SEDALAM

Injection, USP is a water-soluble benzodiazepine available as a sterile, nonpyrogenic parenteral dosage form for intravenous or intramuscular injection.

Each mL contains midazolam hydrochloride,USP equivalent to 5 mg midazolam compounded with 0.8% sodium chloride; the pH is adjusted to approximately 3 (2.5 to 3.5) and is adjusted with sodium hydroxide and, if necessary, hydrochloric acid.

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,USP is 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a]benzodiazepine hydrochloride.

Midazolam hydrochloride,USP has the empirical formula C18H13ClFN3•HCl, a calculated molecular weight of 362.25 and the following structural formula: Under the acidic conditions required to solubilize midazolam in the product, midazolam is present as an equilibrium mixture (shown below) of the closed ring form shown above and an open-ring structure formed by the acid-catalyzed ring opening of the 4,5-double bond of the diazepine ring.

The amount of open-ring form is dependent upon the pH of the solution.

At the specified pH of the product, the solution may contain up to about 25% of the open-ring compound.

At the physiologic conditions under which the product is absorbed (pH of 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.

Midazolam img-3.

The treatment is used as a drug/sedentary and disillusionment agent, given before surgery or diagnostic or photographic procedures, and for patients who lie in intensive care in the process of urging general anesthesia before the operation begins, and to maintain anesthesia during it as well as using the suspended drink to prepare children for the dentist's appointment to reduce anxiety and irritability.

The treatment is not recommended for use during pregnancy, as it can harm the foetus, and a pregnancy must be avoided during the period of treatment.

Breastfeeding: the medication is produced in the breast milk of a nursing mother, which may have harmful effects on the infant, so the process of breastfeeding must be avoided during the period of treatment.

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 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 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 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 to 2.5 minutes without narcotic premeditation or other sedative premedication.

Some impairment in a test of memory was noted in 90% of the patients studied.

A dose response study of pediatric patients premedicated with 1 mg/kg intramuscular (IM) meperidine found that only 4 out of 6 pediatric patients who received 600 mcg/kg IV midazolam lost consciousness, with eye closing at 108 ± 140 seconds.

This group was compared with pediatric patients who were given thiopental 5 mg/kg IV; 6 out of 6 closed their eyes at 20 ± 3.2 seconds.

Midazolam did not dependably induce anesthesia at this dose despite concomitant opioid administration in pediatric patients.

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

Gross tests of recovery after awakening (orientation, ability to stand and walk, suitability for discharge from the recovery room, return to baseline Trieger competency) usually indicate recovery within 2 hours but recovery may take up to 6 hours in some cases.

When compared with patients who received thiopental, patients who received midazolam generally recovered at a slightly slower rate.

Recovery from anesthesia or sedation for procedures in pediatric patients depends on the dose of midazolam administered, coadministration of other medications causing CNS depression and duration of the procedure.

In patients without intracranial lesions, induction of general anesthesia with IV midazolam hydrochloride is associated with a moderate decrease in cerebrospinal fluid pressure (lumbar puncture measurements), similar to that observed following IV thiopental.

Preliminary data in neurosurgical patients with normal intracranial pressure but decreased compliance (subarachnoid screw measurements) show comparable elevations of intracranial pressure with midazolam and with thiopental during intubation.

No similar studies have been reported in pediatric patients.

The usual recommended intramuscular premedicating doses of midazolam hydrochloride do not depress the ventilatory response to carbon dioxide stimulation to a clinically significant extent in adults.

Intravenous induction doses of midazolam hydrochloride depress the ventilatory response to carbon dioxide stimulation for 15 minutes or more beyond the duration of ventilatory depression following administration of thiopental in adults.

Impairment of ventilatory response to carbon dioxide is more marked 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 max ) increase.

In one study of pediatric patients under general anesthesia, intramuscular midazolam (100 or 200 mcg/kg) was shown to depress the response to carbon dioxide in a dose-related manner.

In cardiac hemodynamic studies in adults, IV induction of general anesthesia with midazolam hydrochloride was associated with a slight to moderate decrease in mean arterial pressure, cardiac output, stroke volume and systemic vascular resistance.

Slow heart rates (less than 65/minute), particularly in patients taking propranolol for angina, tended to rise slightly; faster heart rates (e.g., 85/minute) tended to slow slightly.

In pediatric patients, a comparison of IV midazolam (500 mcg/kg) with propofol (2.5 mg/kg) revealed a mean 15% decrease in systolic blood pressure in patients who had received IV midazolam vs a mean 25% decrease in systolic blood pressure following propofol.

