Xywav

• •
  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 Central Nervous System Depression

  XYWAV is a central nervous system (CNS) depressant. Clinically significant respiratory depression and obtundation has occurred in adult patients taking sodium oxybate (same active moiety as XYWAV) at recommended doses in clinical trials and may occur in patients treated with XYWAV at recommended doses. XYWAV is contraindicated in combination with alcohol and sedative hypnotics. The concurrent use of XYWAV 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 XYWAV is required, dose reduction or discontinuation of one or more CNS depressants (including XYWAV) should be considered. In addition, if short-term use of an opioid (e.g., post- or perioperative) is required, interruption of treatment with XYWAV should be considered.

  Healthcare providers should caution patients about operating hazardous machinery, including automobiles or airplanes, until they are reasonably certain that XYWAV 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 XYWAV. Patients should be queried about CNS depression‐related events upon initiation of XYWAV therapy and periodically thereafter.

  XYWAV is available only through a restricted program under a REMS

  [see Warnings and Precautions ]

  .

  ,

  5.4 Respiratory Depression and Sleep-Disordered Breathing

  XYWAV may impair respiratory drive, especially in patients with compromised respiratory function. In overdoses of oxybate and with illicit use of GHB, life-threatening respiratory depression has been reported

  [see Overdosage ].

  Increased apnea and reduced oxygenation may occur with XYWAV administration in adult and pediatric patients. A significant increase in the number of central apneas and clinically significant oxygen desaturation may occur in patients with obstructive sleep apnea treated with XYWAV.

  In a study assessing the respiratory-depressant effects of Xyrem (same active moiety as XYWAV) at doses up to 9 g per night in 21 adult patients with narcolepsy, no dose-related changes in oxygen saturation were demonstrated in the group as a whole. One of the four patients with preexisting moderate-to-severe sleep apnea had significant worsening of the apnea/hypopnea index during treatment.

  In a study assessing the effects of Xyrem 9 g per night in 50 adult patients with obstructive sleep apnea, Xyrem did not increase the severity of sleep‑disordered breathing and did not adversely affect the average duration and severity of oxygen desaturation overall. However, there was a significant increase in the number of central apneas in patients taking Xyrem, and clinically significant oxygen desaturation (≤55%) was measured in three patients (6%) after Xyrem administration, with one patient withdrawing from the study and two continuing after single brief instances of desaturation.

  During polysomnographic evaluation (PSG), central sleep apnea and oxygen desaturation were observed in pediatric patients with narcolepsy treated with Xyrem.

  Prescribers should be aware that increased central apneas and clinically relevant oxygen desaturation events have been observed with sodium oxybate administration in adult and pediatric patients.

  In clinical trials of Xyrem in 128 adult patients with narcolepsy, two patients 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 PSG measures in adult 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, in men, in postmenopausal women not on hormone replacement therapy, and among patients with narcolepsy.

  )].

  Many patients who received XYWAV during clinical trials in narcolepsy and idiopathic hypersomnia were receiving central nervous system stimulants

  [see Clinical Studies (

  14.1 Cataplexy and Excessive Daytime Sleepiness (EDS) in Adult Narcolepsy

  Efficacy of XYWAV for the treatment of cataplexy and excessive daytime sleepiness in adult patients with narcolepsy was established in a double‑blind, placebo‑controlled, randomized‑withdrawal study (Study 1; NCT03030599). This study had two parts, consisting of the main study, followed by an optional 24-week open‑label extension (OLE). The main study consisted of a 12‑week open-label optimized treatment and titration period (OL OTTP), followed by a 2-week stable-dose period (SDP), and finally a 2‑week double-blind randomized-withdrawal period (DB RWP).

  Study 1 enrolled 201 patients with narcolepsy with cataplexy, 18 to 70 years of age, with a baseline history of at least 14 cataplexy attacks in a typical 2-week period prior to any treatment for narcolepsy symptoms. Of the 201 patients, 134 were randomized 1:1 to continue treatment with XYWAV or to placebo in the 2‑week DB RWP. In the safety population, overall, the median age was 36.0 years (range: 18 to 70). The majority of subjects were female (61%), and most were white (88%) and not Hispanic or Latino (84%).

