Drug Safety-related Labeling Changes (SrLC)

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XYREM (NDA-021196)

(SODIUM OXYBATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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02/11/2021 (SUPPL-35)

5 Warnings and Precautions

5.1 Central Nervous System Depression

(Additions and/or revisions underlined)

XYWAV is a central nervous system (CNS) depressant. Clinically significant respiratory depression and obtundation has occurred in adult patients taking sodium oxybate (same active moiety as XYWAV) at recommended doses in clinical trials and may occur in patients treated with XYWAV at recommended doses. XYWAV is contraindicated in combination with alcohol and sedative hypnotics. The concurrent use of XYWAV with other CNS depressants, including but not limited to opioid analgesics, benzodiazepines, sedating antidepressants or antipsychotics, sedating anti-epileptic drugs, general anesthetics, muscle relaxants, and/or illicit CNS depressants, may increase the risk of respiratory depression, hypotension, profound sedation, syncope, and death.

If use of these CNS depressants in combination with XYWAV is required, dose reduction or discontinuation of one or more CNS depressants (including XYWAV) should be considered. In addition, if short-term use of an opioid (e.g., post- or perioperative) is required, interruption of treatment with XYWAV should be considered.

Healthcare providers should caution patients about operating hazardous machinery, including automobiles or airplanes, until they are reasonably certain that XYWAV does not affect them adversely (e.g., impair judgment, thinking, or motor skills). Patients should not engage in hazardous occupations or activities requiring complete mental alertness or motor coordination, such as operating machinery or a motor vehicle or flying an airplane, for at least 6 hours after taking XYWAV. Patients should be queried about CNS depression-related events upon initiation of XYWAV therapy and periodically thereafter.

XYWAV is available only through a restricted program under a REMS [see Warnings and Precautions (5.3)].

5.2 Abuse and Misuse

(Additions and/or revisions underlined)

XYWAV is a Schedule III controlled substance. The active moiety of XYWAV is oxybate, also known as gamma-hydroxybutyrate (GHB), a Schedule I controlled substance. Abuse of illicit GHB, either alone or in combination with other CNS depressants, is associated with CNS adverse reactions, including seizure, respiratory depression, decreases in the level of consciousness, coma, and death. The rapid onset of sedation, coupled with the amnestic features of GHB, particularly when combined with alcohol, has proven to be dangerous for the voluntary and involuntary user (e.g., assault victim). Because illicit use and abuse of GHB have been reported, healthcare providers should carefully evaluate patients for a history of drug abuse and follow them closely, particularly for signs of misuse or abuse of GHB (including but not limited to increase in size or frequency of dosing, drug-seeking behavior, feigned cataplexy) [see Drug Abuse and Dependence (9.2)]. If abuse is suspected, treatment with XYWAV should be discontinued.

XYWAV is available only through a restricted program under a REMS [see Warnings and Precautions (5.3)].

5.3 XYWAV and XYREM REMS

(Additions and/or revisions underlined)

XYWAV is available only through a restricted distribution program called the XYWAV and XYREM REMS because of the risks of central nervous system depression and abuse and misuse [see Warnings and Precautions (5.1, 5.2)].

Notable requirements of the XYWAV and XYREM REMS include the following:

• Healthcare Providers who prescribe XYWAV are specially certified

  • XYWAV will be dispensed only by the central pharmacy that is specially certified

  • XYWAV will be dispensed and shipped only to patients who are enrolled in the XYWAV and XYREM REMS with documentation of safe use.

5.4 Respiratory Depression and Sleep-Disordered Breathing

(Additions and/or revisions underlined)

XYWAV may impair respiratory drive, especially in patients with compromised respiratory function. In overdoses of oxybate and with illicit use of GHB, life-threatening respiratory depression has been reported [see Overdosage (10)].

Increased apnea and reduced oxygenation may occur with XYWAV administration in adult andpediatric patients. A significant increase in the number of central apneas and clinically significant oxygen desaturation may occur in patients with obstructive sleep apnea treated with XYWAV.

In a study assessing the respiratory-depressant effects of Xyrem (same active moiety as XYWAV) at doses up to 9 g per night in 21 adult patients with narcolepsy, no dose-related changes in oxygen saturation were demonstrated in the group as a whole. One of the four patients with preexisting, moderate-to­ -severe sleep apnea had significant worsening of the apnea/hypopnea index during treatment.

In a study assessing the effects of Xyrem 9 g per night in 50 adult patients with obstructive sleep apnea, Xyrem did not increase the severity of sleep-disordered breathing and did not adversely affect the average duration and severity of oxygen desaturation overall. However, there was a significant increase in the number of central apneas in patients taking Xyrem, and clinically significant oxygen desaturation (less than or equal to 55%) was measured in three patients (6%) after Xyrem administration, with one patient withdrawing from the study and two continuing after single brief instances of desaturation.