Midazolam's activity is primarily due to the parent drug.

Elimination of the parent drug takes place via hepatic metabolism of midazolam to hydroxylated metabolites that are conjugated and excreted in the urine.

Six single-dose pharmacokinetic studies involving healthy adults yield pharmacokinetic parameters for midazolam in the following ranges: volume of distribution (Vd), 1.0 to 3.1 L/kg; elimination half-life, 1.8 to 6.4 hours (mean approximately 3 hours); total clearance (Cl), 0.25 to 0.54 L/hr/kg. In a parallel group study, there was no difference in the clearance, in subjects administered 0.15 mg/kg (n=4) and 0.3 mg/kg (n=4) IV doses indicating linear kinetics.

The clearance was successively reduced by approximately 30% at doses of 0.45 mg/kg (n=4) and 0.6 mg/kg (n=5) indicating non-linear kinetics in this dose range.

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 max ) and time to peak (T max ) following the IM dose was 90 ng/mL (20% CV) and 0.5 hr (50% CV).

C max for the 1-hydroxy metabolite following the IM dose was 8 ng/mL (T max =1.0 hr).

IM administration, C max for midazolam and its 1-hydroxy metabolite were approximately one-half of those achieved after intravenous injection.

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.

In adults and children older than 1 year, midazolam is approximately 97% bound to plasma protein, principally albumin.

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

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.

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.

In other groups, the relationship between prolonged half-life and duration of effect has not been established.

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 pathway.

The treatment belongs to the benzodiazepine family, which has a tranquilizing and sleeping effect, where it is linked to its own brain receptors, which stimulate the development of the "Gamma Amnoborek acid" receptors that have a tranquilizer effect.

The treatment may cause mental and physical addiction; the treatment is administered only by a specialist doctor.

WARNINGS concerning serious cardiorespiratory events and possible paradoxical reactions.

Fluctuations in vital signs were the most frequently seen findings following parenteral administration of midazolam in adults and included decreased tidal volume and/or respiratory rate decrease (23.3% of patients following IV and 10.8% of patients following IM administration) and apnea (15.4% of patients following IV administration), as well as variations in blood pressure and pulse rate.

The majority of serious adverse effects, particularly those associated with oxygenation and ventilation, have been reported when midazolam hydrochloride is administered with other medications capable of depressing the central nervous system.

The incidence of such events is higher in patients undergoing procedures involving the airway without the protective effect of an endotracheal tube, (e.g., upper endoscopy and dental procedures).

The following additional adverse reactions were reported after intramuscular administration: headache (1.3%) Local effects at IM Injection site pain (3.7%) induration (0.5%) redness (0.5%) muscle stiffness (0.3%) Administration of IM midazolam hydrochloride to elderly and/or higher risk surgical patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression.

In most of these cases, the patients also received other central nervous system depressants capable of depressing respiration, especially narcotics See DOSAGE AND ADMINISTRATION.

The following additional adverse reactions were reported subsequent to intravenous administration as a single sedative/anxiolytic/amnestic agent in adult patients: hiccoughs (3.9%) nausea (2.8%) vomiting (2.6%) coughing (1.3%) “oversedation” (1.6%) headache (1.5%) drowsiness (1.2%) Local effects at the IV site tenderness (5.6%) pain during injection (5.0%) redness (2.6%) induration (1.7%) phlebitis (0.4%) Pediatric Patients: The following adverse events related to the use of IV midazolam hydrochloride in pediatric patients were reported in the medical literature: desaturation 4.6%, apnea 2.8%, hypotension 2.7%, paradoxical reactions 2.0%, hiccough 1.2%, seizure-like activity 1.1% and nystagmus 1.1%.

The majority of airway-related events occurred in patients receiving other CNS depressing medications and in patients where midazolam was not used as a single sedating agent.

For information concerning hypotensive episodes and seizures following the administration of midazolam hydrochloride to neonates, see Boxed WARNING, CONTRAINDICATIONS, WARNINGS and PRECAUTIONS sections.

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.

Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma.

In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia.

Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur.

In severe overdosage cases, patients may develop respiratory depression and coma.

Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal See WARNINGS: Abuse, Misuse, and Addiction.

Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage.

In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway maintenance.

Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency.

The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy.

Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus).

If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage.

See the flumazenil injection Prescribing

Consider contacting a poison center,poisoncontrol.org, or a medical toxicologist for additional overdosage management recommendations.

