Midazolam Hydrochloride

Pronunciation

Class: Benzodiazepines
VA Class: CN302
Chemical Name: 8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine monohydrochloride
Molecular Formula: C18H13ClFN3•HCl
CAS Number: 59467-96-8

Warning(s)

  • Use only when adequate treatment facilities for appropriate management of therapy and complications are available.1 250

  • For deeply sedated pediatric patients, an individual other than the clinician performing the procedure should be dedicated to monitoring the patient throughout the procedure.1 250

  • Respiratory Effects
  • Associated with respiratory depression and respiratory arrest, especially when used for sedation in non-critical-care settings.1 250 (See Respiratory and Cardiovascular Effects under Cautions.)

  • Death or hypoxic encephalopathy has resulted when respiratory depression was not recognized promptly and treated effectively.1 250

  • Dosage and Administration Considerations for Procedural Sedation
  • Initial IV dose for healthy adults should not exceed 2.5 mg.1 250 (See Dosage under Dosage and Administration.)

  • Lower dosages are necessary in patients >60 years of age, debilitated patients, and patients receiving concomitant opiates or other CNS depressants.1 250 (See Dosage and also Special Populations, under Dosage and Administration.)

  • Titrate initial and subsequent dosages slowly; administer the appropriate dose over ≥2 minutes and wait an additional 2 or more minutes to fully evaluate the sedative effect.1

  • Administer by direct IV injection as the 1-mg/mL solution or dilute the 1- or 5-mg/mL solution to facilitate slower administration.1

  • Pediatric Dosage and Administration Considerations
  • Calculate pediatric dosage on a mg/kg basis.1 Initial dose is dependent on age, procedure, and route; titrate subsequent dosages slowly.1 (See Dosage: Pediatric Patients, under Dosage and Administration.)

  • Do not administer by rapid IV injection in neonates.1 Severe hypotension and seizures have been reported following rapid IV administration, particularly with concomitant administration of fentanyl.1

Introduction

Benzodiazepine;2 3 4 5 6 7 17 157 sedative, anxiolytic, amnesic,1 3 157 219 and hypnotic.2 4 7 70 84 86 104 177 178

Uses for Midazolam Hydrochloride

Preoperative Sedation, Anxiolysis, and Anterograde Amnesia

Preoperatively, to produce sedation, relieve anxiety, and provide anterograde amnesia.1 3 157 219

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

Procedural Sedation

For procedural sedation, anxiolysis, and amnesia (alone or in combination with an opiate agonist)1 3 157 when administered prior to dental2 4 7 14 35 66 130 131 176 or minor surgical procedures or diagnostic, therapeutic, or endoscopic procedures such as upper GI endoscopy,1 2 3 7 71 72 73 74 75 76 77 78 79 bronchoscopy,1 2 3 80 157 cystoscopy,1 2 7 115 157 cardiac catheterization,1 2 7 35 85 157 coronary angiography,1 50 85 157 oncology procedures,1 radiologic procedures1 (e.g., computerized tomography),1 89 or suture of lacerations.1

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Some clinicians consider midazolam the benzodiazepine of choice for moderate sedation (formerly known as conscious sedation) prior to short procedures14 181 because of its relatively rapid onset2 4 7 14 74 75 79 86 178 and short duration of action,4 7 26 46 74 75 86 87 176 178 pronounced amnesic effect,7 25 73 74 75 78 79 115 178 and improved local tolerance at the site of injection2 7 14 25 74 75 76 78 79 86 87 176 177 178 compared with other currently available IV benzodiazepines.

Induction and Maintenance of Anesthesia

Induction of general anesthesia prior to administration of other anesthetic agents.1 2 3 4 7 14 25 35 70 84 87 95 99 100 101 102 103 104 105 106 107 108 125 157 Induction with midazolam provides anxiolysis, anterograde amnesia, and dose-related hypnotic effects (progressing from sedation to loss of consciousness), but not analgesia.2 4 7 70 84 86 104 177 178

An acceptable alternative to thiopental for induction of anesthesia; midazolam’s slow onset and long duration of action and variability in response relative to those of thiopental preclude it from becoming the drug of choice for induction of anesthesia in most patients, particularly outpatients and patients undergoing short surgical procedures.2 4 7 181 182

Maintenance of anesthesia during short surgical procedures,1 2 3 4 14 27 100 113 114 usually in conjunction with inhalation anesthetic agents, balanced anesthesia (e.g., nitrous oxide and oxygen), and/or opiate agonists (e.g., fentanyl).1 70 112 113 184 Should not be used alone for maintenance of anesthesia.2 27 70 184