During polysomnographic evaluation (PSG), central sleep apnea and oxygen desaturation were observed in pediatric patients with narcolepsy treated with Xyrem.

Prescribers should be aware that increased central apneas and clinically relevant desaturation events have been observed with sodium oxybate administration in adult and pediatric patients.

In clinical trials of Xyrem in 128 adult patients with narcolepsy, two patients had profound CNS depression, which resolved after supportive respiratory intervention. Two other patients discontinued sodium oxybate because of severe difficulty breathing and an increase in obstructive sleep apnea. In two controlled trials assessing PSG measures in adult patients with narcolepsy, 40 of 477 patients were included with a baseline apnea/hypopnea index of 16 to 67 events per hour, indicative of mild to severe sleep-disordered breathing. None of the 40 patients had a clinically significant worsening of respiratory function, as measured by apnea/hypopnea index and pulse oximetry at doses of 4.5 g to 9 g per night.

5.5 Depression and Suicidality

(Additions and/or revisions underlined)

Depression, and suicidal ideation and behavior can occur in patients treated with XYWAV.

In Study 1, depression and depressed mood were reported in 3% and 4%, respectively, of patients treated with XYWAV. Two patients (1%) discontinued XYWAV because of depression, but in most cases, no change in XYWAV treatment was required.

In clinical trials of Xyrem (same active moiety as XYWAV) in adult patients with narcolepsy (n=781), there were two suicides and two attempted suicides in patients treated with Xyrem, including three patients with a previous history of depressive psychiatric disorder. Of the two suicides, one patient used Xyrem in conjunction with other drugs. Xyrem was not involved in the second suicide. Adverse reactions of depression were reported by 7% of 781 patients treated with Xyrem, with four patients (<1%) discontinuing because of depression. In most cases, no change in Xyrem treatment was required.

In a clinical trial with Xyrem in pediatric patients with narcolepsy (n=104), one patient experienced suicidal ideation and two patients reported depression while taking Xyrem.

5.6 Other Behavioral or Psychiatric Adverse Reactions

(Additions and/or revisions underlined)

Other behavioral and psychiatric adverse reactions can occur in patients taking XYWAV.

In Study 1, confusion occurred in 1% of patients treated with XYWAV and anxiety occurred in 5% of patients treated with XYWAV. One patient experienced visual hallucinations and confusion after ingesting approximately 9 grams of XYWAV. Other neuropsychiatric reactions reported in clinical trials of Xyrem (same active moiety as XYWAV) in adult patients with narcolepsy and in the postmarketing setting included hallucinations, paranoia, psychosis, aggression, and agitation.

In a pediatric clinical trial with Xyrem in patients with narcolepsy, neuropsychiatric reactions, including acute psychosis, confusion, and anxiety, were reported while taking Xyrem.

5.7 Parasomnias

(Additions and/or revisions underlined)

Parasomnias can occur in patients taking XYWAV.

In Study 1, parasomnias, including sleepwalking, were reported in 6% of patients treated with XYWAV. In a clinical trial of Xyrem (same active moiety as XYWAV) in adult patients with narcolepsy, five instances of sleepwalking with potential injury or significant injury were reported. Parasomnias, including sleepwalking, also have been reported in a pediatric clinical trial with sodium oxybate and in postmarketing experience with sodium oxybate.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive changes; please refer to label)

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during postapproval use of sodium oxybate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

Arthralgia, fall*, fluid retention, hangover, hypersensitivity, hypertension, memory impairment, nocturia, and vision blurred.

7 Drug Interactions

7.1 Alcohol, Sedative Hypnotics, and CNS Depressants

(Additions and/or revisions underlined)

XYWAV is contraindicated for use in combination with alcohol or sedative hypnotics. Use of other CNS depressants may potentiate the CNS-depressant effects of XYWAV [see Warnings and Precautions (5.1)].

7.2 Divalproex Sodium

(Additions and/or revisions underlined)

Concomitant use of sodium oxybate with divalproex sodium results in an increase in systemic exposure to GHB, which was shown to cause a greater impairment on some tests of attention and working memory in a clinical study [see Clinical Pharmacology (12.3)]. A similar increase in exposure is expected with concomitant use of XYWAV and divalproex sodium; therefore, an initial dose reduction of XYWAV is recommended when used concomitantly with divalproex sodium [see Dosage and Administration (2.6)]. Prescribers are advised to monitor patient response closely and adjust dose accordingly if concomitant use of XYWAV and divalproex sodium is warranted.

