Midazolam, Midazolam Hydrochloride (Monograph)

Brand names: Nayzilam, Seizalam
Drug class: Benzodiazepines

Medically reviewed by Drugs.com on Nov 10, 2024. Written by ASHP.

Warning

Associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings.¹ ²¹⁹
Death or hypoxic encephalopathy has resulted when respiratory depression was not recognized promptly and treated effectively.¹
Use IV and oral midazolam only in hospital and ambulatory care settings equipped to provide continuous monitoring of cardiorespiratory function; resuscitative drugs, equipment, and personnel should be immediately available.¹ ²¹⁹
For deeply sedated pediatric patients, an individual other than the clinician performing the procedure should be dedicated to monitoring the patient throughout the procedure.¹ ²¹⁹

Must individualize dosage.¹ Initial IV dose for healthy adults should not exceed 2.5 mg.¹
Lower dosages are necessary in patients >60 years of age, debilitated patients, and patients receiving concomitant opiates or other CNS depressants.¹
Titrate initial and subsequent dosages slowly; administer the appropriate dose over ≥2 minutes and wait an additional 2 or more minutes to fully evaluate the sedative effect.¹
Administer by direct IV injection as the 1-mg/mL solution or dilute the 1- or 5-mg/mL solution to facilitate slower administration.¹
Calculate pediatric dosage for sedation on a mg/kg basis.¹ Initial dose is dependent on age, procedure, and route; titrate subsequent dosages slowly.¹
Do not administer by rapid IV injection in neonates.¹ Severe hypotension and seizures have been reported following rapid IV administration, particularly with concomitant administration of fentanyl.¹

Concomitant use of benzodiazepines and opiates may result in profound sedation, respiratory depression, coma, and death.¹ ²¹⁹ ⁷⁰⁰ ⁷⁰¹ ⁷⁰³ ⁷⁰⁵ ⁷⁰⁶ ⁷⁰⁷ ⁷⁷³ ⁷⁷⁴
Reserve concomitant use for patients in whom alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy and monitor closely for respiratory depression and sedation.¹ ²¹⁹ ⁷⁰⁰ ⁷⁰³ ⁷⁷³ ⁷⁷⁴

Introduction

Benzodiazepine;¹ ² ⁴ ⁵ ⁶ ⁷ ¹⁷ ²¹⁹ ⁷⁷³ ⁷⁷⁴ anticonvulsant,⁷⁷³ ⁷⁷⁴ anxiolytic, sedative/hypnotic, and has amnestic properties.¹ ² ⁴ ⁷ ⁷⁰ ⁸⁴ ⁸⁶ ¹⁰⁴ ¹⁷⁷ ¹⁷⁸ ²¹⁹ ⁷⁷³ ⁷⁷⁴

Uses for Midazolam, Midazolam Hydrochloride

Preoperative Sedation, Anxiolysis, and Amnesia

Used preoperatively to produce sedation, anxiolysis, and anterograde amnesia.¹ ² ⁴ ⁵ ⁶ ⁷ ¹⁰ ¹¹ ²⁵ ²⁶ ³² ³⁵ ⁶⁶ ²¹⁹

Particularly useful when relief of anxiety and diminished recall of events associated with the surgical procedure are desired.² ⁴ ⁷ ⁶⁶ ⁶⁹ ⁸³ ¹⁵²

Some clinicians consider midazolam the benzodiazepine of choice for preoperative use for short surgical procedures because of its relatively rapid onset and short duration of effect and improved local tolerance at the site of injection compared with other currently available parenteral benzodiazepines.² ⁴ ⁷ ¹⁴ ³² ¹⁷³ ¹⁷⁴ ¹⁸¹

Use only in monitored settings.¹ ²¹⁹ (See Boxed Warning.)

Procedural Sedation

Used alone or in combination with other CNS depressants for procedural sedation, anxiolysis, and amnesia.¹ ²¹⁹ ⁸²¹ Has been administered prior to dental² ⁴ ⁷ ¹⁴ ³⁵ ⁶⁶ ¹³⁰ ¹³¹ ¹⁷⁶ or other minor surgical procedures; diagnostic, therapeutic, or endoscopic procedures such as upper GI endoscopy,¹ ² ⁷ ⁷¹ ⁷² ⁷³ ⁷⁴ ⁷⁵ ⁷⁶ ⁷⁷ ⁷⁸ ⁷⁹ bronchoscopy,¹ ² ⁸⁰ or cystoscopy;¹ ² ⁷ ¹¹⁵ cardiac catheterization;¹ ² ⁷ ³⁵ ⁸⁵ coronary angiography;¹ ⁵⁰ ⁸⁵ oncology procedures;¹ radiologic procedures¹ (e.g., computerized tomography);¹ ⁸⁹ and suture of lacerations.¹

Particularly useful when relief of anxiety and diminished recall of events associated with the procedure are desired.² ⁴ ⁷ ¹⁷⁷ ¹⁷⁸

Produces amnestic and sedative effects, but no analgesia; therefore, usually administered in conjunction with an analgesic agent.⁸²¹ ⁸²²

Some clinicians consider midazolam the benzodiazepine of choice for moderate sedation (formerly known as conscious sedation) prior to short procedures¹⁴ ¹⁸¹ because of its relatively rapid onset,² ⁴ ⁷ ¹⁴ ⁷⁴ ⁷⁵ ⁷⁹ ⁸⁶ ¹⁷⁸ short duration of action,⁴ ⁷ ²⁶ ⁴⁶ ⁷⁴ ⁷⁵ ⁸⁶ ⁸⁷ ¹⁷⁶ ¹⁷⁸ pronounced amnesic effect,⁷ ²⁵ ⁷³ ⁷⁴ ⁷⁵ ⁷⁸ ⁷⁹ ¹¹⁵ ¹⁷⁸ and improved local tolerance at the site of injection² ⁷ ¹⁴ ²⁵ ⁷⁴ ⁷⁵ ⁷⁶ ⁷⁸ ⁷⁹ ⁸⁶ ⁸⁷ ¹⁷⁶ ¹⁷⁷ ¹⁷⁸ compared with other currently available IV benzodiazepines.

Use only in monitored settings.¹ ²¹⁹ (See Boxed Warning.)

Induction and Maintenance of Anesthesia

Used IV for induction of general anesthesia prior to administration of other anesthetic agents.¹ ² ⁴ ⁷ ¹⁴ ²⁵ ³⁵ ⁷⁰ ⁸⁴ ⁸⁷ ⁹⁵ ⁹⁹ ¹⁰⁰ ¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹⁰⁵ ¹⁰⁶ ¹⁰⁷ ¹⁰⁸ ¹²⁵

Induction with midazolam provides anxiolysis, anterograde amnesia, and dose-related hypnotic effects (progressing from sedation to loss of consciousness), but not analgesia.² ⁴ ⁷ ⁷⁰ ⁸⁴ ⁸⁶ ¹⁰⁴ ¹⁷⁷ ¹⁷⁸

Also may be used for maintenance of anesthesia during short surgical procedures,¹ ² ⁴ ¹⁴ ²⁷ ¹⁰⁰ ¹¹³ ¹¹⁴ usually in conjunction with inhalation anesthetic agents, balanced anesthesia (e.g., nitrous oxide and oxygen), and/or opiate agonists (e.g., fentanyl).¹ ⁷⁰ ¹¹² ¹¹³ ¹⁸⁴ Should not be used alone for maintenance of anesthesia.² ²⁷ ⁷⁰ ¹⁸⁴

Sedation in Critical Care Settings

Used as a continuous IV infusion for sedation of intubated and mechanically ventilated patients in critical care settings (e.g., ICU).¹ ²²⁰ ²²¹ ²²² ²²³ ⁸⁰⁰ ⁸⁰¹

