`
`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 per mL (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 Xyrem
`
`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 Xyrem does not affect them adversely
`
`(5.1).
`
`
`
`
`• Depression and suicidality: Monitor patients for emergent or increased
`
`
`depression and suicidality (5.5).
`
`
`• Confusion/Anxiety: Monitor for impaired motor/cognitive function (5.6).
`
`
`• Parasomnias: Evaluate episodes of sleepwalking (5.7).
`
`
`
`• High sodium content in Xyrem: Monitor patients with heart failure,
`
`
`hypertension, or impaired renal function (5.8).
`
`
`-----------------------------ADVERSE REACTIONS----------------------------­
`
`
`Most common adverse reactions in adults (≥5% and at least twice the incidence
`
`
`
`with placebo) were nausea, dizziness, vomiting, somnolence, enuresis, and
`
`tremor (6.1).
`
`
`
`Most common adverse reactions in pediatric patients (≥5%) were nausea,
`
`
`
`
`enuresis, vomiting, headache, weight decreased, decreased appetite, dizziness,
`
`
`and sleepwalking (6.2).
`
`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 Xyrem dose
`
`
`
`of at least 20% is recommended (2.5, 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 Xyrem (8.5).
`
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide.
`
`
`
`
`Revised: 9/2020
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`XYREM safely and effectively. See full prescribing information for
`
`
`
`
`XYREM.
`
`XYREM® (sodium oxybate) 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
`
` • Xyrem is a CNS depressant, and respiratory depression can occur with
`
`
`
` Xyrem use (5.1, 5.4)
`
` Abuse and Misuse
`
` • Xyrem is the sodium salt of 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)
`Xyrem is available only through a restricted program called the
`
`
` XYWAV and XYREM REMS (5.3)
`
`
`
`----------------------------RECENT MAJOR CHANGES----------------------­
`
`
`
`
` Dosage and Administration (2.1, 2.2, 2.3, 2.5)
`
` 7/2020
`
`
` 7/2020
` Contraindications (4)
` Warnings and Precautions (5.1, 5.3, 5.5)
`
` 9/2020
`
`
`
`
` ----------------------------INDICATIONS AND USAGE--------------------------
`
`
`
` Xyrem is a central nervous system depressant indicated for the treatment
` of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of
`
`
`
`
`
`
`
` age and older with narcolepsy (1)
`
`
`
`
`
`
`
`
`
` -----------------------DOSAGE AND ADMINISTRATION---------------------­
` Dosage for Adult Patients
`
`
`
`
`
`
`
`
`
`• Initiate dosage at 4.5 g per night orally, divided into two doses (2.1).
`
`
`
`
`• Titrate to effect in increments of 1.5 g per night at weekly intervals
`
`
`
`
`
`(0.75 g at bedtime and 0.75 g taken 2.5 to 4 hours later) (2.1).
`
`
`
`
`• Recommended dosage range: 6 g to 9 g per night orally (2.1).
` Total Nightly Dose
` Take at Bedtime Take 2.5 to 4 Hours Later
`
`
` 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
`
`
`
` 4.5 g
` 4.5 g
` 9 g per night
`
`
`
`Dosage for Pediatric Patients (7 years of Age and Older)
`
`
`
`
`
`
`
`
`
`
`
`
`
`• The recommended starting dosage, titration regimen, and maximum
`
`
`
`
`total nightly dosage are based on body weight (2.2).
`
`
`Important Administration Information
`
`
`
`
`
`• Prepare both doses prior to bedtime; dilute each dose with approximately
`
`
`
`¼ cup of water in pharmacy-provided containers (2.3).
`
`
`
`• Allow 2 hours after eating before dosing (2.3).
`
`
`
`
`• Take each dose while in bed and lie down after dosing (2.3).
`
`
`
`
`
`
`Reference ID: 4676451
`
`

