`
` 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)
`
`
`
`----------------------------RECENT MAJOR CHANGES----------------------­
`
`
`
` Warnings and Precautions (5.5)
`
` 10/2020
`
` ----------------------------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
`
` 4.5 g per night
`
`
`
` 2.25 g
`
` 6 g per night
`
`
`
` 3 g
` 3 g
`
` 3.75 g
`
` 7.5 g per night
` 3.75 g
`
`
`
` 9 g per night
`
`
`
` 4.5 g
` 4.5 g
` • 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).
`
`
`
`
`
`
`
`
`
`
`
`
`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 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.
`
`
`------------------------------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: 02/2021
`
`
`Reference ID: 4745184
`
`
`
` 1
`
`
`

`

`
`
`
`
`
`
`
`
`8
`
`
`9
`
`
`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
`
`
`PATIENT COUNSELING INFORMATION
`17
`
`
`
`*Sections or subsections omitted from the full
`
`prescribing information are not listed.
`
`
`
`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
`3
`
`
`CONTRAINDICATIONS
`4
`
`
`5 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
`
`
`
`Reference ID: 4745184
`
`
`
` 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: 4745184
`
`
`3
`
`
`

`

`
`
`
`
`
`
` 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
` 2.25 g
`
`
`
` 4.5 g per night
`
` 6 g per night
`
`
` 3 g
` 3 g
`
` 3.75 g
`
` 3.75 g
`
` 7.5 g per night
`
`
`
` 9 g per night
` 4.5 g
` 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.
`
`
`
`
`
` Table 2: Recommended XYWAV Dosage for Patients 7 Years of Age and Older*
`
`
`
`
`
`
` Initial Dosage
` Maximum Weekly
` Maximum
` Recommended Dosage
`
`Dosage Increase
`
`
`Take 2.5
`
` Take at
` Take at
`Take 2.5 to
`Take 2.5
` Bedtime:
` Bedtime:
`
`
` 4 Hours
`
` to 4 Hours
`
` to 4 Hours
`
` Later:
`
`
`
` Later:
` Later:
`
` There is insufficient information to provide specific dosing recommendations
`
` for patients who weigh less than 20 kg.
`
`
`
`≤1 g
`≤1 g
`0.5 g
`
`Patient
`
` Weight
`
` Take at
`
` Bedtime:
`
`
`
`
` <20 kg**
`
`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)].
`
`
`
`
`
`
`
`
`Reference ID: 4745184
`
`
`4
`
`
`

`

`
`
`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)].
`
`
`
`
`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 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 (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).
`
`
`
`
`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)].
`
`
`
`
`
`• patients with succinic semialdehyde dehydrogenase deficiency [see Clinical
`
`
`
`
`Pharmacology (12.3)].
`
`
`5 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
`
`
`
`
`
`Reference ID: 4745184
`
`5
`
`
`
`

`

`
`
`
`
`
` 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 (5.3)].
`
`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
`
`
`
`
`
`
`
`Reference ID: 4745184
`
`6
`
`
`
`

`

`
`
`
`
`
` 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 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 and two patients reported
`
`depression 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.
`
`
`
`
`
`Reference ID: 4745184
`
`7
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`
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`

`

`
`
`
`
`
`
` 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.
`
`
`
` 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)]
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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,
`
`
`
`Reference ID: 4745184
`
`8
`
`
`
`

`

`
` 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*
`
` Adverse Reaction
` Open-Label Titration Period + Stable Dose Period
`
`
`
`
`
` (14 weeks)
`
`
` (N=201)
`
` %
`
` 20
`
`13
`
`10
`
`8
`
` 6
`
`6
`
` 6
`
`
`
`
` Headache
`
`Nausea
`
`Dizziness
`
`Decreased appetite
`
`Parasomnia†
`
`Diarrhea
`
`Hyperhidrosis‡
`
`Anxiety§
`
`Vomiting
`
`Fatigue¶
`
`
`Dry mouth
`
`Depressed mood
`
`Enuresis
`
`Irritability
`
`
`Paresthesia
`
`Depression
`
`
` 5
`5
`
`
` 4
`
`4
`
`4
`
`4
`
`3
`
`
`3
`
`3
`
`Reference ID: 4745184
`
`
`
` 9
`
`

`

`
`
`
`
` 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*
`
` Adverse Reaction
` Open-Label Titration Period + Stable Dose Period
`
`
`
`
`
` (14 weeks)
`
`
` (N=201)
`
` %
` Tremor
`
` 3
`
`
`
`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 for up to one year [see Clinical Studies (14.2)]. This study included
`
`an open-label safety continuation period in which eligible patients received Xyrem for up to an
`additional 2 years. The median and maximum exposure across the entire study were 371 and 987
`
`days, respectively.
`
`
`Adverse Reactions Leading to Treatment Discontinuation
`
`
`
`In the pediatric clinical trial with Xyrem, 7 of 104 patients reported adverse reactions that
`
`led to withdrawal from the study (hallucination, tactile; suicidal ideation; weight decreased; sleep
`
`
`
`apnea syndrome; affect lability; anger, anxiety, depression; and headache).
`
`
`Adverse Reactions in the Xyrem Pediatric Clinical Trial
`
`
`
`The most common adverse reactions (≥5%) were nausea (20%), enuresis (19%), vomiting
`
`
`(18%), headache (17%), weight decreased (13%), decreased appetite (9%), dizziness (8%), and
`
`sleepwalking (6%).
`
`
`
`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
`
`Reference ID: 4745184
`
`
`10
`
`
`

`

`
`
`
`
`
` 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:
` Art