyrem, and 213 with placebo). A total of 781 patients with narcolepsy were treated with Xyrem in controlled and uncontrolled clinical trials.
Section 6.1 and Table 3 presents adverse reactions from three pooled, controlled trials (N1, N3, N4) in patients with narcolepsy.
Adverse Reactions Leading to Treatment 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.
CommonlyObserved Adverse Reactions in Controlled Clinical Trials
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.
Adverse Reactions Occurring at an Incidence of 2% or greater
Table 3 lists adverse reactions that occurred at a frequency of 2% or more in any treatment group for three controlled trials and were more frequent in any Xyrem treatment group than with placebo. Adverse reactions are summarized by dose at onset. Nearly all patients in these studies initiated treatment at 4.5 g per night. In patients who remained on treatment, adverse reactions tended to occur early and to diminish over time.
Postmarketing Experience
The following additional adverse reactions that have a likely causal relationship to Xyrem exposure have been identified during postmarketing use of Xyrem. These adverse reactions include: arthralgia, decreased appetite, fall, fluid retention, hangover, headache, hypersensitivity, hypertension, memory impairment, panic attack, vision blurred, and weight decreased. Because these reactions are reported voluntarily, it is not always possible to reliably estimate their frequency.
Drug Interactions
Alcohol, Sedative Hypnotics, and CNS Depressants
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.
Divalproex Sodium
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 Xyrem dose reduction of at least 20% is recommended if divalproex sodium is prescribed to patients already taking Xyrem. Prescribers are advised to monitor patient response closely and adjust dose accordingly if concomitant use of Xyrem and divalproex sodium is warranted.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): 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. Oral administration of sodium oxybate to pregnant rats (150, 350, or 1,000 mg/kg/day) or rabbits (300, 600, or 1,200 mg/kg/day) throughout organogenesis produced no clear evidence of developmental toxicity. The highest doses tested in rats and rabbits were approximately 1 and 3 times, respectively, the maximum recommended human dose (MRHD) of 9 g per night on a body surface area (mg/m2) basis.
Oral administration of sodium oxybate (150, 350, or 1,000 mg/kg/day) to rats throughout pregnancy and lactation resulted in increased stillbirths and decreased offspring postnatal viability and body weight gain at the highest dose tested. The no-effect dose for pre- and post-natal developmental toxicity in rats is less than the MRHD on a mg/m2 basis.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sodium oxybate (patient information) in women who are pregnant.
Labor and Delivery
Xyrem has not been studied in labor or delivery. In obstetric anesthesia using an injectable formulation of sodium oxybate, newborns had stable cardiovascular and respiratory measures but were very sleepy, causing a slight decrease in Apgar scores. There was a fall in the rate of uterine contractions 20 minutes after injection. Placental transfer is rapid, but umbilical vein levels of sodium oxybate were no more than 25% of the maternal concentration. No sodium oxybate was detected in the infant’s blood 30 minutes after delivery. Elimination curves of sodium oxybate between a 2-day-old infant and a 15-year-old patient were similar. Subsequent effects of sodium oxybate on later growth, development, and maturation in humans are unknown.
Nursing Mothers
It is not known whether sodium oxybate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Xyrem is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatic Use
Clinical studies of Xyrem in patients with narcolepsy did not include sufficient numbers of subjects age 65 years and older to determine whether they respond differently from younger subjects. In controlled trials in another population, 39 (5%) of 874 patients were 65 years or older. Discontinuations of treatment due to adverse reactions were increased in the elderly compared to younger adults (20.5% v. 18.9%). Frequency of headaches was markedly increased in the elderly (38.5% v. 18.9%). The most common adverse reactions were similar in both age categories. In general, 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.
Gender
There is no FDA guidance on the use of Sodium oxybate (patient information) with respect to specific gender populations.
Race
There is no FDA guidance on the use of Sodium oxybate (patient information) with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Sodium oxybate (patient information) in patients with renal impairment.
Hepatic Impairment
The starting dose of Xyrem should be reduced by one-half in patients with liver impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sodium oxybate (patient information) in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Sodium oxybate (patient information) in patients who are immunocompromised.
Administration and Monitoring
Administration
There is limited information regarding Sodium oxybate (patient information) Administration in the drug label.
Monitoring
There is limited information regarding Sodium oxybate (patient information) Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Sodium oxybate (patient information) and IV administrations.
