Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/830
| Predicate | Object |
|---|---|
| rdf:type | |
| rdfs:label |
Midazolam Hydrochloride (Injection)
|
| dailymed-instance:dosage |
Midazolam hydrochloride injection is a potent
sedative agent that requires slow administration and
individualization of dosage. Clinical experience has shown midazolam
HCl 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 HCl
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 upperairway such as endoscopy or dental 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 HCl . Midazolam HCl
should only be administered IM or IV . Care should be
taken to avoid intra-arterial injection or extravasation . Midazolam HCl
Injection may be mixed in the same syringe with the following frequently
used premedications: morphine sulfate, meperidine, atropine sulfate or
scopolamine. Midazolam HCl, 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 HCl may be diluted with
0.9% sodium chloride or 5% dextrose in water.<br/>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 (ie, pulse oximetry).<br/>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 HCl. 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 .<br/>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.<br/>Usual Adult Dose:<br/>Intramuscularly:<br/>Intravenously:<br/>Continuous
Infusion:<br/>Pediatric Patients:<br/>Intramuscularly:<br/>Intravenously by Intermittent Injection:<br/>Continuous
Intravenous Infusion:<br/>Continuous
Intravenous Infusion: 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 HCl 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 and 0.01% edetate disodium, with 1%
benzyl alcohol as preservative; the pH is adjusted to 2.9-3.7 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 molecular formula
CHCIFN���HCl, a calculated
molecular weight of 362.25 and the following structural formula:
|
| 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 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 HCl
is given IV as an anesthetic induction agent, induction of anesthesia
occurs in approximately 1.5 minutes when narcotic premedication has been
administered and in 2 to 2.5 minutes without narcotic premedication or
other sedative premedication. Some impairment in a test of memory was
noted in 90% of the patients studied. A dose response study of pediatric
patients premedicated with 1.0 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 fromanesthesia 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
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 do not
depress the ventilatory response to carbon dioxide stimulation to a
clinically significant extent in adults. Intravenous induction doses of
midazolam depress the ventilatory response to carbon dioxide stimulation
for 15 minutes or more beyond the duration of ventilatory depression
following administration of thiopental in adults. Impairment of
ventilatory response to carbon dioxide is more marked in adult patients
with chronic obstructive pulmonary disease (COPD). Sedation with IV midazolam does not adversely affect the mechanics of respiration
(resistance, static recoil, most lung volume measurements); total lung
capacity and peak expiratory flow decrease significantly but static
compliance and maximum expiratory flow at 50% of awake total lung
capacity (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 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.<br/>Pharmacokinetics: Midazolam's
activity is primarily due to the parent drug. Elimination of the
parent drug takes place via hepatic metabolism of midazolam to
hydroxylated metabolites that are conjugated and excreted in the
urine. Six single-dose pharmacokinetic studies involving healthy
adults yield pharmacokinetic parameters for midazolam in the following ranges: volume of distribution (Vd), 1.0 to 3.1 L/kg;
elimination half-life, 1.8 to 6.4 hours (mean approximately 3
hours); total clearance (Cl), 0.25 to 0.54 L/hr/kg. In a
parallel group study, there was no difference in the clearance,
in subjects administered 0.15 mg/kg (n=4) and 0.30 mg/kg (n=4)
IV doses indicating linear kinetics. The clearance was
successively reduced by approximately 30% at doses of 0.45 mg/kg
(n=4) and 0.6 mg/kg (n=5) indicating non-linear kinetics in this
dose range.<br/>Absorption: The
absolute bioavailability of the intramuscular route was
greater than 90% in a crossover study in which healthy
subjects (n=17) were administered a 7.5 mg IV or IM
dose. The mean peak concentration (C) and
time to peak (T) following the IM dose was
90 ng/mL (20% CV) and 0.5 hour (50% CV). Cfor the 1-hydroxy metabolite following the IM dose was
8 ng/mL (T=1.0 hour). Following IM administration, Cfor
midazolam and its 1-hydroxy metabolite were
approximately one-half of those achieved after
intravenous injection.<br/>Distribution: The
volume of distribution (Vd) determined from six
single-dose pharmacokinetic studies involving healthy
adults ranged from 1.0 to 3.1 L/kg. Female gender, old
age, and obesity are associated with increased values of
midazolam Vd. In humans, midazolam has been shown to
cross the placenta and enter into fetal circulation and
has been detected in human milk and CSF (see Special Populations). In
adults and children older than 1 year, midazolam is
approximately 97% bound to plasma protein, principally
albumin.<br/>Metabolism: In vitro
studies with human liver microsomes indicate that the
biotransformation of midazolam is mediated by cytochrome
P450 3A4. This cytochrome also appears to be present in
gastrointestinal tract mucosa as well as liver. Sixty to
seventy percent of the biotransformation products is
1-hydroxy-midazolam (also termed
alpha-hydroxy-midazolam) while 4-hydroxy-midazolam
constitutes 5% or less. Small amounts of a dihydroxy
derivative have also been detected but not quantified.