Nonbenzodiazepine sedatives (dexmedetomidine or propofol) are generally preferred to benzodiazepines in mechanically ventilated critically ill adults because of some modest clinical benefits that have been demonstrated (e.g., reduced duration of mechanical ventilation, shorter time to extubation, reduced risk of delirium).²²⁰ ²²¹ ²²³ ⁸⁰⁰ ⁸⁰¹ ⁸¹⁷ ⁸¹⁸ ⁸¹⁹ ⁸²⁰

When selecting an appropriate sedative agent, consider patient's individual sedation goals in addition to specific drug-related (e.g., pharmacology, pharmacokinetics, adverse effects, availability, cost) and patient-related (e.g., comorbid conditions such as anxiety, seizures, or alcohol withdrawal) factors.⁸⁰⁰ ⁸⁰¹

Status Epilepticus

Used IM for treatment of status epilepticus.⁵⁴⁵ ⁷⁶³ ⁷⁷⁴

Benzodiazepines are considered initial drugs of choice for management of status epilepticus because of their rapid onset of action, demonstrated efficacy, safety, and tolerability.⁵⁴⁵ ⁵⁶³ ⁷⁵⁷ ⁷⁵⁸ ⁷⁵⁹ ⁷⁶¹ ⁷⁶² ⁷⁶³ ⁷⁶⁴ ⁷⁶⁵ ⁷⁶⁶ ⁷⁷¹ Evidence supports use of IV lorazepam, IV diazepam, or IM midazolam.⁵⁴⁵ ⁷⁶³ ⁷⁶⁴ ⁷⁶⁵ ⁷⁶⁶ ⁷⁶⁷ ⁷⁶⁸ ⁷⁶⁹ Individualize choice of therapy based on local availability, route of administration, pharmacokinetics, cost, and other factors (e.g., treatment setting).⁵⁴⁵ ⁷⁵⁶ ⁷⁵⁷ ⁷⁵⁸ ⁷⁵⁹ ⁷⁶⁰ ⁷⁶¹ ⁷⁶² ⁷⁶³ ⁷⁶⁴ ⁷⁶⁵ ⁷⁶⁶ ⁷⁶⁷ ⁷⁶⁹

IM midazolam may be useful when IV administration of a benzodiazepine is not possible (e.g., in a prehospital setting).⁷⁶³ ⁷⁶⁵ ⁷⁶⁸

Acute Repetitive Seizures or Seizure Clusters

Used intranasally for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from the patient's usual seizure pattern.⁷⁷³

Agitation

Has been used for management of acute agitation^{† [off-label]}.⁵³ ⁹⁰ ¹⁴⁶ ¹⁴⁷ ¹⁴⁸ ¹⁸¹

Midazolam, Midazolam Hydrochloride Dosage and Administration

General

Administer IV and oral midazolam in a monitored setting equipped to provide continuous monitoring of cardiorespiratory function; resuscitative drugs, personnel, and equipment for airway and ventilation management should be immediately available.¹ ²¹⁹ ⁸²¹ (See Boxed Warning.)
When used for status epilepticus, administer IM midazolam in a setting that allows for immediate access to resuscitative drugs; continuously monitor patient's cardiorespiratory function until stabilized.⁷⁷⁴
In patients at increased risk of benzodiazepine-induced respiratory depression, consider administration of midazolam nasal spray under supervision of a healthcare professional.⁷⁷³

Administration

Administer orally,²¹⁹ by IM injection, or by slow IV injection¹ ² ⁴ ¹⁵⁰ ¹⁸¹ ²¹⁹ or IV infusion.¹ ³⁶ ⁹⁰ ¹⁵⁰ ¹⁸¹ ²¹⁹ ⁵⁸⁰ Has been used in IV patient-controlled analgesia (PCA).²⁵² Also may be administered intranasally.⁷⁷³ Avoid intra-arterial injection or extravasation of the drug.¹ Do not administer intrathecally or epidurally.¹

Oral Administration

Oral solution intended for use in monitored settings (e.g., hospital or ambulatory care setting); do not use for chronic or home use.²¹⁹

Consult manufacturer’s labeling for instruction on use of the special press-in bottle adapter and oral dispensers for administration of the oral solution.²¹⁹

Administer from the individual oral dispenser directly into the child’s mouth; do not mix the oral solution with any other liquid (e.g., grapefruit juice) prior to administration.²¹⁹

Effect of food on absorption of the oral solution has not been determined, but food intake generally is precluded prior to procedural sedation in pediatric patients.²¹⁹

IM Administration

Administer IM injection deeply into a large muscle mass.¹

In patients with status epilepticus, administer IM injection (Seizalam) into mid-outer thigh (vastus lateralis muscle).⁷⁷⁴ Manufacturer recommends administration by a clinician who is adequately trained in the recognition and management of status epilepticus.⁷⁷⁴

IV Administration

Administer by IV injection for procedural or preoperative sedation or for induction of general anesthesia.¹ Administer by continuous IV infusion for sedation in critical care settings.¹

IV injections should be made in incremental doses.¹ ¹⁶³

Use of the 1-mg/mL injection is recommended to facilitate slow direct IV injection of the drug;¹ ¹⁹³ the 1- and 5-mg/mL injections may be diluted with a compatible diluent to facilitate slower injection.¹

For administration as a continuous IV infusion, the manufacturer recommends dilution of the 5-mg/mL injection to a concentration of 0.5 mg/mL with a compatible diluent.¹ Other standard concentrations for continuous IV infusion of midazolam have been recommended by ASHP's Standardize 4 Safety initiative in adults and pediatric patients (see Standardize 4 Safety section below).²⁵⁰ ²⁵¹

Standardize 4 Safety

Standardized concentrations for IV midazolam have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. Multidisciplinary expert panels were convened to determine recommended standard concentrations. Because recommendations from the S4S panels may differ from the manufacturer’s prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. For additional information on S4S (including updates that may be available), see [Web].²⁵⁰ ²⁵¹ ²⁵²

Table 1: Standardize 4 Safety Continuous IV Infusion Standard Concentrations for Midazolam250251
Patient Population	Concentration Standard	Dosing Units
Adults	1 mg/mL 5 mg/mL	mg/hr
Pediatric patients (<50 kg)	0.3 mg/mL (easier pump programming than 0.35 mg/mL less decimal)	mg/kg/hr
	1 mg/mL
	5 mg/mL

Table 2: Standardize 4 Safety PCA Standard Concentrations for Midazolam252
Patient Population	Concentration Standard	Dosing Units
Adults	1 mg/mL	mg/kg/hr
	5 mg/mL
Pediatric patients (<50 kg)	0.1 mg/mL	mg/kg/hr
	2 mg/mL
	5 mg/mL

Rate of Administration in Pediatric Patients

IV injection for preoperative or procedural sedation: Administer IV injection over 2–3 minutes; wait an additional 2–3 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose.¹

Do not administer by rapid IV injection in neonates.¹ (See Boxed Warning.)

Continuous IV infusion: Individualize the infusion rate.¹

Rate of Administration in Adults

IV injection for procedural sedation: Administer appropriate dose as a 1-mg/mL solution over ≥2 minutes; allow ≥2 minutes to evaluate the sedative effect.¹ ¹⁶³ ¹⁹³

IV injection for induction of anesthesia: Administer appropriate dose over 20–30 seconds.¹

Continuous IV infusion: Individualize infusion rate.¹

Intranasal Administration

Administer intranasally using single-dose nasal spray unit supplied by manufacturer.⁷⁷³ Each nasal spray unit delivers 5 mg of midazolam in 0.1 mL of solution.⁷⁷³

Commercially available in boxes of 2 nasal spray units; each unit is contained within an individual blister pack that should not be opened until ready to use.⁷⁷³ Do not test or prime nasal spray unit before use.⁷⁷³

Consult manufacturer's instructions for additional information on use of midazolam nasal spray.⁷⁷³

Dosage

Commercially available as midazolam or midazolam hydrochloride; dosage expressed in terms of midazolam.¹ ²¹⁹ ⁵⁸⁰ ⁷⁷³ ⁷⁷⁴

Individualize dosage, particularly when used with other drugs capable of producing CNS depression.¹ ²¹⁹ Dosage requirements will vary depending on patient response, type and duration of procedure, and concomitantly administered drugs.¹

