Diazepam nasal spray: clinical applications and research advances_Journal of Epilepsy

Authors：

WANG Pinchun , MA Xinnan , LU Yeting , PAN Shengjie , XU Min ,  HU Xiaowei

Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China;

Corresponding author：

HU Xiaowei, Email: huxiaowei@suda.edu.cn

Keywords：

Seizure clusters; Prolonged seizures; Diazepam nasal spray; Safety; Efficacy; Seizure intervals

DOI：

10.7507/2096-0247.202504002

Video：

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Seizure clusters, a severe form of epilepsy requiring urgent intervention, are challenging to manage in out-of-hospital settings due to limitations of traditional benzodiazepine administration routes. Diazepam nasal spray (DZP-NS), a novel intranasal formulation, achieves rapid absorption through the nasal mucosa, bypassing first-pass metabolism, with bioavailability comparable to rectal gel and faster onset. Clinical studies demonstrate its high efficacy in treating seizure clusters and prolonged seizures (≥5 minutes), with an initial control rate of 87.4% and low second-dose utilization (12.6%). No severe adverse reactions, such as cardiorespiratory depression, were observed. Long-term use (12 months) showed no tolerance development, significantly extending seizure intervals (SEIVAL) (from 12.2 to 25.7 days) and improving quality of life scores, particularly in "epilepsy-related concerns" and "social functioning" domains. The non-invasive delivery method was favored by over 80% of patients and healthcare providers for its convenience compared to rectal administration. Subgroup analyses confirmed consistent safety and efficacy across genders, ages, concomitant medications (including cannabidiol), and patients with allergy histories. In conclusion, DZP-NS provides an efficient, safe, and socially accepted out-of-hospital rescue therapy for seizure clusters, positioning it as a potential cornerstone in standardized epilepsy emergency care.

