AHFS Class:

• Benzodiazepines 28:24.08

Generic Name(s):

• Midazolam

• Midazolam Hydrochloride

Associated Monographs

• Benzodiazepines General Statement

Midazolam is a benzodiazepine.1,2,4,5,6,7,17,219,773,774 The drug has anticonvulsant, anxiolytic, sedative/hypnotic, and amnestic properties.1,2,4,7,70,84,86,104,177,178,219,773,774

Preoperative Sedation, Anxiolysis, and Amnesia

Midazolam hydrochloride is used parenterally (IM or IV) or orally for preoperative sedation, anxiolysis, and anterograde amnesia.1,2,4,5,6,7,10,11,25,26,32,35,66,219 The drug should be used only in monitored settings (i.e., hospital or ambulatory care setting).1,219

Like other benzodiazepines (e.g., lorazepam, diazepam),2,4,7,69,92 midazolam is particularly useful as a premedication when relief of anxiety and diminished recall of events associated with the surgical procedure are desired.2,4,7,66,69,83,152 In studies using memory recall tests, IM midazolam produced anterograde amnesia in 40-73% of adults and up to 85% of pediatric patients.1 The degree and duration of anterograde amnesia appear to be dose related and can vary based on concomitantly administered drugs.2,10,66,91

IM administration of midazolam usually results in less irritation at the site of injection than some other agents commonly used for preoperative sedation, including hydroxyzine or diazepam.4,7,10,32,81 In addition, IM midazolam appears to produce a more rapid onset of sedative effects, more pronounced anxiolytic effects during the first hour following administration, and more pronounced anterograde amnesia when compared with IM hydroxyzine.4,10,35 Because of midazolam's relatively rapid onset, short duration of effect, and improved local tolerance at the site of injection compared with other currently available parenteral benzodiazepines, some clinicians consider midazolam the benzodiazepine of choice for preoperative use associated with short surgical procedures.2,4,7,14,32,173,174,181 Midazolam also is used IV for preoperative sedation and anxiolysis with good results.4,7,25,26,66,219

Oral midazolam is commonly used as a premedication to reduce anxiety in pediatric patients undergoing surgery.754 Studies have demonstrated that children may be separated from their parents as early as 10 minutes after receiving the drug.755 Efficacy of oral midazolam as a premedicant to sedate and calm pediatric patients prior to the induction of general anesthesia was evaluated in a randomized, double-blind study in patients 6 months to less than 16 years of age with ASA physical status I, II, or III.219 In this study, more than 90% of patients receiving midazolam achieved satisfactory sedation and anxiolysis within 30 minutes post-treatment.219 Similarly high proportions of patients exhibited satisfactory ease of separation from their parent or guardian and were cooperative at the time of mask induction with nitrous oxide and halothane administration.219

Procedural Sedation

Midazolam hydrochloride is used IV or orally for procedural sedation, anxiolysis, and amnesia, either alone or in combination with other CNS depressants.1,219,821 The drug should be used only in monitored settings (i.e., hospital or ambulatory care setting).1,219 Midazolam produces amnestic and sedative effects, but no analgesia; therefore, the drug is usually administered in conjunction with an analgesic agent.821,822

Procedural sedation is a technique in which sedative or dissociative agents are administered with or without analgesics to allow patients to tolerate painful or unpleasant medical procedures; a depressed state of consciousness is intentionally induced while cardiorespiratory function is maintained.821,822,823 Because sedation is a continuum ranging from minimal sedation to general anesthesia, airway reflexes and cardiorespiratory function may be impaired if a deeper than intended level of sedation is produced.821,822,823 The appropriate level of sedation should be individualized according to the specific procedure and needs of the patient.822

Procedures for which midazolam sedation has been used include dental2,4,7,14,35,66,130,131,176 or minor surgical procedures; diagnostic, therapeutic, or endoscopic procedures such as upper GI endoscopy,1,2,7,71,72,73,74,75,76,77,78,79 bronchoscopy,1,2,80 or cystoscopy;1,2,7,115 cardiac catheterization;1,2,7,35,85 coronary angiography;1,50,85 oncology procedures;1 radiologic procedures1 (e.g., computerized tomography);1,89 and suture of lacerations.1 Like other benzodiazepines,2,4,7,177,178 midazolam is particularly useful for sedation when relief of anxiety and diminished recall of events associated with such procedures are desired.2,4,7,177,178

Anterograde amnesia occurs within 1-5 minutes following IV administration of midazolam and generally persists for 20-40 minutes after IV injection of a single dose.2,4,7,25,26 However, onset and duration of action depend on many factors, including the dose of midazolam, rate of administration, and concurrently administered drugs.1,2,8,9,20,27,28,29,163,181 (See Pharmacokinetics: Absorption.) IV midazolam produced amnestic effects (i.e., no recall of endoscope withdrawal) in 82% of adults in endoscopy studies.1 In pediatric patients, impaired or no recall of events related to lumbar puncture, bone marrow aspiration, or an oncology procedure was observed in 88-91% of those who received IV midazolam.1

Midazolam generally produces less pain and venous irritation (e.g., thrombophlebitis) at the site of IV injection than diazepam.2,7,14,25,74,75,76,78,79,86,87,176,177,178 In addition, IV midazolam may have a slightly more rapid onset of action2,4,7,14,74,75,79,86,178 and more pronounced anterograde amnestic effects7,25,73,74,75,78,79,115,178 when compared with IV diazepam. Although data are conflicting,2,7,75,76,78,79,91,115,176,178 there is some evidence that midazolam's duration of action following IV administration may be slightly shorter than that of diazepam,4,7,46,74,75,86,87,178 but further comparative studies are needed;7,26,178 the duration of action of midazolam is substantially shorter than that of IV lorazepam.7,176,178 Because of the drug's 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 parenteral benzodiazepines, some clinicians consider midazolam the benzodiazepine of choice for moderate sedation (formerly known as conscious sedation) prior to short procedures.14,181

Induction and Maintenance of Anesthesia

Midazolam hydrochloride is used IV for induction of general anesthesia prior to administration of other anesthetic agents.1,2,4,7,14,25,35,70,84,87,95,99,100,101,102,103,104,105,106,107,108,125 Induction with IV midazolam results in 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 Midazolam also is used as a component of balanced anesthesia (e.g., nitrous oxide and oxygen) for maintenance of anesthesia during short surgical procedures.1,2,4,14,27,100,113,114

There is substantial interpatient variation in induction time and in the dose of midazolam required for induction of anesthesia, especially in young patients and/or patients who have not received premedication with an opiate agonist.1,2,4,7,25,30,35,46,70,86,99,101,102,104,113,124,125 Premedication with an opiate agonist results in more rapid and reliable induction of anesthesia within a narrower midazolam dosage range,1,2,7,70,99,100,145 and smaller doses of midazolam generally are required.1,2,7,27,70,87,99,100,102,103,104,106,113 Midazolam should not be used alone for maintenance of anesthesia;2,27,70,184 the drug usually is given 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 Concurrent use of an opiate agonist usually is necessary to maintain adequate anesthesia.27,70,102,184

The benefits of midazolam include its pronounced anterograde amnestic effects4,7,14,70,99,101,113,178,182 and good patient acceptability.2,4,70,182 The incidence of postoperative emergence delirium, nausea, and vomiting is relatively low following midazolam administration as compared with other anesthetic agents.2,27,70,104,114 Because midazolam does not appear to increase intraocular pressure, the drug appears to be safe for use in patients undergoing surgery for ocular trauma.70,129 Use of midazolam in patients without underlying ocular disease may result in moderate reduction of intraocular pressure.1,129 Midazolam generally has been well tolerated in patients with ischemic heart disease,37,70,95,96,110,111 although mild to moderate alterations in cardiovascular function may occur.37,70,95,96,110,111 Severe hypotension has occurred, however, when midazolam was used with high-dose fentanyl anesthesia in patients undergoing coronary artery bypass grafting procedures.4,14,112 Limited data suggest that midazolam attenuates both the postoperative emergence delirium and the cardiovascular stimulation associated with the use of ketamine during surgery.2,4,104,134

IV midazolam has historically been compared with IV thiopental for induction and maintenance of anesthesia, and was considered to be more favorable than thiopental in certain characteristics (e.g., more pronounced anterograde amnesia,4,7,14,70,99,101,113,178 more gradual induction of anesthesia,4,7,14,70,108 less need for adjuvant anesthetic agents),2,14,27,70,95,113 but not in others (e.g., did not induce anesthesia as rapidly2,7,14,70,99,101,103,104,105,106,107,108,113,114,135,145,177,178 or consistently,2,4,7,113,124 required a longer recovery period).2,4,7,27,28,70,99,178 However, thiopental is no longer commercially available in the US and its use has been largely replaced by propofol.715,716

Sedation in Critical Care Settings

Midazolam is used as a continuous IV infusion for sedation of intubated and mechanically ventilated patients in critical care settings (e.g., intensive care unit [ICU]).1,220,221,222,223,800,801

Clinical Perspective

Sedative agents are administered in critically ill patients to reduce agitation and anxiety and increase tolerance to invasive procedures (e.g., mechanical ventilation).800,801 The provision of adequate analgesia and other measures to ensure patient comfort is recommended before sedatives are administered.800,801 Sedative agents should be titrated to the desired level of sedation; in most cases, a light rather than deep level of sedation is recommended in critically ill, mechanically ventilated adults because of improved clinical outcomes that have been demonstrated (e.g., shortened duration of mechanical ventilation and reduced ICU length of stay).800,801 The depth and quality of sedation should be assessed using a validated and reliable assessment tool (e.g., Richmond Agitation-Sedation Scale [RASS], Sedation-Agitation Scale [SAS]).801 Common sedative agents used in the ICU include benzodiazepines (e.g., midazolam, lorazepam), propofol, and dexmedetomidine.800,801,817 These agents appear to be similarly effective in providing adequate sedation in critically ill, mechanically ventilated adults.800,801 However, modest benefits in terms of other clinical outcomes (e.g., reduced duration of mechanical ventilation, shorter time to extubation, reduced risk of delirium) have been observed with the nonbenzodiazepine sedatives (dexmedetomidine and propofol) compared with benzodiazepines.800,801,817,818,819,820

Comparative studies have demonstrated a shorter time to light sedation and shorter time to extubation with propofol compared with benzodiazepines, and a shorter time to extubation and reduced risk of delirium with dexmedetomidine compared with benzodiazepines.800,818,819 In most of these studies, benzodiazepines were administered as a continuous IV infusion rather than as intermittent IV injections.800 Because of the apparent advantages and an overall favorable benefit-to-risk profile, experts state that nonbenzodiazepine sedatives (dexmedetomidine or propofol) may be preferred to benzodiazepines (midazolam or lorazepam) in mechanically ventilated, critically ill adults.800,801 This recommendation should be considered in the context of the specific clinical situation since benzodiazepines may still be preferred in certain situations (e.g., patients with anxiety, seizures, or alcohol or benzodiazepine withdrawal).801 When selecting an appropriate sedative agent, the patient's individual sedation goals should be considered in addition to specific drug-related (e.g., pharmacology, pharmacokinetics, adverse effects, availability, cost) and patient-related (e.g., comorbid conditions) factors.800,801

Because of its greater potency and slower clearance, emergence from short-term sedation with lorazepam may be longer than with midazolam; however, comparative studies have suggested that midazolam is associated with greater variability and a longer time to awakening than lorazepam when used for prolonged sedation.801

Seizure Disorders

Status Epilepticus

Midazolam hydrochloride is used IM for the treatment of status epilepticus.545,763,774 While IM midazolam is FDA-labeled for use only in adults, the drug also has been used in pediatric patients† for the treatment of status epilepticus.545,763,774

Midazolam also has been administered by intranasal† and buccal† routes for treatment of status epilepticus; limitations of these routes include unpredictable absorption, difficulty with administration during an acute seizure episode, and lack of commercial availability.763,765,769,75

Clinical Perspective

Benzodiazepines are considered the initial drugs of choice for the management of status epilepticus because of their rapid onset of action, demonstrated efficacy, safety, and tolerability.545,563,756,757,758,759,761,762,763,764,765,766,767,771

Status epilepticus is a medical emergency that must be treated promptly to reduce substantial morbidity and mortality.545,763,764,766,767 Initial treatment should include standard critical care and supportive therapy (e.g., blood pressure and respiratory support, oxygen, IV access, identification and correction of underlying causes), followed by administration of a benzodiazepine.545,763,765,766 Although IV lorazepam is generally preferred because of its longer duration of action, studies generally have not identified any substantial differences between IV lorazepam, IV diazepam, and IM midazolam in terms of seizure cessation, and experts consider these therapies to be equivalent first-line options.545,763,764,765,766,767,768,769 Selection of an appropriate benzodiazepine should be individualized based on local availability, route of administration, pharmacokinetics, cost, and other factors (e.g., treatment setting).545,756,757,758,759,760,761,762,763,764,765,766,767,769 If seizures continue after initial therapy with a benzodiazepine, a second-line anticonvulsant agent (e.g., IV fosphenytoin or phenytoin, IV valproate sodium, IV levetiracetam, IV phenobarbital) should be administered.757,759,760,762,763,765,766 If refractory status epilepticus occurs, continuous IV infusion of anticonvulsants, IV barbiturates, or general anesthetics may be necessary.757,758,759,760,761,765,766

Although IV administration of a benzodiazepine is the preferred method of treatment to achieve a rapid therapeutic effect in patients with status epilepticus, the need to establish IV access may delay administration of the drug in the prehospital environment.763,765,768 Results of a randomized controlled study (RAMPART) indicate that IM administration of midazolam by paramedics in the prehospital setting may improve outcomes in patients with status epilepticus; in this study, 73% of patients who received IM midazolam achieved seizure resolution at the time of arrival in the emergency department compared with 63% of those who received IV lorazepam.763,765,768

Acute Repetitive Seizures or Seizure Clusters

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

Efficacy of intranasal midazolam for this use has been established in a randomized, double-blind, placebo-controlled study in epileptic patients 12 years of age or older who were receiving a stable anticonvulsant regimen, but were experiencing intermittent seizure activity distinct from their usual seizure pattern.773 The primary efficacy end point (i.e., termination of seizures within 10 minutes after administration of study drug and absence of recurrence within 6 hours) was achieved in substantially more patients receiving intranasal midazolam than those receiving placebo.773 Patients who received midazolam also experienced a longer time to the next seizure than those who received placebo.773

Other Uses

Parenterally administered midazolam has been used in the management of acute agitation†.53,90,146,147,148,181

Administration

Midazolam hydrochloride is administered orally,219 by IM or slow IV injection,1,2,4,7,14,193,580,774 or by IV infusion.1,36,90,150,181,219,580 Midazolam also has been used in IV patient-controlled analgesia (PCA).252 Midazolam is administered intranasally.773 Midazolam also has been orally administered as the maleate salt†;60,61,62,63,64,65,67,116,123,180 however, midazolam maleate currently is not commercially available in the US.

Because serious and life-threatening adverse cardiorespiratory effects can occur during therapy with midazolam, provision should be made for monitoring, detecting, and correcting such effects in every patient in whom the drug is administered, regardless of age or health status.1,219

When IV or oral midazolam is used for sedation or anesthesia, the drug should be administered in a hospital or ambulatory care setting equipped to provide continuous monitoring of cardiorespiratory function.1,219,821 Resuscitative equipment, drugs, and personnel for airway and ventilation management should be immediately available.1,193 For deeply sedated pediatric patients, a dedicated individual other than the clinician performing the procedure should monitor the patient throughout the procedure.1,219

When IM midazolam is used for status epilepticus, the drug should be administered in a monitored setting that allows for immediate access to resuscitative drugs, and the patient's cardiorespiratory function should be continuously monitored until stabilized.774

When midazolam nasal spray is used, consideration should be given to administering the drug under the supervision of a healthcare professional.773

Parenteral Administration

Midazolam Hydrochloride Injection for Sedation or Anesthesia

Midazolam hydrochloride injection is administered IV or IM for sedation or anesthesia; the parenteral preparation should not be administered by any other route (e.g., intrathecal, intra-arterial).1 Care should be taken to avoid intra-arterial injection or extravasation of the drug.1

IM injection: IM injections of midazolam should be administered deep into a large muscle mass.1

IV injection: IV injections of midazolam should be administered in incremental doses.1,163 The drug is a potent sedative that requires slow administration and individualized titration of dosage.1 The manufacturer states that the appropriate dose usually is injected over 2 or more minutes at intervals of at least 2 minutes for procedural sedation in healthy patients;1,163,193 incremental doses and the rate of IV injection should be reduced in patients ≥60 years of age, in debilitated patients, in patients with chronic disease states (e.g., congestive heart failure), and in patients with decreased pulmonary reserve, since such patients are at increased risk of underventilation, airway obstructions, and apnea, and the time to peak effect may be slower.1,163,193 For induction of anesthesia, the appropriate dose usually is injected over 20-30 seconds; supplemental doses may be given at 2-minute intervals.1 To facilitate dosage titration, the commercially available 1-mg/mL midazolam injection may be used, or the 1- or 5-mg/mL injection may be diluted with 0.9% sodium chloride injection or 5% dextrose injection.1,193 For procedural sedation, use of midazolam hydrochloride injection containing 1 mg/mL (of midazolam) is recommended to facilitate slow IV injection of the drug.1,193

IV infusion: the manufacturer recommends that the 5-mg/mL midazolam injection should be diluted to a concentration of 0.5 mg/mL with 0.9% sodium chloride injection or 5% dextrose injection.1 Other standard concentrations for continuous IV infusion of midazolam have been recommended by ASHP's Standardize 4 Safety initiative in adults and pediatric patients (see Standardize 4 Safety section below).250,251

Standardize 4 Safety

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

Midazolam Hydrochloride Injection for Status Epilepticus

Midazolam hydrochloride injection (Seizalam^®) should be administered by IM injection into the mid-outer thigh (vastus lateralis muscle).774 Administration of the injection by a clinician who has adequate training in the recognition and management of status epilepticus is recommended.774

Oral Administration

Midazolam oral solution is intended for use in monitored settings (e.g., hospital or ambulatory care settings, including physician and dental offices) only, and is not intended for chronic or home use.219 (See Cautions: Precautions and Contraindications.) For instruction on use of the special press-in bottle adapter and oral dispensers for administration of midazolam oral syrup, the manufacturer's labeling should be consulted.219 The drug should be administered from the individual oral dispenser directly into the child's mouth; the oral solution should not be mixed with any other liquid (e.g., grapefruit juice) prior to administration. Although the effect of food on absorption of the oral solution has not been determined, food intake generally is precluded prior to procedural sedation in pediatric patients.219

Intranasal Administration

Midazolam nasal spray is administered intranasally using a single-dose nasal spray unit supplied by the manufacturer.773 Each nasal spray unit delivers 5 mg of midazolam in 0.1 mL of solution.773 The intranasal preparation is commercially available in boxes of 2 nasal spray units; each unit is contained within an individual blister pack that should not be opened until ready to use.773 The nasal spray unit should not be tested or primed before use.773 The manufacturer's instructions should be consulted for additional information on use of the midazolam nasal spray.773

Dosage

Midazolam is commercially available as midazolam or the hydrochloride salt; dosage is expressed in terms of midazolam.1,219,580,773,774 Midazolam is a potent sedative that requires individualized dosing.1,163,193

When midazolam is used for sedation or anesthesia, dosage must be carefully adjusted 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 to the drug also may vary independent of these factors.1,163,193,219 Titration should be more gradual in patients 60 years of age and older for procedural sedation, in those 55 years of age and older for induction of anesthesia, and in patients with chronic debilitating diseases.1,163,180 Excessive doses or rapid or single large IV injections may result in respiratory depression and/or arrest, particularly in geriatric or debilitated patients and in patients receiving other cardiorespiratory depressants concomitantly.1,163,193 (See Cautions: Cardiorespiratory Effects.) The smallest effective dose should be used, especially in geriatric and/or debilitated patients.1

It should be recognized that the depth of sedation/anxiolysis needed for pediatric patients depends on the type of procedure performed.1 For example, simple light sedation in the preoperative period is different from the deeper sedation required for a therapeutic or diagnostic procedure (e.g., endoscopy);1 therefore, there is a broad dosage range.1 For all pediatric patients, regardless of the indications for sedation/anxiolysis, it is vital to titrate the midazolam dose and the dose of other concomitant drugs slowly for the desired clinical effect.1 Unlike adults, pediatric patients generally receive increments of midazolam on a mg/kg basis; drug dose in obese pediatric patients should be calculated on the basis of ideal body weight.1,219 Pediatric patients generally require higher dosages of midazolam on a mg/kg basis than adults,1 and pediatric patients younger than 6 years of age generally require higher dosages on a mg/kg basis than older pediatric patients and may require closer monitoring.1,219

When midazolam is used for sedation in geriatric patients, the initial dose should be reduced, since some degree of organ impairment frequently is present.1,163,193 Dosage requirements in this age group generally appear to decrease with increasing age,1,163 and the possibility of profound and/or prolonged effects should be considered in older and/or debilitated patients.1 Low doses of midazolam usually are required in high-risk surgical patients, debilitated patients, and geriatric patients when the drug is administered with or without premedication.1,163,193 (See Cautions: Geriatric Precautions.)

