midazolam hcl 2 mg/ml syrup

Uses

Preoperative Sedation, Anxiolysis, and Anterograde Amnesia

For preoperative sedation, anxiolysis, and anterograde amnesia, midazolam is used IM or IV in adult or pediatric patients; the drug also is used orally in pediatric patients. When administered preoperatively, the drug relieves anxiety and provides sedation, light anesthesia, and anterograde amnesia of perioperative events.

The efficacy of oral midazolam as a premedicant to sedate and calm pediatric patients prior to the induction of general anesthesia was compared across 3 different doses in a randomized, double-blind, parallel-group study. Patients of ASA physical status I, II, or III were stratified to one of 3 age groups (6 months to younger than 2 years, 2 to younger than 6 years, and 6 to younger than 16 years of age) and to one of 3 dosing groups (250 mcg/kg, 500 mcg/kg, and 1 mg/kg up to a maximum of 20 mg). More than 90% of treated patients achieved satisfactory sedation and anxiolysis at least one timepoint within 30 minutes post-treatment. Similarly high proportions of patients exhibited satisfactory ease of separation from parent or guardian and were cooperative at the time of mask induction with nitrous oxide and halothane administration. Onset time of satisfactory sedation or anxiolysis occurred within 10 minutes of treatment for greater than 70% of patients who started with an unsatisfactory baseline rating. Pairwise comparisons (250 mcg/kg versus 500 mcg/kg and 500 mcg/kg versus 1 mg/kg groups) on satisfactory sedation were not clinically different; however, comparative analysis of the clinical response between the higher and lower doses demonstrated that a higher proportion of patients in the 1 mg/kg group exhibited satisfactory sedation and anxiolysis compared with the 250 mcg/kg group.

Like other benzodiazepines, midazolam is especially useful as a preoperative medication when relief of anxiety and diminished recall of events associated with the surgical procedure are desired. The duration of anterograde amnesia following IM administration of midazolam is about 1 hour. Anterograde amnesia about events 30 and 60 minutes after IM injection occurs in approximately 40-75 and 25-40% of patients, respectively. Concomitant preoperative administration with scopolamine may potentiate this effect slightly. Because the degree and duration of anterograde amnesia appear to be dose related, patients receiving large doses of midazolam theoretically may have a more prolonged amnesic effect.

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. 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. Because of midazolam's relatively rapid onset and 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.

Midazolam also is used IV for preoperative sedation and anxiolysis with good results.

Procedural Sedation

For procedural sedation, anxiolysis, and amnesia, midazolam is used IV in adult and pediatric patients, and orally in pediatric patients, either alone or in combination with an opiate agonist. The drug provides sedation without loss of consciousness and also provides relief of anxiety and anterograde amnesia when administered prior to dental or minor surgical procedures, or diagnostic, therapeutic, or endoscopic procedures such as upper GI endoscopy, bronchoscopy, cystoscopy, cardiac catheterization, coronary angiography, oncology procedures, radiologic procedures (e.g., computerized tomography), suture of lacerations, and other procedures, either alone or in combination with other CNS depressants. Like other benzodiazepines, midazolam is particularly useful for sedation when relief of anxiety and diminished recall of events associated with such procedures are desired.

Because laryngospasm and increased cough reflex may occur during peroral endoscopic procedures, concomitant use of topical anesthesia generally is recommended; facilities and equipment for respiratory and cardiovascular assistance should be readily available. The manufacturer recommends that an opiate agonist be used concomitantly as premedication for bronchoscopic procedures.

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. However, onset and duration of action depend on many factors, including the dose of midazolam, rate of administration, and on any concurrently administered drug.(See Pharmacokinetics: Absorption.)

Midazolam generally produces less pain and venous irritation (e.g., thrombophlebitis) at the site of IV injection than diazepam. In addition, IV midazolam may have a slightly more rapid onset of action and more pronounced anterograde amnesic effect when compared with IV diazepam. Although data are conflicting, there is some evidence that midazolam's duration of action following IV administration may be slightly shorter than that of diazepam, but further comparative studies are needed; the duration of action of midazolam is substantially shorter than that of IV lorazepam. Because of the drug's relatively rapid onset and short duration of action, pronounced amnesic effect, and improved local tolerance at the site of injection compared with other currently available IV benzodiazepines, some clinicians consider midazolam the benzodiazepine of choice for moderate sedation (formerly known as conscious sedation) prior to short procedures.

Induction and Maintenance of Anesthesia

Midazolam is used IV for induction of general anesthesia prior to administration of other anesthetic agents. Induction with IV midazolam results in anxiolysis, anterograde amnesia, and dose-related hypnotic effects (progressing from sedation to loss of consciousness), but not analgesia. Midazolam also is used as a component of balanced anesthesia (e.g., nitrous oxide and oxygen) for maintenance of anesthesia during short surgical procedures; use of the drug for maintenance of anesthesia in relatively long surgical procedures has not been fully evaluated to date.

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. Premedication with an opiate agonist results in more rapid and reliable induction of anesthesia within a narrower midazolam dosage range, and smaller doses of midazolam generally are required.

Compared with IV diazepam, induction with IV midazolam appears to cause less local irritation at the site of injection, comparable or more pronounced anterograde amnesic effect, and less variation in response to a given dose; midazolam also has a more rapid onset and shorter duration of action. The incidence of postoperative emergence delirium, nausea, and vomiting is relatively low following midazolam administration as compared with other anesthetic agents. Limited data suggest that midazolam attenuates both the postoperative emergence delirium and the cardiovascular stimulation associated with the use of ketamine during surgery.