Use for maintenance of anesthesia during relatively long surgical procedures has not been fully evaluated to date.1 3 27 70 157 181

Sedation in Critical-care Settings

Sedation of intubated and mechanically ventilated patients in a critical-care setting.1 220 221 222 223

A preferred drug for sedation of acutely agitated patients in critical-care settings because of its rapid onset and short duration of action.235

As effective as propofol and appears to have a better adverse effect profile (e.g., less hypotension) than propofol;220 221 223 however, midazolam appears to have a more variable effect on recovery of consciousness and time to recovery of function after cessation of therapy than propofol.220 223

Recommended for short-term (≤24 hours) sedation only, since the effects of the drug on awakening and the time to extubation are unpredictable when midazolam infusions are administered over longer periods (e.g., exceeding 48–72 hours).235

Insomnia

Has been used for short-term management of insomnia.4 7 116 117 118 119 120 121 122 123

Agitation

Has been used for management of acute agitation.53 90 146 147 148 181

Midazolam Hydrochloride Dosage and Administration

General

  • Adjust dosage according to individual requirements and response, age, body weight, physical and clinical status, underlying pathologic condition(s), type and amount of premedication or concomitant medication, and the nature and duration of the surgical or other procedure; however, individual response also may vary independent of these factors.1 3 157 163 193

  • Facilities for administration of oxygen and controlled respiration should be readily available during and immediately following IV administration.1 3 193

  • Oral solution is intended for use in monitored settings (e.g., hospital, ambulatory care settings including physician and dental offices) only; is not intended for chronic or home use.219

Administration

Administer orally,219 by IM injection, or by slow IV injection 1 2 3 4 7 14 157 193 or continuous IV infusion.1 36 90 150 181 219 Avoid intra-arterial injection or extravasation of the drug.1 Do not administer intrathecally or epidurally.1

Oral Administration

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

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

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

IM Administration

Administer deeply into a large muscle mass.1 3 157

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Direct IV injection should be made in incremental doses.1 3 157 163

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

Dilution

For administration as a continuous IV infusion, dilute the 5-mg/mL injection to a concentration of 0.5 mg/mL with a compatible diluent (see Solution Compatibility under Stability).1

Rate of Administration: General

Rapid IV administration may result in respiratory depression, airway obstruction, and/or respiratory arrest.1

Rate of Administration: Pediatric Patients

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

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

Continuous IV infusion: Individualize the infusion rate.1 (See General and also Pediatric Patients: Sedation in Critical-care Settings, under Dosage and Administration.)

Rate of Administration: Adults

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

IV injection for induction of anesthesia: Administer the appropriate dose as a 1-mg/mL solution over 20–30 seconds; supplemental doses may be given at 2-minute intervals.1 3 157

Continuous IV infusion: Individualize the infusion rate.1 (See General and also Adults: Sedation in Critical-care Settings, under Dosage and Administration.)

Dosage

Available as midazolam hydrochloride; dosage expressed in terms of midazolam.1 3

Pediatric Patients

The depth of sedation/anxiolysis needed depends on the type of procedure being performed.1 It is vital to titrate the midazolam dose and the dose of other concomitant drugs slowly to achieve the desired clinical effect.1

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

It is essential to wait 2–3 minutes to fully evaluate the sedative effect before starting the procedure or administering a repeat dose; peak EEG effects are not achieved as quickly as with diazepam, since midazolam is water soluble.1

Preoperative Sedation, Anxiolysis, and Anterograde Amnesia
Oral

Children 6 months to 16 years of age: 250–500 mcg/kg as a single dose, depending on the status of the patient and the desired effect (maximum 20 mg).219

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

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

Consider an initial dose of 250 mcg/kg for patients 6 months to 16 years of age with cardiac or respiratory compromise, other higher-risk surgical patients, and those who have received concomitant opiates or other CNS depressants.219

IV

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

Children 6 months to 5 years of age: Initially, 50–100 mcg/kg; a total dose of up to 600 mcg/kg may be required to reach the desired endpoint, but total dose usually does not exceed 6 mg.1

Children 6–12 years of age: Initially, 25–50 mcg/kg; a total dose of up to 400 mcg/kg may be required to reach the desired endpoint, but total dose usually does not exceed 10 mg.1