1.	Cloyd J, Haut S, Carrazana E, et al. Overcoming the challenges of developing an intranasal diazepam rescue therapy for the treatment of seizure clusters. Epilepsia, 2021, 62(4): 846-856.
2.	Jafarpour S, Hirsch LJ, Gaínza-Lein M, et al. Seizure cluster: definition, prevalence, consequences, and management. Seizure, 2019, 68: 9-15.
3.	中华医学会. 临床诊疗指南癫痫病分册. 北京: 中国人民卫生出版社, 2022.
4.	Penovich PE, Buelow J, Steinberg K, et al. Burden of seizure clusters on patients with epilepsy and caregivers: survey of patient, caregiver, and clinician perspectives. Neurologist, 2017, 22(6): 207-214.
5.	Haut SR, Shinnar S, Moshé SL. Seizure clustering: risks and outcomes. Epilepsia, 2005, 46(1): 146-149.
6.	Penovich PE, Rao VR, Long L, et al. Benzodiazepines for the Treatment of Seizure Clusters. CNS Drugs, 2024, 38(2): 125-140.
7.	Gidal B, Detyniecki K. Rescue therapies for seizure clusters: Pharmacology and target of treatments. Epilepsia, 2022, 63 Suppl 1(Suppl 1): 34-44.
8.	Neurelis I Valtocoò. Diazepam nasal spray. Full Prescribing Information. Neurelis, Inc. , 2023.
9.	Cornett EM, Amarasinghe SN, Angelette A, et al. VALTOCO(®) (diazepam nasal spray) for the acute treatment of intermittent stereotypic episodes of frequent seizure activity. Neurol Int, 2021, 13(1): 64-78.
10.	Higdon LM, Sperling MR. A review of a diazepam nasal spray for the treatment of acute seizure clusters and prolonged seizures. Expert Rev Neurother, 2021, 21(11): 1207-1212.
11.	Santilli N, Dewar S, Guerra C, et al. Use of intranasal rescue therapy for seizure clusters in students with epilepsy: Nurses' knowledge, perceptions, and practice. Epilepsy Behav Rep, 2023, 22: 100604.
12.	Chmielewska N, Szyndler J. Intranasal administration of antiseizure medications in chronic and emergency treatment: Hopes and challenges. Seizure, 2024, 115: 62-67.
13.	Ghadiri M, Young PM, Traini D. Strategies to enhance drug absorption via nasal and pulmonary routes. Pharmaceutics, 2019, 11(3): 6470976.
14.	Lee D, Minko T. Nanotherapeutics for nose-to-brain drug delivery: an approach to bypass the blood brain barrier. Pharmaceutics, 2021, 13(12): 8704573.
15.	Kaur P, Kim K. Pharmacokinetics and brain uptake of diazepam after intravenous and intranasal administration in rats and rabbits. Int J Pharm, 2008, 364(1): 27-35.
16.	Henney HR, Sperling MR, Rabinowicz AL, et al. Assessment of pharmacokinetics and tolerability of intranasal diazepam relative to rectal gel in healthy adults. Epilepsy Res, 2014, 108(7): 1204-1211.
17.	Hogan RE, Gidal BE, Koplowitz B, et al. Bioavailability and safety of diazepam intranasal solution compared to oral and rectal diazepam in healthy volunteers. Epilepsia, 2020, 61(3): 455-464.
18.	Hogan RE, Tarquinio D, Sperling MR, et al. Pharmacokinetics and safety of VALTOCO (NRL-1, diazepam nasal spray) in patients with epilepsy during seizure (ictal/peri-ictal) and nonseizure (interictal) conditions: a phase 1, open-label study. Epilepsia, 2020, 61(5): 935-943.
19.	Rogawski MA, Slatko G. A randomized, open-label, two-treatment crossover study to evaluate the effect of food on the pharmacokinetics of diazepam nasal spray in healthy adults. Epilepsia, 2023, 64(2): 364-373.
20.	Boddu SHS, Kumari S. A Short review on the intranasal delivery of diazepam for treating acute repetitive seizures. Pharmaceutics, 2020, 12(12): 7761129.
21.	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, 29(Suppl 1): 191-195.
22.	Privitera MD, Mendoza LC, Carrazana E, et al. Intracerebral electrographic activity following a single dose of diazepam nasal spray: a pilot study. Epilepsia Open, 2024, 9(1): 380-387.
23.	Becker DA, Wheless JW, Sirven J, et al. Treatment of seizure clusters in epilepsy: a narrative review on rescue therapies. Neurol Ther, 2023, 12(5): 1439-1455.
24.	O'Hara K, Dewar S, Bougher G, et al. Overcoming barriers to the management of seizure clusters: ease of use and time to administration of rescue medications. Expert Rev Neurother, 2023, 23(5): 425-432.
25.	Penovich P, Wheless JW, Hogan RE, et al. Examining the patient and caregiver experience with diazepam nasal spray for seizure clusters: Results from an exit survey of a phase 3, open-label, repeat-dose safety study. Epilepsy Behav, 2021, 121(Pt A): 108013.
26.	Miller I, Wheless JW, Hogan RE, et al. Consistent safety and tolerability of Valtoco(®) (diazepam nasal spray) in relationship to usage frequency in patients with seizure clusters: Interim results from a phase 3, long-term, open-label, repeat-dose safety study. Epilepsia Open, 2021, 6(3): 504-512.
