MIDAZOLAM: 11,192 Adverse Event Reports & Safety Profile

DESCRIPTION: Midazolam hydrochloride is a water-soluble benzodiazepine available as a sterile, nonpyrogenic parenteral dosage form for intravenous or intramuscular injection. Each mL contains midazolam hydrochloride equivalent to 5 mg midazolam compounded with 0.8% sodium chloride and 0.01% edetate disodium, with 1% benzyl alcohol as preservative; the pH is adjusted to 3 to 3.6 with hydrochloric acid and, if necessary, sodium hydroxide. Midazolam is a white to light yellow crystalline compound, insoluble in water. The hydrochloride salt of midazolam, which is formed in situ , is soluble in aqueous solutions. Chemically, midazolam HCl is 8-chloro-6-(2-fluorophenyl)-1-methyl-4 H -imidazo[1,5-a][1,4]benzodiazepine hydrochloride. Midazolam hydrochloride has the following structural formula: C 18 H 13 ClFN 3

• HCl M.W.

362.25 Under the acidic conditions required to solubilize midazolam in the product, midazolam is present as an equilibrium mixture (shown below) of the closed ring form shown above and an open-ring structure formed by the acid-catalyzed ring opening of the 4,5-double bond of the diazepine ring. The amount of open-ring form is dependent upon the pH of the solution. At the specified pH of the product, the solution may contain up to about 25% of the open-ring compound. At the physiologic conditions under which the product is absorbed (pH of 5 to 8) into the systemic circulation, any open-ring form present reverts to the physiologically active, lipophilic, closed-ring form (midazolam) and is absorbed as such. The following chart plots the percentage of midazolam present as the open-ring form as a function of pH in aqueous solutions. As indicated in the graph, the amount of open-ring compound present in solution is sensitive to changes in pH over the pH range specified for the product: 3.0 to 3.6 for the 5 mg/mL concentration. Above pH 5, at least 99% of the mixture is present in the closed-ring form.

Midazolam

Injection, USP pharmacy bulk package is a sterile solution dosage form for preparing intravenous (IV) or intramuscular (IM) injections. Each pharmacy bulk package contains 500 mg midazolam in a 100 mL vial. The contents are intended for use in a pharmacy admixture program and are restricted to the preparation of IV or IM injection, or preparation of admixture for IV infusion. structure open ring ph fig

INDICATIONS AND USAGE Midazolam hydrochloride injection is indicated: intramuscularly or intravenously for preoperative sedation/anxiolysis/amnesia; intravenously as an agent for sedation/anxiolysis/amnesia prior to or during diagnostic, therapeutic or endoscopic procedures, such as bronchoscopy, gastroscopy, cystoscopy, coronary angiography, cardiac catheterization, oncology procedures, radiologic procedures, suture of lacerations and other procedures either alone or in combination with other CNS depressants; intravenously for induction of general anesthesia, before administration of other anesthetic agents. With the use of narcotic premedication, induction of anesthesia can be attained within a relatively narrow dose range and in a short period of time. Intravenous midazolam can also be used as a component of intravenous supplementation of nitrous oxide and oxygen (balanced anesthesia); continuous intravenous infusion for sedation of intubated and mechanically ventilated patients as a component of anesthesia or during treatment in a critical care setting.

DOSAGE AND ADMINISTRATION: The intent of the pharmacy bulk package for this product is for preparation of intravenous or intramuscular injection, or preparation of admixture for intravenous infusion. NOTE: CONTAINS BENZYL ALCOHOL (see WARNINGS and PRECAUTIONS , Pediatric Use ) Midazolam injection is a potent sedative agent that requires slow administration and individualization of dosage. Clinical experience has shown midazolam to be 3 to 4 times as potent per mg as diazepam. BECAUSE SERIOUS AND LIFE-THREATENING CARDIORESPIRATORY ADVERSE EVENTS HAVE BEEN REPORTED, PROVISION FOR MONITORING, DETECTION AND CORRECTION OF THESE REACTIONS MUST BE MADE FOR EVERY PATIENT TO WHOM MIDAZOLAM INJECTION IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. The potential for these latter effects is increased in debilitated patients, those receiving concomitant medications capable of depressing the CNS, and patients without an endotracheal tube but undergoing a procedure involving the upper airway such as endoscopy or dental (see BOXED WARNING and WARNINGS ). Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, caution should be exercised before continuing administration of midazolam (see WARNINGS ). Midazolam injection should only be administered IM or IV (see WARNINGS ). Care should be taken to avoid intra-arterial injection or extravasation (see WARNINGS ). Midazolam injection may be mixed in the same syringe with the following frequently used premedications: morphine sulfate, meperidine, atropine sulfate or scopolamine. Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with Lactated Ringer’s solution for up to 4 hours.

The

5 mg/mL formulation of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water.

Monitoring

Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other CNS depressants. Continuous monitoring of respiratory and cardiac function is required (i.e., pulse oximetry). Adults and Pediatrics: Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their 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. Titration to effect with multiple small doses is essential for safe administration. It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation. Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration. This is an important consideration for all patients who receive intravenous midazolam. Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured (see WARNINGS ). Pediatrics: For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure. Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

Usual Adult Dose Intramuscularly

The recommended premedication dose of midazolam for good risk (ASA Physical Status I & II) adult patients below the age of 60 years is 0.07 to 0.08 mg/kg IM (approximately 5 mg IM) administered up to 1 hour before surgery. For preoperative sedation/anxiolysis/ amnesia (induction of sleepiness or drowsiness and relief of apprehension and to impair memory of perioperative events). For intramuscular use, midazolam should be injected deep in a large muscle mass. The dose must be individualized and reduced when IM midazolam is administered to patients with chronic obstructive pulmonary disease, other higher risk surgical patients, patients 60 or more years of age, and patients who have received concomitant narcotics or other CNS depressants (see ADVERSE REACTIONS ). In a study of patients 60 years or older, who did not receive concomitant administration of narcotics, 2 to 3 mg (0.02 to 0.05 mg/kg) of midazolam produced adequate sedation during the preoperative period. The dose of 1 mg IM midazolam may suffice for some older patients if the anticipated intensity and duration of sedation is less critical. As with any potential respiratory depressant, these patients require observation for signs of cardiorespiratory depression after receiving IM midazolam. Onset is within 15 minutes, peaking at 30 to 60 minutes. It can be administered concomitantly with atropine sulfate or scopolamine hydrochloride and reduced doses of narcotics.

