Midazolam (injection)

Midazolam (injection)
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]

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Black Box Warning

BOXED WARNING See full prescribing information for complete Boxed Warning. Adults and Pediatric: Intravenous midazolam hydrochloride has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings. In some cases, where this was not recognized promptly and treated effectively, death or hypoxic encephalopathy has resulted. Intravenous midazolam should be used only in hospital or ambulatory care settings, including physicians and dental offices, that provide for continuous monitoring of respiratory and cardiac function, ie., pulse oximetry. Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured (see WARNINGS). For deeply sedated pediatric patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure. The initial intravenous dose for sedation in adult patients may be as little as 1 mg, but should not exceed 2.5 mg in a normal healthy adult. Lower doses are necessary for older (over 60 years) or debilitated patients and in patients receiving concomitant narcotics or other central nervous system (CNS) depressants. The initial dose and all subsequent doses should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. The use of the 1 mg/mL formulation or dilution of the 1 mg/mL or 5 mg/mL formulation is recommended to facilitate slower injection. Doses of sedative medications in pediatric patients must be calculated on a mg/kg basis, and initial doses and all subsequent doses should always be titrated slowly. The initial pediatric dose of midazolam for sedation /anxiolysis/amnesia is age, procedure, and route dependent (see DOSAGE AND ADMINISTRATION for complete dosing information). Neonates: 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 (see DOSAGE AND ADMINISTRATION for complete information).

Overview

Midazolam (injection) is a general anesthetic that is FDA approved for the {{{indicationType}}} of anxiety - induction of amnesia - preoperative sedation, induction of general anesthesia, procedural sedation, sedation for a mechanically ventilated patient.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include neurologic: excessive somnolence] (1.6%), [[]headache]] (1.3% to 1.5%), somnolence(1.2%), respiratory: hiccoughs (3.6% ).

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

• Anxiety good-risk patients less than 60 years of age, 0.07 to 0.08 mg/kg IM (approximately 5 mg) up to 1 hour before surgery.
• Anxiety - Induction of amnesia - Preoperative sedation: patients 60 years or older, patients with COPD, other higher-risk surgical patients, and patients who have received concomitant narcotics or other CNS depressants, 0.02 to 0.05 mg/kg IM (approximately 2 to 3 mg) 1 hour before surgery.
• Anxiety - Induction of amnesia - older patients when the anticipated intensity and duration of sedation is less critical, 1 mg IM 1 hour before surgery.
• Anxiety - Induction of amnesia - Preoperative sedation: healthy adults less than 60 years of age, initial, 1 to 2.5 mg IV over at least 2 minutes, may titrate using small increments to desired level of sedation (allowing 2 additional minutes to evaluate full effect after each increment); reduce dose by 30% with narcotic premedication or other CNS depressants (MAX total dose: 5 mg).
