`Important Administration Information for All Patients
`• Take each dose while in bed and lie down after dosing (2.3).
`• Allow 2 hours after eating before dosing (2.3).
`• Prepare both doses prior to bedtime; dilute each dose with approximately ¼
`cup of water in pharmacy-provided containers (2.3).
`• Patients with Hepatic Impairment: starting dose is one-half of the original
`dosage per night, administered orally divided into two doses (2.4).
`• Concomitant use with Divalproex Sodium: an initial reduction in Xyrem dose
`of at least 20% is recommended (2.5, 7.2).
`
`--------------------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 enuresis,
`nausea, headache, vomiting, weight decreased, decreased appetite, and dizziness
`(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.
`
`----------------------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: 10/2018
`
`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 Xyrem
`REMS Program (5.3)
`
`----------------------------RECENT MAJOR CHANGES-----------------------
`Indications and Usage (1)
`MM/YYYY
`Dosage and Administration (2.1, 2.2, 2.4)
`MM/YYYY
`Warnings and Precautions (5.1, 5.4, 5.5, 5.6, 5.7)
`MM/YYYY
`
`----------------------------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
`4.5 g per night
`2.25 g
`2.25 g
`6 g per night
`3 g
`3 g
`7.5 g per night
`3.75 g
`3.75 g
`9 g per night
`4.5 g
`4.5 g
`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).
`
`
`Reference ID: 4341394
`
`

`

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`
`
`
`
`
`
`
`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
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1 Central Nervous System Depression
`5.2 Abuse and Misuse
`5.3 Xyrem REMS Program
`5.4 Respiratory Depression and Sleep-Disordered
`
`Breathing
`5.5 Depression and Suicidality
`5.6 Other Behavioral or Psychiatric Adverse Reactions
`5.7
`Parasomnias
`5.8 Use in Patients Sensitive to High Sodium Intake
`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
`8
`USE IN SPECIFIC POPULATIONS
`
`6
`
`7
`
`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
`
`
`
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`Reference ID: 4341394
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`

`

`
`
`
`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 Xyrem REMS Program [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. 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
`
`
`
`
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`Reference ID: 4341394
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`

`

`Take 2.5 to
`Take 2.5
`Take 2.5
`4 Hours
`to 4 Hours
`to 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
`
`Take at
`Bedtime:
`
`0.5 g
`
`3 g
`
`3 g
`
`20 kg to
`<30 kg
`30 kg to
`<45 kg
`
`
`
`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.
`
`Table 2: Recommended Pediatric Xyrem Dosage for Patients 7 Years of Age and Older*
`Initial Dosage
`Maximum Weekly
`Maximum
`Dosage Increase
`Recommended Dosage
`
`Take at
`Bedtime:
`
`Patient
`Weight
`
`Take at
`Bedtime:
`
`≤1.5 g
`
`≤1.5 g
`
`0.5 g
`
`0.5 g
`
`3.75 g
`
`3.75 g
`
`≥45 kg
`
`≤2.25 g
`
`≤2.25 g
`
`0.75 g
`
`0.75 g
`
`4.5 g
`
`4.5g
`
`* 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: Unequal dosages may be required for some patients to achieve optimal treatment.
` 2.3 Important Administration Instructions for All Patients
`Take the first dose of Xyrem at least 2 hours after eating [see Clinical Pharmacology (12.3)].
`
`
`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. Patients should take both doses of Xyrem while in bed and lie down immediately after dosing
`as Xyrem may cause them to fall asleep abruptly without first feeling drowsy. 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 should remain in bed
`following ingestion of the first and second doses, and should not take the second dose until 2.5 to
`4 hours after the first dose. 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.
`
`
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`Reference ID: 4341394
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`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
`
`Pharmacokinetic and pharmacodynamic interactions have been observed when Xyrem is
`co-administered with divalproex sodium. For patients already stabilized on Xyrem, it is recommended
`that addition of divalproex sodium should be accompanied by an initial reduction in the nightly dose of
`Xyrem by at least 20%. For patients already taking divalproex sodium, it is recommended that
`prescribers use a lower starting Xyrem dose when introducing Xyrem. Prescribers should monitor
`patient response and adjust dose accordingly [see Drug Interactions (7.2) and Clinical Pharmacology
`(12.3)].
`
` 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 in patients being treated with sedative hypnotic agents [see
`Warnings and Precautions (5.1)].
`• Patients should not drink alcohol when using Xyrem [see Warnings and Precautions
`(5.1)].
`• Xyrem is contraindicated in patients with succinic semialdehyde dehydrogenase
`deficiency [see Clinical Pharmacology (12.3)]. This is a rare disorder of inborn error of
`metabolism variably characterized by mental retardation, hypotonia, and ataxia.
`
`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. Alcohol and sedative hypnotics are contraindicated in patients who are using
`Xyrem. 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
`
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`Reference ID: 4341394
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`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)].
`
`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 Xyrem REMS Program
`Xyrem is available only through a restricted distribution program called the Xyrem REMS
`Program 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 Xyrem REMS Program 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 XYREM
`REMS Program with documentation of safe use
`
`
`Further information is available at www.XYREMREMS.com or 1-866-XYREM88® (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
`
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`Reference ID: 4341394
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`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.
`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 and in postmenopausal women not on hormone replacement therapy as well as
`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 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
`
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`Reference ID: 4341394
`
`