Intravenously

When used for sedation/anxiolysis/amnesia for a procedure, dosage must be individualized and titrated. Midazolam should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. Individual response will vary with age, physical status and concomitant medications, but may also vary independent of these factors (see WARNINGS concerning cardiac/respiratory arrest/airway obstruction/hypoventilation.) Sedation/anxiolysis/amnesia for procedures ( See INDICATIONS AND USAGE ): Narcotic premedication results in less variability in patient response and a reduction in dosage of midazolam. For peroral procedures, the use of an appropriate topical anesthetic is recommended. For bronchoscopic procedures, the use of narcotic premedication is recommended. Midazolam injection 1 mg/mL formulation is recommended for sedation/anxiolysis/amnesia for procedures to facilitate slower injection.

The

5 mg/mL formulation may be diluted with 0.9% sodium chloride or 5% dextrose in water. 1.

Healthy Adults

Below the Age of 60: Titrate slowly to the desired effect (e.g., the initiation of slurred speech). Some patients may respond to as little as 1 mg. No more than 2.5 mg should be given over a period of at least 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If further titration is necessary, continue to titrate, using small increments, to the appropriate level of sedation. Wait an additional 2 or more minutes after each increment to fully evaluate the sedative effect. A total dose greater than 5 mg is not usually necessary to reach the desired endpoint. If narcotic premedication of other CNS depressants are used, patients will require approximately 30% less midazolam than unpremedicated patients. 2.

Patients Age

60 or Older, and Debilitated or Chronically Ill Patients: Because the danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve, and because the peak effect may take longer in these patients, increments should be smaller and the rate of injection slower. Titrate slowly to the desired effect (e.g., the initiation of slurred speech). Some patients may respond to as little as 1 mg. No more than 1.5 mg should be given over a period of no less than 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If additional titration is necessary, it should be given at a rate of no more than 1 mg over a period of 2 minutes, waiting an additional 2 or more minutes each time to fully evaluate the sedative effect. Total doses greater than 3.5 mg are not usually necessary. If concomitant CNS depressant premedications are used in these patients, they will require at least 50% less midazolam than healthy young unpremedicated patients. 3.

Maintenance

Dose: Additional doses to maintain the desired level of sedation may be given in increments of 25% of the dose used to first reach the sedative endpoint, but again only by slow titration, especially in the elderly and chronically ill or debilitated patient. These additional doses should be given only after a thorough clinical evaluation clearly indicates the need for additional sedation. Induction of Anesthesia: For induction of general anesthesia, before administration of other anesthetic agents. Individual response to the drug is variable, particularly when a narcotic premedication is not used. The dosage should be titrated to the desired effect according to the patient’s age and clinical status. When midazolam is used before other intravenous agents for induction of anesthesia, the initial dose of each agent may be significantly reduced, at times to as low as 25% of the usual initial dose of the individual agents.

Unpremedicated

Patients: In the absence of premedication, an average adult under the age of 55 years will usually require an initial dose of 0.3 to 0.35 mg/kg for induction, administered over 20 to 30 seconds and allowing 2 minutes for effect. If needed to complete induction, increments of approximately 25% of the patient’s initial dose may be used; induction may instead be completed with inhalational anesthetics. In resistant cases, up to 0.6 mg/kg total dose may be used for induction, but such larger doses may prolong recovery. Unpremedicated patients over the age of 55 years usually require less midazolam for induction; an initial dose of 0.3 mg/kg is recommended. Unpremedicated patients with severe systemic disease or other debilitation usually require less midazolam for induction. An initial dose of 0.2 to 0.25 mg/kg will usually suffice; in some cases, as little as 0.15 mg/kg may suffice.

Premedicated

Patients: When the patient has received sedative or narcotic premedication, particularly narcotic premedication, the range of recommended doses is 0.15 to 0.35 mg/kg. In average adults below the age of 55 years, a dose of 0.25 mg/kg, administered over 20 to 30 seconds and allowing 2 minutes for effect, will usually suffice. The initial dose of 0.2 mg/kg is recommended for good risk (ASA I & II) surgical patients over the age of 55 years. In some patients with severe systemic disease or debilitation, as little as 0.15 mg/kg may suffice. Narcotic premedication frequently used during clinical trials included fentanyl (1.5 to 2 mcg/kg IV, administered 5 minutes before induction), morphine (dosage individualized, up to 0.15 mg/kg IM), and meperidine (dosage individualized, up to 1 mg/kg IM). Sedative premedications were hydroxyzine pamoate (100 mg orally) and sodium secobarbital (200 mg orally). Except for intravenous fentanyl, administered 5 minutes before induction, all other premedications should be administered approximately 1 hour prior to the time anticipated for midazolam induction. Injectable midazolam can also be used during maintenance of anesthesia, for surgical procedures, as a component of balanced anesthesia. Effective narcotic premedication is especially recommended in such cases. Incremental injections of approximately 25% of the induction dose should be given in response to signs of lightening of anesthesia and repeated as necessary.

Continuous Infusion

Usual Adult Dose: If a loading dose is necessary to rapidly initiate sedation, 0.01 to 0.05 mg/kg (approximately 0.5 to 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, the usual initial infusion rate is 0.02 to 0.10 mg/kg/hr (1 to 7 mg/hr). Higher loading or maintenance infusion rates may occasionally be required in some patients. The lowest recommended doses should be used in patients with residual effects from anesthetic drugs, or in those concurrently receiving other sedatives or opioids. Individual response to midazolam is variable. The infusion rate should be titrated to the desired level of sedation, taking into account the patient’s age, clinical status and current medications. 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 midazolam infusion rate adjusted up or down by 25% to 50% of the initial infusion rate so as to assure adequate titration of sedation level. Larger adjustments or even a small incremental dose may be necessary if rapid changes in the level of sedation are indicated. In addition, the infusion rate should be decreased by 10% to 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 concurrent administration of an opioid analgesic. Addition of an opioid will generally reduce the minimum effective midazolam infusion rate. For continuous infusion, midazolam 5 mg/mL formulation is recommended diluted to a concentration of 0.5 mg/mL with 0.9% sodium chloride or 5% dextrose in water. PEDIATRIC PATIENTS UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring (see tables below). In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. For appropriate patient monitoring see BOXED WARNING , WARNINGS , DOSAGE AND ADMINISTRATION , Monitoring . The healthcare practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation. OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION (OAA/S)