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

Risk Summary

There are no adequate data on the developmental risk associated with the use of XYWAV or sodium oxybate in pregnant women. Oral administration of sodium oxybate to pregnant rats (0, 150, 350, or 1,000 mg/kg/day) or rabbits (0, 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

XYWAV 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 pregnant rats (0, 150, 350, or 1,000 mg/kg/day) or rabbits (0, 300, 600, or 1,200 mg/kg/day) throughout organogenesis produced no clear evidence of developmental toxicity. The highest doses of sodium oxybate 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.

Additionally, oral administration of sodium oxybate (0, 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 Lactation

(Additions and/or revisions underlined)

Risk Summary

GHB is excreted in human milk after oral administration of sodium oxybate. There is insufficient information on the risk to a breastfed infant, and there is insufficient information on milk production in nursing mothers. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XYWAV and any potential adverse effects on the breastfed infant from XYWAV or from the underlying maternal condition.

8.4 Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of XYWAV for the treatment of cataplexy or excessive daytime sleepiness in pediatric patients (7 years of age and older) with narcolepsy have been established. XYWAV has not been studied in a pediatric clinical trial. Use of XYWAV in pediatric patients 7 years of age and older with narcolepsy is supported by evidence from an adequate and well-controlled study of sodium oxybate in pediatric patients 7 to 17 years of age, a study in adults showing a treatment effect of XYWAV similar to that observed with sodium oxybate, pharmacokinetic data of sodium oxybate from adult and pediatric patients, and pharmacokinetic data of XYWAV from healthy adult volunteers [see Adverse Reactions (6.1) and Clinical Studies (14.1, 14.2)].

In the pediatric clinical trial with sodium oxybate administration in patients with narcolepsy, serious adverse reactions of central sleep apnea and oxygen desaturation documented by polysomnography evaluation; depression; suicidal ideation; neuropsychiatric reactions including acute psychosis, confusion, and anxiety; and parasomnias, including sleepwalking, have been reported [see Warnings and Precautions (5.4, 5.5, 5.6, 5.7) and Adverse Reactions (6.1)].

Safety and effectiveness of XYWAV in pediatric patients below the age of 7 years have not been established.

8.5 Geriatric Use

(Additions and/or revisions underlined)

Clinical studies of XYWAV or Xyrem in patients with narcolepsy did not include sufficient numbers of subjects age 65 years and older to determine whether they respond differently from younger subjects.

In clinical studies of sodium oxybate in another population, 39 (5%) of 874 patients were 65 years or older. Discontinuations of treatment due to adverse reactions were increased in the elderly compared to younger adults (21% vs. 19%). Frequency of headaches was markedly increased in the elderly (39% vs. 19%). The most common adverse reactions were similar in both age categories. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Extensive changes; please refer to label)

09/25/2020 (SUPPL-32)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Depression and Suicidality

Additions and/or revisions underlined:

… In the pediatric clinical trial in patients with narcolepsy (n=104), one patient experienced suicidal ideation and two patients reported depression while taking Xyrem.

The emergence of depression in patients treated …

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Pediatric Patients (7 Years of Age and Older)

In the pediatric clinical trial (Trial N5), 104 patients aged 7 to 17 years (37 patients aged 7 to 11 years; 67 patients aged 12 to 17 years) with narcolepsy received Xyrem for up to one year. This study included an open-label safety continuation period in which eligible patients received Xyrem for up to an additional 2 years. The median and maximum exposure across the entire study were 371 and 987 days, respectively.

Adverse Reactions Leading to Treatment Discontinuation

In the pediatric clinical trial, 7 of 104 patients reported adverse reactions that led to withdrawal from the study (hallucination, tactile; suicidal ideation; weight decreased; sleep apnea syndrome; affect lability; anger, anxiety, depression; and headache).

Adverse Reactions in the Pediatric Clinical Trial

The most common adverse reactions (greater than or equal to 5%) were nausea (20%), enuresis (19%), vomiting (18%), headache (17%), weight decreased (13%), decreased appetite (9%), dizziness (8%), and

sleepwalking (6%).

8 Use in Specific Populations

8.4 Pediatric Use

 Additions and/or revisions underlined:

In the pediatric clinical trial with Xyrem administration in patients with narcolepsy, serious adverse reactions of central sleep apnea and oxygen desaturation documented by polysomnography evaluation; depression; suicidal ideation; neuropsychiatric reactions including acute psychosis, confusion, and anxiety; and parasomnias, including sleepwalking, have been reported [see Warnings and Precautions (5.4, 5.5, 5.6, 5.7) and Adverse Reactions (6.1)] …

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

What are the possible side effects of XYREM?

