Sodium oxybate, a CNS depressant, is the active ingredient in Xyrem. The chemical name for sodium oxybate is sodium 4-hydroxybutyrate. The molecular formula is C 4 H 7 NaO 3 , and the molecular weight is 126.09 g/mole. The chemical structure is: Sodium oxybate is a white to off-white, crystalline powder that is very soluble in aqueous solutions. Each mL of Xyrem contains 0.5 g of sodium oxybate (equivalent to 0.413 g/mL of oxybate) in USP Purified Water, neutralized to pH 7.5 with malic acid. chemical structure

Xyrem is indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy. Xyrem is a central nervous system depressant indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy.

Xyrem is a clear to slightly opalescent oral solution, in a concentration of 0.5 g per mL (0.5 g/mL of sodium oxybate equivalent to 0.413 g/mL of oxybate). Oral solution, 0.5 g per mL

Dosage for Adult Patients • Initiate dosage at 4.5 g per night orally, divided into two doses. • 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). • Recommended dosage range: 6 g to 9 g per night orally. Total Nightly Dose Take at Bedtime Take 2.5 to 4 Hours Later 4.5 g per night 2.25 g 2.25 g 6 g per night 3 g 3 g 7.5 g per night 3.75 g 3.75 g 9 g per night 4.5 g 4.5 g Dosage for Pediatric Patients (7 years of Age and Older) • The recommended starting dosage, titration regimen, and maximum total nightly dosage are based on body weight (2.2 ). Important Administration Information • Prepare both doses prior to bedtime; dilute each dose with approximately ¼ cup of water in pharmacy-provided containers. • Allow 2 hours after eating before dosing. • Take each dose while in bed and lie down after dosing. Patients with Hepatic Impairment Recommended starting dosage is one-half of the original dosage per night administered orally, divided into two doses

Adult Dosing Information The recommended starting dosage is 4.5 grams (g) per night administered orally, divided into two doses: 2.25 g at bedtime and 2.25 g taken 2.5 to 4 hours later . Increase the dosage by 1.5 g per night at weekly intervals (additional 0.75 g at bedtime and 0.75 g taken 2.5 to 4 hours later) to the effective dosage range of 6 g to 9 g per night orally. The dosage may be gradually titrated based on efficacy and tolerability. Doses higher than 9 g per night have not been studied and should not ordinarily be administered. Table 1: Recommended Adult Xyrem Dose Regimen (g = grams) If a Patient’s Total Nightly Dose is: 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 2.2 Pediatric Dosing Information Xyrem is administered orally twice nightly. The recommended starting pediatric dosage, titration regimen, and maximum total nightly dosage are based on patient weight, as specified in Table 2. The dosage may be gradually titrated based on efficacy and tolerability. Table 2: Recommended Pediatric Xyrem Dosage for Patients 7 Years of Age and Older* Patient Weight Initial Dosage Maximum Weekly Dosage Increase Maximum Recommended Dosage Take at Bedtime: Take 2.5 to 4 Hours Later: Take at Bedtime: Take 2.5 to 4 Hours Later: Take at Bedtime: Take 2.5 to 4 Hours Later: <20 kg** There is insufficient information to provide specific dosing recommendations for patients who weigh less than 20 kg. 20 kg to <30 kg ≤1 g ≤1 g 0.5 g 0.5 g 3 g 3 g 30 kg to <45 kg ≤1.5 g ≤1.5 g 0.5 g 0.5 g 3.75 g 3.75 g ≥45 kg ≤2.25 g ≤2.25 g 0.75 g 0.75 g 4.5 g 4.5 g * For patients who sleep more than 8 hours per night, the first dose of Xyrem may be given at bedtime or after an initial period of sleep. ** If Xyrem is used in patients 7 years of age and older who weigh less than 20 kg, a lower starting dosage, lower maximum weekly dosage increases, and lower total maximum nightly dosage should be considered. Note: Some patients may achieve better responses with unequal doses at bedtime and 2.5 to 4 hours later

