sodium oxybate
Solution · Oral
• Central Nervous System Depression Sodium Oxybate Oral Solution is a CNS depressant. In clinical trials at recommended doses, obtundation and clinically significant respiratory depression occurred in adult patients treated with Sodium Oxybate Oral Solution [see Warnings and Precautions ( 5.1 )]. Many patients who received Sodium Oxybate Oral Solution during clinical trials in narcolepsy were receiving central nervous system stimulants [see Clinical Trials ( 14 )].
• Abuse and Misuse Sodium Oxybate is the sodium salt of gamma-hydroxybutyrate (GHB). Abuse or misuse 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 [see Warnings and Precautions ( 5.2 )].…
Uses
Sodium Oxybate Oral Solution is indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy. Sodium Oxybate Oral Solution is a central nervous system depressant indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy ( 1 ).
Dosage and administration
Dosage for Adult Patients
• Initiate dosage at 4.5 g per night orally, divided into two doses ( 2.1 ).
• Titrate to effect in increments of 1.5 g per night at weekly intervals (0.75 g at bedtime and 0.75 g taken 2.5 to 4 hours later) ( 2.1 ).
• Recommended dosage range: 6 g to 9 g per night orally ( 2.1 ). Total Nightly Dose Take at Bedtime Take 2.5 to 4 Hours Later 4.5 g per night 2.25 g 2.25 g 6 g per night 3 g 3 g 7.5 g per night 3.75 g 3.75 g 9 g per night 4.5 g 4.5 g Dosage for Pediatric Patients (7 years of Age and Older)
• The recommended starting dosage, titration regimen, and maximum total nightly dosage are based on body weight ( 2.2 ). Important Administration Information
• Prepare both doses prior to bedtime; dilute each dose with approximately ¼ cup of water in pharmacy-provided containers ( 2.3 ).
• Allow 2 hours after eating before dosing ( 2.3 ).
• Take each dose while in bed and lie down after dosing ( 2.3 ). Patients with Hepatic Impairment Recommended starting dosage is one-half of the original dosage per night administered orally, divided into two doses ( 2.4 ). 2.1 Adult Dosing Information The recommended starting dosage is 4.5 grams (g) per night administered orally, divided into two doses: 2.25 g at bedtime and 2.25 g taken 2.5 to 4 hours later (see Table 1). Increase the dosage 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 dosage range of 6 g to 9 g per night orally. The dosage may be gradually titrated based on efficacy and tolerability. Doses higher than 9 g per night have not been studied and should not ordinarily be administered. Table 1: Recommended Adult Sodium Oxybate Oral Solution Dose Regimen (g = grams) If a Patient’s Total Nightly Dose is: Take at Bedtime: Take 2.5 to 4 Hours Later: 4.5 g per night 2.25 g 2.25 g 6 g per night 3 g 3 g 7.5 g per night 3.75 g 3.75 g 9 g per night 4.5 g 4.5 g 2.2 Pediatric Dosing Information Sodium Oxybate Oral Solution is administered orally twice nightly. The recommended starting pediatric dosage, titration regimen, and maximum total nightly dosage are based on patient weight, as specified in Table 2. The dosage may be gradually titrated based on efficacy and tolerability. Table 2: Recommended Pediatric Sodium Oxybate Oral Solution Dosage for Patients 7 Years of Age and Older* Patient Weight Initial Dosage Maximum Weekly Dosage Increase Maximum Recommended Dosage Take at Bedtime: Take 2.5 to 4 Hours Later: Take at Bedtime: Take 2.5 to 4 Hours Later: Take at Bedtime: Take 2.5 to 4 Hours Later: <20 kg ** There is insufficient information to provide specific dosing recommendations for patients who weigh less than 20 kg. 20 kg to <30 kg ≤1 g ≤1 g 0.5 g 0.5 g 3 g 3 g 30 kg to <45 kg ≤1.5 g ≤1.5 g 0.5 g 0.5 g 3.75 g 3.75 g ≥45 kg ≤2.25 g ≤2.25 g 0.75 g 0.75 g 4.5 g 4.5 g *For patients who sleep more than 8 hours per night, the first dose of Sodium Oxybate Oral Solution may be given at bedtime or after an initial period of sleep. **If Sodium Oxybate Oral Solution is used in patients 7 years of age and older who weigh less than 20 kg, a lower starting dosage, lower maximum weekly dosage increases, and lower total maximum nightly dosage should be considered. Note: Some patients may achieve better responses with unequal doses at bedtime and 2.5 to 4 hours later. 