Midazolam-Baxter

New Zealand - English - Medsafe (Medicines Safety Authority)

Active ingredient:
Midazolam 1 mg/mL
Available from:
Baxter Healthcare Ltd
INN (International Name):
Midazolam 1 mg/mL
Dosage:
1 mg/mL
Pharmaceutical form:
Solution for injection
Composition:
Active: Midazolam 1 mg/mL Excipient: Hydrochloric acid Hydrochloric acid (pH adjuster) Sodium chloride Sodium hydroxide Water for injection
Prescription type:
Class C5 Controlled Drug
Manufactured by:
Sun Pharmaceutical Industries Ltd
Therapeutic indications:
Premedication before induction of anaesthesia (i.m. or, especially in children, rectal, intranasal or oral administration).
Product summary:
Package - Contents - Shelf Life: Ampoule, glass, Clear type I glass, 5 mL - 5 dose units - 24 months from date of manufacture stored at or below 30°C protect from light - Ampoule, glass, Clear type I glass, 5 mL - 10 dose units - 24 months from date of manufacture stored at or below 30°C protect from light - Ampoule, glass, Clear type I glass, 5 mL - 25 dose units - 24 months from date of manufacture stored at or below 30°C protect from light
Authorization number:
TT50-9760
Authorization date:
2015-05-18

Read the complete document

NEW ZEALAND DATA SHEET

MIDAZOLAM‐BAXTER Data Sheet 4 March 2019

Page 1 of 15

Baxter Healthcare Ltd

MIDAZOLAM‐BAXTER

MIDAZOLAM‐BAXTER 1mg/mL solution for injection.

MIDAZOLAM‐BAXTER 5mg/mL solution for injection.

QUALITATIVE AND QUANTITATIVE COMPOSITION

MIDAZOLAM‐BAXTER 1mg/mL solution for injection:

Each 5mL ampoule contains 5mg of midazolam (as hydrochloride).

MIDAZOLAM‐BAXTER 5mg/mL solution for injection:

Each 1mL ampoule contains 5mg of midazolam (as hydrochloride).

Each 3mL ampoule contains 15mg of midazolam (as hydrochloride).

Each 10mL ampoule contains 50mg of midazolam (as hydrochloride).

For the full list of excipients, see section 6.1.

PHARMACEUTICAL FORM

Solution for injection.

A clear, colourless to pale yellow, sterile solution, free from particles, with a pH between 2.9 ‐ 3.7.

CLINICAL PARTICULARS

Therapeutic indications

Premedication before induction of anaesthesia (I.M. or, especially in children, rectal, intranasal or

oral administration).

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

infusion).

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).

Dose and method of administration

Method of administration

For intramuscular, intravenous, rectal, intranasal or oral administration (see instructions in section

4.2, ‘Dose’).

Dose

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 2.5mg in 10

seconds for induction of anaesthesia and 1mg in 30 seconds for conscious sedation). The medicine

takes effect about two minutes after the injection is started.

Premedication before an operation

Intramuscular administration

NEW ZEALAND DATA SHEET

MIDAZOLAM‐BAXTER Data Sheet 4 March 2019

Page 2 of 15

Baxter Healthcare Ltd

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.

Adults: 0.07 ‐ 0.10mg per kg bodyweight I.M. according to age and general condition of the patient.

Usual dosage about 5mg.

Children: proportionately higher doses are required than in adults in relation to bodyweight (0.15 ‐

0.20mg per kg bodyweight I.M.).

Elderly and debilitated patients: 0.025 ‐ 0.05mg/kg bodyweight I.M.

Rectal administration

Children: for preoperative sedation. Rectal administration of the ampoule solution by means of a

plastic applicator fixed on the end of a syringe, 0.35 ‐ 0.45mg/kg bodyweight 20 ‐ 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 10mL.

Intranasal administration

Children: 0.2mg/kg, 10 ‐ 15 minutes prior to anaesthesia.

Oral administration

Children: 0.5mg/kg, 15 ‐ 30 minutes prior to anaesthesia.

Conscious sedation

Intravenous conscious sedation

For conscious sedation in diagnostic or surgical interventions carried out under local anaesthesia.