  Patients entering the study were taking a stable dosage of 1) Xyrem only, 2) Xyrem + another anticataplectic, 3) a non-Xyrem anticataplectic, or 4) were cataplexy‑treatment naïve. Patients taking Xyrem at study entry were switched (at a gram for gram dose) from Xyrem to XYWAV for a minimum of 2 weeks and titrated, if needed, to a stable, tolerable, and effective dosage over 8 weeks. Most patients who switched from Xyrem to XYWAV (41/59; 69%) had no change in dosage from study entry to the stable dose period; 27% (16/59) had an increase in dosage, and 3% (2/59) had a decrease in dosage. Among patients whose dosage was changed, most changes were within one titration step (≤1.5 g). Patients not taking Xyrem at study entry were initiated at 4.5 g/night of XYWAV and titrated at a rate of 1 or 1.5 g/night/week to a tolerable dose of XYWAV. Patients taking an anticataplectic other than Xyrem were tapered off the non-Xyrem anticataplectic over 2 to 8 weeks. All patients continued to receive XYWAV only, for the treatment of cataplexy during the last 2 weeks of the OL OTTP.

  CNS stimulants were allowed at entry, and approximately 59% of patients continued taking a stable dose of stimulant throughout the SDP and DB RWP.

  The total nightly dose of XYWAV was administered in two equally divided doses in 90% (62/69) of patients. Unequal doses were administered in 10% (7/69) of patients treated with XYWAV.

  The primary efficacy endpoint was the change in frequency of cataplexy attacks from the 2 weeks of the SDP to the 2 weeks of the DB RWP. The key secondary endpoint was the change in the Epworth Sleepiness Scale (ESS) score, as a measure of reduction in EDS from the end of the SDP to the end of the DB RWP.

  Patients taking stable doses of XYWAV who discontinued XYWAV treatment and were randomized to placebo during the DB RWP experienced a significant worsening in the average weekly number of cataplexy attacks and in ESS score, compared with patients randomized to continue treatment with XYWAV (see Table 6).

  Table 6: Mean and Median Number of Weekly Cataplexy Attacks and Epworth Sleepiness Scale (ESS)

  DB RWP=Double‑blind Randomized-withdrawal Period; SD=standard deviation
  	Average Weekly Number of Cataplexy Attacks		ESS SCORE
  	Placebo (N=65)	XYWAV (N=69)	Placebo (N=65)	XYWAV (N=69)
  Baseline (2 Weeks of the Stable Dose Period)
  Mean (SD)	7.2 (14.4)	8.9 (16.8)	12.6 (5.5)	13.6 (5.3)
  Median	1.0	1.1	13.0	14.0
  Change from Baseline (2 Weeks of the Stable Dose Period) to the 2 Weeks of the DB RWP			Change from End of Stable Dose Period to End of DB RWP
  Mean (SD)	11.5 (24.8)	0.1 (5.8)	3.0 (4.7)	0.0 (2.9)
  Median	2.4	0.0	2.0	0.0
  p-value	<0.0001		<0.0001

  ,

  14.2 Cataplexy and Excessive Daytime Sleepiness in Pediatric Narcolepsy

  The effectiveness of XYWAV in pediatric patients is based upon a clinical study in patients treated with Xyrem, as described below, and additional pharmacokinetic information

  [see Use in Specific Populations ]

  .

  The effectiveness of Xyrem in the treatment of cataplexy and excessive daytime sleepiness in pediatric patients 7 years of age and older with narcolepsy was established in a double-blind, placebo-controlled, randomized-withdrawal study (NCT02221869). The study was conducted in 106 pediatric patients (median age: 12 years; range: 7 to 17 years) with a baseline history of at least 14 cataplexy attacks in a typical 2-week period prior to any treatment for narcolepsy symptoms. Of the 106 patients, 2 did not receive study drug and 63 patients were randomized 1:1 either to continued treatment with Xyrem or to placebo. Randomization to placebo was stopped early as the efficacy criterion was met at the pre-planned interim analysis.

