Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied LUMRYZ is a blend of white to off-white granules for extended-release oral suspension in water. LUMRYZ is supplied in cartons and a 28-day starter pack. Cartons : each carton contains either 7 or 30 packets of LUMRYZ, a mixing cup, Prescribing Information and Medication Guide, and Instructions for Use (see Table 8). Dose packets contain a single dose of LUMRYZ provided in 4.5 g, 6 g, 7.5 g, or 9 g doses. Table 8: LUMRYZ Carton Configurations Strength Package Size NDC Number 4.5 g 7 packets NDC 13551-001-07 30 packets NDC 13551-001-30 6 g 7 packets NDC 13551-002-07 30 packets NDC 13551-002-30 7.5 g 7 packets NDC 13551-003-07 30 packets NDC 13551-003-30 9 g 7 packets NDC 13551-004-07 30 packets NDC 13551-004-30 28-day Starter Pack : contains four 7-count cartons, each containing a mixing cup, Prescribing Information and Medication Guide, and Instructions for Use (see Table 9). Dose packets contain a single dose of LUMRYZ provided in 4.5 g, 6 g, or 7.5 g doses. Table 9: LUMRYZ Starter Pack Contents 28-day Starter Pack Strength Package Size NDC Number Week 1 4.5 g 7 packets NDC 13551-005-01 Week 2 6 g 7 packets Week 3 6 g 7 packets Week 4 7.5 g 7 packets 16.2 Storage Keep out of reach of children. LUMRYZ should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) (see USP Controlled Room Temperature). Suspensions should be consumed within 30 minutes. 16.3 Handling and Disposal LUMRYZ is a Schedule III drug under the Controlled Substances Act. LUMRYZ should be handled according to state and federal regulations. It is safe to dispose of LUMRYZ down the sanitary sewer.; PRINCIPAL DISPLAY PANEL - NDC: 13551-001-01 - 4.5 g Packet Label image description; PRINCIPAL DISPLAY PANEL - NDC: 13551-001-07 - 4.5 g 7-count Carton Label image description; PRINCIPAL DISPLAY PANEL - NDC: 13551-001-30 - 4.5 g 30-count Carton Label image description; PRINCIPAL DISPLAY PANEL - NDC: 13551-002-01 - 6 g Packet Label image description; PRINCIPAL DISPLAY PANEL - NDC: 13551-002-07 - 6 g 7-count Carton Label image description; PRINCIPAL DISPLAY PANEL - NDC: 13551-002-30 - 6 g 30-count Carton Label image description; PRINCIPAL DISPLAY PANEL - NDC: 13551-003-01 - 7.5 g Packet Label image description; PRINCIPAL DISPLAY PANEL - NDC: 13551-003-07 - 7.5 g 7-count Carton Label image description; PRINCIPAL DISPLAY PANEL - NDC: 13551-003-30 - 7.5 g 30-count Carton Label image description; PRINCIPAL DISPLAY PANEL - NDC: 13551-004-01 - 9 g Packet Label image description; PRINCIPAL DISPLAY PANEL - NDC: 13551-004-07 - 9 g 7-count Carton Label image description; PRINCIPAL DISPLAY PANEL - NDC: 13551-004-30 - 9 g 30-count Carton Label image description; Principal Display Panel - NDC: 13551-005-01 - Starter Pack Outer Carton Label image description image description
- 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied LUMRYZ is a blend of white to off-white granules for extended-release oral suspension in water. LUMRYZ is supplied in cartons and a 28-day starter pack. Cartons : each carton contains either 7 or 30 packets of LUMRYZ, a mixing cup, Prescribing Information and Medication Guide, and Instructions for Use (see Table 8). Dose packets contain a single dose of LUMRYZ provided in 4.5 g, 6 g, 7.5 g, or 9 g doses. Table 8: LUMRYZ Carton Configurations Strength Package Size NDC Number 4.5 g 7 packets NDC 13551-001-07 30 packets NDC 13551-001-30 6 g 7 packets NDC 13551-002-07 30 packets NDC 13551-002-30 7.5 g 7 packets NDC 13551-003-07 30 packets NDC 13551-003-30 9 g 7 packets NDC 13551-004-07 30 packets NDC 13551-004-30 28-day Starter Pack : contains four 7-count cartons, each containing a mixing cup, Prescribing Information and Medication Guide, and Instructions for Use (see Table 9). Dose packets contain a single dose of LUMRYZ provided in 4.5 g, 6 g, or 7.5 g doses. Table 9: LUMRYZ Starter Pack Contents 28-day Starter Pack Strength Package Size NDC Number Week 1 4.5 g 7 packets NDC 13551-005-01 Week 2 6 g 7 packets Week 3 6 g 7 packets Week 4 7.5 g 7 packets 16.2 Storage Keep out of reach of children. LUMRYZ should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) (see USP Controlled Room Temperature). Suspensions should be consumed within 30 minutes. 16.3 Handling and Disposal LUMRYZ is a Schedule III drug under the Controlled Substances Act. LUMRYZ should be handled according to state and federal regulations. It is safe to dispose of LUMRYZ down the sanitary sewer.
