 Allow 2 hours after eating before dosing (2.2).
`
`
`
`
`
`
`
`
` Prepare both doses prior to bedtime; dilute each dose with
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`approximately ¼ cup of water in pharmacy-provided vials (2.2).
` Patients with Hepatic Impairment: starting dose is 2.25 g per night
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`administered orally in two equal, divided doses of approximately 1.13 g
`
`
`
`
`
`
`
`
`
`
`at bedtime and approximately 1.13 g taken 2.5 to 4 hours later (2.3).
` Concomitant use with divalproex sodium: an initial reduction in Xyrem
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`dose of at least 20% is recommended (2.4, 7.2).
`
`
`
`--------------------DOSAGE FORMS AND STRENGTHS------------------­
`
`
`
`
`
`
`
`Oral solution, 0.5 g per mL (3)
`
`----------------------------CONTRAINDICATIONS-----------------------------­
` Succinic semialdehyde dehydrogenase deficiency (4)
`
`
`
`
`
`
` In combination with sedative hypnotics or alcohol (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 ( 5% and at least twice the incidence
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`with placebo) were nausea, dizziness, vomiting, somnolence, enuresis, and
`
`
`tremor (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.
`
`
`
`
`----------------------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: 1/2017
`
`
`
`
`
`
` 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 MISUSE AND ABUSE.
`
`
`
`
` See full prescribing information for complete boxed warning.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` • Respiratory depression can occur with Xyrem use (5.4)
`
`
`
`
` • Xyrem is a Schedule III controlled substance and is the sodium salt of
`
`
`
`
`
`
`
`
` gamma hydroxybutyrate (GHB), a Schedule I controlled substance.
`
`
`
`
`
` 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)
`
`
`
`
`
`
`
`
`
`
` • Because of the risks of CNS depression, abuse, and misuse, Xyrem is
`
`
`
`
`
`
`
`
`
` available only through a restricted distribution program called the
`
`
`
`
`
`
` Xyrem REMS Program using the central pharmacy that is specially
`
`
`
`
`
`
`
`
`
` certified. Prescribers and patients must enroll in the program. (5.3)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`----------------------------RECENT MAJOR CHANGES----------------------­
`
`
`
`
`
`
`Warnings and Precautions, Other Behavioral or Psychiatric
`
`
`
`
`
`
`
`
`Adverse Reactions (5.6)
`
`
`
`
`
`
`
`1/2017
`
`
`
`----------------------------INDICATIONS AND USAGE--------------------------
`
`Xyrem is a central nervous system depressant indicated for the treatment of:
`
`
`
`
`
`
`
`
`
` Cataplexy in narcolepsy (1.1)
`
`
`
`
`
`
` Excessive daytime sleepiness (EDS) in narcolepsy (1.2)
`
`
`
`
`
`
`
`
`
`
`
`Xyrem may only be dispensed to patients enrolled in the Xyrem REMS
`
`
`
`
`
`
`
`
`
`
`Program (1).
`
`
`
`
`
`
`-----------------------DOSAGE AND ADMINISTRATION---------------------­
`
` Initiate dose at 4.5 grams (g) per night administered orally in two equal,
`
`
`
`
`
`
`
`
`
`
`
`
`
`divided doses: 2.25 g at bedtime and 2.25 g taken 2.5 to 4 hours later (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 dose 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
`
`
`
`
`
` 4.5 g
`
` 4.5 g
` 9 g per night
`
`
` Take each dose while in bed and lie down after dosing (2.2).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4046630
`
`
`