Adults: the initial dose should not exceed 2.5mg I.V. 5 ‐ 10 minutes before the beginning of the

operation. Further doses of 1mg may be given as necessary. A total dose greater than 5mg 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 ‐ 1.5mg. Total

doses greater than 3.5mg are not usually necessary.

Intranasal conscious sedation

Children: 0.2mg/kg, 10 ‐ 15 minutes before the intervention.

Oral conscious sedation

Children: 0.2 ‐ 0.5mg/kg, 15 ‐ 30 minutes before the intervention.

Sedation in Intensive Care Units (ICU)

Intravenous sedation

For sedation in ICU, the dosage should be individualised and MIDAZOLAM‐BAXTER titrated to the

desired state of sedation according to the clinical need, physical status, age, concomitant

medication.

Adults

Loading dose: 0.03 ‐ 0.3mg/kg.

Maintenance dose: 0.03 ‐ 0.2mg/kg/hr. The dosage should be reduced or the loading dose should

even be omitted in hypovolemic, vaso‐constricted and hypothermic patients.

NEW ZEALAND DATA SHEET

MIDAZOLAM‐BAXTER Data Sheet 4 March 2019

Page 3 of 15

Baxter Healthcare Ltd

Induction and maintenance of anaesthesia

Intravenous injection

Adults

Induction: the dose is 10 ‐ 15mg I.V. in combination with analgesics. A sufficiently deep level of sleep

is generally achieved after 2 ‐ 3 minutes.

Maintenance: for maintenance of the desired level of unconsciousness, further small doses should

be injected I.V. The dose and the intervals between doses vary according to the individual patient's

reaction. Alternatively, MIDAZOLAM‐BAXTER can be administered by continuous infusion.

Intravenous continuous infusion

Adults: for intravenous anaesthesia combined with ketamine, 0.03 ‐ 0.1mg/kg/hr; narcotics, 0.03 ‐

0.3mg/kg/hr. High‐risk surgical patients, elderly and debilitated patients require lower dosages.

Intramuscular administration

Children: a combination of the sleep‐inducing and amnesia‐inducing MIDAZOLAM‐BAXTER with

ketamine (ataralgesia) is recommended. MIDAZOLAM‐BAXTER I.M. (0.15 ‐ 0.20mg per kg

bodyweight) in combination with 50 ‐ 100mg ketamine I.M. (4 ‐ 8mg per kg bodyweight). A

sufficiently deep level of sleep is generally achieved after 2 ‐ 3 minutes.

Rectal administration

Children: see ‘Premedication before an Operation’.

Special dosage instructions

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 analgesic.

For information on compatibility with infusion solutions, see section 6.6.

When administered orally, the bitter taste of midazolam may be masked by small quantities of apple

juice, sweetened fruit syrup or powdered soft drink.

Contraindications

MIDAZOLAM‐BAXTER should not be used in patients with Myasthenia gravis, or those with

hypersensitivity to benzodiazepines.

MIDAZOLAM‐BAXTER should not be administered to patients in shock or coma, or in acute alcoholic

intoxication with depression of vital signs.

Benzodiazepines are contraindicated in patients with acute narrow angle glaucoma.

Benzodiazepines may be used in patients with open angle glaucoma only if they are receiving

appropriate therapy. Measurements of intraocular pressure in patients without eye disease show a

moderate lowering following induction with midazolam; patients with glaucoma have not been

studied.

Special warnings and precautions for use

MIDAZOLAM‐BAXTER should be used only when age‐ and size‐appropriate resuscitation facilities are

available, as I.V. administration 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.

NEW ZEALAND DATA SHEET

MIDAZOLAM‐BAXTER Data Sheet 4 March 2019

Page 4 of 15

Baxter Healthcare Ltd

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 failure

paediatric patients with cardiovascular instability

These higher‐risk patients require lower dosages (see section 4.2) 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 drug

abuse.

Tolerance

Some loss of efficacy has been reported when midazolam has been used as long‐term sedation in

intensive care units (ICU).

Dependence

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.

It is also greater in patients with a medical history of alcohol and/or drug abuse.

