Midazolam 1 mg and 5 mg Injection - Product Information
|Manufacture:||Fresenius Kabi USA, LLC|
|Condition:||ICU Agitation, Light Anesthesia, Light Sedation|
|Form:||Liquid solution, Intramuscular (IM), Intravenous (IV)|
Adult and Pediatric
Intravenous Midazolam Injection has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings. In some cases, where this was not recognized promptly and treated effectively, death or hypoxic encephalopathy has resulted. Intravenous midazolam should be used only in hospital or ambulatory care settings, that provide for continuous monitoring of respiratory and cardiac function, i.e., pulse oximetry. Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured (see Warnings). For deeply sedated patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.
The initial intravenous dose for sedation in adult patients may be as little as 1 mg, but should not exceed 2.5 mg in a normal healthy adult. Lower doses are necessary for older (over 60 years) or debilitated patients and in patients receiving concomitant narcotics or other central nervous system depressants. The initial dose and all subsequent doses should always be titrated slowly; administered over 2 - 3 minutes and allow about 2 minutes to fully evaluate the sedative effect. The use of the 1 mg/mL formulation or dilution of the 1 mg/mL or 5 mg/mL formulation is recommended to facilitate slower injection. Doses of sedative medications in pediatric patients must be calculated on a mg/kg basis, and initial doses and all subsequent doses should always be titrated slowly. The initial pediatric dose of midazolam for sedation/anxiolysis/amnesia is age, procedure, and route dependent (see Dosage and Administration for complete dosing information).
Midazolam should not be administered by rapid injection in the neonatal population. Severe hypotension and seizures have been reported following rapid i.v. administration, particularly with concomitant use of fentanyl (see Dosage and Administration for complete information).
Actions and Clinical Pharmacology
Midazolam is a short-acting, water-soluble benzodiazepine, which has central nervous system depressant effects. Depending on the route of administration and dose used, midazolam can produce sedative-hypnotic effects or induce anesthesia. The administration of midazolam may often be followed by anterograde amnesia.
Onset of sedative effects after intramuscular administration is about 15 minutes, with peak sedation occurring 30 to 60 minutes following injection. Sedation (defined as drowsiness with the ability to respond to verbal commands) after intravenous injection is usually achieved within 3 to 6 minutes; the time of onset is affected by the dose administered, the concurrent administration of narcotic premedications and the condition of the patient. Induction of anesthesia can usually be achieved in 1.5 minutes when narcotic premedication has been administered and in 2 to 2.5 minutes without narcotic premedication. When used as directed, recovery after awakening from general anesthesia usually occurs within two hours, but recovery may take up to six hours in some cases. Recovery in patients receiving midazolam may be slightly slower than in patients who receive thiopental.
Intravenous 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. The ventilatory response to carbon dioxide is markedly impaired in patients with chronic obstructive pulmonary disease. Intravenous sedation with midazolam in healthy volunteers does not adversely affect the mechanics of respiration (pulmonary resistance, static recoil, functional residual capacity or residual volume). However, 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 healthy volunteers, an intramuscular premedicating dose of midazolam (0.07 mg/kg) did not depress the ventilatory response to carbon dioxide stimulation to a clinically significant extent. The intravenous administration of midazolam decreases, in a dose-dependent manner, the minimum alveolar concentration (MAC) of halothane required for general anesthesia.
In cardiac hemodynamic studies, induction with midazolam was associated with a slight to moderate decrease in mean arterial pressure, cardiac output, stroke volume, and systemic vascular resistance. When used in intravenous sedation, midazolam produces a higher incidence of fall in mean arterial pressure than diazepam. Slow heart rates (less than 65/minute), particularly in patients taking propranolol for angina, tended to rise slightly while faster heart rates (e.g., 85/minute) tended to slow slightly.
In patients without any previous history of cerebrospinal diseases scheduled for elective surgery under lumbar spinal anesthesia, intravenous administration of midazolam at a dose of 0.15 mg/kg tended to reduce the cerebrospinal fluid pressure during induction of anesthesia to an extent similar to 3.9 mg/kg of intravenous thiopental. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction with midazolam. Patients with glaucoma have not been studied. The increase in intraocular pressure after succinylcholine administration or endotracheal intubation is not prevented by midazolam, diazepam or thiopental.
Pharmacokinetics in Adults
Midazolam Injection dosing should not be based on pharmacokinetic values; it should always be titrated to achieve a given clinical effect. This is especially important when used for long-term sedation in the Intensive Care Unit (ICU). Elimination half-life of midazolam is increased in congestive heart failure, hepatic cirrhosis, and chronic renal failure. It is markedly and unpredictably increased in critically ill patients with multiorgan failure. The following table summarizes the available data.
|Patient Type||Dose Range (mg/kg)||Elimination
|Volume of Distribution;
|Total Body Clearance;
21 - 50 years
|0.07 - 0.25||1.0b - 2.8||0.80 - 1.64||0.24 - 0.43|
||0.15 - 0.45||3.0 - 3.9||1.67 - 3.21||0.37 - 0.51|
|Congestive heart failure
33 - 67 years
21 - 59 years
|Severe alcoholic cirrhosis
39 - 54
|Chronic renal failurec
24 - 68 years
24 - 33 years
60 - 74 years
23 - 37 years
64 - 79 years
22 - 62 years
a Harmonic mean (hr)
b Lower value of the range in the study (mean not reported)
c In two critically ill patients with impaired renal function and renal failure with impaired hepatic function, t1/2 values of 18 and 21 hours, respectively, were reported (Shelly MP, et al. Anaesthesia 1987;42:619-26).
