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LABEL: MIDAZOLAM- MIDAZOLAM HYDROCHLORIDE INJECTION, SOLUTION
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DRUG LABEL INFO
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* NDC Code(s): 70860-601-05, 70860-601-10, 70860-601-41, 70860-601-42
* Packager: Athenex Pharmaceutical Division, LLC.
* Category: HUMAN PRESCRIPTION DRUG LABEL
* DEA Schedule: CIV
* Marketing Status: Abbreviated New Drug Application
DRUG LABEL INFORMATION
Updated April 25, 2019
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* SPL UNCLASSIFIED SECTION
NOT FOR USE IN NEONATES - CONTAINS BENZYL ALCOHOL - Athenex - Rx only
NOT FOR USE IN NEONATES
CONTAINS BENZYL ALCOHOL
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* BOXED WARNING (What is this?)
Personnel and Equipment for Monitoring and Resuscitation - Adults and
Pediatrics: Intravenous midazolam hydrochloride has been associated with
respiratory depression and respiratory arrest ...
WARNINGS
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 complete information).
Close
* 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 ...
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
C18H13ClFN3•HCl, 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.
Close
* CLINICAL PHARMACOLOGY
Midazolam is a short-acting benzodiazepine central nervous system (CNS)
depressant. Pharmacodynamics - The effects of midazolam hydrochloride on the
CNS are dependent on the dose administered ...
Midazolam is a short-acting benzodiazepine central nervous system (CNS)
depressant.
PHARMACODYNAMICS
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 controls.
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 procedure.
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 propofol.
PHARMACOKINETICS
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.
ABSORPTION
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.
DISTRIBUTION
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%.
METABOLISM
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 midazolam.
EXCRETION
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.
PHARMACOKINETICS-CONTINUOUS INFUSION
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).
SPECIAL POPULATIONS
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 adults.
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.
OBESE
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.
GERIATRIC
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.
HEPATIC IMPAIRMENT
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.
RENAL IMPAIRMENT
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).
DRUG INTERACTIONS
For information concerning pharmacokinetic drug interactions with midazolam
(see PRECAUTIONS).
Close
* 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 ...
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. Close
* 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 ...
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).
Close
* WARNINGS
Personnel and Equipment for Monitoring and Resuscitation - Prior to the
intravenous administration of midazolam hydrochloride in any dose, the
immediate availability of oxygen, resuscitative ...
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 Interactions).
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 dioxide stimulation.
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 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).
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.
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 Use).
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 (see PRECAUTIONS, Pregnancy and Pediatric Use, and ANIMAL TOXICOLOGY
AND/OR PHARMACOLOGY).
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.
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* PRECAUTIONS
General - Intravenous doses of midazolam hydrochloride should be decreased
for elderly and for debilitated patients (see WARNINGS and DOSAGE AND
ADMINISTRATION). These patients will also ...
GENERAL
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 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 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 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.
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 GABAA 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 1200 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 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.
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
Teratogenic Effects: Pregnancy Category D (see WARNINGS).
Published studies in pregnant primates demonstrate that the administration of
anesthetic and sedation drugs that block NMDA receptors and/or potentiate
GABA activity during the period of peak brain development increases neuronal
apoptosis in the developing brain of the offspring when used for longer than
3 hours. There are no data on pregnancy exposures in primates corresponding
to periods prior to the third trimester in humans (see Data).
DATA
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).
LABOR AND DELIVERY
In humans, measurable levels of midazolam were found in maternal venous
serum, umbilical venous and arterial serum and amniotic fluid, indicating
placental transfer of the drug. Following intramuscular administration of
0.05 mg/kg of midazolam, both the venous and the umbilical arterial serum
concentrations were lower than maternal concentrations.
The use of injectable midazolam in obstetrics has not been evaluated in
clinical studies. Because midazolam is transferred transplacentally and
because other benzodiazepines given in the last weeks of pregnancy have
resulted in neonatal CNS depression, midazolam is not recommended for
obstetrical use.
NURSING MOTHERS
Midazolam is excreted in human milk. Caution should be exercised when
midazolam hydrochloride is administered to a nursing woman.
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, 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 health care 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 hydrochloride 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).
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.
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* ADVERSE REACTIONS
See WARNINGS concerning serious cardiorespiratory events and possible
paradoxical reactions. Fluctuations in vital signs were the most frequently
seen findings following parenteral administration ...
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 dental procedures).
ADULTS
The following additional adverse reactions were reported after intramuscular
administration:
headache (1.3%) Local effects at IM Injection site pain (3.7%) induration
(0.5%) redness (0.5%) muscle stiffness (0.3%)
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:
hiccoughs (3.9%) Local effects at the IV site nausea (2.8%) tenderness (5.6%)
vomiting (2.6%) pain during injection (5.0%) coughing (1.3%) redness (2.6%)
“oversedation” (1.6%) induration (1.7%) headache (1.5%) phlebitis (0.4%)
drowsiness (1.2%)
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 Boxed 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, dysphoria, slurred speech,
dysphonia, 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
To report SUSPECTED ADVERSE REACTIONS, contact Athenex Pharmaceutical
Division, LLC. at 1-855-273-0154 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
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* DRUG ABUSE AND DEPENDENCE
Midazolam hydrochloride contains midazolam, a Schedule IV control substance.
