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Midazolam Injection is a sterile, isotonic, clear, colourless to pale yellow solution in a ready-to-
use, single dose presentation. Midazolam Injection contains midazolam, sodium chloride,
hydrochloric acid and Water for Injections. Sodium hydroxide may be present if used for the
adjustment of pH. It does not contain preservatives.
Strength: 1mg/mL and 5mg/mL
Dosage Form: Solution for Injection
Routes of Administration: Intravenous (i.v.), intramuscular (i.m.), rectal, intranasal or oral (see
Premedication before induction of anaesthesia (i.m. or, especially in children, rectal, intranasal or
Conscious sedation before diagnostic or surgical interventions carried out under local anaesthesia
(i.v. administration), or in children intranasal or oral administration.
Long-term sedation in intensive care units (i.v. administration as bolus injection or continuous
Induction and maintenance of anaesthesia. As an induction agent in inhalation anaesthesia or a
sleep-inducing component in combined anaesthesia, including total intravenous anaesthesia (i.v.
injection, i.v. infusion).
Ataralgesia in combination with ketamine in children (i.m. administration).
DOSAGE AND ADMINISTRATION
This product is for single patient use only. Use once and discard any residue.
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In the case of elderly patients with organic cerebral changes or impaired cardiac and respiratory
function, the dosage should be determined with caution, the special factors relating to each
patient being taken into consideration.
Initial and subsequent intravenous injections must be given slowly (approximately 2.5 mg in
10 seconds for induction of anaesthesia and 1 mg in 30 seconds for conscious sedation). The
medicine takes effect about two minutes after the injection is started. Dosage should be
In patients suffering from pain before an intervention.
Administration alone or in combination with anticholinergics and possibly analgesics. These
doses should be administered about 30 minutes before induction of anaesthesia.
patient. Usual dosage about 5 mg.
to 0.20 mg per kg bodyweight i.m.).
plastic applicator fixed on the end of a syringe, 0.35 to 0.45 mg/kg bodyweight 20 to 30 minutes
before induction of general anaesthesia. If the volume to be administered is too small, water may
be added up to a total volume of 10 mL.
For conscious sedation in diagnostic or surgical interventions carried out under local anaesthesia.
operation. Further doses of 1 mg may be given as necessary. A total dose greater than 5 mg is not
usually necessary to reach the desired endpoint. In cases of severe illness, particularly if the
patient is in poor general condition or of advanced age, the initial dose must be reduced to 1 to
1.5 mg. Total doses greater than 3.5 mg are not usually necessary.
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For sedation in ICU, the dosage should be individualised and midazolam titrated to the desired
state of sedation according to the clinical need, physical status, age, concomitant medication.
Loading dose: 0.03 to 0.3 mg/kg.
Maintenance dose: 0.03 to 0.2 mg/kg/hr. The dosage should be reduced or the loading dose
should even be omitted in hypovolemic, vasoconstricted and hypothermic patients.
of sleep is generally achieved after 2 to 3 minutes.
should be injected i.v. The dose and the intervals between doses vary according to the individual
patient's reaction. Alternatively, midazolam can be administered by continuous infusion.
Intravenous continuous infusion
Adults: for intravenous anaesthesia combined with ketamine, 0.03 to 0.1 mg/kg/hr; narcotics,
0.03 to 0.3 mg/kg/hr. High-risk surgical patients, elderly and debilitated patients require lower
Children: a combination of the sleep-inducing and amnesia-inducing midazolam with ketamine
(ataralgesia) is recommended. Midazolam i.m. (0.15 to 0.20 mg per kg bodyweight) in
combination with 50 to 100 mg ketamine i.m. (4 to 8 mg per kg bodyweight). A sufficiently deep
level of sleep is generally achieved after 2 to 3 minutes.
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When midazolam is given with potent analgesics, the latter should be administered first so that
the sedative effects of midazolam can be safely titrated on top of any sedation caused by the
sodium chloride 0.9%, dextrose 5% and 10%, levulose 5%, Ringer's solution and Hartmann's
solution in a mixing ratio of 15 mg midazolam per 100 to 1,000 mL infusion solution. These
solutions remain physically and chemically stable for 24 hours at room temperature (or three
days at 5°C).
