САЩ - английски - NLM (National Library of Medicine)
MIDAZOLAM- midazoalm injection, solution
General Injectables and Vaccines, Inc.
NOT FOR USE IN NEONATES
CONTAINS BENZYL ALCOHOL
Personnel and Equipment for Monitoring and Resuscitation
Adults and Pediatrics: 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 hydrochloride 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, e.g., 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.
Risks From Concomitant Use With Opioids
Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory
depression, coma, and death. Monitor patients for respiratory depression and sedation (see
WARNINGS and PRECAUTIONS, DRUG INTERACTIONS).
Individualization of Dosage
Midazolam hydrochloride must never be used without individualization of dosage. 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
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 2.9 to 3.5 with
hydrochloric acid and, if necessary, sodium hydroxide.
Midazolam is a white or yellowish crystalline powder, 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-4H-imidazo[1,5-a][1,4]benzodiazepine hydrochloride. Midazolam
hydrochloride has the empirical formula C18H13ClFN3HCl, a calculated molecular weight of 362.25
and the following structural formula:
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 is a short-acting benzodiazepine central nervous system (CNS) depressant.
The effects of midazolam hydrochloride on the CNS are dependent on the dose administered, the route
of administration, and the presence or absence of other medications. Onset time of sedative effects after
IM administration in adults is 15 minutes, with peak sedation occurring 30 to 60 minutes following
injection. In one adult study, when tested the following day, 73% of the patients who received
midazolam hydrochloride intramuscularly had no recall of memory cards shown 30 minutes following
drug administration; 40% had no recall of the memory cards shown 60 minutes following drug
administration. Onset time of sedative effects in the pediatric population begins within 5 minutes and
peaks at 15 to 30 minutes depending upon the dose administered. In pediatric patients, up to 85% had no
recall of pictures shown after receiving intramuscular midazolam compared with 5% of the placebo
Sedation in adult and pediatric patients is achieved within 3 to 5 minutes after intravenous (IV) injection;
the time of onset is affected by total dose administered and the concurrent administration of narcotic
premedication. Seventy-one percent of the adult patients in endoscopy studies had no recall of
introduction of the endoscope; 82% of the patients had no recall of withdrawal of the endoscope. In one
study of pediatric patients undergoing lumbar puncture or bone marrow aspiration, 88% of patients had
impaired recall vs 9% of the placebo controls. In another pediatric oncology study, 91% of midazolam
treated patients were amnestic compared with 35% of patients who had received fentanyl alone.
When midazolam hydrochloride is given IV as an anesthetic induction agent, induction of anesthesia
occurs in approximately 1.5 minutes when narcotic premedication has been administered and in 2 to 2.5
minutes without narcotic premedication or other sedative premedication. Some impairment in a test of
memory was noted in 90% of the patients studied. A dose response study of pediatric patients
premedicated with 1 mg/kg intramuscular (IM) meperidine found that only 4 out of 6 pediatric patients
who received 600 mcg/kg IV midazolam lost consciousness, with eye closing at 108 to 140 seconds.
This group was compared with pediatric patients who were given thiopental 5 mg/kg IV; 6 out of 6
closed their eyes at 20 ± 3.2 seconds. Midazolam did not dependably induce anesthesia at this dose
despite concomitant opioid administration in pediatric patients.
Midazolam, used as directed, does not delay awakening from general anesthesia in adults. Gross tests of
recovery after awakening (orientation, ability to stand and walk, suitability for discharge from the
recovery room, return to baseline Trieger competency) usually indicate recovery within 2 hours but
recovery may take up to 6 hours in some cases. When compared with patients who received thiopental,
patients who received midazolam generally recovered at a slightly slower rate. Recovery from
anesthesia or sedation for procedures in pediatric patients depends on the dose of midazolam
administered, coadministration of other medications causing CNS depression and duration of the
In patients without intracranial lesions, induction of general anesthesia with IV midazolam
hydrochloride is associated with a moderate decrease in cerebrospinal fluid pressure (lumbar puncture
measurements), similar to that observed following IV thiopental. Preliminary data in neurosurgical
patients with normal intracranial pressure but decreased compliance (subarachnoid screw measurements)
show comparable elevations of intracranial pressure with midazolam and with thiopental during
intubation. No similar studies have been reported in pediatric patients.
