Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Xyrem is a clear to slightly opalescent oral solution. Each prescription includes one bottle of Xyrem with attached press in bottle adaptor, an oral measuring device (plastic syringe), and a Medication Guide. The pharmacy provides two empty containers with child-resistant caps with each Xyrem shipment. Each amber bottle contains Xyrem oral solution at a concentration of 0.5 g per mL (0.5 g/mL of sodium oxybate equivalent to 0.413 g/mL of oxybate) and has a child-resistant cap. One 180 mL bottle NDC 68727-100-01 16.2 Storage Keep out of reach of children. Xyrem should be stored at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) (see USP Controlled Room Temperature). Dispense in tight containers. Solutions prepared following dilution should be consumed within 24 hours. 16.3 Handling and Disposal Xyrem is a Schedule III drug under the Controlled Substances Act. Xyrem should be handled according to state and federal regulations. It is safe to dispose of Xyrem down the sanitary sewer.; PACKAGE/LABEL PRINCIPAL DISPLAY PANEL bottle-label
- 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Xyrem is a clear to slightly opalescent oral solution. Each prescription includes one bottle of Xyrem with attached press in bottle adaptor, an oral measuring device (plastic syringe), and a Medication Guide. The pharmacy provides two empty containers with child-resistant caps with each Xyrem shipment. Each amber bottle contains Xyrem oral solution at a concentration of 0.5 g per mL (0.5 g/mL of sodium oxybate equivalent to 0.413 g/mL of oxybate) and has a child-resistant cap. One 180 mL bottle NDC 68727-100-01 16.2 Storage Keep out of reach of children. Xyrem should be stored at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) (see USP Controlled Room Temperature). Dispense in tight containers. Solutions prepared following dilution should be consumed within 24 hours. 16.3 Handling and Disposal Xyrem is a Schedule III drug under the Controlled Substances Act. Xyrem should be handled according to state and federal regulations. It is safe to dispose of Xyrem down the sanitary sewer.
- PACKAGE/LABEL PRINCIPAL DISPLAY PANEL bottle-label
Overview
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
Indications & 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 ).
Dosage & 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 ). 2.1 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 (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 2.2 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. 2.3 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 [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 Reactions ( 6.2 )] . 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. 2.4 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 [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )] . 2.5 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 [see Drug Interactions ( 7.2 ) and Clinical Pharmacology ( 12.3 )] . 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.
Warnings & Precautions
• CNS depression: Use caution when considering the concurrent use of Xyrem with other CNS depressants ( 5.1 ). • Caution patients against hazardous activities requiring complete mental alertness or motor coordination within the first 6 hours of dosing or after first initiating treatment until certain that Xyrem does not affect them adversely ( 5.1 ). • Depression and suicidality: Monitor patients for emergent or increased depression and suicidality ( 5.5 ). • Confusion/Anxiety: Monitor for impaired motor/cognitive function ( 5.6 ). • Parasomnias: Evaluate episodes of sleepwalking ( 5.7 ). • High sodium content in Xyrem: Monitor patients with heart failure, hypertension, or impaired renal function ( 5.8 ). 5.1 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 [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 Drug Abuse and Dependence ( 9.2 )]. Xyrem is available only through a restricted program under a REMS [see Warnings and Precautions ( 5.3 )] . 5.3 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 [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 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 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. 5.5 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. 5.6 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. 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 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. 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 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
Boxed Warning