Assessment Categories Responsiveness Speech Facial

Expression Eyes Composite Score Responds readily to name spoken in normal tone normal normal clear, no ptosis 5 (alert) Lethargic response to name spoken in normal tone mild slowing or thickening mild relaxation glazed or mild ptosis (less than half the eye) 4 Responds only after name is called loudly and/or repeatedly slurring or prominent slowing marked relaxation (slack jaw) glazed and marked ptosis (half the eye or more) 3 Responds only after mild prodding or shaking few recognizable words — — 2 Does not respond to mild prodding or shaking — — — 1 (deep sleep) FREQUENCY OF OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION COMPOSITE SCORES IN ONE STUDY OF PEDIATRIC PATIENTS UNDERGOING PROCEDURES WITH INTRAVENOUS MIDAZOLAM FOR SEDATION Age Range (years) n OAA/S Score 1 (deep sleep) 2 3 4 5 (alert) 1 to 2 16 6 (38%) 4 (25%) 3 (19%) 3 (19%) 0 >2 to 5 22 9 (41%) 5 (23%) 8 (36%) 0 0 >5 to 12 34 1 (3%) 6 (18%) 22 (65%) 5 (15%) 0 >12 to 17 18 0 4 (22%) 14 (78%) 0 0 Total (1 to 17) 90 16 (18%) 19 (21%) 47 (52%) 8 (9%) 0 INTRAMUSCULARLY USUAL PEDIATRIC DOSE (NON-NEONATAL) For sedation/anxiolysis/ amnesia prior to anesthesia or for procedures, intramuscular midazolam can be used to sedate pediatric patients to facilitate less traumatic insertion of an intravenous catheter for titration of additional medication. Sedation after intramuscular midazolam is age and dose dependent: higher doses may result in deeper and more prolonged sedation. Doses of 0.1 to 0.15 mg/kg are usually effective and do not prolong emergence from general anesthesia. For more anxious patients, doses up to 0.5 mg/kg have been used. Although not systematically studied, the total dose usually does not exceed 10 mg. If midazolam is given with an opioid, the initial dose of each must be reduced. INTRAVENOUSLY BY INTERMITTENT INJECTION USUAL PEDIATRIC DOSE (NON-NEONATAL) For sedation/ anxiolysis/amnesia prior to and during procedures or prior to anesthesia. It should be recognized that the depth of sedation/anxiolysis needed for pediatric patients depends on the type of procedure to be performed. For example, simple light sedation/anxiolysis in the preoperative period is quite different from the deep sedation and analgesia required for an endoscopic procedure in a child. For this reason, there is a broad range of dosage. For all pediatric patients, regardless of the indications for sedation/anxiolysis, it is vital to titrate midazolam and other concomitant medications slowly to the desired clinical effect. The initial dose of midazolam should be administered over 2 to 3 minutes. Since midazolam is water soluble, it takes approximately three times longer than diazepam to achieve peak EEG effects, therefore one must wait an additional 2 to 3 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose. If further sedation is necessary, continue to titrate with small increments until the appropriate level of sedation is achieved. If other medications capable of depressing the CNS are coadministered, the peak effect of those concomitant medications must be considered and the dose of midazolam adjusted. The importance of drug titration to effect is vital to the safe sedation/anxiolysis of the pediatric patient. The total dose of midazolam will depend on patient response, the type and duration of the procedure, as well as the type and dose of concomitant medications. 1. Pediatric patients less than 6 months of age: Limited information is available in non-intubated pediatric patients less than 6 months of age. It is uncertain when the patient transfers from neonatal physiology to pediatric physiology, therefore the dosing recommendations are unclear. Pediatric patients less than 6 months of age are particularly vulnerable to airway obstruction and hypoventilation, therefore titration with small increments to clinical effect and careful monitoring are essential. 2. Pediatric patients 6 months to 5 years of age: Initial dose 0.05 to 0.1 mg/kg; total dose up to 0.6 mg/kg may be necessary to reach the desired endpoint but usually does not exceed 6 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses. 3. Pediatric patients 6 to 12 years of age: Initial dose 0.025 to 0.05 mg/kg; total dose up to 0.4 mg/kg may be needed to reach the desired endpoint but usually does not exceed 10 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses. 4. Pediatric patients 12 to 16 years of age: Should be dosed as adults. Prolonged sedation may be associated with higher doses; some patients in this age range will require higher than recommended adult doses but the total dose usually does not exceed 10 mg. The dose of midazolam must be reduced in patients premedicated with opioid or other sedative agents including midazolam. Higher risk or debilitated patients may require lower dosages whether or not concomitant sedating medications have been administered (see WARNINGS ). CONTINUOUS INTRAVENOUS INFUSION USUAL PEDIATRIC DOSE (NON-NEONATAL) For sedation/anxiolysis/ amnesia in critical care settings. To initiate sedation, an intravenous loading dose of 0.05 to 0.2 mg/kg administered over at least 2 to 3 minutes can be used to establish the desired clinical effect IN PATIENTS WHOSE TRACHEA IS INTUBATED. (Midazolam should not be administered as a rapid intravenous dose.) This loading dose may be followed by a continuous intravenous infusion to maintain the effect. An infusion of midazolam has been used in patients whose trachea was intubated but who were allowed to breathe spontaneously. Assisted ventilation is recommended for pediatric patients who are receiving other central nervous system depressant medications such as opioids. Based on pharmacokinetic parameters and reported clinical experience, continuous intravenous infusions of midazolam should be initiated at a rate of 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min). The rate of infusion can be increased or decreased (generally by 25% of the initial or subsequent infusion rate) as required, or supplemental intravenous doses of midazolam can be administered to increase or maintain the desired effect. Frequent assessment at regular intervals using standard pain/sedation scales is recommended. Drug elimination may be delayed in patients receiving erythromycin and/or other P450-3A4 enzyme inhibitors (see PRECAUTIONS , Drug Interactions ) and in patients with liver dysfunction, low cardiac output (especially those requiring inotropic support), and in neonates. Hypotension may be observed in patients who are critically ill, particularly those receiving opioids and/or when midazolam is rapidly administered. When initiating an infusion with midazolam in hemodynamically compromised patients, the usual loading dose of midazolam should be titrated in small increments and the patient monitored for hemodynamic instability (e.g., hypotension). These patients are also vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation.

