Introduction
Valtoco® (diazepam nasal spray) is an FDA-approved benzodiazepine formulation indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (seizure clusters, acute repetitive seizures) in patients with epilepsy 6 years of age and older. Unlike traditional rescue medications that require parenteral administration, Valtoco provides a non-invasive, convenient nasal delivery system that can be administered by caregivers outside of healthcare settings.
Mechanism of Action
Valtoco contains diazepam, which potentiates the effects of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Diazepam binds to specific sites on the GABA-A receptor complex, enhancing GABAergic neurotransmission by increasing the frequency of chloride channel opening. This hyperpolarizes neuronal membranes and reduces neuronal excitability, resulting in anticonvulsant, anxiolytic, sedative, and muscle relaxant effects.
Indications
- Acute treatment of intermittent, stereotypic episodes of frequent seizure activity (seizure clusters) in patients 6 years of age and older with epilepsy
- Not indicated for chronic daily use as seizure control
Dosage and Administration
Recommended dosing:- Adults and adolescents (≥12 years): 0.2 mg/kg (maximum 10 mg per dose)
- Children 6-11 years: 0.2 mg/kg (maximum 10 mg per dose)
- A second dose may be administered if needed at least 4 hours after the first dose
- For intranasal use only
- Administer one dose into one nostril
- Prime the device before first use and if not used for 14 days
- No need to prime between doses if administered within 4 hours
- Does not require refrigeration (store at 20-25°C)
- Hepatic impairment: Use with caution; consider dose reduction
- Renal impairment: No specific dosage adjustment recommended
- Elderly: Consider reduced dose due to increased sensitivity
Pharmacokinetics
Absorption: Rapid nasal absorption with peak plasma concentrations achieved within 1.5 hours (Tmax) Distribution: Highly protein-bound (98-99%), crosses blood-brain barrier and placenta Metabolism: Extensive hepatic metabolism via CYP2C19 and CYP3A4 to active metabolites (desmethyldiazepam, temazepam, oxazepam) Elimination: Terminal elimination half-life of diazepam is 30-56 hours; primarily renal excretion of metabolitesContraindications
- Hypersensitivity to diazepam or any component of the formulation
- Acute narrow-angle glaucoma
- Significant respiratory depression
- Myasthenia gravis
- Severe hepatic insufficiency
- Sleep apnea syndrome
Warnings and Precautions
Boxed Warning: Risks of concomitant use with opioids (profound sedation, respiratory depression, coma, and death)- CNS depression: May impair mental and/or physical abilities
- Abuse and dependence: Potential for misuse, abuse, and dependence
- Suicidal behavior and ideation: Antiepileptic drugs increase risk
- Glaucoma: May increase intraocular pressure
- Withdrawal symptoms: Abrupt discontinuation may precipitate withdrawal seizures
- Status epilepticus: Not for treatment of status epilepticus
Drug Interactions
Major interactions:- Opioids: Increased CNS and respiratory depression (contraindicated)
- Other CNS depressants: Alcohol, barbiturates, sedatives (additive effects)
- CYP3A4 inhibitors (ketoconazole, clarithromycin): Increased diazepam levels
- CYP3A4 inducers (carbamazepine, phenytoin): Decreased diazepam levels
- Proton pump inhibitors: May decrease diazepam absorption
Adverse Effects
Most common (≥4%):- Somnolence (14%)
- Headache (10%)
- Nasal discomfort (7%)
- Rhinorrhea (4%)
- Dysgeusia (4%)
- Respiratory depression
- Psychological and physical dependence
- Suicidal ideation and behavior
- Withdrawal symptoms
- Paradoxical reactions (agitation, aggression)
Monitoring Parameters
- Seizure frequency and characteristics
- Respiratory rate and oxygen saturation (especially with concomitant CNS depressants)
- Signs of excessive sedation
- Mental status changes
- Nasal mucosa integrity with repeated use
- Signs of misuse, abuse, or dependence
- Suicidal ideation and behavior
Patient Education
- Administer exactly as prescribed (not for daily use)
- Proper administration technique: Insert tip into nostril and press plunger firmly
- Do not use more than one dose per seizure cluster episode
- Wait at least 4 hours before administering a second dose if needed
- Avoid activities requiring mental alertness (driving, operating machinery) until effects known
- Avoid alcohol and other CNS depressants
- Report any signs of respiratory depression, excessive sedation, or suicidal thoughts
- Store at room temperature; do not refrigerate or freeze
- Proper disposal of used devices
References
1. FDA prescribing information: Valtoco (diazepam nasal spray) 2. Detyniecki K, Van Ess PJ, Sequeira DJ, et al. Safety and efficacy of midazolam nasal spray in the outpatient treatment of patients with seizure clusters: A randomized, double-blind, placebo-controlled trial. Epilepsia. 2019;60(9):1797-1808. 3. Wheless JW, Isojarvi J, Lee D, et al. Safety and efficacy of diazepam nasal spray in patients with epilepsy: A phase 3, double-blind, randomized trial. Epilepsia. 2020;61(3):455-464. 4. Sperling MR, Klein P, Tsai J. Randomized, double-blind, placebo-controlled phase 3 study of the efficacy and safety of diazepam nasal spray in patients with seizure clusters. Epilepsy Res. 2021;169:106531. 5. National Institute for Health and Care Excellence (NICE). Diazepam nasal spray for treating seizure clusters. 2021. 6. Epilepsy Foundation. Rescue Therapies for Seizure Clusters. 2022.