Personnel and Equipment for Monitoring and Resuscitation 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 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, 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.

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.

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.

Midazolam must never be used without individualization of dosage particularly when used with other medications capable of producing central nervous system depression.

ADMINISTRATION for complete information.

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 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.

Because elderly patients frequently have inefficient function of one or more organ systems and because dosage requirements have been shown to decrease with age, reduced initial dosage of midazolam hydrochloride is recommended, and the possibility of profound and/or prolonged effect should be considered.

Injectable midazolam should not be administered to adult or pediatric patients in shock or coma, or in acute alcohol intoxication with depression of vital signs.

Particular care should be exercised in the use of intravenous midazolam in adult or pediatric patients with uncompensated acute illnesses, such as severe fluid or electrolyte disturbances.

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

Adverse events have included local reactions, as well as isolated reports of seizure activity in which no clear causal relationship was established.

Precautions against unintended intra-arterial injection should be taken.

Extravasation should also be avoided.

The safety and efficacy of midazolam following nonintravenous and nonintramuscular routes of administration have not been established.

Midazolam hydrochloride should only be administered intramuscularly or intravenously.

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 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.

Neonatal Sedation and Withdrawal Syndrome Use of Midazolam Injection, USP late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate.

Monitor neonates exposed to Midazolam

Injection, USP during pregnancy or labor for signs of sedation and monitor neonates exposed to Midazolam Injection, USP during pregnancy for signs of withdrawal; manage these Neonatal accordingly.

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 toxicitymay occur is not known.

If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the dailymetabolic load of benzyl alcohol from these combined sources See WARNINGS and PRECAUTIONS - Pediatric Use.

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.

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 and pregnant women 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.

Midazolam 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.

Midazolam is not intended for intrathecal or epidural administration due to the presence of the preservative benzyl alcohol in the dosage form.

Midazolam injection is contraindicated for use in premature infants because the formulation contains benzyl alcohol See WARNINGS and PRECAUTIONS, Pediatric Use.

ALCOHOL See WARNINGS and PRECAUTIONS, Pediatric Use Midazolam hydrochloride injection is a potent sedative agent that requires slow administration and individualization of dosage.

Clinical experience has shown midazolam hydrochloride to be to 4 times as potent per mg as diazepam.

BECAUSE SERIOUS AND LIFE-THREATENING CARDIORESPIRATORY ADVERSE EVENTS HAVE BEEN REPORTED, PROVISION FOR MONITORING, DETECTION AND CORRECTION OF THESE REACTIONS MUST BE MADE FOR EVERY PATIENT T0 WHOM MIDAZOLAM HYDROCHLORIDE INJECTION IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS.

Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest.

The potential for these latter effects is increased in debilitated patients, those receiving concomitant medications capable of depressing the CNS, and patients without an endotracheal tube but undergoing a procedure involving the upper airway such as endoscopy or dental.

Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients.

Should such reactions occur, caution should be exercised before continuing administration of midazolam hydrochloride See WARNINGS.

Midazolam hydrochloride injection should only be administered IM or IV See WARNINGS.

Care should be taken to avoid intra-arterial injection or extravasation See WARNINGS.

Injection may be mixed in the same syringe with the following frequently used premedications: morphine sulfate, meperidine, atropine sulfate or scopolamine.

Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with lactated Ringer's solution for up to 4 hours.

Both the 1 mg/mL and 5 mg/mL formulations of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water.

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).

Sedation guidelines recommend a careful presedation history to determine how a patient's underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities.

Further recommendations include appropriate presedation fasting.

Titration to effect with multiple small doses is essential for safe administration.

It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation.

Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration.

This is an important consideration for all patients who receive intravenous midazolam.

Immediate availability of resuscitative drugs and age.

• and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured See WARNINGS.

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.

For preoperative sedation/anxiolysis/ amnesia (induction of sleepiness or drowsiness and relief of apprehension and to impair memory of perioperative events).

For intramuscular use, midazolam hydrochloride should be injected deep in a large muscle mass.

The recommended premedication dose of midazolam for good risk (ASA Physical Status I & II) adult patients below the age of 60 years is 0.07 to 0.08 mg/kg IM (approximately 5 mg IM) administered up to 1 hour before surgery.

The dose must be individualized and reduced when IM midazolam is administered to patients with chronic obstructive pulmonary disease, other higher risk surgical patients, patients 60 or more years of age, and patients who have received concomitant narcotics or other CNS depressants See ADVERSE REACTIONS.