Pediatric Patients

Unlike adults, pediatric patients generally receive increments of midazolam on a mg/kg basis; calculate dosage in obese children based on ideal body weight.¹ ²¹⁹ Pediatric patients generally require higher dosages on a mg/kg basis than adults;¹ patients <6 years of age generally require higher drug dosages on a mg/kg basis than older children and may require closer monitoring.¹ ²¹⁹

Preoperative Sedation, Anxiolysis, and Amnesia

Oral

Children 6 months to 16 years of age: 0.25–0.5 mg/kg as a single dose, depending on the status of the patient and the desired effect (up to maximum of 20 mg).²¹⁹

A dose of 0.25 mg/kg may be sufficient for older children 6–16 years of age or for cooperative patients, especially if the anticipated intensity and duration of sedation is less critical.²¹⁹

Younger children (e.g., 6 months to <6 years of age) and less cooperative patients may require a higher than usual dose of up to 1 mg/kg (maximum 20 mg).²¹⁹

Consider a dose of 0.25 mg/kg for patients with cardiac or respiratory compromise, other higher-risk surgical patients, and those who have received concomitant opiates or other CNS depressants.²¹⁹

IV

Nonintubated patients <6 months of age: Limited dosing information is available.¹ Dosing recommendations are unclear because of uncertainty about when a patient transfers from a neonatal to pediatric physiology.¹ However, titration of the dose in small increments to clinical effect and careful monitoring are essential, since such patients are vulnerable to airway obstruction and hypoventilation.¹

Children 6 months to 5 years of age: Initially, 0.05–0.1 mg/kg; a total dose of up to 0.6 mg/kg may be required to reach the desired endpoint, but total dose usually does not exceed 6 mg.¹

Children 6–12 years of age: Initially, 0.025–0.05 mg/kg; a total dose of up to 0.4 mg/kg may be required to reach the desired endpoint, but total dose usually does not exceed 10 mg.¹

Adolescents 12–16 years of age: Dose as adults; although some patients in this age range may require higher than recommended adult doses, total dose usually does not exceed 10 mg.¹

Wait 2–3 minutes to fully evaluate sedative effect before initiating procedure or repeating a dose.¹ If further sedation is necessary, continue to titrate in small increments until appropriate level of sedation is achieved.¹

Dosage must be reduced in pediatric patients receiving opiates or other sedatives as premedications; higher-risk or debilitated patients may require lower dosages regardless of whether sedating premedication was administered.¹

IM

Non-neonatal pediatric patients: Usual dose is 0.1–0.15 mg/kg; doses up to 0.5 mg/kg have been used for more anxious patients.¹ Total dose usually does not exceed 10 mg, although this has not been systematically studied.¹

If midazolam is administered with an opiate, reduce the initial dose of each drug.¹

Procedural Sedation

The depth of sedation/anxiolysis needed depends on the type of procedure performed.¹ Sedation is a continuum ranging from minimal sedation to general anesthesia; titrate dosage slowly to desired clinical effect.⁸²¹ ⁸²² ⁸²³

Oral

Children 6 months to 16 years of age: 0.25–0.5 mg/kg as a single dose, depending on the status of the patient and the desired effect (up to maximum of 20 mg).²¹⁹

A dose of 0.25 mg/kg may be sufficient for older children 6–16 years of age or for cooperative patients, especially if the anticipated intensity and duration of sedation are less critical.²¹⁹

Younger children (e.g., 6 months to <6 years of age) and less cooperative patients may require a higher than usual dose of up to 1 mg/kg (maximum 20 mg).²¹⁹

Consider an initial dose of 0.25 mg/kg for patients with cardiac or respiratory compromise, other higher-risk surgical patients, and those who have received concomitant opiates or other CNS depressants.²¹⁹

IV

Nonintubated patients <6 months of age: Limited dosing information is available.¹ Dosing recommendations are unclear because of uncertainty about when a patient transfers from a neonatal to pediatric physiology; however, titration of the dose in small increments to clinical effect and careful monitoring are essential, since such patients are vulnerable to airway obstruction and hypoventilation.¹

Children 6 months to 5 years of age: Initially, 0.05–0.1 mg/kg; a total dose of up to 0.6 mg/kg may be required to reach the desired endpoint, but total dose usually does not exceed 6 mg.¹

Children 6–12 years of age: Initially, 0.025–0.05 mg/kg; a total dose of up to 0.4 mg/kg may be required to reach the desired endpoint, but total dose usually does not exceed 10 mg.¹

Adolescents 12–16 years of age: Dose as adults;¹ some patients may require higher than recommended adult doses, but total dose usually does not exceed 10 mg.¹

IM

If midazolam is administered with an opiate, reduce the initial dose of each drug.¹

Sedation in Critical Care Settings

Neonates (Intubated)

IV loading doses should not be used in neonates; rather, the infusion may be administered more rapidly for the first several hours to establish therapeutic plasma drug concentrations.¹

Preterm neonates (born at <32 weeks’ gestation): Initially, 0.03 mg/kg per hour (0.5 mcg/kg per minute).¹

Term neonates (born after 32 weeks’ gestation): Initially, 0.06 mg/kg per hour (1 mcg/kg per minute).¹

Reassess infusion rate carefully and frequently, particularly after the first 24 hours, to administer the lowest possible effective dosage and reduce potential for drug accumulation.¹ This is particularly important because of the potential for adverse effects related to benzyl alcohol metabolism if not using the preservative-free formulation.¹

Non-neonatal Pediatric Patients (Intubated)

Initially, 0.05–0.2 mg/kg over at least 2–3 minutes as a loading dose; may be followed by a continuous IV infusion initiated at a rate of 0.06–0.12 mg/kg per hour (1–2 mcg/kg per minute) to maintain the clinical effect.¹

Increase or decrease the infusion rate as required, generally by 25% of the initial or subsequent infusion rate, or administer supplemental IV doses to increase or maintain the desired effect.¹ Perform frequent patient assessments at regular intervals using standard pain/sedation scales.¹

Midazolam infusions have been used in children whose trachea was intubated but who were allowed to breathe spontaneously; however, assisted ventilation is recommended in those who are receiving other CNS depressants (e.g., opiates).¹

In hemodynamically compromised children, initiate therapy by titrating the usual loading dose in small increments; monitor the patient closely for hemodynamic instability (e.g., hypotension).¹

Status Epilepticus

Some clinicians recommend an IM dose of 10 mg for patients weighing >40 kg and a dose of 5 mg for those 13–40 kg.⁷⁶³

Other clinicians have recommended usual dose of 0.15–0.3 mg/kg.⁵⁴⁵

Acute Repetitive Seizures or Seizure Clusters

Intranasal

Pediatric patients ≥12 years of age: 1 spray (5 mg) into one nostril.⁷⁷³ May administer an additional spray into opposite nostril after 10 minutes if no response to first dose; however, a second dose should not be administered if patient has difficulty breathing or excessive sedation that is uncharacteristic for the patient during a seizure cluster episode.⁷⁷³

Do not use more than 2 doses to treat a single seizure episode.⁷⁷³

Manufacturer recommends not to use to treat more than one seizure episode every 3 days and more than 5 seizure episodes a month.⁷⁷³

Adults

Preoperative Sedation, Anxiolysis, and Amnesia

IM

Adults <60 years of age with good risk (ASA Physical Status I and II): Usual dose is 0.07–0.08 mg/kg (about 5 mg), administered by IM injection approximately 30–60 minutes prior to surgery.¹ ¹⁴ ¹⁸⁰ ¹⁸¹

Reduce dose in patients with COPD, higher-risk surgical patients, patients ≥60 years of age, and patients who have received concomitant therapy with opiate agonists or other CNS depressants.¹

Procedural Sedation

Sedation is a continuum ranging from minimal sedation to general anesthesia; titrate dosage slowly to desired clinical effect.⁸²¹ ⁸²² ⁸²³