CENTRAL NERVOUS SYSTEM DEPRESSION and ABUSE AND MISUSE. • 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 [see Warnings and Precautions ( 5.1 )]. Many patients who received Xyrem during clinical trials in narcolepsy were receiving central nervous system stimulants [see Clinical Trials ( 14 )]. • 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 [see Warnings and Precautions ( 5.2 )]. 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 XYWAV and XYREM REMS [see Warnings and Precautions ( 5.3 )]. WARNING: CENTRAL NERVOUS SYSTEM (CNS) DEPRESSION and ABUSE AND MISUSE. See full prescribing information for complete boxed warning. Central Nervous System Depression • Xyrem is a CNS depressant, and respiratory depression can occur with Xyrem use ( 5.1 , 5.4 ) Abuse and Misuse • Xyrem is the sodium salt of gamma-hydroxybutyrate (GHB). Abuse or misuse of illicit GHB is associated with CNS adverse reactions, including seizure, respiratory depression, decreased consciousness, coma, and death ( 5.2 , 9.2 ) Xyrem is available only through a restricted program called the XYWAV and XYREM REMS ( 5.3 )
Contraindications
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 )] . • In combination with sedative hypnotics or alcohol ( 4 ) • Succinic semialdehyde dehydrogenase deficiency ( 4 )
Adverse Reactions
The following clinically significant adverse reactions appear in other sections of the labeling: • CNS depression [see Warnings and Precautions ( 5.1 )] • Abuse and Misuse [see Warnings and Precautions ( 5.2 )] • Respiratory Depression and Sleep-Disordered Breathing [see Warnings and Precautions ( 5.4 )] • Depression and Suicidality [see Warnings and Precautions ( 5.5 )] • Other Behavioral or Psychiatric Adverse Reactions [see Warnings and Precautions ( 5.6 )] • Parasomnias [see Warnings and Precautions ( 5.7 )] • Use in Patients Sensitive to High Sodium Intake [see Warnings and Precautions ( 5.8 )] Most common adverse reactions in adults (≥5% and at least twice the incidence with placebo) were nausea, dizziness, vomiting, somnolence, enuresis, and tremor ( 6.1 ). Most common adverse reactions in pediatric patients (≥5%) were nausea, enuresis, vomiting, headache, weight decreased, decreased appetite, dizziness, and sleepwalking ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Jazz Pharmaceuticals, Inc. at 1-800-520-5568, or FDA at 1-800-FDA-1088 or www.fda.gov/Medwatch . 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. Adult Patients 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 4 present adverse reactions from three pooled, controlled trials (N1, N3, N4) in patients with narcolepsy. Adverse Reactions Leading to Treatment Discontinuation: Of the 398 patients with narcolepsy treated with Xyrem, 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 patients treated with Xyrem were nausea, dizziness, vomiting, somnolence, enuresis, and tremor. Adverse Reactions Occurring at an Incidence of 2% or Greater: Table 4 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. 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 Adverse Reaction Placebo (n=213) % Xyrem 4.5g (n=185) % Xyrem 6g (n=258) % Xyrem 9g (n=178) % ANY ADVERSE REACTION 62 45 55 70 GASTROINTESTINAL DISORDERS Nausea 3 8 13 20 Vomiting 1 2 4 11 Diarrhea 2 4 3 4 Abdominal pain upper 2 3 1 2 Dry mouth 2 1 2 1 GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS Pain 1 1 <1 3 Feeling drunk 1 0 <1 3 Edema peripheral 1 3 0 0 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Cataplexy 1 1 1 2 Muscle spasms 2 2 <1 2 Pain in extremity 1 3 1 1 NERVOUS SYSTEM DISORDERS Dizziness 4 9 11 15 Somnolence 4 1 3 8 Tremor 0 0 2 5 Disturbance in attention 0 1 0 4 Paresthesia 1 2 1 3 Sleep paralysis 1 0 1 3 PSYCHIATRIC DISORDERS Disorientation 1 1 2 3 Irritability 1 0 <1 3 Sleepwalking 0 0 0 3 Anxiety 1 1 1 2 RENAL AND URINARY DISORDERS Enuresis 1 3 3 7 SKIN AND SUBCUTANEOUS TISSUE DISORDERS Hyperhidrosis 0 1 1 3 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. 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 (≥5%) were nausea (20%), enuresis (19%), vomiting (18%), headache (17%), weight decreased (13%), decreased appetite (9%), dizziness (8%), and sleepwalking (6%). Additional information regarding safety in pediatric patients appears in the following sections: • 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 )] The overall adverse reaction profile of Xyrem in the pediatric clinical trial was similar to that seen in the adult clinical trial program. 6.2 Postmarketing Experience 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.
Drug Interactions
• Concomitant use with divalproex sodium: An initial reduction in Xyrem dose of at least 20% is recommended ( 2.5 , 7.2 ). 7.1 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 [see Warnings and Precautions ( 5.1 )] . 7.2 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 [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.
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