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MIDAZOLAM 5 MG/ML SOLUTION FOR INJECTION

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OUTSIDE SPREAD

PATIENT INFORMATION LEAFLET

MIDAZOLAM 2 mg/ml or 5 mg/ml Solution for Injection
(Midazolam as Midazolam Hydrochloride)
Please read all of this leaflet carefully before taking your medicine.
• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor, nurse or pharmacist.
• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their
symptoms are the same as yours.
• If any of the side effects become serious, or if you notice any side effects not listed in this leaflet, please tell
your doctor or pharmacist.
What is MIDAZOLAM and what is it for
Before you are given MIDAZOLAM
How MIDAZOLAM is used
Possible side effects
Storing MIDAZOLAM
Further information

1. What is MIDAZOLAM and what
is it used for?
What is MIDAZOLAM?
MIDAZOLAM belongs to a group of medicines known as
benzodiazepines. It is a short-acting medicine that is used
to induce sedation (a very relaxed state of calm,
drowsiness or sleep) and relieves anxiety and muscle
tension.
What is MIDAZOLAM used for?
This medicine is used for:
• Conscious sedation (an awake but very relaxed state of
calm or drowsiness during a medical test or procedure)
in adults and children.
• Sedation of adults and children, in intensive care units.
• Anaesthesia in adults, used alone or with other
medicines.
• Premedication (medicine used to cause relaxation, calm
and drowsiness before an anaesthetic) in adults and
children.

2. Before you are given MIDAZOLAM

Special Precautions
Your doctor may take special precautions when giving you
MIDAZOLAM if any of the points listed below applies to
you:
Children and babies
If your child is going to be given this medicine:
• It is particularly important to tell your doctor or nurse if
your child has cardiovascular disease (heart problems).
Your child will be carefully monitored and the dose will
be adjusted specially.
• Children must be carefully monitored. For infants and
babies under 6 months this will include monitoring of
breathing and oxygen levels.
Adults
Before MIDAZOLAM is given, let your doctor or nurse
know if:
• You are over 60 years of age.
• You have a long term illness (such as breathing problems
or kidney, liver or heart problems).
• You are debilitated (have an illness that makes you feel
very weak, run down and short of energy).
• You have myasthenia gravis (a neuromuscular disease
causing muscle weakness).
• You regularly drink large amounts of alcohol or you have
had problems with alcohol use in the past.
• You regularly take recreational drugs or you have had
problems with drug use in the past.
• You are pregnant or think you may be pregnant (see
‘Pregnancy and breast-feeding’).
If any of the above applies to you talk to your doctor, nurse
or pharmacist.

If any of the above applies to you, do not use this
medicine and talk to your doctor, nurse or pharmacist.

INFORMATION FOR THE HEALTHCARE PROFESSIONAL
(Please detach prior to giving the leaflet to the patient)

MIDAZOLAM 2 mg/ml or 5 mg/ml Solution for Injection
(Midazolam as Midazolam Hydrochloride)
1. NAME OF THE MEDICINAL PRODUCT
Midazolam 2 mg/ml Solution for Injection.
Midazolam 5 mg/ml Solution for Injection.
2. QUALITATIVE AND QUANTITATIVE
COMPOSITION
1 ml of Midazolam solution for injection contains 2 mg midazolam as
midazolam hydrochloride.
1 ml of Midazolam solution for injection contains 5 mg midazolam as
midazolam hydrochloride.
Also contains 8 mg of sodium chloride in each ml of Midazolam solution for
injection.
For a full list of excipients, see section 6.1.

Conscious
sedation

CONSCIOUS SEDATION DOSAGE
For conscious sedation prior to diagnostic or surgical intervention,
midazolam is administered i.v. The dose must be individualised and titrated,
and should not be administered by rapid or single bolus injection. The onset
of sedation may vary individually depending on the physical status of the
patient and the detailed circumstances of dosing (e.g. speed of
administration, amount of dose). If necessary, subsequent doses may be
administered according to the individual need. The onset of action is about
2 minutes after the injection. Maximum effect is obtained in about
5 to 10 minutes.
Adults
The i.v. injection of midazolam should be given slowly at a rate of
approximately 1 mg in 30 seconds.
In adults below the age of 60 the initial dose is 2 to 2.5 mg given 5 to10
minutes before the beginning of the procedure. Further doses of 1mg may be
given as necessary. Mean total doses have been found to range from 3.5 to
7.5 mg. A total dose greater than 5 mg is usually not necessary.
In adults over 60 years of age, debilitated or chronically ill patients, the initial
dose must be reduced to 0.5-1.0 mg and given 5-10 minutes before the
beginning of the procedure. Further doses of 0.5 to 1 mg may be given as
necessary. Since in these patients the peak effect may be reached less rapidly,
additional midazolam should be titrated very slowly and carefully. A total
dose greater than 3.5 mg is usually not necessary.
Children
I.V. administration: midazolam should be titrated slowly to the desired clinical
effect. The initial dose of midazolam should be administered over 2 to 3
minutes. One must wait an additional 2 to 5 minutes to fully evaluate the
sedative effect before initiating a procedure or repeating a dose. If further
sedation is necessary, continue to titrate with small increments until the
appropriate level of sedation is achieved. Infants and young children less than
5 years of age may require substantially higher doses (mg/kg) than older
children and adolescents.