IV

Healthy adults <60 years of age: Titrate dose slowly to desired sedative effect (e.g., onset of slurred speech).¹ Manufacturer states that no more than 2.5 mg should be administered initially; some patients may respond to as little as 1 mg.¹ ¹⁹³ Wait at least 2 minutes to fully evaluate the sedative effect.¹ If additional sedation is necessary, continue to titrate using small increments to the appropriate level of sedation.¹ Total dose of ≤5 mg generally is adequate.¹

Reduce dose in patients ≥60 years of age and debilitated or chronically ill patients, and patients with decreased pulmonary reserve.¹

If a thorough clinical evaluation clearly indicates a need for additional doses to maintain the desired level of sedation, administer additional doses in increments of approximately 25% of the initial dose used to reach the first sedative end point.¹

Some clinicians recommend initiating dosing with 0.5–2 mg and repeating doses, as necessary, at 2- to 3-minute intervals up to a total dose of 0.1–0.15 mg/kg.¹⁴ ¹⁸¹

When used concomitantly with an opiate agonist or other CNS depressant, reduce midazolam dosage by about 30% in healthy adults <60 years of age and by at least 50% in patients ≥60 years of age and debilitated or chronically ill patients, and patients with decreased pulmonary reserve.¹ ¹⁴

Induction and Maintenance of Anesthesia

IV

Individual response is variable, especially when opiate agonist premedication is not used; therefore, titrate dosage carefully to the desired clinical effect, taking into consideration the patient’s age and clinical status.¹ ² ⁷⁰

When used prior to other anesthetic agents for the induction of general anesthesia,¹ the initial dose of each of these agents may be substantially reduced, in some instances to as low as 25% of the usual initial dose of the individual agents.¹

Induction without Opiate or Sedative Premedication

Average adults <55 years of age: Usual initial dose is 0.3–0.35 mg/kg administered IV over 20–30 seconds for induction of anesthesia; allow approximately 2 minutes for clinical effect.¹ ¹⁸⁰ Some clinicians have suggested a lower initial dose of 0.2 mg/kg.¹⁴ ¹⁴⁴ ¹⁸¹

Supplemental doses of about 25% of the initial dose may be given as necessary to complete induction.¹ ¹⁴ Alternatively, induction of anesthesia may be completed with inhalation agents.¹

Total IV induction doses of up to 0.6 mg/kg may be required in some resistant patients, but such doses may prolong recovery from anesthesia.¹ ⁴ ¹⁰⁰

Induction with Opiate or Sedative Premedication

Average adults <55 years of age: Usual induction dose is 0.25 mg/kg administered IV over 20–30 seconds; allow approximately 2 minutes for clinical effect.¹

Maintenance of Anesthesia

For maintenance of anesthesia (as a component of balanced anesthesia) during surgical procedures,¹ administer in incremental IV doses of approximately 25% of the induction dose when lightening of anesthesia is evident.¹ Repeat as necessary according to patient’s response to maintain the required level of anesthesia.¹ Premedication with an opiate agonist is especially recommended when midazolam is used for maintenance.¹

Sedation in Critical Care Settings

IV

If a loading dose is necessary to initiate sedation rapidly, 0.01–0.05 mg/kg (approximately 0.5–4 mg for a typical adult) administered slowly or infused over several minutes.¹ ⁸⁰¹ May repeat this dose at 10- to 15-minute intervals until adequate sedation is achieved.¹ Usual initial infusion rate for maintenance of sedation is 0.02–0.1 mg/kg per hour (approximately 1–7 mg per hour).¹ ⁸⁰¹ Higher loading doses or maintenance infusion rates occasionally may be required.¹

In patients with residual effects from anesthetic agents or in those currently receiving other sedatives or opiates, use the lowest recommended dosage.¹

Infuse at the lowest rate that produces the desired level of sedation.¹ Assess sedation at regular intervals and adjust the infusion rate up or down by 25–50% of the initial infusion rate to ensure adequate titration of the sedation level.¹ Larger adjustments or even a small, incremental dose may be necessary if rapid changes in the level of sedation are required.¹ Decrease infusion rate by 10–25% every few hours to find the minimum effective infusion rate.¹

Consider administering an opiate concomitantly in patients experiencing agitation, hypertension, or tachycardia in response to noxious stimuli but who otherwise are adequately sedated.¹ Addition of an opiate generally will reduce the minimum effective midazolam infusion rate.¹

Status Epilepticus

IM

Manufacturer recommends single dose of 10 mg.⁷⁷⁴

Some clinicians recommend usual dose of 0.15–0.3 mg/kg.⁵⁴⁵

Acute Repetitive Seizures or Seizure Clusters

Intranasal

1 spray (5 mg) into one nostril.⁷⁷³ May administer an additional spray into opposite nostril after 10 minutes if no response to first dose; however, a second dose should not be administered if patient has difficulty breathing or excessive sedation that is uncharacteristic for the patient during a seizure cluster episode.⁷⁷³

Do not use more than 2 doses to treat a single seizure episode.⁷⁷³

Manufacturer recommends not to use to treat more than 1 seizure episode every 3 days and more than 5 seizure episodes a month.⁷⁷³

Prescribing Limits

Pediatric Patients

Preoperative Sedation, Anxiolysis, and Amnesia or Procedural Sedation

Oral

Children 6 months to 16 years of age: Maximum 20 mg.²¹⁹

IV

Manufacturer states that the total dose usually does not exceed 6 mg in pediatric patients 6 months to 5 years of age or 10 mg in those 6–16 years of age.¹

IM

Manufacturer states that the total dose usually does not exceed 10 mg in non-neonatal pediatric patients, although this has not been systematically studied.¹

Acute Repetitive Seizures or Seizure Clusters

Intranasal

Children ≥12 years of age: Maximum of 2 doses for a single seizure episode.⁷⁷³ Manufacturer recommends not to use to treat more than 1 seizure episode every 3 days and more than 5 episodes a month.⁷⁷³

Adults

Procedural Sedation

IV

Initial dose for sedation should not exceed 2.5 mg (or 1.5 mg in patients ≥60 years of age or chronically ill or debilitated patients).¹

Acute Repetitive Seizures or Seizure Clusters

Intranasal

Maximum of 2 doses for a single seizure episode.⁷⁷³ Do not use to treat more than 1 seizure episode every 3 days and more than 5 episodes a month.⁷⁷³

Special Populations

Renal Impairment

Use with caution and individualize dosage carefully.¹ ² ⁴ ⁷ ³¹ ³³ ³⁴ ⁴² ⁷⁰ ¹⁶³

CHF

Use with caution and individualize dosage carefully.¹ ³⁵ ⁵⁰ ¹⁶³

Geriatric Patients

Reduce initial dose since some degree of organ impairment frequently is present.¹ ¹⁶³ ¹⁹³ Dosage requirements in this age group generally appear to decrease with increasing age;¹ ¹⁶³ consider possibility of profound and/or prolonged effects in older and/or debilitated patients.¹ Low doses usually are required when midazolam is administered with or without premedication.¹ ¹⁶³ ¹⁹³

Dosage titration should be more gradual in patients ≥60 years of age receiving midazolam for procedural sedation and in those ≥55 years of age receiving the drug for induction of anesthesia.¹ ¹⁶³ ¹⁸⁰

Use smallest effective dose.¹ Excessive doses or rapid or single large IV injections may result in respiratory depression and/or arrest.¹ ¹⁶³ ¹⁹³

Safe oral dosing regimen not established in geriatric patients.²¹⁹

Preoperative Sedation, Anxiolysis, and Amnesia in Patients ≥60 Years of Age

IM: In patients ≥60 years of age who did not receive concomitant opiate agonist therapy, doses of 2–3 mg (0.02–0.05 mg/kg) have produced adequate preoperative sedation;¹ 1 mg may be sufficient in some geriatric patients if the anticipated intensity and duration of sedation are less critical.¹