• Anxiety - Induction of amnesia - Preoperative sedation: patients 60 years or older, and debilitated or chronically ill patients, initial, 1 to 1.5 mg IV over at least 2 minutes, may titrate by no more than 1-mg increments (allowing 2 additional minutes to evaluate full effect after each increment); reduce dose by 50% with narcotic premedication or other CNS depressants (MAX total dose: 3.5 mg) [2]
• Anxiety - Induction of amnesia - Preoperative sedation: maintenance, additional doses of 25% of total initial dose required to achieved desired sedation may be administered IV if additional sedation is required.
• Induction of general anesthesia: unpremedicated patients less than 55 years of age, initial, 0.3 to 0.35 mg/kg IV over 20 to 30 seconds; may increase by 25% of initial dose to desired effect (allowing 2 minutes for effect) to MAX total dose of 0.6 mg/kg.
• Induction of general anesthesia: unpremedicated patients greater than 55 years of age, initial, 0.3 mg/kg IV over 20 to 30 seconds.
• Induction of general anesthesia: unpremedicated patients with severe systemic disease or other debilitation, initial, 0.15 to 0.25 mg/kg IV over 20 to 30 seconds.
• Induction of general anesthesia: premedicated patients less than 55 years of age, initial, 0.25 mg/kg IV over 20 to 30 seconds.
• Induction of general anesthesia: premedicated good-risk patients greater than 55 years of age, initial, 0.2 mg/kg IV over 20 to 30 seconds.
• Induction of general anesthesia: premedicated patients with severe systemic disease or debilitation, initial, 0.15 mg/kg IV over 20 to 30 seconds.
• Induction of general anesthesia: maintenance dose, incremental injections of approximately 25% of the induction dose should be given in response to signs of lightening of anesthesia .and repeated as necessary.
• Procedural sedation: healthy adults below 60 years of age, initial, 1 to 2.5 mg IV over at least 2 minutes, may titrate using small increments to desired level of sedation (allowing 2 additional minutes to evaluate full effect after each increment); reduce dose by 30% with narcotic premedication or other CNS depressants (MAX total dose: 5 mg).
• Procedural sedation: patients 60 years or older, and debilitated or chronically ill patients, initial, 1 to 1.5 mg IV over at least 2 minutes, may titrate by no more than 1-mg increments (allowing 2 additional minutes to evaluate full effect after each increment); reduce dose by 50% with narcotic premedication or other CNS depressants (MAX total dose: 3.5 mg).
• Procedural sedation: maintenance, additional doses of 25% of total initial dose required to achieved desired sedation may be administered IV if additional sedation is required.
• Sedation for a mechanically ventilated patient: loading dose, 0.01 to 0.05 mg/kg IV administered over several minutes; may repeat at 10- to 15-minute intervals until adequate sedation is achieved.
• Sedation for a mechanically ventilated patient: maintenance, continuous IV infusion initiated at a rate of 0.02 to 0.1 mg/kg/hr; may adjust rate up or down by 25% to 50% of initial infusion rate to achieve adequate sedation.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