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

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

IM

Pediatric patients ≥1 month of age: 100–150 mcg/kg; doses up to 500 mcg/kg have been used for more anxious patients.1 Total dose usually does not exceed 10 mg, although this has not been systematically studied.1

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

Procedural Sedation
Oral

Children 6 months to 16 years of age: 250–500 mcg/kg as a single dose, depending on the status of the patient and the desired effect (maximum 20 mg).219

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

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

Consider an initial dose of 250 mcg/kg for patients 6 months to 16 years of age with cardiac or respiratory compromise, other higher-risk surgical patients, and those who have received concomitant opiates or other CNS depressants.219

IV

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

Children 6 months to 5 years of age: Initially, 50–100 mcg/kg; a total dose of up to 600 mcg/kg may be required to reach the desired endpoint, but total dose usually does not exceed 6 mg.1

Children 6–12 years of age: Initially, 25–50 mcg/kg; a total dose of up to 400 mcg/kg may be required to reach the desired endpoint, but total dose usually does not exceed 10 mg.1

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

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

IM

Children ≥1 month of age: 100–150 mcg/kg; doses up to 500 mcg/kg have been used for more anxious patients.1 Total dose usually does not exceed 10 mg, although this has not been systematically studied.1

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

Sedation in Critical-care Settings
Neonates
IV

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

Preterm neonates (<32 weeks’ gestation): Initially, 30 mcg/kg per hour (0.5 mcg/kg per minute).1

Term neonates (≥32 weeks’ gestation): Initially, 60 mcg/kg per hour (1 mcg/kg per minute).1

Reassess the infusion rate carefully and frequently, particularly after approximately the first 24 hours, to administer the lowest possible effective dosage and to reduce the potential for drug accumulation.1 This is particularly important because of the potential for adverse effects related to benzyl alcohol metabolism.1 (See Pediatric Use under Cautions.)

Non-neonatal Pediatric Patients (Intubated)
IV

Initially, 50–200 mcg/kg as a loading dose, followed by a continuous IV infusion initiated at a rate of 60–120 mcg/kg per hour (1–2 mcg/kg per minute) to maintain the clinical effect.1

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

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

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

Adults

Preoperative Sedation, Anxiolysis, and Anterograde Amnesia
IM

70–80 mcg/kg (about 5 mg) administered approximately 30–60 minutes prior to surgery.1 3 14 180 181 If administered concomitantly with an opiate agonist or other CNS depressant, the midazolam dosage must be individualized and reduced.1

Procedural Sedation
IV

Initial dose of ≤2.5 mg in healthy adults <60 years of age; some patients may respond to as little as 1 mg.1 193 Total dose of ≤5 mg generally is adequate.1

If a thorough clinical evaluation clearly indicates a need for additional doses to maintain the desired level of sedation, administer additional doses in increments of approximately 25% of the initial dose.1 3

A total dose up to 200 mcg/kg has been used rarely, particularly if an opiate agonist was not used concomitantly;3 157 191 192 avoid such doses, if possible.180

Some clinicians recommend initiating dosing with 0.5–2 mg and repeating doses, as necessary, at 2- to 3-minute intervals up to a total dose of 100–150 mcg/kg.14 181

When used concomitantly with an opiate agonist or other CNS depressant, reduce midazolam dosage by about 30%.1 3 14 157

Induction and Maintenance of Anesthesia
IV

Individual response is variable, especially when opiate agonist premedication is not used; therefore, titrate dosage carefully to the desired clinical effect, taking into consideration the patient’s age and clinical status.1 2 3 70

When used prior to other anesthetic agents for the induction of general anesthesia,1 3 the initial dose of each of these agents may be substantially reduced, in some instances to as low as 25% of the usual initial dose of the individual agents.1

Without Opiate Premedication
IV

Initial dose of 300–350 mcg/kg administered IV over 20–30 seconds in patients <55 years of age; allow approximately 2 minutes for clinical effect.1 3 157 180 Alternatively, some clinicians recommend an initial dose of 200 mcg/kg.14 144 181

Supplemental doses of about 25% of the initial dose may be given as necessary to complete induction or for maintenance of sedation or anesthesia.1 3 14 157 Alternatively, induction of anesthesia may be completed with inhalation agents.1 3 157

Total IV induction doses of up to 600 mcg/kg may be required in some resistant patients, but such doses may prolong recovery from anesthesia.1 3 4 100 157

With Opiate or Sedative Premedication
IV

Initial dose of 150–350 mcg/kg as an induction dose in patients <55 years of age.1 3 157 Usual induction dose is 250 mcg/kg administered IV over 20–30 seconds; allow approximately 2 minutes for clinical effects.1 3 157