Withdrawal symptoms

During prolonged treatment with midazolam in ICU, physical dependence may develop. Therefore,

abrupt termination of the treatment will be accompanied by withdrawal symptoms. The following

symptoms may occur: 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.

Concomitant use of alcohol/CNS depressants

The concomitant use of midazolam with alcohol and/or CNS depressants should be avoided. Such

concomitant use has the potential to increase the clinical effects of midazolam possibly including

severe sedation, clinically relevant respiratory and/or cardiovascular depression.

Medical history of alcohol or drug abuse

Midazolam should be avoided in patients with a medical history of alcohol or drug abuse.

Amnesia

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.

Discharging criteria

After receiving midazolam parenterally, patients should be discharged from hospital or consulting

room only if accompanied by an attendant. It is recommended that the patient is accompanied

when returning home after discharge.

NEW ZEALAND DATA SHEET

MIDAZOLAM‐BAXTER Data Sheet 4 March 2019

Page 5 of 15

Baxter Healthcare Ltd

"Paradoxical" reactions

Paradoxical reactions such as agitation, involuntary movements (including tonic/clonic convulsions

and muscle tremor), hyperactivity, hostility, rage reaction, aggressiveness, paroxysmal excitement

and assault, have been reported to occur with midazolam. These reactions may occur with higher

doses and/or when the injection is given rapidly. The rare incidence of susceptibility to such

reactions has been reported among children and at higher I.V. doses in the elderly. Should such

symptoms suggestive of a paradoxical reaction occur, the response to midazolam should be

evaluated before proceeding.

Altered elimination of midazolam

Elimination of midazolam may be delayed in patients receiving compounds that inhibit or induce

certain hepatic enzymes (particularly cytochrome P450 3A4) and the dose of midazolam may need

to be adjusted accordingly (see section 4.5).

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 section 4.5).

It is advisable to lower doses of intravenous midazolam when co‐administered with erythromycin

(see section 4.5).

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 section 4.5).

Elimination of midazolam may also be delayed, in patients with liver dysfunction, low cardiac output

and in neonates (see section 5.2, ‘Pharmacokinetics in special populations’).

Risks from concomitant use with opioids

Concomitant use of benzodiazepines, including MIDAZOLAM‐BAXTER, and opioids may result in

profound sedation, respiratory depression, coma, and death. Because of these risks, reserve

concomitant prescribing of benzodiazepines and opioids for use in patients for whom alternative

treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and

benzodiazepines increases the risk of drug‐related mortality compared to use of opioids alone. If a

decision is made to prescribe MIDAZOLAM‐BAXTER concomitantly with opioids, prescribe the

lowest effective dosages and minimum durations of concomitant use, and follow patients closely for

signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers

about the risks of respiratory depression and sedation when MIDAZOLAM‐BAXTER is used with

opioids (see section 4.5).

Other

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.

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.

NEW ZEALAND DATA SHEET

MIDAZOLAM‐BAXTER Data Sheet 4 March 2019

Page 6 of 15

Baxter Healthcare Ltd

The neonate also has reduced and/or immature organ function and is also vulnerable to profound

and/or prolonged respiratory effects of midazolam. Careful monitoring of respiratory rate and

oxygen saturation is required.

Paediatric population

Paediatric patients less than 6 months of age are particularly vulnerable to airway obstruction and

hypoventilation, therefore titration with small increments to clinical effect and careful respiratory

rate and oxygen saturation monitoring are essential (see ‘Pre‐term infants and neonates’ above).

Adverse haemodynamic events have been reported in paediatric patients with cardiovascular

instability; rapid intravenous administration should be avoided in this population.

Paediatric neurotoxicity

Published juvenile animal studies demonstrate that the administration of anaesthetic and sedative

agents that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in

the developing brain and result in long‐term cognitive defects when used for longer than 3 hours.

The clinical significance of these findings is not clear. However, based on the available data across

species, the window of vulnerability to these changes is believed to correlate with exposures in the

third trimester of gestation through the first several months of life, but may extend out to

approximately three years of age in humans.

Some published studies in children have observed several cognitive deficits after repeated or

prolonged exposures to anaesthetic agents early in life. These studies have substantial limitations,

and it is not clear if the observed effects are due to the anaesthetic/analgesic/sedation agent

administration or other factors such as the surgery or underlying illness.

