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Calcium, Magnesium, Potassium, And Sodium Oxybates

FDA Drug Information • Also known as: Xywav

Brand Names
Xywav
Route
ORAL
Dosage Form
SOLUTION
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: CENTRAL NERVOUS SYSTEM DEPRESSION and ABUSE AND MISUSE.

  • Central Nervous System Depression XYWAV is a CNS depressant. Clinically significant respiratory depression and obtundation may occur in patients treated with XYWAV at recommended doses [see Warnings and Precautions ( 5.1 , 5.4 )]. Many patients who received XYWAV during clinical trials in narcolepsy and idiopathic hypersomnia were receiving central nervous system stimulants [see Clinical Studies ( 14.1 , 14.2 , 14.3 )].
  • Abuse and Misuse The active moiety of XYWAV is oxybate or 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 )]. Because of the risks of CNS depression and abuse and misuse, XYWAV is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the XYWAV and XYREM REMS [see Warnings and Precautions ( 5.3 )]. WARNING: CENTRAL NERVOUS SYSTEM (CNS) DEPRESSION and ABUSE AND MISUSE. See full prescribing information for complete boxed warning. Central Nervous System Depression
  • XYWAV is a CNS depressant, and respiratory depression can occur with XYWAV use ( 5.1 , 5.4 ) Abuse and Misuse
  • The active moiety of XYWAV is oxybate or gamma-hydroxybutyrate (GHB). Abuse or misuse of illicit GHB is associated with CNS adverse reactions, including seizure, respiratory depression, decreased consciousness, coma, and death ( 5.2 , 9.2 ) XYWAV is available only through a restricted program called the XYWAV and XYREM REMS ( 5.3 )

    • Description

    11 DESCRIPTION XYWAV oral solution contains oxybate, a CNS depressant. The chemical name of oxybate is gamma-hydroxybutyrate (GHB). XYWAV contains a mixture of calcium oxybate, magnesium oxybate, potassium oxybate, and sodium oxybate equivalent to 0.5 g/mL, which corresponds to 0.413 g/mL oxybate. Each mL of XYWAV contains: 0.234 g calcium oxybate, Ca(C 4 H 7 O 3 ) 2 ; 0.096 g magnesium oxybate, Mg(C 4 H 7 O 3 ) 2 ; 0.13 g potassium oxybate, K(C 4 H 7 O 3 ); and 0.04 g sodium oxybate, Na(C 4 H 7 O 3 ) in dissociated form in the solution. The molecular weights of each are as follows: calcium oxybate is 246.3, magnesium oxybate is 230.5, potassium oxybate is 142.2, and sodium oxybate is 126.1. The chemical structure is: y =1 for Na + and K + ; y =2 for Mg 2+ and Ca 2+ The inactive ingredients are purified water and sucralose. XYWAV contains no ingredient made from a gluten‑containing grain (wheat, barley, or rye). chemical structure

    What Is Calcium, Magnesium, Potassium, And Sodium Oxybates Used For?

    1 INDICATIONS AND USAGE XYWAV 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 ( 1.1 ).
  • Idiopathic Hypersomnia (IH) in adults ( 1.2 ). 1.1 Narcolepsy XYWAV is indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy. 1.2 Idiopathic Hypersomnia XYWAV is indicated for the treatment of idiopathic hypersomnia (IH) in adults.

    • Dosage and Administration

    2 DOSAGE AND ADMINISTRATION See Full Prescribing Information for complete dosing instructions ( 2.1 - 2.7 ). Dosage for Adult Patients with Narcolepsy