For maintenance of anesthesia (as a component of balanced anesthesia) during short surgical procedures: Following premedication with an opiate agonist,1 3 administer in incremental IV doses of approximately 25% of the initial induction dose when lightening of anesthesia is evident.1 3 Repeat as necessary according to patient’s response to maintain the required level of anesthesia.1 3

Sedation in Critical-care Settings
IV

If a loading dose is necessary to initiate sedation rapidly, 10–50 mcg/kg (approximately 0.5–4 mg) administered slowly or infused over several minutes.1 Repeat this dose at 10- to 15-minute intervals until adequate sedation is achieved.1 Usual initial infusion rate for maintenance of sedation is 20–100 mcg/kg per hour (approximately 1–7 mg per hour).1 Higher loading doses or maintenance infusion rates occasionally may be required.1

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

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

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

Prescribing Limits

Pediatric Patients

Preoperative Sedation, Anxiolysis, and Anterograde Amnesia or Procedural Sedation
Oral

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

IV

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

IM

Manufacturer states that the total dose usually does not exceed 10 mg in pediatric patients ≥1 month of age, although this has not been systematically studied.1

Procedural Sedation
IV

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

Adults

Procedural Sedation
IV

Initial dose for sedation should not exceed 2.5 mg.1

Special Populations

Renal Impairment

Use with caution and individualize dosage carefully.1 2 4 7 31 33 34 42 70 163 (See Renal Impairment under Cautions.)

CHF

Use with caution and individualize dosage carefully.1 3 35 50 163 (See Special Populations under Pharmacokinetics and also Other Populations under Dosage and Administration.)

Geriatric Patients

Reduce initial dose, since some degree of impairment in 1 or more organ systems frequently is present.1 3 157 163 193 Dosage requirements in this age group generally appear to decrease with increasing age;1 163 consider the possibility of profound and/or prolonged effects in older and/or debilitated patients.1 Low doses usually are required when midazolam is administered with or without premedication.1 3 157 163 193

Dosage titration should be more gradual in patients ≥60 years of age receiving midazolam for procedural sedation and in those ≥55 years of age receiving the drug for induction of anesthesia.1 157 163 180

Use the smallest effective dose.1 3 Excessive doses or rapid or single large IV injections may result in respiratory depression and/or arrest.1 3 157 163 193

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

IM: In patients ≥60 years of age who did not receive concomitant opiate agonist therapy, doses of 2–3 mg (20–50 mcg/kg) have produced adequate preoperative sedation;1 1 mg may be sufficient in some geriatric patients if the anticipated intensity and duration of sedation is less critical.1

Procedural Sedation in Patients ≥60 Years of Age

IV: Initial dose of ≤1.5 mg 1 193 over ≥2 minutes; wait ≥2 minutes to fully evaluate the clinical response.1 If further sedation is required, the dosage may be further titrated in small increments (≤1 mg) of the initial dose to the desired effect (e.g., onset of slurred speech).1 Total dose of ≤3.5 mg usually is adequate.1

If a thorough clinical evaluation clearly indicates a need for additional doses to maintain the desired level of sedation, administer additional doses that are1 3 reduced by ≥25%.14

When used concomitantly with an opiate or other CNS depressant, reduce midazolam dosage to about 50% of that used in young, unpremedicated adults.1

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

IV: Manufacturer recommends an initial IV induction dose of 300 mcg/kg if premedication has not been given.1 3 157

If premedication has been given, manufacturer recommends an initial induction dose of 200 mcg/kg if the patient is a good risk (e.g., ASA I and II) surgical patient.1 3

Other Populations

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

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

Procedural Sedation in Chronically Ill or Debilitated Patients

IV: Smaller increments in dosage and slower rate of injection recommended in patients with chronic debilitating illnesses (e.g., CHF) or decreased pulmonary reserve because of the increased risk of underventilation or apnea and because the peak drug effect may occur later.1 3 157 163 180 193

Administer initial dose of ≤1.5 mg 1 193 over ≥2 minutes; wait ≥2 minutes to fully evaluate the clinical response.1 If further sedation is required, the dosage may be further titrated in small increments (≤1 mg) of the initial dose to the desired effect (e.g., onset of slurred speech).1 Total dose of ≤3.5 mg usually is adequate.1

If a thorough clinical evaluation clearly indicates a need for additional doses to maintain the desired level of sedation, administer additional doses that are1 3 reduced by ≥25%.14