Published animal studies of some anaesthetic/analgesic/sedation drugs have reported adverse

effects on brain development in early life and late pregnancy. The clinical significance of these

nonclinical finding is yet to be determined.

With inhalation or infusion of such drugs, exposure is longer than the period of inhalation or

infusion. Depending on the drug and patient characteristics, as well as dosage, the elimination

phase may be prolonged relative to the period of administration.

Anaesthetic and sedative agents are a necessary part of the care of children and pregnant women

needing surgery, other procedures or tests that cannot be delayed, and no specific medicines have

been shown to be safer than any other. Decisions regarding the timing of any elective procedures

requiring anaesthesia should take into consideration the benefits of the procedure weighed against

the potential risks (see also section 4.6).

Interaction with other medicines and other forms of interaction

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

CYP3A4 subfamily. Inhibitors (see section 4.4) and inducers of this isozyme may lead to interaction

with midazolam.

CYP3A4 inhibitors

Azole antifungals

Ketoconazole increased the plasma concentration of intravenous midazolam by 5‐fold while the

terminal half‐life increased by about 3‐fold. If parenteral midazolam is co‐administered with the

strong CYP3A inhibitor ketoconazole, it should be done in an intensive care unit (ICU) or similar

setting which ensures close clinical monitoring and appropriate medical management in case of

NEW ZEALAND DATA SHEET

MIDAZOLAM‐BAXTER Data Sheet 4 March 2019

Page 7 of 15

Baxter Healthcare Ltd

respiratory depression and/or prolonged sedation. Staggered dosing and dosage adjustment

should be considered, especially if more than a single I.V. dose of midazolam is administered.

Fluconazole and itraconazole both increased the plasma concentrations of intravenous

midazolam by 2 – 3‐folds associated with an increase in terminal half‐life by 2.4‐fold for

itraconazole and 1.5‐fold for fluconazole, respectively.

Posaconazole increased the plasma concentrations of I.V. midazolam by about 2‐fold.

Erythromycin

Co‐administration 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

(see section 4.4).

Cimetidine and ranitidine

Cimetidine increased the steady‐state plasma concentration of 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.

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

medicines can be given concomitantly and no dosage adjustment of midazolam is required.

HIV protease inhibitors

Saquinavir and other HIV protease inhibitors: 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. If parenteral midazolam is co‐administered with HIV

protease inhibitors, treatment setting should follow the description in the section above for

ketoconazole within azole antifungals (see section 4.4).

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.

Other interactions

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 with epilepsy (see section 4.4).

NEW ZEALAND DATA SHEET

MIDAZOLAM‐BAXTER Data Sheet 4 March 2019

Page 8 of 15

Baxter Healthcare Ltd

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 I.V. administration of midazolam decreases the minimum alveolar concentration (MAC) of

halothane required for general anaesthesia.

Opioids

The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression

because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines

interact at GABAA sites, and opioids interact primarily at mu receptors. When benzodiazepines and

opioids are combined, the potential for benzodiazepines to significantly worsen opioid‐related

respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and

opioids, and follow patients closely for respiratory depression and sedation.

Fertility, pregnancy and lactation

Pregnancy

Category C.

Benzodiazepines should be avoided during pregnancy unless there is no safer alternative.

Midazolam crosses the placenta and the administration of midazolam in the last weeks of pregnancy

or at high doses during labour have resulted in neonatal CNS depression and can be expected to

cause irregularities in the foetal heart rate, hypothermia, hypotonia, poor sucking and moderate

respiratory depression due to the pharmacological action of the product. 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. Midazolam is therefore not recommended for obstetric use.

Teratological studies with midazolam in a number of animal species have not shown association

between administration of the drug and disturbances of foetal development, nor has clinical

experience so far yielded any evidence of such an association. Midazolam should not be used in the

first three months of pregnancy.

Published animal studies of some anaesthetic/analgesic/sedation drugs have reported adverse

effects on brain development in early life and late pregnancy.