- PRINCIPAL DISPLAY PANEL - NDC: 13551-001-01 - 4.5 g Packet Label image description
- PRINCIPAL DISPLAY PANEL - NDC: 13551-001-07 - 4.5 g 7-count Carton Label image description
- PRINCIPAL DISPLAY PANEL - NDC: 13551-001-30 - 4.5 g 30-count Carton Label image description
- PRINCIPAL DISPLAY PANEL - NDC: 13551-002-01 - 6 g Packet Label image description
- PRINCIPAL DISPLAY PANEL - NDC: 13551-002-07 - 6 g 7-count Carton Label image description
- PRINCIPAL DISPLAY PANEL - NDC: 13551-002-30 - 6 g 30-count Carton Label image description
- PRINCIPAL DISPLAY PANEL - NDC: 13551-003-01 - 7.5 g Packet Label image description
- PRINCIPAL DISPLAY PANEL - NDC: 13551-003-07 - 7.5 g 7-count Carton Label image description
- PRINCIPAL DISPLAY PANEL - NDC: 13551-003-30 - 7.5 g 30-count Carton Label image description
- PRINCIPAL DISPLAY PANEL - NDC: 13551-004-01 - 9 g Packet Label image description
- PRINCIPAL DISPLAY PANEL - NDC: 13551-004-07 - 9 g 7-count Carton Label image description
- PRINCIPAL DISPLAY PANEL - NDC: 13551-004-30 - 9 g 30-count Carton Label image description
- Principal Display Panel - NDC: 13551-005-01 - Starter Pack Outer Carton Label image description image description
Overview
Sodium oxybate, a CNS depressant, is the active ingredient in LUMRYZ for extended-release oral suspension. 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 solid powder. Each packet of LUMRYZ contains 4.5 g, 6 g, 7.5 g, or 9 g of sodium oxybate, equivalent to 3.7 g, 5.0 g, 6.2 g, or 7.4 g of oxybate, respectively. The inactive ingredients are carrageenan, hydrogenated vegetable oil, hydroxyethyl cellulose, magnesium stearate, malic acid, methacrylic acid copolymer, microcrystalline cellulose, povidone, and xanthan gum. image description
Indications & Usage
LUMRYZ is indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy. LUMRYZ 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
Dosing for Adults: • Initiate dosage at 4.5 g once per night orally ( 2.1 ). • Titrate to effect in increments of 1.5 g per night at weekly intervals ( 2.1 ). • Recommended dosage range: 6 g to 9 g once per night orally ( 2.1 ). Dosing 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 ) • Pediatric patients 7 years and older weighing at least 45 kg : The recommended starting dosage is 4.5 g once per night. Increase the dosage by 1.5 g per night at weekly intervals to the maximum recommended dosage of 9 g once per night orally. The dosage may be gradually titrated based on efficacy and tolerability ( 2.2 ). • Pediatric patients 7 years and older weighing less than 45 kg : Because the recommended starting dosage cannot be achieved with the available strengths of LUMRYZ, use another sodium oxybate product to initiate treatment ( 2.2 ). Important Administration Information • Prepare the dose of LUMRYZ prior to bedtime; suspend dose in approximately ⅓ cup of water (with or without calorie-free drink mix or flavored water enhancer) in the mixing cup provided ( 2.3 ). • Allow 2 hours after eating before dosing ( 2.3 ). • Take LUMRYZ while in bed and lie down after dosing ( 2.3 ). 2.1 Adult Dosing Information The recommended starting dosage of LUMRYZ in adults is 4.5 grams (g) once per night administered orally. Increase the dosage by 1.5 g per night at weekly intervals to the recommended dosage range of 6 g to 9 g once 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. 2.2 Pediatric Dosing Information The recommended starting pediatric dosage, titration regimen, and maximum total nightly dosage are based on patient weight. Pediatric Patients 7 years and Older Weighing at least 45 kg The recommended starting dosage of LUMRYZ in pediatric patients 7 years and older weighing at least 45 kg is 4.5 g once per night administered orally. Increase the dosage by 1.5 g per night at weekly intervals to the maximum recommended dosage of 9 g once per night orally. The dosage may be gradually titrated based on efficacy and tolerability. Pediatric Patients 7 years and Older Weighing Less than 45 kg Because the recommended starting dosage in pediatric patients 7 years and older weighing less than 45 kg cannot be achieved with the available strengths of LUMRYZ, use another sodium oxybate product to initiate treatment. Refer to the Prescribing Information of other sodium oxybate products for the recommended dosage for those products. The maximum recommended dosage for patients 7 years and older weighing 20 kg to <30 kg is 6 g once per night orally, and the maximum recommended dosage for patients 7 years and older weighing 30 kg to <45 kg is 7.5 