Product monograph midazolam injection
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Midazolam Injection Product Monograph Page 1 of 39
PRODUCT MONOGRAPH
MIDAZOLAM INJECTION 5 mg/mL
15 mg/3 mL 5 mg/5mL 50 mg/10 mL
Pfizer Canada Inc. Kirkland, Quebec, H9J 2M5 Date of Preparation: 10 April 2014
Submission Control No: 154667
Midazolam Injection Product Monograph Page 2 of 39
Midazolam Injection Pfizer Canada Inc. 5 mg/mL 15 mg/3 mL 5 mg/5mL 50 mg/10 mL
Premedicant-Sedative-Anesthetic Agent GENERAL
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 opioids 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 Injection Product Monograph Page 3 of 39
Neonates Midazolam should not be administered by rapid injection in the neonatal population. Severe hypotension and seizures have been reported following rapid intravenous administration, particularly with concomitant use of fentanyl (see DOSAGE AND ADMINISTRATION for complete information).
Midazolam is a short-acting, water-soluble benzodiazepine which has central nervous system (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 intramuscular administration is about 15 minutes, with peak sedation occurring 30 to 60 minutes following injection. Sedation (defined as drowsiness with 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 opioid premedications and the condition of the patient. When midazolam is used intravenously, induction of anesthesia can usually be achieved in 1.5 minutes when opioid premedication has been administered and in 2 to 2.5 minutes without opioid 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.
Intravenous doses of midazolam depress the ventilatory response to CO 2 stimulation for 15 minutes or more beyond the duration of ventilator depression following administration of thiopental. The ventilatory response to CO 2 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 (TLC) and peak expiratory flow decrease significantly, but static compliance and maximum expiratory flow at 50% of awake TLC (V max
) increase. In healthy volunteers an intramuscular premedicating dose of 0.07 mg/kg did not depress the ventilator response to CO 2 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
Midazolam Injection Product Monograph Page 4 of 39
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.
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). The 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. Midazolam Injection Product Monograph Page 5 of 39
Dose Range (mg/kg) Elimination t 1/2 a (hr) Volume of Distribution Vd (L/kg) Total Body Clearance: TBC (L/hr/kg) Normal Subjects 21-50 years
0.07-0.25 1.0
b -2.8
0.80-1.64
0.24-0.43 Surgical (Elective) 30-54 years
0.15-0.45 3.0-3.9
1.67-3.21
0.37-0.51 Congestive Heart Failure 33-67 years
0.1
6.5
2.50
0.27
Hepatic Dysfunction 21-59 years
Severe Alcoholic Cirrhosis 39-54 years
0.07
0.075 2.4
3.9 1.77
1.49 0.50
0.32 Chronic Renal Failure c
24-68 years
0.20 3.3
3.40
0.60
Volunteers:
Male 24-33 years 60-74 years
23-37 years
64-79 years Patients:
Male 30 years e
82 years e
Female
31 years e
86 years e
5 mg d
5 mg d
5 mg
d
5 mg d
0.2 0.2
0.2 0.2
1.9
4.0
2.3 3.0
2.3 8.5
2.9 3.0
1.34 1.64
2.00 2.11
1.44 3.63
1.36 2.30
0.47
0.26
0.56 0.45
0.49 0.34
0.36 0.55
Obese volunteers 22-62 years
5 mg d
6.5
2.66 0.25
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 t½ values of 18 hours and 21 hours, respectively, were reported (Shelly MP, et al. Anesthesia 1987;42:619- 26).
d Absolute dose
e Mean age
Midazolam Injection Product Monograph Page 6 of 39
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 intramuscular 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.
The pharmacokinetics of midazolam following continuous intravenous infusion was determined in intubated, mechanically ventilated patients although not critically ill. The kinetics in critically ill patients with multisystem dysfunction is unpredictable and it is recommended that midazolam be titrated to the desired effect.
Dosing Pharmacokinetic values Bolus*
Doses (mg/kg)
Maintenance Infusion Rate (mg/kg/hr) Css
(ng/mL) T 1/2 (h) Total Body Clearance (l/kg/hr) Coronary artery bypass graft surgery (n=30) 45-71 years 0.015 0.03
0.05 0.014
to 0.017
66
9.3
0.26
Abdominal aortic surgery (n=30) 50-76 years 0.03 0.06
0.10 0.036
0.054 0.080
76 132
205 6.2
6.2 6.5
0.52 0.40
0.41 * 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.
