f anesthesia or during treatment in a critical care setting.

datives (see dosage and administration), it should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintaining a patent airway, and supporting ventilation. when used for sedation/anxiolysis/amnesia, midazolam should always be titrated slowly in adult or pediatric patients. adverse hemodynamic events have been reported in pediatric patients with cardiovascular instability; rapid intravenous administration should also be avoided in this population (see dosage and administration for complete information). risks from concomitant use with opioids concomitant use of benzodiazepines, including midazolam, and opioids may result in profound sedation, respiratory depression, coma, and death. if a decision is made to use midazolam concomitantly with opioids, monitor patients closely for respiratory depression and sedation (see precautions, drug interactions). risk of respiratory adverse events serious cardiorespiratory adverse events have occurred after administration of midazolam. these have included respiratory depression, airway obstruction, oxygen desaturation, apnea, respiratory arrest and/or cardiac arrest, sometimes resulting in death or permanent neurologic injury. there have also been rare reports of hypotensive episodes requiring treatment during or after diagnostic or surgical manipulations particularly in adult or pediatric patients with hemodynamic instability. hypotension occurred more frequently in the sedation studies in patients premedicated with a narcotic. individualization of dosage midazolam must never be used without individualization of dosage particularly when used with other medications capable of producing central nervous system depression. see dosage and administration for complete information. other adverse events reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients. these reactions may be due to inadequate or excessive dosing or improper administration of midazolam; however, consideration should be given to the possibility of cerebral hypoxia or true paradoxical reactions. should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding. reversal of such responses with flumazenil has been reported in pediatric patients. concomitant use of central nervous system depressants concomitant use of barbiturates, alcohol or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect. narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation. debilitation and comorbid considerations higher risk adult and pediatric surgical patients, elderly patients and debilitated adult and pediatric patients require lower dosages, whether or not concomitant sedating medications have been administered. adult or pediatric patients with copd are unusually sensitive to the respiratory depressant effect of midazolam. pediatric and adult patients undergoing procedures involving the upper airway such as upper endoscopy or dental care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction. adult and pediatric patients with chronic renal failure and patients with congestive heart failure eliminate midazolam more slowly (see clinical pharmacology). because elderly patients frequently have inefficient function of one or more organ systems and because dosage requirements have been shown to decrease with age, reduced initial dosage of midazolam is recommended, and the possibility of profound and/or prolonged effect should be considered. injectable midazolam should not be administered to adult or pediatric patients in shock or coma, or in acute alcohol intoxication with depression of vital signs. particular care should be exercised in the use of intravenous midazolam in adult or pediatric patients with uncompensated acute illnesses, such as severe fluid or electrolyte disturbances. risk of intra-arterial injection there have been limited reports of intra-arterial injection of midazolam. adverse events have included local reactions, as well as isolated reports of seizure activity in which no clear causal relationship was established. precautions against unintended intra-arterial injection should be taken. extravasation should also be avoided. the safety and efficacy of midazolam following nonintravenous and nonintramuscular routes of administration have not been established. midazolam should only be administered intramuscularly or intravenously. return to full cognitive function midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours. the decision as to when patients who have received injectable midazolam, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized. gross tests of recovery from the effects of midazolam (see clinical pharmacology) cannot be relied upon to predict reaction time under stress. it is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided or until one full day after anesthesia and surgery, whichever is longer. for pediatric patients, particular care should be taken to assure safe ambulation. usage in pregnancy an increased risk of