2.3 Important Administration Instructions for All Patients The total nightly dosage of Sodium Oxybate Oral Solution is divided into two doses. Prepare both doses of Sodium Oxybate Oral Solution prior to bedtime. Prior to ingestion, each dose of Sodium Oxybate Oral Solution should be diluted with approximately ¼ cup (approximately 60 mL) of water in the empty pharmacy containers provided. Take the first nightly dose of Sodium Oxybate Oral Solution at least 2 hours after eating [see Clinical Pharmacology ( 12.3 )]. Take the second nightly dose 2.5 to 4 hours after the first dose. Patients should take both doses of Sodium Oxybate Oral Solution while in bed and lie down immediately after dosing, and remain in bed following ingestion of each dose. Sodium Oxybate Oral Solution may cause patients to fall asleep abruptly without first feeling drowsy [see Adverse Reactions ( 6.2 )] . Patients will often fall asleep within 5 minutes of taking Sodium Oxybate Oral Solution, 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 may need to set an alarm to awaken for the second dose. Rarely, patients may take up to 2 hours to fall asleep. If the second dose is missed, that dose should be skipped and Sodium Oxybate Oral Solution should not be taken again until the next night. Both Sodium Oxybate Oral Solution doses should never be taken at one time. 2.4 Dosage Modification in Patients with Hepatic Impairment The recommended starting dosage in patients with hepatic impairment is one-half of the original dosage per night, administered orally divided into two doses [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )] . 2.5 Dosage Adjustment with Co-administration of Divalproex Sodium When initiating divalproex sodium in patients taking a stable dosage of Sodium Oxybate Oral Solution, a reduction of the Sodium Oxybate Oral Solution dosage by at least 20% is recommended with initial concomitant use [see Drug Interactions ( 7.2 ) and Clinical Pharmacology ( 12.3 )] . When initiating Sodium Oxybate Oral Solution in patients already taking divalproex sodium, a lower starting dosage of Sodium Oxybate Oral Solution is recommended. Subsequently, the dosage of Sodium Oxybate Oral Solution can be adjusted based on individual clinical response and tolerability.
Dosage forms and strengths
Sodium Oxybate Oral Solution is a clear to slightly opalescent oral solution, in a concentration of 0.5 g per mL (0.5 g/mL of sodium oxybate equivalent to 0.413 g/mL of oxybate). Oral solution, 0.5 g per mL ( 3 )
Contraindications
Sodium Oxybate Oral Solution is contraindicated for use in:
• combination with sedative hypnotics [see Warnings and Precautions ( 5.1 )] .
• combination with alcohol [see Warnings and Precautions ( 5.1 )] .
• patients with succinic semialdehyde dehydrogenase deficiency [see Clinical Pharmacology ( 12.3 )] .
• In combination with sedative hypnotics or alcohol ( 4 )
• Succinic semialdehyde dehydrogenase deficiency ( 4 )
Warnings and precautions
• CNS depression: Use caution when considering the concurrent use of Sodium Oxybate Oral Solution with other CNS depressants ( 5.1 ).
• Caution patients against hazardous activities requiring complete mental alertness or motor coordination within the first 6 hours of dosing or after first initiating treatment until certain that Sodium Oxybate Oral Solution does not affect them adversely ( 5.1 ).
• Depression and suicidality: Monitor patients for emergent or increased depression and suicidality ( 5.5 ).
• Confusion/Anxiety: Monitor for impaired motor/cognitive function ( 5.6 ).
