Midazolam

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Injection:

Generic: 2 mg/2 mL (2 mL); 5 mg/5 mL (5 mL); 10 mg/10 mL (10 mL); 5 mg/mL (1 mL); 10 mg/2 mL (2 mL); 25 mg/5 mL (5 mL); 50 mg/10 mL (10 mL)

Solution, Injection [preservative free]:

Generic: 2 mg/2 mL (2 mL); 5 mg/5 mL (5 mL); 5 mg/mL (1 mL); 10 mg/2 mL (2 mL)

Solution, Nasal:

Nayzilam: 5 mg/0.1 mL (2 ea) [contains propylene glycol]

Syrup, Oral:

Generic: 2 mg/mL (118 mL)

Pharmacology

Mechanism of Action

Binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the central nervous system, including the limbic system, reticular formation. Enhancement of the inhibitory effect of GABA on neuronal excitability results by increased neuronal membrane permeability to chloride ions. This shift in chloride ions results in hyperpolarization (a less excitable state) and stabilization. Benzodiazepine receptors and effects appear to be linked to the GABA-A receptors. Benzodiazepines do not bind to GABA-B receptors (Brunton 2011).

Pharmacokinetics/Pharmacodynamics

Absorption

IM: Rapid, complete; Intranasal (nasal spray): Rapid; Oral, Intranasal (solution, injection): Rapid (Lee-Kim 2004)

Distribution

Widely distributed in body including CSF; V_d:

Preterm infants (n=24; GA: 26 to 34 weeks; PNA: 3 to 11 days): IV: Median: 1.1 L/kg (range: 0.4 to 4.2 L/kg) (de Wildt 2001)

Infants and Children 6 months to 16 years: IV: 1.24 to 2.02 L/kg

Adults: 1 to 3.1 L/kg; increased in CHF, chronic renal failure, females, elderly, and obesity

Metabolism

Extensively hepatic CYP3A4; 60% to 70% of biotransformed midazolam is the active metabolite 1-hydroxy-midazolam (or alpha-hydroxymidazolam)

Excretion

Intranasal (nasal spray): Urine (primarily as glucuronide conjugates of the hydroxylated metabolites); IV: Urine (primarily as metabolites); Oral: Urine (~90% within 24 hours; primarily [60% to 70%] as glucuronide conjugates of the hydroxylated metabolites; <0.03% as unchanged drug); feces (~2% to 10% over 5 days) (Kanto 1985; Smith 1981)

Clearance:

Preterm infants (n=24; GA: 26 to 34 weeks; PNA: 3 to 11 days): Median: 1.8 mL/minute/kg (range: 0.7 to 6.7 mL/minute/kg) (de Wildt 2001)

Neonates <39 weeks GA: 1.17 mL/minute/kg

Neonates >39 weeks GA: 1.84 mL/minute/kg

Seriously ill neonates: 1.2 to 2 mL/minute/kg

Infants >3 months of age: 9.1 mL/minute/kg

Children >1 year of age: 3.2 to 13.3 mL/minute/kg

Healthy adults: 4.2 to 9 mL/minute/kg

Adults with acute renal failure: 1.9 mL/minute/kg

Onset of Action

IM: Sedation: Children: Within 5 minutes; Adults: ~15 minutes; IV: 3 to 5 minutes; Oral: 10 to 20 minutes; Intranasal (nasal spray): Within 10 minutes; Intranasal (solution, injection): Children: 5.55 ± 2.22 minutes (Lee-Kim 2004); Adults: Within 5 minutes

Peak effect: IM: Children: 15 to 30 minutes; Adults: 30 to 60 minutes; IV: 3 to 5 minutes; Intranasal (nasal spray): 30 minutes; Intranasal (solution, injection): Children: 10 minutes (al-Rakaf 2001)

Time to Peak

IM: 0.5 to 1 hour; Intranasal (nasal spray): median 17.3 minutes (7.8 to 28.2 minutes); Oral: 0.17 to 2.65 hours

Duration of Action

IM: Up to 6 hours; Mean: 2 hours; Intranasal (solution, injection): Children: 23.1 minutes (Chiaretti 2011); IV: Single dose: <2 hours (dose-dependent) (Fragen 1997)

Half-Life Elimination

Prolonged in cirrhosis, congestive heart failure, obesity, renal failure, and elderly. Note: In patients with renal failure, reduced elimination of active hydroxylated metabolites leads to drug accumulation and prolonged sedation.

Preterm infants (n=24; GA: 26 to 34 weeks; PNA: 3 to 11 days): IV: Median: 6.3 hours (range: 2.6 to 17.7 hours) (de Wildt 2001)

Neonates: 4 to 12 hours; seriously ill neonates: 6.5 to 12 hours

Children: IV: 2.9 to 4.5 hours; Syrup: 2.2 to 6.8 hours

Adults: 3 hours (range: 1.8 to 6.4 hours); IM: 4.2 ± 1.87 hours; Intranasal (nasal spray): 2.1 to 6.2 hours

Protein Binding

~97%, primarily albumin; in patients with cirrhosis, protein binding is reduced with a free fraction of ~5% (Trouvin 1988)

Use in Specific Populations

Special Populations: Renal Function Impairment

Elimination half-life is prolonged and clearance is reduced.

