MIDAZOLAM- midazoalm injection, solution

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MIDAZOLAM HYDROCHLORIDE (UNII: W7TTW573JJ) (MIDAZOLAM - UNII:R60L0SM5BC)
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General Injectables and Vaccines, Inc.
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PRESCRIPTION DRUG
Терапевтични показания:
Midazolam Injection, USP is indicated: intramuscularly or intravenously for preoperative sedation/anxiolysis/amnesia; intravenously as an agent for sedation/anxiolysis/amnesia prior to or during diagnostic, therapeutic or endoscopic procedures, such as bronchoscopy, gastroscopy, cystoscopy, coronary angiography, cardiac catheterization, oncology procedures, radiologic procedures, suture of lacerations and other procedures either alone or in combination with other CNS depressants; intravenously for induction of general anesthesia, before administration of other anesthetic agents. With the use of narcotic premedication, induction of anesthesia can be attained within a relatively narrow dose range and in a short period of time. Intravenous midazolam can also be used as a component of intravenous supplementation of nitrous oxide and oxygen (balanced anesthesia); continuous intravenous infusion for sedation of intubated and mechanically ventilated patients as a component of anesthesia or during treatment in a crit
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Abbreviated New Drug Application
Номер на разрешението:
52584-749-01

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MIDAZOLAM- midazoalm injection, solution

General Injectables and Vaccines, Inc.

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MIDAZOLAM

Rx only

NOT FOR USE IN NEONATES

CONTAINS BENZYL ALCOHOL

BOXED WARNING

WARNINGS

Personnel and Equipment for Monitoring and Resuscitation

Adults and Pediatrics: Intravenous midazolam hydrochloride has been associated with respiratory

depression and respiratory arrest, especially when used for sedation in noncritical care settings.

In some cases, where this was not recognized promptly and treated effectively, death or hypoxic

encephalopathy has resulted. Intravenous midazolam hydrochloride should be used only in

hospital or ambulatory care settings, including physicians' and dental offices, that provide for

continuous monitoring of respiratory and cardiac function, e.g., pulse oximetry. Immediate

availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask

ventilation and intubation, and personnel trained in their use and skilled in airway management

should be assured (see WARNINGS). For deeply sedated pediatric patients, a dedicated

individual, other than the practitioner performing the procedure, should monitor the patient

throughout the procedure.

Risks From Concomitant Use With Opioids

Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory

depression, coma, and death. Monitor patients for respiratory depression and sedation (see

WARNINGS and PRECAUTIONS, DRUG INTERACTIONS).

Individualization of Dosage

Midazolam hydrochloride must never be used without individualization of dosage. The initial

intravenous dose for sedation in adult patients may be as little as 1 mg, but should not exceed 2.5

mg in a normal healthy adult. Lower doses are necessary for older (over 60 years) or debilitated

patients and in patients receiving concomitant narcotics or other central nervous system (CNS)

depressants. The initial dose and all subsequent doses should always be titrated slowly;

administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the

sedative effect. The use of the 1 mg/mL formulation or dilution of the 1 mg/mL or 5 mg/mL

formulation is recommended to facilitate slower injection. Doses of sedative medications in

pediatric patients must be calculated on a mg/kg basis, and initial doses and all subsequent doses

should always be titrated slowly. The initial pediatric dose of midazolam for

sedation/anxiolysis/amnesia is age, procedure, and route dependent (see DOSAGE AND

ADMINISTRATION for complete dosing information).

Neonates: Midazolam should not be administered by rapid injection in the neonatal population.

Severe hypotension and seizures have been reported following rapid IV administration,

particularly with concomitant use of fentanyl (see DOSAGE AND ADMINISTRATION for

complete information).

DESCRIPTION

Midazolam hydrochloride is a water-soluble benzodiazepine available as a sterile, nonpyrogenic

parenteral dosage form for intravenous or intramuscular injection. Each mL contains midazolam

hydrochloride equivalent to 5 mg midazolam compounded with 0.8% sodium chloride and 0.01%

edetate disodium, with 1% benzyl alcohol as preservative; the pH is adjusted to 2.9 to 3.5 with

hydrochloric acid and, if necessary, sodium hydroxide.