• Parasomnias: Evaluate episodes of sleepwalking ( 5.7 ).
• High sodium content in Sodium Oxybate Oral Solution: Monitor patients with heart failure, hypertension, or impaired renal function ( 5.8 ). 5.1 Central Nervous System Depression Sodium Oxybate Oral Solution is a central nervous system (CNS) depressant. In adult clinical trials at recommended doses, obtundation and clinically significant respiratory depression occurred in patients treated with Sodium Oxybate Oral Solution. Sodium Oxybate Oral Solution is contraindicated in combination with alcohol and sedative hypnotics. The concurrent use of Sodium Oxybate Oral Solution 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 Oral Solution is required, dose reduction or discontinuation of one or more CNS depressants (including Sodium Oxybate Oral Solution) 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 Oral Solution should be considered. Healthcare providers should caution patients about operating hazardous machinery, including automobiles or airplanes, until they are reasonably certain that Sodium Oxybate Oral Solution 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 Sodium Oxybate Oral Solution. Patients should be queried about CNS depression‑related events upon initiation of Sodium Oxybate Oral Solution therapy and periodically thereafter. Sodium Oxybate Oral Solution is available only through a restricted program under a REMS [see Warnings and Precautions ( 5.3 )] . 5.2 Abuse and Misuse Sodium Oxybate Oral Solution is a Schedule III controlled substance. The active ingredient of Sodium Oxybate Oral Solution, 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 Oral Solution, 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 Drug Abuse and Dependence ( 9.2 )] . Sodium Oxybate Oral Solution is available only through a restricted program under a REMS [see Warnings and Precautions ( 5.3 )]. 5.3 XYWAV and XYREM REMS Sodium Oxybate Oral Solution is available only through a restricted distribution program called the XYWAV and XYREM REMS because of the risks of central nervous system depression and abuse and misuse [see Warnings and Precautions ( 5.1 , 5.2 )]. Notable requirements of the XYWAV and XYREM REMS include the following:
• Healthcare Providers who prescribe Sodium Oxybate Oral Solution are specially certified
• Sodium Oxybate Oral Solution will be dispensed only by the central pharmacy that is specially certified
• Sodium Oxybate Oral Solution will be dispensed and shipped only to patients who are enrolled in the XYWAV and XYREM REMS with documentation of safe use Further information is available at www.XYWAVXYREMREMS.com or 1-866-997-3688. 5.4 Respiratory Depression and Sleep-Disordered Breathing Sodium Oxybate Oral Solution may impair respiratory drive, especially in patients with compromised respiratory function. In overdoses, life-threatening respiratory depression has been reported [see Overdosage ( 10 )] . In an adult study assessing the respiratory-depressant effects of Sodium Oxybate Oral Solution 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 an adult study assessing the effects of Sodium Oxybate Oral Solution 9 g per night in 50 patients with obstructive sleep apnea, Sodium Oxybate Oral Solution did not increase the severity of sleep-disordered breathing and did not adversely affect the average duration and severity of oxygen desaturation overall.
