Get to Know VALTOCO

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.1

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Heritage and Innovation Come Together1-3

VALTOCO is a reliable nasal spray that was carefully formulated to address the principal limitations of intranasal drug delivery.1,2

VALTOCO® (diazepam nasal spray) product VALTOCO® (diazepam nasal spray) product

Nearly complete absorption

VALTOCO bioavailability

bioavailability relative to intravenous diazepam1,4,5

VALTOCO combines the established history of diazepam with novel formulation technology.1,3,6

Optimized for Nasal Delivery1,7

diazepam icon

Diazepam

  • Recognized as a safe and effective seizure treatment for more than 50 years1,3
    • Has been prescribed as a seizure rescue treatment for nonmedical care partner use for >20 years8,9
  • Highly lipophilic molecule readily crosses the blood-brain barrier10,11
  • Half-life contributes to sustained plasma levels1
Intravail® icon

Intravail®

  • Designed to increase bioavailability and reliability of nasal drug delivery2,12
  • Generally safe, non-toxic substance12
  • Facilitates increased drug absorption across the nasal mucosa in 2 ways2,12:
    • Increases permeability of cell membranes2,12
    • Temporarily loosens tight junctions between cells, allowing the drug to pass through2,12
vitamin e icon

Vitamin E

  • Primary solvent provides adequate drug concentration within a small liquid volume13
  • Coats the nasal cavity14,15

Inactive ingredients: benzyl alcohol, dehydrated alcohol, n-dodecyl beta-D-maltoside, vitamin E.1

Reliable Absorption With Sustained Plasma Levels Throughout the Day1,4,5

Pharmacokinetic (PK) studies were conducted in patients with epilepsy and healthy volunteers1

  • 97% absolute bioavailability relative to IV diazepam1,4,5
  • Plasma levels sustained for 24 hours1
  • Predictable PK with low interpatient and intrapatient variability1
    • Diazepam PK 2- to 4-fold less variable than diazepam rectal gel regardless of patient weight1,16

Nasal spray administration coupled with the proprietary VALTOCO formulation account for key PK differences vs IV diazepam1,4,5

diazepam concentration graph

Seizure clusters occur over a 24-hour period17

Data from an open-label, crossover study of the bioavailability and pharmacokinetics of diazepam after intranasal and intravenous administration to healthy volunteers (N=24) under fasted conditions (Study 01).

Efficacy Based on Comparable Bioavailability to Diazepam Rectal Gel

VALTOCO has demonstrated comparable bioavailability to diazepam rectal gel, an established formulation of diazepam, approved by the FDA in 1997 for the intermittent treatment of bouts of increased seizure activity in children and adults.1,18,19 The efficacy of diazepam rectal gel was demonstrated in 2 randomized, placebo-controlled trials.20,21 As a result, the FDA allowed for the utilization of diazepam rectal gel efficacy data in support of the approval of VALTOCO.22,23

See How VALTOCO Works

Learn how the unique formulation of VALTOCO® (diazepam nasal spray) optimizes diazepam for nasal delivery, and how it helps patients manage episodes of frequent seizure activity wherever, whenever.1,7

how VALTOCO works video
 
more information on seizure treatment

Learn about the proven safety and tolerability of VALTOCO.1

See the Data

IMPORTANT SAFETY INFORMATION,
INCLUDING BOXED WARNING

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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 only be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. VALTOCO is contraindicated in patients with narrow-angle glaucoma.

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 read full Prescribing Information, including Boxed Warning, for additional important safety information.

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 only be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. VALTOCO is contraindicated in patients with narrow-angle glaucoma.

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 read full Prescribing Information, including Boxed Warning, for additional important safety information.