If any of the above applies to you talk to your doctor, nurse
or pharmacist.
Operations
If you are going to have an inhaled anaesthetic (one that you
breathe in) for an operation or for dental treatment, it is
important to tell your doctor or dentist that you have been
given MIDAZOLAM.
Drinking alcohol
Do not drink alcohol if you have been given MIDAZOLAM.
This is because alcohol can increase the sedative effect of
MIDAZOLAM and may cause problems with your breathing.
Pregnancy and breast feeding
Talk to your doctor if you are pregnant, or think you are
pregnant.Your doctor will decide if this medicine is suitable
for you.
Do not breast-feed for 24 hours after being given
MIDAZOLAM. This is because MIDAZOLAM may pass into
your breast milk.
Driving and using machines
• Do not drive or use machinery until you are completely
recovered.Your doctor should advise you when you can
start these again.

Adults <60y

i.v.
Initial dose: 2 - 2.5mg
Titration doses: 1mg
Total dose: 3.5 - 7.5mg

Adults >60y/ debilitated
or chronically ill
i.v.
Initial dose: 0.5 - 1mg
Titration doses: 0.5 -1mg
Total dose: <3.5mg

Children

i.v. in patients 6 months - 5 years
Initial dose: 0.05 - 0.1mg/kg
Total dose: <6mg

i.m .
0.07 - 0.1mg/kg

i.v.
Initial dose: 0.5mg

• Paediatric patients 6 to 12 years of age: initial dose 0.025 to 0.05 mg/kg.
A total dose of up to 0.4 mg/kg to a maximum of 10mg may be necessary.
Prolonged sedation and risk of hypoventilation may be associated with the
higher doses.

Rectal administration: the total dose of midazolam usually ranges from 0.3 to
0.5 mg/kg. Rectal administration of the ampoule solution is performed by
means of a plastic applicator fixed on the end of the syringe. If the volume to
be administered is too small, water may be added up to a total volume of
10 ml. Total dose should be administered at once and repeated rectal
administration avoided.
The use in children less than 6 months of age is not recommended, as
available data in this population are limited.

Slow uptitration as needed

i.m. 1-15 years
0.08 - 0.2mg/kg

i.m .
0.025 - 0.05mg/kg
Anaesthesia
induction

Sedative
component
in combined
anaesthesia
Sedation
in ICU

i.v.
0.15 - 0.2mg/kg
(0.3 - 0.35
without premedication)

i.v.

intermittent doses of
0.03 - 0.1mg/kg or continuous
infusion of 0.03 - 0.1mg/kg/h

Adults
For preoperative sedation and to impair memory of preoperative events, the
recommended dose for adults of ASA Physical Status I and II and below 60
years is 1-2 mg i.v. repeated as needed, or 0.07 to 0.1 mg/kg administered
i.m.

i.v.
0.05 - 0.15mg/kg
(0.15 - 0.3
without premedication)

i.v.

lower doses than
recommended
for adults <60 years

i.v.
Loading dose: 0.03 - 0.3mg/kg in increments of 1 - 2.5mg
Maintenance dose: 0.03 - 0.2mg/kg/h

ANAESTHESIA DOSAGE
PREMEDICATION
Premedication with midazolam given shortly before a procedure produces
sedation (induction of sleepiness or drowsiness and relief of apprehension)
and preoperative impairment of memory. Midazolam can also be
administered in combination with anticholinergics. For this indication
midazolam should be administered i.v. or i.m., deep into a large muscle mass
20 to 60 minutes before induction of anaesthesia, or preferably via the rectal
route in children (see below). Close and continuous monitoring of the
patients after administration of premedication is mandatory as
interindividual sensitivity varies and symptoms of overdose may occur.

