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By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved midazolam nasal spray (midazolam NS) for the acute treatment of seizure clusters. Midazolam is a widely used short-acting benzodiazepine sedative/anxiolytic (available since 1985). Intranasal administration, using the parenteral form, has been used for years as a rescue drug for seizures. The new nasal formulation is distributed as Nayzilam.
Midazolam NS should be prescribed to treat acute intermittent, stereotypic episodes of frequent seizure activity (acute repetitive seizures, seizure clusters) that are distinct from the patient’s usual seizure patterns. The drug is for patients with epilepsy who are ≥ 12 years of age.1
The recommended initial dose is 5 mg (one spray) into one nostril.1 A second dose may be given into the opposite nostril after 10 minutes (if the patient has not responded to the first dose). For patients at risk for respiratory depression from a benzodiazepine, a test dose should be administered under supervision in the absence of a seizure episode.1 Midazolam NS is available as a single-dose nasal spray unit (with a plunger) containing 5 mg of midazolam per 0.1 mL.
Midazolam NS is the first intranasal benzodiazepine approved for this indication. It is 10 times more concentrated than the off-label solution using the parenteral form (5 mg/mL), which typically would require administering 1 mL. The nostril has limited capacity to handle more than about 0.25 mL; administer too much, and the patient may swallow the excess.2 Midazolam NS (base form) is potentially less irritating to the nasal mucosal because of lower acidity compared to the parenteral acidic form (pH of 5-9 vs. 3-5).1,3
The most common adverse reactions are sleepiness, headache, runny nose, nasal discomfort, and throat irritation.1 Midazolam NS is contraindicated for patients with acute narrow angle glaucoma and moderate or strong CYP3A4 inhibitors. It shares the same warnings and precautions with benzodiazepines and antiepileptic drugs. Currently, it is not FDA-approved for use in patients younger than 12 years of age.
The effectiveness of midazolam NS was evaluated in a randomized, double-blind, placebo-controlled trial that included participants with intermittent, stereotypic episodes of frequent seizure activity that was distinct from their usual seizure patterns.1 Eligible participants (i.e., those predetermined to tolerate the drug in the absence of a seizure episode) were randomized to midazolam NS (n = 134) or placebo (n = 67). If seizure activity recurred or persisted, a subsequent dose (drug or placebo) was administered between 10 minutes and six hours after the initial dose. Treatment success was termination of seizure within 10 minutes after the initial dose and absence of a recurrence within six hours. Success rates were 53.7% for midazolam NS and 34.3% for placebo. Initial success rates (within 10 minutes) were 80.6% vs. 70.1% and absences of recurrence were 37.3% vs. 46.3%, along with statistically longer time to next seizure.
Seizure clusters are common in patients with severe and intractable epilepsy.4 The definition of seizure cluster has not been uniformly accepted. Still, a common definition is ≥ 2 seizures in 24 hours, two to four seizures in < 48 hours, two generalized tonic clonic seizures or three complex partial seizures in four hours, or a three- or four-fold increase in seizure frequency within a three-day period.4 Mainly, benzodiazepines are used as rescue medicine for seizure clusters. The most commonly used types are oral lorazepam, rectal diazepam, oral diazepam, and intranasal midazolam.4 Only rectal diazepam is FDA-approved to control more bouts of seizure activity. Intranasal midazolam has been administered in various ways, using the parenteral solution by instilling the solution directly with a syringe (with or without an atomizer) or even instilling directly into the nostril from the ampules.5,6 Generally, intranasal midazolam is considered to be at least as effective as (and possibly more effective than) rectal diazepam and, traditionally, is preferred by caregivers.7,8 Midazolam NS offers an FDA-approved treatment with greater ease of use and likely is better tolerated. It will be a schedule IV drug. Currently, cost information is unavailable.
Internal Medicine Alert’s Physician Editor Stephen Brunton, MD, is a retained consultant for Abbott, Acadia, Allergan, AstraZeneca, Avadel, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Mylan, and Salix; he serves on the speakers bureau of AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, and Novo Nordisk. Peer Reviewer Gerald Roberts, MD; Editor Jonathan Springston; Editorial Group Manager Leslie Coplin; and Accreditations Manager Amy M. Johnson, MSN, RN, CPN, report no financial relationships relevant to this field of study.