Published studies in pregnant and juvenile animals demonstrate that the use of

anaesthetic/analgesic and sedation drugs that block NMDA receptors and/or potentiate GABA

activity during the period of rapid brain growth or synaptogenesis may result in neuronal and

oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and

neurogenesis when used for longer than 3 hours. These studies included anaesthetic agents from a

variety of drug classes.

Risk summary statement

Anaesthetic and sedative agents are a necessary part of the care of children and pregnant women

needing surgery, other procedures or tests that cannot be delayed, and no specific medicines have

been shown to be safer than any other. Decisions regarding the timing of any elective procedures

requiring anaesthesia should take into consideration the benefits of the procedure weighed against

the potential risks.

NEW ZEALAND DATA SHEET

MIDAZOLAM‐BAXTER Data Sheet 4 March 2019

Page 9 of 15

Baxter Healthcare Ltd

Preclinical data

Published studies in pregnant primates demonstrate that the administration of anaesthetic and

sedative agents that block NMDA receptors and/or potentiate GABA activity during the period of

peak brain development increases neuronal apoptosis in the developing brain of the offspring when

used for longer than 3 hours. There are no data on pregnancy exposures in primates corresponding

to periods prior to the third trimester in humans (see also section 5.3).

Breastfeeding

There is evidence that midazolam is excreted in breast milk and its effects on the new born are not

known. Therefore midazolam is not recommended for use in nursing mothers.

Fertility

A reproduction study in male and female rats did not show any impairment of fertility at dosages up

to 10 times the human I.V. dose of 0.35mg/kg.

Effects on ability to drive and use machines

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.

Undesirable effects

Tabulated summary of adverse reactions

The following undesirable effects have been reported to occur when midazolam is injected.

Frequency categories are as follows:

Very common: ≥1/10;

Common: ≥1/100 to <1/10;

Uncommon: ≥1/1,000 to <1/100

Rare: ≥1/10,000 to <1/1,000

Very rare: <1/10,000

Not known: cannot be estimated from the available data.

Immune system disorders

Frequency not known

Hypersensitivity, angioedema, anaphylactic shock

Psychiatric disorders

Frequency not known

Confusional state, euphoric mood, hallucinations

Agitation*, hostility*, rage*, aggressiveness*, excitement*

Physical drug dependence and withdrawal syndrome

Abuse

Nervous system disorders

Frequency not known

Involuntary movements (including tonic/clonic movements

and muscle tremor)*, hyperactivity*

Sedation (prolonged and postoperative), alertness

decreased, somnolence, headache, dizziness, ataxia,

anterograde amnesia**, the duration of which is directly

related to the administered dose

Convulsions have been reported in premature infants and

neonates

Drug withdrawal convulsions

NEW ZEALAND DATA SHEET

MIDAZOLAM‐BAXTER Data Sheet 4 March 2019

Page 10 of 15

Baxter Healthcare Ltd

Cardiac disorders

Frequency not known

Cardiac arrest, bradycardia

Vascular disorders

Frequency not known

Hypotension, vasodilation, thrombophlebitis, thrombosis

Respiratory, thoracic and mediastinal disorders

Frequency not known

Respiratory depression, apnoea, respiratory arrest,

dyspnea, laryngospasm, hiccups

Gastrointestinal disorders

Frequency not known

Nausea, vomiting, constipation, dry mouth

Skin and subcutaneous tissue disorders

Frequency not known

Rash, urticaria, pruritis

General disorders and administration site conditions

Frequency not known

Fatigue, injection site erythema, injection site pain

Injury, poisoning and procedural complications

Frequency not known

Falls, fractures***

Social circumstances

Frequency not known

Assault*

*Such paradoxical drug reactions have been reported, particularly among children and the elderly

(see section 4.4)

**Anterograde amnesia may still be present at the end of the procedure and in few cases prolonged

amnesia has been reported (see section 4.4).

***There have been reports of falls and fractures in benzodiazepine users. The risk of falls and

fractures is increased in those taking concomitant sedatives (including alcoholic beverages) and in

the elderly.

Description of selected adverse reactions

Dependence

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 withdrawal convulsions (see

section 4.4). Cases of abuse have been reported.