In a study of patients 60 years or older, who did not receive concomitant administration of narcotics, 2 to 3 mg (0.02 to 0.05 mg/kg) of midazolam produced adequate sedation during the preoperative period.

The dose of 1 mg IM midazolam hydrochloride may suffice for some older patients if the anticipated intensity and duration of sedation is less critical.

As with any potential respiratory depressant, these patients require observation for signs of cardiorespiratory depression after receiving IM midazolam.

Onset is within 15 minutes, peaking at to 60 minutes.

It can be administered concomitantly with atropine sulfate or scopolamine hydrochloride and reduced doses of narcotics.

Sedation/anxiolysis/amnesia for procedures: Narcotic premedication results in less variability in patient response and a reduction in dosage of midazolam.

For peroral procedures, the use of an appropriate topical anesthetic is recommended.

For bronchoscopic procedures, the use of narcotic premedication is recommended.

Midazolam hydrochloride 1 mg/mL formulation is recommended for sedation/anxiolysis/amnesia for procedures to facilitate slower injection.

Both the 1 mg/mL and the 5 mg/mL formulations may be diluted with 0.9% sodium chloride or 5% dextrose in water.

When used for sedation/anxiolysis/amnesia for a procedure, dosage must be individualized and titrated.

Midazolam hydrochloride should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect.

Individual response will vary with age, physical status and concomitant medications, but may also vary independent of these factors. See WARNINGS concerning cardiac/respiratory arrest/airway obstruction/ hypoventilation. Healthy Adults Below the Age of 60: Titrate slowly to the desired effect, (e.g., the initiation of slurred speech).

Some patients may respond to as little as 1 mg. No more than 2.5 mg should be given over a period of at least 2 minutes.

Wait an additional 2 or more minutes to fully evaluate the sedative effect.

If further titration is necessary, continue to titrate, using small increments, to the appropriate level of sedation.

Wait an additional 2 or more minutes after each increment to fully evaluate the sedative effect.

A total dose greater than 5 mg is not usually necessary to reach the desired endpoint.

If narcotic premedication or other

CNS depressants are used, patients will require approximately 30% less midazolam than unpremedicated patients.

Age 60 or Older, and Debilitated or Chronically Ill Patients: Because the danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve, and because the peak effect may take longer in these patients, increments should be smaller and the rate of injection slower.

Titrate slowly to the desired effect, (e.g., the initiation of slurred speech).

Some patients may respond to as little as 1 mg. No more than 1.5 mg should be given over a period of no less than 2 minutes.

If additional titration is necessary, it should be given at a rate of no more than 1 mg over a period of 2 minutes, waiting an additional 2 or more minutes each time to fully evaluate the sedative effect.

Total doses greater than 3.5 mg are not usually necessary.

If concomitant

CNS depressant premedications are used in these patients, they will require at least 50% less midazolam than healthy young unpremedicated patients.

Additional doses to maintain the desired level of sedation may be given in increments of 25% of the dose used to first reach the sedative endpoint, but again only by slow titration, especially in the elderly and chronically ill or debilitated patient.

These additional doses should be given only after a thorough clinical evaluation clearly indicates the need for additional sedation.

For induction of general anesthesia, before administration of other anesthetic agents.

Individual response to the drug is variable, particularly when a narcotic premedication is not used.

The dosage should be titrated to the desired effect according to the patient's age and clinical status.

When midazolam is used before other intravenous agents for induction of anesthesia, the initial dose of each agent may be significantly reduced, at times to as low as 25% of the usual initial dose of the individual agents.

In the absence of premedication, an average adult under the age of 55 years will usually require an initial dose of 0.3 to 0.35 mg/kg for induction, administered over to 30 seconds and allowing 2 minutes for effect.

If needed to complete induction, increments of approximately 25% of the patient's initial dose may be used; induction may instead be completed with inhalational anesthetics.

In resistant cases, up to 0.6 mg/kg total dose may be used for induction, but such larger doses may prolong recovery.

Unpremedicated patients over the age of 55 years usually require less midazolam for induction; an initial dose of 0.3 mg/kg is recommended.

Unpremedicated patients with severe systemic disease or other debilitation usually require less midazolam for induction.

An initial dose of 0.2 to 0.25 mg/kg will usually suffice; in some cases, as little as 0.15 mg/kg may suffice.