Overdosage
Human Experience
Information regarding overdose with Xyrem 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 was common, and may have influenced the presentation and severity of clinical manifestations of overdose.
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 Xyrem 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 have been 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 Xyrem 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 healthcare provider 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.
Pharmacology
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Sodium oxybateSodium oxybate
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| Systematic (IUPAC) name | |
| Sodium 4-hydroxybutanoate | |
| Identifiers | |
| CAS number | |
| ATC code | N07 |
| PubChem | |
| Chemical data | |
| Formula | Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox |
| Mol. mass | 126.09 g/mol |
| SMILES | & |
| Pharmacokinetic data | |
| Bioavailability | 25% |
| Protein binding | 1% |
| Metabolism | ? |
| Half life | 0.5 to 1 hour. |
| Excretion | Almost entirely by biotransformation to carbon dioxide, which is then eliminated by expiration |
| Therapeutic considerations | |
| Licence data |
, |
| Pregnancy cat. |
C(US) |
| Legal status |
?(CA) ?(UK) Schedule III(US) Rx Only |
| Routes | Oral |
Mechanism of Action
Xyrem is a CNS depressant. The mechanism of action of Xyrem in the treatment of narcolepsy is unknown. Sodium oxybate is the sodium salt of gamma hydroxybutyrate, an endogenous compound and metabolite of the neurotransmitter GABA. It is hypothesized that the therapeutic effects of Xyrem on cataplexy and excessive daytime sleepiness are mediated through GABAB actions at noradrenergic and dopaminergic neurons, as well as at thalamocortical neurons.
Structure
There is limited information regarding Sodium oxybate (patient information) Structure in the drug label.
Pharmacodynamics
There is limited information regarding Sodium oxybate (patient information) Pharmacodynamics in the drug label.
Pharmacokinetics
Pharmacokinetics of sodium oxybate are nonlinear and are similar following single or repeat dosing
Absorption
Following oral administration, sodium oxybate is absorbed rapidly across the clinical dose range, with an absolute bioavailability of about 88%. The average peak plasma concentrations (Cmax) following administration of each of the two 2.25 g doses given under fasting conditions 4 hours apart were similar. The average time to peak plasma concentration (Tmax) ranged from 0.5 to 1.25 hours. Following oral administration, the plasma levels of sodium oxybate increased more than dose-proportionally, with blood levels increasing 3.7‑fold as total daily dose is doubled from 4.5 g to 9 g. Single doses greater than 4.5 g have not been studied. Administration of Xyrem immediately after a high-fat meal resulted in delayed absorption (average Tmax increased from 0.75 hr to 2 hr) and a reduction in Cmax by a mean of 59% and of systemic exposure (AUC) by 37%.
Distribution
Sodium oxybate is a hydrophilic compound with an apparent volume of distribution averaging 190 mL/kg to 384 mL/kg. At sodium oxybate concentrations ranging from 3 mcg/mL to 300 mcg/mL, less than 1% is bound to plasma proteins.
Metabolism
Animal studies indicate that metabolism is the major elimination pathway for sodium oxybate, producing carbon dioxide and water via the tricarboxylic acid (Krebs) cycle and secondarily by beta-oxidation. The primary pathway involves a cytosolic NADP+-linked enzyme, GHB dehydrogenase, that catalyzes the conversion of sodium oxybate to succinic semialdehyde, which is then biotransformed to succinic acid by the enzyme succinic semialdehyde dehydrogenase. Succinic acid enters the Krebs cycle where it is metabolized to carbon dioxide and water. A second mitochondrial oxidoreductase enzyme, a transhydrogenase, also catalyzes the conversion to succinic semialdehyde in the presence of α-ketoglutarate. An alternate pathway of biotransformation involves β-oxidation via 3,4-dihydroxybutyrate to carbon dioxide and water. No active metabolites have been identified.
Elimination
The clearance of sodium oxybate is almost entirely by biotransformation to carbon dioxide, which is then eliminated by expiration. On average, less than 5% of unchanged drug appears in human urine within 6 to 8 hours after dosing. Fecal excretion is negligible. Sodium oxybate has an elimination half-life of 0.5 to 1 hour.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Administration of sodium oxybate to rats at oral doses of up to 1,000 mg/kg/day for 83 (males) or 104 (females) weeks resulted in no increase in tumors. Plasma exposure (AUC) at the highest dose tested was 2 times that in humans at the maximum recommended human dose (MRHD) of 9 g per night.
