Midazolam has been associated with profound sedation, 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, where this was not recognized promptly and treated effectively, hypoxic encephalopathy, coma, and death have resulted. Midazolam should be used only in hospital or ambulatory care settings, including physicians' and dentists' offices, that can provide for continuous monitoring of respiratory and cardiac function (eg, 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 pediatric patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.
Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor patients for respiratory depression and sedation.
The use of benzodiazepines, including midazolam, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing midazolam and throughout treatment, assess each patient's risk for abuse, misuse, and addiction.
The continued use of benzodiazepines may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Although midazolam is indicated only for intermittent use, if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of midazolam may precipitate acute withdrawal reactions, which can be life-threatening. For patients using midazolam more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue midazolam.
Midazolam must never be used without individualization of dosage. The initial intravenous dose for sedation in adult patients 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 or more 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.
Midazolam should not be administered by rapid injection in the neonatal population. Severe hypotension and seizures have been reported following rapid IV administration, particularly with concomitant use of fentanyl.
Note: Dosage must be individualized and based on patient's age, underlying diseases, concurrent medications, and desired effect. Patients receiving extracorporeal membrane oxygenation (ECMO) may require higher doses due to drug absorption in the ECMO circuit (Ref). To minimize excipient load, preservative-free preparations should be used; alternatively, use the more concentrated midazolam injection (eg, 5 mg/mL) and dilute with SWFI without preservatives.
Sedation, intermittent dosing or procedural (intubation): IM, IV: 0.05 to 0.1 mg/kg/dose over 5 minutes (Ref).
Sedation, mechanically ventilated patient: Note: Use the lowest effective dose to reduce potential for drug accumulation and adverse effects:
Loading dose: Note: Some recommend against the use of a loading or bolus dose in preterm and term neonates to minimize risk of hypotension; to rapidly achieve sedation, it has been suggested to begin the continuous infusion at a faster rate for the first several hours (Ref).
GA ≥24 weeks: IV: 0.2 mg/kg/dose once (administered over ≥1 hour to minimize risk of hypotension) (Ref).
Continuous IV infusion: Note: Insufficient evidence exist to support the routine use of midazolam infusions for sedation in preterm neonates (Ref):
GA 24 to 26 weeks: IV: Initial: 0.015 to 0.03 mg/kg/hour (0.25 to 0.5 mcg/kg/minute) (Ref).
GA 27 to 29 weeks: IV: Initial: 0.015 to 0.04 mg/kg/hour (0.25 to 0.67 mcg/kg/minute) (Ref).
GA ≥30 weeks: IV: Initial: 0.015 to 0.06 mg/kg/hour (0.25 to 1 mcg/kg/minute) (Ref).
Sedation tapering (after prolonged therapy): After prolonged therapy, consider a slow taper of therapy to prevent signs and symptoms of withdrawal. The following regimen has been reported (Ref):
If duration of therapy ≤4 days: Taper over 1 to 2 days beginning with an initial dosage reduction of 30% to 50% followed by 20% to 30% dosage reductions every 6 to 8 hours; monitor closely for signs and symptoms of withdrawal with each reduction in dose.
If duration of therapy is >4 days: Decrease infusion rate by 25% to 50% every 12 hours, then convert to an intermittent dose every 4 hours and lastly, every 8 hours; monitor closely for signs and symptoms of withdrawal with each reduction in dose.
Seizures, refractory; status epilepticus: IV: Dosage regimens variable, reported doses are higher than sedative doses: Note: Consider omitting loading dose if patient has received an IV dose of a benzodiazepine; begin continuous IV infusion at lower end of range and titrate to lowest effective dose: Loading dose: 0.06 to 0.15 mg/kg/dose followed by a continuous infusion of 0.06 to 0.4 mg/kg/hour (1 to 7 mcg/kg/minute); maximum reported rate: 1.1 mg/kg/hour (18 mcg/kg/minute) (Ref).
Note: Dosage must be individualized and based on patient's age, underlying diseases, concurrent medications, and desired effect; calculate dose based on ideal body weight for patients with obesity; 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: IM: Usual dose: 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 <6 months: IV: 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 <6 years: IV: Initial: 0.05 to 0.1 mg/kg; titrate dose carefully to desired clinical effect; total dose of 0.6 mg/kg may be required; usual maximum total dose: 6 mg.
Children ≥6 years: IV: Initial: 0.025 to 0.05 mg/kg; titrate dose carefully to desired clinical effect; total doses of 0.4 mg/kg may be required; usual maximum total dose: 10 mg.
Adolescents: IV: Initial: 1 to 2.5 mg over ≥2 minutes; titrate dose carefully to desired clinical effect; usual maximum total dose: 10 mg. Note: Based on experience in adults, smaller initial doses (eg, 0.5 mg) may be considered (Ref).
Intranasal: Limited data available: Note: Administer using parenteral solution for injection product via intranasal route; use of mucosal atomizer device (MAD) is recommended.
Infants, Children, and Adolescents: Intranasal: Usual dose: 0.2 mg/kg as a single dose, may repeat in 15 minutes; reported range: 0.2 to 0.8 mg/kg; maximum dose: 10 mg/dose (Ref). Note: Some investigators suggest premedication with intranasal lidocaine to decrease irritation and subsequent agitation (Ref).
Oral: Infants >6 months, Children, and Adolescents <16 years: Oral: 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 (Ref).
Rectal: Limited data available: Infants >6 months and Children: Rectal: Usual: 0.25 to 0.5 mg/kg once (Ref); 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 (Ref).