Special Populations: Hepatic Function Impairment

In patients with cirrhosis, following oral administration, C_max and bioavailability were 43% and 100% higher, and following IV administration clearance was reduced 50%, half-life increased 2.5-fold, and V_d increased by 20%.

Special Populations: Elderly

IM, IV: Plasma half-life was ~2-fold higher; mean V_d increased consistently between 15% to 100%, and mean clearance decreased ~25%; Intranasal (nasal spray): AUC and C_max increased 21% to 45%.

Special Populations Note

Heart failure: Following oral administration (7.5 mg), half-life increased 43%. Two-fold increase in the elimination half-life, a 25% decrease in the plasma clearance and a 40% increase in V_d following parenteral administration.

Obesity: Mean half-life is prolonged (5.9 hours) and V_d increased ~50%.

Use: Labeled Indications

Anesthesia: IV: Induction of general anesthesia before administration of other anesthetic agents; maintenance of anesthesia as a component of balanced anesthesia.

Sedation/anxiolysis/amnesia (preoperative/procedural):

IM: Preoperative sedation, anxiolysis, and amnesia.

IV: Sedation, anxiolysis, and amnesia prior to or during diagnostic, therapeutic, or endoscopic procedures, or prior to surgery.

Oral: Sedation, anxiolysis, and amnesia in children prior to diagnostic, therapeutic or endoscopic procedures or before induction of anesthesia.

Sedation for mechanically-ventilated patients: IV: Sedation of intubated and mechanically-ventilated patients as a component of anesthesia or during treatment in a critical care setting by continuous IV infusion.

Seizures, acute intermittent: Intranasal: Acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) that are distinct from a patient's usual seizure pattern in patients with epilepsy ≥12 years of age.

Use: Off Label

Status epilepticusayes

Data from a double-blind, randomized, noninferiority trial comparing the use of intramuscular midazolam to intravenous lorazepam supports the use of intramuscular midazolam for the treatment of status epilepticus Silbergleit 2012.

Based on the Neurocritical Care Society Guidelines for the Evaluation and Management of Status Epilepticus and the American Epilepsy Society Guidelines for the Treatment of Convulsive Status Epilepticus in Children and Adults, the use of intramuscular midazolam is an effective and recommended treatment and is the drug of choice when intramuscular administration is necessary for emergent control of status epilepticus.

Status epilepticus, refractorycyes

Data from four retrospective studies and one prospective, open-label study suggests that intravenous midazolam may be beneficial for the treatment of patients with refractory status epilepticus Claassen 2001, Fernandez 2014, Kumar 1992, Prasad 2001, Ulvi 2002. Additional trials may be necessary to further define the role of midazolam for this condition.

Based on the Neurocritical Care Society Guidelines for the Evaluation and Management of Status Epilepticus, the use of intravenous midazolam is an effective and recommended treatment for refractory status epilepticus in adults.

Palliative sedationcyes

Data from a prospective trial suggests that a protocol utilizing midazolam as a continuous infusion for palliative sedation in patients with advanced cancer may be beneficial for intolerable suffering refractory to other therapies Mercadante 2014. Additional data may be necessary to further define the role of midazolam in this setting. Due to its short half-life, palliative care experts consider the use of midazolam as a subcutaneous or intravenous continuous infusion as first-line therapy for respite sedation (ie, transient use to relieve severe symptoms [eg, pain, agitation] not necessarily refractory) Protus 2015. Note: Use of midazolam in this setting should be done in close consult with or by an experienced palliative care provider.

Based on the ESMO clinical practice guidelines for the management of refractory symptoms at the end of life and the use of palliative sedation, the use of midazolam is an effective and recommended sedative agent to relieve severe and refractory symptoms at the end of life ESMO [Cherney 2014].

Contraindications

Injection, oral: 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.

Concurrent use of oral midazolam with protease inhibitors (atazanavir, atazanavir-cobicistat, darunavir, indinavir, lopinavir-ritonavir, nelfinavir, ritonavir, saquinavir, tipranavir); concurrent use of oral or injectable midazolam with fosamprenavir.

Intranasal: Hypersensitivity to midazolam or any component of the formulation; acute narrow-angle glaucoma.

Documentation of allergenic cross-reactivity for benzodiazepines is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to benzodiazepines; acute pulmonary insufficiency; severe chronic obstructive pulmonary disease.

Dosage and Administration

Dosing: Adult

Note: The dose of midazolam needs to be individualized based on the patient's age, underlying diseases, and concurrent medications. Consider reducing dose by 20% to 50% in elderly, chronically ill, or debilitated patients and those receiving opioids or other CNS depressants (Miller 2010).

Anesthesia: IV:

Induction: Adults <55 years of age:

Unpremedicated patients: Initial: 0.3 to 0.35 mg/kg over 20 to 30 seconds; after 2 minutes, may repeat if necessary at ~25% of initial dose every 2 minutes, up to a total dose of 0.6 mg/kg in resistant cases.