d Absolute dose
e Mean age
Following intravenous administration, midazolam is rapidly metabolized to 1-hydroxymethyl midazolam, which is the major metabolite, and to 4-hydroxy and 1,4-dihydroxy midazolam, which are minor metabolites. Mean peak plasma concentration of midazolam is several fold greater than that of 1-hydroxymethyl midazolam. The half-life of elimination of this metabolite is similar to that of the parent compound. Less than 0.03% of the dose is excreted in the urine as intact midazolam, 45% to 81% of the dose is excreted in urine as the conjugates of the metabolites. Midazolam is approximately 97% plasma protein-bound in normal subjects. In patients with chronic renal failure, the free fraction of drug in plasma can be significantly higher than in healthy subjects.
The mean relative bioavailability of midazolam following intramuscular administration is greater than 90%. Following intramuscular administration, the mean time to peak midazolam plasma concentrations is one half hour. Peak concentrations of midazolam as well as 1-hydroxymethyl midazolam after intramuscular administration are about one-half of those achieved after equivalent intravenous doses. There is, however, no direct correlation between clinical effects and blood levels of midazolam. The elimination half-life of intramuscularly administered midazolam is comparable to that observed following intravenous administration.
In animals and humans, midazolam has been shown to cross the placenta and to enter the fetal circulation. Clinical data indicate that midazolam is excreted in human milk. Following oral intake, low concentrations of midazolam could be detected for short periods of time.
Pharmacokinetics in Adult Patients in Intensive Care Unit (ICU)
The pharmacokinetics of midazolam following continuous intravenous infusion were determined in intubated, mechanically ventilated patients although not critically ill. The kinetics in critically ill patients with multisystem dysfunction are unpredictable and it is recommended that midazolam be titrated to the desired effect.
|Patient Type||Bolus* Doses (mg/kg)||Maintenance Infusion Rate (mg/kg/hr)||Css (ng/mL)||t½ (hr)||Total Body Clearance (L/kg/hr)|
|Coronary artery bypass graft surgery (n = 30) 45 - 71 years||0.015
|Abdominal-aortic surgery (n = 30) 50 - 76 years||0.03
* Bolus doses of 0.05, 0.06 and 0.10 mg/kg administered in these studies are not recommended in clinical practice (see Dosage and Administration).
The elimination half-life of midazolam was longer following continuous infusion in ICU patients than following the injection of single intravenous doses. The data were derived from studies in which midazolam was infused for less than 24 hours. Steady-state plasma levels increased with increasing rates of infusion.
In patients with acute renal failure (n = 6, mean age 48 years), total body clearance was lower (132 mL/min versus 198 mL/min), and the elimination half-life of midazolam was longer (13.2 hours versus 7.6 hours) than in patients with normal kidney function (n = 33, mean age 62 years). In patients with impaired kidney function, the excretion of 1-hydroxymethyl midazolam glucuronide, the major metabolite of midazolam, is impaired. The de-glucuronidation of this metabolite may increase its plasma concentration, which in turn may interfere with the hydroxylation of midazolam itself.
Pharmacokinetics in the Pediatric Population
In healthy children aged one year and older, the pharmacokinetic properties of midazolam are similar to those in adults. Weight-normalized clearance is similar to or higher than adult, and elimination half-life is similar to or shorter than adult. As with adults, absolute bioavailability of intramuscular midazolam is greater than 80%.
In seriously ill neonates and children, the half-life of midazolam is substantially prolonged and the clearance reduced compared to healthy adults or other groups of children (see Selected Bibliography). It cannot be determined if these differences are due to age, immature organ function or immature metabolic pathways, underlying illness or debility.
In the literature, midazolam is reported to be administered orally and rectally in pediatric patients, as well as via the recommended parenteral routes, intravenously and intramuscularly. When administered via the non-parenteral routes, the elimination half-life is similar to that of the parenteral administration; however, the bioavailability is less than 50% versus greater than 80% when administered intramuscularly.
The following tables display pharmacokinetic data on midazolam in pediatric patients. This information was collected from published scientific literature (see Selected Bibliography):
|Number of Patients||Age (years)||Dose (mg/kg)||Vd, area method (L/kg)||Elimination t½ (hours)||Clearance (mL/min/kg)|
|20||8 - 17b||up to 0.1||0.6||0.78||10.0|
|21||3.8 - 7.3c||0.075 - 0.6||1.4 - 1.7c||1.4 - 1.7c||4.8 - 11.2c|
|8||1 - 10b||0.15||-||1.2||9.1|
|12||5 - 9b||0.5||2.2||1.8||15.4|
|17||1.3 - 5.2c||0.3||2.4 - 2.7c||2.8 - 3.3c||8.5 - 12.0c|
|9||2 - 9b||0.2||-||0.6||7.6|
|6||5 - 7||0.1||-||1.8||3.2|
|10||2 - 5 days||0.2||-||6.5||2.0|
a Mean value
b Actual mean
c Range of mean values for subgroups
|Number of Patients||Age (years)||Infusion Rate (μg/kg/min)||Infusion Duration (hr)||Elimination t½ (hours)||Clearance (mL/min/kg)|
|10||0.5 - 8.8b||2 - 5||21 - 114||4.0 (n = 5)||-|
|15||1 - 5 daysb||1.0||60||12.0||1.7|
|187||0 - 10 daysb||1.15a||62a||-||1.17a|
a Mean value
b Actual mean
Indications and Clinical Use
Midazolam Injection has been found useful:
- as an intramuscular premedication prior to surgical or diagnostic procedures;
- as an intravenous agent for patients requiring sedation/anxiolysis/amnesia prior to and during short endoscopic or short diagnostic procedures and direct-current cardioversion;
- as an alternative intravenous agent for the induction of anesthesia.