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: 0.05 to 0.12 mg/kg/hour (0.8 to 2 mcg/kg/minute); titrate to the desired effect; maximum initial dose: 10 mg/hour (Ref).
Sedation tapering (after prolonged therapy): After prolonged therapy, consider a slow taper of therapy or conversion to a long-acting benzodiazepine to prevent signs and symptoms of withdrawal. Reported conversion strategies are based on potency, half-life, and oral bioavailability of diazepam and lorazepam but are variable and based on limited clinical evidence (Ref).
If duration of therapy <3 to 5 days: Decrease dose by 10% to 15% every 6 to 8 hours (Tobias 2000); monitor closely for signs and symptoms of withdrawal with each reduction in dose.
If duration of therapy >5 days, the following regimens have been reported:
Conversion to oral diazepam: After first dose of oral diazepam, decrease midazolam infusion by 50%; after the second dose of oral diazepam, discontinue the midazolam infusion (Ref); monitor closely for signs and symptoms of withdrawal with each reduction in dose.
Conversion to oral lorazepam: After second dose of oral lorazepam, decrease midazolam infusion by 50%; after third dose of oral lorazepam, decrease the midazolam infusion by an additional 50%; after fourth dose of oral lorazepam, discontinue the midazolam infusion (Ref); monitor closely for signs and symptoms of withdrawal with each reduction in dose.
Seizures, acute treatment:
Buccal: Limited data available (Ref): Note: Reserve for patients without IV access; if seizure does not cease within 5 minutes, some studies describe repeating dose (Ref):
Weight-directed dosing: Infants ≥3 months, Children, and Adolescents: Buccal: 0.2 to 0.5 mg/kg once; maximum dose: 10 mg/dose.
Age-directed dosing:
Infants ≥3 months: Buccal: 2.5 mg.
Children 1 to 4 years: Buccal: 5 mg.
Children 5 to 9 years: Buccal: 7.5 mg.
Children and Adolescents ≥10 years: Buccal: 10 mg.
IM: Limited data available:
Weight-directed dosing: Infants, Children, and Adolescents: IM: 0.2 mg/kg/dose (Ref).
Fixed dosing (Ref):
13 to 40 kg: IM: 5 mg.
>40 kg: IM: 10 mg.
Intranasal:
Nasal spray (Nayzilam): Children ≥12 years and Adolescents: Intranasal: 5 mg administered as 1 spray into 1 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 1 episode every 3 days and 5 episodes per month.
Parenteral solution for injection product: Limited data available: Use of mucosal atomizer device (MAD) is recommended:
Infants, Children, and Adolescents: Intranasal (using parenteral solution): 0.2 mg/kg/dose, divide dose between nares; maximum dose: 10 mg/dose; may repeat once to a total maximum of 0.4 mg/kg (Ref). Note: A higher dose of 0.3 mg/kg has been described in patients ≥6 months (Ref).
Status epilepticus:
Standard treatment: Infants, Children, and Adolescents: Limited data available:
IM:
Weight-based dosing: IM: 0.2 mg/kg once; maximum dose: 10 mg/dose (Ref).
Fixed dosing (Ref):
13 to 40 kg: IM: 5 mg once.
>40 kg: IM: 10 mg once.
Intranasal: 0.2 mg/kg once; maximum dose: 10 mg/dose (Ref).
Buccal: 0.5 mg/kg once; maximum dose: 10 mg/dose (Ref).
Refractory to standard treatment (Ref): 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.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution; half-life of midazolam and metabolites may be prolonged. Adult patients with renal failure receiving a continuous infusion cannot adequately eliminate the active hydroxylated metabolites (eg, 1-hydroxymidazolam) contributing to prolonged sedation sometimes for days after discontinuation (Ref).
Hemodialysis: Supplemental dose is not necessary.
Peritoneal dialysis: Significant drug removal is unlikely based on physiochemical characteristics
There are no dosage adjustments provided in the manufacturer's labeling; use with caution. Based on experience in adult patients, the following have been suggested and may be considered in pediatric patients:
Single dose (eg, induction): No dosage adjustment recommended; patients with hepatic impairment may be more sensitive compared to patients without hepatic impairment; anticipate longer duration of action (Ref).
Multiple dosing or continuous infusion: Expect longer duration of action and accumulation; based on patient response, dosage reduction likely to be necessary (Ref).
(For additional information see "Midazolam: Drug information")
Note: Safety: In general, reduced doses and/or longer dosing intervals are used in patients with renal or hepatic disease, chronically ill patients, or debilitated patients (Ref). Repeated doses or continuous infusion can accumulate in adipose tissue, increasing the risk of prolonged sedation (Ref).
Agitation, acute/severe (monotherapy or adjunctive therapy) (off-label use):
IV, IM: Initial: 2.5 to 5 mg; repeat doses may be administered every 3 to 5 minutes (IV route) or every 5 to 10 minutes (IM route) until sedation is adequate and appropriate; some patients may require a total dose of ~20 mg; monitor respiratory status; may give alone or in combination with an antipsychotic (Ref).
General anesthesia or monitored anesthesia care:
Note: Individualize dosing based on patient factors and concomitant anesthesia.
Premedication/preinduction: Note: Generally, avoid routine administration as a premedication for general anesthesia due to adverse effects (Ref).
IV: Usual dosing range: 0.5 to 2 mg; administered in 0.5 to 1 mg increments based on clinical effect (Ref).