The usual recommended intramuscular premedicating doses of midazolam hydrochloride do not depress
the ventilatory response to carbon dioxide stimulation to a clinically significant extent in adults.
Intravenous induction doses of midazolam hydrochloride depress the ventilatory response to carbon
dioxide stimulation for 15 minutes or more beyond the duration of ventilatory depression following
administration of thiopental in adults. Impairment of ventilatory response to carbon dioxide is more
marked in adult patients with chronic obstructive pulmonary disease (COPD). Sedation with IV
midazolam does not adversely affect the mechanics of respiration (resistance, static recoil, most lung
volume measurements); total lung capacity and peak expiratory flow decrease significantly but static
compliance and maximum expiratory flow at 50% of awake total lung capacity (Vmax) increase. In one
study of pediatric patients under general anesthesia, intramuscular midazolam (100 mcg/kg or 200
mcg/kg) was shown to depress the response to carbon dioxide in a dose-related manner.
In cardiac hemodynamic studies in adults, IV induction of general anesthesia with midazolam
hydrochloride was associated with a slight to moderate decrease in mean arterial pressure, cardiac
output, stroke volume and systemic vascular resistance. Slow heart rates (less than 65/minute),
particularly in patients taking propranolol for angina, tended to rise slightly; faster heart rates (e.g.,
85/minute) tended to slow slightly. In pediatric patients, a comparison of IV midazolam hydrochloride
(500 mcg/kg) with propofol (2.5 mg/kg) revealed a mean 15% decrease in systolic blood pressure in
patients who had received IV midazolam vs a mean 25% decrease in systolic blood pressure following
Midazolam's activity is primarily due to the parent drug. Elimination of the parent drug takes place via
hepatic metabolism of midazolam to hydroxylated metabolites that are conjugated and excreted in the
urine. Six single-dose pharmacokinetic studies involving healthy adults yield pharmacokinetic
parameters for midazolam in the following ranges: volume of distribution (Vd), 1.0 to 3.1 L/kg;
elimination half-life, 1.8 to 6.4 hours (mean approximately 3 hours); total clearance (Cl), 0.25 to 0.54
L/hr/kg. In a parallel group study, there was no difference in the clearance, in subjects administered 0.15
mg/kg (n=4) and 0.30 mg/kg (n=4) IV doses indicating linear kinetics. The clearance was successively
reduced by approximately 30% at doses of 0.45 mg/kg (n=4) and 0.6 mg/kg (n=5) indicating non-linear
kinetics in this dose range.
The absolute bioavailability of the intramuscular route was greater than 90% in a crossover study in
which healthy subjects (n=17) were administered a 7.5 mg IV or IM dose. The mean peak concentration
(Cmax) and time to peak (Tmax) following the IM dose was 90 ng/mL (20% CV) and 0.5 hour (50%
CV). Cmax for the 1-hydroxy metabolite following the IM dose was 8 ng/mL (Tmax=1.0 hour).
Following IM administration, Cmax for midazolam and its 1-hydroxy metabolite were approximately
one-half of those achieved after intravenous injection.
The volume of distribution (Vd) determined from six single-dose pharmacokinetic studies involving
healthy adults ranged from 1.0 to 3.1 L/kg. Female gender, old age, and obesity are associated with
increased values of midazolam Vd. In humans, midazolam has been shown to cross the placenta and enter
into fetal circulation and has been detected in human milk and CSF (see SPECIAL POPULATIONS).
In adults and pediatric patients older than 1 year, midazolam is approximately 97% bound to plasma
protein, principally albumin and that for 1-hydroxy metabolite is about 89%.
In vitro studies with human liver microsomes indicate that the biotransformation of midazolam is
mediated by cytochrome P450-3A4. This cytochrome also appears to be present in gastrointestinal tract
mucosa as well as liver. Sixty to seventy percent of the biotransformation products is 1-hydroxy-
midazolam (also termed alpha-hydroxy-midazolam) while 4-hydroxy-midazolam constitutes 5% or less.
Small amounts of a dihydroxy derivative have also been detected but not quantified. The principal
urinary excretion products are glucuronide conjugates of the hydroxylated derivatives.
Drugs that inhibit the activity of cytochrome P450-3A4 may inhibit midazolam clearance and elevate
steady-state midazolam concentrations.
