IPNODIS

Midazolam is a short-acting hypnotic-sedative drug with anxiolytic, muscle relaxant, anticonvulsant, sedative, hypnotic, and amnesic properties.

It belongs to a class of drugs called benzodiazepines.

This drug is unique from others in this class due to its rapid onset of effects and short duration of action.

Midazolam is available by oral, rectal, intranasal, intramuscular (Intramuscular), and intravenous (Intravenous) routes and has been used in various biomedical applications, including dentistry, cardiac surgery, and endoscopic procedures as pre-anesthetic medication, and as an adjunct to local anesthesia.

This drug was initially approved by the US FDA in 1985, and has been approved for various indications since.

In late 2018, the intramuscular preparation was approved by the FDA for the treatment of status epilepticus in adults.

In May 2019, the nasal spray of midazolam was approved for the acute treatment of distinctive intermittent, stereotypic seizure episodes in patients 12 years of age and older.

Midazolam is considered a schedule Intravenous drug in the United States due to the low potential for abuse and low risk of dependence.

Midazolam has different indications depending on its formulation by the FDA.

For the nasal spray formulation, midazolam is indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient's usual seizure pattern in patients with epilepsy 12 years of age and older.

For the intravenous injection formulation, midazolam is indicated as an agent for sedation/anxiolysis/amnesia and 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.

The sedative, anxiolytic and amnestic use of midazolam can also be employed pre-operatively.

It can also be indicated for induction of general anesthesia, before administration of other anesthetic agents or as a component of intravenous supplementation of nitrous oxide and oxygen for a balanced anesthesia.

A relatively narrower dose range of midazolam and a shorter period of induction can be achieved if midazolam is combined with narcotic premedication.

Finally, midazolam can be indicated as a continous intravenous infusion for sedation of intubated and mechanically ventilated patients as a component of anesthesia or during treatment in a critical care setting.

For the intramusuclar injection formulation, midazolam is indicated for preoperative sedation/anxiolysis/amnesia or for treatment of status epilepticus in adults. 14, 15 Oral Midazolam syrup is indicated for use in pediatric patients for sedation, anxiolysis and amnesia prior to diagnostic, therapeutic or endoscopic procedures or before induction of anesthesia.

It is only approved in monitored settings only and not for chronic or home use.

In Europe, a buccal formulation of midazolam is also approved for the treatment of prolonged, acute, convulsive seizures in infants, toddlers, children and adolescents (from 3 months to < 18 years).

For infants between 3-6 months of age treatment should be in a hospital setting where monitoring is possible and resuscitation equipment is available.

General effects

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

Pharmacodynamic properties of midazolam and its metabolites, which are similar to those of other benzodiazepine drugs, include sedative, anxiolytic, amnestic, muscle relaxant, as well as hypnotic activities.

Benzodiazepines enhance the inhibitory action of the amino acid neurotransmitter gamma-aminobutyric acid (GABA).

Receptors for GABA are targeted by many important drugs that affect GABA function and are commonly used in the treatment of anxiety disorder, epilepsy, insomnia, spasticity, and aggressive behavior.

Sedation and memory

The onset of sedation after intramuscular administration in adults is 15 minutes, with maximal sedation occurring 30-60 minutes after injection.

In one study of adults, when tested the following day, 73% of the patients who were administered midazolam Intramuscular had no recollection of memory cards shown 30 minutes following drug administration; 40% had no recollection of the memory cards shown 60 minutes after drug administration.

Onset time of sedative effects in pediatric patients begins within 5 minutes and peaks at 15-30 minutes depending upon the dose administered.

In the pediatric population, up to 85% had no memory of pictures shown after receiving intramuscular midazolam compared to 5% of the placebo control group.

Sedation in both adult and pediatric patients is reached within 3-5 minutes post intravenous (Intravenous) injection.

The time of onset is affected by the dose administered and the simultaneous administration of narcotic pre-medication.

Seventy-one (71%) percent of the adult patients in clinical endoscopy studies had no memory of insertion of the endoscope; 82% of the patients had no memory of withdrawal of the endoscope.