Procedural Sedation in Patients ≥60 Years of Age

IV: Administer initial dose of 1–1.5 mg ¹ ¹⁹³ over ≥2 minutes; wait ≥2 minutes to fully evaluate the clinical response.¹ If further sedation is required, dosage may be further titrated in incremental doses of no more than 1 mg to the desired effect (e.g., onset of slurred speech).¹ Total dose of ≤3.5 mg usually is adequate.¹

If a thorough clinical evaluation clearly indicates a need for additional doses to maintain the desired level of sedation, administer additional doses that are¹ reduced by ≥25%.¹⁴

When used concomitantly with an opiate or other CNS depressant, midazolam dosage requirements may be reduced by at least 50%.¹

Induction and Maintenance of Anesthesia in Patients ≥55 Years of Age

IV: Manufacturer recommends an initial IV induction dose of 0.3 mg/kg if premedication has not been given.¹

If premedication has been given, manufacturer recommends an initial induction dose of 0.2 mg/kg if the patient is a good risk (e.g., ASA I and II) surgical patient.¹

Other Populations

Preoperative Sedation, Anxiolysis, and Amnesia in Patients with COPD or Other Higher-risk Surgical Patients

IM: Individualize and reduce dosage in patients with COPD and in other higher-risk surgical patients.¹

Procedural Sedation in Chronically Ill or Debilitated Patients

IV: Smaller increments in dosage and slower rate of injection recommended in patients with chronic debilitating illnesses (e.g., CHF) or decreased pulmonary reserve because of the increased risk of underventilation or apnea and because the peak drug effect may occur later.¹ ¹⁶³ ¹⁸⁰ ¹⁹³

Administer initial dose of 1–1.5 mg ¹ ¹⁹³ over ≥2 minutes; wait ≥2 minutes to fully evaluate the clinical response.¹ If further sedation is required, dosage may be further titrated in incremental doses of no more than 1 mg to the desired effect (e.g., onset of slurred speech).¹ Total dose of ≤3.5 mg usually is adequate.¹

If a thorough clinical evaluation clearly indicates a need for additional doses to maintain the desired level of sedation, administer additional doses that are¹ reduced by ≥25%.¹⁴

When used concomitantly with an opiate or other CNS depressant, midazolam dosage requirements may be decreased by at least 50%.¹

Induction and Maintenance of Anesthesia in Patients with Severe Systemic Disease or Other Debilitation

IV: Initial dose of 0.2–0.25 mg/kg usually is adequate if premedication has not been given; doses as low as 0.15 mg/kg may be adequate for induction in some patients.¹

If premedication has been given, initial induction dose of 0.15 mg/kg may be sufficient.¹

Cautions for Midazolam, Midazolam Hydrochloride

Contraindications

Known hypersensitivity to midazolam or any ingredient in the formulation; oral solution contraindicated in patients with allergies to cherries.¹ ²¹⁹
Acute angle-closure glaucoma (but may be administered to patients with open-angle glaucoma who are receiving appropriate therapy).¹ ²¹⁹ ⁷⁷³
Preparations containing benzyl alcohol are not intended for intrathecal or epidural administration.¹

Warnings/Precautions

Warnings

Concomitant Use with Opiates

Concomitant use of benzodiazepines, including midazolam, and opiates may result in profound sedation, respiratory depression, coma, and death.⁷⁰⁰ ⁷⁰¹ ⁷⁰³ ⁷⁰⁵ ⁷⁰⁶ ⁷⁰⁷ ⁷⁷³ ⁷⁷⁴ (See Boxed Warning.) Substantial proportion of fatal opiate overdoses involve concurrent benzodiazepine use.⁷⁰⁰ ⁷⁰¹ ⁷⁰⁵ ⁷⁰⁶ ⁷⁰⁷ ⁷¹¹

Reserve concomitant use of midazolam and opiates for patients in whom alternative treatment options are inadequate.⁷⁰⁰ ⁷⁰³ ⁷⁷³

Respiratory and Cardiovascular Effects

Serious and occasionally fatal adverse effects, including respiratory depression, airway obstruction, oxygen desaturation, apnea, respiratory arrest, and/or cardiac arrest reported, sometimes resulting in death or permanent neurologic injury.¹ ² ³⁷ ¹³⁷ ¹³⁹ ¹⁶³ ¹⁷⁵ ¹⁹³ (See Boxed Warning.) Risk is increased in patients receiving midazolam concomitantly with other CNS depressants,¹ ²¹⁹ patients undergoing procedures involving the airway without the protective effect of an endotracheal tube, geriatric or debilitated patients, and patients with limited pulmonary reserve or unstable cardiovascular status; risk also increased if the drug is administered IV too rapidly.¹ ¹⁶³ ¹⁹³

Possible hypotensive episodes requiring treatment during or following diagnostic or surgical manipulation.¹ Concomitant administration of an opiate agonist may increase the risk of severe hypotension.¹ ⁴ ¹⁴ ¹¹²

Do not administer parenterally to patients with shock, those who are comatose, or those with acute alcohol intoxication and accompanying depression of vital signs.¹ Exercise caution if administered IV to patients with uncompensated acute illnesses, including severe fluid or electrolyte imbalances.¹

Slow administration and individualized titration of dosage is required.¹ ²¹⁹

Administer orally or IV only in settings in which continuous monitoring of respiratory and cardiac function (i.e., pulse oximetry) is possible.¹ ²¹⁹ Potential for hypoxia and/or cardiac arrest if early signs of hypoventilation, airway obstruction, or apnea are not corrected immediately.¹ Monitoring of vital signs should continue during recovery period.¹

Should be used for sedation, anxiolysis, and amnesia only in the presence of personnel experienced in early detection of underventilation, maintenance of an adequate airway, and respiratory support.¹ ¹⁶³ ¹⁹³ ²¹⁹ For deeply sedated pediatric patients, an individual other than the clinician performing the procedure should be dedicated to monitoring the patient throughout the procedure.¹ ²¹⁹

Facilities, resuscitative drugs, oxygen, age- and size-appropriate equipment for bag/mask/valve ventilation and intubation, drugs, and skilled personnel necessary for maintenance of a patent airway and support of ventilation should be immediately available when IV or oral midazolam is administered.¹ ²¹⁹

Immediate availability of a specific benzodiazepine reversal agent (e.g., flumazenil) is highly recommended when the drug is used for induction or maintenance of anesthesia or for diagnostic or therapeutic procedures.¹

CNS Depression

Performance of activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle) may be impaired;¹ such activities should not be performed until the effects of the drug (e.g., drowsiness) have subsided or until the day after anesthesia and surgery, whichever is longer.¹

Concurrent use of other CNS depressants may increase extent and duration of impaired performance, cause excessive sedation, and interfere with recall and recognition of events on the day of surgery and the following day.¹ ⁴ ⁷

Paradoxical Reactions

Agitation, involuntary movements, hyperactivity, and/or combativeness reported with midazolam used for sedation; may be manifestations of paradoxical reactions or may be signs of inadequate or excessive dosing, improper administration, or cerebral hypoxia.¹ ¹⁶³ ⁷⁷³ ⁷⁷⁴ Evaluate patient’s response to each dose as well as to any concomitantly administered drug, including local anesthetics, before proceeding.¹ ¹⁶³

Intra-arterial Injection

Local reactions and isolated reports of seizure activity (causal relationship not established) reported following intra-arterial injection.¹ Avoid extravasation and take precautions against unintended intra-arterial injection.¹

Withdrawal Syndrome

Patients receiving continuous infusions of midazolam in critical care settings over an extended period of time may experience symptoms of withdrawal following discontinuance.¹

Suicidality Risk with Use of Midazolam Nasal Spray

Increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders, and other conditions; risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%).⁷⁷³ Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.⁷⁷³ Relative risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.⁷⁷³

Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.⁷⁷³

Balance risk of suicidality with risk of untreated illness.⁷⁷³ Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.⁷⁷³ If suicidal thoughts or behavior emerges during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.⁷⁷³

