Sodium oxybate

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# Black Box Warning

# Overview
Sodium oxybate is a central nervous system agent 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 nausea, dizziness, vomiting, somnolence, enuresis, and tremor.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
Healthcare professionals who prescribe Sodium oxybate must enroll in the Sodium oxybate Success Program and must comply with the requirements to ensure safe use of Sodium oxybate.
- The recommended starting dose is 4.5 grams (g) per night administered orally in two equal, divided doses: 2.25 g at bedtime and 2.25 g taken 2.5 to 4 hours later (see Table 1). Increase the dose by 1.5 g per night at weekly intervals (additional 0.75 g at bedtime and 0.75 g taken 2.5 to 4 hours later) to the effective dose range of 6 g to 9 g per night orally. Doses higher than 9 g per night have not been studied and should not ordinarily be administered.
- Take the first dose of Sodium oxybate at least 2 hours after eating because food significantly reduces the bioavailability of sodium oxybate.
- Prepare both doses of Sodium oxybate prior to bedtime. Prior to ingestion, each dose of Sodium oxybate should be diluted with approximately 14 cup (approximately 60 mL) of water in the empty pharmacy vials provided. Patients should take both doses of Sodium oxybate while in bed and lie down immediately after dosing as Sodium oxybate may cause them to fall asleep abruptly without first feeling drowsy. Patients will often fall asleep within 5 minutes of taking Sodium oxybate, and will usually fall asleep within 15 minutes, though the time it takes any individual patient to fall asleep may vary from night to night. Patients should remain in bed following ingestion of the first and second doses, and should not take the second dose until 2.5 to 4 hours after the first dose. Patients may need to set an alarm to awaken for the second dose. Rarely, patients may take up to 2 hours to fall asleep.
- The recommended starting dose in patients with hepatic impairment is 2.25 g per night administered orally in two equal, divided doses: approximately 1.13 g at bedtime and approximately 1.13 g taken 2.5 to 4 hours later.
- Pharmacokinetics and pharmacodynamics interactions have been observed when Sodium oxybate is co-administered with divalproex sodium. For patients already stabilized on Sodium oxybate, it is recommended that addition of divalproex sodium should be accompanied by an initial reduction in the nightly dose of Sodium oxybate by at least 20%. For patients already taking divalproex sodium, it is recommended that prescribers use a lower starting Sodium oxybate dose with introducing Sodium oxybate. Prescribers should monitor patient response and adjust dose accordingly.

## 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.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-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 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.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Sodium oxybate (patient information) in pediatric patients.