Side effects
The following clinically significant adverse reactions appear in other sections of the labeling:
• CNS depression [see Warnings and Precautions ( 5.1 )]
• Abuse and Misuse [see Warnings and Precautions ( 5.2 )]
• Respiratory Depression and Sleep-Disordered Breathing [see Warnings and Precautions ( 5.4 )]
• Depression and Suicidality [see Warnings and Precautions ( 5.5 )]
• Other Behavioral or Psychiatric Adverse Reactions [see Warnings and Precautions ( 5.6 )]
• Parasomnias [see Warnings and Precautions ( 5.7 )]
• Use in Patients Sensitive to High Sodium Intake [see Warnings and Precautions ( 5.8 )] Most common adverse reactions in adults (≥5% and at least twice the incidence with placebo) were nausea, dizziness, vomiting, somnolence, enuresis, and tremor ( 6.1 ). Most common adverse reactions in pediatric patients (≥5%) were nausea, enuresis, vomiting, headache, weight decreased, decreased appetite, dizziness, and sleepwalking ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Jazz Pharmaceuticals, Inc. at 1-800-520-5568, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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. Adult Patients Sodium Oxybate Oral Solution 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 Oral Solution, and 213 with placebo). A total of 781 patients with narcolepsy were treated with Sodium Oxybate Oral Solution in controlled and uncontrolled clinical trials. Section 6.1 and Table 4 present adverse reactions from three pooled, controlled trials (N1, N3, N4) in patients with narcolepsy. Adverse Reactions Leading to Treatment Discontinuation: Of the 398 patients with narcolepsy treated with Sodium Oxybate Oral Solution, 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. Commonly Observed Adverse Reactions in Controlled Clinical Trials: The most common adverse reactions (incidence ≥5% and twice the rate seen with placebo) in patients treated with Sodium Oxybate Oral Solution were nausea, dizziness, vomiting, somnolence, enuresis, and tremor. Adverse Reactions Occurring at an Incidence of 2% or Greater: Table 4 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 Oral Solution 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. Table 4 Adverse Reactions Occurring in ≥2% of Adult Patients and More Frequently with Sodium Oxybate Oral Solution than Placebo in Three Controlled Trials (N1, N3, N4) by Body System and Dose at Onset Adverse Reaction Placebo (n=213) % Sodium Oxybate Oral Solution 4.5g (n=185) % Sodium Oxybate Oral Solution 6g (n=258) % Sodium Oxybate Oral Solution 9g (n=178) % ANY ADVERSE REACTION 62 45 55 70 GASTROINTESTINAL DISORDERS Nausea 3 8 13 20 Vomiting 1 2 4 11 Diarrhea 2 4 3 4 Abdominal pain upper 2 3 1 2 Dry mouth 2 1 2 1 GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS Pain 1 1 <1 3 Feeling drunk 1 0 <1 3 Edema peripheral 1 3 0 0 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Cataplexy 1 1 1 2 Muscle spasms 2 2 <1 2 Pain in extremity 1 3 1 1 NERVOUS SYSTEM DISORDERS Dizziness 4 9 11 15 Somnolence 4 1 3 8 Tremor 0 0 2 5 Disturbance in attention 0 1 0 4 Paresthesia 1 2 1 3 Sleep paralysis 1 0 1 3 PSYCHIATRIC DISORDERS Disorientation 1 1 2 3 Irritability 1 0 <1 3 Sleepwalking 0 0 0 3 Anxiety 1 1 1 2 RENAL AND URINARY DISORDERS Enuresis 1 3 3 7 SKIN AND SUBCUTANEOUS TISSUE DISORDERS Hyperhidrosis 0 1 1 3 Dose-Response Information In clinical trials in narcolepsy, a dose-response relationship was observed for nausea, vomiting, paresthesia, disorientation, irritability, disturbance in attention, feeling drunk, sleepwalking, and enuresis. The incidence of all these reactions was notably higher at 9 g per night. In controlled trials in narcolepsy, discontinuations of treatment due to adverse reactions were greater at higher doses of Sodium Oxybate Oral Solution. Pediatric Patients (7 Years of Age and Older) In the pediatric clinical trial (Trial N5), 104 patients aged 7 to 17 years (37 patients aged 7 to 11 years; 67 patients aged 12 to 17 years) with narcolepsy received Sodium Oxybate Oral Solution for up to one year. This study included an open-label safety continuation period in which eligible patients received Sodium Oxybate Oral Solution for up to an additional 2 years. The median and maximum exposure across the entire study were 371 and 987 days, respectively. Adverse Reactions Leading to Treatment Discontinuation In the pediatric clinical trial, 7 of 104 patients reported adverse reactions that led to withdrawal from the study (hallucination, tactile; suicidal ideation; weight decreased; sleep apnea syndrome; affect lability; anger, anxiety, depression; and headache). Adverse Reactions in the Pediatric Clinical Trial The most common adverse reactions (≥5%) were nausea (20%), enuresis (19%), vomiting (18%), headache (17%), weight decreased (13%), decreased appetite (9%), dizziness (8%), and sleepwalking (6%).
