Midazolam

Agitation, acute/severe (monotherapy or adjunctive therapy) (off-label use):

IV, IM: Initial: 2.5 to 5 mg; repeat doses may be administered every 3 to 5 minutes (IV route) or every 5 to 10 minutes (IM route) until sedation is adequate and appropriate; some patients may require a total dose of ~20 mg; monitor respiratory status; may give alone or in combination with an antipsychotic

General anesthesia or monitored anesthesia care:

IV: Usual dosing range: 0.5 to 2 mg; administered in 0.5 to 1 mg increments based on clinical effect

Mechanically ventilated patients in the ICU, sedation (alternative agent):

Intermittent: Initial: 0.5 to 5 mg or 0.01 to 0.05 mg/kg over ≥2 minutes; may repeat at 10- to 15- minute intervals as needed until goal level of sedation is achieved

Continuous infusion: Loading dose: 0.5 to 5 mg every 1 to 5 minutes (if needed), followed by 1 to 8 mg/hour or 0.01 to 0.1 mg/kg/hour continuous infusion; titrate infusion rate to clinical effect. To prevent high basal continuous infusion rates, consider using additional bolus doses instead to achieve goal level of sedation or clinical effect

Contraindications:

Hypersensitivity to midazolam or any component of the formulation; intrathecal or epidural injection of parenteral forms containing preservatives (ie, benzyl alcohol); use in premature infants for parenteral forms containing benzyl alcohol; acute narrow-angle glaucoma.

Interactions:

CloZAPine: Benzodiazepines may enhance the adverse/toxic effect of CloZAPine. Management: Consider decreasing the dose of (or possibly discontinuing) benzodiazepines prior to initiating clozapine. Risk D: Consider therapy modification

 CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Midazolam. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Midazolam. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Midazolam. Management: Avoid concomitant use of nasal midazolam and moderate CYP3A4 inhibitors. Consider alternatives to use with oral midazolam whenever possible and consider using lower midazolam doses. Monitor patients for sedation and respiratory depression if combined. Risk D: Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Midazolam. Management: Avoid use of nasal midazolam and strong CYP3A4 inhibitors whenever possible, and consider alternatives to use with other routes of midazolam (oral, IV, IM). If combined, consider lower midazolam doses and monitor for increased midazolam toxicities. Risk D: Consider therapy modification

CYP3A4 Inhibitors (Weak): May increase the serum concentration of Midazolam. Risk C: Monitor therapy

Pregnancy and Lactation:

Midazolam crosses the placenta and can be detected in the serum of the umbilical vein and artery, as well as the amniotic fluid. Teratogenic effects have been observed with some benzodiazepines; however, additional studies are needed. The incidence of premature birth and low birth weights may be increased following maternal use of benzodiazepines; hypoglycemia and respiratory problems in the neonate may occur following exposure late in pregnancy.

Midazolam and hydroxymidazolam are present in breast milk, in general, breastfeeding is considered acceptable.

Warning and Precaution:

• Cardiorespiratory effects: Risk of cardiorespiratory adverse events is increased in patients with abnormal airway anatomy, cyanotic congenital heart disease, sepsis, or severe pulmonary disease. In patients with a risk of respiratory depression, consider administering the first dose of intranasal midazolam under health care supervision; this may be performed in the absence of a seizure episode.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving). A minimum of one day should elapse after midazolam administration before attempting these tasks. Elapsed time to resume these tasks must be individualized, as pharmacologic effects are dependent on dose, route, duration of procedure, and presence of other medications.
• Hypotension: May cause hypotension, particularly in pediatric patients or patients with hemodynamic instability. Hypotension may occur more frequently in patients who have received opioid analgesics.
• Paradoxical reactions: Paradoxical reactions, including hyperactive or aggressive behavior, have been reported with benzodiazepines; risk may be increased in adolescent/pediatric patients, geriatric patients, or patients with a history of alcohol use disorder or psychiatric/personality disorders.

Adverse Reactions:

Gastrointestinal: Vomiting (≤11%)

Respiratory: Apnea (adults: 15%; children: 3%), bradypnea (adults: ≤23%), decreased tidal volume (adults: ≤23%), nasal discomfort (intranasal: 5% to 16%)

Storage:

Store below 30°C and protect from freezing.