Midazolam was actively self-administered in primate models used to assess the
positive reinforcing effects of ...
Midazolam hydrochloride contains midazolam, a Schedule IV control substance.
Midazolam was actively self-administered in primate models used to assess the
positive reinforcing effects of psychoactive drugs.
Midazolam produced physical dependence of a mild to moderate intensity in
cynomolgus monkeys after 5 to 10 weeks of administration. Available data
concerning the drug abuse and dependence potential of midazolam suggest that
its abuse potential is at least equivalent to that of diazepam.
Withdrawal symptoms, similar in character to those noted with barbiturates
and alcohol (convulsions, hallucinations, tremor, abdominal and muscle
cramps, vomiting and sweating), have occurred following abrupt
discontinuation of benzodiazepines, including midazolam. Abdominal
distention, nausea, vomiting, and tachycardia are prominent symptoms of
withdrawal in infants. The more severe withdrawal symptoms have usually been
limited to those patients who had received excessive doses over an extended
period of time. Generally milder withdrawal symptoms (e.g., dysphoria and
insomnia) have been reported following abrupt discontinuance of
benzodiazepines taken continuously at therapeutic levels for several months.
Consequently, after extended therapy, abrupt discontinuation should generally
be avoided and a gradual dosage tapering schedule followed. There is no
consensus in the medical literature regarding tapering schedules; therefore,
practitioners are advised to individualize therapy to meet patient's needs.
In some case reports, patients who have had severe withdrawal reactions due
to abrupt discontinuation of high-dose long-term midazolam, have been
successfully weaned off of midazolam over a period of several days.
Close
* OVERDOSAGE
Symptoms - The manifestations of midazolam overdosage reported are similar to
those observed with other benzodiazepines, including sedation, somnolence,
confusion, impaired coordination ...
SYMPTOMS
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
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 overdosage.
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 benzodiazepine-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.
Close
* DOSAGE AND ADMINISTRATION
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 ...
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 hydrochloride 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 hydrochloride (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
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 hydrochloride should be injected deep in a
large muscle mass.
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.
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 hydrochloride 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
Sedation/anxiolysis/amnesia for procedures (see INDICATIONS): 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.
When used for sedation/anxiolysis/amnesia for a procedure, dosage must be
individualized and titrated. Midazolam hydrochloride 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.)
Midazolam hydrochloride 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 or 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 hydrochloride 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
For continuous infusion, midazolam hydrochloride 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.
Usual Adult Dose: If a loading dose is necessary to rapidly initiate
sedation, 0.01 to 0.05 mg/kg (approximately 0.5 to 4.0 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 hydrochloride infusion rate. PEDIATRIC
PATIENTS
UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF
MIDAZOLAM HYDROCHLORIDE ON A MG/KG BASIS. As a group, pediatric patients
generally require higher dosages of midazolam hydrochloride (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, Monitoring
subsection of DOSAGE AND ADMINISTRATION. The health care 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
ResponsivenessSpeechFacial ExpressionEyesComposite 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) 1-2 16 6
(38%) 4
(25%) 3
(19%) 3
(19%) 0 >2-5 22 9
(41%) 5
(23%) 8
(36%) 0 0 >5-12 34 1
(3%) 6
(18%) 22
(65%) 5
(15%) 0 >12-17 18 0 4
(22%) 14
(78%) 0 0 Total (1-17) 90 16
(18%) 19
(21%) 47
(52%) 8
(9%) 0
INTRAMUSCULARLY
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.
USUAL PEDIATRIC DOSE (NON-NEONATAL)
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
For sedation/anxiolysis/amnesia prior to and during procedures or prior to
anesthesia.
USUAL PEDIATRIC DOSE (NON-NEONATAL)
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 hydrochloride 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
hydrochloride 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; a 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 hydrochloride 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
For sedation/anxiolysis/amnesia in critical care settings.
USUAL PEDIATRIC DOSE (NON-NEONATAL)
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 injection 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 hydrochloride 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 hydrochloride 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
For sedation in critical care settings.
USUAL NEONATAL DOSE
Based on pharmacokinetic parameters and reported clinical experience in
preterm and term neonates WHOSE TRACHEA WAS INTUBATED, continuous intravenous
infusions of midazolam injection 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.
Close
* HOW SUPPLIED
Midazolam Injection, USP is supplied as follows: NDCMidazolam Injection, USP
(5 mg per mL)Package Factor - 70860-601-05 - 25 mg per 5 mL Multi-Dose Vial -
10 vials per carton - 70860-601-10 - 50 ...