When compared with IV thiopental (no longer commercially available in the US) for induction and maintenance of anesthesia, IV midazolam appears to produce more pronounced anterograde amnesia and more gradual induction of anesthesia and usually requires fewer adjuvant anesthetic agents to maintain an acceptable depth of anesthesia, but thiopental induces anesthesia more rapidly, produces a less variable response (particularly in young and/or non-premedicated patients), and requires a shorter recovery period. Apnea appears to occur less frequently and may be of shorter duration in patients receiving IV midazolam than in those receiving IV thiopental. Limited data suggest that IV midazolam also produces somewhat less severe adverse cardiovascular effects than IV thiopental, but further comparative studies are necessary. Midazolam appears to be an acceptable alternative to thiopental for induction of anesthesia, but midazolam's slow onset and long duration of action and variability in response relative to those of thiopental preclude it from becoming the drug of choice for induction of anesthesia in most patients, particularly outpatients and patients undergoing short surgical procedures. Midazolam may prove to be particularly useful as an alternative agent in patients with cardiac disease, geriatric patients, and patients in whom IV barbiturates are not tolerated or are contraindicated. In addition, because of midazolam's pronounced anterograde amnesic effect and good patient acceptability and because the drug generally requires fewer dosage increments and adjuvant anesthetics to maintain anesthesia than thiopental, some clinicians consider midazolam superior to thiopental for maintenance of balanced anesthesia; however, further comparative studies are needed. Midazolam appears to be a relatively safe and effective alternative to IV barbiturates for induction of anesthesia in patients with intracranial pathology (e.g., intracranial mass lesions, hydrocephalus, abnormal intracranial compliance) because midazolam produces little change in intracranial pressure (ICP); however, midazolam does not fully attenuate the increase in ICP associated with laryngoscopy and intubation.

Midazolam should not be used alone for maintenance of anesthesia; 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). Concurrent use of an opiate agonist usually is necessary to maintain adequate anesthesia.

Because midazolam does not appear to increase intraocular pressure, the drug appears to be safe for use in patients undergoing surgery for ocular trauma. Use of midazolam in patients without underlying ocular disease may result in moderate reduction of intraocular pressure.

Midazolam generally has been well tolerated in patients with ischemic heart disease, although mild to moderate alterations in cardiovascular function may occur. Severe hypotension has occurred, however, when midazolam was used with high-dose fentanyl anesthesia in patients undergoing coronary artery bypass grafting procedures.

Sedation in Critical-Care Settings

Midazolam is used as a continuous IV infusion for sedation of intubated and mechanically ventilated adults, pediatric patients, and neonates during treatment in a critical-care setting (e.g., an ICU) or as a component of anesthesia. The drug has been shown to be as effective as propofol in terms of sedation and appears to have a better adverse effect profile (e.g., less hypotension); however, midazolam appears to have a more variable effect on recovery of consciousness and time to recovery of function after cessation of therapy than propofol. In addition, results of several clinical studies indicate that midazolam is as effective as lorazepam in terms of level of sedation, the time required to achieve adequate sedation, and usually, the number of daily dose adjustments. However, in one study, midazolam IV infusions did require more frequent dosage adjustments to maintain the desired level of sedation than did lorazepam.

Because of the rapid onset and short duration of action of single doses of midazolam, some clinicians recommend midazolam as one of the preferred drugs for sedation in acutely agitated patients in critical-care settings. It is recommended, however, that midazolam be used only for short-term sedation (up to 24 hours), because the effects of the drug on awakening and time to extubation are unpredictable when infusions of the drug are administered over longer periods (e.g., exceeding 48-72 hours).

Other Uses

Parenterally administered midazolam has been used in the management of acute agitation.

Midazolam has decreased EEG interictal spike activity in some patients, suggesting that the drug possesses anticonvulsant activity, but the efficacy of the drug for the management of seizure disorders has not been fully determined.

Dosage and Administration

Administration

Midazolam hydrochloride is administered orally, by IM or slow IV injection, or by IV infusion. The manufacturer states that the safety and efficacy of midazolam hydrochloride parenterally administered by other than the IM or IV route have not been established and that the drug should only be parenterally administered IM or IV. Care should be taken to avoid intra-arterial injection or extravasation of the drug. Midazolam also has been orally administered as the maleate salt; however, midazolam maleate currently is not commercially available in the US.

For IM administration, midazolam hydrochloride is injected deep into a large muscle mass.

For IV injection, midazolam hydrochloride is injected in incremental doses. The drug is a potent sedative that requires slow administration and individualized titration of dosage. For procedural sedation, the drug should not be injected rapidly or as large incremental doses. 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; incremental doses and the rate of IV injection should be reduced in patients 60 years of age and older, 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 effects may be slower. For induction of anesthesia, the appropriate dose usually is injected over 20-30 seconds; supplemental doses may be given at 2-minute intervals. To facilitate dosage titration, midazolam hydrochloride injection containing 1 mg/mL may be used. For procedural sedation, use of the midazolam hydrochloride injection containing 1mg/mL (of midazolam) is recommended to facilitate slow IV injection of the drug. For continuous IV infusion, the 5-mg/mL injection should be diluted to a concentration of 0.5 mg/mL with 0.9% sodium chloride injection or 5% dextrose injection. The 1- or 5-mg/mL injection may be diluted with 0.9% sodium chloride injection or 5% dextrose injection.

Facilities for administration of oxygen and controlled respiration should be readily available during and immediately following IV administration of midazolam hydrochloride. Because serious and life-threatening adverse cardiorespiratory effects can occur during therapy with the drug, provision should be made for monitoring, detecting, and correcting such effects in every patient in whom midazolam is administered, regardless of age or health status.(See Cautions: Precautions and Contraindications.)

Midazolam hydrochloride injection and diluted solutions of the drug should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

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.(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. 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.

Dosage

Dosage of midazolam hydrochloride is expressed in terms of midazolam. The drug is a potent sedative that requires individualized dosing. 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.(See Cautions: Cardiorespiratory Effects.) 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. 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.(See Cautions: Cardiorespiratory Effects.) The smallest effective dose should be used, especially in geriatric and/or debilitated patients.

It should be recognized that the depth of sedation/anxiolysis needed for pediatric patients depends on the type of procedure performed. 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); therefore, there is a broad dosage range. 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.

Unlike adult patients, 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. Pediatric patients generally require higher dosage of midazolam on a mg/kg basis than adults, and pediatric patients younger than 6 years of age generally require higher drug dosages on a mg/kg basis than older pediatric patients and may require closer monitoring.

The initial dose should be reduced in geriatric patients, since some degree of impairment in one or more organ systems frequently is present. Dosage requirements in this age group generally appear to decrease with increasing age, and the possibility of profound and/or prolonged effects should be considered in older and/or debilitated patients. 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. (See Cautions: Geriatric Precautions.)