Induction (adjunctive agent): Note: Consider reducing dose or avoiding in hemodynamically unstable patients or if already administered with premedication/preinduction. Generally, avoid routine administration for induction of general anesthesia due to adverse effects (Ref).
IV: Usual dosing range: 0.5 to 2 mg; administered in 0.5 to 1 mg increments based on clinical effect (Ref).
Note: Use as a sole or co-induction agent is described in the manufacturer's labeling and relevant textbooks (ie, 0.1 to 0.25 mg/kg [premedicated patients] and up to 0.35 mg/kg [unpremedicated patients]) (Ref); however, this dosing is uncommonly used and may prolong recovery.
Intoxication: Cocaine, methamphetamine, and other sympathomimetics (alternative agent) (off-label use):
Note : If IV access is not available, consider IM administration; however, effect will be delayed (~10 minutes or greater) (Ref).
IV, IM: 1 to 5 mg every 3 to 10 minutes as needed for agitation, sedation, hyperthermia, hypertension, and tachycardia until desired symptom control is achieved. Large cumulative doses may be required for some patients; monitor for respiratory depression (Ref).
Mechanically ventilated patients in the ICU, sedation (alternative agent):
Note: Used as part of a multimodal strategy. In general, nonbenzodiazepine sedation is preferred due to risk of prolonged sedation and delirium with continuous benzodiazepine use (eg, >48 hours). Intermittent administration is preferred to avoid drug accumulation and prolonged sedation associated with continuous infusions. Titrate to a light level of sedation (eg, Richmond Agitation Sedation Scale 0 to −2) or clinical effect (eg, ventilator dyssynchrony) (Ref). Refer to institutional policies and procedures.
IV:
Intermittent: Initial: 0.5 to 5 mg or 0.01 to 0.05 mg/kg over ≥2 minutes; may repeat at 10- to 15-minute intervals as needed until goal level of sedation is achieved (Ref).
Continuous infusion: Loading dose: 0.5 to 5 mg every 1 to 5 minutes (if needed), followed by 1 to 8 mg/hour or 0.01 to 0.1 mg/kg/hour continuous infusion; titrate infusion rate to clinical effect. To prevent high basal continuous infusion rates, consider using additional bolus doses instead to achieve goal level of sedation or clinical effect (Ref).
Note: Consider a daily awakening trial or nurse protocolized sedation; if agitated after discontinuation of continuous infusion, then restart at ~50% of the previous dose (Ref).
Palliative and end-of-life sedation (off-label use):
Note : Generally used for management of refractory symptoms (eg, anxiety, agitation, palliative sedation) in addition to an opioid and other medications; use in this setting should be done in close consult with an experienced palliative care provider. Ensure that flumazenil is readily available in the case of inadvertent overdose (Ref).
IV, SubQ:
Intermittent: Initial: 1 to 5 mg, then repeat dose every 5 to 15 minutes as needed for symptom management; usual dosage range: 0.25 to 5 mg. Note: Onset of action is delayed with SubQ administration and may influence the frequency of administration (Ref).
Continuous infusion: Initial: 0.25 to 1 mg/hour; titrate as needed for symptom management; usual dosage range: 0.5 to 5 mg/hour; some patients may need up to 20 mg/hour. Note: Generally used after failure of intermittent therapy. SubQ continuous infusion dose is equivalent to IV continuous infusion dose (Ref).
Procedural sedation, outside the operating room (alternative agent):
Note: Reduce dose when given in conjunction with opioids or other CNS depressants.
IV: Usual dosage range: 0.5 to 2 mg over ≥2 minutes; repeat every 2 to 5 minutes as needed; titrate to clinical effect; maximum total dose: 5 mg (Ref).
Intranasal (using injectable solution) (off-label route): 0.1 mg/kg; administer 15 minutes prior to surgery/procedure; maximum single dose: 10 mg (based on volume) (Ref). Note: Use 5 mg/mL injectable solution to deliver dose (Ref). Due to the low pH of the solution, a burning sensation upon administration is likely to occur; consider using an atomizer for delivery or instilling intranasal lidocaine prior to administration (Ref).
Rapid sequence intubation, outside the operating room (alternative agent) (off-label use):
Note: May cause hypotension; consider alternative agent in patients who are hemodynamically unstable and/or patients with head injury. When used as monotherapy, the onset of action may be up to 5 minutes, which may be too prolonged in some clinical situations (Ref).
IV: 0.2 mg/kg once; use 0.1 mg/kg in hemodynamically unstable patients; usual dosage range: 0.1 to 0.3 mg/kg (Ref).
Seizures:
Intermittent (repetitive or cluster): Note: Can be administered by non–health care professionals to patients who are actively seizing or during a seizure cluster. In patients at increased risk of respiratory depression, the first dose should be administered under health care supervision to assess response and tolerability.
Intranasal (Nayzilam nasal spray): 5 mg (1 spray) as a single dose in 1 nostril; may repeat same 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 1 episode every 3 days and treatment of 5 episodes in 1 month.
Status epilepticus (convulsive and nonconvulsive):
Note: IM midazolam is the preferred benzodiazepine in patients without IV access. Intranasal and buccal administration are effective alternatives in patients without IV access (Ref).
IM: 10 mg once or 0.2 mg/kg once (maximum dose: 10 mg) (Ref). Note: Only the injectable product Seizalam is FDA approved for status epilepticus; however, any parenteral product approved for IM administration may be used off label for this indication.