• Etomidate adverse reaction -myoclonia
• Insomnia.
• Postoperative nausea and vomiting.
• Seizure.

Non–Guideline-Supported Use

There is limited information about Off-Label Non–Guideline-Supported Use of Midazolam in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

• High amounts of benzyl alcohol have been associated with toxicity, particularly in neonates; consider the daily metabolic load of benzyl alcohol being given.
• Anxiety - Induction of amnesia - Preoperative sedation: (6 months or older) 0.25 to 0.5 mg/kg orally as a single dose; up to 1 mg/kg for younger (6 months to less than 6 years) or uncooperative patients (MAX dose: 20 mg).
• Anxiety - Induction of amnesia - Preoperative sedation: 0.1 to 0.15 mg/kg IM as a single dose; 0.5 mg/kg for more anxious patients (MAX total dose: 10 mg).
• Anxiety - Induction of amnesia - Preoperative sedation: (6 months to 5 years of age) initial, 0.05 to 0.1 mg/kg IV over 2 to 3 minutes; may titrate to desired level of sedation (allowing 2 to 3 additional minutes to evaluate full effect after each increment); a total dose up to 0.6 mg/kg may be necessary (MAX total dose: 6 mg).
• Anxiety - Induction of amnesia - Preoperative sedation: (6 to 12 years of age) initial, 0.025 to 0.05 mg/kg IV over 2 to 3 minutes, may titrate to desired level of sedation (allowing 2 to 3 additional minutes to evaluate full effect after each increment); a total dose up to 0.4 mg/kg may be necessary (MAX total dose: 10 mg).
• Anxiety - Induction of amnesia - Preoperative sedation: (12 years or older) initial, 1 to 2.5 mg IV over at least 2 minutes, may titrate using small increments to desired level of sedation (allowing 2 additional minutes to evaluate full effect after each increment) (MAX total dose: 10 mg).
• Procedural sedation: (6 months or older) 0.25 to 0.5 mg/kg ORALLY as a single dose; up to 1 mg/kg for younger (6 months to less than 6 years) or uncooperative patients (MAX dose: 20 mg).
• Procedural sedation: 0.1 to 0.15 mg/kg IM as a single dose; 0.5 mg/kg for more anxious patients (MAX total dose: 10 mg).
• Procedural sedation: (6 months to 5 years of age) initial, 0.05 to 0.1 mg/kg IV over 2 to 3 minutes; may titrate to desired level of sedation (allowing 2 to 3 additional minutes to evaluate full effect after each increment); a total dose up to 0.6 mg/kg may be necessary (MAX total dose: 6 mg).
• Procedural sedation: (6 to 12 years of age) initial, 0.025 to 0.05 mg/kg IV over 2 to 3 minutes, may titrate to desired level of sedation (allowing 2 to 3 additional minutes to evaluate full effect after each increment); a total dose up to 0.4 mg/kg may be necessary (MAX total dose 10 mg).
• Procedural sedation: (12 years or older) initial, 1 to 2.5 mg IV over at least 2 minutes, may titrate using small increments to desired level of sedation (allowing 2 additional minutes to evaluate full effect after each increment) (MAX total dose: 10 mg).
• Sedation for a mechanically ventilated patient: (non-neonatal) loading dose, 0.05 to 0.2 mg/kg IV over at least 2 to 3 minutes.
• Sedation for a mechanically ventilated patient: (non-neonatal), maintenance, continuous IV infusion initiated at a rate of 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min), may adjust rate up or down by 25% of initial or subsequent rate to achieve adequate sedation.
• Sedation for a mechanically ventilated patient: (neonatal younger than 32 weeks) continuous IV infusion initiated at a rate of 0.03 mg/kg/hr (0.5 mcg/kg/min).
• Sedation for a mechanically ventilated patient: (neonatal older than 32 weeks) continuous IV infusion initiated at a rate of 0.06 mg/kg/hr (1 mcg/kg/min).

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information about Off-Label Guideline-Supported Use of Midazolam in pediatric patients.

Non–Guideline-Supported Use

There is limited information about Off-Label Non–Guideline-Supported Use of Midazolam in pediatric patients.

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.

Warnings

BOXED WARNING See full prescribing information for complete Boxed Warning. Adults and Pediatric: Intravenous midazolam hydrochloride has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings. In some cases, where this was not recognized promptly and treated effectively, death or hypoxic encephalopathy has resulted. Intravenous midazolam should be used only in hospital or ambulatory care settings, including physicians and dental offices, that provide for continuous monitoring of respiratory and cardiac function, ie., pulse oximetry. Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured (see WARNINGS). For deeply sedated pediatric patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure. The initial intravenous dose for sedation in adult patients may be as little as 1 mg, but should not exceed 2.5 mg in a normal healthy adult. Lower doses are necessary for older (over 60 years) or debilitated patients and in patients receiving concomitant narcotics or other central nervous system (CNS) depressants. The initial dose and all subsequent doses should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. The use of the 1 mg/mL formulation or dilution of the 1 mg/mL or 5 mg/mL formulation is recommended to facilitate slower injection. Doses of sedative medications in pediatric patients must be calculated on a mg/kg basis, and initial doses and all subsequent doses should always be titrated slowly. The initial pediatric dose of midazolam for sedation /anxiolysis/amnesia is age, procedure, and route dependent (see DOSAGE AND ADMINISTRATION for complete dosing information). Neonates: 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 (see DOSAGE AND ADMINISTRATION for complete information).