The dose must be reduced and individualised when midazolam is
administered to adults over 60 years of age, debilitated or chronically ill
patients. The recommended initial i.v. dose is 0.5 mg and should be slowly
uptitrated as needed. A dose of 0.025 to 0.05 mg/kg administered i.m. is
recommended.
In case of concomitant administration of narcotics the midazolam dose
should be reduced. The usual dose is 2 to 3 mg.
Paediatric Patients
Neonates and children up to 6 months of age:
The use in children less than 6 months of age is not recommended as
available data are limited.

i.v. in neonates <32 weeks
gestational age
0.03mg/kg/h
i.v. in neonates >32 weeks and
children up to 6 months
0.06mg/kg/h
i.v. in patients >6 months of age
Loading dose: 0.05 - 0.2mg/kg
Maintenance dose: 0.06 - 0.12mg/kg/h

Children over 6 months of age
Rectal administration: The total dose of midazolam, usually ranging from 0.3
to 0.5 mg/kg should be administered 15 to 30 minutes before induction of
anaesthesia. Rectal administration of the ampoule solution is performed by
means of a plastic applicator fixed on the end of the syringe. If the volume
to be administered is too small, water may be added up to a total volume
of 10 ml.
I.M. administration: As i.m. injection is painful, this route should only be used
in exceptional cases. Rectal administration should be preferred. However, a
dose range from 0.08 to 0.2 mg/kg of midazolam administered i.m. has been
shown to be effective and safe. In children between ages 1 and 15 years,
proportionally higher doses are required than in adults in relation to
body-weight.
In children less than 15 kg of body weight, midazolam solutions with
concentrations higher than 1 mg/ml are not recommended. Higher
concentrations should be diluted to 1 mg/ml.
INDUCTION
Adults
If midazolam is used for induction of anaesthesia before other anaesthetic
agents have been administered, the individual response is variable. The dose
should be titrated to the desired effect according to the patient's age and
clinical status. When midazolam is used before or in combination with other
i.v. or inhalation agents for induction of anaesthesia, the initial dose of each
agent should be significantly reduced, at times to as low as 25% of the usual
initial dose of the individual agents.

If you think you have been given more
MIDAZOLAM than you should:
Your medicine will be given to you by a doctor or nurse. If
you are accidentally given too much MIDAZOLAM you
may:
• Feel drowsy.
• Lose your co-ordination (ataxia) and reflexes.
• Have problems with your speech (dysarthria).
• Have involuntary eye movements (nystagmus).
• Develop low blood pressure (hypotension).
• Stop breathing (apnoea) and suffer cardiorespiratory
depression (slowed or stopped breathing and heart beat)
and coma.

Important:
MIDAZOLAM should be given only by experienced
healthcare professionals (doctor or nurse). It should be given
in a place (hospital, clinic or surgery) equipped to monitor
and support the patient’s breathing, heart and circulation
(cardiovascular function) and recognise the signs of and
manage the expected side effects of anaesthesia.

Stopping MIDAZOLAM
If you receive long term treatment with MIDAZOLAM (are
given the medicine for a long time) you may:
• Become tolerant to MIDAZOLAM. The medicine
becomes less effective and does not work as well for you.
• Become dependent upon this medicine and get
withdrawal symptoms (see below).

Adults:
Your doctor will decide on a suitable dose for you. The dose
you are given will depend on why you are being treated and
the type of sedation needed.Your weight, age, your state of
health, how you respond to MIDAZOLAM and whether
other medicines are needed at the same time will also
influence the dose that you are given.

Your doctor will reduce your dose gradually to avoid these
effects happening to you.

If you need strong painkillers, you will be given these first and
then be given MIDAZOLAM. The dose will be adjusted
specially for you.
MIDAZOLAM may be given to you in one of four
different ways:
• by slow injection into a vein (intravenous injection)
• through a tube into one of your veins (intravenous
infusion)
• by injection into a muscle (intramuscular injection)
• into your back passage (rectum).
You should always be taken home by a responsible adult after
your treatment.
Children & Babies:
• In infants and babies under 6 months of age MIDAZOLAM
is only recommended for sedation in intensive care units.
The dose will be given gradually into a vein.
• Children 12 years and under will usually be given
MIDAZOLAM into a vein. When MIDAZOLAM is used for
premedication (to cause relaxation, calm and drowsiness
before an anaesthetic) it may be given into the back
passage (rectum).

• Paediatric patients 6 months to 5 years of age: initial dose 0.05 to 0.1
mg/kg. A total dose up to 0.6 mg/kg may be necessary to reach the desired
endpoint, but the total dose should not exceed 6 mg. Prolonged sedation
and risk of hypoventilation may be associated with the higher doses.