# Contraindications
- Sodium oxybate is contraindicated in patients being treated with sedative hypnotic agents.
- Patients should not drink alcohol when using Sodium oxybate.
- Sodium oxybate 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 Depression
- Sodium oxybate is a central nervous system (CNS) depressant. Alcohol and sedative hypnotics are contraindicated in patients who are using Sodium oxybate  The concurrent use of Sodium oxybate 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 Sodium oxybate is required, dose reduction or discontinuation of one or more CNS depressants (including Sodium oxybate) should be considered. In addition, if short-term use of an opioid (e.g. post- or perioperative) is required, interruption of treatment with Sodium oxybate should be considered.
- Healthcare providers should caution patients about operating hazardous machinery, including automobiles or airplanes, until they are reasonably certain that Sodium oxybate 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 Sodium oxybate  Patients should be queried about CNS depressionrelated events upon initiation of Sodium oxybate therapy and periodically thereafter.
- Sodium oxybate is a Schedule III controlled substance. The active ingredient of Sodium oxybate, 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 Sodium oxybate  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).
Because of the risks of central nervous system depression and abuse/misuse, Sodium oxybate is available only through a restricted distribution program called the Sodium oxybate Success Program.
- Required components of the Sodium oxybate Success Program are:
Use of a centralized pharmacy
Healthcare Providers who prescribe Sodium oxybate must complete the enrollment forms and comply with the requirements.
To receive Sodium oxybate, patients must understand the risks and benefits of Sodium oxybate.
Further information is available at WWW.Sodium oxybate.COM or 1-866-Sodium oxybate88 (1-866-997-3688).
- Use of a centralized pharmacy
- Healthcare Providers who prescribe Sodium oxybate must complete the enrollment forms and comply with the requirements.
- To receive Sodium oxybate, patients must understand the risks and benefits of Sodium oxybate.
- Further information is available at WWW.Sodium oxybate.COM or 1-866-Sodium oxybate88 (1-866-997-3688).
- Sodium oxybate may impair respiratory drive, especially in patients with compromised respiratory function. In overdoses, life-threatening respiratory depression has been reported.
- In a study assessing the respiratory-depressant effects of Sodium oxybate 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 Sodium oxybate 9 g per night in 50 patients with obstructive sleep apnea, Sodium oxybate 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 Sodium oxybate  and clinically significant oxygen desaturation (55%) was measured in three patients (6%) after Sodium oxybate 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 Sodium oxybate 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.
- In clinical trials in patients with narcolepsy (n=781), there were two suicides and two attempted suicides in Sodium oxybate-treated patients, including three patients with a previous history of depressive psychiatric disorder. Of the two suicides, one patient used Sodium oxybate in conjunction with other drugs. Sodium oxybate was not involved in the second suicide. Adverse reactions of depression were reported by 7% of 781 Sodium oxybate-treated patients, with four patients (< 1%) discontinuing because of depression. In most cases, no change in Sodium oxybate treatment was required.
- In a controlled trial, with patients randomized to fixed doses of 3 g, 6 g, or 9 g per night Sodium oxybate 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 Sodium oxybate 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 Sodium oxybate.
- During clinical trials in narcolepsy, 3% of 781 patients treated with Sodium oxybate 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 Sodium oxybate 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 Sodium oxybate in clinical trials in another population. The emergence of or increase in anxiety in patients taking Sodium oxybate should be carefully monitored.
- Other neuropsychiatric reactions reported in Sodium oxybate clinical trials included hallucinations, paranoia, psychosis, and agitation. The emergence of thought disorders and/or behavior abnormalities requires careful and immediate evaluation.
- 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 Sodium oxybate 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 Sodium oxybate 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 Sodium oxybate in patients with narcolepsy.
- Parasomnias including sleepwalking have been reported in postmarketing experience with Sodium oxybate. Therefore, episodes of sleepwalking should be fully evaluated and appropriate interventions considered.
- Sodium oxybate 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 Sodium oxybate. Table 2 provides the approximate sodium content per Sodium oxybate 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.
Sodium oxybate 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 Sodium oxybate, and 213 with placebo). A total of 781 patients with narcolepsy were treated with Sodium oxybate 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 Sodium oxybate-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 Sodium oxybate-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 Sodium oxybate 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 Sodium oxybate exposure have been identified during postmarketing use of Sodium oxybate. 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
- Sodium oxybate should not be used in combination with alcohol or sedative hypnotics. Use of other CNS depressants may potentiate the CNS-depressant effects of Sodium oxybate.
- Concomitant use of Sodium oxybate with divalproex sodium resulted in a 25% mean increase in systemic exposure to Sodium oxybate (AUC ratio range of 0.8 to 1.7) and in a greater impairment on some tests of attention and working memory. An initial Sodium oxybate dose reduction of at least 20% is recommended if divalproex sodium is prescribed to patients already taking Sodium oxybate  Prescribers are advised to monitor patient response closely and adjust dose accordingly if concomitant use of Sodium oxybate 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. Sodium oxybate 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 in women who are pregnant.

### Labor and Delivery
- Sodium oxybate 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 infants 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 Sodium oxybate is administered to a nursing woman.

### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.

### Geriatic Use
- Clinical studies of Sodium oxybate 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 with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Sodium oxybate with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Sodium oxybate in patients with renal impairment.

### Hepatic Impairment
The starting dose of Sodium oxybate should be reduced by one-half in patients with liver impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sodium oxybate in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Sodium oxybate in patients who are immunocompromised.

