Valtoco

1 INDICATIONS AND USAGE VALTOCO ® 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 2 years of age and older. VALTOCO 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 2 years of age and older. ( 1 )

2 DOSAGE AND ADMINISTRATION Administer VALTOCO by the nasal route only. ( 2.3 ) Dosage is dependent on the patient's age and weight. ( 2.2 ) Initial Dose: VALTOCO 5 mg and 10 mg doses are administered as a single spray intranasally into one nostril. Administration of 15 mg and 20 mg doses requires two nasal spray devices, one spray into each nostril. ( 2.2 ) Second Dose: A second dose, when required, may be administered at least 4 hours after the initial dose. If administered, use a new blister pack. ( 2.2 ) Maximum Dosage and Treatment Frequency: Do not use more than 2 doses to treat a single episode. It is recommended that VALTOCO be used to treat no more than one episode every five days and no more than five episodes per month. ( 2.2 ) 2.1 Instructions Prior to Dosing Prior to treatment, healthcare professionals should instruct the individual administering VALTOCO on how to identify seizure clusters and use the product appropriately [see Dosage and Administration (2.3) and Patient Counseling Information (17) ]. 2.2 Dosing Information The recommended dose of VALTOCO nasal spray is 0.2 mg/kg to 0.5 mg/kg, depending on the patient's age and weight. See Table 1 and Table 2 for specific recommendations. Table 1: Recommended Dose Based on Age Age (Years) Recommended Dose 2 through 5 0.5 mg/kg 6 through 11 0.3 mg/kg 12 and older 0.2 mg/kg Table 2: Recommended Dosage and Administration for Adults and Pediatric Patients 2 Years of Age and Older Dose Based on Age and Weight Administration 2 to 5 Years of Age (0.5 mg/kg) 6 to 11 Years of Age (0.3 mg/kg) 12 Years of Age and Older (0.2 mg/kg) Dose (mg) Number of Nasal Spray Devices Number of Sprays Weight (kg) 6 to 11 10 to 18 14 to 27 5 One 5 mg device One spray in one nostril 12 to 22 19 to 37 28 to 50 10 One 10 mg device One spray in one nostril 23 to 33 38 to 55 51 to 75 15 Two 7.5 mg devices One spray in each nostril 56 to 74 76 and up 20 Two 10 mg devices One spray in each nostril Second Dose (if needed): A second dose, when required, may be administered after at least 4 hours after the initial dose. If the second dose is to be administered, use a new blister pack of VALTOCO. Maximum Dosage and Treatment Frequency : Do not use more than 2 doses of VALTOCO to treat a single episode. Do not use VALTOCO to treat more than one episode every five days or more than five episodes per month. 2.3 Important Administration Instructions VALTOCO is for intranasal use only. No device assembly is required. VALTOCO nasal spray delivers its entire contents upon activation. Do not prime or attempt to use for more than one administration per device. Patients and caregivers should be counseled to read carefully the "Instructions for Use" for complete directions on how to properly administer VALTOCO.

5 WARNINGS AND PRECAUTIONS CNS Depression: Monitor for central nervous system (CNS) depression. May cause an increased CNS-depressant effect when used with alcohol or other CNS depressants. ( 5.4 , 7.2 ) Suicidal Behavior and Ideation: Monitor patients for suicidal ideation and behavior. ( 5.5 ) Glaucoma: VALTOCO can increase intraocular pressure in patients with glaucoma. VALTOCO may be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. ( 4 , 5.6 ) Neonatal Sedation and Withdrawal Syndrome: VALTOCO use during pregnancy can result in neonatal sedation and/or neonatal withdrawal. ( 5.7 , 8.1 ) 5.1 Risk of Concomitant Use with Opioids Concomitant use of benzodiazepines, including VALTOCO, and opioids may result in profound sedation, respiratory depression, coma, and death [see Drug Interactions (7.1) ]. 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 VALTOCO 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 VALTOCO is used with opioids. 5.2 Abuse, Misuse, and Addiction The use of benzodiazepines, including VALTOCO, 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 VALTOCO and throughout treatment, assess each patient's risk for abuse, misuse, and addiction. Use of VALTOCO, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of VALTOCO 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 VALTOCO More Frequently Than Recommended For patients using VALTOCO more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue VALTOCO (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 VALTOCO 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 VALTOCO, 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…

4 CONTRAINDICATIONS VALTOCO nasal spray is contraindicated in patients with: Known hypersensitivity to diazepam Acute narrow angle glaucoma [see Warnings and Precautions (5.6) ] Hypersensitivity to diazepam. ( 4 ) Acute narrow-angle glaucoma. ( 4 )