Preoperative Sedation, Anxiolysis, and Anterograde Amnesia

For preoperative sedation, anxiolysis and anterograde amnesia in good-risk (e.g., ASA Physical Status I and II) adults younger than 60 years of age, the usual IM dose of midazolam is 70-80 mcg/kg (about 5 mg) administered approximately 30-60 minutes prior to surgery. 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. 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 (20-50 mcg/kg) reportedly produced adequate sedation during the preoperative period; 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 is less critical. As with any potential respiratory depressant, such patients should be observed for signs of cardiorespiratory depression following administration of IM midazolam. Sedative effects usually are apparent within 15 minutes and peak at 30-60 minutes. Midazolam can be administered concomitantly with atropine sulfate, scopolamine hydrochloride, and/or reduced doses of opiate agonists.(See Chemistry and Stability: Stability.)

For preoperative sedation in non-neonatal pediatric patients, the usual IM dose of midazolam is 100-150 mcg/kg; doses in this range usually are effective and do not prolong emergence from general anesthesia. Sedation after IM midazolam administration is age and dose dependent; higher doses may result in deeper and more prolonged sedation. For more anxious patients, doses of up to 500 mcg/kg have been used. The manufacturer states that the total dose usually does not exceed 10 mg, although this has not been systematically studied. If midazolam is administered with an opiate, the initial dose of each must be reduced. The drug may be used IM to sedate pediatric patients to facilitate less traumatic insertion of an IV catheter for titration of additional medication.

For preoperative sedation in pediatric patients, the usual IV (as an intermittent injection) dose of midazolam is age dependent; prolonged sedation and risk of hypoventilation may be associated with the higher doses in each recommended range. IV midazolam should be administered over 2-3 minutes. Because midazolam is water soluble, peak EEG effects are not achieved as quickly as with diazepam; it is essential to wait 2-3 minutes to fully evaluate the sedative effect before starting the procedure or administering a repeat dose. In patients 6 months to 5 years of age, an initial IV dose of 50-100 mcg/kg is recommended; a total dose of up to 600 mcg/kg may be required to reach the desired end point, but usually does not exceed a total of 6 mg. In patients 6-12 years of age, an initial IV dose of 25-50 mcg/kg is recommended; a total dose of up to 400 mcg/kg may be required to reach the desired end point, but usually does not exceed a total of 10 mg. Patients 12-16 years of age should be dosed as adults; although some patients in this age range may require higher than recommended adult doses, the total dose usually does not exceed 10 mg. In nonintubated pediatric patients younger than 6 months of age, limited dosing information is available. The manufacturer states that because it is uncertain when a patient transfers from a neonatal to pediatric physiology, dosing recommendations are unclear; however, because patients younger than 6 months of age are vulnerable to airway obstruction and hypoventilation, titration of drug dose in small increments to clinical effect and careful monitoring are essential.

For preoperative sedation in pediatric patients (6 months up to 16 years of age), a single oral dose of 250-500 mcg/kg is recommended, depending on the status of the patient and the desired effect, up to a maximum of 20 mg. In general, it is recommended that the dose be individualized and modified based on patient age, level of anxiety, and medical need. Younger pediatric patients (e.g., 6 months to younger than 6 years of age) and less cooperative patients may require a higher than usual dose of up to 1 mg/kg (up to a maximum of 20 mg). A dose of 250 mcg/kg may be sufficient for children 6-16 years of age or for cooperative patients, especially if the anticipated intensity and duration of sedation is less critical. For pediatric patients (6 months up to 16 years of age) with cardiac or respiratory compromise, other higher-risk surgical pediatric patients, and pediatric patients who have received concomitant opiates or other CNS depressants, an initial dose of 250 mcg/kg should be considered. Midazolam oral solution has not been studied, nor is it intended, for chronic use.

Procedural Sedation

For sedation prior to short diagnostic (e.g., cardiac catheterization) or endoscopic procedures, midazolam may be used alone or in combination with an opiate agonist. For peroral procedures (e.g., upper GI endoscopy, bronchoscopy), use of a topical anesthetic is generally recommended, and for bronchoscopy, use of an opiate analgesic for premedication also is generally recommended.

For procedural sedation in adults, IV midazolam is administered slowly before the procedure. Initial titration of midazolam dosage should begin with a small dose administered over at least a 2-minute period in average healthy adults younger than 60 years of age. The initial IV dose should not exceed 2.5 mg, although some such patients may respond to as little as 1 mg of the drug. Patients 60 years of age or older, chronically ill and/or debilitated patients, and patients with decreased pulmonary reserve should receive 1-1.5 mg as an initial dose over a longer period of injection. The manufacturer recommends that not more than 1.5 mg over at least 2 minutes be administered as an initial dose in these patients. After waiting at least 2 minutes to fully evaluate the patient's clinical response, midazolam dosage may be further titrated in small increments of the initial dose administered over at least a 2-minute period to the desired effect (e.g., onset of slurred speech) if further sedative effect is required. 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. A total dose of up to 5 mg generally is adequate for conscious 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. Although a total dose up to 200 mcg/kg has been used rarely, particularly if an opiate agonist was not used concomitantly, the manufacturer currently recommends that such doses generally be avoided if possible. 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 over a period of at least 2 minutes in increments of approximately 25% of the initial dose. Some clinicians recommend initiating dosing with 0.5-2 mg and repeating doses, as necessary, at 2- to 3-minute intervals up to a total dose of 100-150 mcg/kg. In patients 60 years of age and older, these clinicians recommend reducing midazolam dosage by 25% or more.

For procedural sedation, premedication with an opiate agonist appears to produce less variable response to midazolam. When used concomitantly with an opiate agonist or other CNS depressant, midazolam dosage should be decreased by about 30% in healthy adults younger than 60 years of age 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. 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.

For procedural sedation in non-neonatal pediatric patients, the usual IM dose of midazolam is 100-150 mcg/kg. Sedation after IM midazolam administration is age and dose dependent; higher doses may result in deeper and more prolonged sedation. For more anxious patients, doses of up to 500 mcg/kg have been used. The manufacturer states that the total dose usually does not exceed 10 mg, although this has not been systematically studied. If midazolam is administered with an opiate, the initial dose of each must be reduced.