Preoperative Sedation, Anxiolysis, and Amnesia

For preoperative sedation, anxiolysis, and amnesia in good-risk (e.g., ASA Physical Status I and II) adults younger than 60 years of age , the usual dose of midazolam is 0.07-0.08 mg/kg (about 5 mg) administered by IM injection approximately 30-60 minutes prior to surgery.1,14,180,181 The dosage must be individualized and reduced when IM midazolam is administered to patients with chronic obstructive pulmonary disease, other higher-risk surgical patients, patients 60 years of age or older, and patients who have received opiate agonists or other CNS depressants concomitantly.1 In a study in patients 60 years of age or older who did not receive concomitant opiate agonist therapy, IM doses of 2-3 mg (0.02-0.05 mg/kg) reportedly produced adequate sedation during the preoperative period;1 the manufacturer states that an IM midazolam dose of 1 mg may be sufficient in some geriatric patients if the anticipated intensity and duration of sedation are less critical.1 As with any potential respiratory depressant, such patients should be observed for signs of cardiorespiratory depression following administration of IM midazolam.1 Sedative effects usually are apparent within 15 minutes and peak at 30-60 minutes.1,2,4,8,9,10,11,12,13,14,15,16,32,81 Midazolam can be administered concomitantly with atropine sulfate, scopolamine hydrochloride, and/or reduced doses of opiate agonists.1,156 (See Chemistry and Stability: Stability.)

If IM midazolam is used for preoperative sedation in non-neonatal pediatric patients , the usual dose is 0.1-0.15 mg/kg; doses in this range usually are effective and do not prolong emergence from general anesthesia.1 Sedation after IM administration of midazolam is age and dose dependent; higher doses may result in deeper and more prolonged sedation.1 For more anxious patients, IM doses of up to 0.5 mg/kg have been used.1 The manufacturer states that the total IM dose usually does not exceed 10 mg, although this has not been systematically studied.1 If midazolam is administered with an opiate, the initial dose of each drug must be reduced.1 IM midazolam may be used to initially sedate pediatric patients in order to facilitate less traumatic insertion of an IV catheter for further dosage titration.1

If IV midazolam is used for preoperative sedation in non-neonatal pediatric patients , the usual dose (as an intermittent injection) is age dependent; prolonged sedation and risk of hypoventilation may be associated with the higher doses in each recommended range.1 IV injections of midazolam should be administered over 2-3 minutes.1 It is essential to wait 2-3 minutes to fully evaluate the sedative effect before starting the procedure or administering a repeat dose.1 In pediatric patients 6 months to 5 years of age , an initial IV dose of 0.05-0.1 mg/kg is recommended; a total dose of up to 0.6 mg/kg may be required to reach the desired end point, but usually does not exceed a total of 6 mg.1 In pediatric patients 6-12 years of age , an initial IV dose of 0.025-0.05 mg/kg is recommended; a total dose of up to 0.4 mg/kg may be required to reach the desired end point, but usually does not exceed a total of 10 mg.1 Pediatric patients 12-16 years of age should be dosed as adults;1 although some patients in this age range may require higher than recommended adult doses, the total dose usually does not exceed 10 mg.1 In nonintubated pediatric patients younger than 6 months of age, limited dosing information is available.1 The manufacturer states that because it is uncertain when a patient transfers from a neonatal to pediatric physiology, dosing recommendations are unclear in nonintubated pediatric patients younger than 6 months of age.1 However, because such patients are vulnerable to airway obstruction and hypoventilation, titration of drug dose in small increments to clinical effect and careful monitoring are essential.1

If oral midazolam is used for preoperative sedation in pediatric patients 6 months to 16 years of age , a single dose of 0.25-0.5 mg/kg is recommended, depending on the status of the patient and the desired effect, up to a maximum of 20 mg.219 In general, it is recommended that the dose be individualized and modified based on patient age, level of anxiety, concomitantly administered drugs, and medical need.219 Younger pediatric patients (e.g., 6 months to younger than 6 years of age) and less cooperative patients may require a higher than usual oral dose of up to 1 mg/kg (up to a maximum of 20 mg).219 A dose of 0.25 mg/kg may be sufficient for older children 6-16 years of age or for cooperative patients, especially if the anticipated intensity and duration of sedation are less critical.219 For pediatric patients with cardiac or respiratory compromise, other higher-risk surgical pediatric patients, and pediatric patients who have received concomitant opiates or other CNS depressants, an oral dose of 0.25 mg/kg should be considered.219 Use of the oral solution in children younger than 6 months of age has not been established.219

Procedural Sedation

For procedural sedation, midazolam may be administered by slow IV injection or as an oral solution before the procedure.1,219 In non-neonatal pediatric patients, IM midazolam may be used to initially sedate the patient in order to facilitate less traumatic insertion of an IV catheter for further dosage titration.1 The manufacturer of midazolam hydrochloride injection states that for peroral procedures (e.g., upper GI endoscopy, bronchoscopy), use of a topical anesthetic is generally recommended,1 and for bronchoscopy, use of an opiate analgesic for premedication also is generally recommended.1 For procedural sedation, premedication with an opiate agonist appears to produce less variable response to midazolam.1,100

If IV midazolam is used for procedural sedation in healthy adults younger than 60 years of age, the manufacturer states that dosage should be titrated slowly to the desired effect (e.g., onset of slurred speech).1,193 The initial IV dose should not exceed 2.5 mg (administered over at least 2 minutes), although some patients may respond to as little as 1 mg of the drug.1,193 Patients 60 years of age or older and debilitated or chronically ill patients, and patients with decreased pulmonary reserve should receive 1-1.5 mg as an initial IV dose over a longer period of injection.1 The manufacturer recommends that not more than 1.5 mg over at least 2 minutes be administered as an initial dose in these patients.1,193 After waiting at least 2 minutes to fully evaluate the patient's clinical response, midazolam dosage may be further titrated in small increments if further sedative effect is required.1 Patients 60 years of age or older, chronically ill and/or debilitated patients, or patients with decreased pulmonary reserve should receive incremental doses of not more than 1 mg of midazolam.1 A total dose of up to 5 mg generally is adequate for procedural sedation in an average healthy adult younger than 60 years of age, and a total dose of up to 3.5 mg usually is adequate for patients 60 years of age or older, chronically ill and/or debilitated patients, and patients with decreased pulmonary reserve.1 If a thorough clinical evaluation clearly indicates a need for additional doses of midazolam to maintain the desired level of sedation, additional doses of the drug may be administered in increments of approximately 25% of the initial dose used to reach the first sedative end point.1 Some clinicians have recommended initiating dosing with 0.5-2 mg and repeating doses, as necessary, at 2- to 3-minute intervals up to a total dose of 0.1-0.15 mg/kg.14,181 In patients 60 years of age and older, these clinicians have recommended reducing midazolam dosage by 25% or more.14

If IV midazolam is used concomitantly with an opiate agonist or other CNS depressant, dosage requirements of midazolam may be reduced by about 30% in healthy adults younger than 60 years of age1,14 and by at least 50% in patients 60 years of age or older, chronically ill and/or debilitated patients, and patients with decreased pulmonary reserve.1 Because the risk of underventilation or apnea is greatest in geriatric patients, patients with chronic debilitating disease, and patients with decreased pulmonary reserve, and because peak effect of the drug may occur later in these patients, increments in dose should be smaller, and the rate of injection should be slower.1,180

If IM midazolam is used for procedural sedation in non-neonatal pediatric patients , the usual dose is 0.1-0.15 mg/kg.1 Sedation after IM administration of midazolam is age and dose dependent; higher doses may result in deeper and more prolonged sedation.1 For more anxious patients, IM doses of up to 0.5 mg/kg have been used.1 The manufacturer states that the total IM dose usually does not exceed 10 mg, although this has not been systematically studied.1 If midazolam is administered with an opiate, the initial dose of each must be reduced.1

If IV midazolam is used for procedural sedation in non-neonatal pediatric patients , the usual IV dose (as an intermittent injection) is age dependent; prolonged sedation and risk of hypoventilation may be associated with the higher doses in each recommended range.1 IV injections of midazolam should be administered over 2-3 minutes.1 It is essential to wait 2-3 minutes to fully evaluate the sedative effect before starting the procedure or administering a repeat dose.1 In pediatric patients 6 months to 5 years of age , an initial IV dose of 0.05-0.1 mg/kg is recommended; a total dose of up to 0.6 mg/kg may be required to reach the desired end point, but usually does not exceed a total of 6 mg.1 In pediatric patients 6-12 years of age , an initial IV dose of 0.025-0.05 mg/kg is recommended; a total dose of up to 0.4 mg/kg may be required to reach the desired end point, but usually does not exceed a total of 10 mg.1 Pediatric patients 12-16 years of age should be dosed as adults;1 although some patients in this age range may require higher than recommended adult doses, the total dose usually does not exceed 10 mg.1 In nonintubated pediatric patients younger than 6 months of age, limited dosing information is available.1 The manufacturer states that because it is uncertain when a patient transfers from a neonatal to pediatric physiology, dosing recommendations are unclear in nonintubated pediatric patients younger than 6 months of age.1 However, because such patients are vulnerable to airway obstruction and hypoventilation, titration of drug dose in small increments to clinical effect and careful monitoring are essential.1

If oral midazolam is used for procedural sedation in pediatric patients 6 months to 16 years of age , a single dose of 0.25-0.5 mg/kg is recommended, depending on the status of the patient and the desired effect, up to a maximum of 20 mg.219 In general, it is recommended that the dose be individualized and modified based on patient age, level of anxiety, concomitantly administered drugs, and medical need.219 Younger pediatric patients (e.g., 6 months to younger than 6 years of age) and less cooperative patients may require a higher than usual oral dose of up to 1 mg/kg (up to a maximum of 20 mg).219 A dose of 0.25 mg/kg may be sufficient for older children 6-16 years of age or for cooperative patients, especially if the anticipated intensity and duration of sedation are less critical.219 For pediatric patients with cardiac or respiratory compromise, other higher-risk surgical pediatric patients, and pediatric patients who have received concomitant opiates or other CNS depressants, an oral dose of 0.25 mg/kg should be considered.219 Use of the oral solution in children younger than 6 months of age has not been established.219

Induction and Maintenance of Anesthesia

For induction of general anesthesia, midazolam should be administered prior to other anesthetic agents.1 Because individual response to midazolam is variable, especially when opiate agonist premedication is not used, dosage of midazolam should be titrated carefully to the desired clinical effect, taking into consideration the patient's age and clinical status.1,2,70 When midazolam is administered prior to other IV agents for induction of anesthesia, 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

For induction of general anesthesia prior to administration of other anesthetic agents, average adults younger than 55 years of age who have not received premedications usually require an initial midazolam dose of 0.3-0.35 mg/kg, administered IV over 20-30 seconds; approximately 2 minutes should be allowed for clinical effect.1,180 Some clinicians have suggested a lower initial dose (e.g., 0.2 mg/kg) in these adults.14,144,181 Supplemental doses of about 25% of the initial dose may be given as necessary to complete induction.1,14 Alternatively, induction of anesthesia may be completed with inhalation agents.1 Total IV induction doses of up to 0.6 mg/kg may be required in some resistant patients, but such doses may prolong recovery from anesthesia.1,4,100 Patients 55 years of age or older who have not been premedicated usually require lower induction doses of midazolam;1,2 the manufacturer recommends an initial IV induction dose of 0.3 mg/kg in these patients.1 Patients with severe systemic disease or other debilitation who have not been premedicated also usually require lower induction doses.1 Initial IV doses of 0.2-0.25 mg/kg usually are adequate in such patients, and doses as low as 0.15 mg/kg may be adequate for induction in some debilitated patients.1

In premedicated patients, especially those who have received an opiate agonist, the usual IV induction dose of midazolam is 0.15-0.35 mg/kg.1 In premedicated adults younger than 55 years of age, the usual induction dose is 0.25 mg/kg administered IV over 20-30 seconds; about 2 minutes should be allowed for clinical effect.1 In premedicated, good-risk (e.g., ASA I and II) adults older than 55 years of age, an initial IV induction dose of 0.2 mg/kg is recommended by the manufacturer.1 In some premedicated patients with severe systemic disease or debilitation, an initial IV induction dose of 0.15 mg/kg may be sufficient.1

For maintenance of anesthesia as a component of balanced anesthesia during surgical procedures, premedication with an opiate agonist is especially recommended.1 Midazolam may be administered in incremental IV doses of approximately 25% of the induction dose when lightening of anesthesia is evident and repeated, as necessary, to maintain the required level of anesthesia.1

Sedation in Critical Care Settings

Dosage of sedative agents should be titrated to the desired level of sedation; in most cases, a light rather than deep level of sedation is recommended in critically ill mechanically ventilated adults because of improved clinical outcomes that have been demonstrated (e.g., shortened duration of mechanical ventilation, reduced ICU length of stay).800,801 The depth and quality of sedation should be assessed frequently using a validated and reliable assessment tool (e.g., Richmond Agitation-Sedation Scale [RASS], Sedation-Agitation Scale [SAS]).800

For sedation in intubated and mechanically ventilated adult patients in critical care settings (e.g., ICU), midazolam is administered as a continuous IV infusion.1 In adults, if a loading dose is necessary to initiate sedation rapidly, 0.01-0.05 mg/kg (approximately 0.5-4 mg for a typical adult) may be given slowly or infused over several minutes.1,801 This dose may be repeated at 10- to 15-minute intervals until adequate sedation is achieved.1 For maintenance of sedation in adults, the usual initial infusion rate is 0.02-0.1 mg/kg per hour (approximately 1-7 mg per hour).1,801 Higher loading or maintenance infusion rates occasionally may be required in some patients.1 The lowest recommended doses should be used in patients with residual effects from anesthetic drugs, or in those currently receiving other sedatives or opiates.1 Individual response to midazolam is variable and the infusion rate should be titrated to the desired level of sedation, taking into account the patient's age, clinical status, and current drugs.1 In general, midazolam should be infused at the lowest rate that produces the desired level of sedation.1 Assessment of sedation should be performed at regular intervals and the infusion rate adjusted 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 In addition, the infusion rate should be decreased by 10-25% every few hours to find the minimum effective infusion rate.1 Finding the minimum effective infusion rate decreases the potential accumulation of midazolam and provides for the most rapid recovery once the infusion is terminated.1 Patients who exhibit agitation, hypertension, or tachycardia in response to noxious stimulation, but who are otherwise adequately sedated, may benefit from concomitant administration of an opioid analgesic; however, addition of an opiate generally will reduce the minimum effective midazolam infusion rate.1

For sedation of intubated non-neonatal pediatric patients, midazolam generally is initiated with an IV loading dose of 0.05-0.2 mg/kg administered over at least 2-3 minutes; the drug should not be administered as a rapid IV injection.1 The loading dose may be followed by a continuous IV infusion to maintain the desired clinical effect.1 Based on pharmacokinetic parameters and clinical experience, continuous IV infusions of midazolam should be initiated at a rate of 0.06-0.12 mg/kg per hour (1-2 mcg/kg per minute).1 The infusion rate may be increased or decreased (generally by 25% of the initial or subsequent infusion rate) as required, or supplemental IV doses of midazolam may be administered to increase or maintain the desired effect.1 Frequent patient assessment at regular intervals using standard pain/sedation scales is recommended.1 Midazolam infusions have been used in pediatric patients whose trachea was intubated but who were allowed to breathe spontaneously; however, assisted ventilation is recommended for pediatric patients who are receiving other CNS depressants (e.g., opiates).1 Midazolam elimination may be delayed in patients receiving concomitant drugs (e.g., drugs interfering with midazolam metabolism), patients with hepatic dysfunction, patients with low cardiac output (especially those requiring inotropic support), and in neonates.1 Hypotension may be observed in patients who are critically ill, particularly those receiving opiates and/or if midazolam is administered rapidly.1 When initiating a midazolam infusion in pediatric patients who are hemodynamically compromised, the usual loading dose should be titrated in small increments and the patient monitored for hemodynamic instability (e.g., hypotension).1 These patients also are vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation.1

For sedation of intubated preterm neonates (i.e., born at less than 32 weeks' gestation) in critical care settings, midazolam generally is initiated as an IV infusion at a rate of 0.03 mg/kg per hour (0.5 mcg/kg per minute); for sedation of intubated neonates who were born after 32 weeks of gestation, midazolam is generally initiated as an IV infusion at a rate of 0.06 mg/kg per hour (1 mcg/kg per minute).1 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 The infusion rate should be reassessed carefully and frequently, particularly after the first 24 hours, to administer the lowest possible effective dose 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 if not using the preservative-free formulation.1 (See Cautions: Pediatric Precautions.) Hypotension may be observed in critically ill neonates and in preterm and term neonates, especially in those receiving fentanyl and/or in patients in whom midazolam is administered rapidly.1 Because of an increased risk of apnea, extreme caution is advised when sedating a preterm or former preterm neonate whose trachea is not intubated.1

Status Epilepticus

For the treatment of status epilepticus in adults, the manufacturer recommends a single midazolam dose of 10 mg by IM injection.774 The manufacturer states that safety and efficacy of midazolam for the treatment of status epilepticus have not been established in pediatric patients.774 However, the drug has been used in pediatric patients†.545 Some clinicians recommend an IM midazolam dose of 10 mg for the treatment of status epilepticus in patients weighing more than 40 kg and a dose of 5 mg for those weighing 13-40 kg.763 Other clinicians have recommended a usual weight-based dose of 0.15-0.3 mg/kg in both children and adults.545

Acute Repetitive Seizures or Seizure Clusters

For the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (e.g., seizure clusters, acute repetitive seizures), the recommended initial dose of intranasal midazolam in adults and pediatric patients 12 years of age or older is 1 spray (5 mg) into one nostril.773 An additional spray into the opposite nostril may be administered after 10 minutes if a response is not obtained with the first dose; however, a second dose should not be administered if the patient has difficulty breathing or excessive sedation that is uncharacteristic for the patient during a seizure cluster episode.773 No more than 2 doses should be used to treat a single seizure episode.773

The manufacturer recommends that midazolam nasal spray be used to treat no more than one seizure episode every 3 days and no more than 5 seizure episodes a month.773

Adverse effects reported with midazolam are similar to those reported with other benzodiazepines.1,2,4,7 Changes in vital signs (e.g., respiratory rate, blood pressure, pulse rate) are the most frequent adverse effects associated with parenteral midazolam administration.1 For further information on adverse effects reported with benzodiazepines, see Cautions in the Benzodiazepines General Statement 28:24.08.. The immediate availability of flumazenil, a specific benzodiazepine reversal agent, is highly recommended.1 (See Flumazenil 28:92.)