The results of 2-year carcinogenicity studies in mouse and rat with gamma-butyrolactone, a compound that is metabolized to sodium oxybate in vivo, showed no clear evidence of carcinogenic activity. The plasma AUCs of sodium oxybate achieved at the highest doses tested in these studies were less than that in humans at the MRHD.
Mutagenesis
Sodium oxybate was negative in the in vitro bacterial gene mutation assay, an in vitro chromosomal aberration assay in mammalian cells, and in an in vivo rat micronucleus assay.
Impairment of Fertility
Oral administration of sodium oxybate (150, 350, or 1,000 mg/kg/day) to male and female rats prior to and throughout mating and continuing in females through early gestation resulted in no adverse effects on fertility. The highest dose tested is approximately equal to the MRHD on a mg/m2 basis.
Clinical Studies
14.1 Cataplexy in Narcolepsy The effectiveness of Xyrem in the treatment of cataplexy was established in two randomized, double-blind, placebo-controlled, multicenter, parallel-group trials (Trials N1 and N2) in patients with narcolepsy (see Table 4). In Trials N1 and N2, 85% and 80% of patients, respectively, were also being treated with CNS stimulants. The high percentages of concomitant stimulant use make it impossible to assess the efficacy and safety of Xyrem independent of stimulant use. In each trial, the treatment period was 4 weeks and the total nightly Xyrem doses ranged from 3 g to 9 g, with the total nightly dose administered as two equal doses. The first dose each night was taken at bedtime and the second dose was taken 2.5 to 4 hours later. There were no restrictions on the time between food consumption and dosing.
Trial N1 enrolled 136 narcoleptic patients with moderate to severe cataplexy (median of 21 cataplexy attacks per week) at baseline. Prior to randomization, medications with possible effects on cataplexy were withdrawn, but stimulants were continued at stable doses. Patients were randomized to receive placebo, Xyrem 3 g per night, Xyrem 6 g per night, or Xyrem 9 g per night.
Trial N2 was a randomized withdrawal trial with 55 narcoleptic patients who had been taking open-label Xyrem for 7 to 44 months prior to study entry. To be included, patients were required to have a history of at least 5 cataplexy attacks per week prior to any treatment for cataplexy. Patients were randomized to continued treatment with Xyrem at their stable dose (ranging from 3 g to 9 g per night) or to placebo for 2 weeks. Trial N2 was designed specifically to evaluate the continued efficacy of sodium oxybate after long-term use.
The primary efficacy measure in Trials N1 and N2 was the frequency of cataplexy attacks.
In Trial N1, both the 6 g and 9 g per night Xyrem doses resulted in statistically significant reductions in the frequency of cataplexy attacks. The 3 g per night dose had little effect. In Trial N2, patients randomized to placebo after discontinuing long-term open-label Xyrem therapy experienced a significant increase in cataplexy attacks (p < 0.001), providing evidence of long-term efficacy of Xyrem. In Trial N2, the response was numerically similar for patients treated with doses of 6 g to 9 g per night, but there was no effect seen in patients treated with doses less than 6 g per night, suggesting little effect at these doses.
14.2 Excessive Daytime Sleepiness in Narcolepsy The effectiveness of Xyrem in the treatment of excessive daytime sleepiness in patients with narcolepsy was established in two randomized, double-blind, placebo-controlled trials (Trials N3 and N4) (see Tables 7 to 9). Seventy-eight percent of patients in Trial N3 were also being treated with CNS stimulants.
Trial N3 was a multicenter randomized, double-blind, placebo-controlled, parallel-group trial that evaluated 228 patients with moderate to severe symptoms at entry into the study including a median Epworth Sleepiness Scale (see below) score of 18, and a Maintenance of Wakefulness Test (see below) score of 8.3 minutes. Patients were randomized to one of 4 treatment groups: placebo, Xyrem 4.5 g per night, Xyrem 6 g per night, or Xyrem 9 g per night. The period of double-blind treatment in this trial was 8 weeks. Antidepressants were withdrawn prior to randomization; stimulants were continued at stable doses.