Premedicated patients: Usual dosage range: 0.05 to 0.2 mg/kg (Barash 2009; Miller 2010). Use of 0.2 mg/kg administered over 5 to 10 seconds has been shown to safely produce anesthesia within 30 seconds (Samuelson 1981) and is recommended for ASA physical status P1 and P2 patients. When used with other anesthetic drugs (ie, coinduction), the dose is <0.1 mg/kg (Miller 2010).

ASA physical status >P3 or debilitation: Reduce dose by at least 20% (Miller 2010).

Maintenance: 0.05 mg/kg as needed (Miller 2010), or continuous infusion 0.015 to 0.06 mg/kg/hour (0.25 to 1 mcg/kg/minute) (Barash 2009; Miller 2010).

Palliative sedation (off-label use): Note: Use of midazolam in this setting should be done in close consult with or by an experienced palliative care provider. Ensure that flumazenil is readily available in the case of inadvertent overdose (ESMO [Cherney 2014]).

IV, SubQ: Continuous infusion: Initial: 0.5 to 1 mg/hour; may increase as needed. Usual dosage range: 1 to 20 mg/hour; may also intermittently administer 1 to 5 mg during infusion as needed (ESMO [Cherney 2014]). Some have recommended an initial bolus dose of 5 to 10 mg (size of dose depending on patient weight, age, and degree of debility) (Johanson 1993).

Sedation/anxiolysis/amnesia (preoperative/procedural):

Healthy adults <60 years of age:

Intranasal (solution, injection; off-label route): 0.1 mg/kg; administer 15 minutes prior to surgery/procedure (Uygur-Bayramiçli 2002). Note: Use 5 mg/mL injectable solution to deliver dose (Bailey 2017; Rech 2017).

IM: 0.07 to 0.08 mg/kg 30 to 60 minutes prior to surgery/procedure; usual dose: 5 mg.

IV: Initial: 0.5 to 2 mg over at least 2 minutes; slowly titrate to effect by repeating doses every 2 to 3 minutes if needed; usual total dose: 2.5 to 5 mg (ASGE [Waring 2003]).

Manufacturer's labeling: Dosing in the prescribing information may not reflect current clinical practice. Initial: Some patients respond to doses as low as 1 mg; no more than 2.5 mg should be administered over a period of at least 2 minutes. A total dose >5 mg is generally not needed.

Premedicated patients: Reduce initial dose by 30%.

Maintenance: 25% of dose used to reach sedative effect.

Adults ≥60 years of age, debilitated, or chronically ill: Refer to geriatric dosing.

Sedation in mechanically ventilated ICU patients: Note: Nonbenzodiazepine sedation may be preferred (SCCM [Devlin 2018]). IV: Initial: 0.01 to 0.05 mg/kg (~0.5 to 4 mg); may repeat at 10- to 15-minute intervals until adequate sedation achieved; maintenance infusion: 0.02 to 0.1 mg/kg/hour (0.3 to 1.7 mcg/kg/minute). Titrate to reach desired level of sedation (SCCM [Barr 2013]). Titration to maintain a light rather than a deep level of sedation is recommended unless clinically contraindicated (SCCM [Devlin 2018]). Consider a trial of daily awakening; if agitated after discontinuation of drip, then restart at 50% of the previous dose (Kress 2000).

Seizures, acute intermittent: Intranasal (nasal spray): 5 mg (one spray) as a single dose in one nostril; may repeat dose in 10 minutes in alternate nostril based on response and tolerability (do not repeat if the patient is having trouble breathing or excessive sedation). Maximum dose: 10 mg (2 sprays) per single episode. Maximum treatment frequency: Treatment of one episode every 3 days and treatment of 5 episodes in one month.

Status epilepticus (off-label use):

IM: 10 mg once (AES [Glauser 2016]) or 0.2 mg/kg once (maximum dose: 10 mg) (NCS [Brophy 2012]). Note: Midazolam IM is the preferred treatment in patients without IV access. Buccal and intranasal midazolam administration has also been used in patients without IV access, although these off-label routes are less well studied (AES [Glauser 2016]; Bailey 2017; deHaan 2010; NCS [Brophy 2012]; Scheepers 2000).

Prehospital status epilepticus: IM: 10 mg once; has been administered by paramedics when convulsions last >5 minutes or if convulsions are occurring after having intermittent seizures without regaining consciousness for >5 minutes (Silbergleit 2012).

Intranasal (solution, injection): Limited data available: 0.2 mg/kg (NCS [Brophy 2012]). Note: Use 5 mg/mL injectable concentrated solution to deliver dose (Bailey 2017; Rech 2017).

Buccal: Limited data available: 0.5 mg/kg (NCS [Brophy 2012]).

Status epilepticus, refractory (off-label use): IV: Note: Mechanical ventilation and cardiovascular monitoring required; titrate dose to cessation of electrographic seizures or burst suppression (NCS [Brophy 2012]).