  Patients entered the study either taking a stable dosage of Xyrem or were Xyrem-naïve. CNS stimulants were allowed at entry, and approximately 50% of patients continued taking a stable dose of stimulant throughout the stable-dose and double-blind periods. Xyrem-naïve patients were initiated and titrated based on body weight over a period of up to 10 weeks. The total nightly dose was administered in two divided doses, with the first dose given at nighttime and the second given 2.5 to 4 hours later

  [see Dosage and Administration ]

  . Once a stable dosage of Xyrem had been achieved, these patients entered the 2-week stable-dose period; patients on a stable dosage of Xyrem at study entry remained on this dosage for 3 weeks prior to randomization. Efficacy was established at dosages ranging from 3 g to 9 g of Xyrem per night.

  The primary efficacy measure was the change in frequency of cataplexy attacks. In addition, change in cataplexy severity was evaluated with the Clinical Global Impression of Change for cataplexy severity. The efficacy of Xyrem in the treatment of excessive daytime sleepiness in pediatric patients with narcolepsy was evaluated with the change in the Epworth Sleepiness Scale (Child and Adolescent) score. The Epworth Sleepiness Scale (Child and Adolescent) is a modified version of the scale used in the adult clinical trial described above. The overall change in narcolepsy condition was assessed by the Clinical Global Impression of Change for narcolepsy overall. Efficacy was assessed during or at the end of the 2-week double-blind treatment period, relative to the last 2 weeks or end of the stable-dose period (see Tables 7 and 8).

  Pediatric patients taking stable dosages of Xyrem who discontinued Xyrem treatment and were randomized to placebo during the double-blind treatment period experienced a statistically significant increase in weekly cataplexy attacks compared with patients who were randomized to continue treatment with Xyrem. Patients randomized to receive placebo during the double-blind treatment period experienced a statistically significant worsening of EDS compared with patients randomized to continue receiving Xyrem (see Table 7).

  Table 7: Number of Weekly Cataplexy Attacks and Epworth Sleepiness Scale (Child and Adolescent) Score

  *For weekly number of cataplexy attacks, baseline value is calculated from the last 14 days of the stable-dose period. †For Epworth Sleepiness Scale score, baseline value is collected at the end of stable-dose period. ‡Weekly number of cataplexy attacks is calculated from all days within the double-blind treatment period. §For Epworth Sleepiness Scale, value is collected at the end of the double-blind treatment period. ¶P-value from rank-based analysis of covariance (ANCOVA) with treatment as a factor and rank baseline value as a covariate. **One patient in each of the treatment groups did not have baseline ESS score available and were not included in this analysis.
  Treatment Group	Baseline*,†	Double-blind Treatment Period‡,§	Median Change from Baseline	Comparison to Placebo (p-value¶)
  Median Number of Cataplexy Attacks (attacks/week)
  Placebo (n=32)	4.7	21.3	12.7	-
  Xyrem (n=31)	3.5	3.8	0.3	<0.0001
  Median Epworth Sleepiness Scale (Child and Adolescent) Score
  Placebo (n=31**)	11	12	3	-
  Xyrem (n=30**)	8	9	0	0.0004

  Patients randomized to receive placebo during the double-blind treatment period experienced a statistically significant worsening of cataplexy severity and narcolepsy overall according to the clinician’s assessment compared with patients randomized to continue receiving Xyrem (see Table 8).

  Table 8: Clinical Global Impression of Change (CGIc) for Cataplexy Severity and Narcolepsy Overall

  *Responses indicate change of severity or symptoms relative to receiving Xyrem treatment at baseline. †Percentages based on total number of observed values. ‡Two patients randomized to Xyrem did not have the CGIc assessments completed and were excluded from the analysis. §P-value from Pearson’s chi-square test.
  Worsened, %†	CGIc Cataplexy Severity*		CGIc Narcolepsy Overall*
  	Placebo (n=32)	Xyrem (n=29)‡	Placebo (n=32)	Xyrem (n=29)‡
  Much worse or very much worse	66%	17%	59%	10%
  p-value§	0.0001		<0.0001

  ,

  14.3 Idiopathic Hypersomnia (IH) in Adults

  Efficacy of XYWAV for the treatment of IH in adult patients as a once or twice nightly regimen was established in a double-blind, placebo-controlled, randomized-withdrawal, study (Study 2, NCT03533114). Study 2 consisted of a minimum of 10‑week open‑label treatment titration and optimization period (OL OTTP), (with up to 4 additional weeks) to allow for an optimally effective and tolerable dose and regimen followed by a 2‑week stable dose period (SDP), a 2‑week double-blind, randomized withdrawal period (DB RWP), and a 24‑week open label safety extension period (OLE).