The principal urinary excretion products are glucuronide
conjugates of the hydroxylated derivatives. Drugs that inhibit the activity of cytochrome P450 3A4
may inhibit midazolam clearance and elevate steady-state
midazolam concentrations. Studies of the intravenous administration of
1-hydroxy-midazolam in humans suggest that
1-hydroxy-midazolam is at least as potent as the parent
compound and may contribute to the net pharmacologic
activity of midazolam. In
vitro studies have demonstrated that the
affinities of 1- and 4-hydroxy-midazolam for the
benzodiazepine receptor are approximately 20% and 7%,
respectively, relative to midazolam.<br/>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 singleIV infusion in 5 healthy volunteers,
45% to 57% of the dose was excreted in the urine as
1-hydroxymethyl midazolam conjugate.<br/>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 canbe 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 withincreased loading doses. Patients with renal impairment may have longer
elimination half-lives for midazolam (see Special Populations: Renal
Failure).<br/>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 experiencedelayed recovery (see Special
Populations: Renal Failure). In other groups, the
relationship between prolonged half-life and duration of effect
has not been established.<br/>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.<br/>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.<br/>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.<br/>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.<br/>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.<br/>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 hours) in the ARF patients. The renal clearance of
the 1-hydroxy-midazolam glucuronide was prolonged in the
ARF group (4 vs 136 mL/min) and the half-life was
prolonged (12 hr vs>25 hours). Plasma levels
accumulated in all ARF patients to about ten times that
of the parent drug. The relationship between
accumulating metabolite levels and prolonged sedation is
unclear. In
a study of chronic renal failure patients (n=15)
receiving a single IV dose, there was a two-fold increase in the clearance and volume of distribution but the half-life remained unchanged. Metabolite levels were
not studied.<br/>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).<br/>Drug
Interactions: For
information concerning pharmacokinetic drug interactions
with midazolam, see PRECAUTIONS.
|
| dailymed-instance:activeIng... | |
| dailymed-instance:contraind... |
Midazolam 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 HCl ; patients with glaucoma
have not been studied. Midazolam HCl is
not intended for intrathecal or epidural administration due to the
presence of the preservative benzyl alcohol in the dosage
form.
|
| dailymed-instance:supply |
Package
configurations containing midazolam hydrochloride equivalent to 5mg midazolam/mL: 1-mL vials
(5mg)���boxes of 25 (NDC 10019-027-03) 2-mL vials (10
mg)���boxes of 25 (NDC 10019-027-04) 5-mL vials (25
mg)���boxes of 10 (NDC 10019-027-05) 10-mL vials (50
mg)���boxes of 10 (NDC 10019-027-10) Package
configurations containing midazolam hydrochloride equivalent to 1mg midazolam/mL: 2-mL vials (2
mg)���boxes of 10 (NDC 10019-028-02) 2-mL vials (2
mg)���boxes of 25 (NDC 10019-028-03) 5-mL vials (5
mg)���boxes of 10 (NDC 10019-028-05) 10-mL vials (10
mg)���boxes of 10 (NDC 10019-028-10)<br/>Storage: Store at 20��-25��C (68��-77��F),
excursions permitted to 15��-30��C (59��-86��F) [see USP
Controlled Room Temperature]. Manufactured for Baxter Healthcare
Corporation By: MOVA PHARMACEUTICAL CORPORATION Caguas,
Puerto Rico 00725 USA For Product
Inquiry 1 800 ANA DRUG (1-800-262-3784) MLT-01716/1.0
|
| dailymed-instance:boxedWarn... |
BOXED WARNING:<br/>Adult and
Pediatrics: Intravenous
midazolam HCl 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 HCl 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 . For deeply sedated pediatric patients, a
dedicated individual, other than the practitioner performing the
procedure, should monitor the patient throughout the procedure. The initial
intravenous dose for sedation in adult patients may be as little
as 1 mg, but should not exceed 2.5 mg in a normal healthy adult.