Neurocritical Care Society recommendations:

Loading dose: 0.2 mg/kg followed by a continuous infusion (NCS [Brophy 2012]).

Continuous infusion: 0.05 to 2 mg/kg/hour (0.83 to 33.2 mcg/kg/minute) titrated to cessation of electrographic seizures or burst suppression. If patient experiences breakthrough status epilepticus while on the continuous infusion, administer a bolus of 0.1 to 0.2 mg/kg and increase infusion rate by 0.05 to 0.1 mg/kg/hour (0.83 to 1.66 mcg/kg/minute) every 3 to 4 hours (NCS [Brophy 2012]). Doses up to 2.9 mg/kg/hour have been described in the literature (Fernandez 2014). Note: A period of at least 24 to 48 hours of electrographic control is recommended prior to withdrawing the continuous infusion; withdraw gradually to prevent recurrent status epilepticus.

Dosing: Geriatric

Intranasal (nasal spray): Refer to adult dosing; use with caution due to potential prolonged drug exposure.

Oral: Use is not recommended.

Parenteral: The dose of midazolam needs to be individualized based on the patient's age, underlying diseases, and concurrent medications. Consider reducing dose by 20% to 50% in elderly, chronically ill, or debilitated patients and those receiving opioids or other CNS depressants (Miller 2010). Titration of doses should also be slower (Strøm 2016).

Anesthesia: IV:

Induction: Adults ≥55 years of age:

Unpremedicated patients: Initial: 0.3 mg/kg.

Premedicated patients: Reduce dose by at least 20% (Miller 2010).

Maintenance: Refer to adult dosing.

Sedation/Anxiolysis/Amnesia (preoperative/procedural):

IM: 2 to 3 mg (or 0.02 to 0.05 mg/kg) 30 to 60 minutes prior to surgery/procedure; some may only require 1 mg if anticipated intensity and duration of sedation is less critical.

IV: Initial: 0.5 to 2 mg administered over at least 2 minutes (smaller doses may be used in the elderly); slowly titrate to effect by repeating doses every 2 to 3 minutes if needed; usual total dose: 2.5 to 5 mg (ASGE [Waring 2003]).

Manufacturer's labeling: Dosing in the prescribing information may not reflect current clinical practice. Initial: Some patients respond to doses as low as 1 mg; no more than 1.5 mg should be administered over a period of at least 2 minutes. A total dose of >3.5 mg is generally not needed.

Premedicated patients: Reduce initial dose by 50%.

Maintenance: 25% of dose used to reach sedative effect.

Dosing: Pediatric

Dosage must be individualized and based on patient's age, underlying diseases, concurrent medications, and desired effect; decrease dose (by ∼30%) if opioids or other CNS depressants are administered concomitantly; use multiple small doses and titrate to desired sedative effect; allow 3 to 5 minutes between doses to decrease the chance of oversedation. The nasal spray formulation delivers a fixed dose of 5 mg and is not appropriate for all pediatric patients; for smaller intranasal doses, parenteral solution for injection can be used; ensure appropriate product selection and administration technique.

Sedation, anxiolysis, and amnesia prior to procedure or before induction of anesthesia:

IM: Infants, Children, and Adolescents: Usual: 0.1 to 0.15 mg/kg 30 to 60 minutes before surgery or procedure; range: 0.05 to 0.15 mg/kg; doses up to 0.5 mg/kg have been used in more anxious patients; maximum total dose: 10 mg.

IV:

Infants 1 to 5 months: Limited data available in nonintubated infants; infants <6 months are at higher risk for airway obstruction and hypoventilation; titrate dose with small increments to desired clinical effect; monitor carefully.

Infants 6 months to Children 5 years: Initial: 0.05 to 0.1 mg/kg; titrate dose carefully; total dose of 0.6 mg/kg may be required; usual total dose maximum: 6 mg.

Children 6 to 12 years: Initial: 0.025 to 0.05 mg/kg; titrate dose carefully; total doses of 0.4 mg/kg may be required; usual total dose maximum: 10 mg.

Children 12 to 16 years: Dose as adults; usual total dose maximum: 10 mg.

Intranasal (parenteral solution for injection product): Limited data available: Note: Some investigators suggest premedication with intranasal lidocaine to decrease irritation and subsequent agitation (Chiaretti 2011; Lugo 1993):

Infants 1 to 5 months: 0.2 mg/kg (single dose) (Harcke 1995; Mittal 2006).

Infants ≥6 months, Children, and Adolescents: 0.2 to 0.3 mg/kg (maximum single dose: 10 mg); may repeat in 5 to 15 minutes to a maximum of 0.5 mg/kg (maximum total dose: 10 mg) (Acworth 2001; Chiaretti 2011; Harcke 1995; Lane 2008).

Oral: Infants >6 months, Children, and Adolescents <16 years: Single dose: 0.25 to 0.5 mg/kg once, depending on patient status and desired effect, usual: 0.5 mg/kg; maximum dose: 20 mg; Note: Younger patients (6 months to <6 years) and those less cooperative may require higher doses (up to 1 mg/kg); use lower initial doses (0.25 mg/kg) in older patients (6 to <16 years) and in patients with cardiac or respiratory compromise, concomitant CNS depressant, or high-risk surgical patients.