Midazolam is a white or yellowish crystalline powder, insoluble in water. The hydrochloride salt of

midazolam, which is formed in situ, is soluble in aqueous solutions. Chemically, midazolam HCl is 8-

chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine hydrochloride. Midazolam

hydrochloride has the empirical formula C18H13ClFN3HCl, a calculated molecular weight of 362.25

and the following structural formula:

Under the acidic conditions required to solubilize midazolam in the product, midazolam is present as an

equilibrium mixture (shown below) of the closed ring form shown above and an open-ring structure

formed by the acid-catalyzed ring opening of the 4,5-double bond of the diazepine ring. The amount of

open-ring form is dependent upon the pH of the solution. At the specified pH of the product, the

solution may contain up to about 25% of the open-ring compound. At the physiologic conditions under

which the product is absorbed (pH of 5 to 8) into the systemic circulation, any open-ring form present

reverts to the physiologically active, lipophilic, closed-ring form (midazolam) and is absorbed as such.

The following chart plots the percentage of midazolam present as the open-ring form as a function of

pH in aqueous solutions. As indicated in the graph, the amount of open-ring compound present in

solution is sensitive to changes in pH over the pH range specified for the product: 3.0 to 3.6 for the 5

mg/mL concentration. Above pH 5, at least 99% of the mixture is present in the closed-ring form.

CLINICAL PHARMACOLOGY

Midazolam is a short-acting benzodiazepine central nervous system (CNS) depressant.

Pharmacodynamics

The effects of midazolam hydrochloride on the CNS are dependent on the dose administered, the route

of administration, and the presence or absence of other medications. Onset time of sedative effects after

IM administration in adults is 15 minutes, with peak sedation occurring 30 to 60 minutes following

injection. In one adult study, when tested the following day, 73% of the patients who received

midazolam hydrochloride intramuscularly had no recall of memory cards shown 30 minutes following

drug administration; 40% had no recall of the memory cards shown 60 minutes following drug

administration. Onset time of sedative effects in the pediatric population begins within 5 minutes and

peaks at 15 to 30 minutes depending upon the dose administered. In pediatric patients, up to 85% had no

recall of pictures shown after receiving intramuscular midazolam compared with 5% of the placebo

controls.

Sedation in adult and pediatric patients is achieved within 3 to 5 minutes after intravenous (IV) injection;

the time of onset is affected by total dose administered and the concurrent administration of narcotic

premedication. Seventy-one percent of the adult patients in endoscopy studies had no recall of

introduction of the endoscope; 82% of the patients had no recall of withdrawal of the endoscope. In one

study of pediatric patients undergoing lumbar puncture or bone marrow aspiration, 88% of patients had

impaired recall vs 9% of the placebo controls. In another pediatric oncology study, 91% of midazolam

treated patients were amnestic compared with 35% of patients who had received fentanyl alone.

When midazolam hydrochloride is given IV as an anesthetic induction agent, induction of anesthesia

occurs in approximately 1.5 minutes when narcotic premedication has been administered and in 2 to 2.5

minutes without narcotic premedication or other sedative premedication. Some impairment in a test of

memory was noted in 90% of the patients studied. A dose response study of pediatric patients

premedicated with 1 mg/kg intramuscular (IM) meperidine found that only 4 out of 6 pediatric patients

who received 600 mcg/kg IV midazolam lost consciousness, with eye closing at 108 to 140 seconds.

This group was compared with pediatric patients who were given thiopental 5 mg/kg IV; 6 out of 6

closed their eyes at 20 ± 3.2 seconds. Midazolam did not dependably induce anesthesia at this dose

despite concomitant opioid administration in pediatric patients.