General Precautions

General Anesthesia

Does not fully prevent the increase in intracranial pressure or the cardiovascular effects (e.g., increase in BP and/or heart rate) associated with endotracheal intubation under light general anesthesia.¹ ² ³⁷ ⁷⁰ ⁹³ ⁹⁴ ¹²⁶

Does not appear to prevent the usual cardiovascular stimulatory effects associated with administration of some neuromuscular blocking agents (e.g., succinylcholine, pancuronium) or the increase in intracranial pressure associated with succinylcholine.¹

Interactions with CYP3A4 Inhibitors

Expect more intense and prolonged sedation when midazolam is administered concomitantly with a CYP3A4 inhibitor; use concomitantly with caution.²¹⁹ ⁶¹¹ Consider dosage adjustments.²¹⁹

Specific Populations

Pregnancy

Category D.¹

Based on animal data, repeated or prolonged use of general anesthetics and sedation drugs, including midazolam, during the third trimester of pregnancy may result in adverse neurodevelopmental effects in the fetus.⁷⁵⁰ ⁷⁵³

Use for obstetric procedures not recommended.¹

Lactation

Distributed into milk.¹ Use with caution.¹

Pediatric Use

Safety and efficacy of the oral solution not established in infants <6 months of age.²¹⁹

Safety and efficacy of the nasal spray not established in pediatric patients <12 years of age.⁷⁷³

Safety and efficacy of the injection for status epilepticus not established in pediatric patients.⁷⁷⁴ Manufacturer states that benzodiazepines are not recognized as a treatment for status epilepticus in neonates and should not be used in this population.⁷⁷⁴

Children generally require a higher parenteral dosage on a mg/kg basis than do adults;¹ children <6 years of age generally require higher drug dosages on a mg/kg basis than do older pediatric patients and may require closer monitoring.¹ Higher-risk surgical patients may require lower doses, whether or not concomitant sedating drugs have been administered.²¹⁹

Increased potential for respiratory depression, airway obstruction, or hypoventilation when administered in conjunction with opiates or other sedatives.¹

Take particular care to ensure safe ambulation following sedation.¹ ²¹⁹

Children with cardiac or respiratory compromise may be unusually sensitive to the respiratory depressant effects.²¹⁹ Pediatric patients undergoing procedures involving the upper airway (e.g., upper endoscopy, dental care) are particularly vulnerable to episodes of oxygen desaturation and hypoventilation secondary to partial airway obstruction.²¹⁹

Neonates are vulnerable to profound and/or prolonged adverse respiratory effects because of reduced and/or immature organ function.¹ Do not administer by rapid IV injection (i.e., over <2 minutes) in neonates, since rapid administration has been associated with severe hypotension (particularly when coadministered with fentanyl) and seizures.¹

Repeated or prolonged use of general anesthetics and sedation drugs, including midazolam, in children <3 years of age or during the third trimester of pregnancy may adversely affect neurodevelopment.⁷⁵⁰ ⁷⁵³ In animals, use for >3 hours of anesthetic and sedation drugs that block N-methyl-d-aspartic acid (NMDA) receptors and/or potentiate GABA activity leads to widespread neuronal apoptosis in the brain and long-term deficits in cognition and behavior;⁷⁵⁰ ⁷⁵¹ ⁷⁵² ⁷⁵³ clinical relevance to humans is unknown.⁷⁵⁰ Some evidence suggests similar deficits may occur in children following repeated or prolonged exposure to anesthesia early in life.⁷⁵⁰ ⁷⁵² Some evidence also indicates that a single, relatively brief exposure to general anesthesia in generally healthy children is unlikely to cause clinically detectable deficits in global cognitive function or serious behavioral disorders.⁷⁵⁰ ⁷⁵¹ ⁷⁵² Most studies to date have substantial limitations; further research needed to fully characterize effects, particularly for prolonged or repeated exposures and in more vulnerable populations (e.g., less healthy children).⁷⁵⁰ Consider benefits and potential risks when determining the timing of elective procedures requiring anesthesia.⁷⁵⁰ FDA states that medically necessary procedures should not be delayed or avoided.⁷⁵⁰ ⁷⁵³

Some preparations of midazolam contain benzyl alcohol and should not be used in neonates or infants.¹ ⁷⁷⁴ Large amounts of benzyl alcohol (i.e., 100–400 mg/kg daily) have been associated with toxicity in neonates.²²⁴ ²²⁵ ²²⁶ ²²⁷ ²²⁸ ²²⁹ ²³⁰ Each mL of midazolam hydrochloride injection in these preparations contains 10 mg of benzyl alcohol.¹ ⁷⁷⁴

Geriatric Use

Safety and efficacy of midazolam oral solution not established in geriatric patients.²¹⁹ Increased incidence of hypoxia reported in geriatric patients receiving midazolam hydrochloride 7.5 mg as premedication prior to general anesthesia.²¹⁹ Until further information available, oral midazolam not recommended in geriatric patients.²¹⁹

Clinical studies of the intranasal preparation did not include sufficient numbers of geriatric patients ≥65 years of age to determine whether they respond differently than younger adults⁷⁷³

Select parenteral dosage carefully, since distribution may be altered and patients may have decreased hepatic and/or renal function.¹ Reduce the dosage, particularly in those ≥70 years of age.¹

When used for induction of anesthesia, time to recovery may be delayed.¹

Fatalities (possibly associated with cardiac or respiratory depression) reported rarely in geriatric and/or high-risk surgical patients receiving IV or IM midazolam (often in combination with other CNS depressants [e.g., opiates]).¹ ⁷⁷⁴ Monitor closely for signs of cardiac or respiratory depression.¹ ⁷⁷⁴

Hepatic Impairment

Plasma clearance may be decreased in some patients with chronic liver disease.⁴⁸

Renal Impairment

Use with caution since the pharmacokinetics of the drug may be altered.¹ ² ⁴ ⁷ ³¹ ³³ ³⁴ ⁴² ⁷⁰ ¹⁶³ Induction of anesthesia may occur more rapidly, and recovery may be prolonged.² ⁴ ³¹ ³³ ³⁴ ⁴² ⁷⁰

Common Adverse Effects

Parenteral administration: Changes in respiratory rate, BP, pulse rate.¹ ² ⁴ ⁷

IM administration for status epilepticus: Upper airway obstruction, agitation, pyrexia.⁷⁷⁴

Oral administration: Emesis, nausea, hypoxia, laryngospasm, agitation.²¹⁹

Intranasal administration: Somnolence, headache, nasal discomfort, throat irritation, rhinorrhea.⁷⁷³

Drug Interactions

Metabolized by CYP3A4.¹ ²¹⁹

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (increased plasma midazolam concentrations) with inhibitors of CYP3A4.¹ ²¹⁹ Use concomitantly with caution and monitor for excessive sedation.¹ ²¹⁶ Dosage adjustment of midazolam and/or other drugs may be needed.²¹⁹ ²³³

Potential pharmacokinetic interaction (decreased plasma midazolam concentrations) with inducers of CYP3A4.¹ ²¹⁹ Use concomitantly with caution.²¹⁹ ²³² ²³³ Dosage adjustment of midazolam and/or other drugs may be needed.²¹⁹ ²³³

Commonly Used Drugs During Anesthesia or Surgery

No adverse interactions when midazolam was administered concomitantly with common premedications or drugs used during anesthesia or surgery (e.g., atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, succinylcholine, nondepolarizing neuromuscular blocking agents, topical local anesthetics).¹