congenital malformations associated with the use of benzodiazepine drugs (diazepam and chlordiazepoxide) has been suggested in several studies. if this drug is used during pregnancy, the patient should be apprised of the potential hazard to the fetus. withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines (see drug abuse and dependence). usage in preterm infants and neonates rapid injection should be avoided in the neonatal population. midazolam administered rapidly as an intravenous injection (less than 2 minutes) has been associated with severe hypotension in neonates, particularly when the patient has also received fentanyl. likewise, severe hypotension has been observed in neonates receiving a continuous infusion of midazolam who then receive a rapid intravenous injection of fentanyl. seizures have been reported in several neonates following rapid intravenous administration. the neonate also has reduced and/or immature organ function and is also vulnerable to profound and/or pro-longed respiratory effects of midazolam. exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. there have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. the amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. administration of high dosages of medications (including midazolam) containing this preservative must take into account the total amount of benzyl alcohol administered. the recommended dosage range of midazolam for preterm and term infants includes amounts of benzyl alcohol well below that associated with toxicity; however, the amount of benzyl alcohol at which toxicity may occur is not known. if the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources (see warnings and precautions, pediatric use). pediatric neurotoxicity published animal studies demonstrate that the administration of anesthetic and sedation drugs that block nmda receptors and/or potentiate gaba activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. the clinical significance of these findings is not clear. however, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans (see precautions, pregnancy and pediatric use and animal toxicology and/or pharmacology). some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. these studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness. anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

nd warnings). reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. should such reactions occur, caution should be exercised before continuing administration of midazolam (see warnings). midazolam injection should only be administered im or iv (see warnings). care should be taken to avoid intra-arterial injection or extravasation (see warnings). midazolam 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. monitoring patient response to sedative agents, and resultant respiratory status, is variable. regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. this is especially true in pediatric patients. sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other cns depressants. continuous monitoring of respiratory and cardiac function is required (i.e., pulse oximetry). adults and pediatrics: sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. further recommendations include appropriate presedation fasting. titration to effect with multiple small doses is essential for safe administration. it should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation. sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration. this is an important consideration for all patients who 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). pediatrics: for deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure. intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining iv access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

amuscular administration: administration of im midazolam to elderly and/or higher risk surgical patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression. in most of these cases, the patients also received other central nervous system depressants capable of depressing respiration, especially narcotics (see dosage and administration). the following additional adverse reactions were reported subsequent to intravenous administration as a single sedative/anxiolytic/amnestic agent in adult patients: pediatric patients the following adverse events related to the use of iv midazolam 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. neonates for information concerning hypotensive episodes and seizures following the administration of midazolam to neonates (see boxed warning, contraindications, warnings and precautions). other adverse experiences, observed mainly following iv injection as a single sedative/anxiolytic/amnesia agent and occurring at an incidence of <1.0% in adult and pediatric patients, are as follows: respiratory: laryngospasm, bronchospasm, dyspnea, hyperventilation, wheezing, shallow respirations, airway obstruction, tachypnea cardiovascular: bigeminy, premature ventricular contractions, vasovagal episode, bradycardia, tachycardia, nodal rhythm gastrointestinal: acid taste, excessive salivation, retching cns/neuromuscular: retrograde amnesia, euphoria, hallucination, confusion, argumentativeness, nervousness, anxiety, grogginess, restlessness, emergence delirium or agitation, prolonged emergence from anesthesia, dreaming during emergence, sleep disturbance, insomnia, nightmares, athetoid movements, seizure-like activity, ataxia, dizziness, dysphoria, slurred speech, dysphonia, paresthesia special senses: blurred vision, diplopia, nystagmus, pinpoint pupils, cyclic movements of eyelids, visual disturbance, difficulty focusing eyes, ears blocked, loss of balance, light-headedness integumentary: hive-like elevation at injection site, swelling or feeling of burning, warmth or coldness at injection site hypersensitivity: allergic reactions including anaphylactoid reactions, hives, rash, pruritus miscellaneous: yawning, lethargy, chills, weakness, toothache, faint feeling, hematoma image2.jpg image3.jpg

ation in adult and pediatric patients is achieved within 3 to 5 minutes after intravenous (iv) injection; the time of onset is affected by total dose administered and the concurrent administration of narcotic premedication. seventy-one percent of the adult patients in endoscopy studies had no recall of introduction of the endoscope; 82% of the patients had no recall of withdrawal of the endoscope. in one study of pediatric patients undergoing lumbar puncture or bone marrow aspiration, 88% of patients had impaired recall vs. 9% of the placebo controls. in another pediatric oncology study, 91% of midazolam treated patients were amnestic compared with 35% of patients who had received fentanyl alone. when midazolam is given iv as an anesthetic induction agent, induction of anesthesia occurs in approximately 1.5 minutes when narcotic premedication has been administered and in 2 to 2.5 minutes without narcotic premedication or other sedative premedication. some impairment in a test of memory was noted in 90% of the patients studied. a dose response study of pediatric patients premedicated with 1 mg/kg intramuscular (im) meperidine found that only 4 out of 6 pediatric patients who received 600 mcg/kg iv midazolam lost consciousness, with eye closing at 108 to 140 seconds. this group was compared with pediatric patients who were given thiopental 5 mg/kg iv; 6 out of 6 closed their eyes at 20 ± 3.2 seconds. midazolam did not dependably induce anesthesia at this dose despite concomitant opioid administration in pediatric patients. midazolam, used as directed, does not delay awakening from general anesthesia in adults. gross tests of recovery after awakening (orientation, ability to stand and walk, suitability for discharge from the recovery room, return to baseline trieger competency) usually indicate recovery within 2 hours but recovery may take up to 6 hours in some cases. when compared with patients who received thiopental, patients who received midazolam generally recovered at a slightly slower rate. recovery from anesthesia or sedation for procedures in pediatric patients depends on the dose of midazolam administered, coadministration of other medications causing cns depression and duration of the procedure. in patients without intracranial lesions, induction of general anesthesia with iv midazolam is associated with a moderate decrease in cerebrospinal fluid pressure (lumbar puncture measurements), similar to that observed following iv thiopental. preliminary data in neurosurgical patients with normal intracranial pressure but decreased compliance (subarachnoid screw measurements) show comparable elevations of intracranial pressure with midazolam and with thiopental during intubation. no similar studies have been reported in pediatric patients. the usual recommended intramuscular premedicating doses of midazolam do not depress the ventilatory response to carbon dioxide stimulation to a clinically significant extent in adults. intravenous induction doses of midazolam depress the ventilatory response to carbon dioxide stimulation for 15 minutes or more beyond the duration of ventilatory depression following administration of thiopental in adults. impairment of ventilatory response to carbon dioxide is more marked in adult patients with chronic obstructive pulmonary disease (copd). sedation with iv midazolam does not adversely affect the mechanics of respiration (resistance, static recoil, most lung volume measurements); total lung capacity and peak expiratory flow decrease significantly but static compliance and maximum expiratory flow at 50% of awake total lung capacity (vmax) increase. in one study of pediatric patients under general anesthesia, intramuscular midazolam (100 mcg/kg or 200 mcg/kg) was shown to depress the response to carbon dioxide in a dose-related manner. in cardiac hemodynamic studies in adults, iv induction of general anesthesia with midazolam 