In children less than 15 kg of body weight, midazolam solutions with
concentrations higher than 1mg/ml are not recommended. Higher
concentrations should be diluted to 1 mg/ml.

rectal >6 months
0.3 - 0.5mg/kg

3. How you will be given MIDAZOLAM

• In premedicated adults below the age of 60 years, an i.v. dose of 0.15 to
0.2 mg/kg will usually suffice.

rectal >6 months 0.3 - 0.5mg/kg

Anaesthesia
premedication i.v.
1 - 2mg repeated

Warnings about the ingredients:
MIDAZOLAM is essentially ‘sodium free’ as it contains less
than 1 mmol sodium (23 mg) per ampoule (small glass bottle).

The desired level of anaesthesia is reached by stepwise titration. The i.v.
induction dose of midazolam should be given slowly in increments. Each
increment of not more than 5 mg should be injected over 20 to 30 seconds
allowing 2 minutes between successive increments.

I.M. administration: the doses used range between 0.05 and 0.15 mg/kg. A
total dose greater than 10.0 mg is usually not necessary. This route should
only be used in exceptional cases. Rectal administration should be preferred
as i.m. injection is painful.

i.m. 1-15 years 0.05 - 0.15mg/kg

• MIDAZOLAM may make you sleepy, forgetful or affect your
concentration and co-ordination. This may affect your
performance at skilled tasks such as driving or using
machines.
• You should always be taken home by a responsible adult
after your treatment.

• Paediatric patients less than 6 months of age: paediatric patients less than
6 months of age are particularly vulnerable to airway obstruction and
hypoventilation. For this reason, the use in conscious sedation in children
less than 6 months of age is not recommended.

i.v. in patients 6-12 years
Initial dose: 0.025 - 0.05mg/kg
Total dose: <10mg

In children
• CONSCIOUS SEDATION before and during diagnostic or therapeutic
procedures with or without local anaesthesia
• ANAESTHESIA
• Premedication before induction of anaesthesia
• SEDATION IN INTENSIVE CARE UNITS
4.2 Posology and method of administration
STANDARD DOSAGE
Midazolam is a potent sedative agent that requires titration and slow
administration. Titration is strongly recommended to safely obtain the
desired level of sedation according to the clinical need, physical status, age
and concomitant medication. In adults over 60 years, debilitated or
chronically ill patients and paediatric patients, dose should be determined
with caution and risk factors related to each patient should be taken into
account. Standard dosages are provided in the table below. Additional details
are provided in the text following the table.

In particular, tell your doctor or nurse if you are taking any of
the following medicines:
• tranquilisers (for anxiety or to help you sleep)
• hypnotics (medicines to make you sleep)
• sedatives (to make you feel calm or sleepy)
• antidepressants (medicines for depression)
• narcotic analgesics (very strong pain killers)
• antihistamines (used to treat allergies)
• medicines to treat fungal infections (ketoconazole,
voriconazole, fluconazole, itraconazole, posaconazole)
• macrolide antibiotics (such as erythromycin or
clarithromycin)
• diltiazem (used to treat high blood pressure)
• medicines for HIV called protease inhibitors (such as
saquinavir)
• atorvastatin (used to treat high cholesterol)
• rifampicin (used to treat mycobacterial infections such as
tuberculosis)
• the herbal medicine St John’s Wort.

• Paediatric patients 12 to 16 years of age: should be dosed as adults.

Indication

3. PHARMACEUTICAL FORM
Solution for injection.
A clear colourless solution.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Midazolam is a short-acting sleep-inducing drug that is indicated:
In adults
• CONSCIOUS SEDATION before and during diagnostic or therapeutic
procedures with or without local anaesthesia
• ANAESTHESIA
• Premedication before induction of anaesthesia
• Induction of anaesthesia
• As a sedative component in combined anaesthesia
• SEDATION IN INTENSIVE CARE UNITS

Taking other medicines
Always tell your doctor if you are taking any other medicines,
including medicines obtained without a prescription and
herbal medicines because taking some medicines together
can be harmful. Remember that the doctor at the hospital
may not have been informed if you have recently begun a
course of treatment for another illness.