XYREM can cause serious side effects, including:

The most common side effects of XYREM in children include:

Addition of ‘sleepwalking’

07/21/2020 (SUPPL-33)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

Xyrem is contraindicated for use in:

• combination with sedative hypnotics [see Warnings and Precautions (5.1)].

• combination with alcohol [see Warnings and Precautions (5.1)].

• patients with succinic semialdehyde dehydrogenase deficiency [see Clinical Pharmacology (12.3)].

5 Warnings and Precautions

5.1 Central Nervous System Depression

(Additions and/or revisions underlined)

Xyrem is contraindicated in combination with alcohol and sedative hypnotics.

5.3 XYWAV and XYREM REMS

(Section title revised)

(Additions and/or revisions underlined)

Xyrem is available only through a restricted distribution program called the XYWAV and XYREM REMS because of the risks of central nervous system depression and abuse and misuse [see Warnings and Precautions (5.1, 5.2)].

Notable requirements of the XYWAV and XYREM REMS include the following:

• Healthcare Providers who prescribe Xyrem are specially certified

• Xyrem will be dispensed only by the central pharmacy that is specially certified

• Xyrem will be dispensed and shipped only to patients who are enrolled in the XYWAV and XYREM REMS with documentation of safe use

Further information is available at www.XYWAVXYREMREMS.com or 1-866-997-3688.

5.4 Respiratory Depression and Sleep-Disordered Breathing

(Additions and/or revisions underlined)

Prescribers should be aware that sleep-related breathing disorders tend to be more prevalent in obese patients, in men, in postmenopausal women not on hormone replacement therapy and among patients with narcolepsy.

5.7 Parasomnias

(Additions and/or revisions underlined)

It is unclear if some or all of the reported sleepwalking episodes correspond to true somnambulism, which is a parasomnia occurring during non-REM sleep, or to any other specific medical disorder. Five instances of sleepwalking with potential injury or significant injury were  reported during a clinical trial of Xyrem in patients with narcolepsy.

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

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.

*The sudden onset of sleep in patients taking sodium oxybate, including in a standing position or while rising from bed, has led to falls complicated by injuries, in some cases requiring hospitalization.

7 Drug Interactions

7.1 Alcohol, Sedative Hypnotics, and CNS Depressants

(Additions and/or revisions underlined)

Xyrem is contraindicated for use 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

(Additions and/or revisions underlined)

Concomitant use of Xyrem with divalproex sodium results in an increase in systemic exposure to GHB, which was shown to cause a greater impairment on some tests of attention and working memory in a clinical study [see Clinical Pharmacology (12.3)]. An initial dose reduction of Xyrem is recommended when used concomitantly with divalproex sodium [see Dosage and Administration (2.5)]. 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

8.6 Hepatic Impairment

(Additions and/or revisions underlined)

Because of an increase in exposure to Xyrem, the starting dose should be reduced by half in patients with hepatic impairment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

(Extensive changes; please refer to label)

Patient Counseling Information

(Additions and/or revisions underlined)

XYWAV and XYREM REMS

Xyrem is available only through a restricted program called the XYWAV and XYREM REMS [see Warnings and Precautions (5.3)]. Inform the patient and/or caregiver of the following notable requirements:

• Xyrem is dispensed only by the central pharmacy

• Xyrem will be dispensed and shipped only to patients enrolled in the XYWAV and XYREM REMS

  Sedation

• Inform patients and/or caregivers that the patient is likely to fall asleep quickly after taking Xyrem (often within 5 and usually within 15 minutes), but the time it takes to fall asleep can vary from night to night. The sudden onset of sleep, including in a standing position or while rising from bed, has led to falls complicated by injuries, in some cases requiring hospitalization [see Adverse Reactions (6.2)]. Instruct patients and/or caregivers that the patient should remain in bed following ingestion of the first and second nightly doses. Instruct patients and/or caregivers that the patient should not take their second nightly dose until 2.5 to 4 hours after the first dose [see Dosage and Administration (2.3)].

• Food Effects on Xyrem

  Inform patients and/or caregivers that the first nightly dose should be taken at least 2 hours after eating.

• Respiratory Depression and Sleep-Disordered Breathing

Inform patients that Xyrem may impair respiratory drive, especially in patients with compromised respiratory function, and may cause apnea [see Warnings and Precautions (5.4)].

10/26/2018 (SUPPL-30)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

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.  Many patients who received Xyrem during clinical trials in narcolepsy were receiving central nervous system stimulants.

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.