Midazolam, used as directed, does not delay awakening from general anesthesia in adults. Gross tests of

recovery after awakening (orientation, ability to stand and walk, suitability for discharge from the

recovery room, return to baseline Trieger competency) usually indicate recovery within 2 hours but

recovery may take up to 6 hours in some cases. When compared with patients who received thiopental,

patients who received midazolam generally recovered at a slightly slower rate. Recovery from

anesthesia or sedation for procedures in pediatric patients depends on the dose of midazolam

administered, coadministration of other medications causing CNS depression and duration of the

procedure.

In patients without intracranial lesions, induction of general anesthesia with IV midazolam

hydrochloride is associated with a moderate decrease in cerebrospinal fluid pressure (lumbar puncture

measurements), similar to that observed following IV thiopental. Preliminary data in neurosurgical

patients with normal intracranial pressure but decreased compliance (subarachnoid screw measurements)

show comparable elevations of intracranial pressure with midazolam and with thiopental during

intubation. No similar studies have been reported in pediatric patients.

The usual recommended intramuscular premedicating doses of midazolam hydrochloride do not depress

the ventilatory response to carbon dioxide stimulation to a clinically significant extent in adults.

Intravenous induction doses of midazolam hydrochloride depress the ventilatory response to carbon

dioxide stimulation for 15 minutes or more beyond the duration of ventilatory depression following

administration of thiopental in adults. Impairment of ventilatory response to carbon dioxide is more

marked in adult patients with chronic obstructive pulmonary disease (COPD). Sedation with IV

midazolam does not adversely affect the mechanics of respiration (resistance, static recoil, most lung

volume measurements); total lung capacity and peak expiratory flow decrease significantly but static

compliance and maximum expiratory flow at 50% of awake total lung capacity (Vmax) increase. In one

study of pediatric patients under general anesthesia, intramuscular midazolam (100 mcg/kg or 200

mcg/kg) was shown to depress the response to carbon dioxide in a dose-related manner.

In cardiac hemodynamic studies in adults, IV induction of general anesthesia with midazolam

hydrochloride was associated with a slight to moderate decrease in mean arterial pressure, cardiac

output, stroke volume and systemic vascular resistance. Slow heart rates (less than 65/minute),

particularly in patients taking propranolol for angina, tended to rise slightly; faster heart rates (e.g.,

85/minute) tended to slow slightly. In pediatric patients, a comparison of IV midazolam hydrochloride

(500 mcg/kg) with propofol (2.5 mg/kg) revealed a mean 15% decrease in systolic blood pressure in

patients who had received IV midazolam vs a mean 25% decrease in systolic blood pressure following

propofol.

Pharmacokinetics

Midazolam's activity is primarily due to the parent drug. Elimination of the parent drug takes place via

hepatic metabolism of midazolam to hydroxylated metabolites that are conjugated and excreted in the

urine. Six single-dose pharmacokinetic studies involving healthy adults yield pharmacokinetic

parameters for midazolam in the following ranges: volume of distribution (Vd), 1.0 to 3.1 L/kg;

elimination half-life, 1.8 to 6.4 hours (mean approximately 3 hours); total clearance (Cl), 0.25 to 0.54

L/hr/kg. In a parallel group study, there was no difference in the clearance, in subjects administered 0.15

mg/kg (n=4) and 0.30 mg/kg (n=4) IV doses indicating linear kinetics. The clearance was successively

reduced by approximately 30% at doses of 0.45 mg/kg (n=4) and 0.6 mg/kg (n=5) indicating non-linear

kinetics in this dose range.

Absorption

The absolute bioavailability of the intramuscular route was greater than 90% in a crossover study in

which healthy subjects (n=17) were administered a 7.5 mg IV or IM dose. The mean peak concentration

(Cmax) and time to peak (Tmax) following the IM dose was 90 ng/mL (20% CV) and 0.5 hour (50%

CV). Cmax for the 1-hydroxy metabolite following the IM dose was 8 ng/mL (Tmax=1.0 hour).