Important Administration Instructions for All Patients The total nightly dosage of Xyrem is divided into two doses. Prepare both doses of Xyrem prior to bedtime. Prior to ingestion, each dose of Xyrem should be diluted with approximately ¼ cup (approximately 60 mL) of water in the empty pharmacy containers provided. Take the first nightly dose of Xyrem at least 2 hours after eating . Take the second nightly dose 2.5 to 4 hours after the first dose. Patients should take both doses of Xyrem while in bed and lie down immediately after dosing, and remain in bed following ingestion of each dose. Xyrem may cause patients to fall asleep abruptly without first feeling drowsy . Patients will often fall asleep within 5 minutes of taking Xyrem, and will usually fall asleep within 15 minutes, though the time it takes any individual patient to fall asleep may vary from night to night. Patients may need to set an alarm to awaken for the second dose. Rarely, patients may take up to 2 hours to fall asleep. If the second dose is missed, that dose should be skipped and Xyrem should not be taken again until the next night. Both Xyrem doses should never be taken at one time

Dosage Modification in Patients with Hepatic Impairment The recommended starting dosage in patients with hepatic impairment is one-half of the original dosage per night, administered orally divided into two doses

Dosage Adjustment with Co-administration of Divalproex Sodium When initiating divalproex sodium in patients taking a stable dosage of Xyrem, a reduction of the Xyrem dosage by at least 20% is recommended with initial concomitant use . When initiating Xyrem in patients already taking divalproex sodium, a lower starting dosage of Xyrem is recommended. Subsequently, the dosage of Xyrem can be adjusted based on individual clinical response and tolerability.

• CNS depression: Use caution when considering the concurrent use of Xyrem with other CNS depressants. • 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. • Depression and suicidality: Monitor patients for emergent or increased depression and suicidality. • Confusion/Anxiety: Monitor for impaired motor/cognitive function. • Parasomnias: Evaluate episodes of sleepwalking. • High sodium content in Xyrem: Monitor patients with heart failure, hypertension, or impaired renal function

Central Nervous System Depression Xyrem is a central nervous system (CNS) depressant. In adult clinical trials at recommended doses, obtundation and clinically significant respiratory depression occurred in patients treated with Xyrem. Xyrem is contraindicated in combination with alcohol and sedative hypnotics. The concurrent use of Xyrem with other CNS depressants, including but not limited to opioid analgesics, benzodiazepines, sedating antidepressants or antipsychotics, sedating anti-epileptic drugs, general anesthetics, muscle relaxants, and/or illicit CNS depressants, may increase the risk of respiratory depression, hypotension, profound sedation, syncope, and death. If use of these CNS depressants in combination with Xyrem is required, dose reduction or discontinuation of one or more CNS depressants (including Xyrem) should be considered. In addition, if short-term use of an opioid (e.g., post- or perioperative) is required, interruption of treatment with Xyrem should be considered. Healthcare providers should caution patients about operating hazardous machinery, including automobiles or airplanes, until they are reasonably certain that Xyrem does not affect them adversely (e.g., impair judgment, thinking, or motor skills). Patients should not engage in hazardous occupations or activities requiring complete mental alertness or motor coordination, such as operating machinery or a motor vehicle or flying an airplane, for at least 6 hours after taking Xyrem. Patients should be queried about CNS depression‐related events upon initiation of Xyrem therapy and periodically thereafter. Xyrem is available only through a restricted program under a REMS

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

XYWAV and XYREM REMS Xyrem is available only through a restricted distribution program called the XYWAV and XYREM REMS because of the risks of central nervous system depression and abuse and misuse . 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