Continuous Intravenous Infusion Usual Neonatal Dose

For sedation in critical care settings. Based on pharmacokinetic parameters and reported clinical experience in preterm and term neonates WHOSE TRACHEA WAS INTUBATED, continuous intravenous infusions of midazolam should be initiated at a rate of 0.03 mg/kg/hr (0.5 mcg/kg/min) in neonates <32 weeks and 0.06 mg/kg/hr (1 mcg/kg/min) in neonates >32 weeks. Intravenous loading doses should not be used in neonates, rather the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. The rate of infusion should be carefully and frequently reassessed, particularly after the first 24 hours so as to administer the lowest possible effective dose and reduce the potential for drug accumulation. This is particularly important because of the potential for adverse effects related to metabolism of the benzyl alcohol (see WARNINGS , Usage in Preterm Infants and Neonates ) . Hypotension may be observed in patients who are critically ill and in preterm and term infants, particularly those receiving fentanyl and/or when midazolam is administered rapidly. Due to an increased risk of apnea, extreme caution is advised when sedating preterm and former preterm patients whose trachea is not intubated. NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. DIRECTIONS FOR DISPENSING AND PROPER USE OF PHARMACY BULK PACKAGE: Pharmacy Bulk Package – Not for Direct Infusion The Pharmacy Bulk Package is for use in the hospital pharmacy admixture service only under a laminar flow hood. Using aseptic technique, the container closure may be penetrated only one time using a suitable sterile dispensing set or transfer device that allows measured dispensing of the contents. Use of a syringe and needle is not recommended as it may cause leakage. The withdrawal of the container contents should be accomplished without delay. However, should this not be possible, a maximum time of 4 HOURS from initial port closure entries is permitted to complete fluid transfer operations.

CONTRAINDICATIONS Injectable midazolam hydrochloride is contraindicated in patients with a known hypersensitivity to the drug. Benzodiazepines are contraindicated in patients with acute narrow-angle glaucoma. Benzodiazepines may be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction with midazolam hydrochloride; patients with glaucoma have not been studied. Midazolam hydrochloride is not intended for intrathecal or epidural administration due to the presence of the preservative benzyl alcohol in the dosage form. Midazolam hydrochloride is contraindicated for use in premature infants because the formulation contains benzyl alcohol (see WARNINGS and PRECAUTIONS , Pediatric Use ).

ADVERSE REACTIONS The distribution of adverse events occurring in patients evaluated in a randomized, double-blind, parallel- group trial are presented in Tables 5 and 6 by body system in order of decreasing frequency: for the premedication period (eg, sedation period prior to induction of anesthesia) alone, see Table 5; for over the entire monitoring period including premedication, anesthesia and recovery, see Table 6. The distribution of adverse events occurring during the premedication period, before induction of anesthesia, is presented in Table 5. Emesis, which occurred in 31/397 (8%) patients over the entire monitoring period, occurred in 3/397 (0.8%) of patients during the premedication period (from midazolam administration to mask induction). Nausea, which occurred in 14/397 (4%) patients over the entire monitoring period (premedication, anesthesia and recovery), occurred in 2/397 (0.5%) patients during the premedication period. This distribution of all adverse events occurring in ≥1% of patients over the entire monitoring period are presented in Table 6. For the entire monitoring period (premedication, anesthesia and recovery), adverse events were reported by 82/397 (21%) patients who received midazolam overall. The most frequently reported adverse events were emesis occurring in 31/397 (8%) patients and nausea occurring in 14/397 (4%) patients. Most of these gastrointestinal events occurred after the administration of other anesthetic agents. For the respiratory system overall, adverse events (hypoxia, laryngospasm, rhonchi, coughing, respiratory depression, airway obstruction, upper-airway congestion, shallow respirations), occurred during the entire monitoring period in 31/397 (8%) patients and increased in frequency as dosage was increased: 7/132 (5%) patients in the 0.25 mg/kg dose group, 9/132 (7%) patients in the 0.5 mg/kg dose group, and 15/133 (11%) patients in the 1.0 mg/kg dose group. Most of the respiratory adverse events occurred during induction, general anesthesia or recovery. One patient (0.25%) experienced a respiratory system adverse event (laryngospasm) during the premedication period. This adverse event occurred precisely at the time of induction. Although many of the respiratory complications occurred in settings of upper airway procedures or concurrently administered opioids, a number of these events occurred outside of these settings as well. In this study, administration of midazolam HCl syrup was generally accompanied by a slight decrease in both systolic and diastolic blood pressures, as well as a slight increase in heart rate.

Table

5: Adverse Events Occurring During the Premedication Period Before Mask Induction in the Randomized, Double-Blind, Parallel-Group Trial Body System Treatment Regimen Overall No. Patients with Adverse Events 0.25 mg/kg (n=132) 0.50 mg/kg (n=132) 1.0 mg/kg (n=133) (n=397) No. (%) No. (%) No. (%) No. (%)

Gastrointestinal System Disorders Emesis

1 (0.76%) 1 (0.76%) 1 (0.75%) 3 (0.76%)

Nausea

2 (1.5%) 2 (0.50%)

Respiratory System Disorders Laryngospasm

1* (0.75%) 1 (0.25%)

Sneezing/Rhinorrhea

1 (0.75%) 1 (0.25%) ALL BODY SYSTEMS 1 (0.76%) 1 (0.76%) 5 (3.8%) 7 (1.8%) *This adverse event occurred precisely at the time of induction.

Table

6: Adverse Events (≥1%) From the Randomized, Double-Blind, Parallel-Group Trial on Entire Monitoring Period (premedication, anesthesia, recovery)

Body System Treatment Regimen

Overall No. Patients with Adverse Events 0.25 mg/kg (n=132) 0.50 mg/kg (n=132) 1.0 mg/kg (n=133) (n=397) No. (%) No. (%) No. (%) No. (%)

Gastrointestinal System Disorders Emesis

11 (8%) 5 (4%) 15 (11%) 31 (8%)

Nausea

6 (5%) 2 (2%) 6 (5%) 14 (4%)

Overall

16 (12%) 8 (6%) 16 (12%) 40 (10%)

Respiratory System Disorders Hypoxia

0 5 (4%) 4 (3%) 9 (2%)

Laryngospasm

0 1 (<1%) 5 (4%) 6 (2%)

Respiratory Depression

2 (2%) 1 (<1%) 2 (2%) 5 (1%)

Rhonchi

2 (2%) 1 (<1%) 2 (2%) 5 (1%)

Airway Obstruction

2 (2%) 2 (2%) 0 4 (1%)

Upper Airway Congestion

2 (2%) 0 2 (2%) 4 (1%)