`

` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
` WARNING: CENTRAL NERVOUS SYSTEM (CNS)
` DEPRESSION and ABUSE AND MISUSE
`
`
`
`
`
` 1
` INDICATIONS AND USAGE
`
` 2
` DOSAGE AND ADMINISTRATION
`
`
` 2.1 Adult Dosing Information
`
` 2.2
` Pediatric Dosing Information
`
`
` 2.3
` Important Administration Instructions for All
`
` Patients
` 2.4 Dosage Modification in Patients with Hepatic
`
`
` Impairment
` 2.5 Dosage Adjustment with Co-administration of
`
`
` Divalproex Sodium
` DOSAGE FORMS AND STRENGTHS
`
` 3
`
`
` 4
` CONTRAINDICATIONS
`
` 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
`
` Parasomnias
`
` 5.7
`
`
`
` 5.8 Use in Patients Sensitive to High Sodium Intake
` ADVERSE REACTIONS
`
`
` 6.1 Clinical Trials Experience
`
`
` Postmarketing Experience
`
` 6.2
` DRUG INTERACTIONS
`
` 7.1 Alcohol, Sedative Hypnotics, and CNS
`
`
` Depressants
`
`
` 7.2 Divalproex Sodium
`
`
` USE IN SPECIFIC POPULATIONS
`
`
`
`
`
`
`
`
`
`
`
`
`9
`
`
`
`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 in Adult Narcolepsy
`
`
`
`14.2 Excessive Daytime Sleepiness in Adult Narcolepsy
`
`
`
`
`14.3 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 6
`
`
`
` 7
`
`
`
` 8
`
`
`
`
`Reference ID: 4676451
`
`

`

`
`
`
` FULL PRESCRIBING INFORMATION
`
`
` WARNING: CENTRAL NERVOUS SYSTEM DEPRESSION
`
` and ABUSE AND MISUSE.
`
`
`
`
` • Central Nervous System Depression
`
`
`
`Xyrem (sodium oxybate) is a CNS depressant. In clinical trials at recommended doses,
`
`
`obtundation and clinically significant respiratory depression occurred in adult patients
`
`treated with Xyrem [see Warnings and Precautions (5.1)]. Many patients who received
`
`
`Xyrem during clinical trials in narcolepsy were receiving central nervous system
`
`stimulants [see Clinical Trials (14)].
`
`
`• Abuse and Misuse
`
`
` Xyrem® (sodium oxybate) is the sodium salt of gamma-hydroxybutyrate (GHB). Abuse
`
`
`
`
` or misuse of illicit GHB, either alone or in combination with other CNS depressants, is
`
` associated with CNS adverse reactions, including seizure, respiratory depression,
`
`
` decreases in the level of consciousness, coma, and death [see Warnings and Precautions
`
`
`
`
` (5.2)].
`
` Because of the risks of CNS depression and abuse and misuse, Xyrem 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
`
`
`
`
` Xyrem 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 1.5 g per night at weekly intervals (additional 0.75 g at bedtime and 0.75 g taken 2.5
`
`
`
`
`
`
` to 4 hours later) to the effective dosage range of 6 g to 9 g per night orally. The dosage may be
` gradually titrated based on efficacy and tolerability. Doses higher than 9 g per night have not
`
`
`
` been studied and should not ordinarily be administered.
`
`
`
`
`
`
`
` Table 1: Recommended Adult Xyrem Dose Regimen
`
`
`
` (g = grams)
`
` Take at
`
`
` Bedtime:
` 2.25 g
`
`
` 3 g
`
` 3.75 g
`
` 4.5 g
`
`
`
` If A Patient’s Total
`
` Nightly Dose is:
`
` 4.5 g per night
`
` 6 g per night
`
` 7.5 g per night
`
` 9 g per night
`
`Take 2.5 to 4
`
` Hours Later:
`
` 2.25 g
`
` 3 g
`
` 3.75 g
`
` 4.5 g
`
`
`
`Reference ID: 4676451
`
`

