Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/415
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Midazolam Hydrochloride (Injection, Solution)
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Midazolam hydrochloride 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
T0 WHOM MIDAZOLAM HYDROCHLORIDE 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
hydrochloride injection should only be administered IM or IV (see WARNINGS). Care should be
taken to avoid intra-arterial injection or extravasation (see WARNINGS). Midazolam Hydrochloride 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. Both the 1 mg/mL and 5 mg/mL formulations 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.
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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 1 mg or 5 mg midazolam compounded with 0.8% sodium chloride. The pH is
approximately 3 (2.5 to 3.5) and is adjusted with hydrochloric acid and, if
necessary, sodium hydroxide. Midazolam is a white to
light yellow crystalline compound, insoluble in water. The hydrochloride salt
of midazolam, which is formed in situ,
is soluble in aqueous solutions. Chemically, midazolam HCl is 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine hydrochloride.
Midazolam hydrochloride has the chemical formula CHClFN���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 4.0 for the 1 mg/mL
concentration and 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.
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Midazolam is a short-acting benzodiazepine central nervous
system (CNS) depressant. The effects of midazolam 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 premeditation
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��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 inadult 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 (V) increase. In one study of pediatric patients under
general anesthesia, intramuscular midazolam (100 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 (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 0.3 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 cross-over study in which
healthy subjects (n=17) were administered a 7.5 mg IV or IM dose. The mean
peak concentration (C) and time to peak (T) following
the IM dose was 90 ng/mL (20% CV) and 0.5 hr (50% CV). Cfor
the 1-hydroxy metabolite following the IM dose was 8 ng/mL (T=1.0
hr). Following IM administration, Cfor
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 1.0-3.1 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 CLINICAL PHARMACOLOGY, Special Populations). In
adults and children older than 1 year, midazolam is approximately 97% bound
to plasma protein, principally albumin. 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-hydroxymidazolam) 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-hydroxymidazolam
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 CLINICAL
PHARMACOLOGY, Special Populations: Renal Failure). 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 CLINICAL
PHARMACOLOGY, Special Populations: Renal Failure). 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 hrs). 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 Insufficiency: 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 determinedby creatinine clearance,
no changes in the pharmacokinetics of midazolam or 1-hydroxy-midazolam were
observed when compared to healthy individuals. Renal Failure: 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 hr) 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 hr vs>25
hr). 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 (eg, 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.
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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.
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Package configurations containing preservative-free midazolam
hydrochloride equivalent to 1 mg midazolam/mL: Package configurations containing preservative-free midazolam
hydrochloride equivalent to 5 mg midazolam/mL: Store at 20 to 25��C (68 to 77��F). [See USP Controlled
Room Temperature.] Discard unused portion. December, 2004 HOSPIRA, INC., LAKE FOREST,
IL 60045 USA
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WARNING Adult and Pediatric: Intravenous midazolam hydrochloride
has been associated with respiratory depression and respiratory arrest, especially
when used for sedation in noncritical care settings. In some cases, where
this was not recognized promptly and treated effectively, death or hypoxic
encephalopathy has resulted. Intravenous midazolam 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, ie, pulse oximetry. Immediate availability of resuscitative
drugs and age- and size-appropriate equipment for bag/valve/mask ventilation
and intubation, and personnel trained in their use and skilled in airway management
should be assured (see WARNINGS). For
deeply sedated pediatric patients, a dedicated individual, other than the
practitioner performing the procedure, should monitor the patient throughout
the procedures. 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 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 (see DOSAGE AND
ADMINISTRATION for complete information).
