Nayzilam

1 INDICATIONS AND USAGE NAYZILAM is indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient's usual seizure pattern in patients with epilepsy 12 years of age and older. NAYZILAM is a benzodiazepine indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient's usual seizure pattern in patients with epilepsy 12 years of age and older. ( 1 )

2 DOSAGE AND ADMINISTRATION Administer NAYZILAM by the nasal route only. ( 2.2 ) Initial Dose : Administer one spray (5 mg dose) into one nostril. ( 2.2 ) Second Dose : One additional spray (5 mg dose) into the opposite nostril may be administered after 10 minutes if the patient has not responded to the initial dose. ( 2.2 ) Maximum Dosage and Treatment Frequency: Do not use more than 2 doses of NAYZILAM to treat a seizure cluster. It is recommended that NAYZILAM be used to treat no more than one episode every three days and treat no more than five episodes per month. ( 2.2 ) 2.1 Instructions Prior to Dosing NAYZILAM prescribers should consider the following prior to initiation of treatment: For patients at increased risk of respiratory depression from benzodiazepines, administration of NAYZILAM under healthcare professional supervision should be considered prior to treatment with NAYZILAM; this administration may be performed in the absence of a seizure episode [see Warnings and Precautions (5.4) ] . Prior to treatment, the healthcare professional should instruct the individual administering NAYZILAM on how to identify seizure clusters and use the product appropriately [see Patient Counseling Information: Administration Information (17) ] . Patients and caregivers should be counseled to read carefully the "Instructions for Use" for complete directions on how to properly administer NAYZILAM. 2.2 Dosage Information Administer NAYZILAM by the nasal route only. Initial Dose: Administer one spray (5 mg dose) into one nostril. Second Dose (if needed): One additional spray (5 mg dose) into the opposite nostril may be administered after 10 minutes if the patient has not responded to the initial dose. A second dose of NAYZILAM should not be administered if the patient has trouble breathing or if there is excessive sedation that is uncharacteristic of the patient during a seizure cluster episode [see Warnings and Precautions (5.4) ]. Maximum Dosage and Treatment Frequency: Do not use more than 2 doses of NAYZILAM to treat a single episode. It is recommended that NAYZILAM be used to treat no more than one episode every three days and no more than 5 episodes per month [see Drug Abuse and Dependence (9.4) ] .

4 CONTRAINDICATIONS NAYZILAM is contraindicated in patients with: Known hypersensitivity to midazolam. Acute narrow-angle glaucoma [see Warnings and Precautions (5.8) ]. Patients with hypersensitivity to midazolam ( 4 ) Patients with acute narrow-angle glaucoma ( 4 )