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.

5 Warnings and Precautions

5.1 Central Nervous System Depression

Additions and/or revisions underlined:

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 …

…Patients should not engage in hazardous occupations or activities requiring complete mental alertness or motor coordination, such as operating machinery or a motor vehicle or flying an airplane, for at least 6 hours after taking Xyrem. Patients should be queried about CNS depression-related events upon initiation of Xyrem therapy and periodically thereafter.

Xyrem is available only through a restricted program under a REMS.

5.2 Abuse and Misuse

Addition of the following to the end of the subsection:

Xyrem is available only through a restricted program under a REMS.

5.3 Xyrem REMS Program

Additions and/or revisions underlined:

… Notable requirements of the Xyrem REMS Program include the following: …

5.4 Respiratory Depression and Sleep-Disordered Breathing

Adult is inserted prior to study, clinical trials and trial throughout the subsection.

Addition (underlined) of the following:

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.

5.5 Depression and Suicidality

Adult is inserted prior to study, clinical trials and trial throughout the subsection.

Addition of the following:

…In the pediatric clinical trial in patients with narcolepsy (n=104), one patient experienced suicidal ideation while taking Xyrem …

5.6 Other Behavioral or Psychiatric Adverse Reactions

Additions underlined throughout subsection: adult clinical trials in patients with narcolepsy

Addition of the following at the end of the subsection:

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

Additions and/or revisions underlined:

Parasomnias, including sleepwalking, also have been reported in the pediatric clinical trial and in postmarketing experience with Xyrem.

6 Adverse Reactions

Additions and/or revisions underlined:

The following clinically significant adverse reactions …

6.1 Clinical Trials Experience

Addition of Adult Patients subheading above Xyrem was studied in three placebo-controlled …

Following 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 and Dose-Response Information, addition of the following:

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).

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

• Depression and Suicidality

• Other Behavioral or Psychiatric Adverse Reactions

• Parasomnias

The overall adverse reaction profile of Xyrem in the pediatric clinical trial was similar to that seen in the adult clinical trial program.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of Xyrem in the treatment of cataplexy or excessive daytime

sleepiness in pediatric patients (7 years of age and older) with narcolepsy have been established in a double-blind, placebo-controlled, randomized-withdrawal study.

In the pediatric clinical trial with Xyrem administration in patients with narcolepsy, serious adverse reactions of central sleep apnea and oxygen desaturation documented by polysomnography evaluation; suicidal ideation in one patient; neuropsychiatric reactions including acute psychosis, confusion, and anxiety; and parasomnias, including sleepwalking, have been reported.

Safety and effectiveness of Xyrem in pediatric patients below the age of 7 years have not been established.

Juvenile Animal Toxicity Data

In a study in which sodium oxybate (0, 100, 300, or 900 mg/kg/day) was orally administered to rats during the juvenile period of development (postnatal days 21 through 90), mortality was observed at the two highest doses tested. Deaths occurred during the first week of dosing and were associated with clinical signs (including decreased activity and respiratory rate) consistent with the pharmacological effects of the drug. Reduced body weight gain in males and females and delayed sexual maturation in males were observed at the highest dose tested. The no-effect dose for adverse effects in juvenile rats is associated with plasma exposures (AUC) less than that at the maximum recommended human dose (9 g/night).

8.6 Hepatic Impairment

Additions and/or revisions underlined:

Because of an increase in exposure to Xyrem, the starting dose should be reduced …

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Extensively changed; please refer to label for complete information.

PATIENT COUNSELING INFORMATION

Extensively changed; please refer to label for complete information.

Other

REMS materials updated; please refer to label for complete information.

11/16/2017 (SUPPL-28)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

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

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

Risk Summary

There are no adequate data on the developmental risk associated with the use of sodium oxybate in pregnant women…

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

…Placental transfer is rapid and gamma hydroxybutyrate (GHB) has been detected in newborns at delivery after intravenous administration of GHB to mothers…

 

Data

Animal Data

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…

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

Risk Summary

GHB is excreted in human milk after oral administration of sodium oxybate. There is insufficient information on the risk to a breastfed infant, and there is insufficient information on milk production in nursing mothers. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Xyrem and any potential adverse effects on the breastfed infant from Xyrem or from the underlying maternal condition.

01/26/2017 (SUPPL-27)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Other Behavioral or Psychiatric Adverse Reactions

(Additions and/or revisions are underlined)

Other neuropsychiatric reactions reported in Xyrem clinical trials and the post-marketing setting included hallucinations, paranoia, psychosis, aggression, and agitation.

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

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, nocturia, panic attack, vision blurred, and weight decreased.