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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. Use with Other CNS Depressants: 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 bothmidazolam 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).<br/>Information for Patients:: To assure safe and effective use of benzodiazepines, the
following information and instructions should be communicated to the patient
when appropriate:<br/>Drug Interactions:: The sedative effect of intravenous midazolam is accentuated
by any concomitantly administered medication, which depresses the central
nervous system, particularly narcotics (e.g., morphine, meperidine and fentanyl)
and also secobarbital and droperidol. Consequently, the dosage of midazolam
should be adjusted according to the type and amount of concomitant medications
administered and the desired clinical response (see DOSAGEAND ADMINISTRATION). Caution is advised when
midazolam is administered concomitantly with drugs that are known to inhibit
the P450-3A4 enzyme system such as cimetidine (not ranitidine), erythromycin,
diltiazem, verapamil, ketoconazole and itraconazole. These drug interactions
may result in prolonged sedation due to a decrease in plasma clearance of
midazolam. The effect of single oral doses of 800 mg
cimetidine and 300 mg ranitidine on steady-state concentrations of midazolam
was examined in a randomized crossover study (n=8). Cimetidine increased the
mean midazolam steady-state concentration from 57 to 71 ng/mL. Ranitidine
increased the mean steady-state concentration to 62 ng/mL. No change in choice
reaction time or sedation index was detected after dosing with the H2 receptor
antagonists. In a placebo-controlled study, erythromycin
administered as a 500 mg dose, tid, for 1 week (n=6), reduced the clearance
of midazolam following a single 0.5 mg/kg IV dose. The half-life was approximately
doubled. Caution is advised when midazolam is administered
to patients receiving erythromycin since this may result in a decrease in
the plasma clearance of midazolam. The effects of diltiazem
(60 mg tid) and verapamil (80 mg tid) on the pharmacokinetics and pharmacodynamics
of midazolam were investigated in a three-way crossover study (n=9). The half-life
of midazolam increased from 5 to 7 hours when midazolam was taken in conjunction
with verapamil or diltiazem. No interaction was observed in healthy subjects
between midazolam and nifedipine. In a placebo-controlled
study, saquinavir administered as a 1200 mg dose, tid, for 5 days (n=12),
a 56% reduction in the clearance of midazolam following a single 0.05 mg/kg
IV dose was observed. The half-life was approximately doubled. A
moderate reduction in induction dosage requirements of thiopental (about 15%)
has been noted following use of intramuscular midazolam hydrochloride for
premedication in adults. The intravenous administration
of midazolam hydrochloride decreases the minimum alveolar concentration (MAC)
of halothane required for general anesthesia. This decrease correlates with
the dose of midazolam hydrochloride administered; no similar studies have
been carried out in pediatric patients but there is no scientific reason to
expect that pediatric patients would respond differently than adults. Although
the possibility of minor interactive effects has not been fully studied, midazolam
and pancuronium have been used together in patients without noting clinically
significant changes in dosage, onset or duration in adults. Midazolam hydrochloride
does not protect against the characteristic circulatory changes noted after
administration of succinylcholine or pancuronium and does not protect against
the increased intracranial pressure noted following administration of succinylcholine.
Midazolam does not cause a clinically significant change in dosage, onset
or duration of a single intubating dose of succinylcholine; no similar studies
have been carried out in pediatric patients but there is no scientific reason
to expect that pediatric patients would respond differently than adults. No
significant adverse interactions with commonly used premedications or drugs
used during anesthesia and surgery (including atropine, scopolamine, glycopyrrolate,
diazepam, hydroxyzine, d-tubocurarine, succinylcholine and other nondepolarizing
muscle relaxants) or topical local anesthetics (including lidocaine, dyclonine
HCl and Cetacaine) have been observed in adults or pediatric patients. In
neonates, however, severe hypotension has been reported with concomitant administration
of fentanyl. This effect has been observed in neonates on an infusion of midazolam
who received a rapid injection of fentanyl and in patients on an infusion
of fentanyl who have received a rapid injection of midazolam.<br/>Drug/Laboratory Test Interactions:: Midazolam has not been shown to interfere with results obtained
in clinical laboratory tests.<br/>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 (25 times a human dose of 0.35 mg/kg) 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: A reproduction study
in male and female rats did not show any impairment of fertility at dosages
up to 10 times the human IV dose of 0.35 mg/kg.<br/>Pregnancy:: Teratogenic Effects: Pregnancy Category D (see WARNINGS). Segment II teratology studies, performed
with midazolam maleate injectable in rabbits and rats at 5 and 10 times
the human dose of 0.35 mg/kg, did not show evidence of teratogenicity. Nonteratogenic
Effects: Studies in rats showed no adverse effects on reproductive parameters
during gestation and lactation. Dosages tested were approximately 10 times
the human dose of 0.35 mg/kg.<br/>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.<br/>Nursing Mothers:: Midazolam is excreted in human milk. Caution should be exercised
when midazolam hydrochloride is administered to a nursing woman.<br/>Pediatric Use:: The safety and efficacy of midazolam for sedation/anxiolysis/amnesia
following single dose intramuscular administration, intravenously by intermittent
injections and continuous infusion have been established in pediatric and
neonatal patients. For specific safety monitoring and dosage guidelines see Boxed WARNING, CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE,
WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, OVERDOSAGE and DOSAGE AND ADMINISTRATION. UNLIKE ADULT PATIENTS,
PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS.