`

`8.2 Labor and Delivery
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`8.3 Nursing Mothers
`
`
`
`WARNING: CENTRAL NERVOUS SYSTEM (CNS)
`
`
`8.4
`Pediatric Use
`
`
`DEPRESSION and MISUSE AND ABUSE
`
`
`
`8.5 Geriatric Use
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`8.6 Hepatic Impairment
`
`1.1 Cataplexy in Narcolepsy
`
`
`
`
`
`
`
`DRUG ABUSE AND DEPENDENCE
`
`1.2 Excessive Daytime Sleepiness in Narcolepsy
`
`
`
`
`
`
`
`
`9.1 Controlled Substance
`
`
`
`DOSAGE AND ADMINISTRATION
`
`9.2 Abuse
`
`2.1 Dosing Information
`
`
`
`
`
`9.3 Dependence
`
`2.2
`Important Administration Instructions
`
`
`
`
`
`2.3 Dose Modification in Patients with Hepatic Impairment 10 OVERDOSAGE
`
`
`
`
`
`
`
`
`
`
`10.1 Human Experience
`
`2.4 Dose Adjustment with Co-administration of
`
`
`
`
`
`
`
`
`Divalproex Sodium
`10.2 Signs and Symptoms
`
`
`
`
`
`
`10.3 Recommended Treatment of Overdose
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`
`10.4 Poison Control Center
`
`
`
`CONTRAINDICATIONS
`4
`
`
`5 WARNINGS AND PRECAUTIONS
`11 DESCRIPTION
`
`
`
`
`
`12 CLINICAL PHARMACOLOGY
`
`5.1 Central Nervous System Depression
`
`
`
`
`
`12.1 Mechanism of Action
`
`5.2 Abuse and Misuse
`
`
`
`
`
`
`
`
`12.3 Pharmacokinetics
`
`5.3 Xyrem REMS Program
`
`
`
`
`
`
`5.4 Respiratory Depression and Sleep-Disordered Breathing 13 NONCLINICAL TOXICOLOGY
`
`
`
`
`
`
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`5.5 Depression and Suicidality
`
`
`
`
`
`
`
`14 CLINICAL STUDIES
`
`5.6 Other Behavioral or Psychiatric Adverse Reactions
`
`
`
`
`
`14.1 Cataplexy in Narcolepsy
`
`5.7
`Parasomnias
`
`
`
`
`
`
`14.2 Excessive Daytime Sleepiness in Narcolepsy
`
`5.8 Use in Patients Sensitive to High Sodium Intake
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`ADVERSE REACTIONS
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`
`16.1 How Supplied
`
`6.1 Clinical Trials Experience
`
`
`
`
`
`16.2 Storage
`
`6.2
`Postmarketing Experience
`
`
`
`
`
`16.3 Handling and Disposal
`
`
`
`
`
`DRUG INTERACTIONS
`
`
`PATIENT COUNSELING INFORMATION
`
`Alcohol, Sedative Hypnotics, and CNS Depressants
`7.1
`
`
`
`
`
`
`
`Divalproex Sodium
`
`7.2
`
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`
`Pregnancy
`8.1
`
`
`
`
`
`9
`
`
`17
`
`
`*Sections or subsections omitted from the full prescribing
`
`
`
`
`
`
`information are not listed
`
`
`
`
`2
`
`
`6
`
`
`7
`
`
`
`8
`
`
`
`
`
`
`
`Reference ID: 4046630
`
`

`

`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`WARNING: CENTRAL NERVOUS SYSTEM DEPRESSION
`
`and MISUSE AND ABUSE.
`
`
`Xyrem (sodium oxybate) is a CNS depressant. In clinical trials at recommended doses
`
`
`obtundation and clinically significant respiratory depression occurred in Xyrem-treated
`
`
`patients. Almost all of the patients who received Xyrem during clinical trials in narcolepsy
`
`were receiving central nervous system stimulants [see Warnings and Precautions (5.1)].
`
`
`Xyrem® (sodium oxybate) is the sodium salt of gamma hydroxybutyrate (GHB). Abuse of
`
`
`
`
`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, abuse, and misuse, Xyrem is available only through
`
`
`
`
`
`a restricted distribution program called the Xyrem REMS Program, using the central
`
`pharmacy that is specially certified. Prescribers and patients must enroll in the program.
`For further information go to www.XYREMREMS.com or call 1-866-XYREM88® (1-866­
`
`
`
` 997-3688) [see Warnings and Precautions (5.3)].
`
`
`
`
`
`1
`
`
`INDICATIONS AND USAGE
`
`
`
`Limitations of Use
`
`Xyrem may only be dispensed to patients enrolled in the Xyrem REMS Program [see
`
`
`
`
`
`
`
`
`Warnings and Precautions (5.3)].
`
`
`1.1 Cataplexy in Narcolepsy
`
`
`
`Xyrem (sodium oxybate) oral solution is indicated for the treatment of cataplexy in
`
`narcolepsy.
`
`
`1.2 Excessive Daytime Sleepiness in Narcolepsy
`
`
`Xyrem (sodium oxybate) oral solution is indicated for the treatment of excessive daytime
`
`
`sleepiness (EDS) in narcolepsy.
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`
`
`Healthcare professionals who prescribe Xyrem must enroll in the Xyrem REMS Program
`
`
`and must comply with the requirements to ensure safe use of Xyrem [see Warnings and
`
`
`Precautions (5.3)].
`
`
`
`
`2.1 Dosing Information
`
`
`
`
`The recommended starting dose is 4.5 grams (g) per night administered orally in two equal,
`
`
`
`
`
`divided doses: 2.25 g at bedtime and 2.25 g taken 2.5 to 4 hours later (see Table 1). Increase the
`
`
`
`
`
`
`dose 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 dose 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.
`
`
`
`
`Reference ID: 4046630
`
`

