Versed (Midazolam)

VERSED®

Roche

Midazolam

Premedicant – Sedative – Anesthetic

Action And Clinical Pharmacology: General: Adult and Pediatric: I.V. midazolam 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. I.V. 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 i.v. 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 CNS depressants. The initial dose and all subsequent doses should always be titrated slowly; administer over 2 to 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 for complete dosing information).

Neonates: Midazolam should not be administered by rapid injection in the neonatal population. Severe hypotension and seizures have been reported following rapid i.v. administration, particularly with concomitant use of fentanyl (see Dosage for complete information).

Midazolam injection is a short-acting, water soluble benzodiazepine which has CNS 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 i.m. 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 i.v. 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 2 hours, but recovery may take up to 6 hours in some cases. Recovery in patients receiving midazolam may be slightly slower than in patients who receive thiopental.

I.V. doses of midazolam depress the ventilatory response to CO2 stimulation for 15 minutes or more beyond the duration of ventilatory depression following administration of thiopental. The ventilatory response to CO2 is markedly impaired in patients with chronic obstructive pulmonary disease. I.V. 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 (TLC) and peak expiratory flow decrease significantly, but static compliance and maximum expiratory flow at 50% of awake TLC (Vmax) increase. In healthy volunteers an i.m. premedicating dose of midazolam (0.07 mg/kg) did not depress the ventilatory response to CO2 stimulation to a clinically significant extent. The i.v. 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 i.v. 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, i.v. administration of midazolam at a dose of 0.15 mg/kg tended to reduce the cerebrospinal fluid pressure during the induction of anesthesia to an extent similar to 3.9 mg/kg i.v. 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: Midazolam 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. Table I summarizes the available data.

Following i.v. 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 i.m administration is greater than 90%. Following i.m. administration, the mean time to peak midazolam plasma concentrations is 0.5 hour. Peak concentrations of midazolam as well as 1-hydroxymethyl midazolam after i.m. administration are about one-half of those achieved after equivalent i.v. doses. There is, however, no direct correlation between clinical effects and blood levels of midazolam. The elimination half-life of i.m. administered midazolam is comparable to that observed following i.v. 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 i.v. infusion were determined in intubated, mechanically ventilated patients although not critically ill. The kinetics in critically ill patients with mutisystem dysfunction are unpredictable and it is recommended that midazolam be titrated to the desired effect

The elimination half-life of midazolam was longer following continuous infusion in ICU patients than following the injection of single i.v. 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 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 1 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 i.m. 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. 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, i.v. and i.m. When administered via the nonparenteral 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 i.m.

Indications And Clinical Uses: Adult Population: As i.m. premedication prior to surgical or diagnostic procedures. As an i.v. agent for patients requiring sedation/anxiolysis/amnesia prior to and during short endoscopic or diagnostic procedures and direct-current cardioversion. As an alternative i.v. agent for the induction of anesthesia.

Midazolan may also be administered as a continuous i.v. infusion in intubated, mechanically ventilated patients requiring sedation in the ICU.

When used i.v. as an agent for sedation/anxiolysis/amnesia for short endoscopic or other short diagnostic procedures, the desired psychosedation can usually be attained within 3 to 6 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 2 or more minutes with or without a nonnarcotic premedicant. Duration of effect when used for induction of anesthesia is generally dose-dependent.

Pediatric Patients: Midazolam has been clinically used for i.v. (including continuous infusion) or i.m. 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.

Contra-Indications: 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 i.v. sedation must be avoided in elderly or debilitated patients. All patients receiving midazolam for i.v. sedation should, of course, remain sufficiently alert to respond appropriately to verbal requests.

Benzodiazepines are contraindicated in patients with acute narrow angle glaucoma. Midazolam 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 is not intended for intrathecal or epidural administration due to the presence of the preservative benzyl alcohol in the dosage form.

Manufacturers’ Warnings In Clinical States:

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 i.v. midazolam in any dose.

Because i.v. midazolam depresses respiration and because opioid agonists and other sedatives can add to this depression, midazolam 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 countermeasures 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.

Midazolam should be used for i.v. sedation only with caution and must not be administered by single bolus or rapid i.v. administration. Doses used for i.v. sedation should be always restricted to the special low levels recommended (see Dosage) 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 especially 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 i.v. sedation, continuous monitoring of patients to detect reversible adverse effects which may occur in individual patients and the means and setting required for immediate management of these patients are essential prior to the administration of midazolam for i.v. 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; 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 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 i.v. 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 be used for sedation.