Cardiorespiratory Effects

Midazolam can depress respiration.1,2,4,7,37,137,138,139,140,163,189,193 Relatively small doses, such as those used for preoperative sedation, usually do not substantially impair respiratory function;1,2 however, relatively large doses (e.g., more than 0.1-0.2 mg/kg) may substantially depress the ventilatory response to carbon dioxide (CO₂) stimulation.1,2,37,137,138,139 In addition, some patients (e.g., geriatric patients, patients with chronic obstructive pulmonary disease) may be predisposed to respiratory depression induced by midazolam.1,2,7,14,70,139,140,163,189

Decreases in tidal volume and/or respiratory rate occur in about 23 or 11% of adults following IV or IM administration of midazolam, respectively.1 Apnea1,2,4,7,14,25,27,33,35,37,42,70 occurs in approximately 15% of adults receiving the drug parenterally.1 Desaturation or apnea has been reported in 4.6 or 2.8%, respectively, of pediatric patients receiving the drug IV.1 Hypoxia and laryngospasm were each reported in 2% of pediatric patients receiving the drug orally, and respiratory depression, rhonchi, airway obstruction, or upper airway obstruction was reported in 1% of these patients.219 Hypercarbia and stridor generally have been reported in less than 1% of patients receiving the drug orally.219 Serious, occasionally fatal, cardiorespiratory effects, including respiratory depression, apnea, respiratory arrest, and/or cardiac arrest, have occurred in patients receiving midazolam, particularly when the drug was used for procedural sedation.1,2,37,137,139,163,175,193 In some patients in whom midazolam-induced respiratory depression was not promptly recognized and effectively managed, hypoxic encephalopathy or death has resulted.1,193 Although many of the serious cardiorespiratory adverse effects reported to date have occurred in patients receiving excessive doses or rapid IV injection or infusion of midazolam, in geriatric or debilitated and/or higher-risk surgical patients, and in patients receiving other cardiorespiratory depressants concomitantly, some of these adverse reactions have occurred in younger, healthy patients, including those who did not receive concomitant drugs, and in patients receiving midazolam doses within the dosage range recommended by the manufacturer.1,2,37,137,139,163,175,193 Patients with chronic obstructive pulmonary disease appear to be particularly sensitive to the respiratory depressant effects of midazolam (e.g., impairment of the ventilatory response to CO₂),1,2,7,14,70,139,140,163 exhibiting more marked and prolonged depression than patients with healthy lungs.1,2,7,70,139,163

Underventilation or apnea can result in potentially serious hypoxia and/or cardiac arrest unless effective countermeasures are initiated at the earliest sign of compromised respiration or ventilation.1,163,175,193 Early recognition and treatment of underventilation and apnea are necessary to avoid hypoxic cardiac arrest.1,163,175,193 Therefore, cardiorespiratory status should be monitored continuously during parenteral or oral midazolam use, dosage of the drug must be carefully individualized, and facilities and equipment for respiratory and ventilatory support should be readily available.1,163,175,193,219 (See Cautions: Precautions and Contraindications.) Concomitant administration of CNS depressants may increase the risk of underventilation and apnea and may prolong and/or exacerbate the effects of midazolam.1,4,14,163,175,189,190 (See Drug Interactions: CNS Depressants.) Use of supplemental oxygen should be considered when heavy sedation is anticipated or required.189

Changes in systolic or diastolic blood pressure, principally decreases,1,2,4,7,14,70,79,89,96,108,141,219 and in heart rate1,2,7,59,70,194,219 are frequently associated with parenteral or oral administration of midazolam;1,219 however, in some cases, these effects may be associated with endotracheal intubation, changes in the depth of anesthesia, concomitantly administered drugs, and/or surgical manipulation rather than with midazolam itself.1 Hypotensive episodes requiring treatment have been reported rarely during or following diagnostic or surgical manipulation in patients receiving midazolam.1 Concomitant administration of an opiate agonist (e.g., as premedication for moderate sedation [formerly known as conscious sedation]) appears to increase the risk of severe hypotension associated with midazolam administration.1,4,14,112 Severe hypotensive effects may be alleviated by the judicious administration of IV fluids, repositioning the patient, and/or the cautious use of vasopressors.1 Induction of anesthesia with midazolam in patients with a relatively slow baseline heart rate (less than 65 beats/minute) is associated with a slight increase in heart rate, especially in patients receiving a β-adrenergic blocking agent for angina.1 However, use of midazolam in patients with a relatively fast baseline heart rate (greater than 85 beats/minute) appears to result in slight slowing of the heart rate.1

Other adverse respiratory effects of midazolam include hiccups1,2,35,56,70,89,99,100,124,127,130,219 and coughing,1,2,70,124 which occur in up to 4 and 1% of patients, respectively, receiving the drug IV.1 Laryngospasm,1,4 bronchospasm,1,4 dyspnea,1 hyperventilation,1 wheezing,1 shallow respiration,1 airway obstruction,1 and tachypnea1 occur in less than 1% of patients, principally those receiving the drug IV.1

Other adverse cardiovascular effects of midazolam include decreases in systemic vascular resistance,1,2,4,7,95,96,109,110 cardiac index,1,85,110 and stroke index.85,96 Bradycardia has been reported in up to 1% of pediatric patients receiving midazolam oral solution.1,219 Bigeminy,1,59,194,219 ventricular premature complexes,1,59 vasovagal episodes,1 tachycardia,1,194 and nodal rhythms1 reportedly occur in less than 1% of patients.1,219 Trigeminy also has been reported in patients receiving midazolam.194

Nervous System Effects

Adverse nervous system effects of midazolam generally are extensions of the pharmacologic actions of the drug;20,86 however, some reactions (e.g., agitation, involuntary movements) may be paradoxical in nature, manifestations of an underlying iatrogenic disorder (e.g., cerebral hypoxia), and/or associated with the surgical or other procedures employed.1,71,83,91 Paradoxical reactions have been reported in 2% of pediatric patients receiving the drug IV.1

Excessive sedation,1 headache,1,35,127 and drowsiness1,4,10,21,89,102 occur in 1-2% of patients following parenteral administration of midazolam.1 Agitation,1 involuntary movements (e.g., tonic/clonic movements, muscle tremor),1,163 hyperactivity,1 and combativeness1,89 also have been reported.1 Such reactions may have resulted from inadequate or excessive doses of midazolam, improper administration of the drug, or cerebral hypoxia, or may have been paradoxical.1,71,83,91,163 (See Cautions: Precautions and Contraindications.) Agitation has been reported in 2% of pediatric patients receiving the drug orally.219 Seizure-like activity or nystagmus was reported in 1.1% of pediatric patients receiving the drug IV.1

Other adverse nervous system effects that occur in less than 1% of patients receiving oral or IV midazolam include retrograde amnesia,1,115 euphoria,1 hallucinations,1,219 dysphoria,1,4,219 prolonged emergence from anesthesia,1 emergence delirium or agitation,1,219 dreaming during emergence,1 prolonged sedation,219 sleep disturbance,1 insomnia,1 nightmares,1,132 paresthesia,1 adverse behavior,219 mood swings,219 aggression,219 excitation,219 disinhibition,219 argumentativeness,1 nervousness,1 anxiety,1 restlessness,1,83 seizure-like activity,1 dysarthria,219 and athetoid movements.1 Confusion,1,4,83,219 grogginess,1 ataxia,1,20,219 dizziness,1,32,66,131,219 loss of balance or vertigo,1,219 lightheadedness,1,25 lethargy,1 yawning,1 faint feeling,1 weakness,1 slurred speech,1,20,102 blurred vision,219 strabismus,219 diplopia,219 and dysphonia1 have also been reported in less than 1% of patients.1,219

Somnolence, headache, and dysarthria have been reported in 10, 4, and 2%, respectively, of patients receiving midazolam nasal spray.773

Midazolam has reduced cerebral blood flow and oxygen consumption in animals and humans.152,153,154,155 In patients without intracranial pathology, induction of anesthesia with midazolam results in a moderate decrease in CSF pressure, similar to that occurring with thiopental (no longer commercially available in the US).1 There is some evidence that, in patients with normal intracranial pressure but decreased intracranial compliance who are undergoing intracranial surgery, induction of anesthesia with midazolam results in increased intracranial pressure during intubation similar to that occurring with thiopental.1

GI Effects

Nausea1,2,4,7,25,32,35,70,81 and/or vomiting1,2,27,35,70,81 occurs in 2-3% of adult patients receiving midazolam IV and in up to 4 or 8%, respectively, of pediatric patients receiving the drug orally.1,219 Acid taste,1 excessive salivation,1,219 gagging,219 drooling,219 and retching1 occur in less than 1% of patients.1 Other adverse GI effects include metallic taste,127 dry mouth,4,59 and constipation.4

Sensitivity Reactions

Hypersensitivity reactions reported in less than 1% of patients receiving midazolam include anaphylactoid reactions,1 urticaria,1 rash,1,219 and pruritus.1

Local Effects

Tenderness at the site of injection1,35,71,73,78 and pain during injection1,2,7,21,71,74,78,81,87,100 occur in 5-6% of patients receiving midazolam IV.1 Erythema1,71,78 and induration1,78 occur at the IV site in 2-3% of patients,1 and phlebitis1,2,7,70,71,100 occurs in less than 1%.1 Pain at the site of IM injection1,7,11,35 occurs in about 4% of patients, and local induration,1,11 erythema,1,10 and muscle stiffness1 occur in less than 1% of patients receiving midazolam IM.1 Adverse local effects associated with IM or IV administration occur less frequently and generally are less severe with midazolam than with other currently available parenteral benzodiazepines (e.g., diazepam).2,4,7,14,25,32,70,74,75,76,78,79,86,87,176,177,178

Urticaria-like elevation at the injection site,1 swelling or feeling of burning,1 and warmth or coldness at the injection site occur in less than 1% of patients receiving midazolam parenterally, principally in those receiving the drug IV.1

Nasal discomfort, throat irritation, rhinorrhea, and abnormal taste were reported in 9, 3, 3, and 2%, respectively, of patients receiving midazolam nasal spray.773

Ocular Effects

Adverse ocular effects occur in less than 1% of patients receiving parenteral midazolam, principally in those receiving the drug IV, and include blurred vision,1,66 diplopia,1,102,131 nystagmus,1,20,89,127 pinpoint pupils,1 cyclic movements of eyelids,1 visual disturbances,1 and focusing difficulty.1

Increased lacrimation was reported in 2% of patients receiving midazolam nasal spray.773

Other Adverse Effects

Chills,1 toothache,1 blockage of ears,1 and hematoma1 occur in less than 1% of patients receiving midazolam parenterally, principally in those receiving the drug IV.1 Limited data suggest that administration of midazolam as an adjunct to anesthesia may result in transient decreases in renal blood flow and glomerular filtration rate.7,142

Precautions and Contraindications

Midazolam shares the toxic potentials of the benzodiazepines, and the usual precautions of benzodiazepine administration should be observed. (See Cautions in the Benzodiazepines General Statement 28:24.08.)

Concomitant use of benzodiazepines, including midazolam, and opiate agonists or opiate partial agonists may result in profound sedation, respiratory depression, coma, and death.700,701,703,705,706,707,773,774 Patients receiving midazolam and/or their caregivers should be apprised of the risks associated with concomitant therapeutic or illicit use of benzodiazepines and opiates.700,703 (See Opiate Agonists and Opiate Partial Agonists under Drug Interactions: CNS Depressants.)

Agitation, involuntary movements, hyperactivity, and/or combativeness may be signs of inadequate or excessive dosing, improper administration, or cerebral hypoxia or may be paradoxical.1,163,773,774 If such adverse reactions occur during midazolam therapy, the patient's response to each dose of midazolam as well as to any concomitantly administered drug, including local anesthetics, should be evaluated before proceeding.1,163

Midazolam should be used with caution and dosage individualized carefully in patients with renal impairment, since the pharmacokinetics of the drug may be altered in such patients.1,2,4,7,31,33,34,42,70,163 Induction of anesthesia may occur more rapidly in patients with renal impairment, and recovery may be prolonged.2,4,31,33,34,42,70

Although the clinical importance has not been determined, some clinicians state that midazolam should be used with caution and dosage individualized carefully in patients with congestive heart failure.1,35,50,163 Pharmacokinetics of the drug may be substantially altered in such patients (e.g., prolonged elimination half-life, increased volume of distribution, delayed onset of action secondary to prolonged circulation time).1,35,50,163

Patients should be informed of the potentially profound pharmacologic effects of midazolam (e.g., sedation, relief of anxiety, lack of recall) and that the duration of these effects varies considerably among individuals, so that they may adequately perceive the risks and benefits of use of the drug.4,35 Patients should also be warned that midazolam may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle).1 The decision regarding when patients who have received midazolam can safely perform such activities must be individualized, especially when the patient received the drug as part of an outpatient procedure.1 Gross tests of recovery after awakening (e.g., orientation, ability to stand and walk, return to baseline Trieger competency) cannot be relied on alone to predict reaction time under stress.1 Patients should not operate a motor vehicle or hazardous machinery until the effects of the drug (e.g., drowsiness) have subsided or the day after anesthesia and surgery, whichever is longer.1 Impaired performance may persist for longer periods in geriatric patients, in patients using other drugs concomitantly, and secondary to the stress of surgery or general condition of the patient.1 For pediatric patients, particular care should be taken to ensure safe ambulation.219 Patients should be warned that concomitant use of midazolam with 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.1,4,7

Some preparations of midazolam hydrochloride injection contain the preservative benzyl alcohol and should not be used in neonates and infants.1,774

Midazolam is contraindicated in patients with known hypersensitivity to the drug.1,219,773,774 Midazolam oral solution also is contraindicated in patients allergic to cherries or to formulation excipients.219 Benzodiazepines can increase intraocular pressure in patients with glaucoma and some manufacturers state that the drug is contraindicated in patients with acute angle-closure glaucoma, but may be used in patients with open-angle glaucoma if they are receiving appropriate treatment.1,219,773 However, the clinical rationale for this contraindication has been questioned.164,165,166,180,181 The manufacturer of midazolam nasal spray states that patients with open-angle glaucoma may need an ophthalmologic evaluation following treatment with the drug.773

Precautions Specific to the Use of Midazolam for Sedation or Anesthesia

Midazolam should be administered orally or IV only in hospital or ambulatory-care settings, including physicians' or dentists' offices, in which continuous monitoring of respiratory and cardiac function (i.e., pulse oximetry) is possible.1,193,219,236,237 Safety and efficacy of midazolam may vary in patients as functions of the dose administered and clinical status of the patient.1 Midazolam is a potent sedative and requires slow administration and individualized titration of dosage.1 Since the drug is capable of producing several levels of CNS depression—from mild to deep sedation, facilities, age- and size-appropriate equipment for bag/mask/valve ventilation and intubation, drugs, and skilled personnel necessary for ventilation and intubation, administration of oxygen, assisted or controlled respiration, airway management, and cardiovascular support should be immediately available whenever midazolam is administered.1,163,175,193,219 The immediate availability of specific benzodiazepine reversal agent (e.g., flumazenil) is highly recommended when the drug is administered IV or orally.1,219 Pediatric and adult patients undergoing procedures involving the upper airway, such as upper endoscopy or dental care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction.1 The incidence of such adverse events is higher in patients undergoing procedures involving the airway without the protective effect of an endotracheal tube.1 Patients receiving midazolam should be monitored continuously for early signs of underventilation or apnea since hypoxia and/or cardiac arrest can occur unless effective countermeasures are undertaken immediately.1,163,175,193,219 Monitoring of vital signs also should continue during the recovery period.1 Because midazolam can depress respiration and because opiate agonists or other sedatives can potentiate this effect, midazolam should be administered as an induction agent only by individuals who are experienced in the use of general anesthesia and 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 For deeply sedated pediatric patients, a dedicated individual other than the clinician performing the procedure should monitor the patient throughout the procedure.1,219,236,237 In addition, the possibility that the procedure may obscure early recognition of potential complications (e.g., performance of endoscopy in diminished light which can make visual observation of the patient difficult) or may interfere with effective countermeasures (e.g., patient positioning during colonoscopy) should be considered.163,175

Careful monitoring and individualization of dosing are essential when parenteral midazolam is used for sedation or anesthesia; dosage individualization is particularly important in certain patient populations (e.g., geriatric patients, patients with various underlying disease states [e.g., chronic obstructive pulmonary disease, renal failure, congestive heart failure], and patients receiving other CNS depressants).1,163,175

Midazolam should not be administered parenterally to patients with shock or who are comatose or to patients with acute alcohol intoxication and accompanying depression of vital signs.1 Caution should be exercised if midazolam is administered IV to patients with uncompensated acute illnesses, including severe fluid or electrolyte imbalances.1 Sedation guidelines recommend a careful presedation history to determine how a patient's underlying medical condition or concomitant drugs may affect the response to sedation/analgesia, as well as a physical examination including a focused examination of the airway for abnormalities.1 Further recommendations include appropriate presedation fasting.1

There have been limited reports of intra-arterial injection of midazolam; adverse effects have included local reactions as well as isolated reports of seizure activity in which no clear causal relationship was established.1 Precautions against unintended intra-arterial injection should be taken, and drug extravasation should be avoided.1

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

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

Precautions Specific to the Use of Midazolam Nasal Spray

If midazolam nasal spray is used in patients at risk of benzodiazepine-induced respiratory depression, it is recommended that the drug be administered under the supervision of a clinician.773

The possibility of an increased risk of suicidality (suicidal behavior or ideation) should be considered in patients receiving midazolam nasal spray.773 An analysis of suicidality reports from 199 placebo-controlled studies found that patients receiving anticonvulsants for any indication had approximately twice the risk of suicidal behavior or ideation compared with those receiving placebo; the increased risk was observed as early as one week after beginning therapy and continued through 24 weeks.773 Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to be at increased risk for suicidality when compared with those receiving placebo, the relative suicidality risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.773 Clinicians should inform patients, their families, and caregivers of the potential for an increased risk of suicidality with anticonvulsant therapy; all patients currently receiving or beginning therapy with any anticonvulsant should be closely monitored for the emergence or worsening of suicidal thoughts or behavior or depression.773 (See Suicidality under Cautions: CNS Effects, in the Anticonvulsants General Statement 28:12.)

