` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`212690Orig1s000
`
`
`LABELING
`
`

`

`
`
`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. (2.4).
`Patients with Hepatic Impairment
`Recommended starting dosage is one-half of the original dosage per night
`administered orally, divided into two doses (2.4).
`
`--------------------DOSAGE FORMS AND STRENGTHS-----------
`Oral solution: 0.5 g/mL total salts (equivalent to 0.413 g/mL of oxybate)
`(3)
`
`----------------------------CONTRAINDICATIONS----------------------
`• 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
`XYWAV 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 XYWAV 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).
`
`-----------------------------ADVERSE REACTIONS--------------------
`Most common adverse reactions in adults (≥5%) were headache, nausea,
`dizziness, decreased appetite, parasomnia, diarrhea, hyperhidrosis, anxiety,
`and vomiting (6.1).
`In a pediatric study with sodium oxybate, (same active moiety as
`XYWAV), the most common adverse reactions (≥5%) were enuresis,
`nausea, headache, vomiting, weight decreased, decreased appetite, and
`dizziness (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.
`
`----------------------------------DRUG INTERACTIONS-------------------------
`• Concomitant use with divalproex sodium: An initial reduction in
`XYWAV dose of at least 20% is recommended (2.6, 7.2).
`
`----------------------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 XYWAV (8.5).
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`Medication Guide
`
`
`Revised: 7/2020
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`XYWAVTM safely and effectively. See full prescribing information for
`XYWAV.
`XYWAVTM (calcium, magnesium, potassium, and sodium oxybates) oral
`solution, CIII
`Initial U.S. Approval: 2002
`
`
`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)
`
`----------------------------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).
`
`-----------------------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 up to 1.5 g per night per week (2.1).
`• Recommended dosage range: 6 g to 9 g per night orally (2.1).
`Total Nightly
`Take at Bedtime Take 2.5 to 4 Hours Later
`Dose
`2.25 g
`2.25 g
`4.5 g per night
`3 g
`3 g
`6 g per night
`3.75 g
`3.75 g
`7.5 g per night
`4.5 g
`4.5 g
`9 g per night
`• Some patients may achieve better responses with unequal doses at
`bedtime and 2.5 to 4 hours later.
`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).
`• Take the first nightly dose of XYWAV at least 2 hours after eating (2.3).
`• Take each dose while in bed and lie down after dosing (2.3).
`
`
`Reference ID: 4644289
`
`1
`
`

`

`
`
`
`
`
`
`3
`4
`5
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: CENTRAL NERVOUS SYSTEM (CNS)
`DEPRESSION and ABUSE AND MISUSE
`INDICATIONS AND USAGE
`1
`DOSAGE AND ADMINISTRATION
`2
`2.1 Adult Dosing Information
`2.2
`Pediatric Dosing Information
`2.3
`Important Administration Instructions for All Patients
`2.4
`Patients Transitioning from Xyrem to XYWAV
`2.5 Dosage Modification in Patients with Hepatic
`
`Impairment
`2.6 Dosage Adjustment with Co-administration of
`
`Divalproex Sodium
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1 Central Nervous System Depression
`5.2 Abuse and Misuse
`5.3 XYWAV and XYREM REMS
`5.4 Respiratory Depression and Sleep-Disordered
`
`Breathing
`5.5 Depression and Suicidality
`5.6 Other Behavioral or Psychiatric Adverse Reactions
`5.7
`Parasomnias
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2
`Postmarketing Experience
`DRUG INTERACTIONS
`7.1 Alcohol, Sedative Hypnotics, and CNS Depressants
`7.2 Divalproex Sodium
`
`6
`
`7
`
`9
`
`8
`
`
`USE IN SPECIFIC POPULATIONS
`Pregnancy
`8.1
`8.2 Lactation
`8.4
`Pediatric Use
`8.5 Geriatric Use
`8.6 Hepatic Impairment
`DRUG ABUSE AND DEPENDENCE
`9.1 Controlled Substance
`9.2 Abuse
`9.3 Dependence
`10 OVERDOSAGE
`10.1 Human Experience
`10.2 Signs and Symptoms
`10.3 Recommended Treatment of Overdose
`10.4 Poison Control Center
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Cataplexy and Excessive Daytime Sleepiness (EDS) in
`Adult Narcolepsy
`14.2 Cataplexy and Excessive Daytime Sleepiness in Pediatric
`Narcolepsy
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage
`16.3 Handling and Disposal
`17
`PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full
`prescribing information are not listed.
`
`
`Reference ID: 4644289
`
`2
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`
`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 were receiving central nervous system stimulants [see
`Clinical Trials (14.1)].
`
`
`
`• 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)].
`
` 1
`
`
`
`INDICATIONS AND USAGE
`XYWAV is indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7
`years of age and older with narcolepsy.
`
`2 DOSAGE AND ADMINISTRATION
`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 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.
`
`
`
`
`
`
`
`Reference ID: 4644289
`
`1
`
`