When used concomitantly with an opiate or other CNS depressant, reduce midazolam dosage to about 50% of that used in young, unpremedicated adults.1

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

IV: Unpremedicated patients: Initial dose of 200–250 mcg/kg usually is adequate; doses as low as 150 mcg/kg may be adequate for induction in some patients.1 3 157

Premedicated patients: Doses as low as 150 mcg/kg may be adequate for induction in some patients.1 3 157

Cautions for Midazolam Hydrochloride

Contraindications

  • Known hypersensitivity to midazolam or any ingredient in the formulation; oral solution contraindicated in patients with allergies to cherries.1 219

  • Acute angle-closure glaucoma (but may be administered to patients with open-angle glaucoma who are receiving appropriate therapy).1

  • Midazolam hydrochloride injection contains benzyl alcohol and is not intended for intrathecal or epidural administration.1

Warnings/Precautions

Warnings

Respiratory and Cardiovascular Effects

Possible serious and occasionally fatal adverse effects, including respiratory depression, airway obstruction, oxygen desaturation, apnea, respiratory arrest, and/or cardiac arrest,1 2 37 137 139 157 163 175 193 particularly in patients receiving midazolam concomitantly with other CNS depressants1 250 and in those undergoing procedures involving the airway without the protective effect of an endotracheal tube, in geriatric or severely ill patients, or in patients with limited pulmonary reserve or unstable cardiovascular status, or if the drug is administered IV too rapidly.1

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

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

Slow administration and individualized titration of dosage is required.1

Administer orally or IV only in settings in which continuous monitoring of respiratory and cardiac function (i.e., pulse oximetry) is possible.1 250 Potential for hypoxia and/or cardiac arrest if early signs of hypoventilation, airway obstruction, or apnea are not corrected immediately.1 Monitoring of vital signs should continue during recovery period.1

Should be administered as an induction agent only by individuals who are experienced in the use of general anesthesia.1 163 193 219

Should be used for procedural sedation only in the presence of personnel experienced in early detection of underventilation, maintenance of an adequate airway, and respiratory support.1 163 193 219 When the complexity of the procedure prohibits adequate monitoring by the attending clinician, additional personnel competent in monitoring and managing potential complications should be in attendance.1 163 175 For deeply sedated pediatric patients, an individual other than the clinician performing the procedure should be dedicated to monitoring the patient throughout the procedure.1 250

Facilities, age- and size-appropriate equipment for bag/mask/valve ventilation and intubation, drugs, skilled personnel necessary for ventilation and intubation, administration of oxygen, assisted or controlled respiration, airway management, and cardiovascular support should be immediately available when midazolam is administered.1 250 Immediate availability of specific reversal agents (e.g., flumazenil) is recommended.1

CNS Depression

Performance of activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle) may be impaired;1 157 such activities should not be performed until the effects of the drug (e.g., drowsiness) have subsided or until the day after anesthesia and surgery, whichever is longer.1 157

Concurrent use of other CNS depressants may increase the extent and duration of impaired performance, cause excessive sedation, and interfere with recall and recognition of events on the day of surgery and the following day.1 250 (See Specific Drugs under Interactions.)

Paradoxical Reactions

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

Intra-arterial Injection

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

Withdrawal Syndrome

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

General Precautions

General Anesthesia

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

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

Interactions with CYP3A4 Inhibitors

Expect more intense and prolonged sedation when midazolam is administered concomitantly with a CYP3A4 inhibitor; use concomitantly with caution.250 Use lower than recommended oral doses.250 (See Interactions.)

Specific Populations

Pregnancy

Category D.1

Preoperative use for obstetric procedures (e.g., cesarean section) or during labor and delivery is not recommended.1 3

Lactation

Distributed into milk.1 Use with caution.1

Pediatric Use

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

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

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

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

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

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

Large amounts of benzyl alcohol (i.e., 100–400 mg/kg daily) have been associated with toxicity in neonates;224 225 226 227 228 229 230 each mL of midazolam hydrochloride injection contains 10 mg of benzyl alcohol.1

Geriatric Use

Safe oral dosing regimen of midazolam has not been established.250 Increased incidence of hypoxia reported in geriatric patients receiving midazolam hydrochloride 7.5 mg as premedication prior to general anesthesia.250 Until further information is available, oral midazolam is not recommended in geriatric patients.250

Select parenteral dosage carefully, since distribution may be altered and patients may have decreased hepatic and/or renal function.1 Reduce the dosage, particularly in those ≥70 years of age.1 (See Geriatric Patients under Dosage and Administration.)