Studies of the intravenous administration of 1-hydroxy-midazolam in humans suggest that 1-hydroxy-
midazolam is at least as potent as the parent compound and may contribute to the net pharmacologic
activity of midazolam. In vitro studies have demonstrated that the affinities of 1- and 4-hydroxy-
midazolam for the benzodiazepine receptor are approximately 20% and 7%, respectively, relative to
Clearance of midazolam is reduced in association with old age, congestive heart failure, liver disease
(cirrhosis) or conditions which diminish cardiac output and hepatic blood flow.
The principal urinary excretion product is 1-hydroxy-midazolam in the form of a glucuronide conjugate;
smaller amounts of the glucuronide conjugates of 4-hydroxy- and dihydroxy-midazolam are detected as
well. The amount of midazolam excreted unchanged in the urine after a single IV dose is less than 0.5%
(n=5). Following a single IV infusion in 5 healthy volunteers, 45% to 57% of the dose was excreted in
the urine as 1-hydroxymethyl midazolam conjugate.
The pharmacokinetic profile of midazolam following continuous infusion, based on 282 adult subjects,
has been shown to be similar to that following single-dose administration for subjects of comparable
age, gender, body habitus and health status. However, midazolam can accumulate in peripheral tissues
with continuous infusion. The effects of accumulation are greater after long-term infusions than after
short-term infusions. The effects of accumulation can be reduced by maintaining the lowest midazolam
infusion rate that produces satisfactory sedation.
Infrequent hypotensive episodes have occurred during continuous infusion; however, neither the time to
onset nor the duration of the episode appeared to be related to plasma concentrations of midazolam or
alpha-hydroxy-midazolam. Further, there does not appear to be an increased chance of occurrence of a
hypotensive episode with increased loading doses.
Patients with renal impairment may have longer elimination half-lives for midazolam (see SPECIAL
POPULATIONS, RENAL IMPAIRMENT).
Changes in the pharmacokinetic profile of midazolam due to drug interactions, physiological variables,
etc., may result in changes in the plasma concentration-time profile and pharmacological response to
midazolam in these patients. For example, patients with acute renal failure appear to have a longer
elimination half-life for midazolam and may experience delayed recovery (see SPECIAL
POPULATIONS, RENAL IMPAIRMENT). In other groups, the relationship between prolonged half-
life and duration of effect has not been established.
Pediatrics and Neonates
In pediatric patients aged 1 year and older, the pharmacokinetic properties following a single dose of
midazolam reported in 10 separate studies of midazolam are similar to those in adults. Weight-
normalized clearance is similar or higher (0.19 to 0.80 L/hr/kg) than in adults and the terminal
elimination half-life (0.78 to 3.3 hours) is similar to or shorter than in adults. The pharmacokinetic
properties during and following continuous intravenous infusion in pediatric patients in the operating
room as an adjunct to general anesthesia and in the intensive care environment are similar to those in
In seriously ill neonates, however, the terminal elimination half-life of midazolam is substantially
prolonged (6.5 to 12.0 hours) and the clearance reduced (0.07 to 0.12 L/hr/kg) compared to healthy
adults or other groups of pediatric patients. It cannot be determined if these differences are due to age,
immature organ function or metabolic pathways, underlying illness or debility.
In a study comparing normals (n=20) and obese patients (n=20) the mean half-life was greater in the
obese group (5.9 vs 2.3 hours). This was due to an increase of approximately 50% in the Vd corrected
for total body weight. The clearance was not significantly different between groups.
In three parallel group studies, the pharmacokinetics of midazolam administered IV or IM were
compared in young (mean age 29, n=52) and healthy elderly subjects (mean age 73, n=53). Plasma half-
life was approximately two-fold higher in the elderly. The mean Vd based on total body weight
increased consistently between 15% to 100% in the elderly. The mean Cl decreased approximately 25%
in the elderly in two studies and was similar to that of the younger patients in the other.
Congestive Heart Failure
In patients suffering from congestive heart failure, there appeared to be a two-fold increase in the
elimination half-life, a 25% decrease in the plasma clearance and a 40% increase in the volume of
distribution of midazolam.
Midazolam pharmacokinetics were studied after an IV single dose (0.075 mg/kg) was administered to 7
patients with biopsy proven alcoholic cirrhosis and 8 control patients. The mean half-life of midazolam
increased 2.5-fold in the alcoholic patients. Clearance was reduced by 50% and the Vd increased by
20%. In another study in 21 male patients with cirrhosis, without ascites and with normal kidney function
as determined by creatinine clearance, no changes in the pharmacokinetics of midazolam or 1-hydroxy-
midazolam were observed when compared to healthy individuals.