When administered orally, the bitter taste of midazolam injection may be masked by small
quantities of apple juice, sweetened fruit syrup or powdered soft drink.
Patients with a hypersensitivity to benzodiazepines or any other component of the product.
Intravenous midazolam should only be used when age- and size-appropriate resuscitation
facilities are available, as i.v. administration of midazolam may depress myocardial contractility
and cause apnoea. Severe cardiorespiratory adverse events have occurred on rare occasions.
These have included respiratory depression, apnoea, respiratory arrest and/or cardiac arrest. Such
life-threatening incidents are more likely to occur in adults over 60 years of age, those with pre-
existing respiratory insufficiency or impaired cardiac function and paediatric patients with
cardiovascular instability, particularly when the injection is given too rapidly or when a high
dosage is administered.
Special caution should be exercised when administering midazolam parenterally to patients
representing a higher risk group:
adults over 60 years of age
debilitated or chronically ill patients
patients with chronic respiratory insufficiency
patients with chronic renal failure, impaired hepatic function or with congestive heart
paediatric patients with cardiovascular instability.
These higher-risk patients require lower dosages (see DOSAGE AND ADMINISTRATION)
and should be continuously monitored for early signs of alterations of vital functions.
Benzodiazepines should be used with extreme caution in patients with a history of alcohol or
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As with any substance with CNS depressant and/or muscle-relaxant properties, particular care
should be taken when administering midazolam to a patient with myasthenia gravis, owing to
pre-existing muscle weakness.
Some loss of efficacy has been reported when midazolam has been used as long-term sedation in
intensive care units (ICU).
When midazolam is used in long-term sedation in ICU, it should be borne in mind that physical
dependence may develop. The risk of dependence increases with dose and duration of treatment.
During prolonged treatment with midazolam in ICU, physical dependence may develop. Abrupt
cessation of therapy may lead to withdrawal symptoms such as headaches, muscle pain, anxiety,
tension, restlessness, confusion, irritability, rebound insomnia, mood changes, hallucinations and
convulsions. Since the risk of withdrawal symptoms is greater after abrupt discontinuation of
treatment, it is recommended that the dose is decreased gradually.
Midazolam causes anterograde amnesia (frequently this effect is very desirable in situations such
as before and during surgical and diagnostic procedures), the duration of which is directly related
to the administered dose. Prolonged amnesia can present problems in outpatients, who are
scheduled for discharge following intervention. After receiving midazolam parenterally, patients
should be discharged from hospital or consulting room only if accompanied by an attendant.
Reactions such as agitation, involuntary movements (including tonic/clonic movements and
muscle tremor), hyperactivity, hostility, rage reaction, aggression, paroxysmal excitement and
assault have been reported. The highest incidence of susceptibility to such reactions has been
reported among children and the elderly. Should such reactions occur, the response to each dose
of midazolam and all other drugs including local anaesthetics should be evaluated before
Elimination of midazolam may be delayed in patients receiving compounds that inhibit certain
hepatic enzymes (particularly cytochrome P450 3A4) (see INTERACTIONS).
When midazolam is given intravenously for a prolonged period and in combination with
saquinavir, an initial dose reduction of midazolam of 50% is recommended (see
It is advisable to lower doses of intravenous midazolam when co-administered with
erythromycin (see INTERACTIONS).
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Displacement of midazolam from its plasma protein binding sites by sodium valproate may
increase the response to midazolam. Care should be taken to adjust the midazolam dose in
patients with epilepsy on treatment with sodium valproate (see INTERACTIONS).
Elimination of midazolam may also be delayed, in patients with liver dysfunction, low cardiac
output and in neonates (see Pharmacokinetics in special populations).
Adverse haemodynamic events have been reported in paediatric patients with cardiovascular
instability and therefore rapid intravenous administration should be avoided in this population.
Pre-term infants and neonates
Due to an increased risk of apnoea, extreme caution is advised when sedating pre-term and
former pre-term patients whose trachea is not intubated.
Rapid injection should be avoided in the neonatal population.
Neonates have reduced and/or immature organ function and are vulnerable to profound and/or
prolonged respiratory effects of midazolam.