Midazolam hydrochloride must never be used without individualization of dosage particularly when used with other medications capable of producing central nervous system depression. Prior to the intravenous administration of midazolam hydrochloride in any dose, 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 should be ensured. Patients should be continuously monitored with some means of detection for early signs of hypoventilation, airway obstruction, or apnea, i.e., pulse oximetry. Hypoventilation, airway obstruction, and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately. The immediate availability of specific reversal agents (flumazenil) is highly recommended. Vital signs should continue to be monitored during the recovery period. Because intravenous midazolam depresses respiration (see CLINICAL PHARMACOLOGY) and because opioid agonists and other sedatives can add to this depression, midazolam should be administered as an induction agent only by a person trained in general anesthesia and 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. 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. See DOSAGE AND ADMINISTRATION for complete information.

Serious cardiorespiratory adverse events 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 a narcotic.

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 hydrochloride; 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 hydrochloride and all other drugs, including local anesthetics, should be evaluated before proceeding. Reversal of such responses with flumazenil has been reported in pediatric 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.

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 hydrochloride. 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 (see CLINICAL PHARMACOLOGY). 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 hydrochloride is recommended and the possibility of profound and/or prolonged effect should be considered.

Injectable midazolam should not be administered 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.

There have been limited reports of intra-arterial injection of midazolam hydrochloride. 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 following nonintravenous and nonintramuscular routes of administration have not been established. Midazolam hydrochloride should only be administered intramuscularly or intravenously.

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 (see CLINICAL PHARMACOLOGY) 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.

Usage in Pregnancy:

An increased risk of congenital malformations associated with the use of benzodiazepine drugs (diazepam and chlordiazepoxide) has been suggested in several studies. If this drug is used during pregnancy, the patient should be apprised of the potential hazard to the fetus.

Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE section).

Usage In Preterm Infants And Neonates:

Rapid injection should be avoided in the neonatal population. Midazolam hydrochloride administered rapidly as an intravenous injection (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.

Adverse Reactions

Clinical Trials Experience

See WARNINGS concerning serious cardiorespiratory events and possible paradoxical reactions. Fluctuations in vital signs were the most frequently seen findings following parenteral administration of midazolam in adults and included decreased tidal volume and/or respiratory rate decrease (23.3% of patients following IV and 10.8% of patients following IM administration) and apnea (15.4% of patients following IV administration), as well as variations in blood pressure and pulse rate. The majority of serious adverse effects, particularly those associated with oxygenation and ventilation, have been reported when midazolam hydrochloride is administered with other medications capable of depressing the central nervous system. The incidence of such events is higher in patients undergoing procedures involving the airway without the protective effect of an endotracheal tube (e.g., upper endoscopy and procedures).

Adults: The following additional adverse reactions were reported after intramuscular administration:

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Administration of IM midazolam hydrochloride to elderly and/or higher 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).

The following additional adverse reactions were reported subsequent to intravenous administration as a single sedative/anxiolytic/amnestic agent in adult patients:

Pediatric Patients:

The following adverse events related to the use of IV midazolam hydrochloride in pediatric patients were reported in the medical literature: desaturation 4.6%, apnea 2.8%, hypotension 2.7%, paradoxical reactions 2.0%, hiccough 1.2%, seizure-like activity 1.1% and nystagmus 1.1%. The majority of airway-related events occurred in patients receiving other CNS depressing medications and in patients where midazolam was not used as a single sedating agent.

Neonates: For information concerning hypotensive episodes and seizures following the administration of midazolam hydrochloride to neonates, see Box WARNING, CONTRAINDICATIONS, WARNINGS and PRECAUTIONS.