`

`
`
`Table 1: Recommended Adult XYWAV Dosage
`Regimen (g = grams)
`Take 2.5 to 4
`If a Patient’s Total
`Take at
`Hours Later:
`Nightly Dosage Is:
`Bedtime:
`2.25 g
`4.5 g per night
`2.25 g
`3 g
`6 g per night
`3 g
`3.75 g
`7.5 g per night
`3.75 g
`4.5 g
`9 g per night
`4.5 g
`Note: Some patients may achieve better responses with unequal nightly
`doses at bedtime and 2.5 to 4 hours later.
`
`2.2 Pediatric Dosing Information
`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.
`
`
`Patient
`Weight
`
`Take at
`Bedtime:
`
`Table 2: Recommended Initial XYWAV Dosage for Patients 7 Years of Age and Older*
`Initial Dosage
`Maximum Weekly
`Maximum
`Dosage Increase
`Recommended Dosage
`Take at
`Take 2.5
`Take at
`Take 2.5 to
`Take 2.5
`Bedtime:
`to 4 Hours
`to 4 Hours
`Bedtime:
`4 Hours
`Later:
`Later:
`Later:
`<20 kg** There is insufficient information to provide specific dosing recommendations
`for patients who weigh less than 20 kg.
`≤1 g
`0.5 g
`≤1 g
`
`20 kg to
`<30 kg
`30 kg to
`<45 kg
`≥45 kg
`
`0.5 g
`
`3 g
`
`3 g
`
`≤1.5 g
`
`≤1.5 g
`
`0.5 g
`
`0.5 g
`
`3.75 g
`
`3.75 g
`
`≤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 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.
`
`2.3
`
`Important Administration Instructions for All Patients
`The total nightly dosage of XYWAV is divided into two doses. Prepare both 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 containers provided. Solutions prepared following dilution should be
`consumed within 24 hours.
`Take the first nightly dose of XYWAV at least 2 hours after eating. Take the second nightly dose 2.5 to 4
`hours after the first dose [see Clinical Pharmacology (12.3)].
`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 (6.2)].
`
`2
`
`
`
`Reference ID: 4644289
`
`

`

`
`
`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.
`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.
`2.4 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 (2.1)].
`2.5 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)].
`2.6 Dose 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 (7.2) and
`Clinical Pharmacology (12.3)]. 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.
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`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).
`
`CONTRAINDICATIONS
`4
`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)].
`• patients with succinic semialdehyde dehydrogenase deficiency [see Clinical Pharmacology (12.3)].
`
`WARNINGS AND PRECAUTIONS
`5
`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
`
`
`
`Reference ID: 4644289
`
`3
`
`

`

`
`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
`(5.3)].
`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 (9.2)].
`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
`(5.3)].
`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 (5.1, 5.2)].
`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.com or 1-866-997-3688.
`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 (10)].
`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.
`
`
`
`Reference ID: 4644289
`
`4
`
`

`

`
`
`Prescribers should be aware that increased central apneas and clinically relevant 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.
`5.5 Depression and Suicidality
`Depression, and suicidal ideation and behavior can occur in patients treated with XYWAV.
`In Study 1, depression and depressed mood were reported in 3% and 4%, respectively, of patients treated
`with XYWAV. Two patients (1%) discontinued XYWAV because of depression, but in most cases, no change
`in XYWAV treatment was required.
`In clinical trials of Xyrem (same active moiety as XYWAV) in adult patients with narcolepsy (n=781),
`there were two suicides and two attempted suicides in patients treated with Xyrem, including three patients with
`a previous history of depressive psychiatric disorder. Of the two suicides, one patient used Xyrem in
`conjunction with other drugs. Xyrem was not involved in the second suicide. Adverse reactions of depression
`were reported by 7% of 781 patients treated with Xyrem, with four patients (<1%) discontinuing because of
`depression. In most cases, no change in Xyrem treatment was required. In a clinical trial with Xyrem in
`pediatric patients with narcolepsy (n=104), one patient experienced suicidal ideation while taking Xyrem.
`The emergence of depression in patients treated with XYWAV requires careful and immediate evaluation.
`Patients with a previous history of a depressive illness and/or suicide attempt should be monitored carefully for
`the emergence of depressive symptoms while taking XYWAV.
`5.6 Other Behavioral or Psychiatric Adverse Reactions
`Other behavioral and psychiatric adverse reactions can occur in patients taking XYWAV.
`In Study 1, confusion occurred in 1% of patients treated with XYWAV and anxiety occurred in 5% of
`patients treated with XYWAV. One patient experienced visual hallucinations and confusion after ingesting
`approximately 9 grams of XYWAV. Other neuropsychiatric reactions reported in clinical trials of Xyrem (same
`active moiety as XYWAV) in adult patients with narcolepsy and in the postmarketing setting included
`hallucinations, paranoia, psychosis, aggression, and agitation.
`In a pediatric clinical trial with Xyrem in patients with narcolepsy, neuropsychiatric reactions, including
`acute psychosis, confusion, and anxiety, were reported while taking Xyrem.
`The emergence or increase in the occurrence of behavioral or psychiatric events in patients taking XYWAV
`should be carefully monitored.
`5.7 Parasomnias
`Parasomnias can occur in patients taking XYWAV.
`In Study 1, parasomnias, including sleepwalking, were reported in 6% of patients treated with XYWAV. In
`a clinical trial of Xyrem (same active moiety as XYWAV) in adult patients with narcolepsy, five instances of
`sleepwalking with potential injury or significant injury were reported. Parasomnias, including sleepwalking,
`also have been reported in a pediatric clinical trial with sodium oxybate and in postmarketing experience with
`sodium oxybate.
`Episodes of sleepwalking should be fully evaluated and appropriate interventions considered.
`
`
`
`Reference ID: 4644289
`
`5
`
`