For procedural sedation in pediatric patients, the usual IV (as an intermittent injection) dose of midazolam is age dependent; prolonged sedation and risk of hypoventilation may be associated with the higher doses in each recommended range. IV midazolam should be administered over 2-3 minutes. Because midazolam is water soluble, peak EEG effects are not achieved as quickly as with diazepam; it is essential to wait 2-3 minutes to fully evaluate the sedative effect before starting the procedure or administering a repeat dose. In patients 6 months to 5 years of age, an initial IV dose of 50-100 mcg/kg is recommended; a total dose of up to 600 mcg/kg may be required to reach the desired end point, but usually does not exceed a total of 6 mg. In patients 6-12 years of age, an initial IV dose of 25-50 mcg/kg is recommended; a total dose of up to 400 mcg/kg may be required to reach the desired end point, but usually does not exceed a total of 10 mg. Patients 12-16 years of age should be dosed as adults; although some patients in this age range may require higher than recommended adult doses, the total dose usually does not exceed 10 mg. In nonintubated pediatric patients younger than 6 months of age, limited dosing information is available. The manufacturer states that because it is uncertain when a patient transfers from a neonatal to pediatric physiology, dosing recommendations are unclear; however, because patients younger than 6 months of age are vulnerable to airway obstruction and hypoventilation, titration of drug dose in small increments to clinical effect and careful monitoring are essential.

For procedural sedation in pediatric patients (6 months up to 16 years of age), a single oral midazolam dose of 250-500 mcg/kg is recommended, depending on the status of the patient and the desired effect, up to a maximum of 20 mg. In general, it is recommended that the dose be individualized and modified based on patient age, level of anxiety, and medical need. Younger pediatric patients (e.g., 6 months to younger than 6 years of age) and less cooperative patients may require a higher than usual dose of up to 1 mg/kg (up to a maximum of 20 mg). A dose of 250 mcg/kg may be sufficient for children 6-16 years of age or for cooperative patients, especially if the anticipated intensity and duration of sedation is less critical. For pediatric patients (6 months up to 16 years of age) with cardiac or respiratory compromise, other higher-risk surgical pediatric patients, and pediatric patients who have received concomitant narcotics or other CNS depressants, an initial oral dose of 250 mcg/kg should be considered. Midazolam oral solution has not been studied, nor is it intended, for chronic use. In addition, use of the oral solution in children younger than 6 months of age has not been established.

Induction and Maintenance of Anesthesia

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. For induction of general anesthesia, midazolam should be administered prior to other anesthetic agents. 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.

For sedation of intubated and mechanically ventilated patients as a component of anesthesia, midazolam is administered as a continuous IV infusion. In adults, if a loading dose is necessary to initiate sedation rapidly, 10-50 mcg/kg (approximately 0.5-4 mg for a typical adult) may be given slowly or infused over several minutes. This dose may be repeated at 10- to 15-minute intervals until adequate sedation is achieved. For maintenance of sedation in adults, the usual initial infusion rate is 20-100 mcg/kg per hour (approximately 1-7 mg per hour). Higher loading or maintenance infusion rates occasionally may be required in some patients. The lowest recommended doses should be used in patients with residual effects from anesthetic drugs, or in those currently receiving other sedatives or opioids. Individual response to midazolam is variable and infusion rate should be titrated to the desired level of sedation, taking into account the patient's age, clinical status, and current drugs. In general, midazolam should be infused at the lowest rate that produces the desired level of sedation. 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. Larger adjustments or even a small, incremental dose may be necessary if rapid changes in the level of sedation are required. In addition, the infusion rate should be decreased by 10-25% every few hours to find the minimum effective infusion rate. Finding the minimum effective infusion rate decreases the potential accumulation of midazolam and provides for the most rapid recovery once the infusion is terminated. 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 opiate analgesic; however, addition of an opiate generally will reduce the minimum effective midazolam infusion rate.

For patients who have not been premedicated, an initial midazolam dose of 300-350 mcg/kg is administered IV over 20-30 seconds in healthy adults younger than 55 years of age, allowing approximately 2 minutes for clinical effect; however, some clinicians suggest that a lower initial dose (e.g., 200 mcg/kg) be used in these adults. Supplemental doses of about 25% of the initial dose may be given as necessary to complete induction or for maintenance of sedation or anesthesia. Alternatively, induction of anesthesia may be completed with inhalation agents. Total IV induction doses of up to 600 mcg/kg may be required in some resistant patients, but such doses may prolong recovery from anesthesia.

Patients 55 years of age and older who have not been premedicated usually require lower induction doses of midazolam; the manufacturer recommends an initial IV induction dose of 300 mcg/kg in these patients. Patients with severe systemic disease or other debilitation who have not been premedicated also usually require lower induction doses. Initial IV doses of 200-250 mcg/kg usually are adequate in such patients, and doses as low as 150 mcg/kg may be adequate for induction in some debilitated patients.

In premedicated patients, especially those who have received an opiate agonist, the usual induction dose of midazolam is 150-350 mcg/kg. In premedicated adults younger than 55 years of age, the usual induction dose is 250 mcg/kg administered IV over 20-30 seconds; about 2 minutes should be allowed for clinical effects. In premedicated patients 55 years of age and older who are good risk (e.g., ASA I and II) surgical patients, an initial induction dose of 200 mcg/kg is recommended by the manufacturer. In some premedicated patients with severe systemic disease or debilitation, an initial induction dose of 150 mcg/kg may be sufficient.

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

Sedation in Critical-Care Settings

For sedation in intubated and mechanically ventilated adult patients during treatment in critical-care settings (e.g., an ICU), midazolam is administered as a continuous IV infusion. In adults, if a loading dose is necessary to initiate sedation rapidly, 10-50 mcg/kg (approximately 0.5-4 mg for a typical adult) may be given slowly or infused over several minutes. This dose may be repeated at 10- to 15-minute intervals until adequate sedation is achieved. For maintenance of sedation in adults, the usual initial infusion rate is 20-100 mcg/kg per hour (approximately 1-7 mg per hour). Higher loading or maintenance infusion rates occasionally may be required in some patients. The lowest recommended doses should be used in patients with residual effects from anesthetic drugs, or in those currently receiving other sedatives or opiates. 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. In general, midazolam should be infused at the lowest rate that produces the desired level of sedation. 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. Larger adjustments or even a small, incremental dose may be necessary if rapid changes in the level of sedation are required. In addition, the infusion rate should be decreased by 10-25% every few hours to find the minimum effective infusion rate. Finding the minimum effective infusion rate decreases the potential accumulation of midazolam and provides for the most rapid recovery once the infusion is terminated. 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.