Overall

7 (5%) 9 (7%) 15 (11%) 31 (8%)

Psychiatric Disorders Agitated

1 (<1%) 2 (2%) 3 (2%) 6 (2%)

Overall

1 (<1%) 3 (2%) 4 (3%) 8 (2%)

Heart

Rate, Rhythm Disorders Bradycardia 1 (<1%) 3 (2%) 0 4 (1%)

Bigeminy

2 (2%) 0 0 2 (<1%)

Overall

3 (2%) 3 (2%) 1 (<1%) 7 (2%) Central & Peripheral Nervous System Disorders Prolonged Sedation 0 0 2 (2%) 2 (<1%)

Overall

2 (2%) 0 3 (2%) 5 (1%) Skin and Appendages Disorders Rash 2 (2%) 0 0 2 (<1%)

Overall

2 (2%) 2 (2%) 0 4 (1%) ALL BODY SYSTEMS 26 (20%) 23 (17%) 33 (25%) 82 (21%) There were no deaths during the study and no patient withdrew from the study due to adverse events. Serious adverse events (both respiratory disorders) were experienced postoperatively by two patients: one case of airway obstruction and desaturation (SpO 2 of 33%) in a patient given midazolam HCl syrup 0.25 mg/kg, and one case of upper airway obstruction and respiratory depression following 0.5 mg/kg. Both patients had received intravenous morphine sulfate (1.5 mg total for both patients). Other adverse events that have been reported in the literature with the oral administration of midazolam (not necessarily midazolam HCl syrup), are listed below. The incidence rate for these events was generally <1%. Respiratory: apnea, hypercarbia, desaturation, stridor. Cardiovascular: decreased systolic and diastolic blood pressure, increased heart rate. Gastrointestinal: nausea, vomiting, hiccoughs, gagging, salivation, drooling.

Central Nervous

System: dysphoria, disinhibition, excitation, aggression, mood swings, hallucinations, adverse behavior, agitation, dizziness, confusion, ataxia, vertigo, dysarthria.

Special

Senses: diplopia, strabismus, loss of balance, blurred vision.

AND PRECAUTIONS Cardiorespiratory Adverse Reactions: Serious cardiorespiratory adverse reactions have occurred, sometimes resulting in death or permanent neurologic injury. ( 5.3 )

Paradoxical

Behavior: Agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients. ( 5.4 ) Dependence and Withdrawal with Long-Term Use: Use for several days to weeks may lead to physical dependence to midazolam. Do not abruptly discontinue midazolam. Gradually taper the dosage using a tapering schedule that is individualized to the patient. ( 5.5 ) Debilitation and Comorbid Considerations : Higher risk adult and pediatric surgical patients, elderly patients and debilitated adult and pediatric patients require lower dosages, whether or not concomitant sedating medications have been administered. ( 5.6 ) Risk of Intra-Arterial Injection: There have been limited reports of intra-arterial injection of midazolam. Adverse events have included local reactions, as well as isolated reports of seizure activity in which no clear causal relationship was established. ( 5.7 )

Impaired Cognitive

Function : Because of partial or complete impairment of recall, patients should not operate hazardous machinery or a motor vehicle until drug effects have subsided. ( 5.8 ) Hypotension and Seizure in Preterm Infants and Neonates: Avoid rapid injection in the neonatal population. ( 5.9 )

Neonatal

Sedation and Withdrawal Syndrome: Receiving Midazolam in 0.9% Sodium Chloride Injection during pregnancy can result in neonatal sedation and/or neonatal withdrawal. ( 5.10 , 8.1 )

Pediatric

Neurotoxicity : In developing animals, exposures greater than 3 hours cause neurotoxicity. Weigh benefits against potential risks when considering elective procedures in children under 3 years old. ( 5.11 )

5.1 Personnel and Equipment for Monitoring and Resuscitation Prior to the intravenous administration of midazolam in any dose, ensure the immediate availability of oxygen, resuscitative drugs, age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and skilled personnel for the maintenance of a patent airway and support of ventilation. Only personnel trained in the administration of procedural sedation, and not involved in the conduct of the diagnostic or therapeutic procedure, should administer Midazolam in 0.9% Sodium Chloride Injection. Administering personnel must be trained in the detection and management of airway obstruction, hypoventilation, and apnea, including the maintenance of a patent airway, supportive ventilation, and cardiovascular resuscitation. Continuously monitor patients for early signs of hypoventilation, airway obstruction, or apnea, with means readily available (e.g., pulse oximetry). Hypoventilation, airway obstruction, and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately. A benzodiazepine reversal agent (i.e., flumazenil) should be immediately available during administration of Midazolam in 0.9% Sodium Chloride Injection. Continuously monitor vital signs during the recovery period. Because intravenous midazolam can depress respiration <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12 )]</span> , especially when used concomitantly with opioid agonists and other sedatives <span class="opacity-50 text-xs">[see Dosage and Administration ( 2 )]</span> , it should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintaining a patent airway, and supporting ventilation.

5.2 Risks from Concomitant Use with Opioids, Other Sedative Hypnotics, or Other Central Nervous System Depressants Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Monitor patients for respiratory depression and sedation <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7.1 )]</span> . Titrate the dose of Midazolam in 0.9% Sodium Chloride Injection when administered with opioid analgesics and sedative-hypnotics to the desired clinical response. Continuously monitor sedated patients for hypotension, airway obstruction, hypoventilation, apnea, and oxygen desaturation. These cardiorespiratory effects may be more likely to occur in patients with obstructive sleep apnea, the elderly, and ASA‑PS III or IV patients. Concomitant use of barbiturates, alcohol, or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect. Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation.

5.3 Risk of Cardiorespiratory Adverse Reactions Serious cardiorespiratory adverse reactions have occurred after administration of midazolam. These have included respiratory depression, airway obstruction, oxygen desaturation, apnea, respiratory arrest and/or cardiac arrest, sometimes resulting in death or permanent neurologic injury. There have also been rare reports of hypotensive episodes requiring treatment during or after diagnostic or surgical manipulations particularly in adult or pediatric patients with hemodynamic instability. Hypotension occurred more frequently in the sedation studies in patients premedicated with an opioid. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. When used for sedation/anxiolysis/amnesia, midazolam should always be titrated slowly in adult or pediatric patients. Adverse hemodynamic events have been reported in pediatric patients with cardiovascular instability; rapid intravenous administration should also be avoided in this population. Continuously monitor patients for early signs of hypoventilation, airway obstruction, and apnea using capnography, pulse oximetry, and clinical assessment <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> .