`

`
`
`
`
` Table 1: Xyrem Dose Regimen (g = grams)
`
`If A Patient’s Total
`Take at
`Take 2.5 to 4
`
`
` Hours Later:
` Nightly Dose is:
`
` Bedtime:
`
`
`4.5 g per night
`
` 2.25 g
` 2.25 g
`
`
`
` 6 g per night
` 3 g
` 3 g
`
` 7.5 g per night
`
` 3.75 g
` 3.75 g
`
`
`
`
` 9 g per night
` 4.5 g
` 4.5 g
`
`
`
`
`
`
`
`
` 2.2 Important Administration Instructions
` Take the first dose of Xyrem at least 2 hours after eating because food significantly reduces
`
` the bioavailability of sodium oxybate.
`
`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
`
`
`
`
`
`
`
` vials 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.
`
`
`
`
`
`
`
`
` 2.3 Dose Modification in Patients with Hepatic Impairment
`
` The recommended starting dose in patients with hepatic impairment is 2.25 g per night
`
` administered orally in two equal, divided doses: approximately 1.13 g at bedtime and
`
`
` approximately 1.13 g taken 2.5 to 4 hours later [see Use in Specific Populations (8.6); Clinical
`
`
`
` Pharmacology (12.3)].
`
`
`
`
` 2.4 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.
`
`
`
`
`
`
` 4 CONTRAINDICATIONS
`
` Xyrem is contraindicated in patients being treated with sedative hypnotic agents.
`
`
`
` Patients should not drink alcohol when using Xyrem.
`
`
`
` Xyrem is contraindicated in patients with succinic semialdehyde dehydrogenase
`
`
`
` deficiency. This is a rare disorder of inborn error of metabolism variably characterized
`
`
` by mental retardation, hypotonia, and ataxia.
`
`
`
`
`
`
`Reference ID: 4046630
`
`

`

`
`
`
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
` 5.1 Central Nervous System Depression
`
`
`
`
`
` Xyrem is a central nervous system (CNS) depressant. 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
`
`taking the second nightly dose of Xyrem. Patients should be queried about CNS
`
`depression-related events upon initiation of Xyrem therapy and periodically thereafter [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 Warnings and
`
`
`
`Precautions (5.3) and Drug Abuse and Dependence (9.2)].
`
`
`
`
`
`
`
`5.3 Xyrem REMS Program
`
`
`
`Because of the risks of central nervous system depression and abuse/misuse, Xyrem is
`available only through a restricted distribution program called the Xyrem REMS Program.
`
`
`Required components of the Xyrem REMS Program include:
`
`
`
`  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)].
`
`
`
`Reference ID: 4046630
`
`

`

`
`
`
`
`
`In a 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 a 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. Prescribers should be aware that increased central apneas and
`
`
`clinically relevant desaturation events have been observed with Xyrem administration.
`
`In 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 polysomnographic (PSG) measures in 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 clinical trials in patients with narcolepsy (n=781), there were two suicides and two
`attempted suicides in Xyrem-treated patients, 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 Xyrem-treated patients, with four patients (< 1%) discontinuing
`
`because of depression. In most cases, no change in Xyrem treatment was required.
`
`In a controlled 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
`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.
`
`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 clinical trials in 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 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
`
`
`
`Reference ID: 4046630
`
`