For sedation of intubated pediatric (i.e., non-neonatal) patients during treatment in critical-care settings, midazolam generally is initiated with an IV loading dose of 50-200 mcg/kg administered over at least 2-3 minutes; the drug should not be administered as a rapid IV injection. The loading dose should be followed by a continuous IV infusion to maintain the clinical effect. Midazolam infusion has 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). Based on pharmacokinetic parameters and clinical experience, continuous IV infusions of midazolam should be initiated at a rate of 60-120 mcg/kg per hour (1-2 mcg/kg per minute). 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. Frequent patient assessment at regular intervals using standard pain/sedation scales is recommended. 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. Hypotension may be observed in patients who are critically ill, particularly those receiving opiates and/or if midazolam is administered rapidly. 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). These patients also are vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation.

For sedation of intubated preterm (i.e., born at less than 32 weeks' gestation) or term (i.e., born at 32 weeks' gestation or later) neonatal patients during treatment in critical-care settings, midazolam generally is initiated as an IV infusion at a rate of 30 mcg/kg per hour (0.5 mcg/kg per minute) or 60 mcg/kg per hour (1 mcg/kg per minute), respectively. 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. The infusion rate should be reassessed carefully and frequently, particularly after approximately the first 24 hours, to administer the lowest possible effective dose and to reduce the potential for drug accumulation. This is particularly important because of the potential for adverse effects related to benzyl alcohol metabolism.(See Cautions: Pediatric Precautions.) Hypotension may be observed in ill preterm and term neonates, especially in those receiving fentanyl or in patients in whom midazolam is administered rapidly. Because of an increased risk of apnea, extreme caution is advised when sedating a preterm or former preterm neonate whose trachea is not intubated.

Cautions

Adverse effects reported with midazolam hydrochloride are similar to those reported with other benzodiazepines. Changes in vital signs (e.g., respiratory rate, blood pressure, pulse rate) are the most frequent adverse effects associated with parenteral midazolam administration. For further information on adverse effects reported with benzodiazepines, . 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.

Cardiorespiratory Effects

Midazolam can depress respiration. Relatively small doses, such as those used for preoperative sedation, usually do not substantially impair respiratory function; however, relatively large doses (e.g., more than 100-200 mcg/kg) may substantially depress the ventilatory response to carbon dioxide (CO₂) stimulation. In addition, some patients (e.g., geriatric patients, patients with chronic obstructive pulmonary disease) may be predisposed to respiratory depression induced by midazolam.

Decreases in tidal volume and/or respiratory rate occur in about 23 or 11% of adults following IV or IM administration of midazolam, respectively. Apnea occurs in approximately 15% of adults receiving the drug parenterally. Desaturation or apnea has been reported in 4.6 or 2.8%, respectively, of pediatric patients receiving the drug IV. 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. Hypercarbia and stridor generally have been reported in less than 1% of patients receiving the drug orally. 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. In some patients in whom midazolam-induced respiratory depression was not promptly recognized and effectively managed, hypoxic encephalopathy or death has resulted. 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. 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), exhibiting more marked and prolonged depression than patients with healthy lungs.

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. Early recognition and treatment of underventilation and apnea are necessary to avoid hypoxic cardiac arrest. Therefore, respiratory status should be monitored continuously during parenteral midazolam use, dosage of the drug must be carefully individualized, and facilities and equipment for respiratory and cardiovascular support should be readily available.(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.(See Drug Interactions: CNS Depressants.) Use of supplemental oxygen should be considered when heavy sedation is anticipated or required.

Changes in systolic or diastolic blood pressure, principally decreases, and in heart rate are frequently associated with parenteral or oral administration of midazolam; 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. Hypotensive episodes requiring treatment have been reported rarely during or following diagnostic or surgical manipulation in patients receiving midazolam. 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. Severe hypotensive effects may be alleviated by the judicious administration of IV fluids, repositioning the patient, and/or the cautious use of vasopressors. 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. 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.

Other adverse respiratory effects of midazolam include hiccups and coughing, which occur in up to 4 and 1% of patients, respectively, receiving the drug IV. Laryngospasm, bronchospasm, dyspnea, hyperventilation, wheezing, shallow respiration, airway obstruction, and tachypnea occur in less than 1% of patients, principally those receiving the drug IV.

Other adverse cardiovascular effects of midazolam include decreases in systemic vascular resistance, cardiac index, and stroke index. Bradycardia has been reported in up to 1% of pediatric patients receiving midazolam oral solution. Bigeminy, ventricular premature complexes, vasovagal episodes, tachycardia, and nodal rhythms reportedly occur in less than 1% of patients. Trigeminy also has been reported in patients receiving midazolam.

Nervous System Effects

Adverse nervous system effects of midazolam generally are extensions of the pharmacologic actions of the drug; 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. Paradoxical reactions have been reported in 2% of pediatric patients receiving the drug IV.

Excessive sedation, headache, and drowsiness occur in 1-2% of patients following parenteral administration of midazolam. Adverse reactions manifested as agitation, involuntary movements (e.g., tonic/clonic movements, muscle tremor), hyperactivity, and combativeness have occurred in less than 1% of patients receiving parenteral midazolam, principally in those receiving the drug IV. 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.(See Cautions: Precautions and Contraindications.) Agitation has been reported in 2% of pediatric patients receiving the drug orally. Seizure-like activity or nystagmus was reported in 1.1% of pediatric patients receiving the drug IV.

Other adverse nervous system effects occur in less than 1% of patients receiving midazolam, either orally or IV. Such effects include retrograde amnesia, euphoria, hallucination, dysphoria, prolonged emergence from anesthesia, emergence delirium or agitation, dreaming during emergence, prolonged sedation, sleep disturbance, insomnia, nightmares, paresthesia, adverse behavior, mood swings, aggression, excitation, disinhibition, argumentativeness, nervousness, anxiety, restlessness, seizure-like activity, dysarthria, and athetoid movements. Confusion, grogginess, ataxia, dizziness, loss of balance or vertigo, lightheadedness, lethargy, yawning, faint feeling, weakness, slurred speech, blurred vision, strabismus, diplopia, and dysphonia have also been reported in less than 1% of patients.

Midazolam has reduced cerebral blood flow and oxygen consumption in animals and humans. 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). 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.