`

`
`
`
` 2.2 Pediatric Dosing Information
`
` Xyrem is administered orally twice nightly. The recommended starting pediatric dosage,
`
`
`titration regimen, and maximum total nightly dosage are based on patient weight, as specified in
`
`
`
`
`Table 2. The dosage may be gradually titrated based on efficacy and tolerability.
`
`
`
`
`
`Patient
`Weight
`
`
`
`
` <20 kg**
`
`20 kg to
`
`<30 kg
`30 kg to
`
`<45 kg
`
`
`≥45 kg
`
` Take at
`
` Bedtime:
`
`
` Take at
`
` Bedtime:
`
`
`Take 2.5 to
`Take 2.5
`Take 2.5
`
` 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
`
`0.5 g
` ≤1 g
`
`
`
` 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
`
`Table 2: Recommended Pediatric Xyrem Dosage for Patients 7 Years of Age and Older*
`
`
`
` Initial Dosage
` Maximum Weekly
`
`
`
` Maximum
` Recommended Dosage
`Dosage Increase
`
`
` Take at
`
` Bedtime:
`
`
`
`
`
`
`
`
`
`
` * For patients who sleep more than 8 hours per night, the first dose of Xyrem may be given at bedtime or after an initial
`
` period of sleep.
`
` **If Xyrem is used in patients 7 years of age and older who weigh less than 20 kg, a lower starting dosage, lower maximum
`
` weekly dosage increases, and lower total maximum nightly dosage should be considered.
`
`
`
`
` Note: Some patients may achieve better responses with unequal doses at bedtime and 2.5 to 4 hours later.
`
`
`
`
`
`
`
`
` 2.3 Important Administration Instructions for All Patients
`
`
`
`
`
`
` The total nightly dosage of Xyrem is divided into two doses. Prepare both doses of Xyrem
` prior to bedtime. Prior to ingestion, each dose of Xyrem should be diluted with approximately
`
`
`
`
`
`
`¼ cup (approximately 60 mL) of water in the empty pharmacy containers provided.
`
`
`
`
`Take the first nightly dose of Xyrem at least 2 hours after eating [see Clinical
`
`
`
`Pharmacology (12.3)]. Take the second nightly dose 2.5 to 4 hours after the first dose.
`
`
`
`Patients should take both doses of Xyrem while in bed and lie down immediately after
`
`
`
`dosing, and remain in bed following ingestion of each dose. Xyrem 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 Xyrem, and will usually fall asleep within 15 minutes, though
`
`
`the time it takes any individual patient to fall asleep may vary from night to night. Patients may
`
`need to set an alarm to awaken for the second dose. Rarely, patients may take up to 2 hours to
`
`fall asleep.
`
`If the second dose is missed, that dose should be skipped and Xyrem should not be taken
`
`again until the next night. Both Xyrem doses should never be taken at one time.
`
`
`
`Reference ID: 4676451
`
`

`

`
`
`
`
`
` 2.4 Dosage Modification in Patients with Hepatic Impairment
` The recommended starting dosage in patients with hepatic impairment is one-half of the
`
`
`
`
` original dosage per night, administered orally divided into two doses [see Use in Specific
`
` Populations (8.6) and Clinical Pharmacology (12.3)].
`
`
` 2.5 Dose Adjustment with Co-administration of Divalproex Sodium
`
`
` When initiating divalproex sodium in patients taking a stable dosage of Xyrem, a reduction
`
`
`
`
`of the Xyrem dosage by at least 20% is recommended with initial concomitant use [see Drug
`
`
`
`
`
`
`Interactions (7.2) and Clinical Pharmacology (12.3)]. When initiating Xyrem in patients already
`
`
`
`
`
`taking divalproex sodium, a lower starting dosage of Xyrem is recommended. Subsequently, the
`
`
`
`
`dosage of Xyrem can be adjusted based on individual clinical response and tolerability.
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`Xyrem is a clear to slightly opalescent oral solution, in a concentration of 0.5 g per mL
`
`
`
`
`(0.5 g/mL of sodium oxybate equivalent to 0.413 g/mL of oxybate).
`
`
`
`
`4 CONTRAINDICATIONS
`
`
`Xyrem 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
`
`
`Xyrem is a central nervous system (CNS) depressant. In adult clinical trials at recommended
`
`
`
`
`
`
`
`doses, obtundation and clinically significant respiratory depression occurred in patients treated
`
`
`
`
`with Xyrem. Xyrem is contraindicated in combination with alcohol and sedative hypnotics. The
`
`
`concurrent use of Xyrem 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 Xyrem is required, dose reduction or discontinuation of
`
`
`one or more CNS depressants (including Xyrem) should be considered. In addition, if short-term
`
`
`use of an opioid (e.g., post- or perioperative) is required, interruption of treatment with Xyrem
`
`
`should be considered.
`
`Healthcare providers should caution patients about operating hazardous machinery,
`
`
`including automobiles or airplanes, until they are reasonably certain that Xyrem 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 Xyrem. Patients should be queried about CNS depression-related events upon initiation of
`
`
`Xyrem therapy and periodically thereafter.
`
`Xyrem is available only through a restricted program under a REMS [see Warnings and
`
`
`
`Precautions (5.3)].
`
`
`
`
`Reference ID: 4676451
`
`