Intranasal (may use injectable solution) (off-label route): Initial: 5 to 10 mg. May repeat dose if needed; maximum total dose: 15 mg (Ref). Note: May use 5 mg/mL parenteral concentrated solution to deliver dose (Ref). Due to the low pH of the solution, a burning sensation upon administration is likely to occur; consider using an atomizer for delivery or instilling intranasal lidocaine prior to administration (Ref).
Buccal (may use injectable solution) (off-label route): Initial: 10 mg. May repeat dose if needed; maximum total dose: 30 mg (Ref).
Status epilepticus, refractory (off-label use):
Note : Mechanical ventilation and hemodynamic support generally required; titrate dose to cessation of electrographic seizures or burst suppression (Ref).
IV:
Loading dose: 0.2 mg/kg administered slowly, followed by a continuous infusion; repeat loading dose every 3 to 5 minutes (maximum total dose: 2 mg/kg) as needed for electrographic/burst suppression (Ref).
Continuous infusion: After initial loading dose, begin continuous infusion at 0.05 to 2 mg/kg/hour and titrate to cessation of electrographic seizures/burst suppression. For breakthrough status epilepticus, administer bolus of 0.1 to 0.2 mg/kg every 3 to 5 minutes in addition to increasing infusion rate by 0.05 to 0.1 mg/kg/hour every 3 to 4 hours (Ref). Some experts use doses up to 3 mg/kg/hour (Ref).
Note: Generally, a period of at least 24 hours of electrographic suppression is suggested prior to down titrating the continuous infusion; withdraw gradually by decreasing the dose 50% every 3 hours to prevent recurrent status epilepticus or taper off over 4 to 6 hours (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Note: Use with caution in kidney dysfunction and/or those receiving renal replacement therapies. The half-life of midazolam and active metabolites are prolonged in acutely ill patients with acute kidney injury receiving continuous infusions and may accumulate, contributing to prolonged sedation (Ref).
Altered kidney function:
Buccal, intranasal, parenteral: No initial dosage adjustments necessary for any degree of kidney impairment; however, use with caution and monitor closely for excessive sedation in patients with severe impairment (eg, CrCl <30 mL/minute); consider longer dosing intervals for intermittent dosing and slower titration of continuous infusions. In some situations (eg, sedation in mechanically ventilated patients) additional boluses may be considered to prevent higher basal continuous infusion rates (Ref).
Hemodialysis, intermittent (thrice weekly): Buccal, intranasal, parenteral: Unlikely to be significantly dialyzable (highly protein bound) (Ref):
No initial dosage adjustments necessary; however, use with caution and monitor closely for excessive sedation; consider longer dosing intervals for intermittent dosing and slower titration of continuous infusions. In some situations (eg, sedation in mechanically ventilated patients), additional boluses may be considered to prevent higher basal continuous infusion rates (Ref).
Peritoneal dialysis: Unlikely to be significantly dialyzable (highly protein bound) (Ref):
Buccal, intranasal, parenteral: No initial dosage adjustments necessary; however, use with caution and monitor closely for excessive sedation; consider longer dosing intervals for intermittent dosing and slower titration of continuous infusions. In some situations (eg, sedation in mechanically ventilated patients) additional boluses may be considered to prevent higher basal continuous infusion rates (Ref).
CRRT: Buccal, intranasal, parenteral: Midazolam and 1-hydroxy-midazolam (active metabolite) are not effectively removed by CRRT, although 1-alpha hydroxymidazolam glucuronide (also hypothesized to be active) is significantly removed (Ref). No initial dosage adjustments necessary; however, use with caution and monitor closely for excessive sedation; consider longer dosing intervals for intermittent dosing and slower titration of continuous infusions. In some situations (eg, sedation in mechanically ventilated patients) additional boluses may be considered to prevent higher basal continuous infusion rates (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): Buccal, intranasal, parenteral: Midazolam and 1-hydroxymidazolam are not expected to be effectively removed by PIRRT, although 1-alpha hydroxymidazolam glucuronide (also hypothesized to be active) may be significantly removed (Ref). No initial dosage adjustments necessary; however, use with caution and monitor closely for excessive sedation; consider longer dosing intervals for intermittent dosing and slower titration of continuous infusions. In some situations (eg, sedation in mechanically ventilated patients), additional boluses may be considered to prevent higher basal continuous infusion rates (Ref).
There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
IV:
Single dose (eg, induction): No dosage adjustment recommended; patients with hepatic impairment may be more sensitive compared to patients without hepatic impairment; anticipate longer duration of action (Ref).
Multiple dosing or continuous infusion: Expect longer duration of action and accumulation; based on patient response, dosage reduction likely to be necessary (Ref).
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, Intravenous:
Generic: 100 mg/100 mL in NaCl 0.8% (100 mL); 50 mg/50 mL in NaCl 0.8% (50 mL)
Solution, Intravenous [preservative free]:
Generic: 100 mg/100 mL in NaCl 0.9% (100 mL); 50 mg/50 mL in NaCl 0.9% (50 mL)
Solution, Nasal:
Nayzilam: 5 mg/0.1 mL (1 ea) [contains propylene glycol]
Syrup, Oral:
Generic: 2 mg/mL (2.5 mL, 5 mL, 118 mL)
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Injection:
Generic: 1 mg/mL (2 mL, 5 mL, 10 mL, 100 mL); 5 mg/mL (1 mL, 2 mL, 10 mL, 50 mL); 50 mg/10 mL (10 mL)
C-IV
An FDA-approved patient medication guide, which is available with the product and as follows, must be dispensed with this medication:
Nayzilam: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211321s000lbl.pdf#page=24
Buccal: A buccal formulation is not currently available in the United States. Some trials used an injectable solution administered buccally (Ref). International studies used a 10 mg/mL commercially available buccal formulation (Ref). 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 (Ref).