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Aminophylline	Possible antagonism of sedative effect during anesthesia¹³²
Anesthetic agents, inhalation		Patients who have received midazolam as an induction agent may require reduced amounts of inhalation agents during maintenance of anesthesia¹ ² ⁷⁰ ¹⁴¹
Anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin)	Substantially decreased peak plasma concentrations and AUC of midazolam with concomitant use of phenytoin or carbamazepine;²¹⁹ similar effects expected with phenobarbital²¹⁹	Use concomitantly with caution and consider dosage adjustments if necessary²¹⁹ ²³² ²³³
Antifungals, azole (fluconazole, itraconazole, ketoconazole)	Substantially increased peak plasma concentrations and AUC of midazolam;²¹⁹ potential for intense and prolonged sedation and respiratory depression²¹⁹	Use concomitantly with caution and consider dosage adjustments¹ ²¹⁹ ⁶¹¹ Administer oral midazolam concomitantly with itraconazole or ketoconazole only if absolutely necessary and with appropriate equipment and personnel available to manage respiratory insufficiency²¹⁹
Antimycobacterials (rifabutin, rifampin)	Substantially decreased peak plasma concentrations and AUC of midazolam with concomitant use of rifampin; similar effects expected with rifabutin²¹⁹	Use concomitantly with caution and consider dosage adjustments if necessary²¹⁹
Calcium-channel blocking agents (diltiazem, nifedipine, verapamil)	Substantially increased peak plasma concentrations and AUC of midazolam with concomitant use of diltiazem or verapamil;²¹⁹ ²³¹ ²³³ potential for increased and prolonged sedation²¹⁹ Pharmacokinetic interaction unlikely with nifedipine¹	Use concomitantly with caution and consider dosage adjustments¹ ²¹⁹ ²³³ ⁶¹¹
CNS depressants (e.g., barbiturates, sedatives, anesthetics, alcohol)	Additive CNS effects, possibly resulting in respiratory depression and profound and/or prolonged underventilation or apnea¹ ⁴ ¹⁴ ¹⁶³ ¹⁷⁵ ¹⁸⁹ ¹⁹⁰ ²¹⁹	Use with caution and adjust dosage appropriately to avoid overdosage¹ ⁴ ¹⁴ ²¹⁹
Delavirdine	Potential for decreased midazolam metabolism resulting in intense and prolonged sedation and respiratory depression²⁴⁷	Manufacturer of delavirdine states that concomitant use is contraindicated;²⁴⁷ however, some experts state that a single midazolam dose can be used with caution for procedural sedation in monitored situations²⁴⁹
Efavirenz	Potential for decreased midazolam metabolism resulting in intense and prolonged sedation and respiratory depression²⁴⁸	Manufacturer of efavirenz states that concomitant use is contraindicated;²⁴⁸ however, some experts state that a single midazolam dose can be used with caution for procedural sedation in monitored situations²⁴⁹
Grapefruit juice	Increased bioavailability of oral midazolam with concomitant administration;¹⁹⁶ ¹⁹⁷ ²¹⁹ does not appear to interfere with metabolism following IV administration¹⁹⁷ ²⁰³	Manufacturer states that oral midazolam should not be taken in conjunction with grapefruit juice²¹⁹
Histamine H₂-receptor antagonists (e.g., cimetidine, ranitidine)	Possible increased plasma midazolam concentrations¹⁴³ ¹⁶⁰ ¹⁶¹ ²¹⁹	Carefully observe patient for CNS and respiratory depression; reduce midazolam dosage if necessary¹⁶⁰ ¹⁶¹ ¹⁶²
HIV protease inhibitors (e.g., atazanavir, fosamprenavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, tipranavir)	Substantially increased plasma concentrations and AUC of midazolam with concomitant use of saquinavir;¹ ²¹⁹ ²³⁸ potential for intense and prolonged sedation and respiratory depression²³⁸ ²⁴⁰ ²⁴¹ ²⁴² ²⁴³ ²⁴⁴ ²⁴⁵ ²⁴⁶	Manufacturers of HIV protease inhibitors state that concomitant use is contraindicated;²³⁸ ²⁴⁰ ²⁴¹ ²⁴² ²⁴³ ²⁴⁴ ²⁴⁵ ²⁴⁶ ²⁵¹ however, some experts state that a single midazolam dose can be used with caution for procedural sedation in monitored situations²⁴⁹
Ketamine	Midazolam may antagonize the cardiovascular stimulatory effects and postoperative emergence delirium usually associated with ketamine⁴ ¹⁰⁴ ¹³⁴
Macrolide antibiotics	Decreased clearance and increased plasma concentrations of midazolam with concomitant use of erythromycin;¹⁹⁵ ²¹⁶ ²¹⁸ ²¹⁹ potential for increased and prolonged sedation¹⁹⁵ ²¹⁶ ²¹⁹ Pharmacokinetic interaction unlikely with azithromycin²¹⁹	Manufacturer states that caution is advised if midazolam is used concomitantly with erythromycin²¹⁹ Some clinicians state that erythromycin should not be given to patients receiving midazolam or, alternatively, that the midazolam dosage should be reduced in patients receiving the anti-infective¹⁹⁵
Neuromuscular blocking agents	Pancuronium: Has been used concomitantly in adults without clinically important changes in dosage, onset, or duration¹ Succinylcholine: Has been used concomitantly in adults without clinically important changes in dosage, onset, or duration of a single intubating dose¹
Opiate agonists and partial agonists (e.g., fentanyl)	Increased risk of hypotension and prolongation of the recovery period;¹ ² ¹³⁹ severe hypotension reported with concomitant administration of fentanyl in neonates¹ Risk of profound sedation, respiratory depression, airway obstruction, hypoventilation, coma, and death¹ ²¹⁹ ⁷⁰⁰ ⁷⁰¹ ⁷⁰³ ⁷⁰⁵ ⁷⁰⁶ ⁷⁰⁷	Monitor patients closely for respiratory depression and sedation and adjust midazolam dosage appropriately to avoid overdosage¹ ⁴ ¹⁴ Opiate analgesics: Use concomitantly only if alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy; monitor closely for respiratory depression and sedation⁷⁰⁰ ⁷⁰³ Opiate antitussives: Avoid concomitant use⁷⁰⁰ ⁷⁰⁴
Quinupristin and Dalfopristin	Increased peak plasma concentrations and AUC of midazolam²³⁴	Use concomitantly with caution; monitor patients for excessive sedation¹ ²¹⁶
Terbinafine	No change in midazolam pharmacokinetics²¹⁹

Midazolam, Midazolam Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following IM administration,¹ ⁴ ⁵ ⁶ ⁸ ⁹ ¹⁰ ¹¹ ¹² ¹³ ¹⁴ ¹⁵ ¹⁶ with peak plasma concentrations generally attained within 30–45 minutes.¹ ⁸ ⁷⁷⁴ Absolute bioavailability is >90%.¹ ⁴ ⁸ ⁹

Rapidly absorbed from the GI tract following oral administration,² ⁴ ⁷ ¹⁸ ¹⁹ ²⁰ ²¹ ²² ²³ ²¹⁹ with peak plasma concentrations usually attained within 1–2 hours.² ⁴ ⁷ ¹⁸ ¹⁹ ²⁰ ²¹ ²² ²³ ²⁴ ²¹⁹ The drug undergoes substantial first-pass metabolism in the liver and intestine;² ⁷ ¹⁸ ²² ²⁴ ³⁵ ²¹⁹ only about 40–50% (range: 28–72%) of a dose reaches systemic circulation unchanged.² ⁴ ⁷ ¹⁸ ¹⁹ ²⁰ ²¹ ²² ²⁴

Following intranasal administration, peak plasma concentrations attained in approximately 17 minutes.⁷⁷³ Absolute bioavailability is approximately 44%.⁷⁷³

Onset

Following IM administration, effects usually are apparent within 5–15 minutes¹ ⁴ ⁹ ¹⁴ ³² ⁸¹ but may not be maximal until 15–60 minutes.¹ ² ⁴ ⁸ ⁹ ¹⁰ ¹¹ ¹² ¹³ ¹⁵ ¹⁶ ⁸¹

Following IV administration, the onset of sedative, anxiolytic, and amnesic action usually occurs within 1–5 minutes.¹ ² ⁴ ⁷ ⁹ ¹³ ²¹ ²⁵ ²⁶ ⁸⁶ ⁸⁷

Induction of anesthesia usually occurs in about 1.5 minutes when midazolam is administered concurrently with opiate agonists and in 2–2.5 minutes when administered without an opiate agonist or other sedatives.¹ ² ²⁷ ²⁸

