`
`
`
`
`
`
`
`
`
` CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
` Approval Package for:
`
`APPLICATION NUMBER:
`
`
`
` 021196Orig1s013
`
`
`
`
`
`
`
`
`
` Trade Name:
`
`
`
` Generic or
`
`
`
` Established:
`
`
`
` Sponsor:
`
`
`
`
`
` Approval Date:
`
`
`
`
`
`
` Xyrem
`
` Sodium Oxybate
`
`
`
`
`
`
`
` Jazz Pharmaceuticals
`
`
` December 17, 2012
`
`
`
`
`

`

`
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` CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
` 021196Orig1s013
`
`
`
` CONTENTS
`
`
` Reviews / Information Included in this NDA Review.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Approval Letter
`
`
` Other Action Letters
` Labeling
`
`
` REMS
` Summary Review
`
`
` Officer/Employee List
`
` Office Director Memo
`
` Cross Discipline Team Leader Review
`
` Medical Review(s)
` Chemistry Review(s)
`
`
` Environmental Assessment
`
` Pharm/Tox Review(s)
`
`
` Statistical Review(s)
` Microbiology Review(s)
`
` Clinical Pharm/Bio Review(s)
`
` Other Review(s)
` Risk Assessment and Risk Mitigation Review(s)
`
` Proprietary Name Review(s)
` Administrative/Correspondence Document(s)
`
`
`
`
`
`
`
` X
`
`
`
` X
`
`
`
`
`
`
`
`
` X
`
`
`
`
`
`
`
`
`
` X
`
`
`
`
`

`

`
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`
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`
`
` CENTER FOR DRUG EVALUATION AND
`
` RESEARCH
`
`
`
`
`
`
` APPLICATION NUMBER:
`
`
` 021196Orig1s013
`
`
`
`APPROVAL LETTER
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
` NDA 021196/S-013
`
`
`
`
`
`
`
`
`
`Food and Drug Administration
`
`Silver Spring MD 20993
`
`
`SUPPLEMENT APPROVAL
`
`
`Jazz Pharmaceuticals
`Attention: Jennifer Ekelund
`Executive Director, Regulatory Affairs
`
`3481 Porter Drive
`Palo Alto, CA 94304
`
`
`Dear Ms. Ekelund:
`
`We refer to your new drug application submitted under section 505(b) of the Federal Food, Drug,
`and Cosmetic Act for Xyrem (Sodium Oxybate) 500 mg/ml oral solution.
`
`Please refer to your Supplemental New Drug Application (sNDA) dated August 13, 2007,
`received August 15, 2007, submitted under section 505(b) of the Federal Food, Drug, and
`Cosmetic Act (FDCA) for Xyrem (Sodium Oxybate) 500 mg/ml oral solution.
`
`We acknowledge receipt of your amendments dated February 3, 2011, April 24, 2012, and
`October 3, 2012.
`
`This “Prior Approval” supplemental new drug application provides for compliance with the final
`rule, “Requirements on Content and Format of Labeling for Human Prescription Drug and
`Biological Products.”
`
`We have completed our review of this supplemental application, as amended and it is approved,
`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`text.
`
`
`CONTENT OF LABELING
`
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert, text for the
`patient package insert, Medication Guide), with the addition of any labeling changes in pending
`“Changes Being Effected” (CBE) supplements, as well as annual reportable changes not
`included in the enclosed labeling.
`
`
`Reference ID: 3231956
`
`

`

`
`Information on submitting SPL files using eLIST may be found in the guidance for industry
`
`titled “SPL Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible from publicly available labeling repositories.
`
`Also within 14 days, amend all pending supplemental applications for this NDA, including CBE
`supplements for which FDA has not yet issued an action letter, with the content of labeling
`[21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the changes approved in this
`supplemental application, as well as annual reportable changes and annotate each change. To
`facilitate review of your submission, provide a highlighted or marked-up copy that shows all
`changes, as well as a clean Microsoft Word version. The marked-up copy should provide
`appropriate annotations, including supplement number(s) and annual report date(s).
`
`All promotional materials that include representations about your drug product must be promptly
`revised to be consistent with the labeling changes approved in this supplement, including any
`new safety information [21 CFR 314.70(a)(4)]. The revisions in your promotional materials
`should include prominent disclosure of the important new safety information that appears in the
`revised package labeling. Within 7 days of receipt of this letter, submit your statement of intent
`to comply with 21 CFR 314.70(a)(4) to the address above or by fax to 301-847-8444.
`
`REPORTING REQUIREMENTS
`
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`If you have any questions, call Susan Daugherty, Regulatory Project Manager, at
`(301) 796-0878.
`
`
`
`ENCLOSURE(S):
`Content of Labeling
`Medication Guide
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3231956
`
`Sincerely,
`
`{See appended electronic signature page}
`
`
`Russell Katz, MD
`Director
`
`Division of Neurology Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`
`
`
`
`
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RUSSELL G KATZ
`12/17/2012
`
`Reference ID: 3231956
`
`