`

`
`
`
`
`
`
`
`
`
` 5.2 Abuse and Misuse
`
`
`
`
`
` Xyrem is a Schedule III controlled substance. The active ingredient of Xyrem, sodium
` oxybate or gamma-hydroxybutyrate (GHB), is a Schedule I controlled substance. Abuse of illicit
`
`
`
`
` GHB, either alone or in combination with other CNS depressants, is associated with CNS
`
`
`
` adverse reactions, including seizure, respiratory depression, decreases in the level of
` consciousness, coma, and death. The rapid onset of sedation, coupled with the amnestic features
`
`
`
`
` of Xyrem, particularly when combined with alcohol, has proven to be dangerous for the
` voluntary and involuntary user (e.g., assault victim). Because illicit use and abuse of GHB have
`
`
`
`
`
` been reported, physicians should carefully evaluate patients for a history of drug abuse and
` follow such patients closely, observing them for signs of misuse or abuse of GHB (e.g., increase
`
`
`
` in size or frequency of dosing, drug-seeking behavior, feigned cataplexy) [see Drug Abuse and
`
`
`
`
`
` Dependence (9.2)].
` Xyrem is available only through a restricted program under a REMS [see Warnings and
`
`
` Precautions (5.3)].
`
`
` 5.3 XYWAV and XYREM REMS
`
`
`
`
` Xyrem 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 Xyrem are specially certified
`
`
`
`
` • Xyrem will be dispensed only by the central pharmacy that is specially certified
`
`
` • Xyrem 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
`
`
`Xyrem may impair respiratory drive, especially in patients with compromised respiratory
`
`
`function. In overdoses, life-threatening respiratory depression has been reported [see Overdosage
`
`
`(10)].
`
`In an adult study assessing the respiratory-depressant effects of Xyrem at doses up to 9 g per
`
`
`
`
`night in 21 patients with narcolepsy, no dose-related changes in oxygen saturation were
`
`demonstrated in the group as a whole. One of the four patients with preexisting, moderate-to­
`
`
`severe sleep apnea had significant worsening of the apnea/hypopnea index during treatment.
`
`In an adult study assessing the effects of Xyrem 9 g per night in 50 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 Xyrem administration in adult and pediatric
`
`
`
`patients.
`
`
`
`
`
`
`Reference ID: 4676451
`
`
`
`
`
`

`

`
`
`
`
` In adult clinical trials in 128 patients with narcolepsy, two subjects 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
`
` In adult clinical trials in 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 controlled adult trial, with patients randomized to fixed doses of 3 g, 6 g, or 9 g per
`
`
`
`
`
`
`
` night Xyrem or placebo, there was a single event of depression at the 3 g per night dose. In
`
`
`
`
`
` another adult controlled trial, with patients titrated from an initial 4.5 g per night starting dose,
`
`
`
`
` the incidences of depression were 1 (1.7%), 1 (1.5%), 2 (3.2%), and 2 (3.6%) for the placebo,
`
` 4.5 g, 6 g, and 9 g per night doses, respectively.
`
`
`
`
`
`
` In the pediatric clinical trial in 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 Xyrem 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 Xyrem.
`
`
`
`5.6 Other Behavioral or Psychiatric Adverse Reactions
`
`
`
`
`
`During adult clinical trials in patients with narcolepsy, 3% of 781 patients treated with
`
`Xyrem experienced confusion, with incidence generally increasing with dose.
`
`
`
`Less than 1% of patients discontinued the drug because of confusion. Confusion was
`
`
`
`
`reported at all recommended doses from 6 g to 9 g per night. In a controlled trial in adults where
`
`
`
`
`
`patients were randomized to fixed total daily doses of 3 g, 6 g, or 9 g per night or placebo, a
`
`
`
`
`
`dose-response relationship for confusion was demonstrated, with 17% of patients at 9 g per night
`
`experiencing confusion. In all cases in that controlled trial, the confusion resolved soon after
`
`
`
`
`
`termination of treatment. In Trial 3 where sodium oxybate was titrated from an initial 4.5 g per
`
`
`
`
`night dose, there was a single event of confusion in one patient at the 9 g per night dose. In the
`
`majority of cases in all adult clinical trials in patients with narcolepsy, confusion resolved either
`
`
`
`
`
`soon after termination of dosing or with continued treatment.
`
`Anxiety occurred in 5.8% of the 874 patients receiving Xyrem in adult clinical trials in
`
`
`
`another population.
`
`Other neuropsychiatric reactions reported in adult clinical trials in patients with narcolepsy
`
`
`
`and the post-marketing setting included hallucinations, paranoia, psychosis, aggression, and
`
`
`
`agitation.
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4676451
`
`