Intranasal: The nasal spray formulation (Nayzilam) delivers a fixed dose of 5 mg and is not appropriate for all pediatric patients; for smaller intranasal doses, parenteral solution for injection product can be used; ensure appropriate product selection and administration technique.
Nasal spray (Nayzilam): Product delivers a fixed dose and should only be used in Children ≥12 years and Adolescents: Do not test or prime before use; do not open blister packaging until ready to use. Administer 1 spray into 1 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.
Parenteral solution for injection formulation: Administer using a mucosal atomizer (MAD nasal drug delivery device) or via needleless syringe. Administer half of the dose into each nostril. Maximum volume: 1 mL per nostril (Ref).
Oral: Administer on empty stomach (feeding is usually contraindicated prior to sedation for procedures).
Parenteral: Vial for IV or IM administration only; premixed bag for IV administration only. Do not administer vial or premixed bag intra-arterially. Avoid extravasation.
IV (bolus, loading doses, intermittent therapy): Administer by slow IV injection over ≥2 to 5 minutes (Ref). In adults: For induction of anesthesia, may administer IV push over 20 to 30 seconds per the manufacturer. For refractory status epilepticus, the loading dose is recommended to be infused at a rate of 2 mg/minute (Ref).
Neonates: Rapid administration (<2 minutes) has been reported to cause severe hypotension especially if administered concurrently with fentanyl. For loading doses, administration over ≥1 hour have successfully prevented hypotension in neonates (Ref); however, administration over 2 to 5 minutes has also been described in mechanically ventilated patients (Ref); manufacturer recommends against loading doses in neonates and suggests using a faster continuous infusion rate for the first several hours.
Continuous IV infusion: Administer via an infusion pump.
IM: Administer undiluted deep IM into large muscle, generally into anterior-lateral aspect of thigh (vastus lateralis) in pediatric patients (Ref).
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 (Ref).
Buccal (off-label route): A buccal formulation is not currently available in the US. Some trials used an injectable solution administered buccally (Ref). International studies used a 10 mg/mL commercially available buccal formulation (Ref). 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 (Ref).
Intranasal:
Nasal spray: Do not test or prime before use. Administer 1 spray into 1 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 (Ref). 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 (Ref).
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. The manufacturer’s labeling for Seizalam specifically recommends injection in the mid-outer thigh (vastus lateralis 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 (Ref). For refractory status epilepticus, the loading dose is recommended to be infused slowly (Ref). 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 (Ref).
Note: Premixed solutions available.
IV Infusion: 0.1 mg/mL, 0.5 mg/mL, or 1 mg/mL.
Note: Premixed solutions available.
IV infusion: 0.03 mg/mL, 0.5 mg/mL, 1 mg/mL, or 5 mg/mL.
Oral: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Injection:
Prefilled syringe: 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 lactated Ringer's solution.
Premixed bag: Store at 20°C to 25°C (68°F to 77°F); do not freeze. Discard any portion not used within 48 hours of initial penetration.
Vials: Store intact vials at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). The product labeling for some products recommends to protect from light; refer to the manufacturer’s labeling for specific recommendations. 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.
Preoperative sedation, anxiolysis, and amnesia for diagnostic, therapeutic, or radiographic procedures (IV: FDA approved in infants, children, adolescents, and adults); sedation, anxiolysis, and amnesia prior to procedures or before induction of anesthesia (Oral: FDA approved in ages ≥6 months to <16 years); induction of general anesthesia (FDA approved in infants, children, adolescents, and adults); continuous IV sedation of intubated and mechanically ventilated patients (IV: FDA approved in all ages); acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) that are distinct from patient's usual seizure pattern (Intranasal: Nayzilam: FDA approved in ages ≥12 years and adults); treatment of status epilepticus (IM: Seizalam: FDA approved in adults).
Versed may be confused with VePesid, Vistaril
The Institute for Safe Medication Practices (ISMP) includes this medication (IV, oral administration for sedation in children) among its list of drugs which have a heightened risk of causing significant patient harm when used in error.
KIDs List: Midazolam, when used in very low birthweight neonates, is identified on the Key Potentially Inappropriate Drugs in Pediatrics (KIDs) list; use should be avoided due to risk of severe intraventricular hemorrhage, periventricular leukomalacia, or death (strong recommendation; high quality of evidence) (PPA [Meyers 2020]).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. As reported in children, adolescents, and adults unless otherwise noted. Intranasal only adverse reactions include adolescents and adults. Oral only adverse reactions include children and adolescents.