Concomitant use of barbiturates, alcohol, opiates or other CNS depressants increases the risk of apnea and may contribute, to excessive and/or prolonged drug effect.

Midazolam should not be given with a narcotic as an i.m. combination for premedication due to the risk of apnea. If a narcotic premedication is given, the subsequent i.v. dose of midazolam should be reduced.

The safety and efficacy of midazolam following non-i.v. and non-i.m. routes of administration have not been established. Midazolam should only be administered i.m. or i.v. 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 (life-time) toxicity studies in mice and rats indicate carcinogenic activity. 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.

Occupational Hazards: 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 1 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.

Usage in Preterm Infants and Neonates: Versed 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 Versed) containing this preservative must take into account the total amount of benzyl alcohol administered. The recommended dosage range of Versed 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.

Precautions: General: 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 countermeasures are recommended. During routine diagnostic bronchoscopies, in patients with CO2 retention, the use of a narcotic premedication is recommended.

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). 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 Pharmacokinetics). 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 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.

Geriatrics and Debilitated Patients: Doses of midazolam injection should be decreased for elderly and debilitated patients (see Dosage). Complete recovery after midazolam administration in such patients may take longer.

Children: Based upon published literature, pediatric patients generally require higher doses of midazolam than adults (see Dosage). Convulsions have occurred in children, most frequently in premature infants and neonates (see Adverse Effects).

Pregnancy: Safety in pregnancy has not been established. Therefore, midazolam 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.

Obstetrics: The use of midazolam has not been evaluated in obstetric studies; therefore, it 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 i.m. 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 labor have significantly higher midazolam plasma levels, a smaller volume of distribution and a lower clearance than pregnant women undergoing cesarean section or nonpregnant gynecological patients. When given immediately before cesarean section, midazolam can cause depression of the infant.

Lactation: 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 i.v. 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 Pharmacology). Caution should therefore be exercised in administrating midazolam to these patients.

Drug Interactions: The hypnotic effect of i.v. midazolam and the risk of apnea are 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 i.m. 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 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.

Adverse Reactions: 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 i.v. 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 in clinical research programs are reported in Table V. 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 cannot be excluded.

Other adverse reactions (not reported in previous table) occurring at a lower incidence, usually
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, lightheadedness, 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 in pediatric patients. However, based on information obtained from published literature and spontaneous adverse reaction reporting, the safety profile in children more than 1 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: respiratory arrest, respiratory failure, apnea, 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).

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.

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.

Laboratory Abnormalities: Isolated elevations in certain parameters of liver function (AST, ALT, alkaline phosphatase and total bilirubin), as well as isolated changes in total protein and albumin, have been reported.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: The manifestations of midazolam 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 ECG, 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 i.v. infusion line should be established and further measures should be taken to provide critical care. Should hypotension develop, treatment may include i.v. 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, flumazenil is a specific antidote in known or suspected overdose (for conditions of use see flumazenil 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 should further be adjusted according to the type and amount of premedication used. Excess doses or rapid or single bolus i.v. 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/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 i.m. use, midazolam should be injected deep in a large muscle mass. I.V. midazolam should be administered 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 medications must be immediately available to ensure the safety of the procedures and the maintenance of respiratory and cardiovascular functions (see Warnings).

Midazolam injection for i.v. sedation prior to and during short endoscopic or short diagnostic procedures and direct current cardioversion, should always be administered slowly (see Warnings and I.V. Sedation). Rapid i.v. 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 2 minutes must pass to see the effect of the dose. Extreme care should be taken to avoid intra-arterial injection or extravasation.

Midazolam may be mixed in the same syringe with frequently used premedicants: morphine sulfate, meperidine HCl, atropine sulfate or scopolamine hydrobromide. However, if an opioid is mixed with midazolam, the initial doses of both products should be reduced and constant monitoring is recommended. Midazolam is compatible with 5% dextrose in water, normal saline, and lactated Ringer’s solution. 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: I.M. Premedication: For preoperative sedation and to impair memory of perioperative events: For premedication, the recommended dose is 0.07 to 0.08 mg/kg i.m. (usual dose is about 5 mg i.m. for an average adult) administered 30 to 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 to 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 i.m. midazolam. Onset of action is within 15 minutes, with peak effect occurring 30 to 60 minutes following injection. Midazolam can be administered concomitantly with atropine sulfate or scopolamine hydrobromide. When administered concomitantly with a narcotic, the dose of midazolam should be reduced.