Following IM administration, Cmax for midazolam and its 1-hydroxy metabolite were approximately

one-half of those achieved after intravenous injection.

Distribution

The volume of distribution (Vd) determined from six single-dose pharmacokinetic studies involving

healthy adults ranged from 1.0 to 3.1 L/kg. Female gender, old age, and obesity are associated with

increased values of midazolam Vd. In humans, midazolam has been shown to cross the placenta and enter

into fetal circulation and has been detected in human milk and CSF (see SPECIAL POPULATIONS).

In adults and pediatric patients older than 1 year, midazolam is approximately 97% bound to plasma

protein, principally albumin and that for 1-hydroxy metabolite is about 89%.

Metabolism

In vitro studies with human liver microsomes indicate that the biotransformation of midazolam is

mediated by cytochrome P450-3A4. This cytochrome also appears to be present in gastrointestinal tract

mucosa as well as liver. Sixty to seventy percent of the biotransformation products is 1-hydroxy-

midazolam (also termed alpha-hydroxy-midazolam) while 4-hydroxy-midazolam constitutes 5% or less.

Small amounts of a dihydroxy derivative have also been detected but not quantified. The principal

urinary excretion products are glucuronide conjugates of the hydroxylated derivatives.

Drugs that inhibit the activity of cytochrome P450-3A4 may inhibit midazolam clearance and elevate

steady-state midazolam concentrations.

Studies of the intravenous administration of 1-hydroxy-midazolam in humans suggest that 1-hydroxy-

midazolam is at least as potent as the parent compound and may contribute to the net pharmacologic

activity of midazolam. In vitro studies have demonstrated that the affinities of 1- and 4-hydroxy-

midazolam for the benzodiazepine receptor are approximately 20% and 7%, respectively, relative to

midazolam.

Excretion

Clearance of midazolam is reduced in association with old age, congestive heart failure, liver disease

(cirrhosis) or conditions which diminish cardiac output and hepatic blood flow.

The principal urinary excretion product is 1-hydroxy-midazolam in the form of a glucuronide conjugate;

smaller amounts of the glucuronide conjugates of 4-hydroxy- and dihydroxy-midazolam are detected as

well. The amount of midazolam excreted unchanged in the urine after a single IV dose is less than 0.5%

(n=5). Following a single IV infusion in 5 healthy volunteers, 45% to 57% of the dose was excreted in

the urine as 1-hydroxymethyl midazolam conjugate.

Pharmacokinetics-Continuous Infusion

The pharmacokinetic profile of midazolam following continuous infusion, based on 282 adult subjects,

has been shown to be similar to that following single-dose administration for subjects of comparable

age, gender, body habitus and health status. However, midazolam can accumulate in peripheral tissues

with continuous infusion. The effects of accumulation are greater after long-term infusions than after

short-term infusions. The effects of accumulation can be reduced by maintaining the lowest midazolam

infusion rate that produces satisfactory sedation.

Infrequent hypotensive episodes have occurred during continuous infusion; however, neither the time to

onset nor the duration of the episode appeared to be related to plasma concentrations of midazolam or

alpha-hydroxy-midazolam. Further, there does not appear to be an increased chance of occurrence of a

hypotensive episode with increased loading doses.

Patients with renal impairment may have longer elimination half-lives for midazolam (see SPECIAL

POPULATIONS, RENAL IMPAIRMENT).

Special Populations

Changes in the pharmacokinetic profile of midazolam due to drug interactions, physiological variables,

etc., may result in changes in the plasma concentration-time profile and pharmacological response to

midazolam in these patients. For example, patients with acute renal failure appear to have a longer

elimination half-life for midazolam and may experience delayed recovery (see SPECIAL

POPULATIONS, RENAL IMPAIRMENT). In other groups, the relationship between prolonged half-

life and duration of effect has not been established.