`

`
`
`
` CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
`
`
`
` APPLICATION NUMBER:
`
`
`
`021196Orig1s013
`
`
`
` LABELING
`
`
`
`
`
`
`

`

`
` 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).
`
`--------------------DOSAGE FORMS AND STRENGTHS-------------------
`WARNING: CENTRAL NERVOUS SYSTEM (CNS) DEPRESSION Oral solution, 0.5 g per mL (3)
`
`
`and MISUSE AND ABUSE.
`
`
`
`----------------------------CONTRAINDICATIONS----------------------------­
`See full prescribing information for complete boxed warning.
`
`
`
` Succinic semialdehyde dehydrogenase deficiency (4).
`
`
`
`
`
` In combination with sedative hypnotics or alcohol (4).
`
`• Respiratory depression can occur with Xyrem use (5.4)
`• Xyrem is a Schedule III controlled substance and is the sodium salt of
`
`
`
`---------------------WARNINGS AND PRECAUTIONS----------------------
`gamma hydroxybutyrate (GHB), a Schedule I controlled substance.
`
`
`
` CNS depression: Use caution when considering the concurrent use of
`
`Abuse or misuse of illicit GHB is associated with CNS adverse reactions, Xyrem with other CNS depressants (5.1).
`
`
`
`
`including seizure, respiratory depression, decreased consciousness,
`
`
` Caution patients against hazardous activities requiring complete mental
`
`coma and death (5.2, 9.2)
`
`
`
`
`alertness or motor coordination within the first 6 hours of dosing or after
`• Because of the risks of CNS depression, abuse, and misuse, Xyrem is
`
`
`first initiating treatment until certain that Xyrem does not affect them
`available only through a restricted distribution program called the
`adversely (5.1).
`Xyrem Success Program® using a centralized pharmacy. Prescribers
`
` Depression and suicidality: Monitor patients for emergent or increased
`
`and patients must enroll in the program. (5.3)
`depression and suicidality (5.4).
`
`
` Confusion/Anxiety: Monitor for impaired motor/cognitive function (5.5).
`
`
`
`
`
` Parasomnias: evaluate episodes of sleepwalking (5.7).
`
`
`
`
` High sodium content in Xyrem: Monitor patients with heart failure,
`
`
`
`
`hypertension, or impaired renal function (5.7).
`-----------------------------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 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: 12/2012
`
`6
`
`7
`8
`
`9
`
`10
`
`11
`
`ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2
`Postmarketing Experience
`
`DRUG INTERACTIONS
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`
`Labor and Delivery
`8.2
`8.3
`Nursing Mothers
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`8.6
`Hepatic Impairment
`DRUG ABUSE AND DEPENDENCE
`9.1
`Controlled Substance Class
`9.2
`Abuse
`9.3
`Dependence
`
`OVERDOSAGE
`10.1 Human Experience
`
`
`10.2 Signs and Symptoms
`
`10.3 Recommended Treatment of Overdose
`10.4 Poison Control Center
`
`
`DESCRIPTION
`
`
`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
`
`
`
`
`
`
`---------------------RECENT MAJOR CHANGES--------------------
`Contraindications, concomitant use with alcohol (4) -------------2/2012
`----------------------------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
`
`Success 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
`9 g per night
`4.5 g
`4.5 g
`
` Take each dose while in bed and lie down after dosing (2.2).
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: CENTRAL NERVOUS SYSTEM (CNS)
`DEPRESSION and MISUSE AND ABUSE
`1
`INDICATIONS AND USAGE
`
`Cataplexy in Narcolepsy
`1.1
`Excessive Daytime Sleepiness in Narcolepsy
`1.2
`
`DOSAGE AND ADMINISTRATION
`Dosing Information
`2.1
`2.2
`Important Administration Instructions
`
`2.3
`Dose Modification in Patients with Hepatic Impairment
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`
`Central Nervous System Depression
`5.1
`5.2 Abuse and Misuse
`
`
`Xyrem Success Program
`5.3
`
`Respiratory Depression and Sleep-Disordered Breathing
`5.4
`Depression and Suicidality
`5.5
`5.6
`Other Behavioral or Psychiatric Adverse Reactions
`5.7
`Parasomnias
`
`5.8
`Use in Patients Sensitive to High Sodium Intake
`
`2
`
`3
`4
`5
`
`
`Reference ID: 3231956
`
`
`
`­
`