GI Effects

Nausea and/or vomiting occur in 2-3% of adult patients receiving midazolam IV and in up to 4 or 8%, respectively, of pediatric patients receiving the drug orally. Acid taste, excessive salivation, gagging, drooling, and retching occur in less than 1% of patients. Other adverse GI effects include metallic taste, dry mouth, and constipation.

Sensitivity Reactions

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

Local Effects

Tenderness at the site of injection and pain during injection occur in 5-6% of patients receiving midazolam IV. Erythema and induration occur at the IV site in 2-3% of patients, and phlebitis occurs in less than 1%. Pain at the site of IM injection occurs in about 4% of patients, and local induration, erythema, and muscle stiffness occur in less than 1% of patients receiving midazolam IM. 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).

Urticaria-like elevation at the injection site, swelling or feeling of burning, 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.

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, diplopia, nystagmus, pinpoint pupils, cyclic movements of eyelids, visual disturbances, and focusing difficulty.

Other Adverse Effects

Chills, toothache, blockage of ears, and hematoma occur in less than 1% of patients receiving midazolam parenterally, principally in those receiving the drug IV. 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.

Precautions and Contraindications

Midazolam hydrochloride shares the toxic potentials of the benzodiazepines, and the usual precautions of benzodiazepine administration should be observed.

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

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. Safety and efficacy of midazolam may vary in patients as functions of the dose administered and clinical status of the patient. Midazolam is a potent sedative and requires slow administration and individualized titration of dosage. 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. The immediate availability of specific reversal agents (e.g., flumazenil) is highly recommended. 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. The incidence of such adverse events is higher in patients undergoing procedures involving the airway without the protective effect of an endotracheal tube. 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. Monitoring of vital signs also should continue during the recovery period. 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. When the complexity of the procedure prohibits adequate monitoring by the attending clinician, additional personnel competent in monitoring and managing potential complications should be in attendance. For deeply sedated pediatric patients, a dedicated individual other than the clinician performing the procedure should monitor the patient throughout the procedure. 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.

Careful monitoring and individualization of dosing are particularly important when IV midazolam is used prior to colonoscopy, gastroscopy, or bronchoscopy in geriatric patients, patients with various underlying disease states (e.g., chronic obstructive pulmonary disease, renal failure, congestive heart failure) that may be associated with an increased risk of complications, and patients receiving other 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. 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.

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. Precautions against unintended intra-arterial injection should be taken, and drug extravasation should be avoided.

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. 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.

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. Caution should be exercised if midazolam is administered IV to patients with uncompensated acute illnesses, including severe fluid or electrolyte imbalances. 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. Further recommendations include appropriate presedation fasting.

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. Induction of anesthesia may occur more rapidly in patients with renal impairment, and recovery may be prolonged.

Although the clinical importance has not been determined, midazolam also should be used with caution and dosage individualized carefully in patients with congestive heart failure. 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).

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

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. 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). 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. 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. 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. 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. For pediatric patients, particular care should be taken to ensure safe ambulation. 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.

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

Midazolam is contraindicated in patients with known hypersensitivity to the drug. Midazolam oral solution also is contraindicated in patients allergic to cherries or to formulation excipients. The manufacturer states that the drug also is contraindicated in patients with acute angle-closure glaucoma, but may be administered to patients receiving appropriate treatment for open-angle glaucoma; however, the clinical rationale for this contraindication has been questioned.

Pediatric Precautions

The safety and efficacy of midazolam oral solution have not been established in patients younger than 6 months of age.

Unlike in adult patients, in pediatric patients the dose of midazolam is calculated on a mg/kg basis. As a group, pediatric patients require a higher parenteral dosage of midazolam hydrochloride on a mg/kg basis than do adults, and pediatric patients younger than 6 years of age generally require higher drug dosages on a mg/kg basis than do older pediatric patients and may require closer monitoring. In obese pediatric patients, the drug dose should be calculated on the basis of ideal body weight. 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. Particular care should be taken to ensure safe ambulation of pediatric patients following sedation with midazolam. Clinicians who use this drug in pediatric patients should be aware of, and follow, accepted professional guidelines for pediatric sedation appropriate to the situation.

Higher-risk pediatric surgical patients may require lower midazolam doses, whether or not concomitant sedating drugs have been administered. Pediatric patients with cardiac or respiratory compromise may be unusually sensitive to the respiratory depressant effect of midazolam. 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.

Because of reduced and/or immature organ function, neonates are vulnerable to profound and/or prolonged adverse respiratory effects of midazolam. The drug should not be administered by rapid IV injection in neonates. 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. Likewise, severe hypotension has been observed in neonates receiving midazolam as a continuous infusion who then also received a rapid IV injection of fentanyl. Seizures also have been reported in neonates receiving midazolam as a rapid IV injection.

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. 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. 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. The clinical relevance of these animal findings to humans is not known. 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. 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). 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; 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).

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; no specific general anesthetic or sedation drug has been shown to be less likely to cause neurocognitive deficits than any other such drug. 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. 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. FDA states that procedures that are considered medically necessary should not be delayed or avoided.

Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates. Toxicity appears to have resulted from administration of large amounts (i.e., 100-400 mg/kg daily) of benzyl alcohol in these neonates. 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. There have been reports of death, particularly in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. Although use of drugs preserved with benzyl alcohol should be avoided in neonates whenever possible, 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. The amount of benzyl alcohol exposure from drugs usually is considered negligible compared with that from benzyl alcohol-containing flush solutions. Administration of high dosages of drugs containing this preservative, including midazolam hydrochloride, must take into account the total amount of benzyl alcohol administered. 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. 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.

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 recommends that dosage of the drug be selected carefully in this age group. IV or IM dosage of midazolam should be reduced in geriatric or debilitated patients, particularly in those 70 years of age and older.(See Dosage and Administration: Dosage.) When midazolam is used for induction of anesthesia, time to recovery may be delayed in this population. 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]).(See Cautions: Cardiorespiratory Effects.)

Mutagenicity and Carcinogenicity

In vitro and in vivo microbial and mammalian test systems using midazolam have not revealed evidence of mutagenicity. 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. However, an increased incidence of liver tumors was observed following oral administration of 80 mg/kg daily for 24 months in female mice, and an increased incidence of benign thyroid follicular cell tumors was observed following this dosage in male rats. The pathogenesis of induction of these tumors is not known. 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.