Pediatrics and Neonates

In pediatric patients aged 1 year and older, the pharmacokinetic properties following a single dose of

midazolam reported in 10 separate studies of midazolam are similar to those in adults. Weight-

normalized clearance is similar or higher (0.19 to 0.80 L/hr/kg) than in adults and the terminal

elimination half-life (0.78 to 3.3 hours) is similar to or shorter than in adults. The pharmacokinetic

properties during and following continuous intravenous infusion in pediatric patients in the operating

room as an adjunct to general anesthesia and in the intensive care environment are similar to those in

adults.

In seriously ill neonates, however, the terminal elimination half-life of midazolam is substantially

prolonged (6.5 to 12.0 hours) and the clearance reduced (0.07 to 0.12 L/hr/kg) compared to healthy

adults or other groups of pediatric patients. It cannot be determined if these differences are due to age,

immature organ function or metabolic pathways, underlying illness or debility.

Obese

In a study comparing normals (n=20) and obese patients (n=20) the mean half-life was greater in the

obese group (5.9 vs 2.3 hours). This was due to an increase of approximately 50% in the Vd corrected

for total body weight. The clearance was not significantly different between groups.

Geriatric

In three parallel group studies, the pharmacokinetics of midazolam administered IV or IM were

compared in young (mean age 29, n=52) and healthy elderly subjects (mean age 73, n=53). Plasma half-

life was approximately two-fold higher in the elderly. The mean Vd based on total body weight

increased consistently between 15% to 100% in the elderly. The mean Cl decreased approximately 25%

in the elderly in two studies and was similar to that of the younger patients in the other.

Congestive Heart Failure

In patients suffering from congestive heart failure, there appeared to be a two-fold increase in the

elimination half-life, a 25% decrease in the plasma clearance and a 40% increase in the volume of

distribution of midazolam.

Hepatic Impairment

Midazolam pharmacokinetics were studied after an IV single dose (0.075 mg/kg) was administered to 7

patients with biopsy proven alcoholic cirrhosis and 8 control patients. The mean half-life of midazolam

increased 2.5-fold in the alcoholic patients. Clearance was reduced by 50% and the Vd increased by

20%. In another study in 21 male patients with cirrhosis, without ascites and with normal kidney function

as determined by creatinine clearance, no changes in the pharmacokinetics of midazolam or 1-hydroxy-

midazolam were observed when compared to healthy individuals.

Renal Impairment

Patients with renal impairment may have longer elimination half-lives for midazolam and its metabolites

which may result in slower recovery.

Midazolam and 1-hydroxy-midazolam pharmacokinetics in 6 ICU patients who developed acute renal

failure (ARF) were compared with a normal renal function control group. Midazolam was administered

as an infusion (5 to 15 mg/hr). Midazolam clearance was reduced (1.9 vs 2.8 mL/min/kg) and the half-life

was prolonged (7.6 vs 13 hours) in the ARF patients. The renal clearance of the 1-hydroxy-midazolam

glucuronide was prolonged in the ARF group (4 vs 136 mL/min) and the half-life was prolonged (12 vs

>25 hours). Plasma levels accumulated in all ARF patients to about ten times that of the parent drug. The

relationship between accumulating metabolite levels and prolonged sedation is unclear.

In a study of chronic renal failure patients (n=15) receiving a single IV dose, there was a two-fold

increase in the clearance and volume of distribution but the half-life remained unchanged. Metabolite

levels were not studied.

Plasma Concentration-Effect Relationship

Concentration-effect relationships (after an IV dose) have been demonstrated for a variety of

pharmacodynamic measures (e.g., reaction time, eye movement, sedation) and are associated with

extensive intersubject variability. Logistic regression analysis of sedation scores and steady-state

plasma concentration indicated that at plasma concentrations greater than 100 ng/mL there was at least a

50% probability that patients would be sedated, but respond to verbal commands (sedation score = 3). At

200 ng/mL there was at least a 50% probability that patients would be asleep, but respond to glabellar

tap (sedation score = 4).

Drug Interactions

For information concerning pharmacokinetic drug interactions with midazolam (see PRECAUTIONS).