I.V. Sedation (see Warnings): See Table VII. For short endoscopic or short diagnostic procedures and direct current cardioversion: Midazolam 1 mg/mL formulation is recommended for i.v. sedation to facilitate slow injection.

Midazolam 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.

Administration: When used for i.v. sedation, midazolam should not be administered by rapid or single bolus i.v. administration (see Warnings).

Midazolam 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 Table V) 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 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, and in patients with limited pulmonary reserve (see Table V). 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.

I.V. Induction of Anesthesia: See Table VIII. For induction of general anesthesia before administration of other anesthetic agents: Individual response to midazolam is variable, particularly when a narcotic premedicant is not used. The dosage should be titrated according to the patient’s age and clinical status.

Doses are administered over 20 to 30 seconds, allowing 2 minutes for effect.

ICU Sedation: For initiation and maintenance of ICU sedation in intubated, mechanically ventilated patients

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 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 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.

I.M. Usual Pediatric Dose: For sedation prior to anesthesia or procedures (for longer and/or more stimulating procedures, i.m. midazolam can be used to facilitate insertion of an i.v. catheter for titration of additional medication). Sedation with i.m. midazolam is age and dose dependent: higher doses may result in deeper and more prolonged sedation. Doses of 0.1 to 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 and an opioid should not be mixed as a premedication, however if required then constant monitoring is recommended. Should both be required the inital dose of each must be reduced and the second agent of the two should be administered i.v. on arrival at the procedure area.

I.V. 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 to 3 minutes. Wait an additional 2 to 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.

The dose of midazolam must be reduced in patients premedicated with opioids or other sedative agents including midazolam.

Continuous I.V. Infusion: For sedation in critical care settings: Usual Pediatric Dose: To initiate sedation, an i.v. 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. I.V. loading doses should not be used in neonates (midazolam should not be administered as a rapid i.v. dose to preterm and term neonates. See below for Preterm and Neonatal Dosing Information). This loading dose may be followed by a continuous i.v. infusion to maintain the effect. Based on pharmacokinetic parameters and reported clinical experience, continuous i.v. infusions of midazolam should be initiated at a rate of 0.001 to 0.002 mg/kg/min (1 to 2 µg/kg/min). The rate of infusion can be increased or decreased as required, or supplemental i.v. 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 is rapidly administered.

When initiating an infusion with midazolam in hemodynamically compromised patients, the usual loading dose of midazolam should be titrated in small increments, separated by 2 to 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.

Neonatal Dosage: Based on the pharmacokinetic parameters and reported clinical experience in preterm and term neonates, continuous i.v. infusion of midazolam should be initiated at a rate of 0.0005 to 0.001 mg/kg/min (0.5 to 1 µg/kg/min). I.V. 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.

Stability and Storage: The recommended storage temperature for midazolam injection is 15 to 30°C. As with all parenteral drug products whenever solutions and container permit, midazolam injection should be inspected for particulate matter and discoloration prior to administration.

Reconstitution: None required.

Stability of Solutions: Midazolam injection may be mixed and is stable for 30 minutes in the same syringe with frequently used premedicants: morphine sulfate, meperidine HCl, atropine sulfate or scopolamine hydrobromide.

Midazolam injection is compatible and stable for 24 hours with 5% dextrose in water, and normal saline. The potency of midazolam decreases when mixed with lactated Ringer’s solution (or Hartmann’s solution) and should be used within 4 hours.

There is no evidence of the adsorption of midazolam onto the plastic of infusion apparatus or syringes.

Availability And Storage: 1 mg/mL: Each mL contains: midazolam HCl equivalent to midazolam 1 mg. Nonmedicinal ingredients: sodium chloride and disodium edetate, benzyl alcohol as preservative and hydrochloric acid or sodium hydroxide to adjust pH. Paraben- and sulfite-free. Vials of 2, 5 and 10 mL. Boxes of 10.

5 mg/mL: Each mL contains: midazolam HCl equivalent to midazolam 5 mg. Nonmedicinal ingredients: sodium chloride and disodium edetate, benzyl alcohol as preservative and hydrochloric acid or sodium hydroxide to adjust pH. Paraben- and sulfite-free. Vials of 1, 2 and 10 mL. Boxes of 10.

VERSED® Roche Midazolam Premedicant – Sedative – Anesthetic

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