Midazolam Injection may also be administered as a continuous intravenous infusion in intubated, mechanically ventilated patients requiring sedation in the Intensive Care Unit (ICU).
When used intravenously as an agent for sedation/anxiolysis/amnesia for short endoscopic or other short diagnostic procedures, the desired psychosedation can usually be attained within three to six minutes, depending on the dose administered and whether or not narcotic premedication is used concomitantly.
Induction of anesthesia with midazolam occurs in approximately 1.5 minutes when a narcotic premedicant has been administered and in two or more minutes with or without a non-narcotic premedicant. Duration of effect when used for induction of anesthesia is generally dose-dependent.
Midazolam Injection has been clinically used for intravenous (including continuous infusion) or intramuscular sedation of pediatric patients. Sedation, anxiolysis, and/or amnesia may be necessary for diagnostic or therapeutic procedures, preanesthesia, as a component of anesthesia during surgical procedures, or during treatment in critical care settings.
Midazolam Injection is contraindicated in patients with a known hypersensitivity to benzodiazepines, and acute pulmonary insufficiency, and also in patients with severe chronic obstructive pulmonary disease (see Warnings). Careful monitoring and slow administration is essential if the drug is used in elderly or debilitated patients. Marked hypoventilation is common if the patient is not responsive to verbal commands.
Outside the ICU setting, marked intravenous sedation must be avoided in elderly or debilitated patients. All patients receiving midazolam for intravenous sedation should, of course, remain sufficiently alert to respond appropriately to verbal requests.
Benzodiazepines are contraindicated in patients with acute narrow angle glaucoma. Midazolam Injection lowered the intraocular pressure in subjects without eye disease, but did not prevent the increases elicited by succinylcholine or endotracheal intubation. Patients with glaucoma have not been studied.
Midazolam Injection is not intended for intrathecal or epidural administration due to the presence of the preservative benzyl alcohol in the dosage form.
Midazolam Injection must never be used without individualization of dose. The immediate availability of oxygen and other appropriate medication, and the equipment necessary for resuscitation, the maintenance of a patent airway, support of ventilation and cardiac function, should be ensured prior to the use of intravenous midazolam in any dose.
Because intravenous midazolam depresses respiration and because opioid agonists and other sedatives can add to this depression, Midazolam Injection should be administered as an induction agent only by a person trained in general anesthesia and should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintenance of a patent airway and support of ventilation.
Patients should be continuously monitored for early signs of hypoventilation or apnea, which can lead to hypoxia/cardiac arrest unless effective counter measures are taken. This should include pulse oximetry. Vital signs should continue to be monitored during the recovery period. Opioid agonists and other sedatives add to the respiratory depression produced by Midazolam Injection.
Midazolam Injection should be used for intravenous sedation only with caution and must not be administered by single bolus or rapid intravenous administration. Doses used for intravenous sedation should always be restricted to the special low levels recommended (see Dosage and Administration) and careful attention should be given in the selection and exclusion of patients that might be specially susceptible to adverse cardiac and respiratory reactions. Older chronically ill patients and those with concomitant use of other cardiorespiratory depressant agents are also specially susceptible to adverse reactions. It should be borne in mind that a fall in oxygen saturation will increase the probability of arrhythmias and other potentially fatal events in susceptible patients. Oxygen supplementation should be used in elderly patients with chronic respiratory or cardiac disease and patients who are seriously ill. Experience in the administration of drugs for intravenous sedation, continuous monitoring of patients to detect reversible adverse effects which may occur in individual patients, and the means and setting required for immediate and appropriate management of these patients are essential prior to the administration of midazolam for intravenous sedation.
Serious cardiorespiratory events have occurred. These have included respiratory depression, apnea, respiratory arrest and/or cardiac arrest, sometimes resulting in death. Strict adherence to the cautions and warnings recommended in the use of this drug is therefore required in order to minimize the incidence of these reactions.
Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported. These reactions may be due to inadequate or excessive dosing or improper administration of Midazolam Injection; 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.
Outside the ICU setting, Midazolam Injection should not be administered to patients in shock, coma, acute alcoholic intoxication, renal failure, or with severe depression of vital signs. Extreme care must be used in administering midazolam, particularly by the intravenous route to the elderly, to very ill patients and to those with limited pulmonary reserve due to the possible occurrence of excessive sedation and/or of apnea or respiratory depression. Patients with chronic obstructive pulmonary disease are unusually sensitive to the respiratory depressant effect of midazolam (see Contraindications).