`

`
`
`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.
`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 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 significant injury or potential injury were
`associated with sleepwalking 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)
`Xyrem Dose
`Sodium Content/Total
`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)]
`
`
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`Reference ID: 4341394
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`
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`• 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)]
`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.
`
`
`
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`Reference ID: 4341394
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`

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`
`
`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
`
`System Organ Class/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
`Pain
`1
`1
`Feeling drunk
`1
`0
`Edema peripheral
`1
`3
`MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
`Pain in extremity
`1
`Cataplexy
`1
`Muscle spasms
`2
`NERVOUS SYSTEM DISORDERS
`Dizziness
`Somnolence
`Tremor
`Paresthesia
`Disturbance in attention
`Sleep paralysis
`PSYCHIATRIC DISORDERS
`Disorientation
`Anxiety
`Irritability
`Sleep walking
`RENAL AND URINARY DISORDERS
`1
`Enuresis
`SKIN AND SUBCUTANEOUS TISSUE DISORDERS
`Hyperhidrosis
`0
`
`4
`4
`0
`1
`0
`1
`
`1
`1
`1
`0
`
`3
`1
`2
`
`9
`1
`0
`2
`1
`0
`
`1
`1
`0
`0
`
`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
`1
`0
`1
`
`2
`1
`<1
`0
`
`3
`
`1
`
`20
`11
`4
`2
`1
`
`3
`3
`0
`
`1
`2
`2
`
`15
`8
`5
`3
`4
`3
`
`3
`2
`3
`3
`
`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 up to 377 days
`(median exposure 332 days).
`
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`Reference ID: 4341394
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`Adverse Reactions Leading to Treatment Discontinuation
`In the pediatric clinical trial, 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 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.
`
`6.2 Postmarketing Experience
`The following adverse reactions have been identified during postapproval use of Xyrem.
`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, decreased appetite, fall, fluid retention, hangover, headache, hypersensitivity,
`hypertension, memory impairment, nocturia, panic attack, vision blurred, and weight
`decreased.
`
`7 DRUG INTERACTIONS
`7.1 Alcohol, Sedative Hypnotics, and CNS Depressants
`Xyrem should not be used in combination with alcohol or sedative hypnotics. Use of other
`CNS depressants may potentiate the CNS-depressant effects of Xyrem [see Warnings and
`Precautions (5.1)].
`7.2 Divalproex Sodium
`Concomitant use of Xyrem with divalproex sodium resulted in a 25% mean increase in
`systemic exposure to Xyrem (AUC ratio range of 0.8 to 1.7) and in a greater impairment on
`some tests of attention and working memory. An initial Xyrem dose reduction of at least 20% is
`recommended if divalproex sodium is prescribed to patients already taking Xyrem [see Dosage
`and Administration (2.5) and Clinical Pharmacology (12.3)]. Prescribers are advised to monitor
`patient response closely and adjust dose accordingly if concomitant use of Xyrem 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 sodium
`oxybate in pregnant women. Oral administration of sodium oxybate to pregnant rats (150, 350,
`
`
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`Reference ID: 4341394
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`

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`or 1,000 mg/kg/day) or rabbits (300, 600, or 1,200 mg/kg/day) throughout organogenesis
`produced no clear evidence of developmental toxicity; however, oral administration to rats
`throughout pregnancy and lactation resulted in increased stillbirths and decreased offspring
`postnatal viability and growth, at a clinically relevant dose [see Data].
`In the U.S. general population, the estimated background risk of major birth defects and
`miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The
`background risk of major birth defects and miscarriage for the indicated population is unknown.
`Clinical Considerations
`Labor or Delivery
`Xyrem 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 pregna