>10%:
Gastrointestinal: Vomiting (≤11%)
Respiratory: Apnea (adults: 15%; children: 3%), bradypnea (adults: ≤23%), decreased tidal volume (adults: ≤23%), nasal discomfort (intranasal: 5% to 16%)
1% to 10%:
Cardiovascular: Atrioventricular nodal arrhythmia (≤1%), bigeminy (≤2%), bradycardia (≤2%), hypotension (≤3%), syncope (≤1%), tachycardia (≤1%), ventricular premature contractions (≤1%)
Dermatologic: Pruritus (≤1%), skin rash (≤2%), urticaria (≤1%), urticaria at injection site (≤1%)
Gastrointestinal: Acidic taste (≤1%), dysgeusia (intranasal: 4%), hiccups (1% to 4%), nausea (2% to 5%), retching (≤1%), sialorrhea (≤1%)
Hematologic & oncologic: Hematoma (≤1%), oxygen desaturation (≤5%)
Hypersensitivity: Anaphylaxis (≤1%), hypersensitivity reaction (≤1%)
Local: Burning sensation at injection site (≤1%), erythema at injection site (adults: ≤3%), induration at injection site (adults: ≤2%), injection site reaction (coldness: ≤1%), pain at injection site (adults: 4% to 5%), swelling at injection site (≤1%), tenderness at injection site (adults: 6%), warm sensation at injection site (≤1%)
Nervous system: Abnormal dreams (emergence: 1%), agitation (≤4%, including emergence agitation), anxiety (≤1%), ataxia (≤1%), athetosis (≤1%), behavioral changes (argumentativeness: ≤1%), chills (≤1%), confusion (≤1%), delirium (emergence: ≤1%), dizziness (≤1%), drowsiness (injection [adults]: 1%; intranasal: 9% to 10%), dysarthria (intranasal: 2%), dysphoria (≤1%), euphoria (≤1%), hallucination (≤1%), headache (adults and adolescents: 1% to 7%), impaired consciousness (adults: 3%), insomnia (≤1%), intoxicated feeling (≤1%), lethargy (≤1%), loss of balance (≤1%), mental status changes (adults: 3%), nervousness (≤1%), nightmares (≤1%), paresthesia (≤1%), prolonged emergence from anesthesia (≤1%), psychiatric signs and symptoms (oral: ≤3%), restlessness (≤1%), retrograde amnesia (≤1%), sedated state (prolonged: oral: 2%), seizure-like activity (≤1%), severe sedation (adults: 2%), sleep disturbance (≤1%), slurred speech (≤1%), voice disorder (≤1%), yawning (≤1%)
Neuromuscular & skeletal: Asthenia (≤1%), laryngospasm (≤4%)
Ophthalmic: Accommodation disturbance (≤1%), blurred vision (≤1%), diplopia (≤1%), increased lacrimation (intranasal: 1% to 2%), miosis (≤1%), nystagmus disorder (≤1%), visual disturbance (≤1%)
Otic: Blockage of external ear (≤1%)
Renal: Acute renal failure (adults: 2%)
Respiratory: Airway obstruction (≤5%), bronchospasm (≤1%), cough (adults: 1%), dyspnea (≤1%), hyperventilation (≤1%), hypoxia (oral: 3% to 4%), respiratory congestion (upper; oral: 2%), respiratory depression (≤2%), rhinorrhea (intranasal and oral: ≤5%), rhonchi (children: ≤2%), shallow respiration (≤1%), tachypnea (≤1%), throat irritation (intranasal: 2% to 7%), wheezing (≤1%)
Miscellaneous: Fever (adults: 4%), paradoxical reaction (children: 2%)
<1%:
Local: Injection site phlebitis
Neuromuscular & skeletal: Muscle rigidity
Respiratory: Sneezing
Postmarketing:
Nervous system: Aggressive behavior, cognitive dysfunction, drug dependence (physical and psychological dependence with prolonged use), hyperactive behavior, involuntary body movements, suicidal ideation, suicidal tendencies, tonic-clonic movements
Neuromuscular & skeletal: Tremor
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.
Canadian labeling: Additional contraindications (not in the US labeling): Injection: Acute pulmonary insufficiency; severe chronic obstructive pulmonary disease; IV sedation in elderly or debilitated patients outside ICU setting and in patients not sufficiently alert to respond appropriately to verbal requests.
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.
Concerns related to adverse effects:
• Anterograde amnesia: Benzodiazepines have been associated with anterograde amnesia (Nelson 1999).
• Cardiorespiratory effects: Serious cardiorespiratory adverse events have occurred with midazolam administration, including cardiac arrest, permanent neurologic injury, and death. Risk of 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, older adults, or patients with a history of alcohol use disorder or psychiatric/personality disorders (Mancuso 2004). Midazolam may cause involuntary movements (eg, tonic/clonic movements, tremor) and combativeness when used for sedation; may cause agitation when used for sedation or status epilepticus. Reactions may be due to improper dosing or administration; cerebral hypoxia should also be considered as a cause.
• Suicidal ideation: Intranasal: Pooled analysis of trials involving various antiseizure medications (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; may increase intraocular pressure. May consider use in patients with open-angle glaucoma only if receiving appropriate therapy; consider evaluating ophthalmologic status after midazolam use.
• Renal impairment: Use with caution in patients with renal impairment; half-life of midazolam and metabolites may be prolonged.
• Respiratory disease: Reduce dose or avoid use in patients with respiratory disease, including chronic obstructive pulmonary disease or sleep apnea. Benzodiazepines may cause significant respiratory depression.
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.
• 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).
• Neonates: Injection: Neonates are vulnerable to profound and/or prolonged respiratory effects of midazolam.
• Obesity: Use benzodiazepines with caution in patients with obesity; may have prolonged action when discontinued.
• Older adults: Use with caution in older adults; decreased dosages and slower titration is recommended due to an increased volume of distribution seen with lipophilic drugs in older adults, resulting in slower distribution and lower clearance. The risk of hypoventilation, airway obstruction, and apnea is higher in older patients. Older adults 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 older adults. Older adults may be at an increased risk of death with use; risk has been found highest within the first 4 months of use in older patients with dementia (Jennum 2015; Saarelainen 2018).
• 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.