Anesthesia induction When midazolam is administered

Intravenous (Intravenous) for anesthetic induction, induction of anesthesia occurs in about 1.5 minutes when narcotic pre-medication has been given and in 2-2.5 minutes without narcotic pre-medication/ other sedative pre-medication.

Impairment in a memory test was observed in 90% of the patients.

Receptor Positive allosteric modulator

GABA(A) Receptor Benzodiazepine Binding Site Ligand.

Intramuscular administration of a single 10 mg midazolam dose to healthy subjects, midazolam was absorbed with median T max (range) of 0.5 hours; midazolam's mean (±SD) C max and AUC 0-∞ were 113.9 (±30.9) ng/mL and 402.7 (±97.0) ng∙h/mL, respectively.

After rectal administration midazolam is absorbed rapidly.

Maximum plasma concentration is reached within 30 minutes.

The absolute bioavailability is approximately 50%.

Following the nasal administration of a single 5 mg midazolam dose to healthy adults, midazolam was absorbed with a median T max (range) of 17.3 minutes; midazolam's mean (±SD) C max and AUC 0-∞ were 54.7 (±30.4) ng/mL and 126.2 (±59) ng∙h/mL, respectively.

The mean absolute bioavailability is approximately 44%.

In pediatric patients from 6 months to <16 years old, the mean T max values across dose groups (0.25, 0.5, and 1.0 mg/kg) range from 0.17-2.65 hours.

Midazolam also exhibits linear pharmacokinetics within this dose range (up to a maximum dose of 40 mg).

Linearity was also demonstrated across the doses within the of 2 years to <12 years having 18 patients at each of the three doses.

Due to first-pass metabolism, only 40-50% of the administered oral dose reaches the circulation.

The absolute bioavailability of midazolam is about 36%, which is not affected by pediatric age or weight.

C max and

AUC 0-∞ were also calculated to range from 28-201 ng/mL and 67.6-821 ng∙h/mL respectively.

After oromucosal administration midazolam is absorbed rapidly.

Maximum plasma concentration is reached within 30 minutes in children.

The absolute bioavailability of oromucosal midazolam is about 75% in adults.

The bioavailability of oromucosal midazolam has been estimated at 87% in children with severe malaria and convulsions.

AUC 0-∞ were also calculated to range from 87-148 ng/mL and 168-254 ng∙h/mL respectively.

Female gender, old age, and obesity may increase the volume of distribution.

Midazolam may also cross the placenta and has been detected in human milk and cerebrospinal fluid.

Label, 20 Intravenous administration In pediatric patients (6 months to <16 years) receiving 0.15 mg/kg Intravenous midazolam, the mean steady-state volume of distribution ranged from 1.24-2.02 L/kg.

For healthy adult patients, the volume of distribution determined from six single-dose pharmacokinetic studies ranged from 1.0-3.1 L/kg.

Intramuscular administration

The mean (±SD) apparent volume of distribution (Vz/F) of midazolam following a single Intramuscular dose of 10 mg midazolam was 2117 (±845.1) mL/kg in healthy subjects.

The estimated total volume of distribution of midazolam is 226.5 L.

The steady-state volume of distribution following oromucosal administration is estimated to be 5.3 l/kg.

In vitro studies with human liver microsomes indicate that the biotransformation of midazolam is mediated by the cytochrome P450-3A4 (CYP3A4).

This enzyme is present in gastrointestinal tract mucosa, as well as in the liver.

The 1-hydroxy-midazolam (also termed alpha-hydroxymidazolam) metabolite comprises 60% to 70% of the biotransformation products of midazolam, while 4-hydroxy-midazolam constitutes 5% or less.

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

Midazolam also undergoes N-glucuronidation via

UGT1A4 after the process of hepatic oxidation by cytochrome enzymes.

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

Hover over products below to view reaction partners Midazolam 1-hydroxymidazolam 1-hydroxymidazolam-N-glucuronide 1-hydroxymidazolam-O-glucuronide 1,4-dihydroxymidazolam 4-hydroxymidazolam 4-hydroxymidazolam-N-glucuronide 4-hydroxymidazolam-O-glucuronide 1,4-dihydroxymidazolam Midazolam-N-glucuronide.

The α-hydroxymidazolam glucuronide conjugate of midazolam is excreted in the urine.