INDICATIONS AND USAGE

Midazolam Injection, USP is indicated:

intramuscularly or intravenously for preoperative sedation/anxiolysis/amnesia;

intravenously as an agent for sedation/anxiolysis/amnesia prior to or during diagnostic, therapeutic or

endoscopic procedures, such as bronchoscopy, gastroscopy, cystoscopy, coronary angiography,

cardiac catheterization, oncology procedures, radiologic procedures, suture of lacerations and other

procedures either alone or in combination with other CNS depressants;

intravenously for induction of general anesthesia, before administration of other anesthetic agents. With

the use of narcotic premedication, induction of anesthesia can be attained within a relatively narrow

dose range and in a short period of time. Intravenous midazolam can also be used as a component of

intravenous supplementation of nitrous oxide and oxygen (balanced anesthesia);

continuous intravenous infusion for sedation of intubated and mechanically ventilated patients as a

component of anesthesia or during treatment in a critical care setting.

CONTRAINDICATIONS

Injectable midazolam hydrochloride is contraindicated in patients with a known hypersensitivity to the

drug. Benzodiazepines are contraindicated in patients with acute narrow-angle glaucoma.

Benzodiazepines may be used in patients with open-angle glaucoma only if they are receiving

appropriate therapy. Measurements of intraocular pressure in patients without eye disease show a

moderate lowering following induction with midazolam hydrochloride; patients with glaucoma have not

been studied.

Midazolam hydrochloride is not intended for intrathecal or epidural administration due to the presence

of the preservative benzyl alcohol in the dosage form. Midazolam hydrochloride is contraindicated for

use in premature infants because the formulation contains benzyl alcohol (see WARNINGS and

PRECAUTIONS, PEDIATRIC USE).

WARNINGS

Personnel and Equipment for Monitoring and Resuscitation

Prior to the intravenous administration of midazolam hydrochloride in any dose, the immediate

availability of oxygen, resuscitative drugs, age- and size-appropriate equipment for bag/valve/mask

ventilation and intubation, and skilled personnel for the maintenance of a patent airway and support of

ventilation should be ensured. Patients should be continuously monitored for early signs of

hypoventilation, airway obstruction, or apnea with means readily available (e.g., pulse oximetry).

Hypoventilation, airway obstruction, and apnea can lead to hypoxia and/or cardiac arrest unless

effective countermeasures are taken immediately. The immediate availability of specific reversal agents

(flumazenil) is highly recommended. Vital signs should continue to be monitored during the recovery

period. Because intravenous midazolam can depress respiration (see CLINICAL PHARMACOLOGY),

especially when used concomitantly with opioid agonists and other sedatives (see DOSAGE AND

ADMINISTRATION), it should be used for sedation/anxiolysis/amnesia only in the presence of

personnel skilled in early detection of hypoventilation, maintaining a patent airway, and supporting

ventilation. When used for sedation/anxiolysis/amnesia, midazolam should always be titrated slowly in

adult or pediatric patients. Adverse hemodynamic events have been reported in pediatric patients with

cardiovascular instability; rapid intravenous administration should also be avoided in this population

(see DOSAGE AND ADMINISTRATION for complete information).

Risks From Concomitant Use With Opioids

Concomitant use of benzodiazepines, including midazolam, and opioids may result in profound sedation,

respiratory depression, coma, and death. If a decision is made to use midazolam concomitantly with

opioids, monitor patients closely for respiratory depression and sedation (see PRECAUTIONS, DRUG

INTERACTIONS).

Risk of Respiratory Adverse Events

Serious cardiorespiratory adverse events have occurred after administration of midazolam. These have

included respiratory depression, airway obstruction, oxygen desaturation, apnea, respiratory arrest

and/or cardiac arrest, sometimes resulting in death or permanent neurologic injury. There have also

been rare reports of hypotensive episodes requiring treatment during or after diagnostic or surgical

manipulations particularly in adult or pediatric patients with hemodynamic instability. Hypotension

occurred more frequently in the sedation studies in patients premedicated with a narcotic.