5.4 Risk of Paradoxical Behavior Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients. These reactions may be due to inadequate or excessive dosing or improper administration of midazolam; however, consideration should be given to the possibility of cerebral hypoxia or true paradoxical reactions. Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding. Reversal of such responses with flumazenil has been reported in pediatric patients.

5.5 Risk of Dependence and Withdrawal with Long-Term Use of Midazolam in 0.9% Sodium Chloride Injection The continued use of benzodiazepines for several days to weeks may lead to clinically significant physical dependence. If used for long-term use (i.e., for several days to weeks), abrupt discontinuation or rapid dosage reduction of midazolam, or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use. After extended therapy, do not abruptly discontinue Midazolam in 0.9% Sodium Chloride Injection. When discontinuing midazolam in a physically-dependent patient, gradually taper the dosage using a tapering schedule that is individualized to the patient <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 ), Dependence ( 9.3 )]</span> .

5.6 Debilitation and Comorbid Considerations Higher risk adult and pediatric surgical patients, elderly patients and debilitated adult and pediatric patients require lower dosages, whether or not concomitant sedating medications have been administered. Adult or pediatric patients with COPD are unusually sensitive to the respiratory depressant effect of midazolam. 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. Adult and pediatric patients with chronic renal failure and patients with congestive heart failure eliminate midazolam more slowly <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . Because elderly patients frequently have inefficient function of one or more organ systems and because dosage requirements have been shown to decrease with age, reduced initial dosage of midazolam is recommended, and the possibility of profound and/or prolonged effect should be considered. Do not administer Midazolam in 0.9% Sodium Chloride Injection to adult or pediatric patients in shock or coma, or in acute alcohol intoxication with depression of vital signs. Particular care should be exercised in the use of intravenous midazolam in adult or pediatric patients with uncompensated acute illnesses, such as severe fluid or electrolyte disturbances.

5.7 Risk of Intra-Arterial Injection There have been limited reports of intra-arterial injection of midazolam. Adverse events 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. Extravasation should also be avoided. The safety and efficacy of Midazolam in 0.9% Sodium Chloride Injection following nonintravenous routes of administration have not been established. Midazolam in 0.9% Sodium Chloride Injection should only be administered intravenously.

5.8 Impaired Cognitive Function Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours. The decision as to when patients who have received injectable midazolam, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized. Gross tests of recovery from the effects of midazolam <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> cannot be relied upon to predict reaction time under stress. It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided or until one full day after anesthesia and surgery, whichever is longer. For pediatric patients, particular care should be taken to assure safe ambulation.

5.9 Risk of Hypotension and Seizure in Preterm Infants and Neonates Rapid injection should be avoided in the neonatal population. Midazolam administered rapidly as an intravenous injection (i.e., less than 2 minutes) has been associated with severe hypotension in neonates, particularly when the patient has also received fentanyl. Likewise, severe hypotension has been observed in neonates receiving a continuous infusion of midazolam who then receive a rapid intravenous injection of fentanyl. Seizures have been reported in several neonates following rapid intravenous administration. The neonate also has reduced and/or immature organ function and is also vulnerable to profound and/or prolonged respiratory effects of midazolam.

5.10 Neonatal Sedation and Withdrawal Syndrome Receiving Midazolam in 0.9% Sodium Chloride Injection late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate. Monitor neonates exposed to Midazolam in 0.9% Sodium Chloride Injection during pregnancy or labor for signs of sedation and manage these neonates accordingly <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 )]</span>.

5.11 Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of these findings is not clear. However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans <span class="opacity-50 text-xs">[see Nonclinical Pharmacology ( 13.2 )]</span> . Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness. Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

5.12 Risk of Increased Intraocular Pressure in Patients with Glaucoma Benzodiazepines, including Midazolam in 0.9% Sodium Chloride Injection, can increase intraocular pressure in patients with glaucoma. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction with midazolam. Midazolam in 0.9% Sodium Chloride Injection may be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. Patients with open-angle glaucoma may need to have their ophthalmologic status evaluated following treatment with Midazolam in 0.9% Sodium Chloride Injection. Midazolam in 0.9% Sodium Chloride Injection is contraindicated in patients with narrow-angle glaucoma.

PRECAUTIONS: General Intravenous doses of midazolam should be decreased for elderly and for debilitated patients (see WARNINGS and DOSAGE AND ADMINISTRATION ). These patients will also probably take longer to recover completely after midazolam administration for the induction of anesthesia. Midazolam does not protect against the increase in intracranial pressure or against the heart rate rise and/or blood pressure rise associated with endotracheal intubation under light general anesthesia. The efficacy and safety of midazolam in clinical use are functions of the dose administered, the clinical status of the individual patient, and the use of concomitant medications capable of depressing the CNS. Anticipated effects range from mild sedation to deep levels of sedation virtually equivalent to a state of general anesthesia where the patient may require external support of vital functions. Care must be taken to individualize and carefully titrate the dose of midazolam to the patient's underlying medical/surgical conditions, administer to the desired effect being certain to wait an adequate time for peak CNS effects of both midazolam and concomitant medications, and have the personnel and size-appropriate equipment and facilities available for monitoring and intervention (see BOXED WARNING , WARNINGS and DOSAGE AND ADMINISTRATION ). Practitioners administering midazolam must have the skills necessary to manage reasonably foreseeable adverse effects, particularly skills in airway management. For information regarding withdrawal (see DRUG ABUSE AND DEPENDENCE ). Information for Patients To assure safe and effective use of benzodiazepines, the following information and instructions should be communicated to the patient when appropriate: 1. Inform your physician about any alcohol consumption and medicine you are now taking, especially blood pressure medication and antibiotics, including drugs you buy without a prescription. Alcohol has an increased effect when consumed with benzodiazepines; therefore, caution should be exercised regarding simultaneous ingestion of alcohol during benzodiazepine treatment. 2. Inform your physician if you are pregnant or are planning to become pregnant. 3. Inform your physician if you are nursing. 4. Patients should be informed of the pharmacological effects of midazolam, such as sedation and amnesia, which in some patients may be profound. The decision as to when patients who have received injectable midazolam, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized. 5. Patients receiving continuous infusion of midazolam in critical care settings over an extended period of time, may experience symptoms of withdrawal following abrupt discontinuation. 6. Effect of anesthetic and sedation drugs on early brain development Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains. Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs.