Pediatric Precautions

The safety and efficacy of midazolam oral solution have not been established in pediatric patients younger than 6 months of age.219 Safety and efficacy of midazolam nasal spray have not been established in pediatric patients younger than 12 years of age.773

Unlike adults, the dose of midazolam in pediatric patients is calculated on a mg/kg basis.1 As a group, pediatric patients require a higher parenteral dosage of midazolam on a mg/kg basis than do adults,1 and pediatric patients younger than 6 years of age generally require higher dosages on a mg/kg basis than do older pediatric patients and may require closer monitoring.1 In obese pediatric patients, the drug dose should be calculated on the basis of ideal body weight.1 When midazolam is administered in conjunction with opiates or other sedatives in the pediatric population, the potential for respiratory depression, airway obstruction, or hypoventilation is increased.1 Particular care should be taken to ensure safe ambulation of pediatric patients following sedation with midazolam.1,219 Clinicians who use this drug in pediatric patients should be aware of, and follow, accepted professional guidelines for pediatric sedation appropriate to the situation.1,236,237

Higher-risk pediatric surgical patients may require lower midazolam doses, whether or not concomitant sedating drugs have been administered.219 Pediatric patients with cardiac or respiratory compromise may be unusually sensitive to the respiratory depressant effect of midazolam.219 Pediatric patients undergoing procedures involving the upper airway (e.g., upper endoscopy, dental care) are particularly vulnerable to episodes of desaturation and hypoventilation secondary to partial airway obstruction.219

Because of reduced and/or immature organ function, neonates are vulnerable to profound and/or prolonged adverse respiratory effects of midazolam.1 The drug should not be administered by rapid IV injection in neonates.1 When administered as a rapid (i.e., over less than 2 minutes) IV injection in neonates, the drug has been associated with severe hypotension, particularly when coadministered with fentanyl.1 Likewise, severe hypotension has been observed in neonates receiving midazolam as a continuous infusion who then also received a rapid IV injection of fentanyl.1 Seizures also have been reported in neonates receiving midazolam as a rapid IV injection.1

FDA warns that repeated or prolonged use of general anesthetics and sedation drugs, including midazolam, in children younger than 3 years of age or during the third trimester of pregnancy may affect brain development.750,753 Animal studies in multiple species, including nonhuman primates, have demonstrated that use for longer than 3 hours of anesthetic and sedation drugs that block N -methyl-d-aspartic acid (NMDA) receptors and/or potentiate γ-aminobutyric acid (GABA) activity leads to widespread neuronal and oligodendrocyte cell loss and alterations in synaptic morphology and neurogenesis in the brain, resulting in long-term deficits in cognition and behavior.750,751,752,753 Across animal species, vulnerability to these neurodevelopmental changes occurs during the period of rapid brain growth or synaptogenesis; this period is thought to correlate with the third trimester of pregnancy through the first year of life in humans, but may extend to approximately 3 years of age.750 The clinical relevance of these animal findings to humans is not known.750 While some published evidence suggests that similar deficits in cognition and behavior may occur in children following repeated or prolonged exposure to anesthesia early in life, other studies have found no association between pediatric anesthesia exposure and long-term adverse neurodevelopmental outcomes.750,752 Most studies to date have had substantial limitations, and it is not clear whether the adverse neurodevelopmental outcomes observed in children were related to the drug or to other factors (e.g., surgery, underlying illness).750 There is some clinical evidence that a single, relatively brief exposure to general anesthesia in generally healthy children is unlikely to cause clinically detectable deficits in global cognitive function or serious behavioral disorders;750,751,752 however, further research is needed to fully characterize the effects of exposure to general anesthetics in early life, particularly for prolonged or repeated exposures and in more vulnerable populations (e.g., less healthy children).750 For further information, see Cautions: Pediatric Precautions, in the Benzodiazepines General Statement 28:24.08.

Anesthetic and sedation drugs are an essential component of care for children and pregnant women who require surgery or other procedures that cannot be delayed;750,753 no specific general anesthetic or sedation drug has been shown to be less likely to cause neurocognitive deficits than any other such drug.750 Pending further accumulation of data in humans from well-designed studies, decisions regarding the timing of elective procedures requiring anesthesia should take into consideration both the benefits of the procedure and the potential risks.750 When procedures requiring the use of general anesthetics or sedation drugs are considered for young children or pregnant women, clinicians should discuss with the patient, parent, or caregiver the benefits, risks (including potential risk of adverse neurodevelopmental effects), and appropriate timing and duration of the procedure.750,753 FDA states that procedures that are considered medically necessary should not be delayed or avoided.750,753

Midazolam hydrochloride injections containing benzyl alcohol should not be used in neonates or infants.1,774 Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates.1,224,225,226,227,228,229,230 Toxicity appears to have resulted from administration of large amounts (i.e., 100-400 mg/kg daily) of benzyl alcohol in these neonates.224,225,226,227,228,229,230 Exposure to such excessive amounts of benzyl alcohol has been associated with hypotension and metabolic acidosis in neonates, and an increased incidence of kernicterus, particularly in small, preterm infants.1 There have been reports of death, particularly in preterm infants, associated with exposure to excessive amounts of benzyl alcohol.1 Although use of drugs preserved with benzyl alcohol should be avoided in neonates whenever possible,224,226 the American Academy of Pediatrics (AAP) states that the presence of small amounts of the preservative in a commercially available injection should not proscribe its use when indicated in neonates.224 The amount of benzyl alcohol exposure from drugs usually is considered negligible compared with that from benzyl alcohol-containing flush solutions.1 Administration of high dosages of drugs containing this preservative, including midazolam hydrochloride, must take into account the total amount of benzyl alcohol administered.1 The recommended dosage range of midazolam for preterm and term infants includes amounts of benzyl alcohol well below that associated with toxicity; however, the amount of benzyl alcohol at which toxicity may occur is not known.1 If the patient requires more than the recommended midazolam dosages, or if other benzyl alcohol-containing preparations are to be used in the patient, the clinician must take into account the total daily metabolic load of benzyl alcohol from these sources.1

Geriatric Precautions

Because distribution of midazolam may be altered in geriatric patients and these patients may have decreased hepatic and/or renal function, the manufacturer of midazolam hydrochloride injection recommends that dosage of the drug be selected carefully in this age group.1 IV or IM dosage of midazolam should be reduced in geriatric or debilitated patients, particularly in those 70 years of age and older.1 (See Dosage and Administration: Dosage.) When IV midazolam is used for induction of anesthesia, time to recovery may be delayed in this population.1 In addition, rare fatalities (possibly associated with cardiorespiratory depression) have been reported 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 Cautions: Cardiorespiratory Effects.)

The manufacturer of oral midazolam states that a safe dosing regimen has not been established in geriatric patients and that the drug should not be used in such patients until further information is available.219

Mutagenicity and Carcinogenicity

In vitro and in vivo microbial and mammalian test systems using midazolam have not revealed evidence of mutagenicity.1 No evidence of carcinogenic potential was seen in rats or mice receiving oral midazolam maleate dosages up to 9 mg/kg daily (about 25 times the recommended human dosage) for 24 months.1 However, an increased incidence of liver tumors was observed following oral administration of 80 mg/kg daily for 24 months in female mice,1 and an increased incidence of benign thyroid follicular cell tumors was observed following this dosage in male rats.1 The pathogenesis of induction of these tumors is not known.1 In addition, the relevance of these findings to usual use of midazolam in humans is not known, since these effects occurred after long-term administration of the drug in animals, whereas use in humans usually is short term.1

Pregnancy, Fertility, and Lactation

Pregnancy

An increased risk of congenital malformations associated with the use of benzodiazepines (e.g., chlordiazepoxide, diazepam) during pregnancy has been suggested by several retrospective studies in humans.1,167,168,169,170 Midazolam has been shown to cross the placenta in humans.1,2,31 Reproduction studies in rabbits and rats using IV midazolam in doses up to 1.85 times the human induction dose have not revealed evidence of fetal malformation.1 If the drug is administered during pregnancy, the patient should be informed of the potential hazard to the fetus.1 Use of midazolam injection for obstetric procedures or during labor and delivery is not recommended, since such use has not been evaluated and use of other benzodiazepines during the last weeks of pregnancy has caused CNS depression in the neonate.1

Based on animal data, repeated or prolonged use of general anesthetics and sedation drugs, including midazolam, during the third trimester of pregnancy may result in adverse neurodevelopmental effects in the fetus.750,753 The clinical relevance of these animal findings to humans is not known; the potential risk of adverse neurodevelopmental effects should be considered and discussed with pregnant women undergoing procedures requiring general anesthetics and sedation drugs.750 (See Cautions: Pediatric Precautions.)

Fertility

No evidence of impaired fertility was observed in rats following oral administration of midazolam in doses producing exposures as high as 1.85 times the recommended human IV induction dose of 0.35 mg/kg.1

Women who are pregnant while receiving midazolam nasal spray should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 or [Web].773

Lactation

Midazolam is distributed into milk in humans, and caution should be exercised when midazolam is administered to nursing women.1

Drugs Affecting Hepatic Microsomal Enzymes

Metabolism of midazolam is mediated by cytochrome P-450 (CYP) isoenzyme 3A4.1,219 Concomitant use of midazolam and drugs that inhibit CYP3A4 (e.g., erythromycin, diltiazem, verapamil, ketoconazole, fluconazole, itraconazole, HIV protease inhibitors) may result in clinically important increases in peak plasma concentrations and area under the plasma concentration-time curve (AUC) of midazolam; conversely, concomitant use of midazolam with drugs that induce CYP3A4 (e.g., rifampin, carbamazepine, phenytoin, phenobarbital) may result in clinically important decreases in peak plasma concentrations and AUC of midazolam.219,231,232,233,249 Caution should be observed if midazolam is administered concomitantly with these drugs and dosage adjustments may be necessary.1,219,232,233 The manufacturer states that oral midazolam should be used concomitantly with ketoconazole, itraconazole, or saquinavir only when absolutely necessary and with appropriate equipment and personnel available to respond to respiratory insufficiency.219

Manufacturers of HIV protease inhibitors and the nonnucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine and efavirenz state that concomitant use of midazolam with these antiretroviral agents is contraindicated;238,240,241,242,243,244,245,246,247,248 however, some experts state that a single midazolam dose can be used with caution for procedural sedation in monitored situations in patients receiving these antiretroviral agents.249

Commonly Used Drugs During Anesthesia or Surgery

Concomitant use of IV midazolam and IV fentanyl has resulted in severe hypotension in neonates.1 No adverse interactions have been observed when midazolam was administered concomitantly with other common premedications or drugs used during anesthesia or surgery (e.g., atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, succinylcholine, nondepolarizing neuromuscular blocking agents, topical local anesthetics).1

Anesthetic Agents

Patients who have received midazolam as an induction agent may require reduced amounts of inhalation agents during maintenance of anesthesia.1,2,70,141

The cardiovascular stimulatory effects and the postoperative emergence delirium usually associated with administration of ketamine appear to be antagonized, at least partially, by midazolam.4,104,134

Anticonvulsants

Concomitant administration of oral midazolam and phenytoin or carbamazepine has been shown to decrease peak plasma concentrations and AUC of midazolam by about 93-94%.219 Although not studied specifically, phenobarbital would be expected to have similar effects on the pharmacokinetics of midazolam.219

Antifungal Agents

Concomitant administration of oral midazolam in patients receiving ketoconazole or itraconazole has been shown to increase peak plasma concentrations of midazolam (by 309% or 80-240%, respectively) as a result of decreased plasma clearance.219 Because of the potential for intense and prolonged sedation and respiratory depression, midazolam oral solution should be coadministered with these drugs only if absolutely necessary and with appropriate equipment and personnel available to respond to respiratory insufficiency.219

While fluconazole has been shown to increase peak plasma concentrations of midazolam by 150%, terbinafine does not appear to affect the pharmacokinetics of midazolam.219

Antimycobacterial Agents

Concomitant administration of oral midazolam and rifampin has been shown to decrease the peak plasma concentration of midazolam by 94% and the AUC of midazolam by 96%.219 Although not studied specifically, rifabutin would be expected to have similar effects on the pharmacokinetics of midazolam.219

Antiretroviral Agents

Large increases in peak plasma concentrations and AUC of midazolam (by about 235 and 514%, respectively) have been observed when saquinavir (1.2 g 3 times daily given as liquid-filled capsules [no longer commercially available in the US]) was administered concomitantly with oral midazolam.219,238 In one study, concomitant use of saquinavir (1.2 g 3 times daily for 5 days) with a single 0.05-mg/kg IV dose of midazolam decreased the clearance of midazolam by 56% and approximately doubled the half-life of the benzodiazepine.1 Because of the potential for intense and prolonged sedation and respiratory depression, the manufacturers of HIV protease inhibitors (e.g., atazanavir fosamprenavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, tipranavir) state that concomitant use of midazolam with HIV protease inhibitors is contraindicated.238,240,241,242,243,244,245,246 However, some experts state that a single midazolam dose can be used with caution for procedural sedation in a monitored situation in patients receiving HIV protease inhibitors.249

The manufacturers of delavirdine and efavirenz state that concomitant use of these agents with midazolam should be avoided because of the potential for the NNRTI to decrease metabolism of midazolam and result in intense or prolonged sedation or respiratory depression.247,248 However, some clinicians state that a single midazolam dose can be used with caution for procedural sedation in a monitored situation in patients receiving delavirdine or efavirenz.249

Calcium-channel Blockers

Concomitant administration of oral midazolam and diltiazem or verapamil increased peak plasma concentrations of midazolam by 105 or 97%, respectively, and increased AUC of midazolam by 275 or 192%, respectively.219,231,233 In another study, half-life of midazolam was increased from 5 to 7 hours when the drug was administered in conjunction with diltiazem or verapamil.1,231,232

Nifedipine does not appear to alter the pharmacokinetics of midazolam.1

CNS Depressants

Midazolam may potentiate the action of other CNS depressants, including opiate agonists or other analgesics, barbiturates or other sedatives, anesthetics, or alcohol, possibly resulting in respiratory depression and profound and/or prolonged underventilation or apnea.1,4,14,163,175,189,190,219 When midazolam is used concomitantly with a depressant drug, caution should be exercised and appropriate dosage adjustments should be made to avoid overdosage.1,4,14 (See Cautions: Precautions and Contraindications.)

The sedative effect of IV midazolam is potentiated by premedication with CNS depressants, especially opiates, barbiturates, or combined fentanyl and droperidol.1,163 Midazolam dosage should be adjusted according to the type and amount of premedication administered.1,163 (See Dosage and Administration: Dosage.)

Opiate Agonists and Opiate Partial Agonists

Concomitant use of benzodiazepines, including midazolam, and opiate agonists or opiate partial agonists may result in profound sedation, respiratory depression, coma, and death.700,701,704,773,774 Opiate agonists can impair the ventilatory response to carbon dioxide (CO₂),1,163,189 and appear to increase the risk of hypotension and prolong the recovery period compared with midazolam alone.1,2,139 Severe hypotension, possibly secondary to increased venous pooling, has occurred when midazolam was used concomitantly with high-dose fentanyl.4,14,112 When concomitant therapy is required, the lowest effective dosages and shortest possible duration of concomitant therapy should be used, and the patient should be monitored closely for respiratory depression and sedation.700,703,773,774 Opiate antitussive agents should be avoided in patients receiving benzodiazepines,700,704 and concomitant use of opiate analgesics and benzodiazepines should be reserved for patients in whom alternative treatment options are inadequate.700,703 For further information on potential interactions between benzodiazepines and opiates, see Opiate Agonists and Opiate Partial Agonists under Drug Interactions: CNS Agents, in the Benzodiazepines General Statement 28:24.08.

Grapefruit Juice

Concomitant administration of grapefruit juice with oral midazolam196,197 has been reported to increase bioavailability of the drug.196,197,219 Grapefruit juice does not appear to interfere with metabolism following IV administration of the drug.197,203 The interaction between grapefruit juice and the benzodiazepine bioavailability appears to result from inhibition, probably prehepatic,196,200,201,202,203,204,205,206,207,208 of the cytochrome P-450 enzyme system by some constituent(s) in the juice.197,198,199,200,201,202,203,204,205,206,207,208,210,211,212,213,214,215 Following oral administration of midazolam, such prehepatic inhibition of drug metabolism by grapefruit juice appears mainly to involve the CYP3A4 isoenzyme, principally within the small intestinal wall (e.g., in the jejunum), thus increasing systemic availability of these drugs.196,197,198,203 (See Grapefruit Juice under Drug Interactions: Drugs and Foods Affecting Hepatic Microsomal Enzymes, in Cyclosporine 90:28.28.92). The manufacturer states that oral midazolam should not be taken in conjunction with grapefruit juice.219

Histamine H2-Receptor Antagonists

The effects of concomitant administration of midazolam and cimetidine or ranitidine have not been fully elucidated.143,151,160,161,162 Orally administered cimetidine or ranitidine did not substantially alter the pharmacokinetics of either IV or oral midazolam in one study in healthy adults.151 However, in another study, plasma midazolam concentrations were increased by about 30% following oral administration of cimetidine, but not ranitidine, in healthy adults receiving midazolam IV.143 Oral bioavailability of midazolam may be increased by up to about 30% when cimetidine or ranitidine is given concomitantly,160,161 possibly secondary to a pH-dependent enhancement of gastric absorption of midazolam160 and/or a reduction in hepatic clearance of the drug.143,161 In another study, concomitant administration of oral midazolam and cimetidine (800-1200 mg up to 4 times daily) increased peak plasma concentrations and AUC of midazolam by 6-138 and 10-102%, respectively; and concomitant administration of oral midazolam and ranitidine (150 mg 2 or 3 times daily or 300 mg once daily) increased peak plasma concentrations and AUC of midazolam by 15-67 and 9-66%, respectively.219 If changes in the pharmacokinetics of midazolam occur during concomitant use with one of these histamine H₂-receptor antagonists, enhanced pharmacologic effects of midazolam may result.160,161,162 Pending further accumulation of data, patients receiving midazolam and cimetidine or ranitidine concomitantly should be observed carefully for signs of midazolam-induced CNS and respiratory depression, and dosage of midazolam reduced if necessary.160,161,162

Macrolide Antibiotics

Concomitant administration of midazolam and erythromycin may affect the pharmacokinetics of midazolam.1,216,218,219 In one study, concomitant use of erythromycin (500 mg 3 times daily for 1 week) with a single 0.05-mg/kg IV dose of midazolam doubled the half-life of midazolam and reportedly decreased clearance of the benzodiazepine.195 In another study in healthy individuals, pretreatment with erythromycin (500 mg 3 times daily for 6 days) reportedly increased peak plasma concentrations and AUC of oral midazolam following a single 15-mg oral dose of the benzodiazepine.195,216,218 Because increased plasma concentrations of midazolam may be associated with excessive sedative effects,195,216 some clinicians state that erythromycin should not be given to patients receiving midazolam, or alternatively, the dose of midazolam should be reduced in patients receiving the anti-infective.195

While erythromycin has been shown to increase peak plasma concentrations and AUC of oral midazolam by about 170 and 281-341%, respectively, azithromycin does not appear to affect the pharmacokinetics of midazolam.219

Neuromuscular Blocking Agents

Midazolam and pancuronium have been used concomitantly in adults without any clinically important changes in dosage, onset, or duration.1 Midazolam does not cause a clinically important change in dosage, onset, or duration of a single intubating dose of succinylcholine.1

Quinupristin and Dalfopristin

Concomitant use of midazolam and quinupristin/dalfopristin may affect the pharmacokinetics of midazolam.234 In healthy individuals, concomitant administration of a single IV dose of midazolam with IV quinupristin/dalfopristin increased mean peak plasma concentrations and AUC of midazolam by 14 and 33%, respectively.234

Acute Toxicity

Pathogenesis

Limited information is available on the acute toxicity of midazolam in humans.1 The IV and oral LD₅₀s of midazolam have been reported to be about 86 and 760 mg/kg, respectively, in mice.5,6

Manifestation and Treatment

Overdosage of midazolam hydrochloride is likely to produce symptoms that are mainly extensions of the usual pharmacologic effects of benzodiazepines, such as sedation, somnolence, confusion, impaired coordination, diminished reflexes, coma, and alterations in vital signs.1 The manufacturer states that organ toxicity specific to midazolam overdosage would not be expected.1 Flumazenil, a benzodiazepine antagonist, can be used to completely or partially reverse midazolam-induced sedation when the drug is used for induction or maintenance of anesthesia or for diagnostic or therapeutic procedures.1 Flumazenil also can be used as an adjunct to symptomatic and supportive care in the management of midazolam overdosage.1 (See Flumazenil 28:92.)