• In non-premedicated adults below the age of 60 the dose may be higher
(0.3 to 0.35 mg/kg i.v.). If needed to complete induction, increments of
approximately 25% of the patient's initial dose may be used. Induction may
instead be completed with inhalational anaesthetics. In resistant cases, a
total dose of up to 0.6 mg/kg may be used for induction, but such larger
doses may prolong recovery.
• In premedicated adults over 60 years of age, debilitated or chronically ill
patients, the dose should significantly be reduced, eg., down to
0.05 - 0.15 mg/kg administered i.v. over 20 -30 seconds and allowing
2 minutes for effect.
• Non-premedicated adults over 60 years of age usually require more
midazolam for induction; an initial dose of 0.15 to 0.3 mg/kg is
recommended. Non-premedicated patients with severe systemic disease or
other debilitation usually require less midazolam for induction. An initial
dose of 0.15 to 0.25 mg/kg will usually suffice.
SEDATIVE COMPONENT IN COMBINED ANAESTHESIA
Adults
Midazolam can be given as a sedative component in combined anaesthesia by
either further intermittent small i.v. doses (range between 0.03 and 0.1
mg/kg) or continuous infusion of i.v. midazolam (range between 0.03 and
0.1 mg/kg/h) typically in combination with analgesics. The dose and the
intervals between doses vary according to the patient's individual reaction.
In adults over 60 years of age, debilitated or chronically ill patients, lower
maintenance doses will be required.
SEDATION IN INTENSIVE CARE UNITS
The desired level of sedation is reached by stepwise titration of midazolam
followed by either continuous infusion or intermittent bolus, according to
the clinical need, physical status, age and concomitant medication (see
section 4.5).
Adults
I.V. loading dose: 0.03 to 0.3 mg/kg should be given slowly in increments. Each
increment of 1 to 2.5 mg should be injected over 20 to 30 seconds allowing
2 minutes between successive increments. In hypovolaemic, vasoconstricted,
or hypothermic patients the loading dose should be reduced or omitted.
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.
I.V. maintenance dose: doses can range from 0.03 to 0.2 mg/kg/h. In
hypovolaemic, vasoconstricted, or hypothermic patients the maintenance
dose should be reduced. The level of sedation should be assessed regularly.
With long-term sedation, tolerance may develop and the dose may have to
be increased.
Neonates and children up to 6 months of age
Midazolam should be given as a continuous i.v. infusion, starting at 0.03
mg/kg/h (0.5 µg/kg/min) in neonates with a gestational age <32 weeks, or
0.06 mg/kg/h (1 µg/kg/min) in neonates with a gestational age >32 weeks and
children up to 6 months.
Intravenous loading doses is not recommended in premature infants,
neonates and children up to 6 months, rather the infusion may be run more
rapidly for the first several hours to establish therapeutic plasma levels. The
rate of infusion should be carefully and frequently reassessed, particularly
after the first 24 hours so as to administer the lowest possible effective dose
and reduce the potential for drug accumulation.
Careful monitoring of respiratory rate and oxygen saturation is required.
Children over 6 months of age
In intubated and ventilated paediatric patients, a loading dose of 0.05 to 0.2
mg/kg i.v. should be administered slowly over at least 2 to 3 minutes to
establish the desired clinical effect. Midazolam should not be administered as
a rapid intravenous dose. The loading dose is followed by a continuous i.v.
infusion at 0.06 to 0.12 mg/kg/h (1 to 2 µg/kg/min). The rate of infusion can
be increased or decreased (generally by 25% of the initial or subsequent
infusion rate) as required, or supplemental i.v. doses of midazolam can be
administered to increase or maintain the desired effect.
When initiating an infusion with midazolam in haemodynamically
compromised patients, the usual loading dose should be titrated in small
increments and the patient monitored for haemodynamic instability, e.g.,
hypotension. These patients are also vulnerable to the respiratory depressant
effects of midazolam and require careful monitoring of respiratory rate and
oxygen saturation.
In premature infants, neonates and children less than 15 kg of body weight,
midazolam solutions with concentrations higher than 1mg/ml are not
recommended. Higher concentrations should be diluted to 1mg/ml.

Withdrawal symptoms:
Benzodiazepine medicines, like MIDAZOLAM, may make
you dependent if used for a long time (for instance in
intensive care). This means that if you stop treatment
suddenly, or lower the dose too quickly, you may get
withdrawal symptoms. The symptoms can include:
• headache
• muscle pain
• feeling very worried (anxious), tense, restless, confused
or bad-tempered (irritable)
• problems with sleeping (insomnia)
• mood changes
• hallucinations (seeing and possibly hearing things that are
not there)
• fits (convulsions).
If you have any further questions on the use of this product,
ask your doctor or pharmacist.

4. Possible side effects
Like all medicines MIDAZOLAM Injection can cause side
effects, although not everybody gets them.
Seek immediate medical help if you have any of the
following symptoms.They can be life-threatening
and you may need urgent medical treatment:

right

• Anaphylactic shock (a life-threatening allergic reaction).
Signs may include a sudden rash, itching or lumpy rash
(hives) and swelling of the face, lips, tongue or other parts
of the body.You may also have shortness of breath,
wheezing or trouble breathing.
• Heart attack (cardiac arrest). Signs may include chest pain
which may spread to your neck and shoulders and down
your left arm.
• Breathing problems or complications (sometimes causing
the breathing to stop).
• Choking and sudden blockage of the airway
(laryngospasm).
Life-threatening side effects are more likely to occur in
adults over 60 years of age and those who already have
breathing difficulties or heart problems, particularly if the
injection is given too fast or at a high dose.
For a list of the side effects associated with the
withdrawal of midazolam, please see section 3 of
this leaflet.
Other possible side effects:

Mental and Nervous system problems:
• confusion
• euphoria (an excessive feeling of happiness or
excitement)
• hallucinations (seeing and possibly hearing things that are
not really there)
• drowsiness and prolonged sedation
• reduced alertness
• headache
• dizziness
• difficulty co-ordinating muscles
• fits (convulsions) in premature infants and new-born
babies
• temporary memory loss. How long this lasts depends on
how much MIDAZOLAM you were given.You may
experience this after your treatment. In isolated cases
this has been prolonged (lasted for a long time).

There is no specific data in patients with severe renal impairment (creatinine
clearance below 30 ml/min) receiving midazolam for induction of anaesthesia.

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 high
doses and/or when the injection is given rapidly. The highest incidence to
such reactions has been reported among children and the elderly.

Drugs that inhibit CYP3A4

Midazolam is essentially ‘sodium free’ as it contains less than 1 mmol sodium
(23 mg) per ampoule.
4.3 Contraindications
Use of this drug in patients with known hypersensitivity to benzodiazepines
or to any excipient of the product.

Midazolam elimination may also be delayed in patients with liver dysfunction,
low cardiac output and in neonates (see section 5.2).
Preterm infants and neonates
Due to an increased risk of apnoea, extreme caution is advised when
sedating preterm and former preterm non intubated patients. Careful
monitoring of respiratory rate and oxygen saturation is required.

Midazolam is not known to change the pharmacokinetics of other drugs.

Azole antifungals
• Ketoconazole increased the plasma concentrations 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 CYP3A4
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 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. The
same recommendation may apply also for other azole antifungals (see
further), since increased sedative effects of IV midazolam, although lesser,
are reported.
• Voriconazole increased the exposure of intravenous midazolam by 3-fold
whereas its elimination half-life increased by about 3-fold.

Rapid injection should be avoided in the neonatal population.

Use of this drug for conscious sedation in patients with severe respiratory
failure or acute respiratory depression.
4.4 Special warnings and precautions for use
Midazolam should be administered only by experienced physicians in a
setting fully equipped for the monitoring and support of respiratory and
cardiovascular function and by persons specifically trained in the recognition
and management of expected adverse events including respiratory and
cardiac resuscitation.
Severe cardiorespiratory adverse events have been reported. These have
included respiratory depression, apnoea, respiratory arrest and/or cardiac
arrest. Such life-threatening incidents are more likely to occur when the
injection is given too rapidly or when a high dosage is administered (see
section 4.8).
Special caution is required for the indication of conscious sedation in
patients with impaired respiratory function.
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.
When midazolam is used for premedication, adequate observation of the
patient after administration is mandatory as interindividual sensitivity varies
and symptoms of overdose may occur.
Special caution should be exercised when administering midazolam to
high-risk patients:
• adults over 60 years of age
• chronically ill or debilitated patients, e.g.
• patients with chronic respiratory insufficiency
• patients with chronic renal failure, impaired hepatic function or with
impaired cardiac function
• paediatric patients specially those with cardiovascular instability.
These high-risk patients require lower dosages (see section 4.2) and should
be continuously monitored for early signs of alterations of vital functions.
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.
Tolerance
Some loss of efficacy has been reported when midazolam was 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 on midazolam 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 (see section
4.8).
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 to decrease doses gradually.

• Fluconazole and itraconazole both increased the plasma concentrations of
intravenous midazolam by 2 – 3-fold associated with an increase in
terminal half-life by 2.4-fold for itraconazole and 1.5-fold for fluconazole,
respectively.

Neonates have reduced and/or immature organ function and are also
vulnerable to profound and/or prolonged respiratory effects of midazolam.

• Posaconazole increased the plasma concentrations of intravenous
midazolam by about 2-fold.

Adverse haemodynamic events have been reported in paediatric patients
with cardiovascular instability; rapid intravenous administration should be
avoided in this population.

• It should be kept in mind that if midazolam is given orally, its exposure will
drastically be higher than the above-mentioned ones, notably with
ketoconazole, itraconazole, voriconazole.

Paediatric patients less than 6 months
In this population, midazolam is indicated for sedation in ICU only. 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 also section 'Preterm infants' above).

Macrolide antibiotics
• Erythromycin resulted in an increase in the plasma concentrations of
intravenous midazolam by about 1.6 – 2-fold associated with an increase
of the terminal half-life of midazolam by 1.5 – 1.8-fold.