Pregnancy

Advise pregnant females that use of midazolam late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and PRECAUTIONS: Pregnancy ). Instruct patients to inform their healthcare provider if they are pregnant.

Nursing

Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients receiving midazolam to monitor infants for excessive sedation, poor feeding, and poor weight gain, and to seek medical attention if they notice these signs. A lactating woman may consider pumping and discarding breastmilk for at least 4 to 8 hours after receiving midazolam for sedation or anesthesia to minimize drug exposure to a breastfed infant ( see Precautions, Nursing Mothers ).

Drug Interactions

Effect of Concomitant Use of Benzodiazepines and Opioids The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABA A sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Monitor patients closely for respiratory depression and sedation. Other CNS Depressants The sedative effect of intravenous midazolam is accentuated by any concomitantly administered medication, which depresses the central nervous system, particularly opioids (e.g., morphine, meperidine and fentanyl) and also secobarbital and droperidol. Consequently, the dosage of midazolam should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response (see DOSAGE AND ADMINISTRATION ).

Other Drug Interactions

Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the P450-3A4 enzyme system such as cimetidine (not ranitidine), erythromycin, diltiazem, verapamil, ketoconazole and itraconazole. These drug interactions may result in prolonged sedation due to a decrease in plasma clearance of midazolam. The effect of single oral doses of 800 mg cimetidine and 300 mg ranitidine on steady-state concentrations of oral midazolam was examined in a randomized crossover study (n=8). Cimetidine increased the mean midazolam steady-state concentration from 57 to 71 ng/mL. Ranitidine increased the mean steady-state concentration to 62 ng/mL. No change in choice reaction time or sedation index was detected after dosing with the H2 receptor antagonists. In a placebo-controlled study, erythromycin administered as a 500 mg dose, three times a day, for 1 week (n=6), reduced the clearance of midazolam following a single 0.5 mg/kg IV dose. The half-life was approximately doubled. Caution is advised when midazolam is administered to patients receiving erythromycin since this may result in a decrease in the plasma clearance of midazolam. The effects of diltiazem (60 mg three times a day) and verapamil (80 mg three times a day) on the pharmacokinetics and pharmacodynamics of oral midazolam were investigated in a three-way crossover study (n=9). The half-life of midazolam increased from 5 to 7 hours when midazolam was taken in conjunction with verapamil or diltiazem. No interaction was observed in healthy subjects between midazolam and nifedipine. In a placebo-controlled study where saquinavir or placebo was administered orally as a 1,200 mg dose, three times a day, for 5 days (n=12), a 56% reduction in the clearance of midazolam following a single 0.05 mg/kg IV dose was observed. The half-life was approximately doubled. A moderate reduction in induction dosage requirements of thiopental (about 15%) has been noted following use of intramuscular midazolam for premedication in adults. The intravenous administration of midazolam decreases the minimum alveolar concentration (MAC) of halothane required for general anesthesia. This decrease correlates with the dose of midazolam administered; no similar studies have been carried out in pediatric patients but there is no scientific reason to expect that pediatric patients would respond differently than adults. Although the possibility of minor interactive effects has not been fully studied, midazolam and pancuronium have been used together in patients without noting clinically significant changes in dosage, onset or duration in adults. Midazolam does not protect against the characteristic circulatory changes noted after administration of succinylcholine or pancuronium and does not protect against the increased intracranial pressure noted following administration of succinylcholine. Midazolam does not cause a clinically significant change in dosage, onset or duration of a single intubating dose of succinylcholine; no similar studies have been carried out in pediatric patients but there is no scientific reason to expect that pediatric patients would respond differently than adults.

Drug/Laboratory

Test Interactions Midazolam has not been shown to interfere with results obtained in clinical laboratory tests. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Midazolam maleate was administered with diet in mice and rats for 2 years at dosages of 1, 9 and 80 mg/kg/day. In female mice in the highest dose group there was a marked increase in the incidence of hepatic tumors. In high-dose male rats there was a small but statistically significant increase in benign thyroid follicular cell tumors. Dosages of 9 mg/kg/day of midazolam maleate (4 times a human induction dose of 0.35 mg/kg based on body surface area comparison) do not increase the incidence of tumors. The pathogenesis of induction of these tumors is not known. These tumors were found after chronic administration, whereas human use will ordinarily be of single or several doses. Mutagenesis: Midazolam did not have mutagenic activity in Salmonella typhimurium (5 bacterial strains), Chinese hamster lung cells (V79), human lymphocytes or in the micronucleus test in mice. Impairment of Fertility: Male rats were treated orally with 1, 4, or 16 mg/kg midazolam beginning 62 days prior to mating with female rats treated with the same doses for 14 days prior to mating to Gestation Day 13 or Lactation Day 21. The high dose produced an equivalent exposure (AUC) as 4 mg/kg intravenous midazolam (1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparison). There were no adverse effects on either male or female fertility noted.

Pregnancy Risk Summary

Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome , and Clinical Considerations ). Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations Fetal/Neonatal

Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to Midazolam injection during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems Monitor neonates exposed to Midazolam injection during pregnancy for signs of withdrawal. Manage these neonates accordingly (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome ).

Data Human Data

Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.

Animal Data

Pregnant rats were treated with midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 through 15). Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose. All doses produced slight to moderate ataxia. The high dose produced a 5% decrease in maternal body weight gain compared to control. Pregnant rabbits were treated with midazolam using intravenous doses of 0.2, 0.6, and 2 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 to 18). Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose. The high dose was associated with findings of ataxia and sedation but no evidence of maternal toxicity. Pregnant rats were administered midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during late gestation and through lactation (Gestation Day 15 through Lactation Day 21). All doses produced ataxia. The high dose produced a slight decrease in maternal body weight gain compared to control. There were no clear adverse effects noted in the offspring. The study included no functional assessments of the pups, such as learning and memory testing or reproductive capacity. In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus. In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring. With respect to brain development, this time period corresponds to the third trimester of gestation in the human. The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits ( see WARNINGS, Pediatric Neurotoxicity , PRECAUTIONS, Pediatric Use , and Animal Toxicology and/or Pharmacology ).

Nursing Mothers Risk Summary

The effects of midazolam on lactation are unknown. Because of the potential for serious adverse reactions, including sedation and withdrawal symptoms in breastfed infants, advise patients that breastfeeding is not recommended during treatment with midazolam. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. Based on data from published studies, midazolam is present in human milk in low levels (see Data ) . There are no data on the effects of midazolam on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Midazolam injection and any potential adverse effects on the breastfed infant from Midazolam injection or from the underlying maternal condition.

