Valtoco

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)

2.1Instructions 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.

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)

5.1Risk 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 syndrome with withdrawal symptoms lasting weeks to more than 12 months [see Drug Abuse and Dependence (9.3)]. 5.4 CNS Depression Benzodiazepines, including VALTOCO, produce CNS depression. Caution patients against engaging in hazardous activities requiring mental alertness (e.g., operating machinery, driving a motor vehicle, or riding a bicycle) until the effects of the drug, such as drowsiness, have subsided, and as their medical condition permits. Although VALTOCO is indicated for use solely on an intermittent basis, the potential for synergistic CNS-depressant effects when used simultaneously with alcohol or other CNS depressants must be considered by the prescriber and appropriate recommendations made to the patient and/or caregiver. 5.5 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including VALTOCO, 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 3 shows absolute and relative risk by indication for all evaluated AEDs. Table 3: 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 VALTOCO 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. 5.6 Glaucoma Benzodiazepines, including 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. VALTOCO is contraindicated in patients with narrow-angle glaucoma. 5.7 Neonatal Sedation and Withdrawal Syndrome Use of VALTOCO 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 VALTOCO during pregnancy or labor for signs of sedation and monitor neonates exposed to VALTOCO during pregnancy for signs of withdrawal; manage these neonates accordingly. 5.8 Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative VALTOCO is not approved for use in neonates or infants. Serious and fatal adverse reactions including "gasping syndrome" can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs, including VALTOCO. The "gasping syndrome" is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (VALTOCO contains 10.5 mg of benzyl alcohol per 0.1 mL) [see Use in Specific Populations (8.4)].

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-treated patients were nasal discomfort (5%), dysgeusia (2%), epistaxis (2%), and rhinorrhea (1%). Other Adverse Reactions Diazepam rectal gel has previously been administered to 573 patients with epilepsy during all clinical trials, only some of which were placebo-controlled. All of the events listed below occurred in at least 1% of the 573 individuals exposed to diazepam rectal gel. Body as a Whole: Asthenia Cardiovascular: Hypotension, vasodilatation Nervous: Agitation, confusion, convulsion, dysarthria, emotional lability, speech disorder, thinking abnormal, vertigo Respiratory: Hiccup The following infrequent adverse events have been reported previously with diazepam use: depression, slurred speech, syncope, changes in libido, urinary retention, bradycardia, cardiovascular collapse, nystagmus, urticaria, neutropenia, and jaundice. Paradoxical reactions such as acute hyperexcited states, anxiety, hallucinations, increased muscle spasticity, insomnia, rage, sleep disturbances and stimulation have been reported with other diazepam products. If these events occur with the use of VALTOCO, the prescriber should consider discontinuation of use.

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)

7.1Effect 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.

Pregnancy: Based on animal data, may cause fetal harm. (8.1)

8.1Pregnancy 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. 8.2 Lactation Risk Summary Diazepam is excreted in human milk. There are reports of sedation, poor feeding, and poor weight gain in infants exposed to benzodiazepines through breast milk. There are no data to assess the effects of diazepam and/or its active metabolite(s) on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for VALTOCO nasal spray and any potential adverse effects on the breastfed infant from VALTOCO or from the underlying maternal condition. Clinical Considerations Infants exposed to VALTOCO through breast milk should be monitored for sedation, poor feeding and poor weight gain. 8.4 Pediatric Use Safety and effectiveness of VALTOCO have been established in pediatric patients 2 years to 16 years of age. Use of VALTOCO in this age group is supported by evidence from adequate and well-controlled studies of diazepam rectal gel in adult and pediatric patients, adult bioavailability studies comparing VALTOCO with diazepam rectal gel, patient pharmacokinetic data, and open-label safety studies of VALTOCO including patients 2 years to 16 years of age [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)]. Safety and effectiveness of VALTOCO in pediatric patients below the age of 2 years have not been established. VALTOCO is not approved for use in neonates or infants. Prolonged CNS depression has been observed in neonates treated with diazepam. Serious adverse reactions including fatal reactions and the "gasping syndrome" occurred in premature neonates and low-birth-weight infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth-weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (VALTOCO contains 10.5 mg of benzyl alcohol per 0.1 mL) [see Warnings and Precautions (5.8)]

8.5Geriatric

Use Clinical studies of VALTOCO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Therefore, in elderly patients, VALTOCO should be used with caution because of an increase in half-life with a corresponding decrease in the clearance of free diazepam [see Clinical Pharmacology (12.3)]. It is also recommended that the dosage be decreased to reduce the likelihood of ataxia or oversedation. 8.6 Compromised Respiratory Function VALTOCO should be used with caution in patients with compromised respiratory function related to a concurrent disease process (e.g., asthma, pneumonia) or neurologic damage.