  Study 2 enrolled 154 patients with idiopathic hypersomnia, 19 to 75 years of age. Of the 154 patients, 115 were evaluable for efficacy data and were randomized 1:1 to continue treatment with XYWAV or to placebo in the 2‑week DB RWP. In the safety population, overall, the median age was 39 years (range: 19 to 75). At baseline, 2% of patients were taking Xyrem only, 4% of patients were taking Xyrem and an additional stimulant or alerting agent, 54% of patients were not currently taking Xyrem but were taking a stimulant or alerting agent, and 41% were treatment naïve. CNS stimulants were allowed at entry, and approximately 57% of patients continued taking a stable dose of stimulant throughout the SDP and DB RWP.

  The majority of subjects were female (71%), and most were white (81%) and not Hispanic or Latino (79%).

  The XYWAV dosing regimen was initiated at the discretion of the investigator according to clinical presentation. Patients were considered for XYWAV once nightly if they reported difficulty awakening as a result of sleep inertia or long sleep time. Patients were considered for twice nightly dosing if they reported disrupted nighttime sleep or difficulty with sleep maintenance. For twice nightly regimens, doses were divided equally or unequally, with the first dose administered at bedtime and the second dose administered 2.5 to 4 hours later.

  Based on clinical response during the OTTP, investigators were permitted to switch patients between twice nightly and once nightly dosing regimens. When patients were switched from a twice nightly to a once nightly dosing regimen, the total nightly dose was initially the same as the first dose of the twice nightly dosing regimen. When patients were switched from a once nightly to a twice nightly dosing regimen, the total nightly dose was no more than 1.5 g higher than the current dose, divided into two doses.

  At the start of the DB RWP, 23% (27/115) of patients were taking XYWAV once nightly (median nightly dose 4.5 g), and 77% (88/115) of patients were taking XYWAV twice nightly (median nightly dose 7.5 g). There were no meaningful differences in demographics, baseline characteristics or disease severity between patients receiving XYWAV once nightly vs twice nightly.

  The primary efficacy endpoint was the change in Epworth Sleepiness Scale (ESS) score, as a measure of reduction in EDS from the end of the SDP to the end of the DB RWP. The ESS is an 8-item self-reported questionnaire by which patients rate their perceived likelihood of falling asleep during usual daily life activities. Each of the 8 items on the ESS is rated from 0 (would never doze) to 3 (high chance of dozing), with a maximum score of 24. Key secondary efficacy endpoints included patient global impression of change (PGIc) and the Idiopathic Hypersomnia Severity Scale (IHSS), both assessed as a change from the end of the SDP to the end of the DB RWP. The IHSS is a 14-item self-reported questionnaire assessing the severity of IH symptoms of excessive sleepiness, prolonged sleep duration, cognitive impairment, and sleep inertia. Total scores can range from 0-50, with higher scores indicating a greater severity or frequency of symptoms.

  Change in ESS

  Patients in Study 2 taking stable doses of XYWAV who were withdrawn from XYWAV treatment and randomized to placebo during DB RWP experienced significant worsening in ESS score compared with patients randomized to continue treatment with XYWAV (p<0.0001) across all dosing regimens (see Table 9). These two treatment groups had comparable median ESS scores (Placebo=17; XYWAV=16) at entry into the OTTP.

  Table 9: Median Change in Epworth Sleepiness Scale (ESS)

  SDP=Stable Dose Period DB RWP=Double-blind Randomized-withdrawal Period
  ESS Score
  	Placebo (N=59)	XYWAV (N=56)
  Baseline End of 2-Week SDP
  Median	5.0	6.5
  End of 2-Week DB RWP
  Median	14.0	7.0
  Median Change from End of 2-Week SDP to End of 2-Week DB RWP
  Median	8.0	0.0
  p-value	<0.0001

  PGIc

  Patient Global Impression of change (PGIc) ratings showed that patients randomized to placebo experienced a worsening of symptoms of idiopathic hypersomnia overall compared with patients randomized to XYWAV (Table 10). The percentage of patients with worsening PGIc scores for IH overall (defined as scores of Minimally, Much Worse, or Very Much Worse) was greater for patients receiving placebo (88.1%) compared with patients receiving XYWAV (21.4%) (p<0.0001).