Cardiorespiratory adverse events

Severe cardiorespiratory adverse events have occurred. 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 section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows

continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are

asked to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/

NEW ZEALAND DATA SHEET

MIDAZOLAM‐BAXTER Data Sheet 4 March 2019

Page 11 of 15

Baxter Healthcare Ltd

Overdose

Symptoms

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. Coma, if it occurs, usually lasts a few hours

but it may be more protracted and cyclical especially in elderly patients. Benzodiazepine respiratory

depressant effects are more serious in patients with respiratory disease. Benzodiazepines increase

the effects of other CNS depressants including alcohol.

Treatment

In most cases only observation of vital functions is required. Supportive measures should be

initiated as indicated by the patient’s clinical state. In the management of overdose special

attention should be paid to the respiratory and cardiovascular functions in intensive care.

If CNS depression is severe use of flumazenil should be considered. Flumazenil should only be

administered under closely monitored conditions as flumazenil has only a short half‐life

(approximately 1 hour) and patients will require monitoring after its effects have worn off. Extreme

caution should be observed in the use of flumazenil in the presence of drugs that reduce seizure

threshold e.g. tricyclic antidepressants.

For advice on the management of overdose please contact the National Poisons Centre on 0800

POISON (0800 764766).

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Hypnotics and sedatives (benzodiazepine derivatives), ATC code:

N05CD08.

Mechanism of action

Midazolam is a short‐acting central nervous system depressant which induces sedation, hypnosis,

amnesia and anaesthesia. Pharmacokinetic and pharmacodynamic data in chronic intravenous (I.V.)

usage are not available beyond 15 days.

Pharmacodynamic effects

The mechanism of action of the benzodiazepines is under continuous investigation. Benzodiazepines

appear to intensify the physiological inhibitory mechanisms mediated by gamma‐aminobutyric acid

(GABA), the most common inhibitory neurotransmitter in the brain.

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. Onset time of sedative effects

after intramuscular (IM) administration is 15 min, with peak sedation occurring 30 ‐ 60 min following

injection.

When used I.V. as a sedative for endoscopic or other short therapeutic or diagnostic procedures, the

end point of slurred speech can be attained within 2.8 ‐ 4.8 min, depending on the total dose

administered and whether or not preceded by narcotic premedication. The time to induction of

anaesthesia for surgical procedures is variable, occurring in approximately 1.5 min (0.3 ‐ 8 min) when

an opioid premedicant has been administered and in 2 ‐ 2.5 min without premedication or with a

sedative premedication. Approximately 2 h are required for full recovery from midazolam‐induced

NEW ZEALAND DATA SHEET

MIDAZOLAM‐BAXTER Data Sheet 4 March 2019

Page 12 of 15

Baxter Healthcare Ltd

anaesthesia; however duration of effect is dependent on the dose and other drugs used. Induction

of anaesthesia is unsuccessful in approximately 14% of patients with midazolam alone but in only

about 1% when given with an opioid.

At doses sufficient to induce sedation, I.V. midazolam decreases the sensitivity of the ventilatory

response to elevated carbon dioxide tension in normal subjects and in those with chronic obstructive

lung disease, who are at risk of hypoxia. Sedation with midazolam has no adverse effects on

pulmonary compliance and does not cause bronchoconstriction or significantly affect functional

residual capacity or residual volume.

Although midazolam may cause modest decreases in mean arterial pressure, baroreceptor response

is not affected and decreases in arterial pressure are accompanied by increases in heart rate. I.V.

midazolam at doses of 0.15 ‐ 0.2mg/kg did not have deleterious effects on cardiac haemodynamics.

I.V. administration of midazolam does not alter intracranial pressure unless the patient is intubated.

As with thiopentone, the intracranial pressure rises during intubation. Cerebral blood flow may be

reduced by up to 35%, which is of the same order as caused by equivalent doses of diazepam. The

effect on cerebral metabolism is not clearly established.

Midazolam reduces the intraocular pressure to the same degree as thiopentone and diazepam.

However, the increase in intraocular pressure after succinylcholine administration or endotracheal

intubation is not prevented by midazolam, thiopentone or diazepam.

Pharmacokinetic properties

Absorption

Absorption after I.M. injection: Absorption of midazolam from the muscle tissue is rapid and virtually

complete.