g once per night orally [ see Dosage and Administration ( 2.4 ) ]. There is insufficient information to provide specific dosing recommendations for patients 7 years and older who weigh less than 20 kg. 2.3 Important Administration Instructions LUMRYZ is taken orally as a single dose at bedtime. Prepare the dose of LUMRYZ prior to bedtime. Prior to ingestion, the dose of LUMRYZ should be suspended in approximately 1/3 cup (approximately 80 mL) of water (with or without calorie-free drink mix or flavored water enhancer) in the mixing cup provided [see Instructions for Use ] . Do not use hot water [see Clinical Pharmacology (12.3) ] . After mixing, consume LUMRYZ within 30 minutes. Take LUMRYZ at least 2 hours after eating [see Clinical Pharmacology (12.3) ]. Patients should take LUMRYZ while in bed and lie down immediately after dosing as LUMRYZ may cause them to fall asleep abruptly without first feeling drowsy. Patients will often fall asleep within 5 minutes of taking LUMRYZ, 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 should remain in bed following ingestion of LUMRYZ. 2.4 Switching Patients from Immediate-Release Sodium Oxybate Patients who are currently being treated with immediate-release sodium oxybate may be switched to LUMRYZ at the nearest equivalent dosage in grams per night (e.g., 7.5 g sodium oxybate divided into two 3.75 g doses per night to 7.5 g LUMRYZ once per night).
Warnings & Precautions
• CNS depression: Use caution when considering the concurrent use of LUMRYZ 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 LUMRYZ 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 LUMRYZ: Monitor patients with heart failure, hypertension, or impaired renal function ( 5.8 ). 5.1 Central Nervous System Depression LUMRYZ is a central nervous system (CNS) depressant. Clinically significant respiratory depression and obtundation has occurred in patients treated with immediate-release sodium oxybate at recommended doses in clinical trials and may occur in patients treated with LUMRYZ at recommended doses. LUMRYZ is contraindicated in combination with alcohol and sedative hypnotics. The concurrent use of LUMRYZ with other CNS depressants, including but not limited to opioid analgesics, benzodiazepines, sedating antidepressants or antipsychotics, sedating antiepileptic 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 LUMRYZ is required, dose reduction or discontinuation of one or more CNS depressants (including LUMRYZ) should be considered. In addition, if short-term use of an opioid (e.g., post- or perioperative) is required, interruption of treatment with LUMRYZ should be considered. In addition to coadministration of LUMRYZ and alcohol being contraindicated because of respiratory depression, consumption of alcohol while taking LUMRYZ may also result in a more rapid release of the dose of sodium oxybate [see Clinical Pharmacology (12.3) ] . Healthcare providers should caution patients about operating hazardous machinery, including automobiles or airplanes, until they are reasonably certain that LUMRYZ 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 LUMRYZ. Patients should be queried about CNS depression-related events upon initiation of LUMRYZ therapy and periodically thereafter. LUMRYZ is available only through a restricted program under a REMS [see Warnings and Precautions (5.3) ]. 5.2 Abuse and Misuse LUMRYZ is a Schedule III controlled substance. The active ingredient of LUMRYZ, sodium oxybate, is the sodium salt of 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, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of GHB (e.g., increase in size or frequency of dosing, drug-seeking behavior, feigned cataplexy) [see Warnings and Precautions (5.3) and Drug Abuse and Dependence (9.2) ]. LUMRYZ is available only through a restricted program under a REMS [see Warnings and Precautions (5.3) ]. 5.3 LUMRYZ REMS LUMRYZ is available only through a restricted distribution program called the LUMRYZ 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 LUMRYZ REMS include the following: ● Healthcare providers who prescribe LUMRYZ are specially certified. ● LUMRYZ will be dispensed only by pharmacies that are specially certified. ● LUMRYZ will be dispensed and shipped only to patients who are enrolled in the LUMRYZ REMS with documentation of safe use conditions. Further information is available at www.LUMRYZREMS.com or by calling 1-877-453-1029. 