The primary efficacy measures in Trial N3 were the Epworth Sleepiness Scale and the Clinical Global Impression of Change. The Epworth Sleepiness Scale is intended to evaluate the extent of sleepiness in everyday situations by asking the patient a series of questions. In these questions, patients were asked to rate their chances of dozing during each of 8 activities on a scale from 0-3 (0=never; 1=slight; 2=moderate; 3=high). Higher total scores indicate a greater tendency to sleepiness. The Clinical Global Impression of Change is evaluated on a 7-point scale, centered at No Change, and ranging from Very Much Worse to Very Much Improved. In Trial N3, patients were rated by evaluators who based their assessments on the severity of narcolepsy at baseline.
In Trial N3, statistically significant improvements were seen on the Epworth Sleepiness Scale score at Week 8 and on the Clinical Global Impression of Change score at Week 8 with the 6 g and 9 g per night doses of Xyrem compared to the placebo group.
Trial N4 was a multicenter randomized, double-blind, placebo-controlled, parallel-group trial that evaluated 222 patients with moderate to severe symptoms at entry into the study including a median Epworth Sleepiness Scale score of 15, and a Maintenance of Wakefulness Test (see below) score of 10.3 minutes. At entry, patients had to be taking modafinil at stable doses of 200 mg, 400 mg, or 600 mg daily for at least 1 month prior to randomization. The patients enrolled in the study were randomized to one of 4 treatment groups: placebo, Xyrem, modafinil, or Xyrem plus modafinil. Xyrem was administered in a dose of 6 g per night for 4 weeks, followed by 9 g per night for 4 weeks. Modafinil was continued in the modafinil alone and the Xyrem plus modafinil treatment groups at the patient’s prior dose. Trial N4 was not designed to compare the effects of Xyrem to modafinil because patients receiving modafinil were not titrated to a maximal dose. Patients randomized to placebo or to Xyrem treatment were withdrawn from their stable dose of modafinil. Patients taking antidepressants could continue these medications at stable doses.
The primary efficacy measure in Trial N4 was the Maintenance of Wakefulness Test. The Maintenance of Wakefulness Test measures latency to sleep onset (in minutes) averaged over 4 sessions at 2-hour intervals following nocturnal polysomnography. For each test session, the subject was asked to remain awake without using extraordinary measures. Each test session is terminated after 20 minutes if no sleep occurs, or after 10 minutes, if sleep occurs. The overall score is the mean sleep latency for the 4 sessions.
In Trial N4, a statistically significant improvement in the change in the Maintenance of Wakefulness Test score from baseline at Week 8 was seen in the Xyrem and Xyrem plus modafinil groups compared to the placebo group.
This trial was not designed to compare the effects of Xyrem to modafinil, because patients receiving modafinil were not titrated to a maximally effective dose.
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The contents of this FDA label are provided by the National Library of Medicine.
IMPORTANT WARNING:
Sodium oxybate is another name for GHB, a substance that is often illegally sold and abused, especially by young adults in social settings such as nightclubs. Sodium oxybate may be harmful when taken by people other than the person for whom it was prescribed. Do not sell or give your sodium oxybate to anyone else; selling or sharing it is against the law. Store sodium oxybate in a safe place, such as a locked cabinet or box, so that no one else can take it accidentally or on purpose. Keep track of how much liquid is left in your bottle so you will know if any is missing.
Take sodium oxybate exactly as directed. Do not take more of it or take it more often than prescribed by your doctor. If you take too much sodium oxybate, you may experience life-threatening symptoms including seizures, slowed or stopped breathing, loss of consciousness, and coma. You may also develop a craving for sodium oxybate, feel a need to take larger and larger doses, or want to continue taking sodium oxybate even though it causes unpleasant symptoms. If you have taken sodium oxybate in amounts larger than prescribed by your doctor, and you suddenly stop taking it, you may experience withdrawal symptoms such as difficulty falling asleep or staying asleep, restlessness, anxiety, abnormal thinking, loss of contact with reality, sleepiness, upset stomach, shaking of a part of your body that you cannot control, sweating, muscle cramps, and fast heartbeat.
