Oxybate

1 INDICATIONS AND 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 ).

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action LUMRYZ is a CNS depressant. The mechanism of action of LUMRYZ in the treatment of narcolepsy is unknown. Sodium oxybate is the sodium salt of gamma-hydroxybutyrate (GHB), an endogenous compound and metabolite of the neurotransmitter GABA. It is hypothesized that the therapeutic effects of LUMRYZ on cataplexy and excessive daytime sleepiness are mediated through GABA B actions at noradrenergic and dopaminergic neurons, as well as at thalamocortical neurons. 12.3 Pharmacokinetics Following oral administration of LUMRYZ, the plasma levels of GHB increased dose-proportionally for C max and more than dose-proportionally for area under the plasma concentration-time curve (AUC inf ) (respectively, 2-fold and 2.3-fold increases as total daily dose is doubled from 4.5 g to 9 g). No clinically significant difference in oxybate pharmacokinetics was observed between a single 6 g dose of LUMRYZ and two 3 g doses of immediate-release sodium oxybate administered 4 hours apart. Absorption Following oral administration of a single 6 g dose of LUMRYZ, the peak plasma concentration (C max ) was 66 mcg/mL and the time to peak plasma concentration (T max ) was 1.5 hours. Effect of Food Administration of LUMRYZ immediately after a high-fat meal resulted in a mean reduction in C max and AUC of GHB by 33% and 14%, respectively; average T max increased from 0.5 hours to 1.5 hours [ see Dosage and Administration (2.3) ]. Effect of Ethanol An in vitro study showed alcohol-induced dose-dumping of sodium oxybate from extended-release oral suspension at 1 hour in the presence of 40% alcohol, and approximately 60% increase of drug release at 2 hours in the presence of 20% alcohol [see Contraindications (4) and Warnings and Precautions (5.1) ] . Effect of Water Temperature An in vitro dissolution study showed that LUMRYZ mixed with hot water (90°C) resulted in a dose-dumping phenomenon for the release of sodium oxybate, whereas warm water (50°C) did not significantly affect the drug release from the extended-release suspension [ see Dosage and Administration (2.3) ]. Effect of Water Flavoring An in vitro dissolution study showed that LUMRYZ mixed with water prepared with calorie-free drink mix (e.g., Crystal Light Raspberry Lemonade Drink Mix) or flavored water enhancer (e.g., Mio Fruit Punch Concentrate Liquid Water Enhancer) did not impact the drug release from the extended-release suspension [see Dosage and Administration (2.3) ]. Distribution GHB is a hydrophilic compound with an apparent volume of distribution averaging 190 mL/kg to 384 mL/kg. At GHB concentrations ranging from 3 mcg/mL to 300 mcg/mL, less than 1% is bound to plasma proteins. Elimination Metabolism Animal studies indicate that metabolism is the major elimination pathway for GHB, producing carbon dioxide and water via the tricarboxylic acid (Krebs) cycle, and secondarily by β-oxidation. The primary pathway involves a cytosolic NADP + -linked enzyme, GHB dehy

2 DOSAGE AND 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 t

6 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 oxyba

5 WARNINGS AND 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 restr

4 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 ).

10 OVERDOSAGE 10.1 Human Experience Information regarding overdose with LUMRYZ is derived largely from reports in the medical literature that describe symptoms and signs in individuals who have ingested GHB illicitly. In these circumstances, the co-ingestion of other drugs and alcohol was common and may have influenced the presentation and severity of clinical manifestations of overdose. In adult clinical trials of immediate-release sodium oxybate, two cases of overdose with sodium oxybate were reported. In the first case, an estimated dose of 150 g, more than 15 times the maximum recommended dose, caused a patient to be unresponsive with brief periods of apnea and to be incontinent of urine and feces. This individual recovered without sequelae. In the second case, death was reported following a multiple drug overdose consisting of sodium oxybate and numerous other drugs. 10.2 Signs and Symptoms Information about signs and symptoms associated with overdosage with LUMRYZ derives from reports of illicit use of GHB. Patient presentation following overdose is influenced by the dose ingested, the time since ingestion, the co-ingestion of other drugs and alcohol, and the fed or fasted state. Patients have exhibited varying degrees of depressed consciousness that may fluctuate rapidly between a confusional, agitated combative state with ataxia and coma. Emesis (even when obtunded), diaphoresis, headache, and impaired psychomotor skills have been observed. No typical pupillary changes have been described to assist in diagnosis; pupillary reactivity to light is maintained. Blurred vision has been reported. An increasing depth of coma and acidosis have been observed at higher doses. Myoclonus and tonic-clonic seizures have been reported. Respiration may be unaffected or compromised in rate and depth. Cheyne-Stokes respiration and apnea have been observed. Bradycardia and hypothermia may accompany unconsciousness, as well as muscular hypotonia, but tendon reflexes remain intact. 10.3 Recommended Treatment of Overdose General symptomatic and supportive care should be instituted immediately, and gastric decontamination may be considered if co-ingestants are suspected. Because emesis may occur in the presence of obtundation, appropriate posture (left lateral recumbent position) and protection of the airway by intubation may be warranted. Although the gag reflex may be absent in deeply comatose patients, even unconscious patients may become combative to intubation, and r