Sedation, amnesia, impaired concentration and impaired muscular function may adversely affect
the ability to drive or use machines. Prior to receiving midazolam, the patient should be warned
not to drive a vehicle or operate a machine until recovered.
Insufficient data are available on midazolam to assess its safety during pregnancy.
Benzodiazepines should be avoided during pregnancy unless there is no safer alternative. The
administration of midazolam in the last trimester of pregnancy or at high doses during labour has
been reported to produce irregularities in the foetal heart rate, hypotonia, poor sucking and
hypothermia and moderate respiratory depression in the neonate. Moreover, infants born to
mothers who received benzodiazepines chronically during the latter stage of pregnancy may
have developed physical dependence and may be at some risk of developing withdrawal
symptoms in the postnatal period.
Use in lactation
Since midazolam passes into breast milk, it should not be administered to breast-feeding
The metabolism of midazolam is predominantly mediated by cytochrome P450 3A4 (CYP3A4)
isozyme. Approximately 25 % of the total cytochrome P450 system in the adult liver is from the
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CYP3A4 subfamily. Inhibitors (see PRECAUTIONS) and inducers of this isozyme may lead to
interaction with midazolam.
Azole antifungals: Co-administration with azole antifungals increases the plasma concentrations
of intravenous midazolam by 5-fold for ketoconazole, by 3-fold for voriconazole and by 2 to 3-
fold for both fluconazole and itraconazole. The associated elimination half-life of intravenous
midazolam was increased by 3-fold for ketoconazole and voriconazole, by 2.4-fold for
itraconazole and by 1.5-fold for fluconazole.
When bolus doses of midazolam (given for short-term sedation) were administered to patients
receiving itraconazole or fluconazole the effect of midazolam was not enhanced to a clinically
significant degree, 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 systemic antimycotics, e.g., during
intensive care treatment, may result in long-lasting hypnotic effects if the dose is not titrated
according to the effect.
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 (see PRECAUTIONS).
midazolam by 26%, whereas ranitidine had no effect.
Co-administration 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.
There is no pharmacokinetic and pharmacodynamic interaction between cyclosporin
and midazolam. Therefore, the dosage of midazolam needs no adjustment when given
concomitantly with cyclosporin.
midazolam. Both medicines can be given concomitantly and no dosage adjustment of midazolam
Saquinavir and other HIV-protease inhibitors: Co-administration of a single intravenous dose of
0.05 mg/kg midazolam after 3 or 5 days of saquinavir dosing (1200 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 h. Only the subjective effects 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 (see
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Co-administration with other protease inhibitors may cause a large increase in the concentration
of midazolam. Upon co-administration with ritonavir-boosted lopinavir, the plasma
concentrations of intravenous midazolam increased by 5.4-fold, associated with a similar
increase in terminal half-life.
Oral contraceptives: The pharmacokinetics of intramuscular midazolam was not affected by the
use of oral contraceptives. Both medicines can be given concomitantly and no dosage adjustment
of midazolam is required.
Sodium valproate: Displacement of midazolam from its plasma protein binding sites by sodium
valproate may increase the response to midazolam and, therefore, care should be taken to adjust
the midazolam dosage in patients on treatment with sodium valproate (see PRECAUTIONS).
Lidocaine: Midazolam had no effect on the plasma protein binding of lidocaine in patients
undergoing anti-arrhythmic therapy or regional anaesthesia with lidocaine.
Alcohol may enhance the sedative effect of midazolam.
The intravenous administration of midazolam decreases the minimum alveolar concentration
(MAC) of halothane required for general anaesthesia.
The following adverse reactions have been reported to occur when midazolam is injected:
Drowsiness and prolonged sedation, reduced alertness, confusion, euphoria, hallucinations ,
fatigue, headache, dizziness, ataxia, postoperative sedation, anterograde amnesia, the duration of
which is directly related to the administered dose. Anterograde amnesia may still be present at
the end of the procedure and in isolated cases prolonged amnesia has been reported.
Paradoxical reactions such as agitation, involuntary movements (including tonic/clonic
movements and muscle tremor), hyperactivity, hostility, rage reaction, aggressiveness,
paroxysmal excitement and assault, have been reported, particularly among children and the
Convulsions have been reported in premature infants and neonates.