Myasthenic patients have the potential for respiratory decompensation if a substance with CNS-depressant and/or muscle-relaxant properties is administered. However, those myasthenic patients with established respiratory failure will need mechanical ventilation and for this sedation will be necessary. Careful monitoring of the patients is recommended should Midazolam Injection be used for sedation.
Concomitant use of barbiturates, alcohol, opiates or other central nervous system depressants increases the risk of apnea and may contribute to excessive and/or prolonged drug effect.
Midazolam Injection should not be given with a narcotic as an intramuscular combination for premedication due to the risk of apnea. If a narcotic premedication is given, the subsequent intravenous dose of midazolam should be reduced.
The safety and efficacy of Midazolam Injection following non-intravenous and non-intramuscular routes of administration have not been established. Midazolam Injection should only be administered intramuscularly or intravenously. The hazards of intra-arterial injection of midazolam solutions in humans are unknown; therefore, precautions against unintended intra-arterial injection should be taken. Extravasation should also be avoided.
Twenty-four months (lifetime) toxicity studies in mice and rats indicate carcinogenic activity (see Toxicology). The significance of these findings relative to the infrequent use of midazolam in humans is, at present, unknown. The physician should therefore take these findings into consideration when using midazolam.
Patients receiving Midazolam Injection on an outpatient basis should not engage in hazardous activities requiring complete mental alertness (i.e., operating machinery or driving 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. Patients should also be cautioned about the ingestion of alcohol or other CNS-depressant drugs until the effects of midazolam have subsided.
Use in Preterm Infants and Neonates
Midazolam Injection contains 1% benzyl alcohol (based on volume). 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 Injection) 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 amounts of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages of other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources.
Since an increase in cough reflex and laryngospasm may occur with peroral endoscopic procedures, the use of a topical anesthetic agent and the availability of necessary counter measures are recommended. During routine diagnostic bronchoscopies, in patients with CO2 retention, the use of a narcotic premedication is recommended.
Intensive Care Unit (ICU) Sedation
When administering Midazolam Injection as continuous infusion for ICU sedation, the changes in the rate of administration should be made slowly (at 30-minute intervals) in order to avoid hypotension and/or overdosage. The change in dose should be in increments of 25% to 50% of the original dose (see Dosage and Administration). Dosage should be titrated to a desired level of sedation; reliance on predicted kinetics may result in significant overdosage.
As with other sedative medications, there is wide interpatient variability in midazolam dosage requirements, and these requirements may change with time.
The infusion rate should be adjusted to achieve the required level of sedation according to the patient's age and clinical status. In patients who are still sedated and/or who received large doses of narcotics, a bolus dose may not be necessary and the initial infusion rate should be substantially decreased. The elimination half-life of midazolam is variable and may be considerably longer than seen during short-term administration (e.g., induction of anesthesia) (see Actions and Clinical Pharmacology, Pharmacokinetics in Adult Patients in Intensive Care Unit). Recovery may be dependent upon the duration of infusion and is more prolonged if the infusion exceeds 24 hours.
Physical and Psychological Dependence
Physical and psychological dependence may occur during benzodiazepine treatment. The risk is more pronounced in patients on long-term or high-dose treatment and in predisposed patients, such as those with a history of alcoholism, drug abuse or marked psychiatric disorders.
In order to minimize the risk of dependence, Midazolam Injection should only be administered for the shortest possible duration. Should treatment need to be extended, a careful assessment of the risks and benefits should be made.
Withdrawal symptoms may occur from a few hours to over a week after discontinuing treatment. Symptoms may range from tremor, restlessness, insomnia, anxiety, headache and inability to concentrate, to sweating, muscular/abdominal spasms and perceptual changes in more severe cases. In rare instances, delirium and convulsions may also occur. Consequently, abrupt discontinuation of midazolam should generally be avoided and a gradual tapering of dose followed.
Use in Elderly and Debilitated Patients
Doses of Midazolam Injection should be decreased for elderly and debilitated patients (see Dosage and Administration). Complete recovery after midazolam administration in such patients may take longer.
Use in Children
Based upon published literature, pediatric patients generally require higher doses of midazolam than adults (see Dosage and Administration). Convulsions have occurred in children, most frequently in premature infants and neonates (see Adverse Drug Reactions).
Use in Pregnancy
Safety in pregnancy has not been established. Therefore, Midazolam Injection should not be used in women who may be pregnant. Several studies have suggested an increased risk of congenital malformations associated with the use of some of the benzodiazepines during the first trimester of pregnancy.
Use in Obstetrics
The use of Midazolam Injection has not been evaluated in obstetric studies; therefore, Midazolam Injection is not recommended for obstetrical use. Measurable levels of midazolam were found in maternal venous serum, umbilical venous and arterial serum, and amniotic fluid, indicating placental transfer of the drug in humans. Fifteen to 60 minutes following intramuscular administration of 0.05 mg/kg of midazolam, both the umbilical venous and the umbilical arterial serum concentrations were lower than maternal venous concentrations.