Drug interactions
• Concomitant use with divalproex sodium: An initial reduction in Sodium Oxybate Oral Solution dose of at least 20% is recommended ( 2.5 , 7.2 ). 7.1 Alcohol, Sedative Hypnotics, and CNS Depressants Sodium Oxybate Oral Solution is contraindicated for use in combination with alcohol or sedative hypnotics. Use of other CNS depressants may potentiate the CNS-depressant effects of Sodium Oxybate Oral Solution [see Warnings and Precautions ( 5.1 )]. 7.2 Divalproex Sodium Concomitant use of Sodium Oxybate Oral Solution with divalproex sodium results in an increase in systemic exposure to GHB, which was shown to cause a greater impairment on some tests of attention and working memory in a clinical study [see Clinical Pharmacology ( 12.3 )] . An initial dose reduction of Sodium Oxybate Oral Solution is recommended when used concomitantly with divalproex sodium [see Dosage and Administration ( 2.5 )] . Prescribers are advised to monitor patient response closely and adjust dose accordingly if concomitant use of Sodium Oxybate Oral Solution and divalproex sodium is warranted.
Use in specific populations
• Pregnancy: Based on animal data, may cause fetal harm ( 8.1 ).
• Geriatric patients: Monitor for impaired motor and/or cognitive function when taking Sodium Oxybate Oral Solution ( 8.5 ). 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of sodium oxybate in pregnant women. 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; however, oral administration to rats throughout pregnancy and lactation resulted in increased stillbirths and decreased offspring postnatal viability and growth, at a clinically relevant dose [see Data] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations Labor or Delivery Sodium Oxybate Oral Solution 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 and gamma-hydroxybutyrate (GHB) has been detected in newborns at delivery after intravenous administration of GHB to mothers. Subsequent effects of sodium oxybate on later growth, development, and maturation in humans are unknown. Data Animal Data 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/m 2 ) 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/m 2 basis. 8.2 Lactation Risk Summary GHB is excreted in human milk after oral administration of sodium oxybate. There is insufficient information on the risk to a breastfed infant, and there is insufficient information on milk production in nursing mothers. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Sodium Oxybate Oral Solution and any potential adverse effects on the breastfed infant from Sodium Oxybate Oral Solution or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of Sodium Oxybate Oral Solution in the treatment of cataplexy or excessive daytime sleepiness in pediatric patients (7 years of age and older) with narcolepsy have been established in a double-blind, placebo-controlled, randomized-withdrawal study [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14.3 )] . In the pediatric clinical trial with Sodium Oxybate Oral Solution administration in patients with narcolepsy, serious adverse reactions of central sleep apnea and oxygen desaturation documented by polysomnography evaluation; depression; suicidal ideation; neuropsychiatric reactions including acute psychosis, confusion, and anxiety; and parasomnias, including sleepwalking, have been reported [see Warnings and Precautions ( 5.4 , 5.5 , 5.6 , 5.7 ) and Adverse Reactions ( 6.1 )] . Safety and effectiveness of Sodium Oxybate Oral Solution in pediatric patients below the age of 7 years have not been established. Juvenile Animal Toxicity Data In a study in which sodium oxybate (0, 100, 300, or 900 mg/kg/day) was orally administered to rats during the juvenile period of development (postnatal days 21 through 90), mortality was observed at the two highest doses tested. Deaths occurred during the first week of dosing and were associated with clinical signs (including decreased activity and respiratory rate) consistent with the pharmacological effects of the drug. Reduced body weight gain in males and females and delayed sexual maturation in males were observed at the highest dose tested. The no-effect dose for adverse effects in juvenile rats is associated with plasma exposures (AUC) less than that at the maximum recommended human dose (9 g/night). 8.5 Geriatric Use Clinical studies of Sodium Oxybate Oral Solution 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 (21% vs. 19%). Frequency of headaches was markedly increased in the elderly (39% vs. 19%). 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. 8.6 Hepatic Impairment Because of an increase in exposure to Sodium Oxybate Oral Solution, the starting dose should be reduced by half in patients with hepatic impairment [see Dosage and Administration ( 2.4 ) and Clinical Pharmacology ( 12.3 )] .
