Xyrem sodium oxybate .5 g/mL Solution, 180 mL — NDC 68727-100-01 (Billing 68727-0100-01)

1 INDICATIONS AND USAGE Xyrem is indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy. Xyrem is a central nervous system depressant indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy ( 1 ).

2 DOSAGE AND ADMINISTRATION Dosage for Adult Patients • Initiate dosage at 4.5 g per night orally, divided into two doses ( 2.1 ). • Titrate to effect in increments of 1.5 g per night at weekly intervals (0.75 g at bedtime and 0.75 g taken 2.5 to 4 hours later) ( 2.1 ). • Recommended dosage range: 6 g to 9 g per night orally ( 2.1 ). Total Nightly Dose Take at Bedtime Take 2.5 to 4 Hours Later 4.5 g per night 2.25 g 2.25 g 6 g per night 3 g 3 g 7.5 g per night 3.75 g 3.75 g 9 g per night 4.5 g 4.5 g Dosage for Pediatric Patients (7 years of Age and Older) • The recommended starting dosage, titration regimen, and maximum total nightly dosage are based on body weight (2.2 ).

Important Administration Information • Prepare both doses prior to bedtime; dilute each dose with approximately ¼ cup of water in pharmacy-provided containers ( 2.3 ). • Allow 2 hours after eating before dosing ( 2.3 ). • Take each dose while in bed and lie down after dosing ( 2.3 ). Patients with Hepatic Impairment Recommended starting dosage is one-half of the original dosage per night administered orally, divided into two doses ( 2.4 ).

2.1Adult Dosing Information The recommended starting dosage is 4.5 grams (g) per night administered orally, divided into two doses: 2.25 g at bedtime and 2.25 g taken 2.5 to 4 hours later (see Table 1). Increase the dosage by 1.5 g per night at weekly intervals (additional 0.75 g at bedtime and 0.75 g taken 2.5 to 4 hours later) to the effective dosage range of 6 g to 9 g per night orally. 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

2.2Pediatric 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.

2.3Important 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 [see Clinical Pharmacology ( 12.3 )] . 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 [see Adverse… [Excerpted — this section continues on DailyMed.]

3 DOSAGE FORMS AND STRENGTHS Xyrem is a clear to slightly opalescent oral solution, in a concentration of 0.5 g per mL (0.5 g/mL of sodium oxybate equivalent to 0.413 g/mL of oxybate). Oral solution, 0.5 g per mL ( 3 )

17 PATIENT COUNSELING INFORMATION Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Central Nervous System Depression Inform patients and/or caregivers that Xyrem can cause central nervous system depression, including respiratory depression, hypotension, profound sedation, syncope, and death. Instruct patients to not engage in activities requiring mental alertness or motor coordination, including operating hazardous machinery, for at least 6 hours after taking Xyrem.

Instruct patients and/or their caregivers to inform their healthcare providers of all the medications they take [see Warnings and Precautions ( 5.1 )]. Abuse and Misuse Inform patients and/or caregivers that the active ingredient of Xyrem is gamma-hydroxybutyrate (GHB), which is associated with serious adverse reactions with illicit use and abuse [see Warnings and Precautions ( 5.2 )]. 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 Xyrem is available only from the central pharmacy participating in the program. Therefore, provide patients and/or caregivers with the telephone number and website for information on how to obtain the product. Alcohol or Sedative Hypnotics Advise patients and/or caregivers that alcohol and other sedative hypnotics should not be taken with Xyrem [see Contraindications ( 4 )] .

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 )] .

Depression and Suicidality Instruct patients and/or caregivers to contact a healthcare provider immediately if the patient develops depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, or suicidal ideation [see Warnings and Precautions ( 5.5 )] . Other Behavioral or Psychiatric Adverse Reactions Inform patients and/or caregivers that Xyrem can cause behavioral or psychiatric adverse reactions, including confusion, anxiety, and psychosis.

Instruct them to notify their healthcare provider if any of these types of symptoms occur [see Warnings and Precautions ( 5.6 )]. Sleepwalking Instruct patients and/or caregivers that Xyrem has been associated with sleepwalking and other behaviors during sleep, and to contact their healthcare provider if this occurs [see Warnings and Precautions ( 5.7 )] . Sodium Intake Instruct patients and/or caregivers that Xyrem contains a significant amount of sodium and patients who are sensitive to sodium intake (e.g., those with heart failure, hypertension, or renal impai… [Excerpted — this section continues on DailyMed.]

MEDICATION GUIDE XYREM ® (ZĪE-rem) (sodium oxybate) oral solution, CIII Read this Medication Guide carefully before you start or your child starts taking XYREM and each time you get or your child gets a refill. There may be new information. This information does not take the place of talking to your doctor about your or your child’s medical condition or treatment.

What is the most important information I should know about XYREM? • XYREM is a central nervous system (CNS) depressant. Taking XYREM with other CNS depressants such as medicines used to make you or your child fall asleep, including opioid analgesics, benzodiazepines, sedating antidepressants, antipsychotics, sedating anti-epileptic medicines, general anesthetics, muscle relaxants, alcohol, or street drugs, may cause serious medical problems, including: o trouble breathing (respiratory depression) o low blood pressure (hypotension) o changes in alertness (drowsiness) o fainting (syncope) o death Ask your doctor if you are not sure if you are, or your child is, taking a medicine listed above. • XYREM is a federal controlled substance (CIII).

The active ingredient of XYREM is a form of gamma-hydroxybutyrate (GHB) that is also a federal controlled substance (CI). Abuse of illegal GHB, either alone or with other CNS depressants may cause serious medical problems, including: o seizure o trouble breathing (respiratory depression) o changes in alertness (drowsiness) o coma o death Call your doctor right away if you have or your child has any of these serious side effects. • Anyone who takes XYREM should not do anything that requires them to be fully awake or is dangerous, including driving a car, using heavy machinery, or flying an airplane, for at least 6 hours after taking XYREM.

