Introduction
Nayzilam (midazolam) nasal spray is a benzodiazepine medication approved by the FDA in 2019 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 12 years of age and older. It represents the first FDA-approved nasal spray for seizure cluster treatment, providing a convenient alternative to rectal administration.
Mechanism of Action
Nayzilam exerts its therapeutic effects through potent enhancement of gamma-aminobutyric acid (GABA)-mediated neuronal inhibition. Midazolam, the active ingredient, binds to specific benzodiazepine receptors on the GABA-A receptor complex, facilitating the opening of chloride channels. This hyperpolarizes neuronal membranes and reduces neuronal excitability, resulting in anticonvulsant, anxiolytic, sedative, and muscle relaxant properties.
Indications
- FDA-approved for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (seizure clusters, acute repetitive seizures) in patients 12 years of age and older with epilepsy
- Not indicated for continuous daily use or status epilepticus
Dosage and Administration
Recommended dosage: One spray (5 mg) administered into one nostril Second dose: If needed, a second dose may be administered after 10 minutes if the patient has not responded to the first dose Maximum dosage: Do not use more than 2 doses per seizure cluster episode Administration:- Use exactly as prescribed during a seizure cluster episode
- Administer into one nostril while patient is in the position they are found
- Do not prime before each use
- Do not test or train with the device
- Geriatric: Use with caution due to increased sensitivity
- Renal impairment: Use with caution
- Hepatic impairment: Use with caution due to potential prolonged elimination
Pharmacokinetics
Absorption: Rapid nasal absorption with peak plasma concentrations achieved within 10-20 minutes Distribution: Extensive tissue distribution; crosses blood-brain barrier readily; protein binding approximately 97% Metabolism: Extensive hepatic metabolism primarily via CYP3A4 to active (1-hydroxymidazolam) and inactive metabolites Elimination: Primarily renal excretion (90%) as metabolites; elimination half-life approximately 2-6 hoursContraindications
- Hypersensitivity to midazolam or any component of the formulation
- Patients with acute narrow-angle glaucoma
- Significant respiratory depression
- Acute pulmonary insufficiency
- Concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole)
Warnings and Precautions
Boxed Warning: Risk of concomitant use with opioids: Concomitant use may result in profound sedation, respiratory depression, coma, and death Respiratory depression: May occur, especially in patients with compromised respiratory function Sedation: May cause significant sedation and impair mental alertness and physical coordination Abuse and dependence: Potential for abuse, dependence, and withdrawal symptoms Suicidal behavior and ideation: Antiepileptic drugs may increase risk of suicidal thoughts or behavior Glaucoma: Use with caution in patients with open-angle glaucoma Pregnancy: May cause fetal harm; advise of potential risksDrug Interactions
CNS depressants: Enhanced effects with alcohol, opioids, barbiturates, other sedatives CYP3A4 inhibitors: Strong inhibitors (ketoconazole, itraconazole, clarithromycin) increase midazolam concentrations CYP3A4 inducers: Carbamazepine, phenytoin, rifampin may decrease midazolam concentrations Protease inhibitors: May significantly increase midazolam levelsAdverse Effects
Most common adverse reactions (≥5%):- Somnolence (26%)
- Headache (10%)
- Nasal discomfort (9%)
- Rhinorrhea (6%)
- Throat irritation (5%)
- Respiratory depression
- Hypersensitivity reactions
- Paradoxical reactions (agitation, aggression)
- Withdrawal symptoms with prolonged use
Monitoring Parameters
- Respiratory rate and oxygen saturation, especially after administration
- Seizure frequency and characteristics
- Sedation level and cognitive function
- Signs of abuse or misuse
- Suicidal thoughts or behaviors
- Nasal mucosa examination with repeated use
Patient Education
- Use only for seizure clusters as prescribed, not for regular seizures
- Administer exactly as directed during a seizure episode
- Do not use more than 2 doses for a single seizure cluster
- Wait at least 10 minutes between doses if needed
- May cause significant drowsiness; avoid hazardous activities
- Inform healthcare providers of all medications being taken
- Store at room temperature; discard after 8 weeks of first opening
- Seek emergency care if breathing difficulties occur
- Report any new or worsening depression or suicidal thoughts
References
1. FDA prescribing information: Nayzilam (midazolam) nasal spray. 2019 2. Detyniecki K, et al. Neurology. 2019;92(18):e2102-e2113 3. Wheless JW, et al. Epilepsy Behav. 2019;97:27-33 4. Sperling MR, et al. Epilepsia. 2020;61(3):421-429 5. Epilepsy Foundation consensus guidelines: Seizure clusters. 2021 6. Micromedex Solutions: Midazolam monograph. Truven Health Analytics 7. Lexicomp Online: Midazolam drug information. Wolters Kluwer