Midazolam Injection Product Monograph Page 7 of 39
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.
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 REFERENCES; reference no. 41). 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 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 intramuscularly.
The following tables display pharmacokinetic data on midazolam in pediatric patients. This information was collected from published scientific literature (see REFERENCES, references no. 40-51): Table I: Kinetics of Intravenous Midazolam in Pediatric Patients After Single Intravenous Doses or Short Intravenous Infusions Number of Patients Age (years) Dose (mg/kg) Vd, area method (L/kg) Elimination T 1/2 (hours) Clearance (ml/min/kg) 18
20 21
6 8 12 17 9 6 10
12.8 a
8-17 b
3.8-7.3 c
2.5 a
1-10 b
5-9 b
1.3-5.2 c
2-9 b
5-7 2-5 days 0.08
up to 0.1 0.075-0.6 0.2 0.15
0.5 0.3
0.2 0.1
0.2 - 0.6 1.4-1.7 c
2.4 - 2.2 2.4-2.7 c
- - - 1.45
0.78 1.4-1.7
c
2.4 1.2 1.8
2.8-3.3 c
0.6 1.8
6.5 8.0
10.0 4.8-11.2
c
13.3 9.1 15.4
8.5-12.0 c
7.6 3.2
2.0 a. Mean value b. Actual Range c. Range of Mean Values for Subgroups Midazolam Injection Product Monograph Page 8 of 39
Table II. Kinetics of Intravenous Midazolam in Pediatric Patients During and After Prolonged Intravenous Infusion
Patients Age (years) Infusion Rate Mcg/kg/min) Infusion Duration (hr) Elimination T 1/2 (hours) Clearance (ml/min/kg) 10
10 15
187 0.5-8.8
b
4.9 a
1-5 days b
0-10 days b
2-5 0.8 1.0
1.15 b
21-114 16
60 62 a 4.0 (n=5) 3.1 12.0
-
- 9.6 1.7
1.17 a a. Mean value b. Actual Mean
INDICATIONS AND CLINICAL USE Adult Population Midazolam Injection has been found useful: As 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 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 psycho-sedation can usually be attained within 3 to 6 minutes, depending on the dose administered and whether or not opioid premedication is used concomitantly.
Induction of anesthesia with midazolam occurs in approximately 1.5 minutes when an opioid premedicant has been administered and in 2 or more minutes with or without a nonopioid premedicant. Duration of effect when used for induction of anesthesia is generally dose- dependent.
Midazolam 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 Product Monograph Page 9 of 39
CONTRAINDICATIONS Midazolam injection is contraindicated in patients with a known hypersensitivity to benzodiazepines or any component of the product, 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 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.
Because intravenous 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.
administered by single bolus or rapid intravenous administration. Doses used for intravenous sedation should be always 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 especially 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 Midazolam Injection Product Monograph Page 10 of 39
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 management of these patients are essential prior to the administration of midazolam for intravenous sedation.
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 Injection 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
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, opioids 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 an opioid as an intramuscular combination for premedication due to the risk of apnea. If opioid premedication is given, the subsequent intravenous dose of midazolam should be reduced.
The safety and efficacy of midazolam following non-intravenous and non-intramuscular routes of administration have not been established. Midazolam 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.
Midazolam Injection Product Monograph Page 11 of 39
Twenty-four months (life-time) 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.
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 CO 2
retention, the use of opioid premedication is recommended. ICU Sedation When administering midazolam injection as a 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 opioids, 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 aesthesia) (see GENERAL, 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.
Midazolam Injection Product Monograph Page 12 of 39
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.
Doses of midazolam injection should be decreased for elderly and debilitated patients (see
such patients may take longer.
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).
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.
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 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 Cæsarean section or nonpregnant gynecological patients. When given immediately before Cæsarean section, midazolam can cause depression of the infant.
Midazolam is excreted in human milk. Therefore, midazolam is not recommended for use in nursing mothers.
Midazolam Injection Product Monograph Page 13 of 39
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 CLINICAL PHARMACOLOGY). Caution should therefore be exercised in administering midazolam to these patients. Drug Interactions The hypnotic effect of intravenous midazolam and the risk of apnea is accentuated by premedication, particularly opioids (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 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 anesthetic s (e.g. lidocaine).