The mean absolute bioavailability of midazolam following I.M. administration is >90%. The mean

time of maximum midazolam plasma concentrations following I.M. dosing occurs within 45 min

post‐administration. Peak concentrations of midazolam as well as 1‐hydroxymethyl midazolam after

I.M. administration are about one‐half of those achieved after equivalent I.V. doses.

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% (range 40 – 65%).

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 57%.

Distribution

When midazolam is administered I.V. the plasma concentration‐time curve shows one or two

distinct phases of distribution. The volume of distribution of midazolam at steady state is 0.7 –

1.2L/kg. Midazolam is 97% plasma protein bound. The major fraction of plasma binding is due to

albumin. There is a slow and insignificant passage of midazolam into the cerebrospinal fluid.

Midazolam crosses the placenta and enters the foetal circulation. Small quantities of midazolam are

found in breast milk.

Metabolism

Midazolam is almost entirely eliminated by biotransformation. Midazolam is hydroxylated by the

cytochrome P450 3A4 isozyme. α‐hydroxymidazolam is the major urinary and plasma metabolite.

The plasma concentrations of α‐hydroxymidazolam are 12% of those of the parent compound. The

NEW ZEALAND DATA SHEET

MIDAZOLAM‐BAXTER Data Sheet 4 March 2019

Page 13 of 15

Baxter Healthcare Ltd

fraction of the dose extracted by the liver has been estimated to be 30 ‐ 60%. α‐hydroxymidazolam

is pharmacologically active but contributes only minimally (about 10%) to the effects of I.V.

midazolam. There is no evidence of a genetic polymorphism in the oxidative metabolism of

midazolam (see section 4.5).

Elimination

In healthy subjects the mean elimination half‐life of midazolam is between 1.5 ‐ 2.5h and the plasma

clearance is in the range of 300–5000mL/min. Midazolam is mainly excreted by renal route with 60–

80% of the administered dose of midazolam being excreted in urine as glucoconjugated α–

hydroxymidazolam. Less than 1% is recovered as unchanged drug. The elimination half‐life of this

metabolite is <1 h. When midazolam is given by I.V. infusion, its elimination kinetics do not differ

from those following bolus injection.

Compounds that inhibit or induce cytochrome P450 3A4 (CYP3A) may alter patients’ elimination of

midazolam, and the dose may need to be adjusted accordingly (see section 4.5).

Pharmacokinetics in special populations

Elderly

In adults over 60 years of age, the elimination half‐life of midazolam may be prolonged up to four

times.

Hepatic impairment

The elimination half‐life in cirrhotic patients may be longer and the clearance smaller when

compared to those in healthy volunteers (see section 4.4).

Renal impairment

The elimination half‐life in patients with chronic renal failure is similar to that reported in healthy

volunteers.

Critically ill

Midazolam elimination half‐life is prolonged in critically ill patients.

ardiac insufficiency

Midazolam elimination half‐life is prolonged in patients with congestive heart failure.

Obese

The elimination half‐life of midazolam is prolonged in obese patients. The clearance is not altered.

In patient populations with prolonged elimination half‐life, midazolam infusion at an unchanged rate

resulted in higher plasma levels at steady state. Consequently, the infusion rate should be reduced

once a satisfactory clinical response has been obtained.

Paediatric population

Children: The rate of rectal absorption in children is similar to that in adults. However the

elimination half‐life (t½) after I.V. and rectal administration is shorter in children 3 ‐ 10 years when

compared to that in adults. The difference is consistent with an increased metabolic clearance in

children.

Neonates: In neonates the elimination half‐life is on average 6 ‐ 12 hours, probably due to liver

immaturity and the clearance is reduced (see section 4.4).

NEW ZEALAND DATA SHEET

MIDAZOLAM‐BAXTER Data Sheet 4 March 2019

Page 14 of 15

Baxter Healthcare Ltd

Preclinical safety data

Animal toxicology and/or pharmacology

Published studies in animals demonstrate that the use of anaesthetic and sedative agents during the

period of rapid brain growth or synaptogenesis results in widespread neuronal and oligodendrocyte

cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on

comparisons across species, the window of vulnerability to these changes is believed to correlate

with exposures in the third trimester through the first several months of life, but may extend out to

approximately 3 years of age in humans.