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

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

Hepatic Impairment

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

Renal Impairment

Use with caution since the pharmacokinetics of the drug may be altered.1 2 4 7 31 33 34 42 70 163 (See Renal Impairment under Dosage and Administration.) Induction of anesthesia may occur more rapidly, and recovery may be prolonged.2 4 31 33 34 42 70

Common Adverse Effects

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

Oral administration: Emesis, nausea, hypoxia, laryngospasm, agitation.250

Interactions for Midazolam Hydrochloride

Metabolized by CYP3A4.1 219

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (increased plasma midazolam concentrations) with inhibitors of CYP3A4.1 219 Use with caution and monitor for excessive sedation.1 216 Dosage adjustment of midazolam and/or other drugs may be needed.219 233 When oral midazolam is administered concomitantly with a CYP3A4 inhibitor, expect more intense and prolonged sedation and use lower than recommended oral doses.250

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

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Aminophylline

Possible antagonism of sedative effect during anesthesia132

Anesthetic agents, inhalation

Minimum alveolar concentration of halothane required for general anesthesia appears to be decreased in a linear, dose-related manner with concomitant administration of IV midazolam1 2 3 70 141

Patients who have received midazolam as an induction agent may require reduced amounts of inhalation agents during maintenance of anesthesia1 2 70 141

Anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin)

Decreased peak plasma concentration and AUC of midazolam reported with concomitant use of oral midazolam and phenytoin or carbamazepine;250 similar effects expected with phenobarbital219

Use with caution;219 232 233 consider dosage adjustments, if necessary219 233

Antifungals, azole (fluconazole, itraconazole, ketoconazole)

Decreased plasma clearance and increased peak plasma concentration of midazolam reported with oral midazolam;219 potential for intense and prolonged sedation and respiratory depression219

Use oral or parenteral midazolam with caution in patients receiving these antifungals250

Reduce oral midazolam dosage250

Administer oral midazolam concomitantly with itraconazole or ketoconazole only if absolutely necessary and with appropriate equipment and personnel available to manage respiratory insufficiency219 250

Antimycobacterials (rifabutin, rifampin)

Decreased peak plasma concentration and AUC of midazolam reported with concomitant use of oral midazolam and rifampin; similar effects expected with rifabutin219

Use with caution;1 consider dosage adjustments, if necessary250

Calcium-channel blocking agents (diltiazem, nifedipine, nitrendipine, verapamil)

Increased peak plasma concentration of midazolam reported with concomitant use of oral midazolam and diltiazem or verapamil;219 231 233 potential for intense and prolonged sedation and respiratory depression250

Pharmacokinetic interaction unlikely with nifedipine1 or nitrendipine250

Use oral or parenteral midazolam with caution in patients receiving diltiazem or verapamil;1 reduce oral midazolam dosage233 250

CNS depressants (e.g., opiate agonists or other analgesics, barbiturates, sedatives, anesthetics, alcohol)

Additive CNS effects, possibly resulting in respiratory depression and profound and/or prolonged underventilation or apnea1 3 4 14 163 175 189 190

Use with caution; adjust dosage appropriately to avoid overdosage1 3 4 14 (see Dosage under Dosage and Administration)

Delavirdine

Potential for decreased midazolam metabolism resulting in intense and prolonged sedation and respiratory depression247

Manufacturer of delavirdine states that concomitant use is contraindicated;247 however, some experts state that a single midazolam dose can be used with caution for procedural sedation in monitored situations249

Efavirenz

Potential for decreased midazolam metabolism resulting in intense and prolonged sedation and respiratory depression248

Manufacturer of efavirenz states that concomitant use is contraindicated;248 however, some experts state that a single midazolam dose can be used with caution for procedural sedation in monitored situations249

Grapefruit juice

Increased bioavailability of oral midazolam with concomitant administration;196 197 219 does not appear to interfere with metabolism following IV administration197 203

Manufacturer states that oral midazolam should not be taken in conjunction with grapefruit juice219

Histamine H2-receptor antagonists (e.g., cimetidine, ranitidine)

Possible increased plasma midazolam concentrations143 160 161 219

Carefully observe patient for CNS and respiratory depression; reduce midazolam dosage if necessary160 161 162

HIV protease inhibitors (e.g., amprenavir [no longer commercially available in the US], atazanavir, darunavir, fosamprenavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, tipranavir)