The value of peritoneal dialysis, hemodialysis, forced diuresis, and/or hemoperfusion in the management of midazolam overdosage is not known.1 For further information on the clinical manifestations and management of midazolam toxicity, .

Pharmacology

Midazolam shares the actions of other benzodiazepines.2,4,5,6,7 Although initial data indicated that the sedative potency of midazolam was about 1.5-2.5 times that of diazepam,2,7,46,68,86,87,90,96,98,130,182,185,186,187 clinical experience with the drug suggests that potency may be 3-4 times that of diazepam.1,14,180,182,193

For further information on the pharmacology of midazolam hydrochloride, see Acute Toxicity in the Benzodiazepines General Statement 28:24.08..

Pharmacokinetics

In studies described in the Pharmacokinetics section, midazolam was administered as the hydrochloride, maleate, or lactate salt; dosages and concentrations of the drug are expressed in terms of midazolam. Studies demonstrate that the pharmacokinetic properties of midazolam following administration of a single parenteral dose in pediatric patients aged 1 year and older are similar to those reported in adults.1

Absorption

Absorption of midazolam hydrochloride from IM injection sites is rapid1,4,5,6,8,9,10,11,12,13,14,15,16 and nearly complete (mean absolute bioavailability is greater than 90%).1,4,8,9 IM bioavailability of the lactate appears to be similar to180 or slightly less than that of the hydrochloride;8 however, any such difference does not appear to be clinically important.8,9,180 Pharmacologic effects of midazolam usually are apparent within 5-15 minutes1,4,9,14,32,81 but may not be maximal until 15-60 minutes following IM administration;1,2,4,8,9,10,11,12,13,15,16,81 the duration of action usually is about 2 hours1 (range: 1-6 hours).1,8,9,10,14 Peak plasma midazolam concentrations generally are attained within 30-45 minutes following IM administration.1,8,774 Following IM administration of a single 12.5-mg (of midazolam) dose of the hydrochloride in healthy adults, peak plasma midazolam concentrations of approximately 200 ng/mL (range: 88-269 ng/mL) are attained.8 Peak plasma concentrations of midazolam and 1-hydroxymethylmidazolam (an active metabolite) attained following IM injection are approximately 50% of those attained following IV injection of a dose.1

Following IV administration of usual doses of midazolam hydrochloride, the onset of sedative, anxiolytic, and amnesic action usually occurs within 1-5 minutes.1,2,4,7,9,13,21,25,26,86,87 However, onset is affected by many factors, including total dose administered,1,2 rate of administration,181 patient age,30 serum albumin concentration,31 renal function,2 and the presence of other drugs.1,2 Induction of anesthesia usually occurs in about 1.5 minutes when opiate agonists are administered concurrently with midazolam and in 2-2.5 minutes when midazolam is administered without an opiate agonist or concurrently with other sedatives.1,2,27,28 Duration of action following IV administration is usually less than 2 hours;1,4,7,8,9,21,29 however, the pharmacologic effects may persist up to 6 hours in some patients, and the duration of action appears to be dose related.1,8,9,20,29 Limited data suggest that the onset may be more rapid31,33 and the duration prolonged in patients with chronic renal failure,33,34 probably secondary to decreased protein binding in these patients.4,31,33,34,70

In one study in healthy adults who received a single 75-mcg/kg dose of midazolam IV over 1 minute, peak plasma concentrations of the drug averaged 323.8 ng/mL and plasma concentrations 0.25, 0.5, 1, 2, 4, 6, and 8 hours after the dose averaged 246.8, 206.8, 141.7, 84.2, 37.0, and 20.2 ng/mL, respectively.22 Following single IV doses, plasma concentrations of midazolam generally are 10-30 times higher than those of the principal metabolite, 1-hydroxymethylmidazolam.1

Following intranasal administration of a single 5-mg dose of midazolam in healthy adults, peak plasma concentrations were obtained in approximately 17 minutes.773 Absolute bioavailability is approximately 44%.773 The onset of sedative and psychomotor impairment effects usually occurs within 10 minutes, while maximal effects are achieved within 30 minutes to 2 hours after a dose is administered.773

Midazolam hydrochloride is absorbed rapidly from the GI tract,2,4,7,18,19,20,21,22,23,219 with maximum plasma concentrations usually occurring within 1-2 hours.2,4,7,18,19,20,21,22,23,24,219 Following oral administration, the drug undergoes substantial first-pass metabolism in the liver and intestine,2,7,18,22,24,35,219 with only about 40-50% (range: 28-72%) of an orally administered dose reaching systemic circulation unchanged.2,4,7,18,19,20,21,22,24 Pharmacologic effects of midazolam usually are apparent within 10-20 minutes following administration of midazolam oral solution in pediatric patients.219 In pharmacokinetic studies of pediatric patients (6 months to less than 16 years of age) receiving midazolam oral solution at doses of 250 mcg/kg, 500 mcg/kg, or 1 mg/kg, midazolam exhibited linear pharmacokinetics.219 The mean time to maximal plasma concentration in these patients ranged from 0.17-2.65 hours, and the absolute bioavailability of the drug was about 36%; bioavailability was not affected by pediatric age or weight.219 The effect of food on absorption of midazolam oral solution has not been studied; however, in adults receiving the drug as a 15-mg oral tablet, absorption was not affected by food.219

A relationship between plasma midazolam concentrations and clinical effects has not been clearly established,4,7,8,20,29,32 and the manufacturer states that a direct relationship does not exist.1 However, some data suggest that sedation may be associated with plasma midazolam concentrations greater than 30-100 ng/mL.4,8,20,29,32 In one study, pronounced hypnotic effects (e.g., slurred speech, sleep with dreaming, nystagmus) were noted when plasma concentrations exceeded 100 ng/mL.7,20

Distribution

At physiologic pH, midazolam is highly lipophilic;2,4,5,7,14,18,20,21,24,36,37 however, the lipophilicity of the drug decreases with decreasing pH.2,4,5,7,17 (See Chemistry and Stability: Chemistry.) Following IV administration in humans, midazolam is rapidly and apparently widely distributed.1,2,4,24,35,36,37,38 The apparent volume of distribution of the drug in healthy adults reportedly averages 0.8-2.5 L/kg (range: 0.6-6.6 L/kg).1,2,7,18,19,20,21,22,24,35,36 Volume of distribution of midazolam appears to be 1.5-2 times higher in adults with chronic renal failure1,7,35,42,163 and 2-3 times higher in adults with congestive heart failure1,35,50,163 compared with healthy adults. In pediatric patients (6 months to younger than 16 years of age) receiving IV midazolam 0.15 mg/kg, the mean steady-state volume of distribution ranged from 1.24-2.02 L/kg.219

Following IV administration of midazolam hydrochloride in animals, the drug is widely distributed, with highest concentrations occurring in liver, kidneys, lungs, fat, and heart.180 The drug crosses the blood-brain barrier and distributes into CSF in humans7,14,15,16 and animals.1,39,40 In animals, equilibration of midazolam between plasma and CSF occurs within a few minutes following IV administration,2,40 and CSF:plasma ratios of the drug are highly correlated with unbound midazolam once equilibrium is reached.39,40 Distribution of the drug into human lumbar CSF may be slow and erratic.1,16 Distribution of midazolam may be altered in geriatric patients.219

In both adult and pediatric patients older than 1 year of age, approximately 94-97% of midazolam hydrochloride is bound to plasma proteins,1,2,7,18,20,24,31,36,37,41,42,45,219 mainly to serum albumin; protein binding of the drug is decreased in patients with chronic renal failure.2,4,7,34,37,42 In healthy individuals, the drug's principal metabolite, 1-hydroxymethylmidazolam, is 89% protein bound.219 The degree of protein binding appears to be independent of the plasma concentration of the drug.2,24,41,219

Midazolam crosses the placenta and is distributed into amniotic fluid in animals and humans;1,2,7,23,35,43 however, placental transfer of drug appears to occur more slowly than with diazepam.7,23,35 In humans, measurable midazolam concentrations were achieved in maternal venous serum, umbilical venous serum, umbilical arterial serum, and amniotic fluid following a single 15-mg (of midazolam) oral or 50-mcg/kg (of midazolam) IM dose of the maleate given 15-60 minutes prior to cesarean section;1,23 both umbilical venous and umbilical arterial midazolam concentrations were lower than maternal concentrations.23 Midazolam reportedly is distributed into milk in humans.1 (See Cautions: Pregnancy, Fertility, and Lactation.)

Elimination

Plasma midazolam concentrations appear to decline in a biphasic manner following IV administration.2,20,22,24 Following a single IV dose in healthy adults, the half-life of midazolam in the initial distribution phase (t_½α) averages 6-20 minutes,2,4,18,19,20,56 and the half-life in the terminal elimination phase (t_½β) averages 1-4 hours (range: 1-12.3 hours).1,2,4,7,13,14,19,20,21,22,24,34,35,36,37,38,44,45,46,47,149 Limited data suggest that the half-life of midazolam may be prolonged in obese patients (presumably secondary to an increased volume of distribution),2,4,7,18,24,37,51 geriatric individuals,2,7,18,24,37,49,51,52 and patients with impaired hepatic function48,219 or with congestive heart failure.1,35,50,219 The half-life of midazolam is also reportedly prolonged in patients receiving the drug for induction of anesthesia associated with major surgical procedures.7,52 Elimination half-life does not appear to be altered substantially in patients with chronic renal failure.2,42,180,219 Mean elimination half-life ranged from 2.2-6.8 hours following single oral doses of 250 mcg/kg, 500 mcg/kg, and 1 mg/kg of midazolam oral solution in pediatric patients (6 months to younger than 16 years of age).219 Mean elimination half-life ranged from 2.9-4.5 hours in pediatric patients (6 months to less than 16 years of age) receiving IV midazolam 150 mcg/kg.219 In seriously ill neonates, the terminal elimination half-life is substantially prolonged (i.e., 6.5-12 hours).1 Following IM administration of midazolam 10 mg, elimination half-life of the drug was approximately 4 hours.774 Following intranasal administration of midazolam nasal spray, elimination half-life of the drug ranged from 2.1 to 6.2 hours.773

Midazolam is metabolized extensively in the liver and intestine by cytochrome P-450 CYP3A4.1,7,21,24,54,55,219 The drug rapidly undergoes hydroxylation via hepatic microsomal enzymes to form 1-hydroxymethylmidazolam (α-hydroxymidazolam), the principal metabolite, and 4-hydroxymidazolam; a small portion of 1-hydroxymethylmidazolam is further hydroxylated to 1-hydroxymethyl-4-hydroxymidazolam (α,4-dihydroxymidazolam).1,2,4,5,7,17,24,54,55,57,58,136 These metabolites undergo rapid conjugation with glucuronic acid in the liver.1,2,4,7,17,24,54,55,58 Although the elimination half-life of the principal metabolite, 1-hydroxymethylmidazolam, is not clearly established, it is estimated to be about 60-80 minutes.1,4,7,22 The 1-hydroxymethyl and 4-hydroxy metabolites are reportedly pharmacologically active; potency of 1-hydroxymethylmidazolam appears to be similar to that of midazolam.1,219 The 1-hydroxymethyl-4-hydroxy metabolite appears to have little, if any, pharmacologic activity.5

Midazolam is excreted in urine almost entirely as conjugated metabolites.1,2,4,7,17,24,54,55,58 Approximately 45-57% of an IV dose is excreted in urine as conjugated 1-hydroxymethylmidazolam,1,54 small amounts as conjugates of 4-hydroxymidazolam and 1-hydroxymethyl-4-hydroxymidazolam,54 and less than 0.03% as unchanged drug.1,4,7,21,37 In healthy adults who received a single 10-mg oral dose of radiolabeled midazolam, about 90% of the radioactivity was excreted in urine within 24 hours,4,55 principally (about 60-70% of a dose) as conjugated 1-hydroxymethylmidazolam.55 Approximately 2-10% of an oral dose is excreted in feces.4,55

It is not known whether midazolam is removed by hemodialysis or peritoneal dialysis.1

Following IV administration in healthy individuals and pediatric patients, total apparent plasma clearance of midazolam averages 2.5-12.8 mL/minute per kg.1,2,7,8,13,18,19,20,21,22,38,48,219 In seriously ill neonates, the clearance is reduced to 0.07-0.12 L/hr per kg; it cannot be determined whether these differences are because of age, immature organ function or metabolism, underlying illness, or debility.1 Total apparent plasma clearance of the drug reportedly is decreased in geriatric individuals but, in one study, such clearance was decreased substantially only in geriatric males.2,4,7,18,24,37,51 Total plasma clearance and volume of distribution of total (bound and unbound) midazolam are 1.5-2 times higher in patients with chronic renal failure compared with individuals with normal renal function,1,2,7,42 but these alterations are attributable to changes in protein binding of the drug and are not apparent when these pharmacokinetic parameters are determined for unbound midazolam.2,7,42 Although the effects of hepatic impairment on the elimination of midazolam have not been fully evaluated, preliminary data suggest that total apparent plasma clearance of the drug may be decreased in some patients with chronic liver disease.48 In a limited number of patients with congestive heart failure, total body clearance of midazolam appeared to remain unchanged following a single 5-mg IV dose, although elimination half-life and volume of distribution were increased twofold to threefold.1,35,50,163

Chemistry and Stability

Chemistry

Midazolam is a benzodiazepine.1,2,4,5,6,7,17 The drug is an imidazobenzodiazepine, differing structurally from other benzodiazepines by the presence of an imidazole ring fused at positions 1 and 2 of the benzodiazepine nucleus, which replaces the ketone at position 2 of the nucleus.2,4,5,6,7,17 The imidazole ring results in the ability of midazolam to readily form salts, which have increased aqueous solubility and stability to hydrolysis compared with other benzodiazepines.2,4,5,6,7,17,183 Presence of a methyl group at position 1 of the imidazole ring may result in increased susceptibility to metabolism.2,4,5,6,7,17 In acidic solutions, such as in the commercially available oral solution (pH 2.8-3.6) or parenteral injections (pH 3-4 in the 1 mg/mL solutions and pH 3-3.6 in the 5 mg/mL solutions), a pH-dependent equilibrium exists between midazolam and a ring-opened structure (the corresponding benzophenone) at position 4 of the benzodiazepine nucleus, resulting in up to 40 or 25% ring-opened forms for the oral solution or parenteral injections, respectively.1,2,5,7,17,182,219 At physiologic pH (5-8), under which midazolam is absorbed into the systemic circulation, the drug is almost (at least 99%) completely ring-closed, resulting in increased lipophilicity.1,2,4,5,7,17,182,219

Midazolam occurs as a white to light yellow, crystalline powder.1,180,580 Midazolam is commercially available as the hydrochloride salt, which is formed in situ .1,180,219,580 The aqueous solubility of midazolam hydrochloride is pH dependent; the drug has solubilities of approximately 0.24, 1.09, 3.67, 10.3, or greater than 22 mg (of midazolam) per mL in water at pH 6.2, 5.1, 3.8, 3.4, or 2.8, respectively, at 25°C.180 Midazolam has a pK_a of 6.15.2,17,180 Midazolam also is commercially available as a solution for intranasal administration.773

Midazolam hydrochloride injection is commercially available as a sterile solution for IM or IV administration.1 Hydrochloric acid and, if necessary, sodium hydroxide are added during manufacture of the injection to adjust the pH to about 3.1,156 The injection also contains disodium edetate and sodium chloride; some preparations also may contain benzyl alcohol.1,156 Commercially available midazolam hydrochloride oral solution is a red to purplish-red colored solution containing 2 mg/mL of the drug in a cherry-flavored vehicle.219 The pH of the oral solution has been adjusted to approximately 2.8-3.6 with hydrochloric acid.219 Commercially available midazolam nasal spray is a clear, colorless to yellowish colored solution; each 0.1 mL of solution contains 5 mg of midazolam.773

Stability

Midazolam hydrochloride injection should be stored at 20-25°C, but may be exposed to temperatures ranging from 15-30°C.1,774 The injection was physically stable when frozen for 3-day periods and allowed to thaw at room temperature.180 Preservative-free midazolam hydrochloride injection should be stored at 20-25°C.580 Midazolam oral solution should be stored at 20-25°C.219 Midazolam nasal spray should be stored at 20-25°C, but may be exposed to temperatures ranging from 15-30°C.773

Midazolam hydrochloride injection is chemically and physically compatible with the following IV solutions: 5% dextrose, 0.9% sodium chloride, or lactated Ringer's.1,2,156 Midazolam hydrochloride injection that has been diluted to a final concentration of 0.5 mg or less per mL is stable for 24 hours in 5% dextrose or 0.9% sodium chloride injection and for 4 hours in lactated Ringer's injection when stored in glass or PVC containers at 25°C.156,180 When diluted and stored as recommended, it is not necessary to protect these solutions from light.180

When admixed in the same syringe at room temperature, midazolam hydrochloride injection is reported to be physically compatible for at least 30 minutes with atropine sulfate,1,2,156 meperidine hydrochloride,1,156 morphine sulfate,1,2,156 or scopolamine hydrobromide,1,2,156 and for at least 8 hours with fentanyl citrate, glycopyrrolate, hydroxyzine hydrochloride, ketamine hydrochloride, nalbuphine hydrochloride, promethazine hydrochloride, or sufentanil citrate.156 Since the compatibility of these and other admixtures with midazolam hydrochloride injection depends on several factors (e.g., concentrations of the drugs, specific diluents used, resulting pH, temperature), specialized references should be consulted for specific information.