Lower doses are necessary for older (over 60 years) or
debilitated patients and in patients receiving concomitant
narcotics or other central nervous system (CNS) depressants. The
initial dose and all subsequent doses should always be titrated
slowly; administer over at least 2 minutes and allow an
additional 2 or more minutes to fully evaluate the sedative effect. The use of the 1 mg/mL formulation or dilution of the 1
mg/mL or 5 mg/mL formulation is recommended to facilitate slower injection. Doses of sedative medications in pediatric patients
must be calculated on amg/kg basis, and initial doses and all
subsequent doses should always be titrated slowly. The initial
pediatric dose of midazolam HCl for sedation/anxiolysis/amnesia
is age, procedure and route dependent (see DOSAGE AND
ADMINISTRATION for complete dosing
information).<br/>Neonates: Midazolam
HCl 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 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.<br/>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 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 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 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: 1. Inform
your physician about any alcohol consumption and medicine you
are now taking, especially blood pressure medication and
antibiotics, including drugs you buy without a prescription.
Alcohol has an increased effect when consumed with
benzodiazepines; therefore, caution should be exercised
regarding simultaneous ingestion of alcohol during
benzodiazepine treatment. 2. Inform
your physician if you are pregnant or are planning to become
pregnant. 3. Inform
your physician if you are nursing. 4. Patients
should be informed of the pharmacological effects of midazolam,
such as sedation and amnesia, which in some patients may be
profound. The decision as to when patients who have received
injectable midazolam, particularly on an outpatient basis, may
again engage in activities requiring complete mental alertness,
operate hazardous machinery or drive a motor vehicle must be
individualized. 5. Patients
receiving continuous infusion of midazolam in critical care
settings over an extended period of time, may experience
symptoms of withdrawal following abrupt
discontinuation.<br/>Drug Interactions: The
sedative effect of intravenous midazolam is accentuated by any
concomitantly administered medication, which depresses the
central nervous system, particularly narcotics (eg, morphine,
meperidine and fentanyl) and also secobarbital and droperidol.
Consequently, the dosage of midazolam should be adjusted
according to the type and amount of concomitant medications
administered and the desired clinical response (see DOSAGE AND
ADMINISTRATION). Caution is
advised when midazolam is administered concomitantly with drugs
that are known to inhibit the P450 3A4 enzyme system such as
cimetidine (not ranitidine), erythromycin, diltiazem, verapamil,
ketoconazole and itraconazole. These drug interactions may
result in prolonged sedation due to a decrease in plasma
clearance of midazolam. The effect
of single oral doses of 800 mg cimetidine and 300 mg ranitidine
on steady-state concentrations of midazolam was examined in a
randomized crossover study (n=8). Cimetidine increased the mean
midazolam steady state concentration from 57 to 71 ng/mL.
Ranitidine increased the mean steady-state concentration to 62
ng/mL. No change in choice reaction time or sedation index was
detected after dosing with the Hreceptor
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. 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. A moderate
reduction in induction dosage requirements of thiopental (about
15%) has been noted following use of intramuscular midazolam for
premedication in adults. The
intravenous administration of midazolam decreases the minimum
alveolar concentration (MAC) of halothane required for general
anesthesia. This decrease correlates with the dose of midazolam
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 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) havebeen
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. Caution is
advised when midazolam is administered to patients receiving
erythromycin since this may result in a decrease in the plasma
clearance 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:<br/>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.<br/>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.<br/>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:<br/>Teratogenic
Effects:<br/>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 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, WARNINGS, PRECAUTIONS, ADVERSE
REACTIONS, OVERDOSAGEand 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 medicationin pediatric patients should be aware of
and follow accepted professional guidelines for pediatric
sedation appropriate to their situation. Midazolam
should not be administered by rapid injection in the neonatal
population. Severe hypotension and seizures have been reported
following rapid IV administration, particularly with concomitant
use of fentanyl.<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-risksurgical 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 HCl 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 overdosage has been reported.<br/>Treatment of
Overdosage: Treatment
of injectable midazolam HCl 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 HCl 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.