Pregnancy
8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of sodium oxybate in pregnant women. 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; however, oral administration to rats throughout pregnancy and lactation resulted in increased stillbirths and decreased offspring postnatal viability and growth, at a clinically relevant dose [see Data] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations Labor or Delivery Sodium Oxybate Oral Solution 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 and gamma-hydroxybutyrate (GHB) has been detected in newborns at delivery after intravenous administration of GHB to mothers. Subsequent effects of sodium oxybate on later growth, development, and maturation in humans are unknown. Data Animal Data 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/m 2 ) 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/m 2 basis.
Pediatric use
8.4 Pediatric Use The safety and effectiveness of Sodium Oxybate Oral Solution in the treatment of cataplexy or excessive daytime sleepiness in pediatric patients (7 years of age and older) with narcolepsy have been established in a double-blind, placebo-controlled, randomized-withdrawal study [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14.3 )] . In the pediatric clinical trial with Sodium Oxybate Oral Solution administration in patients with narcolepsy, serious adverse reactions of central sleep apnea and oxygen desaturation documented by polysomnography evaluation; depression; suicidal ideation; neuropsychiatric reactions including acute psychosis, confusion, and anxiety; and parasomnias, including sleepwalking, have been reported [see Warnings and Precautions ( 5.4 , 5.5 , 5.6 , 5.7 ) and Adverse Reactions ( 6.1 )] . Safety and effectiveness of Sodium Oxybate Oral Solution in pediatric patients below the age of 7 years have not been established. Juvenile Animal Toxicity Data In a study in which sodium oxybate (0, 100, 300, or 900 mg/kg/day) was orally administered to rats during the juvenile period of development (postnatal days 21 through 90), mortality was observed at the two highest doses tested. Deaths occurred during the first week of dosing and were associated with clinical signs (including decreased activity and respiratory rate) consistent with the pharmacological effects of the drug. Reduced body weight gain in males and females and delayed sexual maturation in males were observed at the highest dose tested. The no-effect dose for adverse effects in juvenile rats is associated with plasma exposures (AUC) less than that at the maximum recommended human dose (9 g/night).
Geriatric use
8.5 Geriatric Use Clinical studies of Sodium Oxybate Oral Solution 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 (21% vs. 19%). Frequency of headaches was markedly increased in the elderly (39% vs. 19%). 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.
Overdosage
10.1 Human Experience Information regarding overdose with Sodium Oxybate Oral Solution 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 adult clinical trials two cases of overdose with Sodium Oxybate Oral Solution 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 Oral Solution and numerous other drugs. 10.2 Signs and Symptoms Information about signs and symptoms associated with overdosage with Sodium Oxybate Oral Solution derives from reports of illicit use of GHB. 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 and acidosis have 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. 10.3 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 Oral Solution 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, but have been reported in cases of acidosis associated with GHB ingestions of 125 g or greater; however, due to the rapid metabolism of sodium oxybate, these measures may not be warranted. 10.4 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.
Description
Sodium oxybate, a CNS depressant, is the active ingredient in Sodium Oxybate Oral Solution. The chemical name for sodium oxybate is sodium 4‑hydroxybutyrate. The molecular formula is C 4 H 7 NaO 3 , and the molecular weight is 126.09 g/mole. The chemical structure is: Sodium oxybate is a white to off-white, crystalline powder that is very soluble in aqueous solutions. Each mL of Sodium Oxybate Oral Solution contains 0.5 g of sodium oxybate (equivalent to 0.413 g/mL of oxybate) in USP Purified Water, neutralized to pH 7.5 with malic acid. chemical structure
Mechanism of action
12.1 Mechanism of Action Sodium Oxybate Oral Solution is a CNS depressant. The mechanism of action of Sodium Oxybate Oral Solution in the treatment of narcolepsy is unknown. Sodium oxybate is the sodium salt of gamma-hydroxybutyrate (GHB), an endogenous compound and metabolite of the neurotransmitter GABA. It is hypothesized that the therapeutic effects of Sodium Oxybate Oral Solution on cataplexy and excessive daytime sleepiness are mediated through GABA B actions at noradrenergic and dopaminergic neurons, as well as at thalamocortical neurons.