Concomitant use of alcohol / CNS depressants
The concomitant use of midazolam with alcohol or/and CNS depressants
should be avoided. Such concomitant use has the potential to increase the
clinical effects of midazolam possibly including severe sedation or clinically
relevant respiratory depression (see section 4.5).
Medical history of alcohol or drug abuse
Midazolam as other benzodiazepines should be avoided in patients with a
medical history of alcohol or drug abuse.
Discharging criteria
After receiving midazolam, patients should be discharged from hospital or
consulting room only when recommended by treating physician and if
accompanied by an attendant. It is recommended that the patient is
accompanied when returning home after discharge.
4.5 Interaction with other medicinal products and other forms of
interaction
Pharmacokinetic Interactions
Midazolam is metabolised by CYP3A4. Inhibitors and inducers of CYP3A4
have the potential to respectively increase and decrease the plasma
concentrations and, subsequently, the effects of midazolam thus requiring
dose adjustments accordingly. Pharmacokinetic interactions with CYP3A4
inhibitors or inducers are more pronounced for oral as compared to i.v.
midazolam, in particular since CYP3A4 also exists in the upper
gastro-intestinal tract. This is because for the oral route both systemic
clearance and availability will be altered while for the parenteral route only
the change in the systemic clearance becomes effective. After a single dose
of IV midazolam, the consequence on the maximal clinical effect due to
CYP3A4 inhibition will be minor while the duration of effect may be
prolonged. However, after prolonged dosing of midazolam, both the
magnitude and duration of effect will be increased in the presence of
CYP3A4 inhibition.
There are no available studies on CYP3A4 modulation on the
pharmacokinetics of midazolam after rectal and intramuscular
administration.It is expected that these interactionswill be less
pronouncedfor the rectal than for the oral route because the
gastro-intestinal tract is by-passed whereas after i.m. administration the
effects of CYP3A modulation should not substantially differ from those seen
with i.v. midazolam.
It is therefore recommended to carefully monitor the clinical effects and vital
signs during the use of midazolam, taking into account that they may be
stronger and last longer after co-administration of a CYP3A4 inhibitor, be it
given only once. Notably, administration of high doses or long-term infusions
of midazolam to patients receiving strong CYP3A4 inhibitors, e.g. during
intensive care, may result in long-lasting hypnotic effects, delayed recovery
and respiratory depression, thus requiring dose adjustments.

Skin problems:
• rash
• hives (lumpy rash)
• itchiness.

Midazolam ampoules are not indicated for oral administration.

• Clarithromycin increased the plasma concentrations of midazolam by up
to 2.5-fold associated with an increase in terminal half-life by 1.5 – 2-fold.
Additional information from oral midazolam
• Roxithromycin: While no information on roxithromycin with IV
midazolam is available, the mild effect on the terminal half-life of oral
midazolam tablet, increasing by 30%, indicates that the effects of
roxithromycin on intravenous midazolam may be minor.
HIV Protease inhibitors
• Saquinavir and other HIV protease inhibitors: Co-administration with
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. If parenteral
midazolam is coadministered with HIV protease inhibitors, treatment
setting should follow the description in the above section for azole
antifungals, ketoconazole.
Additional information from oral midazolam
Based on data for other CYP3A4 inhibitors, plasma concentrations of
midazolam are expected to be significantly higher when midazolam is given
orally. Therefore protease inhibitors should not be co-administered with
orally administered midazolam.