Rectal: Limited data available: Infants >6 months and Children: Usual: 0.25 to 0.5 mg/kg once (Krauss 2006); doses up to 1 mg/kg have been used in infants and young children (7 months to 5 years of age) but may be associated with a higher incidence of postprocedural agitation (Kanegaye 2003; Tanaka 2000).

Sedation, mechanically ventilated patient: Infants, Children, and Adolescents: IV: Loading dose: 0.05 to 0.2 mg/kg given slow IV over 2 to 3 minutes, then follow with initial continuous IV infusion: 0.06 to 0.12 mg/kg/hour (1 to 2 mcg/kg/minute); titrate to the desired effect; range: 0.024 to 0.36 mg/kg/hour (0.4 to 6 mcg/kg/minute).

Seizures, acute treatment:

Buccal: Limited data available: Reserve for patients without IV access (Ashrafi 2010; Kutlu 2003; McIntyre 2005; Mpimbaza 2008; Talukdar 2009):

Weight-based dosing: Infants ≥3 months, Children, and Adolescents: 0.2 to 0.5 mg/kg once; maximum dose: 10 mg/dose.

Age-based dosing (McIntyre 2005):

Infants 6 to 11 months: 2.5 mg.

Children 1 to 4 years: 5 mg.

Children 5 to 9 years: 7.5 mg.

Children and Adolescents ≥10 years: 10 mg.

IM: Limited data available: Infants, Children, and Adolescents: 0.2 mg/kg/dose; repeat every 10 to 15 minutes; maximum dose: 6 mg/dose (Hegenbarth 2008).

Intranasal:

Nasal spray (Nayzilam): Children ≥12 years and Adolescents: 5 mg administered as one spray into one nostril; may repeat dose in 10 minutes in alternate nostril based on response and tolerability; do not repeat dose if patient has difficulty breathing or excessive sedation; maximum dose: 10 mg/dose per episode (2 sprays); do not exceed maximum treatment frequency of one episode every 3 days and 5 episodes per month.

Parenteral solution for injection product: Limited data available (Bhattachyaryya 2006; Fişgin 2000; Fişgin 2002; Holsti 2007; Holsti 2010; Kutlu 2000): Reserve for patients without IV access; divide dose between nares:

Infants 1 to 5 months: 0.2 mg/kg once; maximum dose: 10 mg/dose.

Infants and Children ≥6 months: 0.2 mg/kg; one study used 0.3 mg/kg (n=9); maximum dose: 10 mg/dose; may repeat once to a total maximum of 0.4 mg/kg.

Status epilepticus:

Standard treatment: Infants, Children, and Adolescents: Limited data available:

IM:

Weight-based dosing: 0.2 mg/kg once; maximum dose: 10 mg/dose (NCS [Brophy 2012]).

Fixed dosing (AES [Glauser 2016]; NCS [Brophy 2012]):

13 to 40 kg: 5 mg once.

>40 kg: 10 mg once.

Intranasal: 0.2 mg/kg once; maximum dose: 10 mg/dose (AES [Glauser 2016]; NCS [Brophy 2012]).

Buccal: 0.5 mg/kg once; maximum dose: 10 mg/dose (AES [Glauser 2016]; McIntyre 2005; NCS [Brophy 2012]).

Refractory to standard treatment (NCS [Brophy 2012]): Note: Mechanical ventilation and cardiovascular monitoring required; titrate dose to cessation of electrographic seizures or burst suppression. Infants, Children, and Adolescents: Limited data available:

Loading dose: IV: 0.2 mg/kg followed by a continuous infusion.

Continuous IV infusion: 0.05 to 2 mg/kg/hour (0.83 to 33.3 mcg/kg/minute) titrated to cessation of electrographic seizures or burst suppression. If patient experiences breakthrough status epilepticus while on the continuous infusion, administer a bolus of 0.1 to 0.2 mg/kg and increase infusion rate by 0.05 to 0.1 mg/kg/hour (0.83 to 1.66 mcg/kg/minute) every 3 to 4 hours.

Reconstitution

For continuous IV infusion, may dilute with NS or D5W to a final concentration of 0.5 mg/mL or 1 mg/mL (Karlage 2011).

Administration

Buccal: A buccal formulation is not currently available in the US. Some trials used an injectable solution administered buccally (McIntyre 2005). International studies used a 10 mg/mL commercially available buccal formulation (Ashrafi 2010). Administer to the buccal mucosa between the gums and the cheek using an oral syringe; gently massage cheek; dose may be divided to both sides of the mouth (Ashrafi 2010; McIntyre 2005).

Intranasal:

Nasal spray: Do not test or prime before use. Administer one spray into one nostril; if a second dose is needed, administer in alternate nostril. A second dose should not be administered if the patient is having trouble breathing or excessive sedation.