The metabolism of midazolam is predominantly mediated by cytochrome P-450 3A4 (CYP3A4) isozyme. Approximately 25% of the total cytochrome P-450 system in the adult liver is from the CYP3A4 subfamily. Inhibitors and inducers of this isozyme may lead to drug interaction with midazolam. 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 P-450 3A4 hepatic enzymes. Data indicate that these compounds (cimetidine, erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole) influence the pharmacokinetics of midazolam (increased C max
and AUC) and may lead to prolonged sedation Midazolam Injection Product Monograph Page 14 of 39
(azithromycin has little or no effect on the pharmacokinetics of midazolam). Therefore patients receiving the above compounds or others which inhibit P-450 3A4 enzymes (including saquinavir) together with midazolam should be monitored for the first few hours after administration of midazolam. For further information see INTERACTION STUDIES
Coadministration of midazolam and itraconazole or fluconazole prolonged the elimination half- life of midazolam from 2.9 to 7.0 hours (itraconazole) or 2.9 to 4.4 hours (fluconazole). Bolus doses of midazolam given for short-term sedation did not enhance the effect of midazolam to a clinically significant degree by itraconazole and fluconazole, and dosage reduction is not required. However, administration of high doses of midazolam may require dosage adjustments. Long-term infusions of midazolam to patients receiving antimycotics, e.g. during intensive care treatment, may result in long-lasting hypnotic effects if the dose is not titrated according to the effect.
Coadministration of midazolam and erythromycin prolonged the elimination half-life of midazolam from 3.5 to 6.2 hours. Although only relatively minor pharmacodynamic changes were observed, it is advised to adjust doses of intravenous midazolam, especially if high doses are being administered. Cimetidine and Ranitidine Cimetidine increased the steady-state plasma concentration of midazolam by 26%, whereas ranitidine had no effect. Coadministration of midazolam and cimetidine or ranitidine had no clinically significant effect on the pharmacokinetics and pharmacodynamics of midazolam. These data indicate that intravenous midazolam can be used in usual doses with cimetidine and ranitidine and dosage adjustment is not required. Cyclosporin There is no pharmacokinetic and pharmacodynamic interaction between cyclosporin and midazolam. Therefore, the dosage of midazolam needs no adjustment when given concomitantly with cyclosporin. Nitrendipine Nitrendipine did not affect the pharmacokinetics and pharmacodynamics of midazolam. Both drugs can be given concomitantly and no dosage adjustment of midazolam is required.
Coadministration of a single intravenous dose of 0.05 mg/kg midazolam after 3 or 5 days of saquinavir dosing (1 200 mg t.i.d.) to 12 healthy volunteers decreased the midazolam clearance by 56 % and increased the elimination half-life from 4.1 to 9.5 hours. Only the subjective effects Midazolam Injection Product Monograph Page 15 of 39
to midazolam (visual analogue scales with the item “overall drug effect”) were intensified by saquinavir. Therefore, bolus doses of intravenous midazolam can be given in combination with saquinavir. During a prolonged midazolam infusion, an initial dose reduction of 50% is recommended.
The pharmacokinetics of intramuscular midazolam was not affected by the use of oral contraceptives. Both drugs can be given concomitantly and no dosage adjustment of midazolam is required. Other Interactions Sodium Valproate Displacement of midazolam from its plasma binding sites by sodium valproate may increase the response to midazolam and, therefore, care should be taken to adjust the midazolam dosage in patients with epilepsy.
Midazolam had no effect on the plasma protein binding of lidocaine in patients undergoing antiarrhythmic therapy or regional anesthesia with lidocaine.
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 in clinical research programs are reported in Table III. 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.