References: 1. VALTOCO® (diazepam nasal spray) Prescribing Information. Neurelis, Inc. 2. Maggio ET. Intravail: highly effective intranasal delivery of peptide and protein drugs. Expert Opin Drug Deliv. 2006;3(4):529-539. 3. Parsonage MJ, Norris JW. Use of diazepam in treatment of severe status epilepticus. Br Med J. 1967;3:85-88. 4. Maglalang PD, Rautiola D, Siegel RA, et al. Rescue therapies for seizure emergencies: new modes of administration. Epilepsia. 2018;59(Suppl 2):207-215. 5. Agarwal SK, Kriel RK, Brundage RC, Ivaturi VD, Cloyd JC. A pilot study assessing the bioavailability and pharmacokinetics of diazepam after intranasal and intravenous administration in healthy volunteers. Epilepsy Res. 2013;105:362-367. 6. Data on file. REF-00208. Neurelis, Inc. 7. Data on file. REF-00253. Neurelis, Inc. 8. Sanchez Fernandez I, Gainza-Lein M, Loddenkemper T. Nonintravenous rescue medications for pediatric status epilepticus: a cost-effectiveness analysis. Epilepsia. 2017;58(8):1349-1359. 9. Drugs@FDA: FDA approved drug products. Approval dates, history, and labels; reviews for NDA 020648. Original approvals. 10. Kapoor M, Cloyd JC, Siegel RA. A review of intranasal formulations for the treatment of seizure emergencies. J Control Release. 2016;237:147-159. 11. Greenblatt DJ, Sethy VH. Benzodiazepine concentrations in brain directly reflect receptor occupancy: studies of diazepam, lorazepam, and oxazepam. Psychopharmacology. 1990;102(3):373-378. 12. Maggio ET, Pillion DJ. High efficiency intranasal drug delivery using Intravail® alkylsaccharide absorption enhancers. Drug Deliv Transl Res. 2013;3:16-25. 13. Yang C, Wu T, Qi Y, Zhang Z. Recent advances in the application of vitamin E TPGS for drug delivery. Theranostics. 2018;8(2):464-485. 14. Pieper-Fürst U, Dao V-A, Shah-Hosseini K, et al. Alpha-tocopherol acetate nasal spray in the treatment of pollen-induced allergic rhinitis. Allergo J Int. 2019;28(5):152-159. 15. Testa D, Marcuccio G, Panin G, et al. Nasal mucosa healing after endoscopic sinus surgery in chronic rhinosinusitis of elderly patients: role of topic alpha-tocopherol acetate. Aging Clin Exp Res. 2017; doi: 10.1007/s40520-016-0647-x. 16. Tanimoto S, Koplowitz LP, Lowenthal RE, Koplowitz B, Rabinowicz AL, Carrazana E. Evaluation of pharmacokinetics and dose proportionality of diazepam after intranasal administration of NRL-1 to healthy volunteers. Clin Pharmacol Drug Dev. 2020; doi: 10.1002/cpdd.767. 17. Fisher RS, Bartfeld E, Cramer JA. Use of an online epilepsy diary to characterize repetitive seizures. Epilepsy Behav. 2015;47:66-71. 18. Diastat (diazepam rectal gel) Prescribing Information. Valeant Pharmaceuticals. 19. Drugs@FDA: FDA approved drug products. Approval dates, history, and labels; reviews for NDA 020648. Original approvals. 20. Dreifuss FE, Rosman NP, Cloyd JC, et al. A comparison of rectal diazepam gel and placebo for acute repetitive seizures. N Engl J Med. 1998;338(26):1869-1875. 21. Cereghino JJ, Mitchell WG, Murphy J, et al. Treating repetitive seizures with a rectal diazepam formulation: a randomized study. Neurology. 1998;51(5):1274-1282. 22. US Food and Drug Administration. NDA 211635 approval letter. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2020/211635Orig1s000ltr.pdf. Published January 10, 2020. Accessed September 9, 2020. 23. Center for Drug Evaluation and Research (CDER). NDA 211635 clinical review. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/211635Orig1s000MedR.pdf. Published January 10, 2020. Accessed September 16, 2020.