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.

Safety and effectiveness of VALTOCO have been established in pediatric patients 2 years to 16 years of age. Use of VALTOCO in this age group is supported by evidence from adequate and well-controlled studies of diazepam rectal gel in adult and pediatric patients, adult bioavailability studies comparing VALTOCO with diazepam rectal gel, patient pharmacokinetic data, and open-label safety studies of VALTOCO including patients 2 years to 16 years of age [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)]. Safety and effectiveness of VALTOCO in pediatric patients below the age of 2 years have not been established. VALTOCO is not approved for use in neonates or infants. Prolonged CNS depression has been observed in neonates treated with diazepam. Serious adverse reactions including fatal reactions and the "gasping syndrome" occurred in premature neonates and low-birth-weight infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth-weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (VALTOCO contains 10.5 mg of benzyl alcohol per 0.1 mL) [see Warnings and Precautions (5.8)]

9.1Controlled Substance

VALTOCO contains diazepam, a Schedule IV controlled substance. 9.2 Abuse VALTOCO is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction. 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. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see Warnings and Precautions (5.2)]. The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo. The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol). In the clinical studies with VALTOCO at recommended doses, abuse-related adverse events included euphoria, somnolence, sedation, anterograde amnesia, depression, anxiety, hallucinations, and restlessness. 9.3 Dependence Physical Dependence After Use of VALTOCO More Frequently Than Recommended VALTOCO may produce physical dependence if used more frequently than recommended. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. 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 or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions (5.3)]. For patients using VALTOCO more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue VALTOCO [see Warnings and Precautions (5.3)]. Acute Withdrawal Signs and Symptoms Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality. Protracted Withdrawal Syndrome Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used. Tolerance Tolerance to VALTOCO may develop after use more frequently than recommended. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of benzodiazepines may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines. It is recommended that patients be treated with VALTOCO no more frequently than every five days and no more than five times per month. VALTOCO is not recommended for chronic, daily use as an anticonvulsant. Chronic daily use of diazepam may increase the frequency and/or severity of tonic clonic seizures, requiring an increase in the dosage of standard anticonvulsant medication. In such cases, abrupt withdrawal of chronic diazepam may also be associated with a temporary increase in the frequency and/or severity of seizures.

Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal [see Warnings and Precautions (5.2)]. Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage. In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway maintenance. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

16.1How Supplied

VALTOCO is available in 5 mg, 7.5 mg, and 10 mg strengths. VALTOCO is supplied and packaged in doses of 5 mg, 10 mg, 15 mg, or 20 mg (see Table 5). Table 5: Available Packaging Configurations Description Contents NDC Each Carton Contains 2 Doses 5 mg carton 2 individual blister packs, each containing one 5 mg nasal spray device 72252-505-02 10 mg carton 2 individual blister packs, each containing one 10 mg nasal spray device 72252-510-02 15 mg carton 2 individual blister packs, each containing two 7.5 mg nasal spray devices 72252-515-04 20 mg carton 2 individual blister packs, each containing two 10 mg nasal spray devices 72252-520-04 Each Carton Contains 5 Doses 5 mg carton 5 individual blister packs, each containing one 5 mg nasal spray device 72252-505-05 10 mg carton 5 individual blister packs, each containing one 10 mg nasal spray device 72252-510-05 15 mg carton 5 individual blister packs, each containing two 7.5 mg nasal spray devices 72252-515-10 20 mg carton 5 individual blister packs, each containing two 10 mg nasal spray devices 72252-520-10 16.2 Storage and Handling Do not open individual blister packs or test nasal spray devices before use. Each single-dose nasal spray device sprays one (1) time and cannot be re-used. Do not use if the nasal spray unit appears damaged. Store VALTOCO at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Do not freeze. Protect from light.