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 Standard 

 

 

 

 

Benzodiazepine 

Premedicant-Sedative-Anesthetic Agent 

 

 



 

 

 



 

 

 



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 

 

THERAPEUTIC CLASSIFICATION  

 

Premedicant-Sedative-Anesthetic Agent  



 

GENERAL 

 

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 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).  

 

ACTION AND CLINICAL PHARMACOLOGY 

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.   

 

Pharmacokinetics in Adults 

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

 

 



 

 

Patient Type 



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  

 

 

Female 



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 

 



 

5 mg 


d

 

5 mg 



 

 



 

 

 



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) 

Lower value of the range in the study (mean not reported) 



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  

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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.  

 

Pharmacokinetics in Adult Intensive Care Unit (ICU) Patients 

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.  

 

Patient type 



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.  

 

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 

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 


12 



17 



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 

 

Number of 



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.  

 

Pediatric Patients 

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  

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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.  

 

 

WARNINGS 

 

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 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. 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 intravenous sedation only with caution and must not be 



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  

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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.  

 

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 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 

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, 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  

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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.  

 

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 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  

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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.  

 

Use in Geriatrics 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 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 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.  

 

Use in Nursing Mothers 

Midazolam is excreted in human milk. Therefore, midazolam is not recommended for use in 

nursing mothers.  

 

 


Midazolam Injection Product Monograph  

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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 

CONDUCTED WITH MIDAZOLAM INJECTION.  

 

Interaction Studies Conducted with Midazolam Injection 

 

CYP3A4 Inhibitors 

Itraconazole and Fluconazole 

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.  

 

Erythromycin 

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.  

 

Saquinavir 

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.  

 

Oral Contraceptives 

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.  

 

Lidocaine 

Midazolam had no effect on the plasma protein binding of lidocaine in patients undergoing 

antiarrhythmic therapy or regional anesthesia with lidocaine.  

 

 

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 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 

  11.5

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.  

 

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.  

 


Midazolam Injection Product Monograph  

Page 17 of 39

 

 



 

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 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.  

 

Respiratory System: 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 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 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.  

 

Laboratory Abnormalities 

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.  

 

DOSAGE AND ADMINISTRATION 



 

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 

single bolus IV administration may result in respiratory depression and/or arrest, 



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