Other adverse experiences, observed mainly following IV injection as a single sedative/anxiolytic/amnesia agent and occurring at an incidence of <1.0% in adult and pediatric patients, are as follows:

Respiratory: Laryngospasm, bronchospasm, dyspnea, hyperventilation, wheezing, shallow respirations, airway obstruction, tachypnea

Cardiovascular: Bigeminy, premature ventricular contractions, vasovagal episode, bradycardia, tachycardia, nodal rhythm

Gastrointestinal: Acid taste, excessive salivation, retching

CNS/Neuromuscular: Retrograde amnesia, euphoria, hallucination, confusion, argumentativeness, nervousness, anxiety, grogginess, restlessness, emergence delirium or agitation, prolonged emergence from anesthesia, dreaming during emergence, sleep disturbance, insomnia, nightmares, athetoid movements, seizure-like activity, ataxia, dizziness, dysphonia, slurred speech, dysphoria, paresthesia

Special senses: Blurred vision, diplopia, nystagmus, pinpoint pupils, cyclic movements of eyelids, visual disturbance, difficulty focusing eyes, ears blocked, loss of balance, light-headedness

Integumentary: Hive-like elevation at injection site, swelling or feeling of burning, warmth or coldness at injection site

Hypersensitivity: Allergic reactions including anaphylactoid reactions, hives, rash, pruritus

Miscellaneous: Yawning, lethargy, chills, weakness, toothache, faint feeling, hematoma.

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Postmarketing Experience

There is limited information regarding Midazolam (injection) Postmarketing Experience in the drug label.

Drug Interactions

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).

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 cross-over 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.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There is no FDA guidance on usage of Midazolam (injection) in women who are pregnant.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Midazolam (injection) in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Midazolam (injection) during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Midazolam (injection) in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of Midazolam (injection) in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Midazolam (injection) in geriatric settings.

Gender

There is no FDA guidance on the use of Midazolam (injection) with respect to specific gender populations.

Race

There is no FDA guidance on the use of Midazolam (injection) with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Midazolam (injection) in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Midazolam (injection) in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Midazolam (injection) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Midazolam (injection) in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Midazolam (injection) Administration in the drug label.

Monitoring

There is limited information regarding Midazolam (injection) Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Midazolam (injection) and IV administrations.

Overdosage

The manifestations of midazolam overdosage reported are similar to those observed with other benzodiazepines, including sedation, somnolence, confusion, impaired coordination, diminished reflexes, coma and untoward effects on vital signs. No evidence of specific organ toxicity from midazolam hydrochloride overdosage has been reported.

Treatment of Overdosage: Treatment of injectable midazolam overdosage is the same as that followed for overdosage with other benzodiazepines. Respiration, pulse rate and blood pressure should be monitored and general supportive measures should be employed. Attention should be given to the maintenance of a patent airway and support of ventilation, including administration of oxygen. An intravenous infusion should be started. Should hypotension develop, treatment may include intravenous fluid therapy, repositioning, judicious use of vasopressors appropriate to the clinical situation, if indicated, and other appropriate countermeasures. There is no information as to whether peritoneal dialysis, forced diuresis or hemodialysis are of any value in the treatment of midazolam overdose.

Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. There are anecdotal reports of reversal of adverse hemodynamic responses associated with midazolam hydrochloride following administration of flumazenil to pediatric patients. Prior to the administration of flumazenil, necessary measures should be instituted to secure the airway, assure adequate ventilation, and establish adequate intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression and other residual benzodiazepine effects for an appropriate period after treatment. Flumazenil will only reverse benzodiazepines-induced effects but will not reverse the effects of other concomitant medications. The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk patients. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert, including CONTRAINDICATIONS, WARNINGS and PRECAUTIONS, should be consulted prior to use.

Pharmacology

Mechanism of Action

There is limited information regarding Midazolam (injection) Mechanism of Action in the drug label.

Structure

There is limited information regarding Midazolam (injection) Structure in the drug label.

Pharmacodynamics

There is limited information regarding Midazolam (injection) Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Midazolam (injection) Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Midazolam (injection) Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Midazolam (injection) Clinical Studies in the drug label.

How Supplied

There is limited information regarding Midazolam (injection) How Supplied in the drug label.

Storage

There is limited information regarding Midazolam (injection) Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Midazolam (injection) Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Midazolam interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Midazolam (injection) Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Midazolam (injection) Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.