Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3351
| Predicate | Object |
|---|---|
| rdf:type | |
| rdfs:label |
MIDAZOLAM Hydrochloride (Injection, Solution)
|
| dailymed-instance:dosage |
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 TO 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
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 hydrochloride, 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 hydrochloride may be diluted with 0.9% sodium chloride
or 5% dextrose inwater. 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 receiveintravenous midazolam hydrochloride. 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. Note: Parenteral drug products should be inspected visually
for particulate matter and discoloration prior to administration,
whenever solution and container permit.
|
| dailymed-instance:descripti... |
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 (2.9 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.
|
| dailymed-instance:clinicalP... |
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 hydrochloride 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
hydrochloride 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 1.0 mg/kg intramuscular
(IM) meperidine found that only 4 out of 6 pediatric patients
who received 600 mcg/kg IV midazolam hydrochloride 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 hydrochloride
did not dependably induce anesthesia at this dose despite concomitant
opioid administration in pediatric patients. Midazolam hydrochloride, 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 forprocedures in
pediatric patients depends on the dose of midazolam hydrochloride
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 hydrochloride 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 hydrochloride
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 hydrochloride (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 hydrochloride 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 nodifference 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 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 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 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 midazolamand may experience delayed recovery (see 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 hydrochloride 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 similarto 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 determined
by 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 hydrochloride, see PRECAUTIONS.
|
| dailymed-instance:activeIng... | |
| dailymed-instance:contraind... |
Midazolam hydrochloride injection 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.
|
| dailymed-instance:supply |
Preservative-Free Midazolam Hydrochloride Injection
is supplied in SLIM-PAK tamper detection packages
as follows: Store at 20 to 25��C (68 to 77��F). [See
USP Controlled Room Temperature.] For Single-use only. Discard unused portion. Revised: April, 2007 Directions
for Prefilled Syringe 1. To release plunger rod, grasp syringe and depress rod until it
releases from the syringe. 2. Attach plunger rod to the syringe by inserting rod into the plunger
end and turning clockwise. 3. Remove luer tip cover. Attach needle or blunt cannula if applicable. 4. Expel air by pushing
on the plunger rod. Do not touch the syringe tip. Administer Drug. Note: To prevent needlestick injuries, needles and blunt
cannulas should not be recapped, purposely bent, or broken by hand.
|
| dailymed-instance:boxedWarn... |
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 procedure. The initial intravenous dose for sedation in adult
patients may be as little as 1 mg, but should not exceed 2.5 mg in
a normal healthy adult. Lower doses are necessary for older (over
60 years) or debilitated patients and in patients receiving concomitantnarcotics 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 useof 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 hydrochloride 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).
|
| dailymed-instance:activeMoi... | |
| dailymed-instance:inactiveI... | |
| dailymed-instance:precautio... |
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 hydrochloride administration
for the induction of anesthesia. Midazolam hydrochloride
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 hydrochloride 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 facilitiesavailable 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 hydrochloride
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 hydrochloride should be adjusted
according to the type and amount of concomitant medications administered
and the desired clinical response (see DOSAGE
AND ADMINISTRATION). Caution is advised
when midazolam is administered concomitantly with drugs that are known
to inhibit the P450-3A4 enzyme system such as cimetidine (not ranitidine),
erythromycin, diltiazem, verapamil, ketoconazole and itraconazole.
These drug interactions may result in prolonged sedation due to a
decrease in plasma clearance of midazolam. The
effect of single oral doses of 800 mg cimetidine and 300 mg ranitidine
on steady-state concentrations of midazolam was examined in a randomized
crossover study (n=8). Cimetidine increased the mean midazolam steady-state
concentration from 57 to 71 ng/mL. Ranitidine increased the mean steady-state
concentration to 62 ng/mL. No change in choice reaction time or sedation
index was detected after dosing with the H2 receptor antagonists. In a placebo-controlled study, erythromycin administered
as a 500 mg dose, tid, for 1 week (n=6), reduced the clearance of
midazolam following a single 0.5 mg/kg IV dose. The half-life was
approximately doubled. Caution is advised when
midazolam is administered to patients receiving erythromycin since
this may result in a decrease in the plasma clearance of midazolam. The effects of diltiazem (60 mg tid) and verapamil (80
mg tid) on the pharmacokinetics and pharmacodynamics of midazolam
were investigated in a three-way 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 hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride
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
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
closer monitoring. In obese PEDIATRIC PATIENTS, the dose should be
calculated based on ideal body weight. When midazolam hydrochloride
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
inpediatric 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 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.
|
| dailymed-instance:overdosag... |
The manifestations of midazolam hydrochloride 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
hydrochloride 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 benzodiazepineoverdose. 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 flumazeniltreatment, 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.
|
| dailymed-instance:genericMe... |
Midazolam Hydrochloride
|
| dailymed-instance:fullName |
MIDAZOLAM Hydrochloride (Injection, Solution)
|
| 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 hydrochloride 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 hydrochloride
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
|
| 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 means of detection for early signs
of hypoventilation, airway obstruction, or apnea, i.e., pulse oximetry.
Hypoventilation, airway obstruction, and apnea can lead to hypoxia
and/or cardiac arrest unless effective countermeasures are taken immediately. The immediate availability of specific reversal agents (flumazenil)
is highly recommended. Vital signs should continue to be monitored
during the recovery period. Because intravenous midazolam hydrochloride
depresses respiration (see CLINICAL PHARMACOLOGY) and because opioid agonists and other sedatives can add to this
depression, midazolam hydrochloride 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 ofpersonnel
skilled in early detection of hypoventilation, maintaining a patent
airway and supporting ventilation. When
used for sedation/anxiolysis/amnesia, midazolam hydrochloride 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 hydrochloride. 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 occurredmore 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 paradoxicalreactions.
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 initialdosage of midazolam hydrochloride is recommended,
and the possibility of profound and/or prolonged effect should be
considered. Injectable midazolam hydrochloride
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 hydrochloride 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
hydrochloride 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 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.
Gross tests of recovery from the effects of midazolam hydrochloride
(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 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 hydrochloride.
|
| dailymed-instance:indicatio... |
Midazolam hydrochloride injection is indicated:
|
| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
MIDAZOLAM Hydrochloride
|