27.	Wheless JW, Miller I, Hogan RE, et al. Final results from a Phase 3, long-term, open-label, repeat-dose safety study of diazepam nasal spray for seizure clusters in patients with epilepsy. Epilepsia, 2021, 62(10): 2485-2495.
28.	Ramsay RE, Becker DA, Vazquez B, et al. Acute abortive therapies for seizure clusters in long-term care. J Am Med Dir Assoc, 2023, 24(8): 1225-1232.
29.	Misra SN, Jarrar R, Stern JM, et al. Rapid rescue treatment with diazepam nasal spray leads to faster seizure cluster termination in epilepsy: an exploratory post hoc cohort analysis. Neurol Ther, 2024, 13(1): 221-231.
30.	Pina-Garza JE, Chez M, Cloyd J, et al. Outpatient management of prolonged seizures and seizure clusters to prevent progression to a higher-level emergency: Consensus recommendations of an expert working group. Epileptic Disord, 2024, 26(4): 484-497.
31.	Misra SN, Sperling MR, Rao VR, et al. Significant improvements in SEIzure interVAL (time between seizure clusters) across time in patients treated with diazepam nasal spray as intermittent rescue therapy for seizure clusters. Epilepsia, 2022, 63(10): 2684-2693.
32.	Wheless JW, Hogan RE, Davis CS, et al. Safety and effectiveness of diazepam nasal spray in male and female patients: Post hoc analysis of data from a phase 3 safety study. Epilepsia Open, 2024, 9(2): 793-799.
33.	Segal EB, Tarquinio D, Miller I, et al. Evaluation of diazepam nasal spray in patients with epilepsy concomitantly using maintenance benzodiazepines: an interim subgroup analysis from a phase 3, long-term, open-label safety study. Epilepsia, 2021, 62(6): 1442-1450.
34.	Tarquinio D, Wheless JW, Segal EB, et al. Safety of diazepam nasal spray in pediatric patients with developmental epileptic encephalopathies: results from a long-term phase 3 safety study. J Child Neurol, 2023, 38(6-7): 389-393.
35.	Tarquinio D, Dlugos D, Wheless JW, et al. Safety of diazepam nasal spray in children and adolescents with epilepsy: results from a long-term phase 3 safety study. Pediatr Neurol, 2022, 132: 50-55.
36.	Cascino GD, Tarquinio D, Wheless JW, et al. Lack of observed tolerance to diazepam nasal spray (Valtoco®) after long-term rescue therapy in patients with epilepsy: Interim results from a phase 3, open-label, repeat-dose safety study. Epilepsy Behav, 2021, 120: 107983.
37.	Cascino GD, Tarquinio D, Wheless JW, et al. Lack of clinically relevant differences in safety and pharmacokinetics after second-dose administration of intranasal diazepam within 4 h for acute treatment of seizure clusters: a population analysis. Epilepsia, 2022, 63(7): 1714-1723.
38.	Sperling MR, Wheless JW, Hogan RE, et al. Use of second doses of Valtoco® (diazepam nasal spray) across 24 hours after the initial dose for out-of-hospital seizure clusters: Results from a phase 3, open-label, repeat-dose safety study. Epilepsia, 2022, 63(4): 836-843.
39.	Cramer JA, Faught E, Davis C, et al. Quality-of-life results in adults with epilepsy using diazepam nasal spray for seizure clusters from a long-term, open-label safety study. Epilepsy Behav, 2022, 134: 108811.
40.	Misra SN, Sperling MR, Rao VR, et al. Analyses of patients who self-administered diazepam nasal spray for acute treatment of seizure clusters. Epilepsy Behav Rep, 2024, 25: 100644.
41.	Fountain NB, Quigg M, Murchison CF, et al. Analysis of seizure-cluster circadian periodicity from a long-term, open-label safety study of diazepam nasal spray. Epilepsia, 2024, 65(4): 920-928.
42.	Liow K, Wheless JW, Cook DF, et al. Diazepam nasal spray administration is effective to control seizure clusters irrespective of time of day. Front Neurol, 2024, 15: 1335421.
43.	Vazquez B, Wheless J, Desai J, et al. Lack of observed impact of history or concomitant treatment of seasonal allergies or rhinitis on repeated doses of diazepam nasal spray administered per seizure episode in a day, safety, and tolerability: Interim results from a phase 3, open-label, 12-month repeat-dose safety study. Epilepsy Behav, 2021, 118: 107898.
44.	Peters JM, Puri V, Segal E, et al. Concomitant cannabidiol does not impact safety and effectiveness of diazepam nasal spray for seizure clusters: Post hoc analysis of a phase 3 safety study. Epilepsy Behav, 2023, 144: 109248.
45.	Jarrar R, Stern JM, Becker DA, et al. Treatment of prolonged seizure with diazepam nasal spray: An exploratory post hoc cohort analysis. Epilepsy Behav, 2024, 159: 109987.
46.	Sperling MR, Haas KF, Krauss G, et al. Dosing feasibility and tolerability of intranasal diazepam in adults with epilepsy. Epilepsia, 2014, 55(10): 1544-1550.