`

`
`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 clinical trials in narcolepsy, confusion resolved either soon after
`
` termination of dosing or with continued treatment. However, patients treated with Xyrem who
`
`
`become confused should be evaluated fully, and appropriate intervention considered on an
`individual basis.
`
`
`
`Anxiety occurred in 5.8% of the 874 patients receiving Xyrem in clinical trials in another
`population. The emergence of or increase in anxiety in patients taking Xyrem should be
`
`carefully monitored.
`
`Other neuropsychiatric reactions reported in Xyrem clinical trials and the post-marketing
`
`
`setting included hallucinations, paranoia, psychosis, aggression, and agitation. The emergence of
`
`thought disorders and/or behavior abnormalities requires careful and immediate evaluation.
`
`
`
`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 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 have been reported 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 2 provides the approximate sodium content per Xyrem dose.
`
`Table 2
`
`
`Approximate Sodium Content per Total Nightly
`
`Dose of Xyrem (g = grams)
`
`
`
`
`
` Xyrem Dose
`
`
`
`Sodium Content/Total
`
` Nightly Exposure
`
`
`
` 3 g per night
`
`
`
` 4.5 g per night
`
`
`
` 6 g per night
`
`
`
` 7.5 g per night
`
`
`
` 9 g per night
`
`
`
` 550 mg
`
`
`
` 820 mg
`
`
`
` 1100 mg
`
`
`
` 1400 mg
`
`
`
` 1640 mg
`
`
`
`
`
`
`
`
`Reference ID: 4046630
`
`

`

`
`
`6 ADVERSE REACTIONS
`
`
`The following 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)]
`
`
`
`
`
`
`
`
`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.
`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 3 presents adverse reactions from three pooled, controlled trials (N1,
`
`N3, N4) in patients with narcolepsy.
`
`
`Adverse Reactions Leading to Treatment Discontinuation:
`
`
`
`
`Of the 398 Xyrem-treated patients with narcolepsy, 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 Xyrem-treated patients were nausea, dizziness, vomiting, somnolence, enuresis, and tremor.
`
`
`Adverse Reactions Occurring at an Incidence of 2% or greater:
`
`Table 3 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: 4046630
`
`