Decreased clearance and increased plasma concentrations of midazolam;1 238 250 potential for intense and prolonged sedation and respiratory depression238 239 240 241 242 243 244 245 246 250 251

Manufacturers of HIV protease inhibitors state that concomitant use is contraindicated;238 239 240 241 242 243 244 245 246 251 however, some experts state that a single midazolam dose can be used with caution for procedural sedation in monitored situations249

Ketamine

Midazolam may antagonize, at least partially, the cardiovascular stimulatory effects and the postoperative emergence delirium usually associated with ketamine4 104 134

Macrolide antibiotics

Decreased clearance of midazolam with concomitant use of erythromycin and IV195 or oral midazolam;195 216 218 may result in excessive sedative effects195 216

Pharmacokinetic interaction unlikely with oral midazolam and azithromycin219

Some clinicians state that erythromycin should not be given to patients receiving midazolam or, alternatively, that the midazolam dosage should be reduced in patients receiving the anti-infective195

Opiates (e.g., fentanyl)

Increased risk of hypotension and prolongation of the recovery period;1 2 139 severe hypotension reported with concomitant administration of fentanyl in neonates1

Increased potential for respiratory depression, airway obstruction, and hypoventilation219 250

Use with caution; adjust midazolam dosage appropriately to avoid overdosage1 3 4 14 (see Dosage under Dosage and Administration)

Quinupristin and Dalfopristin

Increased peak plasma concentration and AUC of midazolam reported with concomitant use of a single IV dose of midazolam with quinupristin and dalfopristin234

Use with caution; monitor patients for excessive sedation1 216

Terbinafine

No change in midazolam pharmacokinetics219

Thiopental

Thiopental dosage requirements for induction of anesthesia reduced by about 15% in patients who received preoperative sedation with IM midazolam1 3

Midazolam Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following IM administration,1 3 4 5 6 8 9 10 11 12 13 14 15 16 157 with peak plasma concentrations generally attained within 45 minutes.1 8 157 Absolute bioavailability is >90%.1 4 8 9 157

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

Onset

Following IM administration, effects usually are apparent within 5–15 minutes1 3 4 9 14 32 81 157 but may not be maximal until 15–60 minutes.1 2 4 8 9 10 11 12 13 15 16 81 157

Following IV administration, the onset of sedative, anxiolytic, and amnesic action usually occurs within 1–5 minutes.1 2 3 4 7 9 13 21 25 26 86 87 157

Induction of anesthesia usually occurs in about 1.5 minutes when midazolam is administered concurrently with opiate agonists and in 2–2.5 minutes when administered without an opiate agonist or other sedatives.1 2 27 28 157

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

Duration

Following IM administration, the duration of action usually is about 2 hours1 3 (range: 1–6 hours).1 3 8 9 10 14 Duration of anterograde amnesia following IM administration is about 1 hour.1 2 10 25 69

Following IV administration, duration of action is usually <2 hours;1 3 4 7 8 9 21 29 157 however, effects may persist up to 6 hours in some patients, and the duration of action appears to be dose related.1 3 8 9 20 29 157 Anterograde amnesia persists for about 20–40 minutes following a single IV dose.2 4 7 25 26

Distribution

Extent

Rapidly and widely distributed following IV administration.1 2 3 4 24 35 36 37 38

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

Crosses the placenta and 1 2 3 7 23 35 43 157 is distributed into milk.1

Plasma Protein Binding

Approximately 94–97% (mainly to serum albumin2 4 7 34 37 42 ) in adults and children >1 year of age.1 2 3 7 18 20 24 31 36 37 41 42 45 157 219 Degree of protein binding appears to be independent of plasma concentration.2 24 41 219

Special Populations

Distribution may be altered in geriatric patients.1

Elimination

Metabolism

Extensively metabolized in the liver and intestine by CYP3A41 3 7 21 24 54 55 157 219 to active and inactive metabolites.1 5 219 Metabolites undergo rapid conjugation with glucuronic acid in the liver.1 2 3 4 7 17 24 54 55 58 157 Activity is related principally to the parent drug.1

Elimination Route

Excreted in urine almost entirely as conjugated metabolites.1 2 3 4 7 17 24 54 55 58 157 Approximately 2–10% of an oral dose is excreted in feces.4 55

Half-life

Biphasic; following IV administration, half-life in the initial distribution phase averages 6–20 minutes in adults;2 4 28 19 20 56 terminal half-life averages 1–4 hours (range: 1–12.3 hours).1 2 3 4 7 13 14 19 20 21 22 24 34 35 36 37 38 44 45 46 47 149 157