5 WARNINGS AND PRECAUTIONS CNS Depression From Concomitant Use With Other CNS Depressants or Moderate or Strong CYP3A4 Inhibitors : May cause an increased CNS-depressant effect when used with alcohol or other CNS depressants. Concomitant use with moderate or strong CYP3A4 inhibitors may result in prolonged sedation because of a decrease in plasma clearance of midazolam. ( 5.5 , 7.3 ) Suicidal Behavior and Ideation: Antiepileptic drugs increase the risk of suicidal ideation and behavior. ( 5.6 ) Impaired Cognitive Function: Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours. ( 5.7 ) Glaucoma: NAYZILAM can increase intraocular pressure in patients with glaucoma. Patients with open-angle glaucoma may need to have their ophthalmologic status evaluated following treatment with NAYZILAM. ( 5.8 ) Neonatal Sedation and Withdrawal Syndrome: NAYZILAM use during pregnancy can result in neonatal sedation and/or neonatal withdrawal. ( 5.9 , 8.1 ) 5.1 Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including NAYZILAM, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of benzodiazepines and opioids for patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe NAYZILAM concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when NAYZILAM is used with opioids [see Drug Interactions (7.2) ] . 5.2 Abuse, Misuse, and Addiction The use of benzodiazepines, including NAYZILAM, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death [see Drug Abuse and Dependence (9.2) ] . Before prescribing NAYZILAM and throughout treatment, assess each patient's risk for abuse, misuse, and addiction. Use of NAYZILAM, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of NAYZILAM along with monitoring for signs and symptoms of abuse, misuse, and addiction. Do not exceed the recommended dosing frequency; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate. 5.3 Dependence and Withdrawal Reactions After Use of NAYZILAM More Frequently Than Recommended For patients using NAYZILAM more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue NAYZILAM (a patient-specific plan should be used to taper the dose). Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use. Acute Withdrawal Reactions The continued use of benzodiazepines may lead to clinically significant physical dependence. Although NAYZILAM is indicated only for intermittent use [see Indications and Usage (1) and Dosage and Administration (2) ] , if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of NAYZILAM, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) [see Drug Abuse and Dependence (9.3) ]. Protracted Withdrawal Syndrome In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months [see Drug Abuse and Dependence (9.3) ] . 5.4 Risks of Cardiorespiratory Adverse Reactions Serious cardiorespiratory adverse reactions have occurred after administration of midazolam. These have included respiratory depression, airway obstruction, oxygen desaturation, apnea, respiratory arrest and/or cardiac arrest, sometimes resulting in death or permanent neurologic injury. There have also been rare reports of hypotensive episodes requiring treatment during or after diagnostic or surgical manipulations, particularly in patients with hemodynamic instability. Hypotension occurs more frequently in patients premedicated with a narcotic. The danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve [see Use in Specific Populations (8.5) ] ; patients with chronic obstructive pulmonary disease are highly sensitive to the respiratory depressant effect of midazolam. Respiratory depression was observed with the administration of NAYZILAM during clinical trials [see Adverse Reactions (6.1) ] . Cardiac or respiratory arrest caused by NAYZILAM was not reported during clinical trials. 5.5 Central Nervous System Depression from Concomitant Use with Other Central Nervous System Depressants, or Moderate or Strong CYP3A4 Inhibitors Drug products containing midazolam, including NAYZILAM, have a central nervous system (CNS) depressant effect. Risks from Concomitant Use with Other CNS Depressants The potential for an increased CNS-depressant effect from concomitant use with alcohol or other CNS depressants (e.g., opioids) must be considered by the prescribing physician, and appropriate recommendations made to the patient and/or caregiver [see Warnings and Precautions (5.1) and Drug Abuse and Dependence (9.3) ] . Concomitant use of barbiturates, alcohol, or other CNS depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect [see Drug Interactions (7.3) ]. Risks from Concomitant Use with Moderate or Strong CYP3A4 Inhibitors There is a potential for prolonged sedation from concomitant use with moderate or strong CYP3A4 enzyme inhibitors because of much higher midazolam exposures [see Drug Interactions (7.2) and Clinical Pharmacology (12.2) ]. 5.6 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including NAYZILAM, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs. Table 1. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events/1000 Patients Drug Patients with Events per 1000 Patients Relative Risk: Incidence of Drug Events in Drug Patients /Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing midazolam or any other AED must balance the risk of suicidal thoughts or behaviors with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. 5.7 Impaired Cognitive Function Midazolam, including NAYZILAM, is associated with a high incidence of partial or complete impairment of recall for several hours following an administered dose. Gross tests of recovery from the effects of midazolam cannot be relied upon to predict reaction time under stress. It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided, and as their medical condition permits. For pediatric patients, particular care should be taken to ensure safe ambulation. 5.8 Glaucoma Benzodiazepines, including NAYZILAM, can increase intraocular pressure in patients with glaucoma. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction with midazolam. NAYZILAM may be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. Patients with open-angle glaucoma may need to have their ophthalmologic status evaluated following treatment with NAYZILAM. NAYZILAM is contraindicated in patients with narrow-angle glaucoma. 5.9 Neonatal Sedation and Withdrawal Syndrome Use of NAYZILAM late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate [see Use in Specific Populations (8.1) ] . Monitor neonates exposed to NAYZILAM during pregnancy or labor for signs of sedation and monitor neonates exposed to NAYZILAM during pregnancy for signs of withdrawal; manage these neonates accordingly. 5.10 Other Adverse Reactions When midazolam was used for sedation, reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity, and combativeness have been reported. These reactions may be caused by inadequate or excessive dosing or improper administration of midazolam; however, consideration should be given to the possibility of cerebral hypoxia or true paradoxical reactions.

7 DRUG INTERACTIONS Table 3: Clinically Significant Drug Interactions With NAYZILAM 7.1 CYP3A4 Inhibitors Clinical Impact: Concomitant use of CYP3A4 inhibitors may result in prolonged sedation because of a decrease in plasma clearance of midazolam. Intervention: Avoid co-administration of NAYZILAM with moderate or strong CYP3A4 inhibitors. NAYZILAM should be used with caution when co-administered with mild CYP3A4 inhibitors. Examples: Moderate CYP3A4 inhibitors: erythromycin, diltiazem, verapamil Strong CYP3A4 inhibitors: ketoconazole, itraconazole, clarithromycin 7.2 Opioids Clinical Impact: The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABA A sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required [see Warnings and Precautions (5.1) ]. Examples: Morphine, hydrocodone, oxymorphone, codeine, fentanyl 7.3 Other Central Nervous System (CNS) Depressants Clinical Impact: Concomitant use of barbiturates, alcohol, or other CNS depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required [see Warnings and Precautions (5.5) ] . Examples: Other benzodiazepines and sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, opioids, alcohol. CYP3A4 Inhibitors : Avoid co-administration of NAYZILAM with moderate or strong CYP3A4 inhibitors. NAYZILAM should be used with caution when co-administered with mild CYP3A4 inhibitors. ( 7.1 ) Opioids : Risk of respiratory depression is increased. ( 7.2 ) Other CNS Depressants : May increase the risks of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect. ( 7.3 )