Pregnant women in active labour have significantly higher midazolam plasma levels, a smaller volume of distribution, and a lower clearance than pregnant women undergoing Caesarian section or non-pregnant gynecological patients. When given immediately before Caesarian section, midazolam can cause depression of the infant.
Midazolam is excreted in human milk. Therefore, midazolam is not recommended for use in nursing mothers.
Patients with Special Conditions
Higher risk surgical patients or debilitated patients require lower dosages, whether as a premedicant or for intravenous sedation or induction of anesthesia. Patients with chronic obstructive pulmonary disease may experience prolonged sedation and prolonged respiratory depression (see Contraindications).
Patients with congestive heart failure and obese subjects have a substantially prolonged elimination half-life and an increased volume of distribution of midazolam. Patients with chronic renal failure or severe alcoholic cirrhosis exhibit changes in elimination half-life, volume of distribution and total body clearance (see Actions and Clinical Pharmacology). Caution should therefore be exercised in administrating Midazolam Injection to these patients.
The hypnotic effect of intravenous midazolam and the risk of apnea is accentuated by premedication, particularly narcotics (e.g., morphine, meperidine and fentanyl), secobarbital, and the droperidol-fentanyl combination. Consequently, the dosage of midazolam should be adjusted according to the type and amount of premedication administered.
A slight reduction in induction dosage requirements of thiopental (about 13%) has been noted following intramuscular use of midazolam for premedication.
The administration of midazolam has resulted in a dose dependent reduction of the minimum alveolar concentration of halothane required during maintenance of anesthesia.
Preliminary data, with a small number of subjects, reveal that midazolam appears to potentiate the effect of pancuronium.
Midazolam Injection does not cause a clinically significant change in onset or duration of action of a single intubating dose of succinylcholine. Midazolam does not protect against the characteristic circulatory changes noted after administration of succinylcholine or pancuronium.
Midazolam Injection has been used as an induction agent in conjunction with commonly used premedicants or drugs used during anesthesia and surgery (including atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, succinylcholine and d-tubocurarine, and other nondepolarizing muscle relaxants) or topical anesthetics (e.g., lidocaine).
Data from spontaneous reports as well as kinetic studies in humans indicate that midazolam may interact with compounds, which affect or are also metabolized by the cytochrome P450 3A4 hepatic enzymes. Data indicate that these compounds (cimetidine, erythromycin, diltiazem, verapamil, ketoconazole and itraconazole) influence the pharmacokinetics of midazolam (increased Cmax and AUC) and may lead to prolonged sedation. Therefore patients receiving the above compounds or others, which inhibit P450 3A4 enzymes together with midazolam, should be monitored for the first few hours after administration of midazolam.
See Warnings concerning serious cardiorespiratory events and possible paradoxical reactions.
Adverse Reactions in Adults
Sedative effects and fluctuations in vital signs were the most frequent findings following parenteral administration of Midazolam Injection. These are affected by the lightening or deepening of anesthesia, instrumentation, intubation and use of concomitant drugs. The more frequently encountered fluctuations in vital signs included decreased tidal volume and/or decreased respiratory rate and apnea, as well as variations in blood pressure and pulse rate. When used in intravenous sedation, midazolam tends to produce a higher incidence of fall in mean arterial pressure than diazepam.
The most frequently reported adverse reactions observed in association with the use of Midazolam Injection in clinical research programs are reported in the following table. Although adverse reactions may not have been observed in all clinical research programs, the possibility of their occurrence with the different clinical uses of Midazolam Injection cannot be excluded.
|Organ System||Adverse Effect||%|
|IM Premed (n = 380)||IV Sedation (n = 512)||IV Induction (n = 1,073)||IV ICU Sedation (n = 115)|
a n = 130
b n = 500
* Hypotension during ICU Sedation was defined as systolic blood pressure 90 mmHg or diastolic blood pressure 50 mmHg or a clinically significant fall in blood pressure.
Other adverse reactions (not reported in previous table) occurring at a lower incidence, usually less than 1%, are:
Cardiovascular: Premature ventricular contractions, bigeminy, vaso-vagal episode, bradycardia, tachycardia and nodal rhythm.
Respiratory: Laryngospasm, bronchospasm, dyspnea, shallow respiration, hyperventilation, and wheezing.
CNS/Neuromuscular: Nervousness, restlessness, anxiety, argumentativeness, aggression, insomnia, nightmares; deep sedation, prolonged sedation, oversedation, disorientation, slurred speech, emergence delirium, agitation during emergence, prolonged emergence from anesthesia, dreaming during emergence; dysphoria, euphoria, anterograde amnesia, light-headedness, feeling faint; tremors, muscle contractions, twitches and abnormal spontaneous muscular activity, tonic/clonic movements, athetoid movements; ataxia.
Gastrointestinal: Acid taste, excessive salivation and retching.
Special Senses: Blurred vision, diplopia, nystagmus, visual disturbance, difficulty focusing eyes, pinpoint pupils, cyclic movement of eyelids, ears blocked and loss of balance.
Dermatological: Erythema, rash, pruritus and hives.
Hypersensitivity: Allergic reactions, including anaphylactic shock.
Miscellaneous: Muscle stiffness, toothache, yawning, cold feeling when drug injected and cool sensation in arm during infusion.