How supplied
16.1 How Supplied Sodium Oxybate Oral Solution is a clear to slightly opalescent oral solution. Each prescription includes one bottle of Sodium Oxybate Oral Solution with attached press in bottle adaptor, an oral measuring device (plastic syringe), and a Medication Guide. The pharmacy provides two empty containers with child-resistant caps with each Sodium Oxybate Oral Solution shipment. Each amber bottle contains Sodium Oxybate Oral Solution at a concentration of 0.5 g per mL (0.5 g/mL of sodium oxybate equivalent to 0.413 g/mL of oxybate) and has a child-resistant cap. One 180 mL bottle NDC 0054-9628-57 16.2 Storage Keep out of reach of children. Sodium Oxybate Oral Solution should be stored at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) (see USP Controlled Room Temperature). Dispense in tight containers. Solutions prepared following dilution should be consumed within 24 hours. 16.3 Handling and Disposal Sodium Oxybate Oral Solution is a Schedule III drug under the Controlled Substances Act. Sodium Oxybate Oral Solution should be handled according to state and federal regulations. It is safe to dispose of Sodium Oxybate Oral Solution down the sanitary sewer. 16.1 How Supplied Sodium Oxybate Oral Solution is a clear to slightly opalescent oral solution. Each prescription includes one bottle of Sodium Oxybate Oral Solution with attached press in bottle adaptor, an oral measuring device (plastic syringe), and a Medication Guide. The pharmacy provides two empty containers with child-resistant caps with each Sodium Oxybate Oral Solution shipment. Each amber bottle contains Sodium Oxybate Oral Solution at a concentration of 0.5 g per mL (0.5 g/mL of sodium oxybate equivalent to 0.413 g/mL of oxybate) and has a child-resistant cap. One 180 mL bottle NDC 0054-9628-57
Patient information
Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Central Nervous System Depression Inform patients and/or caregivers that Sodium Oxybate Oral Solution can cause central nervous system depression, including respiratory depression, hypotension, profound sedation, syncope, and death. Instruct patients to not engage in activities requiring mental alertness or motor coordination, including operating hazardous machinery, for at least 6 hours after taking Sodium Oxybate Oral Solution. Instruct patients and/or their caregivers to inform their healthcare providers of all the medications they take [see Warnings and Precautions ( 5.1 )] . Abuse and Misuse Inform patients and/or caregivers that the active ingredient of Sodium Oxybate Oral Solution is gamma-hydroxybutyrate (GHB), which is associated with serious adverse reactions with illicit use and abuse [see Warnings and Precautions ( 5.2 )] . XYWAV and XYREM REMS Sodium Oxybate Oral Solution is available only through a restricted program called the XYWAV and XYREM REMS [see Warnings and Precautions ( 5.3 )] . Inform the patient and/or caregiver of the following notable requirements:
• Sodium Oxybate Oral Solution is dispensed only by the central pharmacy
• Sodium Oxybate Oral Solution will be dispensed and shipped only to patients enrolled in the XYWAV and XYREM REMS Sodium Oxybate Oral Solution is available only from the central pharmacy participating in the program. Therefore, provide patients and/or caregivers with the telephone number and website for information on how to obtain the product. Alcohol or Sedative Hypnotics Advise patients and/or caregivers that alcohol and other sedative hypnotics should not be taken with Sodium Oxybate Oral Solution [see Contraindications ( 4 )] . Sedation Inform patients and/or caregivers that the patient is likely to fall asleep quickly after taking Sodium Oxybate Oral Solution (often within 5 and usually within 15 minutes), but the time it takes to fall asleep can vary from night to night. The sudden onset of sleep, including in a