`

`16
`
`HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage
`
`16.3 Handling and Disposal
`PATIENT COUNSELING INFORMATION
`
`
`17
`
`
`*Sections or subsections omitted from the full prescribing
`information are not listed
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`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 Success Program®, using a centralized
`pharmacy. Prescribers and patients must enroll in the program. For further information
`
` go to www.XYREM.com or call 1-866-XYREM88® (1-866-997-3688). [see Warnings and
`Precautions (5.3)].
`
`
`
`INDICATIONS AND USAGE
` 1
`
`Limitations of Use
` Xyrem may only be dispensed to patients enrolled in the Xyrem Success 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 [see Clinical Studies (14.1)].
`
`
` 1.2 Excessive Daytime Sleepiness in Narcolepsy
`Xyrem (sodium oxybate) oral solution is indicated for the treatment of excessive daytime
`
` sleepiness (EDS) in narcolepsy [see Clinical Studies (14.2)].
`
`
` 2 DOSAGE AND ADMINISTRATION
`Healthcare professionals who prescribe Xyrem must enroll in the Xyrem Success
`
`Program and must comply with the requirements to ensure safe use of Xyrem [see Warnings and
`
`Precautions (5.3)].
`
`
`
`
`
`
`12
`
`13
`
`14
`
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`12.3 Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`CLINICAL STUDIES
`
`
`14.1 Cataplexy in Narcolepsy
`
`14.2 Excessive Daytime Sleepiness in Narcolepsy
`
`
`Reference ID: 3231956
`
`
`
`

`

`
`
` NDA 021196/S-013
`Page 2
`
` 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.
`
`
`Table 1: Xyrem Dose Regimen (g = grams)
`If A Patient’s Total
`Take at
`Take 2.5 to 4
`Nightly Dose is:
`Bedtime:
`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
`
`
`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 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. Rarely, patients may take up to 2 hours to fall asleep. Therefore, patients should
`remain in bed following ingestion of the first dose, and should not take the second dose until 2.5
`to 4 hours later. Patients may need to set an alarm to awaken for the second dose.
`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)].
`
`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.
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`Reference ID: 3231956
`
`

`

`
`
` NDA 021196/S-013
`Page 3
`
` 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, 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); Drug Abuse and Dependence (9.2)].
`5.3 Xyrem Success 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 Success Program.
`Required components of the Xyrem Success Program are:
` Use of a centralized pharmacy
`
`
` Healthcare Providers who prescribe Xyrem must complete the enrollment forms and
`
`
`comply with the requirements.
` To receive Xyrem, patients must understand the risks and benefits of Xyrem.
`
`
`Further information is available at www.XYREM.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 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
`
`
`Reference ID: 3231956
`
`

`

`
` NDA 021196/S-013
`
`
`
`Page 4
`
`
`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 night dose,
`there was a single event of confusion in one patient at the 9 g per night dose. In the majority of
`
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`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 included hallucinations,
`paranoia, psychosis, 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
`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
`
`
`ADVERSE REACTIONS
`6
`
`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)]
`
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`
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` 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.
`
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`Reference ID: 3231956
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`

`
`
`
`
`
`
`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
`
`
`Placebo
`
`(n=213) %
`62
`
`Xyrem 4.5g
`
`(n=185) %
`45
`
`System Organ Class /MedDRA
`
`Preferred Term
`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
`
`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
`
`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
`
`
`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.
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`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
`include: arthralgia, decreased appetite, fall, fluid retention, hangover, headache, hypersensitivity,
`hypertension, memory impairment, 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
`
`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.
`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