# Administration and Monitoring

### Administration
There is limited information regarding Sodium oxybate Administration in the drug label.

### Monitoring
There is limited information regarding Sodium oxybate Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Sodium oxybate and IV administrations.

# Overdosage
- 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 was common, and may have influenced the presentation and severity of clinical manifestations of overdose.
- In clinical trials two cases of overdose with Sodium oxybate 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 Sodium oxybate and numerous other drugs.
- 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 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.
- 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.
- 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

## Mechanism of Action
- Sodium oxybate is a CNS depressant. The mechanism of action of Sodium oxybate 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 Sodium oxybate on cataplexy and excessive daytime sleepiness are mediated through GABAB actions at noradrenergic and dopaminergic neurons, as well as at thalamocortical neurons.

## Structure
- The molecular formula is C4H7NaO3, and the molecular weight is 126.09 g/mole. The chemical structure is:

## Pharmacodynamics
There is limited information regarding Sodium oxybate Pharmacodynamics in the drug label.

## Pharmacokinetics

### Pharmacokinetics of sodium oxybate are nonlinear and are similar following single or repeat dosing
- 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 3.7fold 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 Sodium oxybate 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%.
- 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.
- 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 -ketoglutarate. An alternate pathway of biotransformation involves -oxidation via 3,4-dihydroxybutyrate to carbon dioxide and water. No active metabolites have been identified.
- 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
- 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.
- 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.
- 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

### Cataplexy in Narcolepsy
- The effectiveness of Sodium oxybate 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 Sodium oxybate independent of stimulant use. In each trial, the treatment period was 4 weeks and the total nightly Sodium oxybate 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, Sodium oxybate 3 g per night, Sodium oxybate 6 g per night, or Sodium oxybate 9 g per night.
- Trial N2 was a randomized withdrawal trial with 55 narcoleptic patients who had been taking open-label Sodium oxybate 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 Sodium oxybate 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 Sodium oxybate 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 Sodium oxybate therapy experienced a significant increase in cataplexy attacks (p < 0.001), providing evidence of long-term efficacy of Sodium oxybate  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.

### Excessive Daytime Sleepiness in Narcolepsy
- The effectiveness of Sodium oxybate 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, Sodium oxybate 4.5 g per night, Sodium oxybate 6 g per night, or Sodium oxybate 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 Sodium oxybate 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, Sodium oxybate,  modafinil, or Sodium oxybate plus modafinil. Sodium oxybate 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 Sodium oxybate plus modafinil treatment groups at the patients prior dose. Trial N4 was not designed to compare the effects of Sodium oxybate to modafinil because patients receiving modafinil were not titrated to a maximal dose. Patients randomized to placebo or to Sodium oxybate 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 Sodium oxybate and Sodium oxybate plus modafinil groups compared to the placebo group.
- This trial was not designed to compare the effects of Sodium oxybate to modafinil, because patients receiving modafinil were not titrated to a maximally effective dose.

# How Supplied
- Sodium oxybate is a clear to slightly opalescent oral solution. Each prescription includes a carton containing one bottle of Sodium oxybate, a press-in-bottle-adaptor, an oral measuring device (plastic syringe), and a Medication Guide. The pharmacy provides two empty vials with child-resistant caps with each Sodium oxybate shipment.
- Each amber bottle contains Sodium oxybate oral solution at a concentration of 0.5 g per mL and has a child-resistant cap.
Carton containing one 180 mL bottle: NDC 68727-100-01
- Carton containing one 180 mL bottle: NDC 68727-100-01

## Storage
- Sodium oxybate should be stored at 25C (77F); excursions permitted to 15 to 30C (59 to 86F)

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
There is limited information regarding Sodium oxybate Patient Counseling Information in the drug label.

# Precautions with Alcohol
- Alcohol-Sodium oxybate (patient information) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Xyrem

# Look-Alike Drug Names
There is limited information regarding Sodium oxybate Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price