In primates, exposure to 3 hours of an anaesthetic regimen that produced a light surgical plane of

anaesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer

increased neuronal cell loss. Data in rodents and in primates suggest that the neuronal and

oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory.

In a published study conducted on rhesus monkeys, administration of an anaesthetic dose of

ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of

the foetus. In other published studies, administration of either isoflurane or propofol for 5 hours on

Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing

brain of the offspring of rhesus macaques. With respect to brain development, this time period

corresponds to the third trimester of gestation in the human. The clinical significance of these

findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with

long‐term cognitive deficits. Healthcare providers should balance the benefits of appropriate

anaesthesia in pregnant women, neonates and young children who require procedures with the

potential risks suggested by the nonclinical data.

PHARMACEUTICAL PARTICULARS

List of excipients

Water for injections.

Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in

section 6.6.

Shelf life

24 months.

MIDAZOLAM‐BAXTER does not contain any anti‐microbial agent. MIDAZOLAM‐BAXTER ampoules

are for single use in one patient only. Discard any unused solution.

Preparations for infusion: To reduce microbiological hazard, it is recommended that the infusion

commence as soon as possible after preparation. Prepared infusion solution should be used within

24 hours when stored under refrigeration (2 – 8 °C) or within 6 hours if stored at room temperature.

The solution should be visually inspected prior to use. Only clear solutions without particles should

be used.

Special precautions for storage

Store below 30°C. Protect from light.

NEW ZEALAND DATA SHEET

MIDAZOLAM‐BAXTER Data Sheet 4 March 2019

Page 15 of 15

Baxter Healthcare Ltd

Nature and contents of container

MIDAZOLAM‐BAXTER 1mg/mL solution for injection:

MIDAZOLAM‐BAXTER 5mg/5mL is supplied in 5mL glass ampoules, in packs of 5, 10 or 25 ampoules.

MIDAZOLAM‐BAXTER 5mg/mL solution for injection:

MIDAZOLAM‐BAXTER 5mg/1mL is supplied in 1mL glass ampoules, in packs of 5, 10 or 25 ampoules.

MIDAZOLAM‐BAXTER 15mg/3mL is supplied in 3mL glass ampoules, in packs of 5, 10 or 25 ampoules.

MIDAZOLAM‐BAXTER 50mg/10mL is supplied in 10mL glass ampoules, in packs of 5 or 10 ampoules.

Special precautions for disposal and other handling

MIDAZOLAM‐BAXTER may be mixed in the same syringe with frequently used premedicants:

morphine sulphate, pethidine, atropine sulphate or scopolamine.

MIDAZOLAM‐BAXTER may be diluted to facilitate slow injection.

MIDAZOLAM‐BAXTER can be diluted with sodium chloride 0.9%, dextrose 5% and 10%, levulose 5%,

Ringer's solution and Hartmann's solution in a mixing ratio of 15mg midazolam per 100 ‐ 1000mL

infusion solution.

For single use only. Discard any unused solution.

MEDICINE SCHEDULE

Class C5 Controlled Drug.

SPONSOR

MIDAZOLAM‐BAXTER is distributed in New Zealand by:

Baxter Healthcare Ltd

33 Vestey Drive

Mt Wellington

Auckland 1060.

Baxter Healthcare Ltd

PO Box 14 062

Panmure

Auckland 1741

Phone (09) 574 2400.

DATE OF FIRST APPROVAL

17 March 2016

10. DATE OF REVISION OF THE TEXT

4 March 2019.

SUMMARY TABLE OF CHANGES

Section changed

Summary of new information

Trade name changed to MIDAZOLAM‐BAXTER

Paediatric population, Paediatric neurotoxicity: New warnings on the use of

general anaesthetic agents and sedative medicines in pregnant women and young

children added.

Pregnancy: New warnings on the use of general anaesthetic agents and sedative

medicines in pregnant women and young children added.

Please refer to the Medsafe website (www.medsafe.govt.nz) for most recent data sheet.

Similar products

Search alerts related to this product

View documents history

Share this information