Sodium oxybate may cause serious side effects even if it is taken as directed. Do not take antidepressants; medications for anxiety, mental illness, or seizures; sedatives; sleeping pills; or tranquilizers while you are taking sodium oxybate. Do not drink alcohol while you are taking sodium oxybate. Tell your doctor if you snore and if you have or have ever had lung disease, difficulty breathing, sleep apnea (a sleep disorder that causes breathing to stop for short periods during sleep), seizures, or depression. Also tell your doctor if you have ever thought about harming or killing yourself or planned or tried to do so, if you use or have ever used street drugs, or if you have overused prescription medications.If you experience any of the following symptoms, call your doctor immediately: depression, confusion, abnormal thoughts, thoughts of harming or killing yourself, anxiety, feeling that others want to harm you, hallucinations (seeing things or hearing voices that do not exist), loss of contact with reality, agitation, memory problems, breathing problems, snoring, sleep apnea, slowed or stopped breathing,or excessive drowsiness during the day.
Sodium oxybate is not available at retail pharmacies. A special program is in place to distribute the medication and provide information about the medication. You will receive written information and an instructional video about the safe use of sodium oxybate. Your medication will be mailed to you from a central pharmacy after you have read the information and talked to a pharmacist. Ask your doctor if you have any questions about how you will receive your medication.
Your doctor or pharmacist will give you the manufacturer's patient information sheet (Medication Guide) when you begin treatment with sodium oxybate and each time you refill your prescription. Read the information carefully and ask your doctor or pharmacist if you have any questions. You can also obtain the Medication Guide from the FDA website: http://www.fda.gov/cder/drug/infopage/xyrem/medicationguide.htm.
Keep all appointments with your doctor. You should see your doctor at least every 3 months.
Talk to your doctor about the risks of taking sodium oxybate.
Why is this medication prescribed
Sodium oxybate is used to prevent attacks of cataplexy (episodes of muscle weakness that begin suddenly and last for a short time) in patients who have narcolepsy (a sleep disorder that may cause extreme sleepiness, sudden uncontrollable urge to sleep during daily activities, and cataplexy). Sodium oxybate is in a class of medications called central nervous system depressants. The way that sodium oxybate works to treat cataplexy is not known.
How should this medicine be used
Sodium oxybate comes as a solution (liquid) to mix with water and take by mouth. It is usually taken twice each night because sodium oxybate wears off after a short time and the effects of one dose will not last for the entire night. The first dose is taken at bedtime, and a second dose is taken 2 1/2 to 4 hours after the first dose. Sodium oxybate must be taken on an empty stomach, so the first dose should be taken several hours after the evening meal. Try to allow the same amount of time between your evening meal and your first dose of sodium oxybate every night. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand.
Do not take your bedtime dose of sodium oxybate until you are in bed and are ready to go to sleep for the night. Sodium oxybate begins to work very quickly and you may have an upset stomach or feel dizzy or lightheaded if you take the medication before you go to bed for the night.
Place your second dose of sodium oxybate in a safe place near your bed before you go to sleep. Use an alarm clock to be sure that you will wake up in time to take the second dose. If you wake up before the alarm goes off and it has been at least 2 1/2 hours since you took your first dose, take your second dose, turn off the alarm, and go back to sleep.
Your doctor will probably start you on a low dose of sodium oxybate and gradually increase your dose, not more often than once every 2 weeks.
Sodium oxybate may help to control your symptoms but will not cure your condition. Continue to take sodium oxybate even if you feel well. Do not stop taking sodium oxybate without talking to your doctor. Your doctor will probably want to decrease your dose gradually. If you suddenly stop taking sodium oxybate, you may have more attacks of cataplexy and you may experience anxiety and difficulty falling asleep or staying asleep.
To prepare doses of sodium oxybate, follow these steps:
- Open the carton that your medicine came in and remove the bottle of medication and the measuring device.
- Remove the measuring device from its wrapper.
- Open the bottle by pushing down on the cap and turning the cap counterclockwise (to the left) at the same time.
- Place the open bottle upright on a table.
- Hold the bottle upright with one hand. Use your other hand to place the tip of the measuring device in the center opening on the top of the bottle. Press the tip firmly into the opening.
- Hold the bottle and measuring device with one hand. Use your other hand to pull back on the plunger until it is even with the marking that matches the dose your doctor prescribed. Be sure to keep the bottle upright to allow the medication to flow into the measuring device.
- Remove the measuring device from the top of the bottle. Place the tip of the measuring device in one of the dosing cups provided with the medication.
- Press down on the plunger to empty the medication into the dosing cup.