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 . In an adult study assessing the respiratory-depressant effects of Xyrem at doses up to 9 g per night in 21 patients with narcolepsy, no dose-related changes in oxygen saturation were demonstrated in the group as a whole. One of the four patients with preexisting, moderate-to-severe sleep apnea had significant worsening of the apnea/hypopnea index during treatment. In an adult study assessing the effects of Xyrem 9 g per night in 50 patients with obstructive sleep apnea, Xyrem did not increase the severity of sleep-disordered breathing and did not adversely affect the average duration and severity of oxygen desaturation overall. However, there was a significant increase in the number of central apneas in patients taking Xyrem, and clinically significant oxygen desaturation (≤55%) was measured in three patients (6%) after Xyrem administration, with one patient withdrawing from the study and two continuing after single brief instances of desaturation. During polysomnographic evaluation (PSG), central sleep apnea and oxygen desaturation were observed in pediatric patients with narcolepsy treated with Xyrem. Prescribers should be aware that increased central apneas and clinically relevant desaturation events have been observed with Xyrem administration in adult and pediatric patients. In adult clinical trials in 128 patients with narcolepsy, two subjects had profound CNS depression, which resolved after supportive respiratory intervention. Two other patients discontinued sodium oxybate because of severe difficulty breathing and an increase in obstructive sleep apnea. In two controlled trials assessing PSG measures in adult patients with narcolepsy, 40 of 477 patients were included with a baseline apnea/hypopnea index of 16 to 67 events per hour, indicative of mild to severe sleep-disordered breathing. None of the 40 patients had a clinically significant worsening of respiratory function as measured by apnea/hypopnea index and pulse oximetry at doses of 4.5 g to 9 g per night. Prescribers should be aware that sleep-related breathing disorders tend to be more prevalent in obese patients, in men, in postmenopausal women not on hormone replacement therapy and among patients with narcolepsy

Depression and Suicidality In adult clinical trials in patients with narcolepsy (n=781), there were two suicides and two attempted suicides in patients treated with Xyrem, including three patients with a previous history of depressive psychiatric disorder. Of the two suicides, one patient used Xyrem in conjunction with other drugs. Xyrem was not involved in the second suicide. Adverse reactions of depression were reported by 7% of 781 patients treated with Xyrem, with four patients (<1%) discontinuing because of depression. In most cases, no change in Xyrem treatment was required. In a controlled adult trial, with patients randomized to fixed doses of 3 g, 6 g, or 9 g per night Xyrem or placebo, there was a single event of depression at the 3 g per night dose. In another adult controlled trial, with patients titrated from an initial 4.5 g per night starting dose, the incidences of depression were 1 (1.7%), 1 (1.5%), 2 (3.2%), and 2 (3.6%) for the placebo, 4.5 g, 6 g, and 9 g per night doses, respectively. In the pediatric clinical trial in patients with narcolepsy (n=104), one patient experienced suicidal ideation and two patients reported depression while taking Xyrem. The emergence of depression in patients treated with Xyrem requires careful and immediate evaluation. Patients with a previous history of a depressive illness and/or suicide attempt should be monitored carefully for the emergence of depressive symptoms while taking Xyrem

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

Parasomnias Sleepwalking, defined as confused behavior occurring at night and at times associated with wandering, was reported in 6% of 781 patients with narcolepsy treated with Xyrem in adult controlled trials and long-term open-label studies, with <1% of patients discontinuing due to sleepwalking. Rates of sleepwalking were similar for patients taking placebo and patients taking Xyrem in controlled trials. It is unclear if some or all of the reported sleepwalking episodes correspond to true somnambulism, which is a parasomnia occurring during non-REM sleep, or to any other specific medical disorder. Five instances of sleepwalking with potential injury or significant injury were reported during a clinical trial of Xyrem in patients with narcolepsy. Parasomnias, including sleepwalking, also have been reported in the pediatric clinical trial and in postmarketing experience with Xyrem. Therefore, episodes of sleepwalking should be fully evaluated and appropriate interventions considered

Use in Patients Sensitive to High Sodium Intake Xyrem has a high salt content. In patients sensitive to salt intake (e.g., those with heart failure, hypertension, or renal impairment), consider the amount of daily sodium intake in each dose of Xyrem. Table 3 provides the approximate sodium content per Xyrem dose. Table 3 Approximate Sodium Content per Total Nightly Dose of Xyrem (g = grams) Xyrem Dose Sodium Content/Total Nightly Exposure 3 g per night 550 mg 4.5 g per night 820 mg 6 g per night 1100 mg 7.5 g per night 1400 mg 9 g per night 1640 mg

• Concomitant use with divalproex sodium: An initial reduction in Xyrem dose of at least 20% is recommended

Alcohol, Sedative Hypnotics, and CNS Depressants 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

Divalproex Sodium 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 . An initial dose reduction of Xyrem is recommended when used concomitantly with divalproex sodium . Prescribers are advised to monitor patient response closely and adjust dose accordingly if concomitant use of Xyrem and divalproex sodium is warranted.