Solution, injection (off-label route): Note: Due to the low pH of the solution, burning upon administration is likely to occur (Mula 2014). Use of an atomizer, such as the MAD 300 Mucosal Atomizer which attaches to a tuberculin syringe, can reduce irritation. If possible, based upon dose to be administered, use higher concentration injectable solution to minimize volume administered intranasal. Smaller volume will reduce irritation and swallowing of administered dose. The maximum recommended dose volume (of the 5 mg/mL concentration) per nare is 1 mL (Bailey 2017).

Using the 5 mg/mL injectable solution, draw up desired dose with a 1 to 3 mL needleless syringe; may attach a nasal mucosal atomization device prior to delivering dose. Deliver half of the total dose volume into the first nare using the atomizer device or by dripping slowly into nostril, then deliver the other half of the dose into the second nare.

Oral: Do not mix with any liquid (such as grapefruit juice) prior to administration. Administer on empty stomach (feeding is usually contraindicated prior to sedation for procedures).

Parenteral: Do not administer intraarterially.

IM: Administer undiluted deep IM into large muscle.

IV: For procedural sedation/anxiolysis/amnesia, administer by slow IV injection over at least 2 minutes using a concentration of 1 mg/mL or a dilution of the 1 or 5 mg/mL concentrations. For induction of anesthesia, administer IV bolus over 5 to 15 seconds (Miller 2010). For refractory status epilepticus, the loading dose is recommended to be infused at a rate of 2 mg/minute (NCS [Brophy 2012]). For other clinical situations (eg, sedation in the mechanically-ventilated patient), a continuous infusion may also be administered.

Rectal: Clinical trials utilized parenteral midazolam for rectal administration; administer a 1 to 5 mg/mL solution through a small, lubricated catheter or tube inserted rectally; hold buttocks closed for ~5 minutes after administration (Kanegaye 2003; Tanaka 2000).

Dietary Considerations

Avoid grapefruit juice with oral syrup.

Storage

Oral: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Injection: Store at 20°C to 25°C (68°F to 77°F). A final concentration of midazolam 0.5 mg/mL is stable for up to 24 hours when diluted with D5W or NS or 4 hours when diluted with LR. A final concentration of 1 mg/mL in NS has been documented to be stable for up to 10 days (McMullin 1995) and up to 27 days in D5W (Karlage 2011).

Intranasal (nasal spray): Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Only open blister pack immediately prior to administration.

Drug Interactions

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Antihepaciviral Combination Products: May increase the serum concentration of Midazolam. Management: Oral midazolam contraindicated with antihepaciviral combination products. When used with intravenous midazolam, monitor for increased midazolam effects (eg, sedation, respiratory depression) and consider using a reduced midazolam dose. Avoid combination

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

AtorvaSTATin: May increase the serum concentration of Midazolam. Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Consider therapy modification

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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

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

Cobicistat: May increase the serum concentration of Midazolam. Management: Oral midazolam use is contraindicated with cobicistat-containing products. IV midazolam should be used with caution, close monitoring, and consideration of lower IV midazolam doses. Avoid combination

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Consider therapy modification

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Elagolix: May decrease the serum concentration of Midazolam. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ginkgo Biloba: May decrease the serum concentration of Midazolam. Monitor therapy

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Itraconazole: May increase the serum concentration of Midazolam. Management: Oral midazolam is contraindicated. Use intravenous midazolam with great caution in patients receiving itraconazole, employing reduced initial doses whenever possible and monitoring closely for enhanced and prolonged effects. Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Ketoconazole (Systemic): May increase the serum concentration of Midazolam. Avoid combination

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Consider therapy modification

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Lumacaftor and Ivacaftor: May decrease the serum concentration of Midazolam. Management: Consider alternatives to midazolam in patients treated with ivacaftor/lumacaftor due to the potential for decreased midazolam exposure and efficacy. Consider therapy modification

Macrolide Antibiotics: May increase the serum concentration of Midazolam. Management: Consider an alternative less likely to interact. Azithromycin is likely a lower-risk macrolide, and benzodiazepines less dependent on CYP3A metabolism (e.g., lorazepam, oxazepam) are similarly less likely to interact. Exceptions: Azithromycin (Systemic); Fidaxomicin; Roxithromycin; Spiramycin. Consider therapy modification

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Melatonin: May enhance the sedative effect of Benzodiazepines. Monitor therapy

Methadone: Benzodiazepines may enhance the CNS depressant effect of Methadone. Management: Clinicians should generally avoid concurrent use of methadone and benzodiazepines when possible; any combined use should be undertaken with extra caution. Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

OLANZapine: May enhance the adverse/toxic effect of Benzodiazepines. Management: Avoid concomitant use of parenteral benzodiazepines and IM olanzapine due to risks of additive adverse events (e.g., cardiorespiratory depression). Olanzapine prescribing information provides no specific recommendations regarding oral administration. Avoid combination

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Propofol: Midazolam may increase the serum concentration of Propofol. Propofol may increase the serum concentration of Midazolam. Monitor therapy

Protease Inhibitors: May increase the serum concentration of Midazolam. Management: Oral midazolam contraindicated with all protease inhibitors. IV midazolam contraindicated with fosamprenavir and nelfinavir; other protease inhibitors recommend caution, close monitoring, and consideration of lower IV midazolam doses with concurrent use. Avoid combination

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Roxithromycin: May increase the serum concentration of Midazolam. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of Midazolam. Monitor therapy

Sodium Oxybate: Benzodiazepines may enhance the CNS depressant effect of Sodium Oxybate. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Tecovirimat: May decrease the serum concentration of Midazolam. Monitor therapy

Teduglutide: May increase the serum concentration of Benzodiazepines. Monitor therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tofisopam: May increase the serum concentration of Midazolam. Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Adverse Reactions

As reported in adults unless otherwise noted.