1. Cloyd J, Haut S, Carrazana E, et al. Overcoming the challenges of developing an intranasal diazepam rescue therapy for the treatment of seizure clusters. Epilepsia, 2021, 62(4): 846-856.
2. Jafarpour S, Hirsch LJ, Gaínza-Lein M, et al. Seizure cluster: definition, prevalence, consequences, and management. Seizure, 2019, 68: 9-15.
3. 中华医学会. 临床诊疗指南癫痫病分册. 北京: 中国人民卫生出版社, 2022.
4. Penovich PE, Buelow J, Steinberg K, et al. Burden of seizure clusters on patients with epilepsy and caregivers: survey of patient, caregiver, and clinician perspectives. Neurologist, 2017, 22(6): 207-214.
5. Haut SR, Shinnar S, Moshé SL. Seizure clustering: risks and outcomes. Epilepsia, 2005, 46(1): 146-149.
6. Penovich PE, Rao VR, Long L, et al. Benzodiazepines for the Treatment of Seizure Clusters. CNS Drugs, 2024, 38(2): 125-140.
7. Gidal B, Detyniecki K. Rescue therapies for seizure clusters: Pharmacology and target of treatments. Epilepsia, 2022, 63 Suppl 1(Suppl 1): 34-44.
8. Neurelis I Valtocoò. Diazepam nasal spray. Full Prescribing Information. Neurelis, Inc. , 2023.
9. Cornett EM, Amarasinghe SN, Angelette A, et al. VALTOCO(®) (diazepam nasal spray) for the acute treatment of intermittent stereotypic episodes of frequent seizure activity. Neurol Int, 2021, 13(1): 64-78.
10. Higdon LM, Sperling MR. A review of a diazepam nasal spray for the treatment of acute seizure clusters and prolonged seizures. Expert Rev Neurother, 2021, 21(11): 1207-1212.
11. Santilli N, Dewar S, Guerra C, et al. Use of intranasal rescue therapy for seizure clusters in students with epilepsy: Nurses' knowledge, perceptions, and practice. Epilepsy Behav Rep, 2023, 22: 100604.
12. Chmielewska N, Szyndler J. Intranasal administration of antiseizure medications in chronic and emergency treatment: Hopes and challenges. Seizure, 2024, 115: 62-67.
13. Ghadiri M, Young PM, Traini D. Strategies to enhance drug absorption via nasal and pulmonary routes. Pharmaceutics, 2019, 11(3): 6470976.
14. Lee D, Minko T. Nanotherapeutics for nose-to-brain drug delivery: an approach to bypass the blood brain barrier. Pharmaceutics, 2021, 13(12): 8704573.
15. Kaur P, Kim K. Pharmacokinetics and brain uptake of diazepam after intravenous and intranasal administration in rats and rabbits. Int J Pharm, 2008, 364(1): 27-35.
16. Henney HR, Sperling MR, Rabinowicz AL, et al. Assessment of pharmacokinetics and tolerability of intranasal diazepam relative to rectal gel in healthy adults. Epilepsy Res, 2014, 108(7): 1204-1211.
17. Hogan RE, Gidal BE, Koplowitz B, et al. Bioavailability and safety of diazepam intranasal solution compared to oral and rectal diazepam in healthy volunteers. Epilepsia, 2020, 61(3): 455-464.
18. Hogan RE, Tarquinio D, Sperling MR, et al. Pharmacokinetics and safety of VALTOCO (NRL-1, diazepam nasal spray) in patients with epilepsy during seizure (ictal/peri-ictal) and nonseizure (interictal) conditions: a phase 1, open-label study. Epilepsia, 2020, 61(5): 935-943.
19. Rogawski MA, Slatko G. A randomized, open-label, two-treatment crossover study to evaluate the effect of food on the pharmacokinetics of diazepam nasal spray in healthy adults. Epilepsia, 2023, 64(2): 364-373.
20. Boddu SHS, Kumari S. A Short review on the intranasal delivery of diazepam for treating acute repetitive seizures. Pharmaceutics, 2020, 12(12): 7761129.
21. 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, 29(Suppl 1): 191-195.
22. Privitera MD, Mendoza LC, Carrazana E, et al. Intracerebral electrographic activity following a single dose of diazepam nasal spray: a pilot study. Epilepsia Open, 2024, 9(1): 380-387.
23. Becker DA, Wheless JW, Sirven J, et al. Treatment of seizure clusters in epilepsy: a narrative review on rescue therapies. Neurol Ther, 2023, 12(5): 1439-1455.
24. O'Hara K, Dewar S, Bougher G, et al. Overcoming barriers to the management of seizure clusters: ease of use and time to administration of rescue medications. Expert Rev Neurother, 2023, 23(5): 425-432.
25. Penovich P, Wheless JW, Hogan RE, et al. Examining the patient and caregiver experience with diazepam nasal spray for seizure clusters: Results from an exit survey of a phase 3, open-label, repeat-dose safety study. Epilepsy Behav, 2021, 121(Pt A): 108013.
26. Miller I, Wheless JW, Hogan RE, et al. Consistent safety and tolerability of Valtoco(®) (diazepam nasal spray) in relationship to usage frequency in patients with seizure clusters: Interim results from a phase 3, long-term, open-label, repeat-dose safety study. Epilepsia Open, 2021, 6(3): 504-512.