As a group, pediatric patients generally require higher dosages of midazolam
(mg/kg) than do adults. Younger (less than six years) pediatric patients may
require higher dosages (mg/kg) than older pediatric patients, and may require
closer monitoring. In obese PEDIATRIC PATIENTS, the dose should be calculated
based on ideal body weight. When midazolam is given in conjunction with opioids
or other sedatives, the potential for respiratory depression, airway obstruction,
or hypoventilation is increased. The 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.<br/>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 deathunder 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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| dailymed-instance:overdosag... |
The manifestations of midazolam overdosage reported are similar
to those observed with other benzodiazepines, including sedation, somnolence,
confusion, impaired coordination, diminished reflexes, coma and untoward effects
on vital signs. No evidence of specific organ toxicity from midazolam hydrochloride
overdosage has been reported. Treatment
of Overdosage: Treatment of injectable midazolam overdosage is the
same as that followed for overdosage with other benzodiazepines. Respiration,
pulse rate and blood pressure should be monitored and general supportive measures
should be employed. Attention should be given to the maintenance of a patent
airway and support of ventilation, including administration of oxygen. An
intravenous infusion should be started. Should hypotension develop, treatment
may include intravenous fluid therapy, repositioning, judicious use of vasopressors
appropriate to the clinical situation, if indicated, and other appropriate
countermeasures. There is no information as to whether peritoneal dialysis,
forced diuresis or hemodialysis are of any value in the treatment of midazolam
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.
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| dailymed-instance:genericMe... |
Midazolam Hydrochloride
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| dailymed-instance:fullName |
Midazolam Hydrochloride (Injection, Solution)
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| dailymed-instance:adverseRe... |
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: Administration of IM midazolam hydrochloride to elderly
and/or higher risk surgical patients has been associated with rare reports
of death under circumstances compatible with cardiorespiratory depression.
In most of these cases, the patients also received other central nervous system
depressants capable of depressing respiration, especially narcotics (see DOSAGE AND ADMINISTRATION). The
following additional adverse reactions were reported subsequent to intravenous
administration as a single sedative/anxiolytic/amnestic agent in adult patients: Pediatric Patients: The
following adverse events related to the use of IV midazolam hydrochloride
in pediatric patients were reported in the medical literature: desaturation
4.6%, apnea 2.8%, hypotension 2.7%, paradoxical reactions 2.0%, hiccough 1.2%,
seizure-like activity 1.1% and nystagmus 1.1%. The majority of airway-related
events occurred in patients receiving other CNS depressing medications and
in patients where midazolam was not used as a single sedating agent. Neonates: For information concerning hypotensive
episodes and seizures following the administration of midazolam hydrochloride
to neonates, see 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
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| dailymed-instance:warning |
Midazolam hydrochloride must never
be used without individualization of dosage particularly when used with other
medications capable of producing central nervous system depression. Prior
to the intravenous administration of midazolam hydrochloride in any dose,
the immediate availability of oxygen, resuscitative drugs, age- and size-appropriate
equipment for bag/valve/mask ventilation and intubation, and skilled personnel
for the maintenance of a patent airway and support of ventilation should be
ensured. Patients should be continuously monitored with some meansof detection
for early signs of hypoventilation, airway obstruction, or apnea, i.e., pulse
oximetry. Hypoventilation, airway obstruction, and apnea can lead to hypoxia
and/or cardiac arrest unless effective countermeasures are taken immediately. The immediate availability of specific reversal agents (flumazenil)
is highly recommended. Vital signs should continue to be monitored during
the recovery period. Because intravenous midazolam depresses respiration (see CLINICAL PHARMACOLOGY) and because opioid agonists
and other sedatives can add to this depression, midazolam should be administered
as an induction agent only by a person trained in general anesthesia and should
be used for sedation/anxiolysis/amnesia only in the presence of personnel
skilled in early detection of hypoventilation, maintaining a patent airway
and supporting ventilation. When used for sedation/anxiolysis/amnesia,
midazolam should always be titrated slowly in adult or pediatric patients. Adverse hemodynamic events have been reported in pediatric patients
with cardiovascular instability; rapid intravenous administration should also
be avoided in this population. See DOSAGE AND ADMINISTRATION for complete information. Serious cardiorespiratory
adverse events have occurred after administration of midazolam. These have
included respiratory depression, airway obstruction, oxygen desaturation,
apnea, respiratory arrest and/or cardiac arrest, sometimes resulting in death
or permanent neurologic injury. There have also been rare reports of hypotensive
episodes requiring treatment during or after diagnostic or surgical manipulations
particularly in adult or pediatric patients with hemodynamic instability.