Individualization of Dosage

Midazolam hydrochloride must never be used without individualization of dosage particularly when

used with other medications capable of producing central nervous system depression (see DOSAGE

AND ADMINISTRATION for complete information).

Other Adverse Events

Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle

tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients. These

reactions may be due to inadequate or excessive dosing or improper administration of midazolam

hydrochloride; however, consideration should be given to the possibility of cerebral hypoxia or true

paradoxical reactions. Should such reactions occur, the response to each dose of midazolam

hydrochloride and all other drugs, including local anesthetics, should be evaluated before proceeding.

Reversal of such responses with flumazenil has been reported in pediatric patients.

Concomitant Use of Central Nervous System Depressants

Concomitant use of barbiturates, alcohol or other central nervous system depressants may increase the

risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or

prolonged drug effect. Narcotic premedication also depresses the ventilatory response to carbon

dioxide stimulation.

Debilitation and Comorbid Considerations

Higher risk adult and pediatric surgical patients, elderly patients and debilitated adult and pediatric

patients require lower dosages, whether or not concomitant sedating medications have been

administered. Adult or pediatric patients with COPD are unusually sensitive to the respiratory

depressant effect of midazolam hydrochloride. Pediatric and adult patients undergoing procedures

involving the upper airway such as upper endoscopy or dental care, are particularly vulnerable to

episodes of desaturation and hypoventilation due to partial airway obstruction. Adult and pediatric

patients with chronic renal failure and patients with congestive heart failure eliminate midazolam more

slowly (see CLINICAL PHARMACOLOGY). Because elderly patients frequently have inefficient

function of one or more organ systems and because dosage requirements have been shown to decrease

with age, reduced initial dosage of midazolam hydrochloride is recommended, and the possibility of

profound and/or prolonged effect should be considered.

Injectable midazolam should not be administered to adult or pediatric patients in shock or coma, or in

acute alcohol intoxication with depression of vital signs. Particular care should be exercised in the use

of intravenous midazolam in adult or pediatric patients with uncompensated acute illnesses, such as

severe fluid or electrolyte disturbances.

Risk of Intra-Arterial Injection

There have been limited reports of intra-arterial injection of midazolam hydrochloride. Adverse events

have included local reactions, as well as isolated reports of seizure activity in which no clear causal

relationship was established. Precautions against unintended intra-arterial injection should be taken.

Extravasation should also be avoided.

The safety and efficacy of midazolam following non-intravenous and non-intramuscular routes of

administration have not been established. Midazolam hydrochloride should only be administered

intramuscularly or intravenously.

Return to Full Cognitive Function

Midazolam is associated with a high incidence of partial or complete impairment of recall for the next

several hours. The decision as to when patients who have received injectable midazolam, particularly

on an outpatient basis, may again engage in activities requiring complete mental alertness, operate

hazardous machinery or drive a motor vehicle must be individualized. Gross tests of recovery from the

effects of midazolam (see CLINICAL PHARMACOLOGY) cannot be relied upon to predict reaction

time under stress. It is recommended that no patient operate hazardous machinery or a motor vehicle

until the effects of the drug, such as drowsiness, have subsided or until 1 full day after anesthesia and

surgery, whichever is longer. For pediatric patients, particular care should be taken to assure safe

ambulation.

Usage in Pregnancy

An increased risk of congenital malformations associated with the use of benzodiazepine drugs

(diazepam and chlordiazepoxide) has been suggested in several studies. If this drug is used during

pregnancy, the patient should be apprised of the potential hazard to the fetus.

Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines

(see DRUG ABUSE AND DEPENDENCE).

Usage in Preterm Infants and Neonates

Rapid injection should be avoided in the neonatal population. Midazolam hydrochloride administered

rapidly as an intravenous injection (less than 2 minutes) has been associated with severe hypotension in

neonates, particularly when the patient has also received fentanyl. Likewise, severe hypotension has

been observed in neonates receiving a continuous infusion of midazolam who then receive a rapid

intravenous injection of fentanyl. Seizures have been reported in several neonates following rapid

intravenous administration.