Those activities should not be done until you know how XYREM affects you or your child. • Keep XYREM in a safe place to prevent abuse and misuse. Selling or giving away XYREM may harm others, and is against the law. Tell your doctor if you have ever abused or been dependent on alcohol, prescription medicines, or street drugs. • Because of the risk of CNS depression, abuse, and misuse, XYREM is available only by prescription, and filled through the central pharmacy in the XYWAV and XYREM REMS.

You or your child must be enrolled in the XYWAV and XYREM REMS to receive XYREM. For information on how to receive XYREM visit www.XYWAVXYREMREMS.COM . Before you receive or your child receives XYREM, your doctor or pharmacist will make sure that you understand how to take XYREM safely and effectively.

If you have any questions about XYREM, ask your doctor or call the XYWAV and XYREM REMS at 1-866-997-3688. What is XYREM? XYREM is a prescription medicine used to treat the following symptoms in people 7 years of age or older with narcolepsy: • sudden onset of weak or paralyzed muscles (cataplexy), or • excessive daytime sleepiness (EDS) It is not known if XYREM is safe and effective in children less than 7 years of age.

Do not take XYREM if you or your child: • takes other sleep medicines or sedatives (medicines that cause sleepiness) • drinks alcohol • has a rare problem called succinic semialdehyde dehydrogenase deficiency Before taking XYREM, tell your doctor about all medical conditions, including if you or your child: • have a history of drug abuse. • have short periods of not breathing while sleeping (sleep apnea) • has trouble breathing or has lung problems. You or your child may have a higher chance of having serious breathing problems when taking XYREM. • have or had depression or has tried to harm yourself or themselves.

You or your child should be watched carefully for new symptoms of depression. • has or had behavior or other psychiatric problems such as: o anxiety o feeling more suspicious (paranoia) o acting aggressive o seeing or hearing things that are not real (hallucinations) o being out of touch with reality (psychosis) o agitation • have liver problems • are on a salt-restricted diet. XYREM… [Excerpted — this section continues on DailyMed.]

Instructions for Use XYREM ® (ZĪE-rem) (sodium oxybate) oral solution, CIII Read this Instructions for Use carefully before you (or your child) start taking XYREM and each time you (or your child) get a refill. There may be new information. This information does not take the place of talking to your doctor about your (or your child’s) medical condition or treatment.

Important Information: • You will need to split your (or your child’s) prescribed XYREM dose into 2 separate pharmacy containers for mixing. • You will need to mix XYREM with water before you take or give your child the dose. • Safely store the prepared XYREM doses and take within 24 hours after mixing. If the prepared dose was not taken within this time, throw the mixture away. See “Throwing away (disposing of) XYREM” section below for instructions about how to safely throw away XYREM. • Both XYREM doses should be taken while in bed. • The pharmacy containers may be rinsed out with water and emptied into the sink drain.

Supplies you will need for mixing and taking (or giving your child) XYREM. See Figure A: • Bottle of XYREM medicine • Dosing syringe for measuring and dispensing the XYREM dose • Measuring cup that is able to measure about ¼ cup of water (not provided with the XYREM shipment) • 2 empty pharmacy containers with child-resistant caps for mixing, storing, and taking the XYREM doses • Alarm clock (not pictured which may be included in the first shipment) • Medication Guide Figure A Step 1: Setup • Take the XYREM bottle, syringe, and pharmacy containers out of the shipping box. • Take the syringe out of the plastic wrapper.

Use only the syringe provided with the XYREM prescription. • Fill a measuring cup (not provided) with about ¼ cup of water available for mixing your dose. • Make sure the pharmacy containers are empty. • Open both pharmacy containers by holding the tab under the cap and turning counterclockwise (to the left). See Figure B. Figure B Remove the tamper evident band by pulling at the perforations and then remove the bottle cap from the XYREM bottle by pushing down while turning the cap counterclockwise.

See Figure C. Figure C Step 2. Prepare the first XYREM dose (prepare before bedtime) Place the XYREM bottle on a hard, flat surface and grip the bottle with one hand and firmly press the syringe into the center opening of the bottle with the other hand.

See Figure D. Figure D Pull back on the plunger until the medicine flows into the syringe and the liquid level is lined up with the marking on the syringe that matches you or your child’s dose. See Figure E.

Figure E Note: The XYREM medicine will not flow into the syringe unless you keep the bottle upright. Figure F shows an example of drawing up a XYREM dose of 2.25 g. Figure G shows an example if an air space forms when drawing up the dose.

Figure F Figure G Note: If an air space forms between the plunger and the liquid when drawing up the medicine, line up the liquid level with the marking on the syringe that matches your or your child’s dose. See Figure G above. • After you draw up the first divided XYREM dose, remove the syringe from the opening of the XYREM bottle. • Empty all of the medicine from the syringe into one of the provided empty pharmacy containers by pushing down on the plunger until it stops. See Figure H.

Figure H • Using a measuring cup, pour about ¼ cup of water into the pharmacy container. Be careful to add only water to the pharmacy container and not more XYREM. • All shipped bottles of XYREM contain the concentrated medicine. Water for mixing the medicine is not provided in the shipment. • After mixing the medicine and water in the provided pharmacy container, place the child-resistant cap on the filled pharmacy container and turn the cap clockwise (to the right) until it clicks and locks into its child-resistant position.

See Figure I. • Caution: the pharmacy container cap is reversible with a non-child resistant side. See Figure J. Make sure the child-resistant si… [Excerpted — this section continues on DailyMed.]