5.4 Respiratory Depression and Sleep-Disordered Breathing LUMRYZ 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 LUMRYZ administration. A significant increase in the number of central apneas and clinically significant oxygen desaturation may occur in patients with obstructive sleep apnea treated with LUMRYZ. During polysomnographic evaluation (PSG), central sleep apnea and oxygen desaturation were observed in pediatric patients with narcolepsy treated with immediate-release sodium oxybate. In adult clinical trials of LUMRYZ in patients with narcolepsy, no subjects with apnea/hypopnea indexes greater than 15 were allowed to enroll. In an adult study assessing the respiratory-depressant effects of immediate-release sodium oxybate 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 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 immediate-release sodium oxybate 9 g per night in 50 patients with obstructive sleep apnea, immediate-release sodium oxybate 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 immediate-release sodium oxybate, and clinically significant oxygen desaturation (≤55%) was measured in three patients (6%) after administration, with one patient withdrawing from the study and two continuing after single brief instances of desaturation. In adult clinical trials in 128 patients with narcolepsy administered immediate-release sodium oxybate, two subjects had profound CNS depression, which resolved after supportive respiratory intervention. Two other patients discontinued immediate-release sodium oxybate because of severe difficulty breathing and an increase in obstructive sleep apnea. In two controlled trials assessing polysomnographic (PSG) measures in adult patients with narcolepsy administered immediate-release sodium oxybate, 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. Increased central apneas and clinically relevant desaturation events have been observed with immediate-release sodium oxybate administration in adult and pediatric patients. 5.5 Depression and Suicidality Depression, and suicidal ideation and behavior, can occur in patients treated with LUMRYZ. In an adult clinical trial in patients with narcolepsy administered LUMRYZ [see Adverse Reactions (6.1) ] , there were no suicide attempts, but one patient developed suicidal ideation at the 9 g dose. In adult clinical trials in patients with narcolepsy (n=781) administered immediate-release sodium oxybate, there were two suicides and two attempted suicides in patients treated with immediate-release sodium oxybate, including three patients with a previous history of depressive psychiatric disorder. Of the two suicides, one patient used immediate-release sodium oxybate in conjunction with other drugs. Immediate-release sodium oxybate was not involved in the second suicide. Adverse reactions of depression were reported by 7% of 781 patients treated with immediate-release sodium oxybate, with four patients (<1%) discontinuing because of depression. In most cases, no change in immediate-release sodium oxybate treatment was required. In a controlled trial in adults with narcolepsy administered LUMRYZ where patients were titrated from 4.5 g to 9 g per night, the incidences of depression were 0% at 4.5 g, 1% at 6 g, 1.1% at 7.5 g, and 1.3% at 9 g. In a controlled adult trial, with patients randomized to fixed doses of 3 g, 6 g, or 9 g per night immediate-release sodium oxybate 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 of immediate-release sodium oxybate, the incidences of depression were 1.7%, 1.5%, 3.2%, and 3.6% for the placebo, 4.5 g, 6 g, and 9 g per night doses, respectively. In a clinical trial in pediatric patients with narcolepsy (n=104) administered immediate-release sodium oxybate, one patient experienced suicidal ideation and two patients reported depression while taking immediate-release sodium oxybate. The emergence of depression in patients treated with LUMRYZ 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 LUMRYZ. 5.6 Other Behavioral or Psychiatric Adverse Reactions Other behavioral and psychiatric adverse reactions can occur in patients taking LUMRYZ. During adult clinical trials in patients with narcolepsy administered LUMRYZ, 2% of 107 patients treated with LUMRYZ experienced a confusional state. During adult clinical trials in patients with narcolepsy administered immediate-release sodium oxybate, 3% of 781 patients treated with immediate-release sodium oxybate experienced confusion, with incidence generally increasing with dose. No patients treated with LUMRYZ discontinued treatment because of confusion. Less than 1% of patients discontinued the immediate-release sodium oxybate because