`

`
`
`
`
`
`
`
`
`
`
` In the pediatric clinical trial 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 adult and
`
`
` pediatric patients taking Xyrem should be carefully monitored.
`
`
`
`
`
`
` 5.7 Parasomnias
`
` Sleepwalking, defined as confused behavior occurring at night and at times associated with
` wandering, was reported in 6% of 781 patients with narcolepsy treated with Xyrem in adult
`
`
`
` controlled trials and long-term open-label studies, with <1% of patients discontinuing due to
` sleepwalking. Rates of sleepwalking were similar for patients taking placebo and patients taking
`
`
`
`
` Xyrem in controlled trials. It is unclear if some or all of the reported sleepwalking episodes
`
`
`
`
`
` correspond to true somnambulism, which is a parasomnia occurring during non-REM sleep, or to
`
` any other specific medical disorder. Five instances of sleepwalking with potential injury or
`
`
`
`
` significant injury were reported during a clinical trial of Xyrem in patients with narcolepsy.
`
` Parasomnias, including sleepwalking, also have been reported in the pediatric clinical trial
`
`
`
`
`
` and in postmarketing experience with Xyrem. Therefore, episodes of sleepwalking should be
`
`
` fully evaluated and appropriate interventions considered.
`
`
` 5.8 Use in Patients Sensitive to High Sodium Intake
`
`
` Xyrem has a high salt content. In patients sensitive to salt intake (e.g., those with heart
`
`
`
`
`
` failure, hypertension, or renal impairment), consider the amount of daily sodium intake in each
`
` dose of Xyrem. Table 3 provides the approximate sodium content per Xyrem dose.
`
`
` Table 3
`
`Approximate Sodium Content per Total Nightly
`
`
` Dose of Xyrem (g = grams)
`
`
` Sodium Content/Total
`
`Xyrem Dose
`
` Nightly Exposure
`
` 550 mg
`
` 820 mg
`
` 1100 mg
`
`1400 mg
`
`1640 mg
`
` 3 g per night
`
`
`
` 4.5 g per night
`
` 6 g per night
`
`7.5 g per night
`
`9 g per night
`
`
`
`
`
`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)]
`
`
`
`
`
`
`• Use in Patients Sensitive to High Sodium Intake [see Warnings and Precautions (5.8)]
`
`
`
`Reference ID: 4676451
`
`

`

`
`
`
`
` 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
`Xyrem was studied in three placebo-controlled clinical trials (Trials N1, N3, and N4,
`
`described in Sections 14.1 and 14.2) in 611 patients with narcolepsy (398 subjects treated with
`Xyrem, and 213 with placebo). A total of 781 patients with narcolepsy were treated with Xyrem
`
`
`in controlled and uncontrolled clinical trials.
`
`Section 6.1 and Table 4 present adverse reactions from three pooled, controlled trials (N1,
`
`
`
`N3, N4) in patients with narcolepsy.
`
`Adverse Reactions Leading to Treatment Discontinuation:
`
`Of the 398 patients with narcolepsy treated with Xyrem, 10.3% of patients discontinued
`
`
`
`
`because of adverse reactions compared with 2.8% of patients receiving placebo. The most
`
`
`
`common adverse reaction leading to discontinuation was nausea (2.8%). The majority of adverse
`
`reactions leading to discontinuation began during the first few weeks of treatment.
`
`
`
`
`Commonly Observed Adverse Reactions in Controlled Clinical Trials:
`The most common adverse reactions (incidence ≥5% and twice the rate seen with placebo)
`
`
`
`in patients treated with Xyrem were nausea, dizziness, vomiting, somnolence, enuresis, and
`
`
`tremor.
`
`Adverse Reactions Occurring at an Incidence of 2% or Greater:
`
`
`Table 4 lists adverse reactions that occurred at a frequency of 2% or more in any treatment
`
`
`
`group for three controlled trials and were more frequent in any Xyrem treatment group than with
`
`placebo. Adverse reactions are summarized by dose at onset. Nearly all patients in these studies
`
`initiated treatment at 4.5 g per night. In patients who remained on treatment, adverse reactions
`
`
`tended to occur early and to diminish over time.
`
`
`
`
`
`
`
`Reference ID: 4676451
`
`