  Table 10: PGIc* at End of the DB RWP†

  *PGIc is a 7‑point patient-reported scale by which patients rated their symptom change from “very much improved” to “very much worse.” †DB RWP=Double‑blind Randomized-withdrawal Period. ‡At the end of the DB RWP/early termination visit, patients rated the change in their condition since the end of the Open-Label Stable-Dose Period.
  	PGIc* IH Overall
  Worsened,%‡†	Placebo (N=59) n (%)	XYWAV (N=56) n (%)
  Proportion Worsened (minimally, much, or very much worse)	52 (88.1)	12 (21.4)
  p‑value	<0.0001	n/a

  IHSS

  At end of DB RWP, patients randomized to placebo experienced a worsening in IHSS total score, compared to patients randomized to XYWAV (p<0.0001) (see Table 11). These two treatment groups had comparable median IHSS scores (Placebo=33; XYWAV=33) at entry into the OTTP.

  Table 11: Median Changes in IHSS Total Score

  SDP=Stable Dose Period DB RWP=Double‑blind Randomized-withdrawal Period
  Total Score
  	Placebo (N=59)	XYWAV (N=56)
  Baseline End of 2-Week SDP
  Median	14.0	14.0
  End of 2-Week DB RWP
  Median	29.0	16.0
  Median Change from End of 2-Week SDP to End of 2-Week DB RWP
  Median	14.0	0.0
  p-value	<0.0001

  )].
  
  
  
  

• •
  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 Abuse and Misuse

  XYWAV is a Schedule III controlled substance. The active moiety of XYWAV is oxybate, also known as gamma-hydroxybutyrate (GHB), 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 GHB, 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, healthcare providers should carefully evaluate patients for a history of drug abuse and follow them closely, particularly for signs of misuse or abuse of GHB (including but not limited to increase in size or frequency of dosing, drug-seeking behavior, feigned cataplexy)

  [see Drug Abuse and Dependence ]

  . If abuse is suspected, treatment with XYWAV should be discontinued

  .

  XYWAV is available only through a restricted program under a REMS

  [see Warnings and Precautions ]

  .

  )].

  
  
  
  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 XYWAV and XYREM REMS

  XYWAV 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 ].

  Notable requirements of the XYWAV and XYREM REMS include the following:

  • •Healthcare Providers who prescribe XYWAV are specially certified
  • •XYWAV will be dispensed only by the central pharmacy that is specially certified
  • •XYWAV 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.comor 1-866-997-3688.

  )].

Dosage and Administration (

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 Narcolepsy

  XYWAV is indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy.
  ).
• •Idiopathic Hypersomnia (IH) in adults (
  1.2 Idiopathic Hypersomnia

  XYWAV is indicated for the treatment of idiopathic hypersomnia (IH) in adults.
  ).

See Full Prescribing Information for complete dosing instructions (

• •XYWAV can be administered as a twice or once nightly regimen in adults (
  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
  ).
• •Twice nightly: Initiate dosage at 4.5 g or less per night orally, divided into two doses (
  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
  ).
  • oTotal nightly doses up to 9 g: Titrate to effect in increments of up to 1.5 g per night per week, up to 9 g total nightly dose.
  • oTotal nightly doses greater than 9 g up to 12 g: Titrate to effect in increments of up to 0.5 g per night per week, up to 12 g total nightly dose.
  • oDoses may be divided equally or unequally with the first dose taken at bedtime and the second dose taken 2.5 to 4 hours later (
    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
    ).
• •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 7.5 g once nightly dose (
  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
  ).

• •The recommended starting dosage, titration regimen, and maximum total nightly dosage are based on body weight
  2 DOSAGE AND ADMINISTRATION

  See Full Prescribing Information for complete dosing instructions .
  