When the patient has received sedative or narcotic premedication, particularly narcotic premedication, the range of recommended doses is 0.15 to 0.35 mg/kg. In average adults below the age of 55 years, a dose of 0.25 mg/kg, administered over to 30 seconds and allowing 2 minutes for effect, will usually suffice.

The initial dose of 0.2 mg/kg is recommended for good risk (ASA I & II) surgical patients over the age of 55 years.

In some patients with severe systemic disease or debilitation, as little as 0.15 mg/kg may suffice.

Narcotic premedication frequently used during clinical trials included fentanyl (1.5 to 2 mcg/kg IV, administered 5 minutes before induction), morphine (dosage individualized, up to 0.15 mg/kg IM), and meperidine (dosage individualized, up to 1 mg/kg IM).

Sedative premedications were hydroxyzine pamoate (100 mg orally) and sodium secobarbital (200 mg orally).

Except for intravenous fentanyl, administered 5 minutes before induction, all other premedications should be administered approximately 1 hour prior to the time anticipated for midazolam induction.

Injectable midazolam hydrochloride can also be used during maintenance of anesthesia, for surgical procedures, as a component of balanced anesthesia.

Effective narcotic premedication is especially recommended in such cases.

Incremental injections of approximately 25% of the induction dose should be given in res.

Injection, USP is supplied as follows: NDC Midazolam Injection, USP (5 mg per mL) Package Factor 70069-818-10 50 mg per 10 mL Multi-Dose Vial 10 vials per carton Storage Conditions Store at 20° to 25°C (68° to 77°F).

Store at 20° to 25°C (68° to 77°F).

Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal See WARNINGS: Neonatal Sedation and Withdrawal Syndrome, and Clinical Considerations.

Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates.

Monitor neonates exposed to

Midazolam injection during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems Monitor neonates exposed to Midazolam injection during pregnancy for signs of withdrawal.

Manage these neonates accordingly See WARNINGS: Neonatal Sedation and Withdrawal Syndrome.

Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects.

Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted.

In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.

Pregnant rats were treated with midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 through 15).

Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose.

All doses produced slight to moderate ataxia.

The high dose produced a 5% decrease in maternal body weight gain compared to control.

Pregnant rabbits were treated with midazolam using intravenous doses of 0.2, 0.6, and 2 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day to 18).

The high dose was associated with findings of ataxia and sedation but no evidence of maternal toxicity.

Pregnant rats were administered midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during late gestation and through lactation (Gestation Day 15 through Lactation Day 21).

All doses produced ataxia.

The high dose produced a slight decrease in maternal body weight gain compared to control.

There were no clear adverse effects noted in the offspring.

The study included no functional assessments of the pups, such as learning and memory testing or reproductive capacity.

In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus.

In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring.

With respect to brain development, this time period corresponds to the third trimester of gestation in the human.

The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits See WARNINGS, Pediatric Neurotoxicity, PRECAUTIONS, Pediatric Use, and Animal Toxicology and/or Pharmacology.

Risk Summary There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk.

Based on data from published studies, midazolam is present in human milk in low levels.

There are no data on the effects of midazolam on milk production.

The effects of

Midazolam on lactation are unknown.

Because of the potential for serious adverse reactions, including sedation and withdrawal symptoms in breastfed neonates and infants, advise patients that breastfeeding is not recommended during treatment with Midazolam injection.

Clinical Considerations Infants exposed to

Midazolam injection through breast milk should be monitored for sedation, poor feeding and poor weight gain.

A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment for a range of at least to 8 hours after midazolam administration in order to minimize drug exposure to a breastfed infant.

The safety and efficacy of midazolam for sedation/anxiolysis/amnesia following single dose intramuscular administration, intravenously by intermittent injections and continuous infusion have been established in pediatric and neonatal patients.

For specific safety monitoring and dosage guidelines see Boxed WARNING, CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE, WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, OVERDOSAGE and DOSAGE AND ADMINISTRATION sections.

PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS.

As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults.

Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require closer monitoring.

In obese PEDIATRIC

PATIENTS, the dose should be calculated based on ideal body weight.

When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased.

The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

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

Severe hypotension and seizures have been reported following rapid IV administration, particularly, with concomitant use of fentanyl.

Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as Midazolam Injection USP, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis.

Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss.

Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory.

The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data See WARNINGS/ Pediatric Neurotoxicity, PRECAUTIONS/ Pregnancy, and Animal Pharmacology and/or Toxicology.

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.