27. Wheless JW, Miller I, Hogan RE, et al. Final results from a Phase 3, long-term, open-label, repeat-dose safety study of diazepam nasal spray for seizure clusters in patients with epilepsy. Epilepsia, 2021, 62(10): 2485-2495.
28. Ramsay RE, Becker DA, Vazquez B, et al. Acute abortive therapies for seizure clusters in long-term care. J Am Med Dir Assoc, 2023, 24(8): 1225-1232.
29. Misra SN, Jarrar R, Stern JM, et al. Rapid rescue treatment with diazepam nasal spray leads to faster seizure cluster termination in epilepsy: an exploratory post hoc cohort analysis. Neurol Ther, 2024, 13(1): 221-231.
30. Pina-Garza JE, Chez M, Cloyd J, et al. Outpatient management of prolonged seizures and seizure clusters to prevent progression to a higher-level emergency: Consensus recommendations of an expert working group. Epileptic Disord, 2024, 26(4): 484-497.
31. Misra SN, Sperling MR, Rao VR, et al. Significant improvements in SEIzure interVAL (time between seizure clusters) across time in patients treated with diazepam nasal spray as intermittent rescue therapy for seizure clusters. Epilepsia, 2022, 63(10): 2684-2693.
32. Wheless JW, Hogan RE, Davis CS, et al. Safety and effectiveness of diazepam nasal spray in male and female patients: Post hoc analysis of data from a phase 3 safety study. Epilepsia Open, 2024, 9(2): 793-799.
33. Segal EB, Tarquinio D, Miller I, et al. Evaluation of diazepam nasal spray in patients with epilepsy concomitantly using maintenance benzodiazepines: an interim subgroup analysis from a phase 3, long-term, open-label safety study. Epilepsia, 2021, 62(6): 1442-1450.
34. Tarquinio D, Wheless JW, Segal EB, et al. Safety of diazepam nasal spray in pediatric patients with developmental epileptic encephalopathies: results from a long-term phase 3 safety study. J Child Neurol, 2023, 38(6-7): 389-393.
35. Tarquinio D, Dlugos D, Wheless JW, et al. Safety of diazepam nasal spray in children and adolescents with epilepsy: results from a long-term phase 3 safety study. Pediatr Neurol, 2022, 132: 50-55.
36. Cascino GD, Tarquinio D, Wheless JW, et al. Lack of observed tolerance to diazepam nasal spray (Valtoco®) after long-term rescue therapy in patients with epilepsy: Interim results from a phase 3, open-label, repeat-dose safety study. Epilepsy Behav, 2021, 120: 107983.
37. Cascino GD, Tarquinio D, Wheless JW, et al. Lack of clinically relevant differences in safety and pharmacokinetics after second-dose administration of intranasal diazepam within 4 h for acute treatment of seizure clusters: a population analysis. Epilepsia, 2022, 63(7): 1714-1723.
38. Sperling MR, Wheless JW, Hogan RE, et al. Use of second doses of Valtoco® (diazepam nasal spray) across 24 hours after the initial dose for out-of-hospital seizure clusters: Results from a phase 3, open-label, repeat-dose safety study. Epilepsia, 2022, 63(4): 836-843.
39. Cramer JA, Faught E, Davis C, et al. Quality-of-life results in adults with epilepsy using diazepam nasal spray for seizure clusters from a long-term, open-label safety study. Epilepsy Behav, 2022, 134: 108811.
40. Misra SN, Sperling MR, Rao VR, et al. Analyses of patients who self-administered diazepam nasal spray for acute treatment of seizure clusters. Epilepsy Behav Rep, 2024, 25: 100644.
41. Fountain NB, Quigg M, Murchison CF, et al. Analysis of seizure-cluster circadian periodicity from a long-term, open-label safety study of diazepam nasal spray. Epilepsia, 2024, 65(4): 920-928.
42. Liow K, Wheless JW, Cook DF, et al. Diazepam nasal spray administration is effective to control seizure clusters irrespective of time of day. Front Neurol, 2024, 15: 1335421.
43. Vazquez B, Wheless J, Desai J, et al. Lack of observed impact of history or concomitant treatment of seasonal allergies or rhinitis on repeated doses of diazepam nasal spray administered per seizure episode in a day, safety, and tolerability: Interim results from a phase 3, open-label, 12-month repeat-dose safety study. Epilepsy Behav, 2021, 118: 107898.
44. Peters JM, Puri V, Segal E, et al. Concomitant cannabidiol does not impact safety and effectiveness of diazepam nasal spray for seizure clusters: Post hoc analysis of a phase 3 safety study. Epilepsy Behav, 2023, 144: 109248.
45. Jarrar R, Stern JM, Becker DA, et al. Treatment of prolonged seizure with diazepam nasal spray: An exploratory post hoc cohort analysis. Epilepsy Behav, 2024, 159: 109987.
46. Sperling MR, Haas KF, Krauss G, et al. Dosing feasibility and tolerability of intranasal diazepam in adults with epilepsy. Epilepsia, 2014, 55(10): 1544-1550.

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