Additional Information

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

1. West-ward Pharmaceuticals. Midazolam hydrochloride injection prescribing information. Eatontown, NJ; 2017 Apr.

2. Reves JG, Fragen RJ, Vinik HR et al. Midazolam: pharmacology and uses. Anesthesiology . 1985; 62:310-24. [PubMed 3156545]

4. Kanto JH. Midazolam: the first water-soluble benzodiazepine: pharmacology, pharmacokinetics and efficacy in insomnia and anesthesia. Pharmacotherapy . 1985; 5:138-55. [PubMed 3161005]

5. Pieri L, Schaffner R, Scherschlicht R et al. Pharmacology of midazolam. Arzneimittelforschung . 1981; 31:2180-201. [PubMed 6120698]

6. Pieri L. Preclinical pharmacology of midazolam. Br J Clin Pharmacol . 1983; 16(Suppl 1):17-27. [PubMed 6349668]

7. Dundee JW, Halliday NJ, Harper KW et al. Midazolam: a review of its pharmacological properties and therapeutic use. Drugs . 1984; 28:519-43. [PubMed 6394264]

8. Crevoisier C, Eckert M, Heizmann P et al. Relation entre l'effet clinique et la pharmacocinétique du midazolam après administration i.v. et i.m. (French; with English abstract.) Arzneim-Forsch . 1981; 31:2211-5.

9. Ziegler WH, Thurneysen JD, Crevoisier C et al. Relation entre l'effet clinique et la pharmacocinétique du midazolam après administration i.m. et i.v. chez des voluntaires. (French; with English abstract.) Arzneim-Forsch . 1981; 31:2206-10.

10. Fragen RJ, Funk DI, Avram MJ et al. Midazolam versus hydroxyzine as intramuscular premedicant. Can Anaesth Soc J . 1983; 30:136-41. [PubMed 6831292]

11. Reves JG, Vinik HR, Wright D. Midazolam efficacy for intramuscular premedication: a double-blind placebo, hydroxyzine, controlled study. Anesthesiology . 1982; 57:A321.

12. Grote B, Doenicke A, Kugler J et al. Intramuskulare Applikation von Midazolam. (German; with English abstract.) Arzneim-Forsch . 1981; 31:2224-5.

13. Amrein R, Cano JP, Eckert M et al. Pharmakokinetik von Midazolam nach intravenöser Verabreichung. (German; with English abstract.) Arzneim-Forsch . 1981; 31:2202-5.

14. Anon. Midazolam. Med Lett Drugs Ther . 1986; 28:73-4. [PubMed 2942752]

15. Heinemeyer G, Reinhart K, Nigam S et al. Correlation of sedative and respiratory effects of midazolam with concentrations on serum and liquor cerebrospinalis. Naunyn-Schmeideberg's Arch Pharmacol . 1982; 321(Suppl):R58.

16. Sjövall S, Kanto J, Himberg JJ et al. CSF penetration and pharmacokinetics of midazolam. Eur J Clin Pharmacol . 1983; 25:247-51. [PubMed 6628509]

17. Gerecke M. Chemical structure and properties of midazolam compared with other benzodiazepines. Br J Clin Pharmacol . 1983 16:11-6S.

18. Greenblatt DJ, Abernethy DR, Locniskar A et al. Effect of age, gender, and obesity on midazolam kinetics. Anesthesiology . 1984; 61:27-35. [PubMed 6742481]

19. Klotz U, Ziegler G. Physiologic and temporal variation in hepatic elimination of midazolam. Clin Pharmacol Ther . 1982; 32:107-12. [PubMed 7083724]

20. Allonen H, Ziegler G, Klotz U. Midazolam kinetics. Clin Pharmacol Ther . 1981; 30:653-61. [PubMed 6117393]

21. Smith MT, Eadie MJ, Brophy TO. The pharmacokinetics of midazolam in man. Eur J Clin Pharmacol . 1981; 19:271-8. [PubMed 6116606]

22. Heizmann P, Eckert M, Ziegler WH. Pharmacokinetics and bioavailability of midazolam in man. Br J Clin Pharmacol . 1983; 16:43-9S.

23. Kanto J, Sjövall S, Erkkola R et al. Placental transfer and maternal midazolam kinetics. Clin Pharmacol Ther . 1983; 33:786-91. [PubMed 6851409]

24. Greenblatt DJ, Abernethy DR. Midazolam pharmacology and pharmacokinetics. Anesthesiol Rev . 1985; 12(Suppl):17-20.

25. Conner JT, Katz RL, Pagano RR et al. RO 21-3981 for intravenous surgical premedication and induction of anesthesia. Anesth Analg . 1978; 57:1-5. [PubMed 564624]

26. Dundee JW, Wilson DB. Amnesic action of midazolam. Anaesthesia . 1980; 35:459-61. [PubMed 7396149]

27. Fragen RJ, Caldwell NJ. Awakening characteristics following anesthesia induction with midazolam for short surgical procedures. Arzneimittelforschung . 1981; 31:2261-3. [PubMed 7199331]

28. Finucane BT, Judelman J, Braswell R. Comparison of thiopentone and midazolam for induction of anaesthesia: influence on diazepam premedication. Can Anaesth Soc J . 1982; 29:227-30. [PubMed 7074402]

29. Crevoisier C, Ziegler WH, Eckert M et al. Relationship between plasma concentration and effect of midazolam after oral and intravenous administration. Br J Clin Pharmacol . 1983; 16:51-61S.

30. Dundee JW, Halliday NJ, Loughran PG. Variation in response to midazolam. Br J Clin Pharmacol . 1984; 17:645-6P.

31. Reves JG, Newfield P, Smith LR. Midazolam induction time association with serum albumin. Anesthesiology . 1981; 55:A259.

32. Mattila MAK, Suurinkeroinen S, Saila K et al. Midazolam and fat-emulsion diazepam as intramuscular premedication: a double-blind clinical trial. Acta Anaesthesiol Scand . 1983; 27:345-8. [PubMed 6356756]

33. Vinik R, Reves JG, Nixon D et al. Midazolam induction and emergence in renal failure patients. Anesthesiology . 1981; 55:A262.

34. Vinik HR, Reves JG, Greenblatt DJ et al. Pharmacokinetics of midazolam in renal failure patients. Anesthesiology . 1982; 57(Suppl):A366.

35. Weintraub M, Evans P. Midazolam: a water-soluble benzodiazepine for preoperative sedation and endoscopic procedures. Hosp Formul . 1986; 21:647-64.

36. Greenblatt DJ, Divoll M, Abernethy DR et al. Clinical pharmacokinetics of the newer benzodiazepines. Clin Pharmacokinet . 1983; 8:233-52. [PubMed 6133664]

37. Davis PJ, Cook DR. Clinical pharmacokinetics of the newer intravenous anaesthetic agents. Clin Pharmacokinet . 1986; 11:18-35. [PubMed 3512140]

38. Greenblatt DJ, Locniskar A, Ochs HR et al. Automated gas chromatography for studies of midazolam pharmacokinetics. Anesthesiology . 1981; 55:176-9. [PubMed 6114686]

39. Arendt RM, Greenblatt DJ, deJong RH et al. Benzodiazepine entry into CSF and brain: kinetic, dynamic, and in vitro correlations. Clin Pharmacol Ther . 1983; 33:239.

40. Arendt RM, Greenblatt DJ, deJong RH et al. In vitro correlates of benzodiazepine cerebrospinal fluid uptake, pharmacodynamic action and peripheral distribution. J Pharmacol Exp Ther . 1983; 227:98-106. [PubMed 6137558]

41. Moschitto LJ, Greenblatt DJ. Concentration-independent plasma protein binding of benzodiazepines. J Pharm Pharmacol . 1983; 35:179-80. [PubMed 6132978]

42. Vinik HR, Reves JG, Greenblatt DJ et al. The pharmacokinetics of midazolam in chronic renal failure patients. Anesthesiology . 1983; 59:390-4. [PubMed 6638545]

43. Vree TB, Reekers-Ketting JJ, Fragen RJ et al. Placental transfer of midazolam and its metabolite 1-hydroxymethylmidazolam in the pregnant ewe. Anesth Analg . 1984; 63:31-4. [PubMed 6691561]

44. Carlisle RJT, Dundee JW, Harper KW et al. Prolonged midazolam elimination half-life in a minority of patients. Br J Clin Pharmacol . 1985; 20:534P.

45. Dundee JW, Collier PS, Carlisle RJT et al. Prolonged midazolam elimination half-life. Br J Clin Pharmacol . 1986; 21:425-9. [PubMed 2939863]

46. Dundee JW, Samuel IO, Toner W et al. Midazolam: a water-soluble benzodiazepine. Anaesthesia . 1980; 35:454-8. [PubMed 7396148]

47. Allonen H, Anttila V, Klotz U. Effect kinetics of midazolam: a new hypnotic benzodiazepine derivative. Naunyn-Schmeideberg's Arch Pharmacol . 1981; 316(Suppl):R74.

48. MacGilchrist AJ, Birnie GG, Cook A et al. Pharmacokinetics and pharmacodynamics of intravenous midazolam in patients with severe alcoholic cirrhosis. Gut . 1986; 27:190-5. [PubMed 2936661]

49. Smith MT, Heazlewood V, Eadie MJ et al. Pharmacokinetics of midazolam in the aged. Eur J Clin Pharmacol . 1984; 26:381-8. [PubMed 6734699]

50. Blumenthal P, Werres R, Rothfeld D et al. Clinical and pharmacokinetic observations after premedication of heart failure patients with midazolam. J Clin Pharmacol . 1984; 24:400.

51. Greenblatt DJ, Abernethy DR, Locniskar A et al. Midazolam kinetics in old age and obesity. Clin Pharmacol Ther . 1984; 35:244.

52. Harper KW, Collier PS, Dundee JW et al. Age and nature of operation influence the pharmacokinetics of midazolam. Br J Anaesth . 1984; 56:1288-9P.

53. Lowry KG, Lyons SM, Carson IW et al. Midazolam v diazepam for sedation in a cardiac surgical intensive care unit. Br J Anaesth . 1984; 56:1288P.

54. Puglisi CV, Meyer JC, D'Arconte L et al. Determination of water-soluble imidazo-1,4-benzodiazepines in blood by electron-capture, gas-liquid chromatography and in urine by differential pulse polarography. J Chromatogr . 1978; 145:81-96. [PubMed 23388]

55. Heizmann P, Ziegler WH. Excretion and metabolism of¹⁴C-midazolam in humans following oral dosing. Arzneimittelforschung . 1980; 31:2220-3.

56. Ziegler WH, Schalch E, Leishman B et al. Comparison of the effects of intravenously administered midazolam, triazolam and their hydroxy metabolites. Br J Clin Pharmacol . 1983; 16:63-9S.

57. Rubio F, Miwa BJ, Garland WA. Determination of midazolam and two metabolites of midazolam in human plasma by gas chromatography—negative chemical-ionization mass spectrometry. J Chromatogr . 1982; 233:157-65. [PubMed 7161330]

58. Vree TB, Baars AM, Booij LHD et al. Simultaneous determination and pharmacokinetics of midazolam and its hydroxymetabolites in plasma and urine of man and dog by means of high-performance liquid chromatography. Arzneimittelforschung . 1981; 31:2215-9. [PubMed 7199323]

59. Sjövall S, Kanto J, Iisalo E et al. Use of atropine in connection with oral midazolam premedication. Int J Clin Pharmacol Ther Toxicol . 1984; 22:184-8. [PubMed 6715087]

60. du Cailar J, Holzer J, Jullien Y et al. Hypnotic efficacy of midazolam in pre-surgical patients: a dose-finding study. Br J Clin Pharmacol . 1983; 16(Suppl):129-32S.

61. Klopfenstein C. Midazolam as oral premedication in local anaesthesia. Arzneimittelforschung . 1981; 31:2238.

62. du Cailar J, Cadi N, Jullien Y et al. Etude en double aveugle du midazolam sur le sommeil pre-operatoire. (French; with English abstract.) Arzneim-Forsch . 1981; 31:2239-43.

63. Sjövall S, Kanto J, Iisalo E et al. Midazolam versus atropine plus pethidine as premedication in children. Anaesthesia . 1984; 39:224-8. [PubMed 6703288]

64. Sjövall S, Kanto J, Kangas L et al. Comparison of midazolam and flunitrazepam for night sedation: a randomized double-blind study. Anaesthesia . 1982; 37:924-8. [PubMed 6127040]

65. Sjövall S, Kanto J, Gronroos M et al. Antidiuretic hormone concentrations following midazolam premedication. Anaesthesia . 1983; 38:1217-20. [PubMed 6140883]

66. Fragen RJ. Parenteral premedication with midazolam. Anesthesiology Rev . 1985; 12:(Suppl):37-9.

67. Kanto J. Benzodiazepines as oral premedicants. Br J Anaesth . 1981; 53:1179-88. [PubMed 6119997]

68. Clarke RSJ. New drugs—boon or bane? Premedication and intravenous induction agents. Can Anaesth Soc J . 1983; 30:166-73. [PubMed 6339010]

69. Miller R. Commentary: premedication with intramuscular midazolam. Anesthesiology Rev . 1985; 12(Suppl):47-8.

70. Vinik HR. Midazolam induction and maintenance. Anesthesiology Rev . 1985; 12(Suppl):49-54.

71. Magni VC, Frost RA, Leung JWC et al. A randomized comparison of midazolam and diazepam for sedation in upper gastrointestinal endoscopy. Br J Anaesth . 1983; 55:1095-1101. [PubMed 6139120]

72. Brophy T, Dundee JW, Heazelwood V et al. Midazolam, a water-soluble benzodiazepine, for gastroscopy. Anaesth Intens Care . 1982; 10:344-7.

73. Berggren L, Eriksson I, Mollenholt P et al. Sedation for fibreoptic gastroscopy: a comparative study of midazolam and diazepam. Br J Anaesth . 1983; 55:289-96. [PubMed 6132613]

74. Al-Khudhairi D, McCloy RF, Whitwam JG. Comparison of midazolam and diazepam in sedation during gastroscopy. Gut . 1982; 23:A432-63.

75. Al-Khudhairi D, Whitwam JG, McCloy RF. Midazolam and diazepam for gastroscopy. Anaesthesia . 1982; 37:1002-6. [PubMed 6127968]

76. Kawar P, Dundee JW, Brophy TO et al. Midazolam: an alternative to diazepam as an intravenous hypnotic for endoscopy. Br J Clin Pharmacol . 1984; 17:221-2P.

77. Green JRB, Ravenscroft MM, Swan CHJ. Diazepam or midazolam for endoscopy. BMJ . 1984; 288:1383. [PubMed 6424864]

78. Bardhan KD, Morris P, Taylor PC et al. Intravenous sedation of upper gastrointestinal endoscopy: diazepam versus midazolam. BMJ . 1984; 288:1046. [PubMed 6142752]

79. Whitwam JG, Al-Khudhairi D, McCloy RF. Comparison of midazolam and diazepam in doses of comparable potency during gastroscopy. Br J Anaesth . 1983; 55:773-7. [PubMed 6136290]

80. Dundee JW, Fee JPH. Diazepam and midazolam for sedation during bronchoscopy. Br J Anaesth . 1986; 58:466-9. [PubMed 2937435]

81. Vinik HR, Reves JG, Wright D. Premedication with intramuscular midazolam: a prospective randomized double-blind controlled study. Anesth Analg . 1982; 61:933-7. [PubMed 6753643]

82. Miller R, Eisenkraft JB, Thys DM et al. Comparison of I.M. midazolam with hydroxyzine as preanesthetic medications. Anesthesiology Rev . 1982; 9:15-9.

83. Taylor MB, Vine PR, Hatch DJ. Intramuscular midazolam premedication in small children. Anaesthesia . 1986; 41:21-6. [PubMed 2936269]

84. Greenblatt DJ, Shader RI, Abernethy DR. Current status of benzodiazepines (second of two parts). N Engl J Med . 1983; 309:410-6. [PubMed 6135990]

85. Marty J, Nitenberg A, Blanchet F et al. Effects of midazolam on the coronary circulation in patients with coronary artery disease. Anesthesiology . 1986; 64:206-10. [PubMed 2936281]

86. Dundee JW. New I.V. anaesthetics. Br J Anaesth . 1979; 51:641-8. [PubMed 317793]

87. Reves JG, Corssen G, Holcomb C. Comparison of two benzodiazepines for anaesthesia induction: midazolam and diazepam. Can Anaesth Soc J . 1978; 25:211-4. [PubMed 656993]

88. George KA, Dundee JW. Relative amnesic actions of diazepam, flunitrazepam and lorazepam in man. Br J Clin Pharmacol . 1977; 4:45-50. [PubMed 14658]

89. Weissman BM, Horwitz SJ, Myers CM et al. Midazolam sedation for computerized tomography (CT) in children: pharmacokinetics and pharmacodynamics. Pediatr Res . 1984; 18(Part 2):162A.

90. Shapiro JM, Westphal LM, White PF et al. Midazolam infusion for sedation in the intensive care unit: effect on adrenal function. Anesthesiology . 1986; 64:394-8. [PubMed 3006554]

91. Driessen JJ, Booij LHD, Vree TB et al. Midazolam as a sedative on regional anesthesia: preliminary results. Arzneimittelforschung . 1981; 31:2245-7. [PubMed 7199328]

92. Kothary SP, Brown ACD, Pandit UA et al. Time course of antirecall effect of diazepam and lorazepam following oral administration. Anesthesiology . 1981; 55:641-4. [PubMed 6118078]

93. Belapavloric M, Buckthal A. Modification of ketamine-induced intracranial hypertension in neurosurgical patients by pretreatment with midazolam. Acta Anaesthesiol Scand . 1982; 26:458-62. [PubMed 6128856]

94. Cottrell JE, Giffin JP, Lim K et al. Intracranial pressure, mean arterial pressure and heart rate following midazolam or thiopental in humans with intracranial masses. Anesthesiology . 1982; 57(Suppl):A323.

95. Reves JG, Samuelson PN, Lewis S. Midazolam maleate induction in patients with ischaemic heart disease; haemodynamic observations. Can Anaesth Soc J . 1979; 26:402-9. [PubMed 487235]

96. Samuelson PM, Reves JG, Kouchoukos NT et al. Hemodynamic responses to anesthetic induction with midazolam or diazepam in patients with ischemic heart disease. Anesth Analg . 1981; 60:802-9. [PubMed 7197492]

97. Popoviciu L, Corfariu O. Efficacy and safety of midazolam in the treatment of night terrors in children. Br J Clin Pharmacol . 1983; 16:97-102S.

98. Fragen RJ, Meyers SN, Barresi V et al. Hemodynamic effects of midazolam in cardiac patients. Anesthesiology . 1979; 51:S103.

99. Freuchen IB, Ostergaard J, Mikkelsen BO. Midazolam compared with thiopentone as an induction agent. Curr Ther Res . 1983; 34:269-73.