Use of midazolam, even in therapeutic doses, may lead to the development of physical
dependence. After prolonged i.v. administration, discontinuation, especially abrupt
discontinuation of the product, may be accompanied by withdrawal symptoms including
Nausea, vomiting, hiccough, constipation, dry mouth.
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Severe cardiorespiratory adverse events have occurred on rare occasions. These have included
respiratory depression, apnoea, respiratory arrest and/or cardiac arrest. Such life-threatening
incidents are more likely to occur in adults over 60 years of age and those with pre-existing
respiratory insufficiency or impaired cardiac function, particularly when the injection is given
too rapidly or when a high dosage is administered (see PRECAUTIONS).
The following other cardiorespiratory adverse events have been reported: hypotension, slight
increase in heart rate, vasodilating effects, dyspnoea. In isolated cases laryngospasm has
occurred following injection of midazolam.
Skin and appendages disorders
Skin rash, urticarial reaction, pruritus.
In isolated cases, generalized hypersensitivity, from skin reactions to anaphylactoid reactions,
have been reported.
Erythema and pain on injection site, thrombophlebitis, thrombosis.
The symptoms of overdose are mainly an intensification of the pharmacological effects;
drowsiness, mental confusion, lethargy and muscle relaxation or paradoxical excitation. As with
other benzodiazepines, overdosage should not present a threat to life unless combined with other
CNS depressants including alcohol. More serious symptoms would be areflexia, hypotension,
cardiorespiratory depression, apnoea and, rarely, coma.
Treatment of midazolam overdosage is the same as that followed for overdosage with other
benzodiazepines. In most cases only observation of vital functions is required. In the
management of overdose special attention should be paid to the respiratory and cardiovascular
functions in intensive care. The effects of overdosage can be controlled with the benzodiazepine
antagonist flumazenil. Caution should be observed in the use of flumazenil in cases of mixed
drug overdosage and in patients with epilepsy treated with benzodiazepines.
Contact the Poisons Information Centre for advice on the management of an overdose.
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Midazolam is a derivative of the imidazobenzodiazepine group. The free base is a lipophilic
substance with low solubility in water. The basic nitrogen in position 2 of the
imidazobenzodiazepine ring system enables midazolam to form water-soluble salts with acids.
These produce a stable and well tolerated injection solution.
Pharmacotherapeutic Group: Central nervous system depressant.
Mechanism of Action: The pharmacological action of midazolam is characterized by rapid onset
and, because of rapid metabolic transformation, short duration. Because of its low toxicity,
midazolam has a wide therapeutic range.
Midazolam has a very rapid sedative and sleep-inducing effect of pronounced intensity. It also
exerts an anxiolytic, an anticonvulsant and a muscle-relaxant effect.
After i.m. or i.v. administration anterograde amnesia of short duration occurs (the patient does
not recall events that occurred during the peak of activity of the compound).
The effects of midazolam on the CNS are dependent on the dose administered, the route of
administration and the presence or absence of other premedications.
Absorption after i.m. injection: Absorption of midazolam from the muscle tissue is rapid and
complete. Maximum plasma concentrations are reached within 30 minutes. The absolute
bioavailability after i.m. injection is over 90%.
Absorption after rectal administration: After rectal administration midazolam is absorbed
quickly. Maximum plasma concentration is reached in about 30 minutes. The absolute
bioavailability is about 50%.
Absorption after intranasal administration: Midazolam is absorbed quickly. Mean peak plasma
concentrations are reached within 10.2 to 12.6 minutes. The bioavailability is between 55 and
Absorption after oral administration: Oral midazolam is absorbed rapidly from the
gastrointestinal tract and undergoes extensive first-pass hepatic metabolism. Peak plasma
concentrations are reached within 1 hour. Bioavailability is between 40 and 50%.
When midazolam is injected i.v., the plasma concentration-time curve shows one or two distinct
phases of distribution. The volume of distribution at steady state is 0.7 to 1.2 l/kg. 96 to 98% of
midazolam is bound to plasma proteins. The major fraction of plasma protein binding is due to
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albumin. There is a slow and insignificant passage of midazolam into the cerebrospinal fluid. In
humans, midazolam has been shown to cross the placenta slowly and to enter foetal circulation.