Adverse Reactions in Pediatric Patients
Limited information is available from published literature regarding the use of Midazolam Injection in pediatric patients. However, based on information obtained from published literature and spontaneous adverse reaction reporting, the safety profile in children more than one month of age appears to be very similar to that observed in adults.
The most frequent acute events were airway compromise and hypoventilation. This most often occurred when used in conjunction with opiates or other anesthetic agents. The next most common adverse event with long-term use was withdrawal syndrome. The following list shows the other reported side effects. This list is not exhaustive.
Respiratory System: Respiratory arrest, respiratory failure, apnoea, hypoxia, oxygen desaturation. Danger of respiratory disorders may increase when midazolam is administered with opioids. Therefore the dosage of both agents should be reduced (see Warnings and Dosage and Administration).
Psychiatric: Withdrawal syndrome, combative reaction, agitation, hallucination.
Central and Peripheral Nervous System: Convulsions, excessive sedation, tonic/clonic convulsions, cerebral convulsion, lethargy. Convulsions occurred primarily in neonates (under 4 months old) and/or children with history of seizures.
Cardiovascular: Hypotension, bradycardia, cardiac/cardiopulmonary arrest.
Miscellaneous: Lack of efficacy, paradoxical response, therapeutic response decreased.
Local and Vein Tolerance
The incidence of local and vein tolerance observed in the early adult experience with Midazolam Injection was as follows:
|Adverse Effects on Local and Vein Tolerance||IM Premed||IV Sedation||IV Induction|
|n = 380||n = 512||n = 1,073|
|Pain at site of injection||3.7||--||--|
|Pain during injection of drug||0.0||0.4||7.5|
|Induration at site of injection||0.5||--||--|
|Swelling at site of injection||0.0||0.0||0.2|
|Erythema at site of injection||0.5||--||--|
|Hive-like elevation at injection site||--||--||0.2|
|Warmth at injection site||--||--||0.1|
|Burning at injection site||--||--||0.1|
|Hematoma at i.v. site||--||--||0.3|
|Tenderness of vein||0.0||1.4||8.0|
|Induration of vein||--||1.6||2.1|
|Redness of vein||0.0||1.4||3.4|
|Red wheal/flare along vein||--||--||0.1|
|Pain in vein after injection||--||--||0.1|
In the pediatric patients similar observations as in adults have been made. Some of the most frequently reported findings include: rash, urticaria, erythema, hives, skin necrosis and wheals.
Isolated elevations in certain parameters of liver function (SGOT, SGPT, alkaline phosphatase and total bilirubin), as well as isolated changes in total protein and albumin, have been reported.
Symptoms and Treatment of Overdosage
The manifestations of Midazolam Injection overdosage are sedation, somnolence, confusion, impaired coordination, diminished reflexes, untoward effects on vital signs, coma and possible cardio-respiratory arrest.
Treatment of overdosage is the same as that followed for overdosage with other benzodiazepines. Continuous monitoring of vital signs including EKG, should be immediately instituted and general supportive measures should be employed. Immediate attention should be given to the maintenance of an adequate airway and support of ventilation. If not already present, an intravenous infusion line should be established and further measures should be taken to provide critical care. Should hypotension develop, treatment may include intravenous fluid therapy, repositioning, and other appropriate countermeasures. Cardiopulmonary resuscitation may be required. At present, there is no information as to whether peritoneal dialysis, forced diuresis or hemodialysis are of value in the treatment of midazolam overdosage.
The benzodiazepine antagonist, 'Anexate' (flumazenil) is a specific antidote in known or suspected overdose. (For conditions of use, see 'Anexate' Product Monograph.)
Dosage and Administration
Midazolam Injection should only be administered i.m. or i.v. (see Warnings). The dosage of midazolam must be carefully individualized. In elderly and debilitated patients, lower doses are required. The dosage of midazolam should further be adjusted according to the type and amount of premedication used. Excess doses or rapid single bolusintravenous administration may result in respiratory depression and/or arrest, particularly in elderly or debilitated patients (see Warnings). Clinical experience has shown midazolam to be more potent than diazepam on a mg per kg basis.
Midazolam Injection has been shown to cause dose-related anterograde amnesia, an impairment or a lack of recall of events following administration of the drug.
Midazolam does not protect against the circulatory effects of succinylcholine administration or against the heart rate rise and/or blood pressure rise associated with endotracheal intubation under light general anesthesia.
For intramuscular use, Midazolam Injection should be injected deep in a large muscle mass.
Intravenous Midazolam Injection should be administered as an induction agent only by a person trained in general anesthesia and should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintenance of a patent airway and support of ventilation. The necessary equipment and the appropriate medications must be immediately available to ensure the safety of the procedures involved and the maintenance of respiratory and cardiovascular functions (see Warnings).
Midazolam Injection for intravenous sedation, prior to and during short endoscopic or short diagnostic procedures and direct current cardioversion, should always be administered slowly (see sections on WARNINGS and DOSAGE AND ADMINISTRATION, Usual Recommended Adult Dosage, Intravenous Sedation). Rapid intravenous injection may cause respiratory depression or apnea requiring respiratory assistance or controlled ventilation.
Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported. Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding with the administration of the drug (see Warnings).