100. Gamble JAS, Kawar P, Dundee JW et al. Evaluation of midazolam as an intravenous induction agent. Anaesthesia . 1981; 36:868-73. [PubMed 7304889]

101. Berggren L, Eriksson I. Midazolam for induction of anaesthesia in outpatients: a comparison with thiopentone. Acta Anaesthesiol Scand . 1981; 25:492-6. [PubMed 7051729]

102. Forster A, Gardaz JP, Suter PM et al. I.V. midazolam as an induction agent for anaesthesia: a study in volunteers. Br J Anaesth . 1980; 52:907-11. [PubMed 6108124]

103. Sung YF, Weinstein MS, Hammonds WD et al. Comparison of midazolam and thiopental for anesthesia induction. Anesthesiology . 1982; 57:A346.

104. White PF. Comparative evaluation of intravenous agents for rapid sequence induction—thiopental, ketamine, and midazolam. Anesthesiology . 1982; 57:279-84. [PubMed 7125264]

105. Fragen RJ, Gahl F, Caldwell N. A water-soluble benzodiazepine, RO 21-3981, for induction of anesthesia. Anesthesiology . 1978; 49:41-3. [PubMed 352195]

106. Pakkanen A, Kanto J. Midazolam compared with thiopentone as an induction agent. Acta Anaesthesiol Scand . 1982; 26:143-6. [PubMed 7102237]

107. Nilsson A, Lee PFS, Revenas B. Midazolam as induction agent prior to inhalational anaesthesia: a comparison with thiopentone. Acta Anaesthesiol Scand . 1984; 28:249-51. [PubMed 6741440]

108. Lebowitz PW, Cote ME, Daniels AL et al. Comparative cardiovascular effects of midazolam and thiopental in healthy patients. Anesth Analg . 1982; 61:771-5. [PubMed 7201758]

109. Al-Khudhairi D, Whitwam JG, Chakrabarti MK et al. Haemodynamic effects of midazolam and thiopentone during induction of anaesthesia for coronary artery surgery. Br J Anaesth . 1982; 54:831-5. [PubMed 6980657]

110. Schulte-Sasse U, Hess W, Tarnow J. Haemodynamic responses to induction of anaesthesia using midazolam in cardiac surgical patients. Br J Anaesth . 1982; 54:1053-8. [PubMed 6982054]

111. Massaut J, d'Hollander A, Barvais L et al. Haemodynamic effects of midazolam in the anaesthetized patient with coronary artery disease. Acta Anaesthesiol Scand . 1983; 27:299-302. [PubMed 6138915]

112. Heikkila H, Jalonen J, Arola M et al. Midazolam as adjunct to high-dose fentanyl anaesthesia for coronary artery bypass grafting operation. Acta Anaesthesiol Scand . 1984; 28:683-9. [PubMed 6335344]

113. Reves JG, Vinik R, Hirschfield AM et al. Midazolam compared with thiopentone as a hypnotic component in balanced anaesthesia: a randomized, double-blind study. Can Anaesth Soc J . 1979; 26:42-9. [PubMed 32961]

114. Crawford ME, Carl P, Andersen RS et al. Comparison between midazolam and thiopentone-based balanced anaesthesia for day-case surgery. Br J Anaesth . 1984; 56:165-9. [PubMed 6691877]

115. Hanno PM, Wein AJ. Anesthetic techniques for cystoscopy in men. J Urol . 1983; 130:1070-2. [PubMed 6358529]

116. Monti JM, Debellis J, Alterwain P et al. Midazolam and sleep in insomniac patients. Br J Clin Pharmacol . 1983; 16(Suppl):87-8S.

117. Monti JM, Debellis J, Gratadoux E et al. Sleep laboratory study of the effects of midazolam in insomniac patients. Eur J Clin Pharmacol . 1982; 21:479-84. [PubMed 7075654]

118. Gath I, Bar-On E, Rogowski Z et al. Automatic scoring of polygraphic sleep recordings: midazolam in insomniacs. Br J Clin Pharmacol . 1983; 16(Suppl):89-96S.

119. Vogel GW, Vogel F. Effect of midazolam on sleep of insomniacs. Br J Clin Pharmacol . 1983; 16(Suppl):103-8S.

120. Hauri P, Roth T, Sateia M et al. Sleep laboratory and performance evaluation of midazolam in insomniacs. Br J Clin Pharmacol . 1983; 16(Suppl):109-14S. [PubMed 6882618]

121. Norman TR, Fulton A, Burrows GD et al. An open evaluation of midazolam as a hypnotic. Curr Ther Res . 1984; 36:461-7.

122. Kramer M, Bonnet M, Schoen LS et al. Efficacy and safety of midazolam 7.5 mg in geriatric insomniacs. Curr Ther Res . 1985; 38:414-22.

123. Lupolover R, Buch JP. Evaluation of efficacy and safety of midazolam administered orally in sleep disorders. Arzneimittelforschung . 1981; 31:2281-3. [PubMed 6120704]

124. Kanto J, Sjövall S, Vuori A. Effect of different kinds of premedication on the induction properties of midazolam. Br J Anaesth . 1982; 54:507-11. [PubMed 7073920]

125. Forster A. Utilisation of midazolam as an induction agent in anesthesia: study on volunteers. Arzneimittelforschung . 1981; 31:2243.

126. Giffin JP, Cottrell JE, Shwiry B et al. Intracranial pressure, mean arterial pressure, and heart rate following midazolam or thiopental in humans with brain tumors. Anesthesiology . 1984; 60:491-4. [PubMed 6370042]

127. Cole WHJ. Midazolam in paediatric anaesthesia. Anaesth Intens Care . 1982; 10:36-9.

128. Holloway AM, Jordaan DG, Brock-Utne JG. Midazolam for the intravenous induction of anaesthesia in children. Anaesth Intens Care . 1982; 10:340-3.

129. Fragen RJ, Hauch T. The effect of midazolam maleate and diazepam on intraocular pressure in adults. Arzneimittelforschung . 1981; 31:2273-5. [PubMed 7199334]

130. Barker I, Butchart DGM, Gibson J et al. IV sedation for conservative dentistry: a comparison of midazolam and diazepam. Br J Anaesth . 1986; 58:371-7. [PubMed 2937434]

131. Dixon RA, Kenyon C, March DRG et al. Midazolam in conservative dentistry: a cross-over trial. Anaesthesia . 1986; 41:276-81. [PubMed 2938518]

132. Kanto JH, Aaltonen L, Himberg JJ et al. Midazolam as an intravenous induction agent in the elderly: a clinical and pharmacokinetic study. Anesth Analg . 1986; 65:15-20. [PubMed 2934006]

133. Marty J, Gauzit R, Lefevre P et al. Effects of diazepam and midazolam on baroreflex control of heart rate and on sympathetic activity in humans. Anesth Analg . 1986; 65:113-9. [PubMed 2935050]

134. White PF. Pharmacologic interaction of midazolam and ketamine in surgical patients. Clin Pharmacol Ther . 1982; 31:280-1.

135. Shih A, Lin R, Wu WH. Further evaluation of midazolam hydrochloride as an intravenous anesthesia induction agent with meperidine and glycopyrrolate as premedicants—safety and efficacy. Pharmacologist . 1983; 25:127.

136. Woo K, Kolis SJ, Schwartz MA. In vitro metabolism of an imidazobenzodiazepine. Pharmacologist . 1977; 19:164.

137. Forster A, Gardaz JP, Suter PM et al. Respiratory depression by midazolam and diazepam. Anesthesiology . 1980; 53:494-7. [PubMed 7457966]

138. Forster A. Respiratory depression by midazolam and diazepam. Arzneimittelforschung . 1981; 31:2226.

139. Gross JB, Zebrowski ME, Carel WD et al. Time course of ventilatory depression after thiopental and midazolam in normal subjects and in patients with chronic obstructive pulmonary disease. Anesthesiology . 1983; 58:540-4. [PubMed 6407363]

140. Morel D, Forster A, Bachmann M et al. Changes in breathing pattern induced by midazolam in normal subjects. Anesthesiology . 1982; 57:A481.

141. Melvin MA, Johnson BH, Quasha AL et al. Induction of anesthesia with midazolam decreases halothane MAC in humans. Anesthesiology . 1982; 57:238-41. [PubMed 7114548]

142. Lebowitz PW, Cote ME, Daniels AL et al. Comparative renal effects of midazolam and thiopental. Anesthesiology . 1982; 57:A35.

143. Klotz U, Arvela P, Rosenkranz B. Effect of single doses of cimetidine and ranitidine on the steady-state plasma levels of midazolam. Clin Pharmacol Ther . 1985; 38:652-5. [PubMed 2933205]

144. Reves JG, Kissin I, Smith LR. The effective dose of midazolam. Anesthesiology . 1981; 55:82. [PubMed 7247063]

145. Jensen S, Schou-Olesen A, Huttel MS. Use of midazolam and an induction agent: comparison with thiopentone. Br J Anaesth . 1982; 54:605-7. [PubMed 7082523]

146. Byatt CM, Lewis LD, Dawling S et al. Accumulation of midazolam after repeated dosage in patients receiving mechanical ventilation in an intensive care unit. BMJ . 1984; 289:799-800. [PubMed 6434086]

147. Byrne AJ, Yeoman PM, Mace P. Accumulation of midazolam in patients receiving mechanical ventilation. BMJ . 1984; 289:1309. [PubMed 6437529]

148. Jardine AD, Nithianandan S, Hall J. Meptazinol-midazolam combination for postoperative analgesia and sedation. Lancet . 1983; 2:395. [PubMed 6135885]

149. Brown CR, Sarnquist FH, Canup CA et al. Clinical, electroencephalographic, and pharmacokinetic studies of a water-soluble benzodiazepine, midazolam maleate. Anesthesiology . 1979; 50:467-70. [PubMed 36818]

150. Lauven PM, Stoeckel H, Schwilden M. Ein pharmakokinetisch begrundetes Infusionsmodell fur Midazolam. (German; with English abstract). Anaesthesist . 1982; 31:15-20. [PubMed 7072920]

151. Greenblatt DJ, Locniskar A, Scavone JM et al. Absence of interaction of cimetidine and ranitidine with intravenous and oral midazolam. Anesth Analg . 1986; 65:176-80. [PubMed 2935051]

152. Nugent M, Artru AA, Michenfelder JD. Cerebral effects of midazolam and diazepam. Anesthesiology . 1980; 53:58.

153. Hoffman WE, Miletich DJ, Albrecht RF. The effects of midazolam on cerebral blood flow and oxygen consumption and its interaction with nitrous oxide. Anesth Analg . 1986; 65:729-33. [PubMed 2940942]

154. Forster A, Juge O, Morel D. Effects of midazolam on cerebral blood flow in human volunteers. Anesthesiology . 1982; 56:453-5. [PubMed 6805365]

155. Messick JM, Newberg LA, Nugent M et al. Principles of neuroanesthesia for the nonsurgical patient with CNS pathophysiology. Anesth Analg . 1985; 64:143-74. [PubMed 3882022]

156. Laudano JB (Roche Laboratories, Nutley, NJ): Personal communication; 1987 Mar 13.

160. Elwood RJ, Hildebrand PJ, Dundee JW et al. Ranitidine influences the uptake of oral midazolam. Br J Clin Pharmacol . 1983; 15:743-5. [PubMed 6135440]

161. Fee JPH, Collier PS, Howard PJ et al. Cimetidine and ranitidine increase midazolam bioavailability. Clin Pharmacol Ther . 1987; 41:80-4. [PubMed 3802710]

162. Salonen M, Aantaa E, Aaltonen L et al. Importance of the interaction of midazolam and cimetidine. Acta Pharmacol Toxicol (Copenh) . 1986; 58:91-5. [PubMed 2939688]

163. Medd BH. Dear doctor letter regarding appropriate use of Versed. Nutley, NJ: Roche Laboratories; 1987 Feb.

164. Reid WH, Blouin P, Schermer M. A review of psychotropic medications and the glaucomas. Int Pharmacopsychiatr . 1976; 11:163-74.

165. Hardin TC, Evens RP. Benzodiazepine use in glaucoma. Drug Intell Clin Pharm . 1979; 13:109.

166. Calixto N, Costa Maia JA. Influence of lorazepam on ocular pressure in patients with glaucoma. Curr Ther Res . 1975; 17:156-60. [PubMed 234358]

167. Hartz SC, Heinonen OP, Shapiro S et al. Antenatal exposure to meprobamate and chlordiazepoxide in relation to malformations, mental development, and childhood mortality. N Engl J Med . 1975; 292:726-8. [PubMed 1113782]

168. Saxen I, Saxen L. Association between maternal intake of diazepam and oral cleft. Lancet . 1975; 2:498. [PubMed 51304]

169. Safra MJ, Oakley GP. Association between cleft lip with or without cleft palate and prenatal exposure to diazepam. Lancet . 1975; 2:478-80. [PubMed 51287]

170. Milkovich L, van den Berg BJ. Effects of prenatal meprobamate and chlordiazepoxide hydrochloride on human embryonic and fetal development. N Engl J Med . 1974; 291:1268-71. [PubMed 4431433]

171. Cole AP, Hailey DM. Diazepam and active metabolite in breast milk and their transfer to the neonate. Arch Dis Child . 1975; 50:741-2. [PubMed 1190825]

172. Anon. Excretion of psychotropic drugs in human breast milk. Int Drug Ther Newsl . 1973; 8:36-40.

173. Klotz U. Midazolam: the first water soluble benzodiazepine. Commentary 1. Pharmacotherapy . 1985; 5:154-5.

174. Reves JG. Midazolam: the first water soluble benzodiazepine. Commentary 2. Pharmacotherapy . 1985; 5:155.

175. Anon. Warning reemphasized in midazolam labeling. FDA Drug Bull . 1987; 17:5.

176. Korttila K. Clinical effectiveness and untoward effects of new agents and techniques used in intravenous sedation. J Dent Res . 1984; 63:848-52. [PubMed 6145735]

177. Stanley TH. Commentary: the place of midazolam in current anesthetic practice. Anesthesiol Rev . 1985; 12(Suppl):66-9.

178. White PF. The role of midazolam in outpatient anesthesia. Anesthesiol Rev . 1985; 12(Suppl):55-60.

179. Drug Enforcement Administration. Schedules of controlled substances; placement of quazepam and midazolam into schedule IV (Docket No. 86-6421). Fed Regist . 1986; 51:10190-2.

180. Medd BH (Roche Laboratories, Nutley, NJ): Personal communication; 1987 Aug 10.

181. Reviewers' comments (personal observations); 1987 Jul.

182. Khanderia U, Pandit SK. Use of midazolam hydrochloride in anaesthesia. Clin Pharm . 1987; 6:533-47. [PubMed 3319363]

183. Reilly CS, Nimmo WS. New intravenous anaesthetics and neuromuscular blocking drugs: a review of their properties and clinical use. Drugs . 1987; 34:98-135. [PubMed 3308413]

184. Nilsson A, Tamsen A, Persson P. Midazolam-fentanyl anesthesia for major surgery: plasma levels of midazolam during prolonged total intravenous anesthesia. Acta Anaesthesiol Scand . 1986; 30:66-9. [PubMed 2938395]

185. McClure JH, Brown DT, Wildsmith JAW. Comparison of the IV administration of midazolam and diazepam as sedation during spinal anaesthesia. Br J Anaesth . 1983; 55:1089-93. [PubMed 6139119]

186. Reinhart K, Dallinger-Stiller G, Dennhardt R et al. Comparison of midazolam, diazepam and placebo IM as premedication for regional anaesthesia: a randomized double-blind study. Br J Anaesth . 1985; 57:294-9. [PubMed 3156614]

187. Aun C, Flynn PJ, Richards J et al. A comparison of midazolam and diazepam for intravenous sedation in dentistry. Anaesthesia . 1984; 39:589-93. [PubMed 6742394]

188. Food and Drug Administration. Prescription drug advertising; content and format for labeling of human prescription drugs. Fed Regist . 1979; 44:37434-67.

189. Tucker MR, Ochs MW, White RP Jr. Arterial blood gas levels after midazolam or diazepam administered with or without fentanyl as an intravenous sedative for outpatient surgical procedures. J Oral Maxillofac Surg . 1986; 44:688-92. [PubMed 2943882]

190. Van Gorder PN, Hoffman WE, Baughman V et al. Midazolam-ethanol interactions and reversal with a benzodiazepine antagonist. Anesth Analg . 1985; 64:129-35. [PubMed 2857540]

191. Roche Laboratories. Versed^® prescribing information. Nutley, NJ; 1985 Dec.

192. Roche Laboratories. Versed^® prescribing information. Nutley, NJ; 1987 Jan.

193. Medd BH. Dear colleague letter regarding important new information on the administration of Versed^® (midazolam hydrochloride/Roche) injection for conscious sedation. Nutley, NJ: Roche Laboratories; 1987 Nov.

194. Arcos GJ. Midazolam-induced ventricular irritability. Anesthesiology . 1987; 67:612. [PubMed 3662101]

195. Olkkola KT, Aranko K, Luurila H et al. A potentially hazardous interaction between erythromycin and midazolam. Clin Pharmacol Ther . 1993; 53:298-305. [PubMed 8453848]

196. Anon. Grapefruit juice interactions with drugs. Med Lett Drugs Ther . 1995; 37:73-4. [PubMed 7630329]

197. Kupferschmidt HHT, Ha HR, Ziegler WH et al. Interaction between grapefruit juice and midazolam in humans. Clin Pharmacol Ther . 1995; 58:208.

198. Hukkinen SK, Varhe A, Olkkola KT et al. Plasma concentrations of triazolam are increased by concomitant ingestion of grapefruit juice. Clin Pharmacol Ther . 1995; 58:127-31. [PubMed 7648762]

199. Bailey DG, Arnold JMO, Spence JD. Grapefruit juice and drugs: how significant is the interaction? Clin Pharmacokinet . 1994; 26:91-8.

200. Benton RE, Honig PK, Zamani K et al. Grapefruit juice alters terfenadine pharmacokinetics, resulting in prolongation of repolarization on the electrocardiogram. Clin Pharmacol Ther . 1996; 59:383-8. [PubMed 8612381]

201. Ducharme MP, Warbasse LH, Edwards DJ. Disposition of intravenous and oral cyclosporine after administration with grapefruit juice. Clin Pharmacol Ther . 1995; 57:485-91. [PubMed 7768070]

202. Cyclosporine/food (grapefruit juice). In: Tatro DS, Olin BR, Hebel SK eds. Drug interaction facts. St. Louis: JB Lippincott Co; 1996(July):233b.

203. Midazolam (Versed) interactions: grapefruit juice. In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 1996:932.