`

`
`ADVERSE REACTIONS
`6
`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)]
`
`
`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
`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, 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 3 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 3: Adverse Reactions Occurring in ≥2% of Adult Patients Treated with XYWAV in the
`Open-Label Titration and Stable Dose Periods in Study 1*
`Open-Label Titration Period + Stable Dose Period
`(14 weeks)
`(N=201)
`%
`20
`13
`
`Adverse Reaction
`
`Headache
`Nausea
`
`
`
`Reference ID: 4644289
`
`6
`
`

`

`
`
`Adverse Reaction
`
`Table 3: Adverse Reactions Occurring in ≥2% of Adult Patients Treated with XYWAV in the
`Open-Label Titration and Stable Dose Periods in Study 1*
`Open-Label Titration Period + Stable Dose Period
`(14 weeks)
`(N=201)
`%
`10
`8
`6
`6
`6
`
`Dizziness
`Decreased appetite
`Parasomnia†
`Diarrhea
`Hyperhidrosis‡
`
`Anxiety§
`Vomiting
`Fatigue¶
`Dry mouth
`Depressed mood
`Enuresis
`Irritability
`
`5
`5
`4
`4
`4
`4
`3
`
`3
`Paresthesia
`3
`Depression
`3
`Tremor
`2
`Somnolence
`2
`Muscle spasms
`*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 Reactions Observed in Clinical Studies with Xyrem (≥2%), but not in Study 1, and Which May Be
`Relevant for XYWAV
`Pain, feeling drunk, pain in extremity, cataplexy, disturbance in attention, sleep paralysis, and
`disorientation.
`Pediatric Patients (7 Years of Age and Older)
`In the pediatric clinical trial with Xyrem (same active moiety as XYWAV), 104 patients aged 7 to 17 years
`(37 patients aged 7 to 11 years; 67 patients aged 12 to 17 years) with narcolepsy received Xyrem up to 377 days
`(median exposure 332 days) [see Clinical Studies (14.2)].
`
`
`
`Reference ID: 4644289
`
`7
`
`

`

`
`Adverse Reactions Leading to Treatment Discontinuation
`In the pediatric clinical trial with Xyrem, 5 of 104 patients reported adverse reactions that led to withdrawal
`from the study (hallucination, tactile; suicidal ideation; weight decreased; sleep apnea syndrome; and affect
`lability).
`Adverse Reactions in the Xyrem Pediatric Clinical Trial
`The most common adverse reactions (≥5%) were enuresis (18%), nausea (17%), headache (16%), vomiting
`(16%), weight decreased (12%), decreased appetite (8%), and dizziness (6%).
`Additional information regarding safety in pediatric patients appears in the following sections:
`• 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)]
`The overall adverse reaction profile of Xyrem in the pediatric clinical trial was similar to that seen in the
`adult clinical trial program. The safety profile in pediatric patients with XYWAV is expected to be similar to
`that of adult patients treated with XYWAV and to that of pediatric patients treated with Xyrem.
`6.2 Postmarketing Experience
`The following adverse reactions have been identified during postapproval use of sodium oxybate. Because
`these reactions are reported voluntarily from a population of uncertain size, it is not always possible to
`reliably estimate their frequency or establish a causal relationship to drug exposure:
`Arthralgia, fall*, fluid retention, hangover, hypersensitivity, hypertension, memory impairment,
`nocturia, and vision blurred.
`
`
`
`*The sudden onset of sleep in patients taking sodium oxybate, including in a standing position or while rising
`from bed, has led to falls complicated by injuries, in some cases requiring hospitalization.
`
`7 DRUG INTERACTIONS
`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 XWYAV is recommended when
`used concomitantly with divalproex sodium [see Dosage and Administration (2.6)]. Prescribers are advised to
`monitor patient response closely and adjust dose accordingly if concomitant use of XYWAV and divalproex
`sodium is warranted.
`
`8 USE IN SPECIFIC POPULATIONS
`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
`
`
`
`Reference ID: 4644289
`
`8
`
`

`

`
`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 organo