7 DRUG INTERACTIONS CYP2C19 and CYP3A4 Inhibitors: Elimination of diazepam could be decreased with concurrent administration; therefore, adverse reactions with VALTOCO may be increased. ( 7.3 ) Inducers of CYP2C19 and CYP3A4 Inducers: Exposure of diazepam with concurrent administration may be decreased; therefore, efficacy with VALTOCO may be decreased. ( 7.3 ) 7.1 Effect of Concomitant Use of Benzodiazepines and Opioids 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 [see Warnings and Precautions (5.1) ]. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and follow patients closely for respiratory depression and sedation. 7.2 CNS Depressants and Alcohol Coadministration of other CNS depressants (e.g., valproate) or consumption of alcohol may potentiate the CNS-depressant effects of diazepam [see Warnings and Precautions (5.4) ]. 7.3 Effect of Other Drugs on VALTOCO Metabolism Potential interactions may occur when diazepam is given concurrently with agents that affect CYP2C19 and CYP3A4 activity. Inhibitors of CYP2C19 and CYP3A4 Inhibitors of CYP2C19 (e.g., cimetidine, quinidine, and tranylcypromine) and CYP3A4 (e.g., ketoconazole, troleandomycin, and clotrimazole) could decrease the rate of diazepam elimination; therefore, adverse reactions to VALTOCO may be increased. Inducers of CYP2C19 and CYP3A4 Inducers of CYP2C19 (e.g., rifampin) and CYP3A4 (e.g., carbamazepine, phenytoin, dexamethasone, and phenobarbital) could increase the rate of diazepam elimination; therefore, efficacy of VALTOCO may be decreased. 7.4 Effect of VALTOCO on the Metabolism of Other Drugs Diazepam is a substrate for CYP2C19 and CYP3A4; therefore, it is possible that VALTOCO may interfere with the metabolism of drugs which are substrates for CYP2C19 (e.g., omeprazole, propranolol, and imipramine) and CYP3A4 (e.g., cyclosporine, paclitaxel, theophylline, and warfarin) leading to a potential drug-drug interaction.

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 VALTOCO, during pregnancy. Healthcare providers are encouraged to recommend that pregnant women who are taking VALTOCO 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 (5.7) 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 Human Data ) . In animal studies, administration of diazepam during the organogenesis period of pregnancy resulted in increased incidences of fetal malformations at doses greater than those used clinically. Data for diazepam and other benzodiazepines suggest the possibility of increased neuronal cell death and long-term effects on neurobehavioral and immunological function based on findings in animals following prenatal or early postnatal exposure at clinically relevant doses (see Animal Data ). 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 VALTOCO during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to VALTOCO during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.7) ] . 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 Diazepam has been shown to produce increased incidences of fetal malformations in mice and hamsters when given orally at single doses of 100 mg/kg or greater (approximately 13 times the maximum recommended human dose [MRHD = 0.6mg/kg/day] or greater on a mg/m 2 basis). Cleft palate and exencephaly are the most common and consistently reported malformations produced in these species by administration of high, maternally-toxic doses of diazepam during organogenesis. In published animal studies, administration of benzodiazepines or other drugs that enhance GABAergic inhibition 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 that takes place during the third trimester of pregnancy in humans.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Risk of 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 VALTOCO More Frequently Than Recommended [see Warnings and Precautions (5.3) ] CNS depression [see Warnings and Precautions (5.4) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.5) ] Glaucoma [see Warnings and Precautions (5.6) ] Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.7) ] Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative [see Warnings and Precautions (5.8) ]. The most common adverse reactions (at least 4%) were somnolence, headache, and nasal discomfort. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Neurelis, Inc. at 1-866-696-3873 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in practice. The safety of VALTOCO is supported by clinical trials using diazepam rectal gel, as well as open-label, repeat-dose studies of VALTOCO in healthy subjects and epilepsy patients. Diazepam Rectal Gel In studies previously conducted with diazepam rectal gel, adverse event data were collected from double-blind, placebo-controlled studies and open-label studies. The majority of adverse events were mild to moderate in severity and transient in nature. Two patients who received diazepam rectal gel died seven to 15 weeks following treatment; neither of these deaths was deemed related to diazepam rectal gel. The most frequent adverse reactions (at least 4%) in the two double-blind, placebo-controlled studies were somnolence, headache, and diarrhea. Adverse events were usually mild or moderate in intensity. Approximately 1.4% of the 573 patients who received diazepam rectal gel in clinical trials of epilepsy discontinued treatment because of an adverse event. The adverse reaction most frequently associated with discontinuation (occurring in three patients) was somnolence. Other adverse reactions most commonly associated with discontinuation and occurring in two patients were hypoventilation and rash. Adverse reactions associated with discontinuation occurring in one patient were asthenia, hyperkinesia, incoordination, vasodilatation, and urticaria. In the two double-blind, placebo-controlled, parallel-group studies [see Clinical Studies (14) ] , the proportion of patients who discontinued treatment because of adverse events was 2% for the group treated with diazepam rectal gel, versus 2% for the placebo group. In the diazepam rectal gel group, one patient discontinued because of rash and one patient discontinued because of lethargy. Table 4: Adverse Reactions That Occurred in Greater Than 1% Of Patients in Parallel-Group, Placebo-Controlled Trials with Diazepam Rectal Gel and More Common Than Placebo Adverse Reaction Diazepam Rectal Gel N=101 % Placebo N=104 % Somnolence 23 8 Headache 5 4 Diarrhea 4 <1 Ataxia 3 <1 Dizziness 3 2 Euphoria 3 0 Incoordination 3 0 Rash 3 0 Asthma 2 0 Vasodilation 2 0 VALTOCO (Diazepam Nasal Spray) Clinical studies of patients with epilepsy 2 years of age and older were conducted to support the safety and tolerability of VALTOCO for the treatment of acute repetitive seizures. A total of 255 patients 2 years of age and older received VALTOCO, of whom 143 received VALTOCO for at least 1 year. Other than adverse reactions related to local nasal administration, the adverse reactions reported in these studies were similar to those seen in the efficacy trials of diazepam rectal gel. The most common local adverse reactions that occurred in at least 1% of VALTOCO-tr…