  • Initiate dosage at 4.5 g per night orally, divided into two doses ( 2.1 ).
  • Titrate to effect in increments of up to 1.5 g per night per week ( 2.1 ).
  • Recommended dosage range: 6 g to 9 g per night orally, divided into two doses ( 2.1 ).
  • Doses may be divided equally or unequally and the first dose taken at bedtime and the second dose taken 2.5 to 4 hours later ( 2.1 ). Dosage for Pediatric Patients with Narcolepsy (7 Years of Age and Older)
  • The recommended starting dosage, titration regimen, and maximum total nightly dosage are based on body weight (2.2 ). Dosage for Adult Patients with Idiopathic Hypersomnia
  • XYWAV can be administered as a twice or once nightly regimen in adults ( 2.3 ).
  • Twice nightly: Initiate dosage at 4.5 g or less per night orally, divided into two doses. Titrate to effect in increments of up to 1.5 g per night per week, up to 9 g total nightly dose ( 2.3 ).
  • Once nightly: Initiate dosage at 3 g or less per night orally, as one dose. Titrate to effect in increments of up to 1.5 g per night per week, up to 6 g total nightly dose ( 2.3 ). Important Administration Information
  • Administer XYWAV at least 2 hours after eating ( 2.4 ).
  • Prepare XYWAV prior to bedtime; dilute with approximately ¼ cup of water in pharmacy-provided containers ( 2.4 ).
  • Take XYWAV while in bed and lie down after dosing ( 2.4 ). For Patients Transitioning from Xyrem to XYWAV: Initiate at the same dose and regimen as Xyrem (gram for gram). Titrate as needed based on efficacy and tolerability ( 2.5 ). Patients with Hepatic Impairment Recommended starting dosage is one-half of the original dosage per night administered orally, divided into two doses ( 2.6 ). 2.1 Dosing Information in Adult Patients with Narcolepsy 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 up to 1.5 g per night per week (e.g., 0.75 g at bedtime and 0.75 g taken 2.5 to 4 hours later), to the recommended dosage range of 6 g to 9 g per night. The dosage may be gradually titrated based on efficacy and tolerability. Some patients may achieve better responses with unequal doses at bedtime and 2.5 to 4 hours later. Doses higher than 9 g per night have not been studied and ordinarily should not be administered. Table 1: Recommended Adult XYWAV Dosage Regimen (g = grams) Note: Some patients may achieve better responses with unequal nightly doses at bedtime and 2.5 to 4 hours later. If a Patient’s Total Nightly Dosage 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 Dosing Information in Pediatric Patients with Narcolepsy For pediatric patients 7 years of age and older,...

    • Side Effects (Adverse Reactions)

    6 ADVERSE REACTIONS 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 )] Most common adverse reactions in adults with narcolepsy or IH (≥5%) were nausea, headache, dizziness, anxiety, insomnia, decreased appetite, hyperhidrosis, vomiting, diarrhea, dry mouth, parasomnia, somnolence, fatigue, and tremor ( 6.1 ). In a pediatric study with sodium oxybate (same active moiety as XYWAV), the most common adverse reactions (≥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 with Narcolepsy The safety of XYWAV was evaluated in a 16‑week double-blind placebo-controlled randomized-withdrawal study in patients with narcolepsy with cataplexy (Study 1), which was followed by an open-label extension phase lasting 24 weeks [see Clinical Studies ( 14.1 )] . Study 1 included an open‑label titration period (OL OTTP), a stable-dose period (SDP), and a double‑blind, placebo‑controlled, randomized-withdrawal period (DB RWP). A total of 201 patients, ages 18 to 70 years, received XYWAV at individually titrated doses for 14 weeks, followed by randomization to XYWAV or matching placebo for 2 weeks of treatment. The mean exposure to XYWAV during this study, including titration, the randomized withdrawal period, and the open-label extension, was 151 days. In patients who remained on treatment, adverse reactions tended to occur early and diminish over time. Adverse Reactions Leading to Treatment Discontinuation in Study 1 In Study 1, 9 of 201 patients (4%) reported adverse reactions that led to withdrawal from the study (anxiety, decreased appetite, depressed mood, depression, fatigue, headache, irritability, nausea, pain in extremity, parasomnia, somnolence, and vomiting). The most common adverse reaction leading to discontinuation was nausea (1.5%). The majority of adverse reactions leading to discontinuation began during the first few weeks of treatment. Commonly Observed Adverse Reactions The most common adverse reactions in Study 1 (incidence ≥5% of XYWAV-treated patients) were headache, nausea, dizziness, decreased appetite, parasomnia, diarrhea, hyperhidrosis, anxiety, and vomiting. Adverse Reactions Occurring at an Incidence of 2% or Greater: Table 4 lists adverse reactions observed in the open-label titration and stable dose periods of Study 1 that occurred at a frequency of 2% or greater in adult patients treated with XYWAV. Table 4: Adverse Reactions Occurring in ≥2% of Adult Patients Treated with XYWAV in the Open-Label Titration and Stable Dose Periods in Study 1 * * Adverse reactions related to XYWAV were reported less frequently, as an overall incidence, in patients on Xyrem at study entry than in Xyrem-naïve patients. † Includes abnormal dreams, abnormal sleep-related event, rapid eye movements sleep abnormal, sleep paralysis, sleep talking, sleep terror, sleep-related eating disorder, somnambulism ‡ Includes hyperhidrosis and night sweats § Includes anxiety, agitation, panic attack, tension ¶ Includes fatigue and asthenia Adverse Reaction Open-Label...