Pregnancy, Fertility, and Lactation

Pregnancy

Midazolam may cause fetal toxicity when administered to pregnant women, but potential benefits from use of the drug may be acceptable in certain conditions despite the possible risks to the fetus. 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. Midazolam has been shown to cross the placenta in humans. Reproduction studies in rabbits and rats using parenteral midazolam maleate in dosages 5 and 10 times the human dosage of 350 mcg/kg have not revealed evidence of fetal malformation. Midazolam should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective. When the drug is administered during pregnancy or if the patient becomes pregnant while receiving this drug, the patient should be informed of the potential hazard to the fetus. Preoperative use of midazolam injection for obstetric procedures (e.g., cesarean section) or during labor and delivery is not recommended, since safety of midazolam has not been established in such procedures and use of other benzodiazepines during the last weeks of pregnancy has caused CNS depression in the neonate.

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. 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.(See Cautions: Pediatric Precautions.)

Fertility

It is not known whether midazolam affects fertility in humans. No evidence of impaired fertility was observed in rats following administration of midazolam maleate dosages up to 10 times the recommended human IV dosage of 350 mcg/kg.

Lactation

Midazolam reportedly is distributed into milk in humans, and the manufacturer states that caution should be exercised when midazolam is administered to nursing women.

Drug Interactions

Metabolism of midazolam is mediated by the cytochrome P-450 (CYP) isoenzyme 3A4, and concomitant use of midazolam with drugs that inhibit this isoenzyme (e.g., some azole antimycotics, HIV protease inhibitors, some calcium-channel blocking agents, some macrolide antibiotics, quinupristin and dalfopristin) may result in increased plasma concentrations of midazolam and increased and prolonged sedation. Midazolam should be administered with caution in patients receiving CYP3A4 inhibitors, and patients should be monitored for excessive sedation. Conversely, concomitant use of midazolam with drugs that induce this isoenzyme may result in decreased plasma concentrations of midazolam. Concomitant administration of erythromycin, diltiazem, verapamil, ketoconazole, fluconazole, itraconazole, or HIV protease inhibitors and oral midazolam may result in clinically important increases in the peak plasma concentrations and areas under the plasma concentration-time curve (AUC) of midazolam, and concomitant administration of rifampin, carbamazepine, phenytoin, or phenobarbital and oral midazolam may result in clinically important decreases in the plasma concentrations and AUCs of midazolam. Caution should be observed if midazolam is administered concomitantly with these drugs. The fact that dosage adjustments of midazolam and/or other drugs may be necessary in patients receiving concomitant therapy with drugs that inhibit or induce the CYP3A4 isoenzyme should be considered; dosage of midazolam should be reduced when the drug is administered orally in patients receiving CYP3A4 inhibitors. The manufacturer states that oral midazolam should be used concomitantly with ketoconazole or itraconazole only when absolutely necessary and with appropriate equipment and personnel available to respond to respiratory insufficiency. 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; 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.

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. When midazolam is used concomitantly with a depressant drug, caution should be exercised and appropriate dosage adjustments made to avoid overdosage.(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. Midazolam dosage should be adjusted according to the type and amount of premedication administered.(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. Opiate agonists can impair the ventilatory response to carbon dioxide (CO₂), and appear to increase the risk of hypotension and prolong the recovery period compared with midazolam alone. Severe hypotension, possibly secondary to increased venous pooling, has occurred when midazolam was used concomitantly with high-dose fentanyl. 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. Opiate antitussive agents should be avoided in patients receiving benzodiazepines, and concomitant use of opiate analgesics and benzodiazepines should be reserved for patients in whom alternative treatment options are inadequate.

Anesthetic Agents

The manufacturer states that thiopental (no longer commercially available in the US) dosage requirements for induction of anesthesia are reduced by about 15% in patients who have received preoperative sedation with IM midazolam.

Patients who have received midazolam as an induction agent may require reduced amounts of inhalation agents during maintenance of anesthesia. IV midazolam appears to decrease the minimum alveolar concentration (MAC) of halothane required for general anesthesia in a linear, dose-related manner.

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

Antifungal Agents

Coadministration of oral midazolam in patients who are taking ketoconazole or itraconazole has been shown to increase the peak plasma concentration of midazolam (309% or 80-240%, respectively) as a result of decreased plasma clearance. 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.

While concomitant administration of oral midazolam and fluconazole has been shown to increase the peak plasma concentration of midazolam by 150%, concomitant administration of oral midazolam and terbinafine does not appear to affect the pharmacokinetics of midazolam.

Macrolide Antibiotics

Concomitant administration of midazolam and erythromycin may affect the pharmacokinetics of midazolam. 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. 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. Because increased plasma concentrations of midazolam may be associated with excessive sedative effects, 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.

While concomitant administration of oral midazolam with erythromycin has been shown to increase the plasma concentration and AUC of midazolam by about 170 and 281-341%, respectively, concomitant administration of oral midazolam and azithromycin does not appear to affect the pharmacokinetics of the benzodiazepine.

Quinupristin and Dalfopristin

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

Cardiovascular Agents

Concomitant administration of oral midazolam and diltiazem or verapamil has resulted in an increase in the peak plasma concentration of midazolam of 105 or 97% and an increase in the AUC of midazolam of 275 or 195%, respectively. In another study, the half-life of midazolam was increased from 5 to 7 hours when the drug was administered in conjunction with diltiazem or verapamil. Concomitant administration of oral midazolam and nitrendipine does not appear to affect the pharmacokinetics of midazolam. Concomitant administration of midazolam and nifedipine does not appear to alter the pharmacokinetics of midazolam.

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%. Although not studied specifically, rifabutin would be expected to decrease the peak plasma concentration and AUC of midazolam.

Anticonvulsants

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

Antiretroviral Agents

Large increases in the peak plasma concentration and AUC of midazolam (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. 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. Because of the potential for intense and prolonged sedation and respiratory depression, the manufacturers of HIV protease inhibitors (e.g., atazanavir, darunavir, fosamprenavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, tipranavir) state that concomitant use of midazolam with HIV protease inhibitors is contraindicated. 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.

The manufacturers of delavirdine and efavirenz state that concomitant use of these agents with midazolam should be avoided because of the potential for the nonnucleoside reverse transcriptase inhibitor (NNRTI) to decrease metabolism of midazolam and result in intense or prolonged sedation or respiratory depression. 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.