of confusion. Confusion was reported at all recommended doses of immediate-release sodium oxybate from 6 g to 9 g per night. In a controlled trial in adults where patients were randomized to immediate-release sodium oxybate in 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 that controlled trial, the confusion resolved in all cases soon after termination of treatment. In one trial where immediate-release 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 administered immediate-release sodium oxybate, confusion resolved either soon after termination of dosing or with continued treatment. Anxiety occurred in 7.5% of 107 patients treated with LUMRYZ in the adult trial in patients with narcolepsy. Anxiety occurred in 5.8% of the 874 patients receiving immediate-release sodium oxybate in adult clinical trials in another population. Other psychiatric reactions reported in adult clinical trials in patients with narcolepsy administered LUMRYZ included irritability, emotional disorder, panic attack, agitation, delirium, and obsessive thoughts. Other neuropsychiatric reactions reported in adult clinical trials in patients with narcolepsy administered immediate-release sodium oxybate and in the postmarketing setting for immediate-release sodium oxybate include hallucinations, paranoia, psychosis, aggression, and agitation. In a clinical trial in pediatric patients with narcolepsy administered immediate-release sodium oxybate, neuropsychiatric reactions, including acute psychosis, confusion, and anxiety were reported while taking immediate-release sodium oxybate. The emergence or increase in the occurrence of behavioral or psychiatric events in patients taking LUMRYZ should be carefully monitored. 5.7 Parasomnias Parasomnias can occur in patients taking LUMRYZ. Sleepwalking, defined as confused behavior occurring at night and at times associated with wandering, was reported in 3% of 107 adult patients with narcolepsy treated with LUMRYZ. No patients treated with LUMRYZ discontinued due to sleepwalking. Sleepwalking was reported in 6% of 781 patients with narcolepsy treated with immediate-release sodium oxybate in adult controlled and long-term open-label studies, with <1% of patients discontinuing due to sleepwalking. In controlled trials, rates of sleepwalking were similar for patients taking placebo and patients taking immediate-release sodium oxybate. 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 immediate-release sodium oxybate in patients with narcolepsy. Parasomnias, including sleepwalking, have been reported in a pediatric clinical trial and in postmarketing experience with immediate-release sodium oxybate. Therefore, episodes of sleepwalking should be fully evaluated, and appropriate interventions considered. 5.8 Use in Patients Sensitive to High Sodium Intake LUMRYZ has a high sodium content. In patients sensitive to sodium intake (e.g., those with heart failure, hypertension, or renal impairment), consider the amount of daily sodium intake in each dose of LUMRYZ. Table 1 provides the approximate sodium content per LUMRYZ dose. Table 1: Approximate Sodium Content per Total Nightly Dose of LUMRYZ (g = grams) LUMRYZ Dose Sodium Content/Total Nightly Exposure 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 (CNS) DEPRESSION AND ABUSE AND MISUSE Central Nervous System Depression LUMRYZ (sodium oxybate) is a CNS depressant. Clinically significant respiratory depression and obtundation may occur in patients treated with LUMRYZ at recommended doses [see Warnings and Precautions (5.1) ] . Many patients who received sodium oxybate during clinical trials in narcolepsy were receiving central nervous system stimulants [see Clinical Trials (14) ] . Abuse and Misuse LUMRYZ (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, LUMRYZ is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the LUMRYZ 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 • LUMRYZ is a CNS depressant, and respiratory depression can occur with LUMRYZ use ( 5.1 , 5.4 ) Abuse and Misuse • LUMRYZ 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 ) LUMRYZ is available only through a restricted program called the LUMRYZ REMS ( 5.3 )
Contraindications