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

Special Populations

Half-life may be prolonged in geriatric patients.2 3 7 18 24 37 49 51 52

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

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

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

In patients with CHF, prolonged elimination half-life, increased volume of distribution, and delayed onset of action secondary to prolonged circulation time.1 3 35 50 157 163

Stability

Storage

Oral

Solution

25°C (may be exposed to 15–30°C).250

Parenteral

Injection

15–30°C.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

Compatible

Dextrose 5% in sodium chloride 0.9%

Dextrose 5% in water

Sodium chloride 0.9%

Incompatible

Ringer’s injection, lactated

Variable

Dextrose 5% in water with potassium chloride 0.15%

Drug Compatibility
Admixture CompatibilityHID

Compatible

Cefuroxime sodium

Ciprofloxacin

Furosemide

Gentamicin sulfate

Hydromorphone HCl

Metronidazole

Ranitidine HCl

Variable

Aminophylline

Sodium bicarbonate

Y-Site CompatibilityHID

Compatible

Abciximab

Amikacin sulfate

Amiodarone HCl

Anidulafungin

Argatroban

Atracurium besylate

Bivalirudin

Calcium gluconate

Caspofungin acetate

Cefazolin sodium

Cefotaxime sodium

Ceftaroline fosamil

Ciprofloxacin

Cisatracurium besylate

Clindamycin phosphate

Dexmedetomidine HCl

Digoxin

Diltiazem HCl

Dopamine HCl

Doripenem

Epinephrine HCl

Erythromycin lactobionate

Esmolol HCl

Etomidate

Famotidine

Fenoldopam mesylate

Fentanyl citrate

Fluconazole

Gentamicin sulfate

Haloperidol lactate

Heparin sodium

Hetastarch in lactated electrolyte injection (Hextend)

Hydromorphone HCl

Hydroxyethyl starch 130/0.4 in sodium chloride 0.9%

Insulin, regular

Labetalol HCl

Linezolid

Lorazepam

Methadone HCl

Methylprednisolone sodium succinate

Metronidazole

Milrinone lactate

Morphine sulfate

Nicardipine HCl

Nitroglycerin

Norepinephrine bitartrate

Palonosetron HCl

Pancuronium bromide

Potassium chloride

Ranitidine HCl

Remifentanil HCl

Sodium nitroprusside

Theophylline

Tirofiban HCl

Tobramycin sulfate

Vancomycin HCl

Vecuronium bromide

Incompatible

Albumin human

Amphotericin B cholesteryl sulfate complex

Ampicillin sodium

Bumetanide

Butorphanol tartrate

Cefepime HCl

Ceftazidime

Cefuroxime sodium

Co-trimoxazole

Dexamethasone sodium phosphate

Foscarnet sodium

Fosphenytoin sodium

Furosemide

Hydrocortisone sodium succinate

Imipenem–cilastatin sodium

Methotrexate sodium

Micafungin sodium

Nafcillin sodium

Omeprazole

Pantoprazole sodium

Sodium bicarbonate

Variable

Clonidine HCl

Dobutamine HCl

Propofol

Actions

  • Effects appear to be mediated through the inhibitory neurotransmitter GABA; the site and mechanism of action within the CNS appear to involve a macromolecular complex (GABAA-receptor-chloride ionophore complex) that includes GABAA receptors, high-affinity benzodiazepine receptors, and chloride channels.

Advice to Patients

  • Importance of informing patients of the pharmacologic effects of midazolam (e.g., sedation, lack of recall), which in some patients may be profound.1 250

  • Potential for midazolam to impair mental alertness or physical coordination; avoid driving or operating machinery until the effects of the drug (e.g., drowsiness) have subsided or until the day after anesthesia and surgery, whichever is longer.1 157

  • Importance of ensuring safe ambulation in pediatric patients receiving oral midazolam.250

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1 250 Use caution with simultaneous ingestion of alcohol during treatment.1 250

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 250

  • Importance of informing patients of other important precautionary information.1 250 (See Cautions.)

Preparations

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

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

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

Midazolam Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

2 mg (of midazolam) per mL*

Midazolam Hydrochloride Syrup (C-IV)

Parenteral

Injection

1 mg (of midazolam) per mL*

Midazolam Hydrochloride Injection (C-IV)

5 mg (of midazolam) per mL*

Midazolam Hydrochloride Injection (C-IV)

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 10, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

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