Following administration of the oral solution in children, pharmacologic effects usually are apparent within 10–20 minutes.²¹⁹

Following intranasal administration, the onset of sedative and psychomotor impairment effects usually occurs within 10 minutes with maximal effects achieved within 30 minutes to 2 hours.⁷⁷³

Duration

Following IM administration, the duration of action usually is about 2 hours¹ (range: 1–6 hours).¹ ⁸ ⁹ ¹⁰ ¹⁴ Duration of anterograde amnesia following IM administration is about 1 hour.¹ ² ¹⁰ ²⁵ ⁶⁹

Following IV administration, duration of action is usually <2 hours;¹ ⁴ ⁷ ⁸ ⁹ ²¹ ²⁹ however, effects may persist up to 6 hours in some patients, and the duration of action appears to be dose related.¹ ⁸ ⁹ ²⁰ ²⁹ Anterograde amnesia persists for about 20–40 minutes following a single IV dose.² ⁴ ⁷ ²⁵ ²⁶

Distribution

Extent

Rapidly and widely distributed following IV administration.¹ ² ⁴ ²⁴ ³⁵ ³⁶ ³⁷ ³⁸

Crosses the blood-brain barrier and distributes into CSF.⁷ ¹⁴ ¹⁵ ¹⁶

Crosses the placenta and ¹ ² ⁷ ²³ ³⁵ ⁴³ is distributed into milk.¹

Plasma Protein Binding

Approximately 94–97% (mainly to serum albumin² ⁴ ⁷ ³⁴ ³⁷ ⁴² ) in adults and children >1 year of age.¹ ² ⁷ ¹⁸ ²⁰ ²⁴ ³¹ ³⁶ ³⁷ ⁴¹ ⁴² ⁴⁵ ²¹⁹ Degree of protein binding appears to be independent of plasma concentration.² ²⁴ ⁴¹ ²¹⁹

Special Populations

Distribution may be altered in geriatric patients.¹

Elimination

Metabolism

Extensively metabolized in the liver and intestine by CYP3A4¹ ⁷ ²¹ ²⁴ ⁵⁴ ⁵⁵ ²¹⁹ to active and inactive metabolites.¹ ⁵ ²¹⁹ Metabolites undergo rapid conjugation with glucuronic acid in the liver.¹ ² ⁴ ⁷ ¹⁷ ²⁴ ⁵⁴ ⁵⁵ ⁵⁸ Activity is related principally to the parent drug.¹

Elimination Route

Excreted in urine almost entirely as conjugated metabolites.¹ ² ⁴ ⁷ ¹⁷ ²⁴ ⁵⁴ ⁵⁵ ⁵⁸ Approximately 2–10% of an oral dose is excreted in feces.⁴ ⁵⁵

Half-life

Biphasic; following IV administration, half-life in the initial distribution phase averages 6–20 minutes in adults;² ⁴ ²⁸ ¹⁹ ²⁰ ⁵⁶ terminal half-life averages 1–4 hours (range: 1–12.3 hours).¹ ² ⁴ ⁷ ¹³ ¹⁴ ¹⁹ ²⁰ ²¹ ²² ²⁴ ³⁴ ³⁵ ³⁶ ³⁷ ³⁸ ⁴⁴ ⁴⁵ ⁴⁶ ⁴⁷ ¹⁴⁹

Terminal elimination half-life of 2.6–6.8 hours reported in pediatric patients 6 months to <16 years of age;²¹⁹ terminal elimination half-life is substantially prolonged (i.e., 6.5–12 hours) in seriously ill neonates.¹

Elimination half-life approximately 4 hours following IM injection.⁷⁷⁴

Elimination half-life 2.1–6.2 hours following intranasal administration.⁷⁷³

Special Populations

Half-life may be prolonged in geriatric patients.² ⁷ ¹⁸ ²⁴ ³⁷ ⁴⁹ ⁵¹ ⁵²

Half-life prolonged in patients receiving the drug for induction of anesthesia associated with major surgical procedures.⁷ ⁵²

In some patients with chronic liver disease, plasma clearance may be decreased.⁴⁸

In patients with CRF, total plasma clearance and volume of distribution of total (bound and unbound) midazolam are increased,¹ ² ⁷ ⁴² but these alterations are attributable to changes in protein binding.² ⁷ ⁴²

In patients with CHF, prolonged elimination half-life, increased volume of distribution, and delayed onset of action secondary to prolonged circulation time.¹ ³⁵ ⁵⁰ ¹⁶³

Stability

Storage

Oral

Solution

20–25°C.²¹⁹

Parenteral

Injection

20–25°C (may be exposed to 15–30°C).¹ ⁷⁷⁴

Preservative-free preparation: 20–25°C.⁵⁸⁰

Intranasal

Solution

20–25°C (may be exposed to 15–30°C).⁷⁷³

Actions

Effects appear to be mediated through the inhibitory neurotransmitter GABA; the site and mechanism of action within the CNS appear to involve a macromolecular complex (GABA_A-receptor-chloride ionophore complex) that includes GABA_A receptors, high-affinity benzodiazepine receptors, and chloride channels.³²⁰ ³⁵⁸ ³⁵⁹ ³⁶⁰ ³⁶¹ ³⁶² ³⁶³ ³⁶⁴ ³⁶⁵ ³⁶⁶ ³⁶⁷ ³⁶⁸ ³⁶⁹ ³⁷⁰

Advice to Patients

Importance of advising patients and caregivers to read the patient information (medication guide) and instructions for use for midazolam nasal spray.⁷⁷³
Importance of informing patients of the pharmacologic effects of midazolam (e.g., sedation, lack of recall), which in some patients may be profound.¹ ²¹⁹
Risk of potentially fatal additive effects (e.g., profound sedation, respiratory depression, coma) if used concomitantly with opiates, either therapeutically or illicitly.⁷⁰⁰ ⁷⁰³ Avoid concomitant use of opiate antitussives;⁷⁰⁰ ⁷⁰⁴ also avoid concomitant use of opiate analgesics unless use is supervised by clinician.⁷⁰⁰ ⁷⁰³
Potential for midazolam to impair mental alertness or physical coordination; avoid driving or operating machinery until the effects of the drug (e.g., drowsiness) have subsided or until the day after anesthesia and surgery, whichever is longer.¹
Importance of ensuring safe ambulation in pediatric patients receiving oral midazolam.²¹⁹
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹ ²¹⁹ Use caution with simultaneous ingestion of alcohol during treatment.¹ ²¹⁹
Risk of suicidality (anticonvulsants, including intranasal midazolam, may increase risk of suicidal thoughts or actions in about 1 in 500 people).⁷⁷³ ⁸²⁴ Importance of patients, family members, and caregivers being alert to day-to-day changes in mood, behavior, and actions and immediately informing clinician of any new or worrisome behaviors (e.g., talking or thinking about wanting to hurt oneself or end ones life, withdrawing from friends and family, becoming depressed, or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).⁷⁷³ ⁸²⁴
When procedures requiring general anesthetics or sedation drugs, including midazolam, are considered for young children or pregnant women, importance of discussing with the patient, parent, or caregiver the benefits, risks (including potential risk of adverse neurodevelopmental effects), and appropriate timing and duration of the procedure.⁷⁵⁰ ⁷⁵³
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹ ²¹⁹
Importance of informing patients of other important precautionary information.¹ ²¹⁹

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.¹ ¹⁷⁹

Midazolam
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Nasal	Solution	5 mg/0.1 mL	Nayzilam Nasal Spray (C-IV)	UCB

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Midazolam Hydrochloride
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Solution	2 mg (of midazolam) per mL*	Midazolam Hydrochloride Syrup ( C-IV )
Parenteral	Injection	1 mg (of midazolam) per mL*	Midazolam Hydrochloride Injection ( C-IV )
		5 mg (of midazolam) per mL*	Midazolam Hydrochloride Injection ( C-IV )
			Seizalam (C-IV)	Meridian

† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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