For induction of general anesthesia in healthy patients, the initial dose should be administered over 20 to 30 seconds for optimal effect. About two minutes must pass to see the effect of the dose. Extreme care should be taken to avoid intra-arterial injection or extravasation.
Midazolam Injection is compatible with 5% dextrose in water and normal saline. Both the 1 mg/mL and 5 mg/mL formulations may be diluted with normal saline or 5% dextrose in water.
Usual Recommended Adult Dosage
For preoperative sedation and to impair memory of perioperative events:
For premedication, the recommended dose of Midazolam Injection is 0.07 - 0.08 mg/kg intramuscularly (usual dose is about 5 mg for an average adult) administered 30 - 60 minutes preoperatively. Lower doses should be used in elderly or debilitated patients. In a study of patients 60 years or older who did not receive concomitant narcotics, 2 - 3 mg of midazolam produced adequate sedation during the preoperative period. Some patients responded to doses as low as 1 mg. As with any potential respiratory depressant, these patients require observation for signs of cardiorespiratory depression after receiving midazolam intramuscularly.
Onset of action is within 15 minutes, with peak effect occurring 30 to 60 minutes following injection. Midazolam Injection can be administered concomitantly with atropine sulfate or scopolamine hydrobromide. When administered concomitantly with a narcotic, the dose of midazolam should be reduced.
For short endoscopic or short diagnostic procedures and direct current cardioversion:
Midazolam Injection 1 mg/mL formulation is recommended for intravenous sedation to facilitate slow injection.
Midazolam Injection can be used either alone or combined with a narcotic immediately before the procedure, with supplemental doses to maintain the desired level of sedation throughout the procedure. For peroral procedures, the use of an appropriate topical anesthetic is recommended. During routine diagnostic bronchoscopies, with no compromise of respiratory function, the use of narcotic premedication is recommended.
Dosage Table for Intravenous Sedation (see Dosage and Administration, Usual Recommended Adult Dosage, Intravenous Sedation, Method of Administration)
|Patient Type||Unpremedicated Patient||Premedicated Patient (Narcotics or CNS Depressants)|
|Initial Dose||Total Dose|
|Patients below age 55||No more than 2 to 2.5 mg||
||Reduce dosage by about 30%.|
|Patients age 55 or older; debilitated patients; chronically ill patients; patients with limited pulmonary reserve||No more than 1 to 1.5 mg||
||Reduce dosage by about 30% (i.e., 60% less than for healthy young unpremedicated patients).|
Method of Administration
When used for intravenous sedation, Midazolam Injection should not be administered by rapid or single bolus intravenous administration (see Warnings).
Midazolam Injection should be administered immediately prior to the procedure in small increments and titrated slowly until the desired sedative effect is achieved. An initial titration with a small dose, such as 2 to 2.5 mg (see Dosage and Administration, Usual Recommended Adult Dosage, Intravenous Sedation, Dosage Table for Intravenous Sedation) administered over a 2- to 3-minute period is suggested for an average healthy adult. After waiting about 2 minutes, the dosage may be further titrated in small increments of the initial dose if necessary to achieve the desired sedative effect. Wait about 2 minutes after each increment to fully evaluate the sedative effect. Additional maintenance doses may be given in increments of 25% of the initial dose to maintain the desired level of sedation, only by slow titration. The desired end point can usually be attained within 3 to 6 minutes, depending on the total dose administered and whether or not it is preceded by narcotic premedication. Narcotic premedication, when indicated, results in less variability of patient response.
The dosage should be lowered in the elderly and debilitated patients, and in patients with limited pulmonary reserve (see Dosage and Administration, Usual Recommended Adult Dosage, Intravenous Sedation, Dosage Table for Intravenous Sedation). Because the danger of underventilation or apnea is greatest in these patients, and because peak effect may take longer, increments should be smaller and the rate of injections slower.
Intravenous Induction of Anesthesia
For induction of general anesthesia before administration of other anesthetic agents:
Individual response to Midazolam Injection is variable, particularly when a narcotic premedicant is not used. The dosage should be titrated according to the patient's age and clinical status.
Dosage Table for Intravenous Induction
(see Dosage and Administration, Usual Recommended Adult Dosage, Intravenous Induction of Anesthesia, Method of Administration)
|Patient Type||Unpremedicated Patients||Premedicated Patients (Narcotics or CNS Depressants)|
|Initial Dose||Increments||Initial Dose||Increments|
|Patients below age 55||0.3 - 0.35 mg/kg||If needed to complete induction, increments of approximately 25% of the initial dose may be used.||0.15 - 0.35 mg/kg
0.25 mg/kg will usually suffice.
|If needed to complete induction, increments of approximately 25% of the initial dose may be used.|
|Patients age 55 or older (ASA I or II surgical patients)||0.3 mg/kg||0.2 mg/kg|
|Patients with severe systemic disease or other debilitation||0.2 - 0.25 mg/kg
In some cases, as little as 0.15 mg/kg will suffice.
|The need for increment doses to complete induction must be evaluated by the anesthesiologist.||0.15 - 0.2 mg/kg
In some cases, as little as 0.15 mg/kg will suffice.
|The need for increment doses to complete induction must be evaluated by the anesthesiologist.|
Method of Administration
Doses are administered over 20 to 30 seconds, allowing 2 minutes for effect.