  

  Dosage for Adult Patients with Narcolepsy

  • •Initiate dosage at 4.5 g per night orally, divided into two doses .
  • •Titrate to effect in increments of up to 1.5 g per night per week .
  • •Recommended dosage range: 6 g to 9 g per night orally, divided into two doses .
  • •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 .

  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 .
  • •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 .
  • •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 .

  
  
  Important Administration Information

  • •Administer XYWAV at least 2 hours after eating .
  • •Prepare XYWAV prior to bedtime; dilute with approximately ¼ cup of water in pharmacy-provided containers .
  • •Take XYWAV while in bed and lie down after dosing .

  
  
  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 .

  
  
  

  Patients with Hepatic Impairment

  Recommended starting dosage is one-half of the original dosage per night administered orally, divided into two doses .
  
  
  
  
  
  

  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, XYWAV is administered orally twice per night. 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. Doses higher than 9 g per night have not been studied and ordinarily should not be administered.

  Table 2: Recommended XYWAV Dosage for Patients 7 Years of Age and Older*

  * For patients who sleep more than 8 hours per night, the first nightly dose of XYWAV may be given at bedtime or after an initial period of sleep. ** If XYWAV 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 nightly doses at bedtime and 2.5 to 4 hours later.
  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

  2.3 Dosing Information in Adult Patients with Idiopathic Hypersomnia (IH)

  The dosage and regimen of XYWAV should be individualized based on clinical presentation

  [see Clinical Studies ]

  .

  XYWAV can be administered as a twice nightly or once nightly regimen. The recommended starting dose, titration guidance, and maximum nightly doses appear in Table 3:

  Table 3: Recommended Nightly Dosage in Adult Patients with IH

  *Some patients may achieve better responses with unequal nightly doses at bedtime and 2.5 to 4 hours later. †The first dose should be taken at bedtime and the second dose taken 2.5 to 4 hours later.
  Dosing Regimen	Starting Nightly Dose	Titration Increments	Maximum Total Nightly Dose
  Twice nightly*,†	≤4.5 g per night divided into two doses (e.g., 2.25 g each)	≤1.5 g per night per week (divided into two doses)	9 g (divided into two doses)
  Once nightly	≤3 g per night	≤1.5 g per night per week	6 g

  The increase in the total nightly dose should not exceed 1.5 g /week. During titration, the dosing regimen may be changed between twice nightly and once nightly, as needed based on efficacy and tolerability

  [see Clinical Studies ]

  . Doses higher than 9 g per night or single dose administrations higher than 6 g have not been studied and should not be administered.

  2.4 Important Administration Instructions for All Patients

  Administer XYWAV at least 2 hours after eating

  [see Clinical Pharmacology ]

  . Prepare all doses of XYWAV prior to bedtime. Prior to ingestion, each dose of XYWAV should be diluted with approximately ¼ cup (approximately 60 mL) of water in the empty pharmacy-provided containers. Solutions prepared following dilution should be consumed within 24 hours.

  Patients should take each dose of XYWAV while in bed and lie down immediately after dosing, and remain in bed following ingestion of each dose. XYWAV may cause patients to fall asleep abruptly without first feeling drowsy

  [see Adverse Reactions ]

  .

  Patients will often fall asleep within 5 minutes of taking XYWAV, 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.

  If dosing twice nightly, patients may need to set an alarm to awaken for the second dose. If the second dose is missed, that dose should be skipped and XYWAV should not be taken again until the next night. Two XYWAV doses should never be taken at one time.

  2.5 Patients Transitioning from Xyrem to XYWAV

  On the first night of dosing with XYWAV, initiate treatment at the same dose (gram for gram) and regimen as Xyrem. Titrate as needed based on efficacy and tolerability

  [see Dosage and Administration ]

  .

  2.6 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 and Clinical Pharmacology ]

  .

  2.7 Dosage Adjustment with Co-administration of Divalproex Sodium

  When initiating divalproex sodium in patients taking a stable dosage of XYWAV, a reduction of the XYWAV dosage by at least 20% is recommended with initial concomitant use

  [see Drug Interactions and Clinical Pharmacology ]

  . When initiating XYWAV in patients already taking divalproex sodium, a lower starting dosage of XYWAV is recommended. Subsequently, the dosage of XYWAV can be adjusted based on individual clinical response and tolerability.
  ).