- Add 2 ounces (60 mL, 1/4 cup, or about 4 tablespoons) of tap water to the dosing cup. The medication will taste best if you mix it with cold water. Do not mix the medication with fruit juice, soft drinks, or any other liquid.
- Repeat steps 5-9 to prepare a dose of sodium oxybate in the second dosing cup.
- Place the caps on both dosing cups. Turn each cap clockwise (to the right) until it clicks and locks in place.
- Rinse the measuring device with water
- Replace the cap on the bottle of sodium oxybate and return the bottle and measuring device to the safe place where they are stored. Place both prepared dosing cups of medication in a safe place near your bed.
- When it is time for you to take the first dose of sodium oxybate, press down on the cap and turn it counterclockwise (to the left). Drink all of the liquid while you are sitting on your bed. Put the cap back on the cup, turn it clockwise (to the right) to lock it in place, and lie down right away.
- When you wake up 2 1/2 - 4 hours later to take the second dose, repeat step 14.
Other uses for this medicine
This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.
What special precautions should I follow
Before taking sodium oxybate:
- tell your doctor and pharmacist if you are allergic to sodium oxybate or any other medications.
- tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking. Be sure to mention the medications listed in the IMPORTANT WARNING section and levodopa (Larodopa, in Sinemet). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
- tell your doctor if you are following a low salt diet for medical reasons and if you have or have ever had succinic semialdehyde dehydrogenase deficiency (an inherited condition in which certain substances build up in the body and cause retardation and developmental delays), heart failure, high blood pressure, or liver or kidney disease.
- tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking sodium oxybate, call your doctor.
- if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking sodium oxybate.
- you should know that you will be very sleepy for at least 6 hours after you take sodium oxybate, and you may also be drowsy during the daytime. Do not drive a car, operate machinery, or perform any other dangerous activities for at least 6 hours after you take your medication. Avoid dangerous activities at all times until you know how sodium oxybate affects you.
What special dietary instructions should I follow
Unless your doctor tells you otherwise, continue your normal diet.
What should I do if I forget a dose
If you miss the first dose of sodium oxybate, you may take a dose when the second dose is scheduled; do not take a second dose of sodium oxybate that night. If you miss the second dose, skip the missed dose and continue your regular dosing schedule on the next night. Do not take a double dose to make up for a missed one. Always allow at least 2 1/2 hours between doses of sodium oxybate.
Side effects
Mild side effects
Sodium oxybate may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:
- bedwetting
- headache
- dizziness
- upset stomach
- vomiting
- diarrhea
- heartburn
- stomach pain
- back pain
- weakness
- difficulty falling asleep or staying asleep
- sweating
- flu-like symptoms
- ringing in the ears
- problems with vision
- painful or irregular menstrual periods
- abnormal sensitivity to touch or sound
Severe side effects
Some side effects can be serious. The following symptoms are uncommon, but if you experience any of them or those listed in the IMPORTANT WARNING section, call your doctor immediately:
- sleepwalking
- abnormal dreams
- sore throat, fever, chills, and other signs of infection
Sodium oxybate may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.
If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online [at http://www.fda.gov/MedWatch/report.htm] or by phone [1-800-332-1088].
What storage conditions are needed for this medicine
Keep this medication in the container it came in, tightly closed, and out of reach of children and pets. Store it at room temperature and away from excess heat and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed. Throw away unused mixtures of sodium oxybate and water 24 hours after you prepare them. When you are ready to throw away a bottle of sodium oxybate, pour any remaining medication down the drain, use a marker to destroy the bottle label, and throw away the bottle with your household trash. Ask your doctor or call the central pharmacy if you have questions about the proper disposal of your medication.
In case of emergency/overdose
In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.
Symptoms of overdose may include:
- confusion
- problems with coordination
- agitation
- loss of consciousness
- coma
- slow, shallow, or interrupted breathing
- loss of bladder control
- loss of bowel control
- vomiting
- sweating
- headache
- blurred vision
- muscle jerks or twitches
- seizure
- slow heartbeat
- low body temperature
- weak muscles
What other information should I know
Ask your doctor or call the central pharmacy if you have any questions about refilling your prescription.
Brand names
- Xyrem®
Other names
- Gamma Hydroxybutyrate Sodium
- GBH Sodium
- GHB Sodium
- γ-Hydroxybutyrate Sodium
- Oxybate Sodium