Intensive Care Unit (ICU) Sedation
For initiation and maintenance of ICU sedation in intubated, mechanically ventilated patients:
|Patient Type||Bolus Dose||Initial Infusion Dose||Max. Dose||Increments|
|No prior narcotics or CNS depressants||0.015 - 0.03 mg/kg||0.01 - 0.03 mg/kg/hr||0.07 - 0.15 mg/kg/hr||For optimal sedation, the maintenance infusion rate may be increased or decreased by increments of 25% - 50% of the initial dose at intervals of 30 minutes.|
|Prior/concomitant narcotics or CNS depressants||0.015 - 0.03 mg/kg||0.01 - 0.03 mg/kg/hr||0.07 mg/kg/hr|
Dosage and rate of infusion should be individualized to achieve the required level of sedation according to the patient’s age and clinical status. In patients who are still sedated and/or who received large doses of narcotics, a bolus dose may not be necessary and the initial infusion rate of midazolam should be substantially decreased.
Recommended Pediatric Dosage
As a group, pediatric patients generally require higher doses of Midazolam Injection than do adults, and younger children may require higher doses than older children. In obese individuals, 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 is increased. For appropriate patient monitoring, see Warnings. Midazolam Injection should be administered as an induction agent only by a person trained in general anesthesia and should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintenance of a patent airway and support of ventilation (see Warnings).
Patients should be discharged in the care of a responsible individual.
Usual Pediatric Dose
For sedation prior to anesthesia or procedures (for longer and/or more stimulating procedures, intramuscular midazolam can be used to facilitate insertion of an intravenous catheter for titration of additional medication):
Sedation with intramuscular midazolam is age- and dose-dependent; higher doses may result in deeper and more prolonged sedation. Doses of 0.1 - 0.15 mg/kg are usually effective and do not prolong emergence from general anesthesia. For more anxious patients, doses up to 0.5 mg/kg may be needed. Midazolam Injection and an opioid should not be mixed as a premedication; however, if required then constant monitoring is recommended. Should both be required, the initial dose of each must be reduced and the second agent of the two should be administered intravenously on arrival at the procedure area.
Intravenously by Intermittent Injection
Usual Pediatric Dose
For sedation prior to and during procedures or prior to anesthesia:
For all patients, titrate slowly to the desired effect. The initial dose should be administered over 2 - 3 minutes. Wait an additional 2 - 3 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose. If further sedation is necessary, continue to titrate with small increments until the appropriate level of sedation is achieved. See dosing table below.
|Age of Child||Initial Dose||Total Dose||Comments|
|6 months - 5 years||0.05 - 0.1 mg/kg||0.6 mg/kg||The initial dose should be administered over 2 - 3 minutes. Wait for an additional 2 - 3 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose. If further sedation is necessary, continue to titrate with small increments until the appropriate level of sedation is achieved.|
|6 - 12 years||0.025 - 0.05 mg/kg||0.4 mg/kg|
|12 - 17 years||Dose as adults|
The dose of midazolam must be reduced in patients premedicated with opioids or other sedative agents including midazolam.
Continuous Intravenous Infusion
For sedation in critical care settings
Usual Pediatric Dose
To initiate sedation, an intravenous loading dose of 0.05 to 0.2 mg/kg administered over at least 2 to 3 minutes can be used to establish the desired clinical effect. Intravenousloading doses should not be used in neonates (Midazolam Injection should not be administered as a rapid intravenous dose to preterm and term neonates. See Neonatal Dosage below for preterm and neonatal information) . This loading dose may be followed by a continuous intravenous infusion to maintain the effect. Based on pharmacokinetic parameters and reported clinical experience, continuous intravenous infusions of midazolam should be initiated at a rate of 0.001 - 0.002 mg/kg/min (1 - 2 µg/kg/min). The rate of infusion can be increased or decreased as required, or supplemental intravenous doses of midazolam can be administered to increase or maintain the desired effect. Frequent assessment using standard pain/sedation scales is recommended. Drug elimination may be delayed in patients receiving erythromycin and/or other P450IIIa enzyme inhibitors (see Precautions, Drug Interactions) and in patients with liver dysfunction, renal dysfunction, low cardiac output (especially those requiring ionotropic support), and in neonates. Hypotension may be observed in patients who are critically ill, particularly those receiving opioids and/or when Midazolam Injection is rapidly administered.
When initiating an infusion with Midazolam Injection in hemodynamically compromised patients, the usual loading dose of midazolam should be titrated in small increments, separated by 2 - 3 minutes, and the patient monitored for hemodynamic instability, e.g., hypotension, respiratory rate and oxygen saturation.
The dose of midazolam must be reduced in patients premedicated with opioids or other sedative agents including midazolam.
Based on the pharmacokinetic parameters and reported clinical experience in preterm and term neonates, continuous intravenous infusion of midazolam should be initiated at a rate of 0.0005 - 0.001 mg/kg/min (0.5 - 1 µg/kg/min). Intravenous loading doses should not be used in neonates, rather the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. Hypotension may be observed in patients who are critically ill, and in preterm and term infants, particularly those receiving fentanyl and/or when midazolam is administered rapidly. Due to an increased risk of apnea, extreme caution is advised when sedating preterm and former preterm patients in combination with regional anesthesia.