Hypotension occurred more frequently in the sedation studies in patients premedicated
with a narcotic. Reactions such as agitation, involuntary
movements (including tonic/clonic movements and muscle tremor), hyperactivity
and combativeness have been reported in both adult and pediatric patients.
These reactions may be due to inadequate or excessive dosing or improper administration
of midazolam hydrochloride; however, consideration should be given to the
possibility of cerebral hypoxia or true paradoxical reactions. Should such
reactions occur, the response to each dose of midazolam hydrochloride and
all other drugs, including local anesthetics, should be evaluated before proceeding.
Reversal of such responses with flumazenil has been reported in pediatric
patients. Concomitant use of barbiturates, alcohol or
other central nervous system depressants may increase the risk of hypoventilation,
airway obstruction, desaturation, or apnea and may contribute to profound
and/or prolonged drug effect. Narcotic premeditation also depresses the ventilatory
response to carbon dioxide stimulation. Higher risk
adult and pediatric surgical patients, elderly patients and debilitated adult
and pediatric patients require lower dosages, whether or not concomitant sedating
medications have been administered. Adult or pediatric patients with COPD
are unusually sensitive to the respiratory depressant effect of midazolam
hydrochloride. Pediatric and adult patients undergoing procedures involving
the upper airway such as upper endoscopy or dental care, are particularly
vulnerable to episodes of desaturation and hypoventilation due to partial
airway obstruction. Adult and pediatric patients with chronic renal failure
and patients with congestive heart failure eliminate midazolam more slowly
(see CLINICAL PHARMACOLOGY). Because elderly
patients frequently have inefficient function of one or more organ systems
and because dosage requirements have been shown to decrease with age, reduced
initial dosage of midazolam hydrochloride is recommended, and the possibility
of profound and/or prolonged effect should be considered. Injectable
midazolam should not be administered to adult or pediatric patients in shock
or coma, or in acute alcohol intoxication with depression of vital signs.
Particular care should be exercised in the use of intravenous midazolam in
adult or pediatric patients with uncompensated acute illnesses, such as severe
fluid or electrolyte disturbances. There have been limited
reports of intra-arterial injection of midazolam hydrochloride. Adverse events
have included local reactions, as well as isolated reports of seizure activity
in which no clear causal relationship was established. Precautions against
unintended intra-arterial injection should be taken. Extravasation should
also be avoided. The safety and efficacy of midazolam
following nonintravenous and nonintramuscular routes of administration have
not been established. Midazolam hydrochloride should only be administered
intramuscularly or intravenously. The decision as to
when patients who have received injectable midazolam, particularly on an outpatient
basis, may again engage in activities requiring complete mental alertness,
operate hazardous machinery or drive a motor vehicle must be individualized.
Gross tests of recovery from the effects of midazolam (see CLINICAL
PHARMACOLOGY) cannot be relied upon to predict reaction time under
stress. It is recommended that no patient operate hazardous machinery or a
motor vehicle until the effects of the drug, such as drowsiness, have subsided
or until one full day after anesthesia and surgery, whichever is longer. For
pediatric patients, particular care should be taken to assure safe ambulation. Usage in Pregnancy: An
increased risk of congenital malformations associated with the use of benzodiazepine
drugs (diazepam and chlordiazepoxide) has been suggested in several studies.
If this drug is used during pregnancy, the patient should be apprised of the
potential hazard to the fetus. Withdrawal
symptoms of the barbiturate type have occurred after the discontinuation of
benzodiazepines (see DRUG ABUSE AND DEPENDENCE). 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 rapidintravenous administration. The
neonate also has reduced and/or immature organ function and is also vulnerable
to profound and/or prolonged respiratory effects of midazolam.
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| dailymed-instance:indicatio... |
Midazolam hydrochloride injection is indicated: Midazolam is associated with a high incidence of partial
or complete impairment of recall for the next several hours (see CLINICAL PHARMACOLOGY).
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| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
Midazolam Hydrochloride
|