204. Proppe DG, Hoch OD, McLean AJ et al. Influence of chronic ingestion of grapefruit juice on steady state blood concentrations of cyclosporine A in renal transplant patients with stable graft function. Br J Clin Pharmacol . 1995; 39:337-8. [PubMed 7619679]

205. Ameer B, Weintraub RA, Johnson JV et al. Flavanone absorption after naringin, hesperidin, and citrus administration. Clin Pharmacol Ther . 1996; 60:34-40. [PubMed 8689809]

206. Edwards DJ, Bellevue FH, Woster PM. Identification of 6',7'-dihydroxybergamottin, a cytochrome P450 inhibitor in grapefruit juice. Drug Metabol Dispos . (in press)

207. Edwards DJ, Bernier SM. Naringin and naringenin are not the primary CYP3A inhibitors in grapefruit juice. Life Sci . 1996; 59:1025-30. [PubMed 8809221]

208. Lundahl J, Regardh CG, Edgar B et al. Relationship between time of intake of grapefruit juice and its effect on pharmacokinetics and pharmacodynamics of felodipine in healthy subjects. Eur J Clin Pharmacol . 1995; 49:61-7. [PubMed 8751023]

209. Bailey DG, Spence JD, Munoz C et al. Interaction of citrus juices with felodipine and nifedipine. Lancet . 1991; 337:268-9. [PubMed 1671113]

210. Yee GC, Stanley DL, Pessa LJ et al. Effect of grapefruit juice on blood cyclosporin concentration. Lancet . 1995; 345:955-6. [PubMed 7715295]

211. Hollander AAMJ, van Rooij J, Lentjes EGWM et al. The effect of grapefruit juice on cyclosporine and prednisone metabolism in transplant patients. Clin Pharmacol Ther . 1995; 57:318-24. [PubMed 7697949]

212. Merkel U, Sigusch H, Hoffmann A. Grapefruit juice inhibits 7-hydroxylation of coumarin in healthy volunteers. Eur J Clin Pharmacol . 1994; 46:175-7. [PubMed 8039540]

213. Soons PA, Vogels BAPM, Roosemalen MCM et al. Grapefruit juice and cimetidine inhibit stereoselective metabolism of nitrendipine in humans. Clin Pharmacol Ther . 1991; 50:394-403. [PubMed 1914375]

214. Fuhr U, Klittich K, Staib AH. Inhibitory effect of grapefruit juice and its bitter principal, naringenin, on CYP1A2 dependent metabolism of caffeine in man. Br J Clin Pharmacol . 1993; 35:431-6. [PubMed 8485024]

215. Campana C, Regazzi MB, Buggia I et al. Clinically significant drug interactions with cyclosporin: an update. Clin Pharmacokinet . 1996; 30:141-179. [PubMed 8906896]

216. Erythromycin interactions: benzodiazepines. In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc., 1993:222-3.

217. Hiller A, Olkkola KT, Isohanni P et al. Unconsciousness associated with midazolam and erythromycin. Br J Anaesth . 1990; 65:826-8. [PubMed 2265054]

218. Aranko K, Olkkola KT, Hiller A et al. Clinically important interaction between erythromycin and midazolam. Br J Clin Pharmacol . 1992; 33:217-8P.

219. West-ward Pharmaceuticals. Midazolam hydrochloride syrup prescribing information. Eatontown, NJ; 2017 Apr.

220. Shafer A. Complications of sedation with midazolam in the intensive care unit and a comparison with other sedative regimens. Crit Care Med . 1998; 26:947-56. [PubMed 9590327]

221. Barrientos-Vega R, Mar Sanchez-Soria M, Morales-Garcia C et al. Prolonged sedation of critically ill patients with midazolam or propofol; impact on weaning and costs. Crit Care Med . 1997; 25:33-40. [PubMed 8989173]

222. Burns AM, Shelly MP, Park GR. The use of sedative agents in critically ill patients. Drugs . 1992; 43:507-15. [PubMed 1377117]

223. Aitkenhead AR, Pepperman ML, Willatts SM et al. Comparison of propofol and midazolam for sedation in critically ill patients. Lancet . 1989; 2:704-9. [PubMed 2570958]

224. American Academy of Pediatrics Committee on Fetus and Newborn and Committee on Drugs. Benzyl alcohol: toxic agent in neonatal units. Pediatrics . 1983; 72:356-8.

225. Anon. Benzyl alcohol may be toxic to newborns. FDA Drug Bull . 1982; 12(2):10-1. [PubMed 7188569]

226. Anon. Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly Rep . 1982; 31:290-1. [PubMed 6810084]

227. Gershanik J, Boecler B, Ensley H et al. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med . 1982; 307:1384-8. [PubMed 7133084]

228. Menon PA, Thach BT, Smith CH et al. Benzyl alcohol toxicity in a neonatal intensive care unit: incidence, symptomatology, and mortality. Am J Perinatol . 1984; 1:288-92. [PubMed 6440575]

229. Anderson CW, Ng KJ, Andresen B et al. Benzyl alcohol poisoning in a premature newborn infant. Am J Obstet Gynecol . 1984; 148:344-6. [PubMed 6695984]

230. Food and Drug Administration. Parenteral drug products containing benzyl alcohol or other antimicrobial preservatives; intent and request for information. [Docket No. 85N-0043] Fed Regist . 1985; 50:20233-5.

231. Forest Pharmaceuticals, Inc. Tiazac (diltiazem hydrochloride) extended release capsules prescribing information. St. Louis, MO; 1999 Oct.

232. Diltiazem (Cardizem) drug interaction: Midazolam (Versed). In: Hansten PD, Horn JR. Drug interactions analysis and management. Vancouver, WA: Applied Therapeutics, Inc; 1997:93.

233. Benzodiazepines/diltiazem. In: Tatro DS, Olin BR, Hebel SK, eds. Drug interaction facts. St. Louis: JB Lippincott Co; 1998 (April):128a.

234. Aventis Pharmaceuticals. Synercid^® (quinupristin/dalfopristin) for injection prescribing information. Collegeville, PA; 1999 July.

235. Task Force of the American College of Critical Care Medicine (ACCM) in collaboration with the American Society of Health-System Pharmacists (ASHP) and in alliance with the American College of Chest Physicians. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Am J Health-Syst Pharm . 2002; 59:150-78. [PubMed 11826570]

236. American Academy of Pediatrics, Committee on Drugs. Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures. Pediatrics . 1992;89:1110-1115. [PubMed 1594358]

237. American Academy of Pediatrics, Committee on Drugs. Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures: addendum. Pediatrics . 2002;110:836-8. [PubMed 12359805]

238. Roche Laboratories. Invirase^® (saquinavir mesylate) capsules prescribing information. Nutley, NJ; 2005 Sep.

240. Bristol-Myers Squibb. Reyataz^®(atazanavir sulfate) prescribing information. Princeton, NJ; 2006 Feb

241. Merck & Company Inc. Crixivan^® (indinavir sulfate) capsules prescribing information. West Point, PA;2006 Apr.

242. Abbott Laboratories. Kaletra^® (lopinavir/ritonavir) oral tablets and solution prescribing information. North Chicago, IL; 2005 Oct.

243. Agouron Pharmaceuticals. Viracept^® (nelfinavir mesylate) tablets and oral powder prescribing information. La Jolla, CA; 2006 Apr

244. Abbott Laboratories. Norvir^® (ritonavir) soft gelatin capsules and oral solution prescribing information. North Chicago, IL; 2006 Jan.

245. Boehringer Ingelheim. Aptivus^® (tipranavir) capsules prescribing information. Ridgefield, CT; 2006 Jun 27.

246. GlaxoSmithKline. Lexiva^® (fosamprenavir calcium) tablets prescribing information. Research Triangle Park, NC; 2006 June.

247. Pfizer. Rescriptor^® (delavirdine mesylate) tablets prescribing information. La Jolla, CA; 2006 Feb.

248. Bristol-Myers Squibb Company. Sustiva^® (efavirenz) capsules and tablets prescribing information. Princeton, NJ; 2006 Mar

249. Panel on Clinical Practices for Treatment of HIV Infection of the Department of Health and Human Services (DHHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (October 10, 2006). From the US Department of Health and Human Services HIV/AIDS Information Services (HIV.gov) website.

250. ASHP. Standardize 4 Safety: adult continuous infusion standards. Updated Mar 2024. From ASHP website. Updates may be available at ASHP website. [Web]

251. ASHP. Standardize 4 Safety: pediatric continuous infusion standards. Updated Mar 2024. From ASHP website. Updates may be available at ASHP website. [Web]

252. ASHP. Standardize 4 Safety: patient controlled analgesia (PCA) and epidural standards. Updated Mar 2024. From ASHP website. Updates may be available at ASHP website [Web]

320. Rall TW. Hypnotics and sedatives; ethanol: benzodiazepines and management of insomnia. In: Gilman AG, Rall TW, Nies AS et al. Goodman and Gilman's the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press; 1990:346-58,369-70.

358. Bloom FE. Neurohumoral transmission and the central nervous system: amino acids. In: Gilman AG, Rall TW, Nies AS et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press; 1990:256-8.

359. Haefely W. The GABA-benzodiazepine interaction fifteen years later. Neurochem Res . 1990; 15:169-74. [PubMed 2159122]

360. De Feudis FV. Overview—GABA_a receptors. Ann NY Acad Sci . 1990; 585:231-40. [PubMed 2162643]

361. Mohler H, Malherbe P, Draguhn A et al. GABA_a-receptors: structural requirements and sites of gene expression in mammalian brain. Neurochem Res . 1990; 15:199-207. [PubMed 2159125]

362. Farrant M, Gibbs TT, Farb DH. Molecular and cellular mechanisms of GABA/benzodiazepine-receptor regulation: electrophysiological and biochemical studies. Neurochem Res . 1990; 15:175-91. [PubMed 2159123]

363. Sieghart W. Benzodiazepine receptor subtypes and their possible clinical significance. Psychopharmacol Ser . 1989; 7:131-7. [PubMed 2574448]

364. Knapp RJ, Malatynska E, Yamamura HI. From binding studies to the molecular biology of GABA receptors. Neurochem Res . 1990; 15:105-12. [PubMed 2159117]

365. Williams M. Anxioselective anxiolytics. J Med Chem . 1983; 26:619-28. [PubMed 6132997]

366. Rogawski MA, Porter RJ. Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol Rev . 1990; 42:223-86. [PubMed 2217531]

367. Haefely WE. Pharmacology of the benzodiazepine receptor. Eur Arch Psychiatry Neurol Sci . 1989; 238:294-301. [PubMed 2569974]

368. Haefely WE. Benzodiazepines. Int Anesthesiol Clin . 1988; 26:262-72. [PubMed 2461909]

369. Schoch P, Richards JG, Haring P et al. Co-localization of GABA receptors and benzodiazepine receptors in the brain shown by monoclonal antibodies. Nature . 1985; 314:168-71. [PubMed 2983231]

370. Haefely W. Endogenous ligands of the benzodiazepine receptor. Pharmacopsychiatry . 1988; 21:43-6. [PubMed 2834760]

545. Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med . 1998; 338:970-6. [PubMed 9521986]

563. Alldredge BK, Gelb AM, Isaacs SM et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med . 2001; 345:631-7. [PubMed 11547716]

580. Hospira. Midazolam hydrochloride injection preservative-free prescribing information. Lake Forest, IL; 2018 Aug.

611. Baxter. Midazolam hydrochloride injection prescribing information. Deerfield, IL; 2005 Sep.

700. US Food and Drug Administration. Drug safety communication: FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines; requires its strongest warning. Silver Spring, MD; 2016 Aug 31. From FDA website. [Web]

701. Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United States, 2010. JAMA . 2013; 309:657-9. [PubMed 23423407]

703. Hughes A. Letter to manufacturers of benzodiazepines: safety labeling change notification. Silver Spring, MD: US Food and Drug Administration. Accessed 2017 Mar 20. [Web]

704. Seymour S. Letter to manufacturers of opioid antitussives: safety labeling change notification. Silver Spring, MD: US Food and Drug Administration. Accessed 2017 Mar 20. [Web]

705. Park TW, Saitz R, Ganoczy D et al. Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics: case-cohort study. BMJ . 2015; 350:h2698. [PubMed 26063215]

706. Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths From Combined Use of Opioids and Benzodiazepines. Am J Prev Med . 2015; 49:493-501. [PubMed 26143953]

707. Dasgupta N, Funk MJ, Proescholdbell S et al. Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose Mortality. Pain Med . 2016; 17:85-98. [PubMed 26333030]

708. Nuckols TK, Anderson L, Popescu I et al. Opioid prescribing: a systematic review and critical appraisal of guidelines for chronic pain. Ann Intern Med . 2014; 160:38-47. [PubMed 24217469]

709. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016. MMWR Recomm Rep . 2016; 65:1-49. [PubMed 26987082]

710. Manchikanti L, Abdi S, Atluri S et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part 2--guidance. Pain Physician . 2012; 15(3 Suppl):S67-116.

711. New York City Department of Health and Mental Hygiene. New York City emergency department discharge opioid prescribing guidelines. From NYC Health website. 2013 Jan. [Web]

712. Washington State Agency Medical Directors' Group (AMDG). Interagency guideline on prescribing opioids for pain, 3rd ed. From Washington State AMDG website. 2015 Jun. [Web]

715. Patel PM, Patel HH, Roth DM. General anesthetics and therapeutic gases. Brunton LL, Chabner BA, and Knollmann BC, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill Company; 2011:527-64.

716. American Society of Anesthesiologists. ASA statement on sodium thiopental's removal from the market. Jan 21, 2011. From the ASA website. [Web]

750. US Food and Drug Administration. Drug safety communication: FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women. Silver Spring, MD; 2016 Dec 14. From FDA website. [Web]

751. Davidson AJ, Disma N, de Graaff JC et al. Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial. Lancet . 2016; 387:239-50. [PubMed 26507180]

752. Sun LS, Li G, Miller TL et al. Association Between a Single General Anesthesia Exposure Before Age 36 Months and Neurocognitive Outcomes in Later Childhood. JAMA . 2016; 315:2312-20. [PubMed 27272582]

753. US Food and Drug Administration. Drug safety communication: FDA approves labeling changes for use of general anesthetic and sedation drugs in young children. Silver Spring, MD; 2017 Apr 27. From FDA website. [Web]

754. Deshmukh PV, Kulkarni SS, Parchandekar MK et al. Comparison of preanesthetic sedation in pediatric patients with oral and intranasal midazolam. J Anaesthesiol Clin Pharmacol . 2016 Jul-Sep; 32:353-8. [PubMed 27625485]

755. Levine MF, Spahr-Schopfer IA, Hartley E et al. Oral midazolam premedication in children: the minimum time interval for separation from parents. Can J Anaesth . 1993; 40:726-9. [PubMed 8403157]

756. Prasad K, Al-Roomi K, Krishnan PR et al. Anticonvulsant therapy for status epilepticus (review). Cochrane Database of Systematic Reviews. 2005, Issue 4. Article No: CD003723. DOI: 10.1002/14651858.CD003723.pub2.

757. Minicucci F, Muscas G, Perucca E et al. Treatment of status epilepticus in adults: guidelines of the Italian League against Epilepsy. Epilepsia . 2006; 47 Suppl 5:9-15. [PubMed 17239099]

758. Meierkord H, Boon P, Engelsen B et al. EFNS guideline on the management of status epilepticus in adults. Eur J Neurol . 2010; 17:348-55. [PubMed 20050893]

759. Kälviäinen R. Status epilepticus treatment guidelines. Epilepsia . 2007; 48 Suppl 8:99-102. [PubMed 18330014]

760. Phelps SJ, Hovinga CA, Wheless JW. Status Epilepticus. In Dipiro, JT, Talbert RL, Yee GC et al., eds. Pharmacotherapy: a pathophysiologic approach. 7th ed. New York: McGraw-Hill; 2008: 953-63.

761. Marik PE, Varon J. The management of status epilepticus. Chest . 2004; 126:582-91. [PubMed 15302747]

762. . Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of America's Working Group on Status Epilepticus. JAMA . 1993; 270:854-9. [PubMed 8340986]

763. Glauser T, Shinnar S, Gloss D et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr . 2016 Jan-Feb; 16:48-61. [PubMed 26900382]

764. Prasad M, Krishnan PR, Sequeira R et al. Anticonvulsant therapy for status epilepticus. Cochrane Database Syst Rev . 2014; :CD003723. [PubMed 25207925]

765. Sánchez Fernández I, Loddenkemper T. Therapeutic choices in convulsive status epilepticus. Expert Opin Pharmacother . 2015; 16:487-500. [PubMed 25626010]

766. Brophy GM, Bell R, Claassen J et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care . 2012; 17:3-23. [PubMed 22528274]

767. Chamberlain JM, Okada P, Holsti M et al. Lorazepam vs diazepam for pediatric status epilepticus: a randomized clinical trial. JAMA . 2014 Apr 23-30; 311:1652-60. [PubMed 24756515]

768. Silbergleit R, Lowenstein D, Durkalski V et al. Lessons from the RAMPART study--and which is the best route of administration of benzodiazepines in status epilepticus. Epilepsia . 2013; 54 Suppl 6:74-7. [PubMed 24001080]

769. McTague A, Martland T, Appleton R. Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children. Cochrane Database Syst Rev . 2018; 1:CD001905. [PubMed 29320603]

770. Teva Pharmaceuticals. Clonazepam tablets prescribing information. North Wales, PA; 2017 Oct.

771. Treiman DM, Meyers PD, Walton NY et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med . 1998; 339:792-8. [PubMed 9738086]

773. UCB. Nayzilam^® (midazolam) nasal spray prescribing information. Smyrna, GA; 2019 May.

774. Hospira. Seizalam^® (midazolam hydrochloride injection) prescribing information. Lake Forest, IL; 2018 Oct.

800. Devlin JW, Skrobik Y, Gélinas C et al. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit Care Med . 2018; 46:e825-e873. [PubMed 30113379]

801. Barr J, Fraser GL, Puntillo K et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med . 2013; 41:263-306. [PubMed 23269131]

817. Gerlach AT, Murphy CV, Dasta JF. An updated focused review of dexmedetomidine in adults. Ann Pharmacother . 2009; 43:2064-74. [PubMed 19934395]

818. Riker RR, Shehabi Y, Bokesch PM et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA . 2009; 301:489-99. [PubMed 19188334]

819. Pandharipande PP, Pun BT, Herr DL et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA . 2007; 298:2644-53. [PubMed 18073360]

820. Jakob SM, Ruokonen E, Grounds RM et al. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA . 2012; 307:1151-60. [PubMed 22436955]

821. Godwin SA, Caro DA, Wolf SJ et al. Clinical policy: procedural sedation and analgesia in the emergency department. Ann Emerg Med . 2005; 45:177-96. [PubMed 15671976]

822. Godwin SA, Burton JH, Gerardo CJ et al. Clinical policy: procedural sedation and analgesia in the emergency department. Ann Emerg Med . 2014; 63:247-58.e18. [PubMed 24438649]

823. . Practice Guidelines for Moderate Procedural Sedation and Analgesia 2018: A Report by the American Society of Anesthesiologists Task Force on Moderate Procedural Sedation and Analgesia, the American Association of Oral and Maxillofacial Surgeons, American College of Radiology, American Dental Association, American Society of Dentist Anesthesiologists, and Society of Interventional Radiology. Anesthesiology . 2018; 128:437-479. [PubMed 29334501]

824. US Food and Drug Administration. FDA Alert: Information for healthcare professionals: suicidal behavior and ideation and antiepileptic drugs. Rockville, MD; 2008 Jan 31; updated 2008 Dec 16. From the FDA website.