>10%: Respiratory: Bradypnea, decreased tidal volume

1% to 10%:

Cardiovascular: Hypotension (children: 3%)

Central nervous system: Drowsiness (1%), headache (1%), seizure-like activity (children: 1%), drug dependence (physical and psychological dependence with prolonged use), myoclonus (preterm infants), severe sedation

Gastrointestinal: Hiccups (adults: 4%; children: 1%), nausea (3%), vomiting (3%)

Local: Injection site reaction (IM: ≤4%, IV: ≤5%; severity less than diazepam), pain at injection site (IM: ≤4%, IV: ≤5%; severity less than diazepam)

Ophthalmic: Nystagmus (children: 1%)

Respiratory: Apnea (children: 3%), cough (1%)

Miscellaneous: Paradoxical reaction (children: 2%)

<1%, postmarketing, and/or case reports: Acidic taste, agitation, amnesia, bigeminy, bradycardia, bronchospasm, confusion, delirium (emergence), dyspnea, euphoria, hallucination, hyperventilation, laryngospasm, sialorrhea, skin rash, tachycardia, ventricular premature contractions, wheezing

Warnings/Precautions

Concerns related to adverse effects:

• Anterograde amnesia: Benzodiazepines have been associated with anterograde amnesia (Nelson 1999).
• Cardiorespiratory effects: [US Boxed Warning]: Injection, oral: Has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings; airway obstruction, desaturation, hypoxia, and apnea have also been reported, most often when used concomitantly with other CNS depressants (eg, opioids). In some cases, death or hypoxic encephalopathy resulted. Use only in hospital or ambulatory care settings that provide for continuous monitoring of respiratory and cardiac function (ie, pulse oximetry). Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured. For deeply sedated patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure. 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 (Mancuso 2004).
• Suicidal ideation: Intranasal: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as one week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify health care provider immediately if symptoms occur.

Disease-related concerns:

• Acute illness: Use IV midazolam with caution in patients with uncompensated acute illnesses, such as severe fluid or electrolyte disturbances.
• Cardiovascular disease: Use with caution in patients with heart failure. Adverse hemodynamic events have been reported in pediatric patients with cardiovascular instability; avoid rapid IV administration in these patients.
• Glaucoma: Use with caution in patients with glaucoma; contraindicated in patients with acute narrow angle glaucoma; may use in patients with open-angle glaucoma only if receiving appropriate therapy.
• Renal impairment: Use with caution in patients with renal impairment; half-life of midazolam and metabolites may be prolonged.
• Respiratory disease: Use with caution in patients with respiratory disease (eg, chronic obstructive pulmonary disease); these patients may be sensitive to the respiratory depressant effects of midazolam.

Concurrent drug therapy issues:

• Concomitant use with opioids: [US Boxed Warning]: Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Debilitated patients: Use with caution in debilitated patients; decreased dosages recommended. These patients take longer to recover completely after midazolam administration for the induction of anesthesia.
• Elderly: Use with caution in the elderly; decreased dosages and slower titration is recommended due to an increased volume of distribution seen with lipophilic drugs in the elderly, resulting in slower distribution and lower clearance. Older patients can also take longer to recover completely after midazolam administration for the induction of anesthesia (Strøm 2016). Use of oral midazolam is not recommended in the elderly. Elderly patients may be at an increased risk of death with use; risk has been found highest within the first 4 months of use in elderly dementia patients (Jennum 2015; Saarelainen 2018).
• Fall risk: Use with extreme caution in patients who are at risk of falls; benzodiazepines have been associated with falls and traumatic injury (Nelson 1999).
• Obese patients: Use benzodiazepines with caution in obese patients; may have prolonged action when discontinued.
• Neonates: Injection: [US Boxed Warning]: Do not administer by rapid IV injection in neonates; severe hypotension and seizures have been reported following rapid IV administration, particularly with concomitant fentanyl use. Neonates are also vulnerable to profound and/or prolonged respiratory effects of midazolam.
• Pediatric: Pediatric patients with cardiac or respiratory compromise may be sensitive to the respiratory depressant effect of midazolam. Pediatric patients undergoing procedures involving the upper airway (eg, upper endoscopy, dental care) are vulnerable to episodes of desaturation and hypoventilation.
• Pediatric neurotoxicity: In pediatric and neonatal patients <3 years of age and patients in third trimester of pregnancy (ie, times of rapid brain growth and synaptogenesis), the repeated or lengthy exposure to sedatives or anesthetics during surgery/procedures may have detrimental effects on child or fetal brain development and may contribute to various cognitive and behavioral problems. Epidemiological studies in humans have reported various cognitive and behavioral problems, including neurodevelopmental delay (and related diagnoses), learning disabilities, and attention-deficit hyperactivity disorder. Human clinical data suggest that single, relatively short exposures are not likely to have similar negative effects. No specific anesthetic/sedative has been found to be safer. For elective procedures, risk versus benefits should be evaluated and discussed with parents/caregivers/patients; critical surgeries should not be delayed (US FDA Safety Communication 2017 Update).