LUMRYZ 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 (incidence ≥ 5% and greater than placebo) reported for any dose of LUMRYZ were nausea, dizziness, enuresis, headache, and vomiting ( 6.1 ). Most common adverse reactions for pediatric patients (≥ 5%) in a study with immediate-release sodium oxybate were nausea, enuresis, vomiting, headache, weight decreased, decreased appetite, dizziness, and sleepwalking ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Avadel CNS Pharmaceuticals, LLC at 1-888-828-2335 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 LUMRYZ was studied in one placebo-controlled trial (Study 1) [see Clinical Studies (14.1) ] in 212 patients with narcolepsy (107 patients treated with LUMRYZ and 105 with placebo). Adverse Reactions Leading to Treatment Discontinuation In Study 1, 15.9% of patients treated with LUMRYZ discontinued because of adverse reactions, compared to 1.9% of patients receiving placebo. The most common adverse reaction leading to discontinuation was dizziness (4.7%). For LUMRYZ, 5.6% of patients discontinued due to adverse reactions on 4.5 g, 4.1% on 6 g, 4.5% on 7.5 g, and 3.9% on 9 g dose. Most Common Adverse Reactions The most common adverse reactions (incidence ≥5% and greater than placebo) reported for any dose of LUMRYZ were nausea, dizziness, enuresis, headache, and vomiting. Adverse Reactions Occurring at an Incidence of 2% or Greater Table 2 lists adverse reactions occurring in 2% or more of LUMRYZ-treated patients on any individual dose and at a rate greater than placebo-treated patients in Study 1. Table 2: Adverse Reactions Occurring in 2% or More of LUMRYZ-Treated Adult Patients and Greater than for Placebo-Treated Patients in Study 1 Adverse Reaction Placebo (N=105) % LUMRYZ 4.5 g (N=107) % LUMRYZ 6 g (N=97) % LUMRYZ 7.5 g (N=88) % LUMRYZ 9 g (N=77) % Gastrointestinal Disorders Vomiting 2 3 3 6 5 Nausea 3 6 8 7 1 Investigations Weight Decreased 0 1 0 0 4 Metabolism and Nutritional Disorders Decreased Appetite 0 4 4 3 3 Nervous System Disorders Dizziness 0 6 4 6 5 Somnolence 1 0 1 2 4 Headache 6 7 5 6 0 Psychiatric Disorders Enuresis 0 2 4 9 9 Anxiety 1 3 1 3 1 Somnambulism 0 1 2 0 0 Dose-Response Information In the clinical trial in adult patients with narcolepsy, a dose-response relationship was observed for enuresis and somnolence. Additional Adverse Reactions Adverse reactions observed in clinical studies with immediate-release sodium oxybate (≥2%), but not observed in Study 1 at a frequency of higher than 2%, and which may be relevant for LUMRYZ: diarrhea, abdominal pain upper, dry mouth, pain, feeling drunk, peripheral edema, cataplexy, muscle spasms, pain in extremity, tremor, disturbance in attention, paresthesia, sleep paralysis, disorientation, irritability, and hyperhidrosis. Pediatric Patients (7 Years of Age and Older) The safety of LUMRYZ for the treatment of cataplexy or excessive daytime sleepiness in pediatric patients 7 years of age and older with narcolepsy is supported by an adequate and well-controlled trial of immediate-release sodium oxybate [see Clinical Studies (14.2) ] . Below is a display of adverse reactions of immediate-release sodium oxybate in this adequate and well-controlled trial. In this trial, 104 patients aged 7 to 17 years (37 patients aged 7 to 11 years; 67 patients aged 12 to 17 years) with narcolepsy received immediate-release sodium oxybate for up to one year. This trial included an open-label safety continuation period in which eligible patients received immediate-release sodium oxybate for up to an additional 2 years. The median and maximum exposure across the entire trial were 371 and 987 days, respectively. Adverse Reactions Leading to Treatment Discontinuation In the pediatric clinical trial with immediate-release sodium oxybate, 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 immediate-release sodium oxybate in the pediatric clinical trial was similar to that seen in the adult clinical trial with immediate-release sodium oxybate. The safety profile in pediatric patients with LUMRYZ is expected to be similar to that of adult patients treated with LUMRYZ and to that of pediatric patients treated with immediate-release sodium oxybate. 6.2 Postmarketing Experience 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, 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
7.1 Alcohol, Sedative Hypnotics, and CNS Depressants LUMRYZ is contraindicated for use in combination with alcohol or sedative hypnotics. Use of other CNS depressants may potentiate the CNS-depressant effects of LUMRYZ [see Warnings and Precautions (5.1) ] . In addition to coadministration of LUMRYZ and alcohol being contraindicated because of respiratory depression, consumption of alcohol while taking LUMRYZ may also result in a more rapid release of the dose of sodium oxybate [see Clinical Pharmacology (12.3) ] .
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