Small quantities of midazolam are found in human milk.
Midazolam is almost entirely eliminated by biotransformation. Less than 1% of the dose is
recovered in urine as the unchanged substance. Midazolam is hydroxylated by the cytochrome
P450 3A4 isozyme. α-hydroxymidazolam is the major urinary and plasma metabolite. 60-80% of
the dose is excreted in urine as glucuroconjugated α-hydroxymidazolam. Plasma concentrations
of α-hydroxymidazolam are 12% those of the parent compound. The fraction of the dose
extracted by the liver has been estimated to be 30 to 60%. The elimination half-life of the
metabolite is shorter than 1 hour. α-hydroxymidazolam is pharmacologically active, but
contributes only minimally (about 10%) to the effects of intravenous midazolam. There is no
evidence of a genetic polymorphism in the oxidative metabolism of midazolam (see
In healthy volunteers, the elimination half-life is between 1.5 to 2.5 hours. Plasma clearance is in
the range of 300 to 500 mL/min. When midazolam is given by i.v. infusion, its elimination
kinetics do not differ from those following bolus injection.
Children: The rate of rectal absorption in children is similar to that in adults. However, the
elimination half-life (t
) after i.v. and rectal administration is shorter in children 3 to 10 years as
immaturity and the clearance is reduced (see PRECAUTIONS).
and the clearance smaller as compared to those in healthy volunteers (see PRECAUTIONS).
similar to that in healthy volunteers.
heart failure compared with that in healthy subjects (see PRECAUTIONS).
Midazolam maleate was administered with diet in mice and rats for two years at dosages of 1, 9
and 80 mg/kg/day. In female mice in the highest dose group there was a marked increase in the
incidence of hepatic tumours. In high dose male rats there was a small but statistically significant
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increase in benign thyroid follicular cell tumours. Dosages of 9 mg/kg/day of midazolam maleate
do not increase the incidence of tumours. The pathogenesis of induction of these tumours is not
known. These tumours were found after chronic administration, whereas human use will
ordinarily be of single dose or of short duration. Midazolam did not have mutagenic activity in
Salmonella typhimurium (5 bacterial strains), Chinese hamster lung cells (V79), human
lymphocytes, or in the micronucleus test in mice.
A reproduction study in male and female rats did not show any impairment of fertility at dosages
up to 10 times the human IV dose of 0.35 mg/kg.
Composition of Midazolam Injection
to adjust tonicity
to produce the ‘hydrochloride’ of
midazolam and to adjust pH
pH Ph. Eur.
Water for Injections
Aqua ad Injectabilia
qs to 1mL
qs to 1mL
*1 All ingredients used in the formulation are of non-animal origin.
*2 Sodium Hydroxide is only needed if the pH is over adjusted with hydrochloride acid.
Do not dilute Midazolam ampoule solutions with macrodex 6% in dextrose.
Do not mix Midazolam ampoule solutions in alkaline injections. Midazolam precipitates in
5mg in 5mL, 5mg in 1mL, 15mg in 3mL and 50mg in 10mL: 36 months from date of
Midazolam Injection does not contain a preservative or bacteriostatic agent, hence, vials are for
single use only and any unused portion should be discarded.
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Store below 25
C. Protect from light. Use once only and discard any remaining portion.
Nature & Contents of Container
Midazolam Injection is presented in ampoules manufactured from medical grade, low density
polyethylene which conforms to the specification of the European Pharmacopoeia 3.1.4
"Polyethylene - Low Density for Containers for Preparations for Parenteral Use and Ophthalmic
Instructions for Use/Handling
Spill Procedures: Where possible, dam the spill. Cover with absorbent towels or pads or other
absorbent material. Place in closed containers for disposal. Wash affected area with copious
quantities of water. Dispose of in an approved facility for controlled incineration.
Controlled Drug C5.
5 mg in 1 mL and 5 mg in 5 mL - 10s.
15 mg in 3 mL and 50 mg in 10 mL - 5s.
NAME AND ADDRESS
Pfizer New Zealand Ltd
P O Box 3998
Auckland, New Zealand, 1140.
Toll Free Number: 0800 736 363.
DATE OF PREPARATION
26 October 2012.