`

`
`
`
`
`Table 3
`
`
`Adverse Reactions Occurring in 2% of 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/MedDRA
` Preferred Term
`
`
`
`
` Placebo
` (n=213) %
`
`
`
`
`
` 62
`
`
`
` Xyrem 4.5g
`
` (n=185) %
`
`
`
` 45
`
`
`
` 3
`
`
`
` 1
`
`
`
` 2
`
`
`
` 2
`
` 2
`
`
`
` 8
`
`
`
` 2
`
`
`
` 4
`
`
`
` 3
`
`
`
` 1
`
`
`
` Xyrem 6g
`
`
` (n=258) %
`
`
`
` Xyrem 9g
`
` (n=178) %
`
`
`
`
` 55
`
`
`
` 13
`
`
`
` 4
`
`
`
` 3
`
`
`
` 1
`
`
`
` 2
`
`
`
` 70
`
`
`
` 20
`
`
`
` 11
`
`
`
` 4
`
`
`
` 2
`
`
`
` 1
`
` ANY ADVERSE REACTION
`
`
`
`
`
`
`
`
`
` GASTROINTESTINAL DISORDERS
`
` Nausea
`
`
`
`
`
` Vomiting
`
`
`
` Diarrhea
`
`
`
` Abdominal pain upper
`
`
`
`
`
` Dry mouth
`
`
`
`
`
`
`
` GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS
`
`
`
`
` Pain
` 1
` 1
`
`
`
`
`
`
`
`
`
`
`
`
`
` Feeling drunk
`
`
`
` Edema peripheral
`
`
`
` 1
`
`
`
` 1
`
` MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
`
`
`
`
`
`
`
`
`
`
`
`
`
` Pain in extremity
`
`
`
`
`
` Cataplexy
`
` Muscle spasms
`
`
`
` 1
`
`
`
` 1
`
`
`
` 2
`
`
`
`
`
` 0
`
`
`
` 3
`
`
`
` 3
`
`
`
` 1
`
`
`
` 2
`
`
`
` <1
`
`
`
` <1
`
`
`
` 0
`
`
`
` 1
`
`
`
` 1
`
`
`
` <1
`
`
`
` 3
`
`
`
` 3
`
`
`
` 0
`
`
`
` 1
`
`
`
` 2
`
`
`
` 2
`
`
`
`
`
`
`
` NERVOUS SYSTEM DISORDERS
`
`
`
`
`
`
`
`
`
` Dizziness
`
`
`
` Somnolence
`
`
`
` Tremor
`
`
`
` Paresthesia
`
`
`
`
`
` Disturbance in attention
`
`
`
`
`
` Sleep paralysis
`
`
`
`
`
`
`
`
`
` 4
`
`
`
` 4
`
`
`
` 0
`
`
`
` 1
`
`
`
` 0
`
`
`
` 1
`
`
`
` 9
`
`
`
` 1
`
`
`
` 0
`
`
`
` 2
`
`
`
` 1
`
`
`
` 0
`
`
`
` 11
`
`
`
` 3
`
`
`
` 2
`
`
`
` 1
`
`
`
` 0
`
`
`
` 1
`
`
`
` 15
`
`
`
` 8
`
`
`
` 5
`
`
`
` 3
`
`
`
` 4
`
`
`
` 3
`
` PSYCHIATRIC DISORDERS
`
` Disorientation
`
`
`
` Anxiety
`
`
`
` Irritability
`
`
`
`
`
` Sleep walking
`
` RENAL AND URINARY DISORDERS
`
`
`
`
`
`
`
`
`
`
`
` 1
`
`
`
` 1
`
`
`
` 1
`
`
`
` 0
`
`
`
` 1
`
`
`
`
`
` 1
`
`
`
` 1
`
`
`
` 0
`
`
`
` 0
`
`
`
` 3
`
`
`
` 1
`
`
`
` 2
`
`
`
` 1
`
`
`
` <1
`
`
`
` 0
`
`
`
` 3
`
`
`
` 1
`
`
`
` 3
`
`
`
` 2
`
`
`
` 3
`
`
`
` 3
`
`
`
` 7
`
`
`
` 3
`
`
`
` Enuresis
`
` SKIN AND SUBCUTANEOUS TISSUE DISORDERS
`
`
`
` Hyperhidrosis
` 0
`
`
`
`
`
`
` 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.
`
`
`
`6.2 Postmarketing Experience
`
`
`
`The following additional adverse reactions that have a likely causal relationship to Xyrem
`
`exposure have been identified during postmarketing use of Xyrem. These adverse reactions
`
`
`
`Reference ID: 4046630
`
`

`

`
`include: arthralgia, decreased appetite, fall, fluid retention, hangover, headache, hypersensitivity,
`
`hypertension, memory impairment, nocturia, panic attack, vision blurred, and weight decreased.
`
`
`
`Because these reactions are reported voluntarily, it is not always possible to reliably estimate
`
`their frequency.
`
`
`
`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.
`
`
`
`
`
`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 (2.4) 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
`
`
`Pregnancy Category C
`
`
`
`There are no adequate and well-controlled studies in pregnant women. Xyrem should be used
`
`during pregnancy only if the potential benefit justifies the potential risk to the fetus. Oral
`
`administration of sodium oxybate to pregnant rats (150, 350, 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. The highest doses tested in rats and rabbits were approximately 1 and 3
`
`times, respectively, the maximum recommended human dose (MRHD) of 9 g per night on a
`body surface area (mg/m2) basis.
`
`Oral administration of sodium oxybate (150, 350, or 1,000 mg/kg/day) to rats throughout
`
`
`pregnancy and lactation resulted in increased stillbirths and decreased offspring postnatal
`
`viability and body weight gain at the highest dose tested. The no-effect dose for pre- and post­
`
`
`
`natal developmental toxicity in rats is less than the MRHD on a mg/m2 basis.
`
`
`
`
`8.2 Labor and 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, but umbilical vein levels of
`sodium oxybate were no more than 25% of the maternal concentration. No sodium oxybate was
`detected in the infant’s blood 30 minutes after delivery. Elimination curves of sodium oxybate
`between a 2-day-old infant and a 15-year-old patient were similar. Subsequent effects of sodium
`oxybate on later growth, development, and maturation in humans are unknown.
`
`
`
`
`Reference ID: 4046630
`
`

`

`
`
`
`
`
`8.3 Nursing Mothers
`
`
`It is not known whether s