1. National Institute of Neurological Disorders and Stroke. The epilepsies and seizures: hope through research. NIH Publication No. 18-NS-156. September 2018. Accessed January 5, 2023. https://catalog.ninds.nih.gov/sites/default/files/publications/epilepsies-seizures-hope-through-research.pdf; 2. Manford M. Recent advances in epilepsy. J Neurol. 2017;264(8):1811-1824. doi:10.1007/s00415-017-8394-2; 3. Detyniecki K, O’Bryan J, Choezom T, et al. Prevalence and predictors of seizure clusters: a prospective observational study of adult patients with epilepsy. Epilepsy Behav. 2018;88:349-356. doi:10.1016/j.yebeh.2018.09.035; 4. Zack MM, Kobau R. National and state estimates of the numbers of adults and children with active epilepsy—United States, 2015. MMWR Morb Mortal Wkly Rep. 2017;66(31):821-825. doi:10.15585/mmwr.mm6631a1; 5. Haut SR, Lipton RB, LeValley AJ, Hall CB, Shinnar S. Identifying seizure clusters in patients with epilepsy. Neurology. 2005;65(8):1313-1315. doi:10.1212/01.wnl.0000180685.84547.7f; 6. Sillanpää M, Schmidt D. Seizure clustering during drug treatment affects seizure outcome and mortality of childhood-onset epilepsy. Brain. 2008;131(pt 4):938-944. doi:10.1093/brain/awn037; 7. Haut SR, Shinnar S, Moshé SL, O’Dell C, Legatt AD. The association between seizure clustering and convulsive status epilepticus in patients with intractable complex partial seizures. Epilepsia. 1999;40(12):1832-1834. doi:10.1111/j.1528-1157.1999.tb01607.x; 8. Penovich PE, Buelow J, Steinberg K, Sirven J, Wheless J. Burden of seizure clusters on patients with epilepsy and caregivers: survey of patient, caregiver, and clinician perspectives. Neurologist. 2017;22(6):207-214. doi:10.1097/NRL.0000000000000140; 9. Haut SR, Shinnar S, Moshé SL. Seizure clustering: risks and outcomes. Epilepsia. 2005;46(1):146-149. doi:10.1111/j.0013-9580.2005.29004.x; 10. Naylor DE. Treating acute seizures with benzodiazepines: does seizure duration matter? Epileptic Disord. 2014;16(spec no 1):S69-S83. doi:10.1684/epd.2014.0691; 11. Niquet J, Baldwin R, Suchomelova L, et al. Benzodiazepine-refractory status epilepticus: pathophysiology and principles of treatment. Ann NY Acad Sci. 2016;1378(1):166-173. doi:10.1111/nyas.13147; 12. Kapoor M, Cloyd JC, Siegel RA. A review of intranasal formulations for the treatment of seizure emergencies. J Control Release. 2016;237:147-159. doi:10.1016/j.jconrel.2016.07.001; 13. Rectal rescue medicines. Epilepsy Foundation. Accessed January 5, 2023. https://www.epilepsy.com/treatment/seizure-rescue-therapies/rectal-rescue-medicines; 14. O’Dell C, Wheless JW, Cloyd J. The personal and financial impact of repetitive or prolonged seizures on the patient and family. J Child Neurol. 2007;22(5)(suppl):61S-70S. doi:10.1177/0883073807303070
Seizures and seizure clusters can have profound consequences
experience breakthrough seizures
~40% of patients with epilepsy continue to experience seizures despite ASM therapy1,2
Seizure clusters occurred in 71% of patients experiencing >4 seizures per year3
170,000 patients in the United States experience seizure clusters4,5
greater risk of premature death
3.5x increased risk of premature death in patients experiencing seizure clusters vs patients without clusters6
Seizure clusters are associated with higher rates of other adverse outcomes3,7-9
More frequent hospitalization
Increased risk of injuries
Reduced quality of life
AFTER JUST 10-15 MINUTES
Benzodiazepine
EFFICACY DECREASED ~50%10
Early seizure
intervention is critical 10,11
During a seizure, several changes at synapses reduce GABA signaling, which in turn reduces the inhibitory effect of benzodiazepines. Waiting to deliver seizure rescue with benzodiazepines could make seizure control more difficult.
Seizure rescue
medications
are effective
yet underutilized3
80% of adult patients who need a rescue medication do not use one.8 Historically, most older children and adults did not use on-hand rescue treatment due to limited options and the inherent difficulties of rectal administration.12,13
A daily ASM regimen coupled with an on-hand rescue medication that can be delivered soon after a seizure cluster begins may provide more comprehensive management for patients at risk.14
Indication
VALTOCO® (diazepam nasal spray) is indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy 6 years of age and older.
IMPORTANT SAFETY INFORMATION
WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS
Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.
The use of benzodiazepines, including VALTOCO, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing VALTOCO and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction.
The continued use of benzodiazepines may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Although VALTOCO is indicated only for intermittent use, if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of VALTOCO may precipitate acute withdrawal reactions, which can be life-threatening. For patients using VALTOCO more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue VALTOCO.
Contraindications: VALTOCO is contraindicated in patients with:
Hypersensitivity to diazepam
Acute narrow-angle glaucoma
Central Nervous System (CNS) Depression
Benzodiazepines, including VALTOCO, may produce CNS depression. Caution patients against engaging in hazardous activities requiring mental alertness, such as 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.
The potential for a synergistic CNS-depressant effect when VALTOCO is used with alcohol or other CNS depressants must be considered, and appropriate recommendations made to the patient and/or care partner.
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including VALTOCO, increase the risk of suicidal ideation and behavior. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or unusual changes in mood or behavior.
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.
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. 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.
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.
Adverse Reactions
The most common adverse reactions (at least 4%) were somnolence, headache, and nasal discomfort.
Diazepam, the active ingredient in VALTOCO, is a Schedule IV controlled substance.
To report SUSPECTED ADVERSE REACTIONS, contact Neurelis, Inc. at 1-866-696-3873 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch).
Please see full Prescribing Information, including Boxed Warning.
IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNING
Indication
VALTOCO® (diazepam nasal spray) is indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy 6 years of age and older.
IMPORTANT SAFETY INFORMATION
WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS
Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.
The use of benzodiazepines, including VALTOCO, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing VALTOCO and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction.
The continued use of benzodiazepines may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Although VALTOCO is indicated only for intermittent use, if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of VALTOCO may precipitate acute withdrawal reactions, which can be life-threatening. For patients using VALTOCO more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue VALTOCO.
Contraindications: VALTOCO is contraindicated in patients with:
Hypersensitivity to diazepam
Acute narrow-angle glaucoma
Central Nervous System (CNS) Depression
Benzodiazepines, including VALTOCO, may produce CNS depression. Caution patients against engaging in hazardous activities requiring mental alertness, such as 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.
The potential for a synergistic CNS-depressant effect when VALTOCO is used with alcohol or other CNS depressants must be considered, and appropriate recommendations made to the patient and/or care partner.
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including VALTOCO, increase the risk of suicidal ideation and behavior. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or unusual changes in mood or behavior.
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.
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. 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.
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.
Adverse Reactions
The most common adverse reactions (at least 4%) were somnolence, headache, and nasal discomfort.
Diazepam, the active ingredient in VALTOCO, is a Schedule IV controlled substance.
To report SUSPECTED ADVERSE REACTIONS, contact Neurelis, Inc. at 1-866-696-3873 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch).
Please see full Prescribing Information, including Boxed Warning.
References
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