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggest that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.
• Injection: [US Boxed Warning]: Midazolam must never be used without individualization of dosage. The initial IV dose for sedation in adults may be as little as 1 mg, but should not exceed 2.5 mg in a healthy adult. Lower doses are necessary for older (>60 years of age) or debilitated patients and in patients receiving concomitant opioids or other CNS depressants. The initial dose and all subsequent doses should always be titrated slowly; administer over at least 2 minutes and allow an additional ≥2 minutes to fully evaluate the sedative effect. The use of the 1 mg/mL formulation or dilution of the 1 mg/mL or 5 mg/mL formulation is recommended to facilitate slower injection. Doses of sedative medications in pediatric patients must be calculated on a mg/kg basis, and initial doses and all subsequent doses should always be titrated slowly. The initial pediatric dose of midazolam for sedation/anxiolysis/amnesia is age, procedure, and route dependent.

Other warnings/precautions:

• Appropriate use: Does not have analgesic, antidepressant, or antipsychotic properties. Does not protect against increases in intracranial pressure, heart rate, and/or blood pressure during intubation. Do not use in shock, coma, or acute alcohol intoxication with depression of vital signs. Avoid intra-arterial administration or extravasation of parenteral formulation. Use during upper airway procedures (ie, endoscopy, dental care) may increase risk of hypoventilation. Prolonged responses have been noted following extended administration by continuous infusion (possibly due to metabolite accumulation) or in the presence of drugs which inhibit midazolam metabolism. Oral midazolam is intended for use in monitored settings only and not for chronic or home use.
• Tolerance: Midazolam is a short half-life benzodiazepine and may be of benefit in patients where a rapidly and short-acting agent is desired (acute agitation). Duration of action after a single dose is determined by redistribution rather than metabolism. Tolerance develops to the sedative and anticonvulsant effects. It does not develop to the anxiolytic effects (Vinkers 2012).
• Withdrawal: Withdrawal symptoms (convulsions, hallucinations, tremor, abdominal and muscle cramps, vomiting and sweating) may occur following abrupt discontinuation or large decreases in dose. Use caution when reducing dose or withdrawing therapy; decrease slowly and monitor for withdrawal symptoms.

Monitoring Parameters

Level of sedation, respiratory rate, heart rate, blood pressure, oxygen saturation (ie, pulse oximetry).

Critically ill patients: Assess and adjust sedation according to scoring system (Richmond Agitation-Sedation Scale [RASS] or Sedation-Agitation Scale [SAS]) (SCCM [Devlin 2018]).

Pregnancy

Pregnancy Considerations

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. Neonatal withdrawal symptoms may occur within days to weeks after birth and "floppy infant syndrome" (which also includes withdrawal symptoms) have been reported with some benzodiazepines (Bergman 1992; Iqbal 2002; Wikner 2007).

Based on animal data, repeated or prolonged use of general anesthetic and sedation medications that block N-methyl-D-aspartate (NMDA) receptors and/or potentiate gamma-aminobutyric acid (GABA) activity may affect brain development. Evaluate benefits and potential risks of fetal exposure to midazolam when duration of surgery is expected to be >3 hours (Olutoye 2018).

Due to pregnancy-induced physiologic changes, some pharmacokinetic properties of midazolam may be altered (Hebert 2008; Wilson 1987). Although use in obstetric procedures is not recommended by the manufacturer, midazolam use in obstetric anesthesia has been described (Frölich 2006; Heyman 1987; Kanto 1984; Neuman 2013; Senel 2014; Shergill 2012).

The ACOG recommends that pregnant women should not be denied medically necessary surgery regardless of trimester. If the procedure is elective, it should be delayed until after delivery (ACOG 775 2019).

Patient Education

What is this drug used for?

• It is used to calm you before a procedure, to cause sleep during a procedure, and to treat seizures.

Frequently reported side effects of this drug

• Stuffy nose
• Sore throat
• Headache
• Nausea
• Vomiting
• Loss of strength and energy
• Injection site irritation
• Trouble with memory

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Difficulty breathing
• Slow breathing
• Shallow breathing
• Severe fatigue
• Chest pain
• Tremors
• Twitching
• Passing out
• Agitation
• Abnormal movements
• Depression like thoughts of suicide, anxiety, emotional instability, or confusion
• Irritability
• Panic attacks
• Mood changes
• Behavioral changes
• Agitation
• Seizures
• Severe dizziness
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.