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail in other sections of the labeling: Risks from Concomitant Use with Opioids [see Warnings and Precautions (5.1) ] Abuse, Misuse, and Addiction [see Warnings and Precautions (5.2) ] Dependence and Withdrawal Reactions After Use of NAYZILAM More Frequently Than Recommended [see Warnings and Precautions (5.3) ] Risks of Cardiorespiratory Adverse Reactions [see Warnings and Precautions (5.4) ] CNS Depression from Concomitant Use with Other CNS Depressants or Moderate or Strong CYP3A4 Inhibitors [see Warnings and Precautions (5.5) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.6) ] Impaired Cognitive Function [see Warnings and Precautions (5.7) ] Glaucoma [see Warnings and Precautions (5.8) ] Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.9) ] Other Adverse Reactions [see Warnings and Precautions (5.10) ] The most common adverse reactions (≥5% in any NAYZILAM treatment group) were somnolence, headache, nasal discomfort, throat irritation, and rhinorrhea ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact UCB, Inc. at 1-844-599-2273 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. NAYZILAM was studied for the outpatient treatment of a single seizure cluster in 292 adult and adolescent patients with epilepsy (Study 1) [see Clinical Studies (14) ] . The study was conducted in two phases; an open-label Test Dose Phase followed by a double-blind, placebo-controlled, Comparative Phase. The mean age of patients enrolled in the Comparative Phase (N=201) was 33 years, 51% were female, and 95% were White. Table 2 lists the adverse reactions occurring in 2% or more of the NAYZILAM-treated patients and at a rate greater than the placebo-treated patients in the Comparative Phase of Study 1. Table 2: Adverse Reactions Adverse reactions that occurred within 2 days after NAYZILAM administration are included that Occurred in ≥2% of Patients (Any NAYZILAM) and Greater than Placebo in the Comparative Phase of Study 1 Body System/Adverse Reaction Placebo NAYZILAM Patients in Study 1 were permitted to take a second, open-label dose of NAYZILAM 5 mg between 10 minutes and 6 hours following the initial blinded dose of NAYZILAM 5 mg or placebo if they experience seizure recurrence or an incomplete resolution of the episode. The Placebo + NAYZILAM 5 mg and NAYZILAM 5 mg + 5 mg columns represent patients who received a second dose of NAYZILAM 5 mg and received a blinded initial dose of placebo or NAYZILAM 5 mg, respectively. NAYZILAM 5 mg Placebo + NAYZILAM 5 mg NAYZILAM 5 mg + 5 mg Any NAYZILAM Treatment Group N = 26 % N = 91 % N = 41 % N = 43 % N = 175 % Nervous System Somnolence 4 10 10 9 10 Headache 0 7 0 2 4 Dysarthria 0 2 2 2 2 Application Site Nasal Discomfort 8 5 7 16 9 Throat Irritation 0 2 2 7 3 Rhinorrhea 0 3 0 5 3 Product Taste Abnormal 0 4 0 0 2 Eye Disorders Lacrimation Increased 0 1 2 2 2 For patients who experienced a decrease in peripheral oxygen saturation in the Test Dose Phase of Study 1, the decreases were generally transitory. Two patients (one with a history of sleep apnea and one with intercurrent seizure) with decreases in peripheral oxygen saturation in the Test Dose Phase required therapeutic supplemental oxygen.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as NAYZILAM, during pregnancy. Healthcare providers are encouraged to recommend that pregnant women who are taking NAYZILAM during pregnancy enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/. Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions (5.9) and Clinical Considerations ]. Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data ). Administration of midazolam to rats and rabbits during the period of organogenesis or to rats during late pregnancy and throughout lactation at doses greater than those used clinically did not result in any apparent adverse effects on development (see Animal Data ). However, published data for midazolam and other benzodiazepines suggest the possibility of neuronal cell death and long-term effects on neurobehavioral and immunological function in animals following prenatal or early postnatal exposure at clinically relevant doses. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to NAYZILAM during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to NAYZILAM during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.9) ] . Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings. Animal Data When midazolam (0, 0.2, 1, or 4 mg/kg/day) was administered intravenously to pregnant rats during the period of organogenesis, no adverse effects on embryofetal development were observed. The highest dose tested, which was associated with minimal evidence of maternal toxicity, is approximately 4 times the maximum recommended human dose (MRHD) of 10 mg based on body surface area (mg/m 2 ). When midazolam (0, 0.2, 0.6, and 2 mg/kg/day) was administered intravenously to rabbits during the period of organogenesis, no adverse effects on embryofetal development were reported. The high dose, which was not associated with evidence of maternal toxicity, is approximately 4 times the MRHD on a mg/m 2 basis. When midazolam (0, 0.2, 1, or 4 mg/kg/day) was administered intravenously to female rats during late gestation and throughout lactation, no clear adverse effects were noted in the offspring. The high dose, which was not associated with evidence of maternal toxicity, is approximately 4 times the MRHD on a mg/m 2 basis. In published animal studies, administration of benzodiazepines, including midazolam, or other drugs that enhance GABAergic neurotransmission to neonatal rats has been reported to result in widespread apoptotic neurodegeneration in the developing brain at plasma concentrations relevant for seizure control in humans. The window of vulnerability to these changes in rats (postnatal days 0-14) includes a period of brain development corresponding to that taking place during the third trimester of pregnancy in humans.