|
| dailymed-instance:genericMe... |
Midazolam Hydrochloride
|
| dailymed-instance:fullName |
Midazolam Hydrochloride (Injection)
|
| 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 HCl 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 HCl is administered with other medications capable of
depressing the central nervous system. The incidence of such events is higher inpatients undergoing procedures
involving the airway without the protective effect of an
endotracheal tube (eg, upper endoscopy and dental
procedures).<br/>Adults: The
following additional adverse reactions were reported after
intramuscular administration: Administration of IM midazolam HCl 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:<br/>Pediatric Patients: The
following adverse events related to the use of IV midazolam HCl
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 HClwas not used as a single sedating
agent.<br/>Neonates: For
information concerning hypotensive episodes and seizures
following the administration of midazolam HCl to neonates, seeBoxed
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:<br/>Respiratory: Laryngospasm, bronchospasm, dyspnea, hyperventilation,
wheezing, shallow respirations, airway obstruction,
tachypnea.<br/>Cardiovascular: Bigeminy,
premature ventricular contractions, vasovagal episode,
bradycardia, tachycardia, nodal rhythm.<br/>Gastrointestinal: Acid taste,
excessive salivation, retching.<br/>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.<br/>Special Senses: Blurred
vision, diplopia, nystagmus, pinpoint pupils, cyclic movements
of eyelids, visual disturbance, difficulty focusing eyes, ears blocked, loss of balance, light-headedness.<br/>Integumentary: Hive-like
elevation at injection site, swelling or feeling of burning, warmth or coldness at injection site.<br/>Hypersensitivity: Allergic
reactions including anaphylactoid reactions, hives, rash,
pruritus.<br/>Miscellaneous: Yawning,
lethargy, chills, weakness, toothache, faint feeling,
hematoma.
|
| dailymed-instance:warning |
Midazolam 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 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 ofhypoventilation, airway obstruction, or apnea, ie, 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;
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 and all other drugs, including local
anesthetics, should be evaluated before proceeding. Reversal of such
responses with flumazenil has been reported in pediatricpatients. Concomitant use of
barbiturates, alcohol or other central nervous system depressants may
increase the risk of hypoventilation, airway obstruction, desaturation
or apnea and may contribute to profound and/or prolonged drug effect.
Narcotic premedication also depresses the ventilatory response to carbon
dioxide stimulation. Higher risk adult
and pediatric surgical patients, elderly patients and debilitated adult
and pediatric patients require lower dosages, whether or not concomitant
sedating medications have been administered. Adult or pediatric patients
with COPD are unusually sensitive to the respiratory depressant effect
of midazolam. 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 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. 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 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.<br/>Usage in Pregnancy: An increased risk of congenital
malformations associated with the use of benzodiazepine
drugs (diazepam and chlordiazepoxide) has been suggested in
several studies. If this drug is used during pregnancy, the
patient should be apprised of the potential hazard to the
fetus. Withdrawal symptoms of the barbiturate type have occurred after the
discontinuation of benzodiazepines (see DRUG ABUSE
AND DEPENDENCE section).<br/>Usage in Preterm
Infants and Neonates: Rapid
injection should be avoided in the neonatal population.
Midazolam 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 havebeen reported in several neonates following rapid intravenous
administration. The neonate also has reduced and/or immature organ function and is also
vulnerable to profound and/or prolonged respiratory effects of
midazolam. Exposure to
excessive amounts of benzyl alcohol has been associated with
toxicity (hypotension, metabolic acidosis), particularly in
neonates, and an increased incidence of kernicterus,
particularly in small preterm infants. There have been rare
reports of deaths, primarily in preterm infants, associated with
exposure to excessive amounts of benzyl alcohol. The amount of
benzyl alcohol from medications is usually considered negligible
compared to that received in flush solutions containing benzyl
alcohol. Administration of high dosages of medications
(including midazolam) containing this preservative must take
into account the total amount of benzyl alcohol administered.
The recommended dosage range of midazolam for preterm and term
infants includes amounts of benzyl alcohol well below that
associated with toxicity; however, the amount of benzyl alcohol
at which toxicity may occur is not known. If the patient
requires more than the recommended dosages or other medications
containing this preservative, the practitioner must consider the
daily metabolic load of benzyl alcohol from these combined
sources.
|
| dailymed-instance:indicatio... |
Midazolam
hydrochloride injection is indicated: ��intramuscularly
or intravenously for preoperative sedation/anxiolysis/amnesia; ��intravenously as
an agent for sedation/anxiolysis/amnesia prior to or during diagnostic,
therapeutic or endoscopic procedures, such as bronchoscopy, gastroscopy,
cystoscopy, coronary angiography, cardiac catheterization, oncology
procedures, radiologic procedures, suture of lacerations and other
procedures either alone or in combination with other CNS depressants; ��intravenously for
induction of general anesthesia, before administration of other
anesthetic agents. With the use of narcotic premedication, induction of
anesthesia can be attained within a relatively narrow dose range and in
a short period of time. Intravenous midazolam can also be used as a
component of intravenous supplementation of nitrous oxide and oxygen
(balanced anesthesia); ��continuous
intravenous infusion for sedation of intubated and mechanically ventilated patients as a component of anesthesia or during treatment in
a critical care setting. Midazolam HCl is
associated with a high incidence of partial or complete impairment of
recall for the next several hours (see CLINICAL
PHARMACOLOGY).
|
| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
Midazolam Hydrochloride
|