`

`
`
`
`
` Table 4
`
`
` Adverse Reactions Occurring in ≥2% of Adult Patients and More Frequently with Xyrem than
`
`
`
`
` Placebo in Three Controlled Trials (N1, N3, N4) by Body System and Dose at Onset
`
`
`
`
`
` Adverse Reaction
`
`
` Placebo
`
` (n=213)
`
` %
`
` 62
`
`
` Xyrem 4.5g
` (n=185)
`
`
` %
`
` 45
`
`
`
`
`
`ANY ADVERSE REACTION
`
`GASTROINTESTINAL DISORDERS
`
`
` 8
`
` 3
`
` Nausea
`
` 2
`
` 1
`
` Vomiting
`
` 4
`
` 2
`
` Diarrhea
`
` 3
`
` 2
`
` Abdominal pain upper
`
` 1
`
` 2
`
` Dry mouth
` GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS
`
`
`
`
` 1
` 1
` Pain
` Feeling drunk
`
` 1
`
` 0
`
`
` 1
`
` 3
`
` Edema peripheral
`
`
` MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
`
`
`
` 1
` Cataplexy
` Muscle spasms
`
` 2
`
`
` 1
` Pain in extremity
`
`NERVOUS SYSTEM DISORDERS
`
`
` Dizziness
`
` Somnolence
`
` Tremor
`
` Disturbance in attention
`
` Paresthesia
` Sleep paralysis
`
`PSYCHIATRIC DISORDERS
`
`
` Disorientation
`
` Irritability
`
` Sleepwalking
`
` Anxiety
`RENAL AND URINARY DISORDERS
`
` 1
`
`
` Enuresis
` SKIN AND SUBCUTANEOUS TISSUE DISORDERS
`
`
` Hyperhidrosis
`
`
` 0
`
`
` 4
`
` 4
`
` 0
`
` 0
`
` 1
`
` 1
`
`
` 1
`
` 1
`
` 0
`
` 1
`
`
`
`
`
`
` 1
`
` 2
`
` 3
`
`
` 9
`
` 1
`
` 0
`
` 1
`
` 2
`
` 0
`
`
` 1
`
` 0
`
` 0
`
` 1
`
`
`
` 3
`
`
`
` 1
`
`
` Xyrem 6g
`(n=258)
`
`
` %
`
` 55
`
`
` Xyrem 9g
`
` (n=178)
`
` %
`
` 70
`
`
` 13
` 4
`
`
` 3
`
` 1
`
` 2
`
`
` <1
`
` <1
`
` 0
`
` 1
`
`
` <1
`
` 1
`
`
` 11
` 3
`
`
` 2
`
` 0
`
` 1
`
` 1
`
` 2
`
`
` <1
`
` 0
`
` 1
`
`
`
` 3
`
`
`
` 1
`
`
` 20
`
` 11
` 4
`
`
` 2
`
` 1
`
`
` 3
`
` 3
`
` 0
`
`
` 2
`
` 2
`
` 1
`
`
` 15
` 8
`
`
` 5
`
` 4
`
` 3
`
` 3
`
`
` 3
`
` 3
`
` 3
`
` 2
`
`
`
` 7
`
`
`
` 3
`
` Dose-Response Information
`
` In clinical trials in narcolepsy, a dose-response relationship was observed for nausea,
`
`vomiting, paresthesia, disorientation, irritability, disturbance in attention, feeling drunk,
`
`
`
`sleepwalking, and enuresis. The incidence of all these reactions was notably higher at 9 g per
`
`night.
`
`In controlled trials in narcolepsy, discontinuations of treatment due to adverse reactions
`
`
`were greater at higher doses of Xyrem.
`
`
`
`Pediatric Patients (7 Years of Age and Older)
`
`
`
`
`
`
`
`In the pediatric clinical trial (Trial N5), 104 patients aged 7 to 17 years (37 patients aged
`
`
`
`
`
`
`
`
`
`7 to 11 years; 67 patients aged 12 to 17 years) with narcolepsy received Xyrem for up to one
`
`
`
`year. This study included an open-label safety continuation period in which eligible patients
`
`
`
`Reference ID: 4676451
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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, 7 of 104 patients reported adverse reactions that led to
`
`
`
`
` withdrawal from the study (hallucination, tactile; suicidal ideation; weight decreased; sleep
`
` apnea syndrome; affect lability; anger, anxiety, depression; and headache).
`
`
`
` Adverse Reactions in the Pediatric Clinical Trial
`
`
`
`
` The most common adverse reactions (≥5%) were nausea (20%), enuresis (19%), vomiting
`
`
` (18%), headache (17%), weight decreased (13%), decreased appetite (9%), dizziness (8%), and
`
`
` sleepwalking (6%).
` 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.
`
`
` 6.2 Postmarketing Experience
`
`
`
` The following adverse reactions have been identified during postapproval use of Xyrem.
`
` Because th