standing position or while rising from bed, has led to falls complicated by injuries, in some cases requiring hospitalization [see Adverse Reactions ( 6.2 )] . Instruct patients and/or caregivers that the patient should remain in bed following ingestion of the first and second nightly doses. Instruct patients and/or caregivers that the patient should not take their second nightly dose until 2.5 to 4 hours after the first dose [see Dosage and Administration ( 2.3 )] . Food Effects on Sodium Oxybate Oral Solution Inform patients and/or caregivers that the first nightly dose should be taken at least 2 hours after eating. Respiratory Depression and Sleep-Disordered Breathing Inform patients that Sodium Oxybate Oral Solution may impair respiratory drive, especially in patients with compromised respiratory function, and may cause apnea [see Warnings and Precautions ( 5.4 )] . Depression and Suicidality Instruct patients and/or caregivers to contact a healthcare provider immediately if the patient develops depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, or suicidal ideation [see Warnings and Precautions ( 5.5 )] . Other Behavioral or Psychiatric Adverse Reactions Inform patients and/or caregivers that Sodium Oxybate Oral Solution can cause behavioral or psychiatric adverse reactions, including confusion, anxiety, and psychosis. Instruct them to notify their healthcare provider if any of these types of symptoms occur [see Warnings and Precautions ( 5.6 )] . Sleepwalking Instruct patients and/or caregivers that Sodium Oxybate Oral Solution has been associated with sleepwalking and other behaviors during sleep, and to contact their healthcare provider if this occurs [see Warnings and Precautions ( 5.7 )] . Sodium Intake Instruct patients and/or caregivers that Sodium Oxybate Oral Solution contains a significant amount of sodium and patients who are sensitive to sodium intake (e.g., those with heart failure, hypertension, or renal impairment) should limit their sodium intake [see Warnings and Precautions ( 5.8 )] . Distributed By: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 Protected by U.S. Patent Nos. 8,772,306; 9,050,302; 9,486,426; 10,213,400; 10,864,181; and 11,253,494.
Label text from the FDA structured product label by Hikma Pharmaceuticals USA Inc. (revised Apr 25, 2023). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Sodium Oxybate in 4 products
sodium oxybate NDC products (4)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 65162-065 | Sodium Oxybate 500 mg/mL Solution | Amneal Pharmaceuticals LLC | ANDA · DEA CIII |
| 31722-891 | Sodium Oxybate .5 g/mL Solution | Camber Pharmaceuticals, Inc. | ANDA · DEA CIII |
| 72865-349 | Sodium Oxybate .5 g/mL Solution | XLCare Pharmaceuticals, Inc. | ANDA · DEA CIII |
| 0054-9628 | Sodium Oxybate .5 g/mL Solution | Hikma Pharmaceuticals USA Inc. | NDA AUTHORIZED GENERIC · DEA CIII |
Frequently asked questions
What is sodium oxybate used for?
Sodium Oxybate Oral Solution is indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy. Sodium Oxybate Oral Solution is a central nervous system depressant indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy ( 1 ).
What are the side effects of sodium oxybate?
The following clinically significant adverse reactions appear in other sections of the labeling: • CNS depression [see Warnings and Precautions ( 5.1 )] • Abuse and Misuse [see Warnings and Precautions ( 5.2 )] • Respiratory Depression and Sleep-Disordered Breathing [see Warnings and Precautions ( 5.4 )] • Depression and Suicidality [see Warnings and Precautions ( 5.5 )] • Other Behavioral or… See the full label for the complete list.
Who makes sodium oxybate?
sodium oxybate is listed by 4 labelers in the FDA NDC directory, including Amneal Pharmaceuticals LLC, Camber Pharmaceuticals, Inc., XLCare Pharmaceuticals, Inc., Hikma Pharmaceuticals USA Inc..