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. pharmacokinetics midazolam’s activity is primarily due to the parent drug. elimination of the parent drug takes place via hepatic metabolism of midazolam to hydroxylated metabolites that are conjugated and excreted in the urine. six single-dose pharmacokinetic studies involving healthy adults yield pharmacokinetic parameters for midazolam in the following ranges: volume of distribution (vd), 1.0 to 3.1 l/kg; elimination half-life, 1.8 to 6.4 hours (mean approximately 3 hours); total clearance (cl), 0.25 to 0.54 l/hr/kg. in a parallel group study, there was no difference in the clearance, in subjects administered 0.15 mg/kg (n=4) and 0.30 mg/kg (n=4) iv doses indicating linear kinetics. the clearance was successively reduced by approximately 30% at doses of 0.45 mg/kg (n=4) and 0.6 mg/kg (n=5) indicating non-linear kinetics in this dose range. absorption the absolute bioavailability of the intramuscular route was greater than 90% in a crossover study in which healthy subjects (n=17) were administered a 7.5 mg iv or im dose. the mean peak concentration (cmax) and time to peak (tmax) following the im dose was 90 ng/ml (20% cv) and 0.5 hour (50% cv). cmax for the 1-hydroxy metabolite following the im dose was 8 ng/ml (tmax=1.0 hour). following im administration, cmax for midazolam and its 1-hydroxy metabolite were approximately one-half of those achieved after intravenous injection. distribution the volume of distribution (vd) determined from six single-dose pharmacokinetic studies involving healthy adults ranged from 1.0 to 3.1 l/kg. female gender, old age, and obesity are associated with increased values of midazolam vd. in humans, midazolam has been shown to cross the placenta and enter into fetal circulation and has been detected in human milk and csf (see clinical pharmacology, special populations). in adults and pediatric patients older than 1 year, midazolam is approximately 97% bound to plasma protein, principally albumin and that for 1-hydroxy metabolite is about 89%. metabolism in vitro studies with human liver microsomes indicate that the biotransformation of midazolam is mediated by cytochrome p450-3a4. this cytochrome also appears to be present in gastrointestinal tract mucosa as well as liver. sixty to seventy percent of the biotransformation products is 1-hydroxy-midazolam (also termed alpha-hydroxy-midazolam) while 4-hydroxy-midazolam constitutes 5% or less. small amounts of a dihydroxy derivative have also been detected but not quantified. the principal urinary excretion products are glucuronide conjugates of the hydroxylated derivatives. drugs that inhibit the activity of cytochrome p450-3a4 may inhibit midazolam clearance and elevate steady-state midazolam concentrations. studies of the intravenous administration of 1-hydroxy-midazolam in humans suggest that 1-hydroxy-midazolam is at least as potent as the parent compound and may contribute to the net pharmacologic activity of midazolam. in vitro studies have demonstrated that the affinities of 1- and 4-hydroxy-midazolam for the benzodiazepine receptor are approximately 20% and 7%, respectively, relative to midazolam. excretion clearance of midazolam is reduced in association with old age, congestive heart failure, liver disease (cirrhosis) or conditions which diminish cardiac output and hepatic blood flow. the principal urinary excretion product is 1-hydroxy-midazolam in the form of a glucuronide conjugate; smaller amounts of the glucuronide conjugates of 4-hydroxy- and dihydroxy-midazolam are detected as well. the amount of midazolam excreted unchanged in the urine after a single iv dose is less than 0.5% (n=5). following a single iv infusion in 5 healthy volunteers, 45% to 57% of the dose was excreted in the urine as 1-hydroxymethyl midazolam conjugate. pharmacokinetics- continuous infusion the pharmacokinetic profile of midazolam following continuous infusion, based on 282 adult subjects, has been shown to be similar to that following single-dose administration for subjects of comparable age, gender, body habitus and health status. however, midazolam can accumulate in peripheral tissues with continuous infusion. the effects of accumulation are greater after long-term infusions than after short-term infusions. the effects of accumulation can be reduced by maintaining the lowest midazolam infusion rate that produces satisfactory sedation. infrequent hypotensive episodes have occurred during continuous infusion; however, neither the time to onset nor the duration of the episode appeared to be related to plasma concentrations of midazolam or alpha-hydroxy-midazolam. further, there does not appear to be an increased chance of occurrence of a hypotensive episode with increased loading doses. patients with renal impairment may have longer elimination half-lives for midazolam (see clinical pharmacology, special populations, renal failure). special populations changes in the pharmacokinetic profile of midazolam