• •Administer XYWAV at least 2 hours after eating (
  2.4 Important Administration Instructions for All Patients

  Administer XYWAV at least 2 hours after eating

  [see Clinical Pharmacology ]

  . Prepare all doses of XYWAV prior to bedtime. Prior to ingestion, each dose of XYWAV should be diluted with approximately ¼ cup (approximately 60 mL) of water in the empty pharmacy-provided containers. Solutions prepared following dilution should be consumed within 24 hours.

  Patients should take each dose of XYWAV while in bed and lie down immediately after dosing, and remain in bed following ingestion of each dose. XYWAV may cause patients to fall asleep abruptly without first feeling drowsy

  [see Adverse Reactions ]

  .

  Patients will often fall asleep within 5 minutes of taking XYWAV, 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.

  If dosing twice nightly, patients may need to set an alarm to awaken for the second dose. If the second dose is missed, that dose should be skipped and XYWAV should not be taken again until the next night. Two XYWAV doses should never be taken at one time.
  ).
• •Prepare XYWAV prior to bedtime; dilute with approximately ¼ cup of water in pharmacy-provided containers (
  2.4 Important Administration Instructions for All Patients

  Administer XYWAV at least 2 hours after eating

  [see Clinical Pharmacology ]

  . Prepare all doses of XYWAV prior to bedtime. Prior to ingestion, each dose of XYWAV should be diluted with approximately ¼ cup (approximately 60 mL) of water in the empty pharmacy-provided containers. Solutions prepared following dilution should be consumed within 24 hours.

  Patients should take each dose of XYWAV while in bed and lie down immediately after dosing, and remain in bed following ingestion of each dose. XYWAV may cause patients to fall asleep abruptly without first feeling drowsy

  [see Adverse Reactions ]

  .

  Patients will often fall asleep within 5 minutes of taking XYWAV, 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.

  If dosing twice nightly, patients may need to set an alarm to awaken for the second dose. If the second dose is missed, that dose should be skipped and XYWAV should not be taken again until the next night. Two XYWAV doses should never be taken at one time.
  ).
• •Take XYWAV while in bed and lie down after dosing (
  2.4 Important Administration Instructions for All Patients

  Administer XYWAV at least 2 hours after eating

  [see Clinical Pharmacology ]

  . Prepare all doses of XYWAV prior to bedtime. Prior to ingestion, each dose of XYWAV should be diluted with approximately ¼ cup (approximately 60 mL) of water in the empty pharmacy-provided containers. Solutions prepared following dilution should be consumed within 24 hours.

  Patients should take each dose of XYWAV while in bed and lie down immediately after dosing, and remain in bed following ingestion of each dose. XYWAV may cause patients to fall asleep abruptly without first feeling drowsy

  [see Adverse Reactions ]

  .

  Patients will often fall asleep within 5 minutes of taking XYWAV, 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.

  If dosing twice nightly, patients may need to set an alarm to awaken for the second dose. If the second dose is missed, that dose should be skipped and XYWAV should not be taken again until the next night. Two XYWAV doses should never be taken at one time.
  ).
  
  
  

Recommended starting dosage is one-half of the usual recommended starting dosage per night administered orally (

XYWAV is a clear to slightly opalescent oral solution at a total salt concentration of 0.5 g per mL. Each mL contains 0.5 g of total salts present as 0.234 g calcium oxybate, 0.096 g magnesium oxybate, 0.13 g potassium oxybate, and 0.04 g sodium oxybate (equivalent to 0.413 g total oxybate).

• •Pregnancy: Based on animal data, may cause fetal harm (
  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/m²) basis.

  Additionally, oral administration of sodium oxybate (0, 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/m²basis.
  ).
• •Geriatric patients: Monitor for impaired motor and/or cognitive function when taking XYWAV (
  8.5 Geriatric Use

  Clinical studies of XYWAV or Xyrem in patients with narcolepsy or IH did not include sufficient numbers of subjects age 65 years and older to determine whether they respond differently from younger subjects.

  In clinical studies of sodium oxybate 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.
  ).