Other warnings/precautions:
• Abuse, misuse, and addiction: Counsel patients at increased risk on proper use and monitoring for signs and symptoms of abuse, misuse, and addiction. Institute early treatment or refer patients in whom substance use disorder is suspected. Limit dosages and durations to the minimum required; counsel on proper disposal of unused drug.
• 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 formulations. 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.
• Dependence and withdrawal reactions: Some patients may develop a protracted withdrawal syndrome lasting >12 months; may be difficult to differentiate withdrawal symptoms from reemergence or continuation of symptoms for which benzodiazepines were prescribed. Flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy.
• Tolerance: Midazolam is a short half-life benzodiazepine and may be of benefit in patients where a rapidly and short-acting agent is desired (eg, for acute agitation). Duration of action after a single dose is determined by redistribution rather than metabolism. Tolerance develops to the sedative and antiseizure effects. It does not develop to the anxiolytic effects (Vinkers 2012).
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 the child's or fetus' brain development and may contribute to various cognitive and behavioral problems; the FDA is requiring warnings be included in the manufacturer's labeling for all general anesthetic/sedative drugs. Multiple animal species studies have shown adverse effects on brain maturation; in juvenile animals, drugs that potentiate GABA activity and/or block NMDA receptors for >3 hours demonstrated widespread neuronal and oligodendrocyte cell loss along with alteration in synaptic morphology and neurogenesis. 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. Further studies are needed to fully characterize findings and ensure that these findings are not related to underlying conditions or the procedure itself. No specific anesthetic/sedative has been found to be safer. For elective procedures, risk vs benefits should be evaluated and discussed with parents/caregivers/patients; critical surgeries should not be delayed (FDA 2017; McCann 2019; Sun 2016).
In neonates, particularly premature neonates, several cases of myoclonus (rhythmic myoclonic jerking) have been reported (~8% incidence).
Substrate of CYP2B6 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Antihepaciviral Combination Products: May increase the serum concentration of Midazolam. Management: Oral midazolam is contraindicated with antihepaciviral combination products. Avoid use with nasal midazolam. Consider alternatives to use with other routes of midazolam (IV, IM) when possible. Consider use of lower midazolam doses if combined. Risk X: Avoid combination
Atorvastatin: May increase the serum concentration of Midazolam. Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification
Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: 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. Risk D: Consider therapy modification
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: 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. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: 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. Monitor for respiratory depression, hypotension, and other toxicities if these agents are combined. Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
Cobicistat: May increase the serum concentration of Midazolam. Management: Oral midazolam is contraindicated with cobicistat. Avoid use with nasal midazolam. Consider alternatives to use with other routes of midazolam (IV, IM) when possible. Consider use of lower midazolam doses if combined. Risk X: Avoid combination
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Midazolam. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Midazolam. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Midazolam. Management: Avoid concomitant use of nasal midazolam and moderate CYP3A4 inhibitors. Consider alternatives to use with oral midazolam whenever possible and consider using lower midazolam doses. Monitor patients for sedation and respiratory depression if combined. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Midazolam. Management: Avoid use of nasal midazolam and strong CYP3A4 inhibitors whenever possible, and consider alternatives to use with other routes of midazolam (oral, IV, IM). If combined, consider lower midazolam doses and monitor for increased midazolam toxicities. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Weak): May increase the serum concentration of Midazolam. Risk C: Monitor therapy
Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Delavirdine: May increase the serum concentration of Midazolam. Risk X: Avoid combination
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: 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. Risk C: 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. Risk D: Consider therapy modification
Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification
Itraconazole: May increase the serum concentration of Midazolam. Management: Oral midazolam is contraindicated with, and for 2 weeks after, itraconazole. Avoid use with nasal midazolam. Consider alternatives to use with other routes of midazolam (IV, IM) when possible. Consider use of lower midazolam doses if combined. Risk X: Avoid combination
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ketoconazole (Systemic): May increase the serum concentration of Midazolam. Management: Oral midazolam is contraindicated with ketoconazole. Avoid use with nasal midazolam. Consider alternatives to use with other routes of midazolam (IV, IM) when possible. Consider use of lower midazolam doses if combined. Risk X: Avoid combination
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
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. Risk D: Consider therapy modification
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lonafarnib: May increase the serum concentration of Midazolam. Management: Combined use is contraindicated. For patients who must receive midazolam, discontinue lonafarnib for 10 to 14 days before and for 2 days after midazolam administration. Risk X: Avoid combination
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Melatonin: May enhance the sedative effect of Benzodiazepines. Risk C: 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. Risk D: 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 the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
OLANZapine: Benzodiazepines may enhance the adverse/toxic effect of OLANZapine. Management: Monitor closely for hypotension, respiratory or central nervous system depression, and bradycardia if olanzapine is combined with benzodiazepines. Use of parenteral benzodiazepines with IM olanzapine is not recommended. Risk C: Monitor therapy
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: 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. Risk D: Consider therapy modification
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: Benzodiazepines may enhance the CNS depressant effect of Oxybate Salt Products. Risk X: 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. Risk D: Consider therapy modification
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Protease Inhibitors: May increase the serum concentration of Midazolam. Management: Oral midazolam is contraindicated with protease inhibitors. Avoid use with nasal midazolam. Consider alternatives to use with other routes of midazolam (IV, IM) when possible. Consider use of lower midazolam doses if combined. Risk X: Avoid combination
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Teduglutide: May increase the serum concentration of Benzodiazepines. Risk C: Monitor therapy
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Risk C: Monitor therapy
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. Risk C: 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. Risk D: Consider therapy modification
Oral: Grapefruit juice may increase serum concentrations of midazolam. Management: Avoid concurrent use of grapefruit juice with oral midazolam.