No significant amount of parent drug or metabolites is found in urine before beta-glucuronidase and sulfatase deconjugation, suggesting that the urinary metabolites are excreted mainly as conjugates.

The amount of midazolam excreted unchanged in the urine when given Intravenous is less than 0.5%. 45% to 57% of the dose was excreted in the urine as 1-hydroxymethyl midazolam conjugate.

The principal urinary excretion products are glucuronide conjugates of hydroxylated derivatives.

Plasma clearance of midazolam is higher in patients that remain in the supine position, because of a 40-60 percent increase in hepatic blood flow during supination.

Pregnancy may also increase the metabolism of midazolam.

Six single-dose pharmacokinetic studies involving healthy adults yield an elimination half-life of 1.8-6.4 hours (mean of approximately 3 hours).

Intramuscular administration of 10 mg midazolam, the mean (±SD) elimination half-life of midazolam was 4.2 (±1.87) hours.

Intranasal Following the administration of

NAYZILAM in clinical trials, median midazolam and 1-hydroxy-midazolam elimination half-lives ranged from 2.1-6.2 hours and 2.7-7.2 hours, respectively, independent of dose.

The mean elimination half-life of midazolam ranged from 2.2-6.8 hours following single oral doses of 0.25, 0.5, and 1.0 mg/kg of midazolam HCl syrup. 11 * Buccal The initial and terminal elimination half-lives are and 204 minutes, respectively.

Intramuscular administration of 10 mg midazolam, the apparent total body clearance (CL/F) of midazolam was 367.3 (±73.5) mL/hr/kg.

Six single-dose pharmacokinetic studies involving healthy adults yield a total clearance (Cl) of 0.25-0.54 L/hr/kg.

Midazolam clearance was calculated to be 1.9 mL/min/kg Oral Following a group of patients receiving the 0.15 mg/kg Intravenous dose, the mean total clearance ranged from 9.3-11.0 mL/min/kg. 11 * Buccal Plasma clearance of midazolam in children following oromucosal administration is 30 ml/kg/min.

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=215 mg/kg, in rats.

Signs of overdose include sedation, somnolence, confusion, impaired coordination, diminished reflexes, coma, and deleterious effects on vital signs.

Serious cardiorespiratory adverse reactions have occurred, sometimes ending in death or permanent neurologic effects, after the administration of midazolam.

Label A note on cardiac and respiratory depression After administration of midazolam, continuous monitoring of respiratory and cardiac function is recommended until the patient is in stable condition.

Serious and life-threatening cardiorespiratory adverse reactions, including hypoventilation, airway obstruction, apnea, and hypotension have been reported with the use of midazolam.

Patients should be monitored in a setting with immediate access to resuscitative drugs if they are required.

Resuscitation equipment and personnel trained in their use and skilled in airway management should be available when midazolam is administered.

The usual recommended intramuscular pre-medicating 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 at least 15 minutes longer than the duration of ventilatory depression following administration of thiopental in adults.

Impairment of ventilatory response to carbon dioxide is more severe in adult patients diagnosed with chronic obstructive pulmonary disease (COPD).

A note on dependence

When midazolam is used in long-term sedation in the ICU (intensive care unit) or other settings, physical dependence on midazolam may develop.

The risk of dependence increases with dose and duration of treatment; this risk is also greater in patients with a medical history of substance abuse.

Special caution should be exercised when administering midazolam in the following populations High-risk patients include adults over 60 years of age, chronically ill or debilitated patients, which may include patients with chronic respiratory insufficiency, patients with chronic renal failure, impaired hepatic function or with impaired cardiac function, pediatric patients (especially those with cardiovascular instability).

These high-risk patients require lower dosages and should be monitored on a continuous basis for early signs of alterations of vital functions, so that appropriate management may be administered.

Midazolam was negative for genotoxicity during in vitro and in vivo assays.

When midazolam (0, 1, 4, or 16 mg/kg) was given Oral to male and female rats before and during mating and continuing in females throughout gestation and lactation, no adverse effects on male or female fertility were observed.

Midazolam plasma exposures (AUC) at the highest dose tested were approximately 6 times that in humans at the recomended human dose.

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.