Patients with renal impairment may have longer elimination half-lives for midazolam and its metabolites
which may result in slower recovery.
Midazolam and 1-hydroxy-midazolam pharmacokinetics in 6 ICU patients who developed acute renal
failure (ARF) were compared with a normal renal function control group. Midazolam was administered
as an infusion (5 to 15 mg/hr). Midazolam clearance was reduced (1.9 vs 2.8 mL/min/kg) and the half-life
was prolonged (7.6 vs 13 hours) in the ARF patients. The renal clearance of the 1-hydroxy-midazolam
glucuronide was prolonged in the ARF group (4 vs 136 mL/min) and the half-life was prolonged (12 vs
>25 hours). Plasma levels accumulated in all ARF patients to about ten times that of the parent drug. The
relationship between accumulating metabolite levels and prolonged sedation is unclear.
In a study of chronic renal failure patients (n=15) receiving a single IV dose, there was a two-fold
increase in the clearance and volume of distribution but the half-life remained unchanged. Metabolite
levels were not studied.
Plasma Concentration-Effect Relationship
Concentration-effect relationships (after an IV dose) have been demonstrated for a variety of
pharmacodynamic measures (e.g., reaction time, eye movement, sedation) and are associated with
extensive intersubject variability. Logistic regression analysis of sedation scores and steady-state
plasma concentration indicated that at plasma concentrations greater than 100 ng/mL there was at least a
50% probability that patients would be sedated, but respond to verbal commands (sedation score = 3). At
200 ng/mL there was at least a 50% probability that patients would be asleep, but respond to glabellar
tap (sedation score = 4).
For information concerning pharmacokinetic drug interactions with midazolam (see PRECAUTIONS).
INDICATIONS AND USAGE
Midazolam Injection, USP 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.
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
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).
Personnel and Equipment for Monitoring and Resuscitation
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 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. 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 can depress respiration (see CLINICAL PHARMACOLOGY),
especially when used concomitantly with opioid agonists and other sedatives (see DOSAGE AND
ADMINISTRATION), 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. 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).
Risks From Concomitant Use With Opioids
Concomitant use of benzodiazepines, including midazolam, and opioids may result in profound sedation,
respiratory depression, coma, and death. If a decision is made to use midazolam concomitantly with
opioids, monitor patients closely for respiratory depression and sedation (see PRECAUTIONS, DRUG
Risk of Respiratory Adverse Events
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.
Individualization of Dosage
Midazolam hydrochloride must never be used without individualization of dosage particularly when
used with other medications capable of producing central nervous system depression (see DOSAGE
AND ADMINISTRATION for complete information).
Other Adverse Events
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 Central Nervous System Depressants
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
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 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.
Risk of Intra-Arterial Injection
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 non-intravenous and non-intramuscular routes of
administration have not been established. Midazolam hydrochloride should only be administered
intramuscularly or intravenously.
Return to Full 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 (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 1 full day after anesthesia and
surgery, whichever is longer. For pediatric patients, particular care should be taken to assure safe
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).
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
The neonate also has reduced and/or immature organ function and is also vulnerable to profound and/or
prolonged respiratory effects of midazolam.
Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension,
metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in
small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated
with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications
is usually considered negligible compared to that received in flush solutions containing benzyl alcohol.
Administration of high dosages of medications (including midazolam hydrochloride) containing this
preservative must take into account the total amount of benzyl alcohol administered. The recommended
dosage range of midazolam hydrochloride for preterm and term infants includes amounts of benzyl
alcohol well below that associated with toxicity; however, the amount of benzyl alcohol at which
toxicity may occur is not known. If the patient requires more than the recommended dosages or other
medications containing this preservative, the practitioner must consider the daily metabolic load of
benzyl alcohol from these combined sources (see WARNINGS and PRECAUTIONS, PEDIATRIC
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 (see
PRECAUTIONS, PREGNANCY and PEDIATRIC USE, and ANIMAL TOXICOLOGY AND/OR
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.
Intravenous doses of midazolam hydrochloride 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
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 hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride, particularly on an outpatient basis, may again engage in activities
requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be