Avoid grapefruit juice with oral syrup.
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 patients should not be denied medically necessary surgery regardless of trimester. If the procedure is elective, it should be delayed until after delivery (ACOG 2019).
Data related to the treatment of status epilepticus in pregnancy is limited; use of midazolam may be considered (NCS [Brophy 2012]; Rajiv 2019).
Data collection to monitor pregnancy and infant outcomes following exposure to antiseizure medications is ongoing. Patients exposed to antiseizure medications during pregnancy are encouraged to enroll themselves into the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334. Additional information is available at http://www.aedpregnancyregistry.org.
Level of sedation, respiratory rate, heart rate, blood pressure, oxygen saturation (ie, pulse oximetry); evidence of delirium (when used for sedative properties).
Binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the central nervous system, including the limbic system and 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).
Onset of action:
Sedation/anesthesia:
IM: Children: Within 5 minutes; Adults: ~15 minutes.
IV: 1 to 5 minutes (dose dependent) (Barr 2013; Horn 2004; Roberts 2019).
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).
Duration: IM: Up to 6 hours; Mean: 2 hours; IV: Single dose: <2 hours (dose-dependent) (Fragen 1997); Intranasal (solution, injection): Children: 23.1 minutes (Chiaretti 2011).
Absorption: IM: Rapid, complete; Intranasal (nasal spray): Rapid; Oral, Intranasal (solution, injection): Rapid (Lee-Kim 2004).
Distribution: Widely distributed in body including CSF; Vd:
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 females, elderly, and obesity.
Protein binding: ~97%, primarily albumin; in patients with cirrhosis, protein binding is reduced with a free fraction of ~5% (Trouvin 1988).
Metabolism: Extensively hepatic via CYP3A4; 60% to 70% of biotransformed midazolam is the active metabolite 1-hydroxy-midazolam (or alpha-hydroxymidazolam).
Bioavailability: Oral: 40% to 50% (Kanto 1985), ~36% (children); IM: >90%; Intranasal (nasal spray): 44%; Intranasal (solution, injection): Children: ~60%; Rectal: Children: ~40% to 65% (mean: 52%) (Clausen 1988).
Half-life elimination:
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.
Time to peak, serum: IM: ~0.5 hours; Intranasal (nasal spray): Median 17.3 minutes (7.8 to 28.2 minutes); Oral: 0.17 to 2.65 hours.
Excretion: Intranasal (nasal spray): Urine (primarily as glucuronide conjugates of the hydroxylated metabolites); IV, IM: 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.
Altered kidney function: Elimination half-life is prolonged and clearance is reduced. In patients with renal failure, reduced elimination of active hydroxylated metabolites leads to drug accumulation and prolonged sedation.
Hepatic function impairment: In patients with cirrhosis, following oral administration, Cmax and bioavailability were 43% and 100% higher, and following IV administration clearance was reduced 50%, half-life increased 2.5-fold, and Vd increased by 20%.
Older adult: IM, IV (mean age: 73 years): Plasma half-life was ~2-fold higher; mean Vd increased consistently between 15% to 100%, and mean clearance decreased ~25%; Intranasal (nasal spray) (>65 years of age): AUC and Cmax increased 21% to 45%.
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 Vd following parenteral administration.
Obesity: Mean half-life is prolonged (5.9 hours) and Vd increased ~50%.
Therapeutic hypothermia: Hypothermia may be associated with a 5-fold increase in plasma concentrations, likely due to decreased total body clearance (~11% decline in clearance for every centigrade decrease in body temperature below 36.5°C [97.7°F]) (Fukuoka 2004; Hostler 2010). During the rewarming phase, plasma concentrations decrease (~11% decline in plasma concentrations as temperature increases from 33°C to 37°C [91.4°F to 98.6°F]) (Bjelland 2014). The Vd in hypothermia (core body temperature <35°C [<95°F]) may decrease ~45% during rewarming phase (Fukuoka 2004); however, some reports found no significant impact of hypothermia on total body clearance (Bastiaans 2013) or Vd (Hostler 2010).
Sodium content of injection: 0.14 mEq/mL. Midazolam is 3 to 4 times as potent as diazepam.
Solution (Midazolam HCl (PF) Injection)
2 mg/2 mL (per mL): $0.58 - $1.65
5 mg/5 mL (per mL): $0.23 - $0.25
5 mg/mL (per mL): $1.25 - $2.98
10 mg/2 mL (per mL): $0.67 - $0.74
Solution (Midazolam HCl Injection)
2 mg/2 mL (per mL): $0.19 - $0.68
5 mg/5 mL (per mL): $0.13 - $0.68
5 mg/mL (per mL): $1.44 - $3.43
10 mg/10 mL (per mL): $0.26 - $0.68
10 mg/2 mL (per mL): $0.75 - $3.38
25 mg/5 mL (per mL): $1.07 - $1.32
50 mg/10 mL (per mL): $0.23 - $3.64
Solution (Midazolam HCl-Sodium Chloride Intravenous)
50MG/50ML 0.8% (per mL): $0.29
100MG/100ML 0.8% (per mL): $0.26
Solution (Midazolam-Sodium Chloride Intravenous)
50 mg/50 mL 0.9% (per mL): $0.53
100 mg/100 mL 0.9% (per mL): $0.36
Solution (Nayzilam Nasal)
5MG/0.1ML (per each): $352.77
Syrup (Midazolam HCl Oral)
2 mg/mL (per mL): $1.48
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