Clinical Considerations

Infants exposed to Midazolam injection through breast milk should be monitored for sedation, poor feeding and poor weight gain. A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment for a range of at least 4 to 8 hours after midazolam administration in order to minimize drug exposure to a breastfed infant.

Pediatric Use

The safety and efficacy of midazolam for sedation/anxiolysis/amnesia following single dose intramuscular administration, intravenously by intermittent injections and continuous infusion have been established in pediatric and neonatal patients. For specific safety monitoring and dosage guidelines see BOXED WARNING , CLINICAL PHARMACOLOGY , INDICATIONS AND USAGE , WARNINGS , PRECAUTIONS , ADVERSE REACTIONS , OVERDOSAGE and DOSAGE AND ADMINISTRATION . UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require closer monitoring. In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. The healthcare practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation. Midazolam should not be administered by rapid injection in the neonatal population. Severe hypotension and seizures have been reported following rapid IV administration, particularly with concomitant use of fentanyl. Midazolam contain benzyl alcohol as a preservative. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome”, (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages greater than 99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.

Animal Data

Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as Midazolam Injection USP, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans. In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data (see WARNINGS, Pediatric Neurotoxicity , PRECAUTIONS, Pregnancy , and Animal Toxicology and/or Pharmacology ). No significant adverse interactions with commonly used premedications or drugs used during anesthesia and surgery (including atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, d-tubocurarine, succinylcholine and other nondepolarizing muscle relaxants) or topical local anesthetics (including lidocaine, dyclonine HCl and Cetacaine) have been observed in adults or pediatric patients. In neonates, however, severe hypotension has been reported with concomitant administration of fentanyl. This effect has been observed in neonates on an infusion of midazolam who received a rapid injection of fentanyl and in patients on an infusion of fentanyl who have received a rapid injection of midazolam.

Geriatric Use

Because geriatric patients may have altered drug distribution and diminished hepatic and/or renal function, reduced doses of midazolam are recommended. Intravenous and intramuscular doses of midazolam should be decreased for elderly and for debilitated patients (see WARNINGS and DOSAGE AND ADMINISTRATION ) and subjects over 70 years of age may be particularly sensitive. These patients will also probably take longer to recover completely after midazolam administration for the induction of anesthesia. Administration of IM and IV midazolam to elderly and/or high-risk surgical patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression. In most of these cases, the patients also received other central nervous system depressants capable of depressing respiration, especially narcotics (see DOSAGE AND ADMINISTRATION ). Specific dosing and monitoring guidelines for geriatric patients are provided in the DOSAGE AND ADMINISTRATION section for premedicated patients for sedation/anxiolysis/amnesia following IV and IM administration, for induction of anesthesia following IV administration and for continuous infusion.

Drug Interactions: Effect of Concomitant Use of Benzodiazepines and Opioids The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABA A sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation. Other CNS Depressants The sedative effect of intravenous midazolam is accentuated by any concomitantly administered medication, which depresses the central nervous system, particularly narcotics (e.g., morphine, meperidine and fentanyl) and also secobarbital and droperidol. Consequently, the dosage of midazolam should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response (see DOSAGE AND ADMINISTRATION ).

Other Drug Interactions

Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the P450-3A4 enzyme system such as cimetidine (not ranitidine), erythromycin, diltiazem, verapamil, ketoconazole and itraconazole. These drug interactions may result in prolonged sedation due to a decrease in plasma clearance of midazolam. The effect of single oral doses of 800 mg cimetidine and 300 mg ranitidine on steady-state concentrations of midazolam was examined in a randomized crossover study (n=8). Cimetidine increased the mean midazolam steady-state concentration from 57 to 71 ng/mL. Ranitidine increased the mean steady-state concentration to 62 ng/mL. No change in choice reaction time or sedation index was detected after dosing with the H2 receptor antagonists. In a placebo-controlled study, erythromycin administered as a 500 mg dose, tid, for 1 week (n=6), reduced the clearance of midazolam following a single 0.5 mg/kg IV dose. The half-life was approximately doubled. Caution is advised when midazolam is administered to patients receiving erythromycin since this may result in a decrease in the plasma clearance of midazolam. The effects of diltiazem (60 mg tid) and verapamil (80 mg tid) on the pharmacokinetics and pharmacodynamics of midazolam were investigated in a three-way crossover study (n=9). The half-life of midazolam increased from 5 to 7 hours when midazolam was taken in conjunction with verapamil or diltiazem. No interaction was observed in healthy subjects between midazolam and nifedipine. In a placebo-controlled study, saquinavir administered as a 1200 mg dose, tid, for 5 days (n=12), a 56% reduction in the clearance of midazolam following a single 0.05 mg/kg IV dose was observed. The half-life was approximately doubled. A moderate reduction in induction dosage requirements of thiopental (about 15%) has been noted following use of intramuscular midazolam hydrochloride for premedication in adults. The intravenous administration of midazolam hydrochloride decreases the minimum alveolar concentration (MAC) of halothane required for general anesthesia. This decrease correlates with the dose of midazolam hydrochloride administered; no similar studies have been carried out in pediatric patients but there is no scientific reason to expect that pediatric patients would respond differently than adults. Although the possibility of minor interactive effects has not been fully studied, midazolam and pancuronium have been used together in patients without noting clinically significant changes in dosage, onset or duration in adults. Midazolam hydrochloride does not protect against the characteristic circulatory changes noted after administration of succinylcholine or pancuronium and does not protect against the increased intracranial pressure noted following administration of succinylcholine. Midazolam does not cause a clinically significant change in dosage, onset or duration of a single intubating dose of succinylcholine; no similar studies have been carried out in pediatric patients but there is no scientific reason to expect that pediatric patients would respond differently than adults. No significant adverse interactions with commonly used premedications or drugs used during anesthesia and surgery (including atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, d-tubocurarine, succinylcholine and other nondepolarizing muscle relaxants) or topical local anesthetics (including lidocaine, dyclonine HCl and Cetacaine) have been observed in adults or pediatric patients. In neonates, however, severe hypotension has been reported with concomitant administration of fentanyl. This effect has been observed in neonates on an infusion of midazolam who received a rapid injection of fentanyl and in patients on an infusion of fentanyl who have received a rapid injection of midazolam. Caution is advised when midazolam is administered to patients receiving erythromycin since this may result in a decrease in the plasma clearance of midazolam.