due to drug interactions, physiological variables, etc., may result in changes in the plasma concentration-time profile and pharmacological response to midazolam in these patients. for example, patients with acute renal failure appear to have a longer elimination half-life for midazolam and may experience delayed recovery (see clinical pharmacology, special populations, renal failure). in other groups, the relationship between prolonged half-life and duration of effect has not been established. pediatrics and neonates: in pediatric patients aged 1 year and older, the pharmacokinetic properties following a single dose of midazolam reported in 10 separate studies of midazolam are similar to those in adults. weight-normalized clearance is similar or higher (0.19 to 0.80 l/hr/kg) than in adults and the terminal elimination half-life (0.78 to 3.3 hours) is similar to or shorter than in adults. the pharmacokinetic properties during and following continuous intravenous infusion in pediatric patients in the operating room as an adjunct to general anesthesia and in the intensive care environment are similar to those in adults. in seriously ill neonates, however, the terminal elimination half-life of midazolam is substantially prolonged (6.5 to 12.0 hours) and the clearance reduced (0.07 to 0.12 l/hr/kg) compared to healthy adults or other groups of pediatric patients. it cannot be determined if these differences are due to age, immature organ function or metabolic pathways, underlying illness or debility. obese: in a study comparing normals (n=20) and obese patients (n=20) the mean half-life was greater in the obese group (5.9 vs 2.3 hours). this was due to an increase of approximately 50% in the vd corrected for total body weight. the clearance was not significantly different between groups. geriatric: in three parallel group studies, the pharmacokinetics of midazolam administered iv or im were compared in young (mean age 29, n=52) and healthy elderly subjects (mean age 73, n=53). plasma half-life was approximately two-fold higher in the elderly. the mean vd based on total body weight increased consistently between 15% to 100% in the elderly. the mean cl decreased approximately 25% in the elderly in two studies and was similar to that of the younger patients in the other. congestive heart failure: in patients suffering from congestive heart failure, there appeared to be a two-fold increase in the elimination half-life, a 25% decrease in the plasma clearance and a 40% increase in the volume of distribution of midazolam. hepatic impairment: midazolam pharmacokinetics were studied after an iv single dose (0.075 mg/kg) was administered to 7 patients with biopsy proven alcoholic cirrhosis and 8 control patients. the mean half-life of midazolam increased 2.5-fold in the alcoholic patients. clearance was reduced by 50% and the vd increased by 20%. in another study in 21 male patients with cirrhosis, without ascites and with normal kidney function as determined by creatinine clearance, no changes in the pharmacokinetics of midazolam or 1-hydroxy-midazolam were observed when compared to healthy individuals. renal impairment: patients with renal impairment may have longer elimination half-lives for midazolam and its metabolites which may result in slower recovery. midazolam and 1-hydroxy-midazolam pharmacokinetics in 6 icu patients who developed acute renal failure (arf) were compared with a normal renal function control group. midazolam was administered as an infusion (5 to 15 mg/hr). midazolam clearance was reduced (1.9 vs 2.8 ml/min/kg) and the half-life was prolonged (7.6 vs 13 hours) in the arf patients. the renal clearance of the 1-hydroxy-midazolam glucuronide was prolonged in the arf group (4 vs 136 ml/ min) and the half-life was prolonged (12 vs > 25 hours). plasma levels accumulated in all arf patients to about ten times that of the parent drug. the relationship between accumulating metabolite levels and prolonged sedation is unclear. in a study of chronic renal failure patients (n=15) receiving a single iv dose, there was a two-fold increase in the clearance and volume of distribution but the half-life remained unchanged. metabolite levels were not studied. plasma concentration-effect relationship: concentration-effect relationships (after an iv dose) have been demonstrated for a variety of pharmacodynamic measures (e.g., reaction time, eye movement, sedation) and are associated with extensive intersubject variability. logistic regression analysis of sedation scores and steady-state plasma concentration indicated that at plasma concentrations greater than 100 ng/ml there was at least a 50% probability that patients would be sedated, but respond to verbal commands (sedation score = 3). at 200 ng/ml there was at least a 50% probability that patients would be asleep, but respond to glabellar tap (sedation score = 4). drug interactions for information concerning pharmacokinetic drug interactions with midazolam (see precautions).