Histamine H2-Receptor Antagonists

The effects of concomitant administration of midazolam and cimetidine or ranitidine have not been fully elucidated. Orally administered cimetidine or ranitidine did not substantially alter the pharmacokinetics of either IV or oral midazolam in one study in healthy adults. 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. Oral bioavailability of midazolam may be increased by up to about 30% when cimetidine or ranitidine is given concomitantly, possibly secondary to a pH-dependent enhancement of gastric absorption of midazolam and/or a reduction in hepatic clearance of the drug. In another study, concomitant administration of oral midazolam and cimetidine (800-1200 mg up to 4 times daily) increased the peak plasma concentration 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 the peak plasma concentration and AUC of midazolam by 15-67 and 9-66%, respectively. 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. 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.

Other Drugs

In one patient, the sedative effect of midazolam during anesthesia was antagonized by administration of aminophylline.

Grapefruit Juice

Concomitant administration of grapefruit juice with oral midazolam has been reported to increase bioavailability of the drug. Grapefruit juice does not appear to interfere with metabolism following IV administration of the drug. The interaction between grapefruit juice and the benzodiazepine bioavailability appears to result from inhibition, probably prehepatic, of the cytochrome P-450 enzyme system by some constituent(s) in the juice. 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. The manufacturer states that oral midazolam should not be taken in conjunction with grapefruit juice.

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.

Absorption

Absorption of midazolam hydrochloride from IM injection sites is rapid and nearly complete (mean absolute bioavailability is greater than 90%). IM bioavailability of the lactate appears to be similar to or slightly less than that of the hydrochloride; however, any such difference does not appear to be clinically important. Pharmacologic effects of midazolam usually are apparent within 5-15 minutes but may not be maximal until 15-60 minutes following IM administration; the duration of action usually is about 2 hours (range: 1-6 hours). Peak plasma midazolam concentrations generally are attained within 45 minutes following IM administration. 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. 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.

Following IV administration of usual doses of midazolam hydrochloride, the onset of sedative, anxiolytic, and amnesic action usually occurs within 1-5 minutes. However, onset is affected by many factors, including total dose administered, rate of administration, patient age, serum albumin concentration, renal function, and the presence of other drugs. 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. Duration of action following IV administration is usually less than 2 hours; however, the pharmacologic effects may persist up to 6 hours in some patients, and the duration of action appears to be dose related. Limited data suggest that the onset may be more rapid and the duration prolonged in patients with chronic renal failure, probably secondary to decreased protein binding in these patients.

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. Following single IV doses, plasma concentrations of midazolam generally are 10-30 times higher than those of the principal metabolite, 1-hydroxymethylmidazolam.

Midazolam hydrochloride is absorbed rapidly from the GI tract, with maximum plasma concentrations usually occurring within 1-2 hours. Following oral administration, the drug undergoes substantial first-pass metabolism in the liver and intestine, with only about 40-50% (range: 28-72%) of an orally administered dose reaching systemic circulation unchanged. Pharmacologic effects of midazolam usually are apparent within 10-20 minutes following administration of midazolam oral solution in pediatric patients. 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. 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. 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.

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

Distribution

At physiologic pH, midazolam is highly lipophilic; however, the lipophilicity of the drug decreases with decreasing pH.(See Chemistry and Stability: Chemistry.) Following IV administration in humans, midazolam is rapidly and apparently widely distributed. 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). Volume of distribution of midazolam appears to be 1.5-2 times higher in adults with chronic renal failure and 2-3 times higher in adults with congestive heart failure 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.

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

In both adult and pediatric patients older than 1 year of age, approximately 94-97% of midazolam hydrochloride is bound to plasma proteins, mainly to serum albumin; protein binding of the drug is decreased in patients with chronic renal failure. In healthy individuals, the drug's principal metabolite, 1-hydroxymethylmidazolam, is 89% protein bound. The degree of protein binding appears to be independent of the plasma concentration of the drug.

Midazolam crosses the placenta and is distributed into amniotic fluid in animals and humans; however, placental transfer of drug appears to occur more slowly than with diazepam. 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; both umbilical venous and umbilical arterial midazolam concentrations were lower than maternal concentrations. Midazolam reportedly is distributed into milk in humans.(See Cautions: Pregnancy, Fertility, and Lactation.)

Elimination

Plasma midazolam concentrations appear to decline in a biphasic manner following IV administration. Following a single IV dose in healthy adults, the half-life of midazolam in the initial distribution phase (t_½α) averages 6-20 minutes, and the half-life in the terminal elimination phase (t_½β) averages 1-4 hours (range: 1-12.3 hours). Limited data suggest that the half-life of midazolam may be prolonged in obese patients (presumably secondary to an increased volume of distribution), geriatric individuals, and patients with impaired hepatic function or with congestive heart failure. The half-life of midazolam is also reportedly prolonged in patients receiving the drug for induction of anesthesia associated with major surgical procedures. Elimination half-life does not appear to be altered substantially in patients with chronic renal failure. 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). 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. In seriously ill neonates, the terminal elimination half-life is substantially prolonged (i.e., 6.5-12 hours).

Midazolam is metabolized extensively in the liver and intestine by cytochrome P-450 CYP3A4. 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). These metabolites undergo rapid conjugation with glucuronic acid in the liver. Although the elimination half-life of the principal metabolite, 1-hydroxymethylmidazolam, is not clearly established, it is estimated to be about 60-80 minutes. The 1-hydroxymethyl and 4-hydroxy metabolites are reportedly pharmacologically active; potency of 1-hydroxymethylmidazolam appears to be similar to that of midazolam. The 1-hydroxymethyl-4-hydroxy metabolite appears to have little, if any, pharmacologic activity.

Midazolam is excreted in urine almost entirely as conjugated metabolites. Approximately 45-57% of an IV dose is excreted in urine as conjugated 1-hydroxymethylmidazolam, small amounts as conjugates of 4-hydroxymidazolam and 1-hydroxymethyl-4-hydroxymidazolam, and less than 0.03% as unchanged drug. 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, principally (about 60-70% of a dose) as conjugated 1-hydroxymethylmidazolam. Approximately 2-10% of an oral dose is excreted in feces.

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

Following IV administration in healthy individuals and pediatric patients, total apparent plasma clearance of midazolam averages 2.5-12.8 mL/minute per kg. 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. 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. 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, 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. 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. 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.