Midazolam Injection, USP is supplied as follows:
NDCMidazolam Injection, USP (5 mg per mL)Package Factor 70860-601-05 25 mg
per 5 mL Multi-Dose Vial 10 vials per carton 70860-601-10 50 mg per 10 mL
Multi-Dose Vial 10 vials per carton
STORAGE CONDITIONS
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]
Protect from light.
Sterile, Nonpyrogenic.
The container closure is not made with natural rubber latex.
Close
* ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY
Published studies in animals demonstrate that the use of anesthetic agents
during the period of rapid brain growth or synaptogenesis results in
widespread neuronal and oligodendrocyte cell loss in ...
Published studies in animals demonstrate that the use of anesthetic agents
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 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 an anesthetic regimen that produced a
light surgical plane of anesthesia did not increase neuronal cell loss,
however, treatment regimens of 5 hours or longer increased neuronal cell
loss. Data in rodents and in primates suggest that the neuronal and
oligodendrocyte cell losses are associated with subtle but 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 neonates and young children who
require procedures against the potential risks suggested by the nonclinical
data (see WARNINGS, Pediatric Neurotoxicity and PRECAUTIONS, Pregnancy and
Pediatric Use).
Athenex
Mfd. for Athenex
Schaumburg, IL 60173 (USA)
Made in India
©2017 Athenex.
Revised: April 2017
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* PRINCIPAL DISPLAY PANEL
PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label - NDC 70860-601-41 -
Midazolam Injection, USP - CIV - 25 mg per 5 mL (5 mg per mL) Rx only -
CONTAINS BENZYL ALCOHOL - For Intravenous or ...
PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label
NDC 70860-601-41
Midazolam Injection, USP
CIV
25 mg per 5 mL (5 mg per mL)
Rx only
CONTAINS BENZYL ALCOHOL
For Intravenous or Intramuscular Use Only
5 mL Multi-Dose Vial
Close
* PRINCIPAL DISPLAY PANEL
PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label - NDC 70860-601-42 -
Midazolam Injection, USP - CIV - 50 mg per 10 mL (5 mg per mL) Rx only -
CONTAINS BENZYL ALCOHOL - For Intravenous or ...
PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label
NDC 70860-601-42
Midazolam Injection, USP
CIV
50 mg per 10 mL (5 mg per mL)
Rx only
CONTAINS BENZYL ALCOHOL
For Intravenous or Intramuscular Use Only
10 mL Multi-Dose Vial
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INGREDIENTS AND APPEARANCE
Product Information
MIDAZOLAM midazolam hydrochloride injection, solution
Product Information Product TypeHUMAN PRESCRIPTION DRUGItem Code
(Source)NDC:70860-601 Route of AdministrationINTRAVENOUS, INTRAMUSCULARDEA
ScheduleCIV
Active Ingredient/Active Moiety Ingredient NameBasis of StrengthStrength
midazolam hydrochloride (UNII: W7TTW573JJ) (midazolam - UNII:R60L0SM5BC)
midazolam5 mg in 1 mL
Inactive Ingredients Ingredient NameStrength sodium chloride (UNII:
451W47IQ8X) edetate disodium (UNII: 7FLD91C86K) benzyl alcohol (UNII:
LKG8494WBH) sodium hydroxide (UNII: 55X04QC32I) hydrochloric acid (UNII:
QTT17582CB) water (UNII: 059QF0KO0R)
Packaging #Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:70860-601-0510 in 1 CARTON12/14/2016 1NDC:70860-601-415 mL in 1 VIAL,
MULTI-DOSE; Type 0: Not a Combination Product 2NDC:70860-601-1010 in 1
CARTON12/14/2016 2NDC:70860-601-4210 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a
Combination Product
Marketing Information Marketing CategoryApplication Number or Monograph
CitationMarketing Start DateMarketing End Date ANDAANDA09085012/14/2016
Labeler - Athenex Pharmaceutical Division, LLC. (080318964)
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MORE INFO ON THIS DRUG
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MIDAZOLAM- MIDAZOLAM HYDROCHLORIDE INJECTION, SOLUTION
NUMBER OF VERSIONS: 5
Published Date (What is this?) Version Files Apr 23, 2019 7 (current) download
Dec 6, 2018 6 download Jul 12, 2017 5 download Dec 29, 2016 4 download Dec 15,
2016 3 download
RXNORM
MIDAZOLAM- MIDAZOLAM HYDROCHLORIDE INJECTION, SOLUTION
RxCUI RxNorm NAME RxTTY 1 311702 midazolam 5 MG/ML Injectable Solution PSN 2
311702 midazolam 5 MG/ML Injectable Solution SCD 3 311702 midazolam (as
midazolam hydrochloride) 5 MG/ML Injectable Solution SY
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NDC CODES
MIDAZOLAM- MIDAZOLAM HYDROCHLORIDE INJECTION, SOLUTION
IF THIS SPL CONTAINS INACTIVATED NDCS LISTED BY THE FDA INITIATED COMPLIANCE
ACTION, THEY WILL BE SPECIFIED AS SUCH.
NDC 1 70860-601-05 2 70860-601-10 3 70860-601-41 4 70860-601-42
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