Midazolam Injection Product Monograph Page 16 of 39
Table III: Most Frequently Reported Adverse Reactions Organ System Adverse Effect % IM Premed N=380 IV Sedation N=512 IV Induction N=1073 IV ICU Sedation N=115 Cardiovascular Increased Mean Arterial Pressure Decreased Mean Arterial Pressure Hypotension Increased Pulse Rate Decreased Pulse Rate 2.6 6.3
7.1
9.5 8.0
29.9
29.9 16.8 16.7
30.8
36.0 12.6 6.9
17.0 26.0*
Respiratory Increased Respiratory Rate / Tachypnea Decreased Respiratory Rate Apnea
Coughing Respiratory Depression Airway Obstruction
a
10.8 a
36.9
25.6 1.0
0.2 0.2
0.2 0.1
0.1 22.9
2.0 25.0
1.0 Central
Nervous System
Headache Drowsiness Excessive Sedation Dizziness Hallucination Agitation Confusion 1.3
0.3 0.8 0.5
0.6 0.2
0.6 2.0 1.7
1.6 1.2
0.9
2.8
1.8 2.8
Gastro- intestinal Hiccoughs Nausea
Emesis/Vomiting 0.3
0.5 0.5
0.4 b
0.8 b
0.6 b
6.0 4.0
3.5 0.9
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 occurring at a lower incidence, usually less than 1% are: Cardiovascular Premature ventricular contractions, bigeminy, vasovagal episode, bradycardia, tachycardia, and nodal rhythm.
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.
Midazolam Injection Product Monograph Page 17 of 39
Gastrointestinal Acid taste, excessive salivation and retching.
Blurred vision, diplopia, nystagmus, visual disturbance, difficulty focusing eyes, pinpoint pupils, cyclic movement of eyelids, ears blocked and loss of balance.
Erythema, rash, pruritus and hives.
Allergic reactions, including anaphylactic shock. Miscellaneous Muscle stiffness, toothache, yawning, cold feeling when drug injected and cool sensation in arm during infusion.
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 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 opioids 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.
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
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.
Hypotension, bradycardia, cardiac/cardiopulmonary arrest.
Lack of efficacy, paradoxical response, therapeutic response decreased. Local and Vein Tolerance The incidence of local and vein tolerance observed in the early experience with midazolam is listed in Table IV.
Midazolam Injection Product Monograph Page 18 of 39
Table IV: Incidence of local and vein tolerance % Incidence Adverse Effects on Local and Vein Tolerance IM Premed IV Sedation IV Induction N = 380 N = 512 N = 1073 LOCAL Pain at injection site Pain during injection of drug Induration at injection site Swelling at injection site Erythema at injection site Hive-like elevation at injection site Warmth at injection site Burning at injection site Hematoma at IV site
3.7
0.0 0,5
0.0 0.5
- - - -
- 0.4 - 0.0 - - - - -
- 7.5
- 0.2
- 0.2
01 0.1
0.3 VEIN Tenderness of vein Induration of vein Redness of vein Red wheal/flare along vein Pain in vein after injection Phlebitis Thrombophlebitis 0.0
- 0.0
- - - -
1.4 1.6 1.4
- - - -
8.0 2.1 3.4
0.1 0.1
0.6 0.1
In 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, e.g. AST(SGOT), ALT(SGPT), alkaline phosphatase and total bilirubin, as well as isolated changes in total protein and albumin, have been reported.
You can report any suspected adverse reactions associated with the use of health products to the Canada Vigilance Program by one of the following 3 ways:
Report online at www.healthcanada.gc.ca/medeffect
Call toll-free at 1-866-234-2345 Complete a Canada Vigilance Reporting Form and: - Fax toll-free to 1-866-678-6789, or - Mail to: Canada Vigilance Program Health Canada Postal Locator 0701 E Ottawa, Ontario K1A 0K9
Postage paid labels, Canada Vigilance Reporting Form and the adverse reaction reporting guidelines are available on the MedEffect™ Canada Web site at
www.healthcanada.gc.ca/medeffect
NOTE: Should you require information related to the management of side effects, contact your health professional. The Canada Vigilance Program does not provide medical advice. Midazolam Injection Product Monograph Page 19 of 39
OVERDOSAGE For management of a suspected drug overdose, contact your regional Poison Control Centre. Symptoms The manifestations of midazolam overdosage are: sedation, somnolence, confusion, impaired coordination, diminished reflexes, untoward effects on vital signs, coma and possible cardiorespiratory arrest. Treatment 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, flumazenil is a specific antidote in known or suspected overdose. (For conditions of use refer to flumazenil Product Monograph). Caution should be observed with the use of flumazenil in cases of mixed drug overdosage and in patients with epilepsy treated with benzodiazepines.
General Midazolam Injection should only be administered intramuscularly or intravenously (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 or
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