The neonate also has reduced and/or immature organ function and is also vulnerable to profound and/or

prolonged respiratory effects of midazolam.

Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension,

metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in

small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated

with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications

is usually considered negligible compared to that received in flush solutions containing benzyl alcohol.

Administration of high dosages of medications (including midazolam hydrochloride) containing this

preservative must take into account the total amount of benzyl alcohol administered. The recommended

dosage range of midazolam hydrochloride for preterm and term infants includes amounts of benzyl

alcohol well below that associated with toxicity; however, the amount of benzyl alcohol at which

toxicity may occur is not known. If the patient requires more than the recommended dosages or other

medications containing this preservative, the practitioner must consider the daily metabolic load of

benzyl alcohol from these combined sources (see WARNINGS and PRECAUTIONS, PEDIATRIC

USE).

Pediatric Neurotoxicity

Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block

NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain

and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance

of these findings is not clear. However, based on the available data, the window of vulnerability to

these changes is believed to correlate with exposures in the third trimester of gestation through the

first several months of life, but may extend out to approximately three years of age in humans (see

PRECAUTIONS, PREGNANCY and PEDIATRIC USE, and ANIMAL TOXICOLOGY AND/OR

PHARMACOLOGY).

Some published studies in children suggest that similar deficits may occur after repeated or prolonged

exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects.

These studies have substantial limitations, and it is not clear if the observed effects are due to the

anesthetic/sedation drug administration or other factors such as the surgery or underlying illness.

Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other

procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer

than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should

take into consideration the benefits of the procedure weighed against the potential risks.

PRECAUTIONS

General

Intravenous doses of midazolam hydrochloride should be decreased for elderly and for debilitated

patients (see WARNINGS and DOSAGE AND ADMINISTRATION). These patients will also

probably take longer to recover completely after midazolam administration for the induction of

anesthesia.

Midazolam does not protect against the increase in intracranial pressure or against the heart rate rise

and/or blood pressure rise associated with endotracheal intubation under light general anesthesia.

The efficacy and safety of midazolam in clinical use are functions of the dose administered, the clinical

status of the individual patient, and the use of concomitant medications capable of depressing the CNS.

Anticipated effects range from mild sedation to deep levels of sedation virtually equivalent to a state of

general anesthesia where the patient may require external support of vital functions. Care must be taken

to individualize and carefully titrate the dose of midazolam hydrochloride to the patient's underlying

medical/surgical conditions, administer to the desired effect being certain to wait an adequate time for

peak CNS effects of both midazolam hydrochloride and concomitant medications, and have the

personnel and size-appropriate equipment and facilities available for monitoring and intervention (see

BOXED WARNING, WARNINGS and DOSAGE AND ADMINISTRATION). Practitioners

administering midazolam hydrochloride must have the skills necessary to manage reasonably

foreseeable adverse effects, particularly skills in airway management. For information regarding

withdrawal (see DRUG ABUSE AND DEPENDENCE).

Information for Patients

To assure safe and effective use of benzodiazepines, the following information and instructions should

be communicated to the patient when appropriate:

1. Inform your physician about any alcohol consumption and medicine you are now taking, especially

blood pressure medication and antibiotics, including drugs you buy without a prescription. Alcohol has

an increased effect when consumed with benzodiazepines; therefore, caution should be exercised

regarding simultaneous ingestion of alcohol during benzodiazepine treatment.

2. Inform your physician if you are pregnant or are planning to become pregnant.

3. Inform your physician if you are nursing.

4. Patients should be informed of the pharmacological effects of midazolam, such as sedation and

amnesia, which in some patients may be profound. The decision as to when patients who have received

injectable midazolam hydrochloride, particularly on an outpatient basis, may again engage in activities

requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be

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