    • Drug Interactions

    7 DRUG INTERACTIONS

  • Concomitant use with divalproex sodium: An initial reduction in XYWAV dose of at least 20% is recommended ( 2.7 , 7.2 ). 7.1 Alcohol, Sedative Hypnotics, and CNS Depressants XYWAV is contraindicated for use in combination with alcohol or sedative hypnotics. Use of other CNS depressants may potentiate the CNS-depressant effects of XYWAV [see Warnings and Precautions ( 5.1 )] . 7.2 Divalproex Sodium Concomitant use of sodium oxybate 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 )] . A similar increase in exposure is expected with concomitant use of XYWAV and divalproex sodium; therefore, an initial dose reduction of XYWAV is recommended when used concomitantly with divalproex sodium [see Dosage and Administration ( 2.7 )]. Prescribers are advised to monitor patient response closely and adjust dose accordingly if concomitant use of XYWAV and divalproex sodium is warranted.

    • Contraindications

    4 CONTRAINDICATIONS XYWAV is contraindicated for use in:

  • combination with sedative hypnotics [see Warnings and Precautions ( 5.1 )] .
  • combination with alcohol [see Warnings and Precautions ( 5.1 , 5.2 )] .
  • patients with succinic semialdehyde dehydrogenase deficiency [see Clinical Pharmacology ( 12.3 )] .
  • In combination with sedative hypnotics or alcohol ( 4 )
  • Succinic semialdehyde dehydrogenase deficiency ( 4 )

    • Pregnancy and Breastfeeding

    8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of XYWAV or sodium oxybate in pregnant women. Oral administration of sodium oxybate to pregnant rats (0, 150, 350, or 1,000 mg/kg/day) or rabbits (0, 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 XYWAV 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 (0, 150, 350, or 1,000 mg/kg/day) or rabbits (0, 300, 600, or 1,200 mg/kg/day) throughout organogenesis produced no clear evidence of developmental toxicity. The highest doses of sodium oxybate 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. Additionally, oral administration of sodium oxybate (0, 150, 350, or 1,000 mg/kg/day)...

    Overdosage

    10 OVERDOSAGE 10.1 Human Experience Information regarding overdose with XYWAV 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 with Xyrem (same active moiety as XYWAV), two cases of overdose 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. No cases of overdose (greater than 9 g) with XYWAV were reported in the XYWAV clinical trials. 10.2 Signs and Symptoms Information about signs and symptoms associated with overdosage with XYWAV 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...

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied XYWAV is a clear to slightly opalescent oral solution. Each prescription includes at least one bottle of XYWAV 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 XYWAV shipment. Each amber bottle contains XYWAV oral solution at a concentration of 0.5 g/mL and has a child-resistant cap. One 180 mL bottle: NDC 68727-150-01 16.2 Storage Keep out of reach of children. XYWAV should be stored between 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 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 XYWAV is a Schedule III drug under the Controlled Substances Act. XYWAV should be handled according to state and federal regulations. It is safe to dispose of XYWAV down the sanitary sewer.

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.