TABLE 1.

Alternative (nonintravenous) routes for rescue therapies ² , ⁵ , ⁶ , ⁷ , ⁹ , ¹⁰ , ²⁶ , ²⁷ , ⁶⁹

Route	Drug(s)	Advantages	Disadvantages
Approved by the US Food and Drug Administration
Rectal	Diazepam Doses: .2, .3, .5 mg/kg Patient age: ≥2 years Bioavailability: 90% vs. IV diazepam AEs in ≥4%: somnolence, diarrhea, headache	Can administer relatively large dose volume Relatively painless	Inconsistent absorption and bioavailability Limited medications can be delivered by this route Poor social acceptability
Intranasal	Diazepam Doses: 5, 10, 15, 20 mg Patient age: ≥6 years Bioavailability: 97% vs. IV diazepam AEs in ≥4%: somnolence, headache, nasal discomfort Midazolam Dose: 5 mg Patient age: ≥12 years Bioavailability: mean absolute ~44% AEs in ≥5%: somnolence, headache, nasal discomfort, throat irritation, rhinorrhea	Quick and easy administration Relatively fast absorption and onset of action Safe Patient cooperation not needed Relatively painless Avoids first‐pass metabolism Socially acceptable vs. rectal route Possible direct brain delivery of drug	Need for delivery device (e.g., atomizer) Possible CNS TEAEs Variable absorption and bioavailability depending on mucosal health and specific benzodiazepine Formulations require high drug concentration in a small volume Nasal/throat discomfort, inflammation, lacrimation, abnormal taste Need to enhance drug solubility
Intramuscular	Midazolam	Easy access Accommodates many medications Relative rapid absorption and high bioavailability Relative rapid onset of action	Need skill for IM injection Injection‐site reactions (lower risk vs. SC); infection Painful
Investigational therapies
Intranasal	Diazepam prodrug	Quick and easy administration Relatively fast absorption and onset of action Safe Patient cooperation not needed Relatively painless Avoids first‐pass metabolism Socially acceptable vs. rectal route Possible direct brain delivery of drug	Need for delivery device (e.g., atomizer) Possible CNS TEAEs Variable absorption and bioavailability depending on mucosal health and specific benzodiazepine Nasal/throat discomfort, inflammation, lacrimation, abnormal taste
Intramuscular	Diazepam Diazepam prodrug Lorazepam	Easy access Accommodates many medications	Slow drug absorption (midazolam exception) Variable onset of action and bioavailability Need skill for IM injection Injection‐site reactions (lower risk vs. SC); infection Painful
Buccal	Diazepam Midazolam	Easy to use Can administer a relatively large dose volume Painless Avoids first‐pass metabolism	Limited medications can be delivered by this route Potentially distasteful Inconsistent absorption Swallowing reduces buccal delivery Difficult when patient is experiencing a seizure Precautions to reduce risk of biting
Sublingual	Lorazepam Diazepam	Easy to use Painless	Must avoid swallowing Requires compliance Precautions to reduce risk of biting Slow to appear in systemic circulation
Intrapulmonary	Alprazolam	Fastest rate of absorption vs. all other routes Rapid onset of action	Dose determination difficult Requires tight control of aerosolized drug particles, drug and excipients, quality, and purity Limited medications can be delivered by this route

Abbreviations: AE, adverse event; CNS, central nervous system; IM, intramuscular; IV, intravenous; SC, subcutaneous; TEAE, treatment‐emergent adverse event.