Additional information from oral midazolam
• Rifampicin decreased the plasma concentrations of oral midazolam by 96%
in healthy subjects and its psychomotor effects were almost totally lost.
• Carbamazepine / phenytoin: Repeat dosages of carbamezepine or
phenytoin resulted in a decrease in plasma concentrations of oral
midazolam by up to 90% and a shortening of the terminal half-life by 60%.
• Efavirenz: The 5-fold increase in the ratio of the CYP3A4 generated
metabolite a-hydroxymidazolam to midazolam confirms its
CYP3A4-inducing effect.
Herbs and food
• St John's Wort decreased plasma concentrations of midazolam by about
20 - 40 % associated with a decrease in terminal half-life of about 15 - 17%.
Depending on the specific St John's Wort extract, the CYP3A4-inducing
effect may vary.
Pharmacodynamic Drug-Drug Interactions (DDI)
The co-administration of midazolam with other sedative/hypnotic agents and
CNS depressants, including alcohol, is likely to result in enhanced sedation
and respiratory depression.
Examples include opiate derivatives (be they used as analgesics, antitussives
or substitutive treatments), antipsychotics, other benzodiazepines used as
anxiolytics or hypnotics, barbiturates, propofol, ketamine, etomidate; sedative
antidepressants, non recent H1-antihistamines and centrally acting
antihypertensive drugs.
Alcohol may markedly enhance the sedative effect of midazolam. Alcohol
intake should be strongly avoided in case of midazolam administration (see
section 4.4).
Midazolam decreases the minimum alveolar concentration (MAC) of
inhalational anaesthetics.
4.6 Pregnancy and lactation
Insufficient data are available on midazolam to assess its safety during
pregnancy. Animal studies do not indicate a teratogenic effect, but
fetotoxicity was observed as with other benzodiazepines. No data on
exposed pregnancies are available for the first two trimesters of pregnancy.
The administration of high doses of midazolam in the last trimester of
pregnancy, during labour or when used as an induction agent of anaesthesia
for caesarean section has been reported to produce maternal or fetal
adverse effects (inhalation risk in mother, irregularities in the fetal heart rate,
hypotonia, poor sucking, hypothermia and respiratory depression in the
neonate).
Moreover, infants born from mothers who received benzodiazepines
chronically during the latter stage of pregnancy might have developed
physical dependence and might be at some risk of developing withdrawal
symptoms in the postnatal period.
Consequently, midazolam may be used during pregnancy if clearly necessary
but it is preferable to avoid using it for caesarean sections.
The risk for neonate should be taken into account in case of administration
of midazolam for any surgery near the term.
Midazolam passes in low quantities into breast milk. Nursing mothers should
be advised to discontinue breast-feeding for 24 hours following
administration of midazolam.
4.7 Effects on ability to drive and use machines
Midazolam has a major influence on the ability to drive and use machines.

Calcium-channel blockers
• Diltiazem: A single dose of diltiazem increased the plasma concentrations
of intravenous midazolam by about 25% and the terminal half-life was
prolonged by 43%.

Sedation, amnesia, impaired attention 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 completely recovered. The physician should decide when these
activities may be resumed. It is recommended that the patient is
accompanied when returning home after discharge.

Additional information from oral midazolam
• Verapamil / diltiazem increased the plasma concentrations of oral
midazolam by 3- and 4-fold, respectively. The terminal- half-life of
midazolam was increased by 41% and 49% respectively.

4.8 Undesirable effects
The following undesirable effects have been reported (very rarely) to occur
when midazolam is injected:

Various drugs/Herbs
• Atorvastatin showed a 1.4-fold increase in plasma concentrations of IV
midazolam compared to control group.
Additional information from oral midazolam
• Nefazodone increased the plasma concentrations of oral midazolam by
4.6-fold with an increase of its terminal half-life by 1.6-fold.
• Aprepitant dose dependently increased the plasma concentrations of oral
midazolam by 3.3-fold after 80 mg/day associated with an increase in
terminal half-life by ca. 2-fold.
Drugs that induce CYP3A4
• Rifampicin decreased the plasma concentrations of intravenous midazolam
by about 60% after 7 days of rifampicin 600mg o.d. The terminal half-life
decreased by about 50-60%.

Immune System Disorders: Generalised hypersensitivity reactions (skin
reactions, cardiovascular reactions, bronchospasm), anaphylactic shock.
Psychiatric Disorders: Confusional state, euphoric mood, hallucinations.
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 elderly.
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).

6. Further Information

The solution for injection also contains sodium chloride,
hydrochloric acid, sodium hydroxide (for pH adjustment)
and water for injections.

Injection site problems:
• redness
• swelling of the skin
• blood clots or pain at the injection site.

What MIDAZOLAM looks like and contents of the
pack:
MIDAZOLAM Injection is a sterile solution for injection in
a clear glass container called an ampoule.

Elderly patients:
• Older patients taking benzodiazepine medicines have a
higher risk of falling and breaking bones.
• Life-threatening side effects are more likely to occur in
adults over 60 years of age and those who already have
breathing difficulties or heart problems, particularly when
the injection is given too quickly or at a high dose.

With respect to induction, it should be considered that the inducing process
needs several days to reach its maximum effect and also several days to
dissipate. Contrary to a treatment of several days with an inducer, a
short-term treatment is expected to result in less apparent DDI with
midazolam. However, for strong inducers a relevant induction even after
short-term treatment cannot be excluded.

Paediatric Population
See above and section 4.4.

Stomach, gut and mouth problems:
• feeling sick or being sick
• constipation
• dry mouth.

Effects on behaviour:
• agitation
• restlessness
• hostility, rage or aggression
• excitement.
Muscle problems:
• muscle spasms and muscle tremors (shaking of your
muscles that you cannot control).

Do not use the medicine if the solution is not clear and
colourless.

What MIDAZOLAM contains:
The active substance is MIDAZOLAM (as midazolam
hydrochloride) 2 mg or 5 mg in each 1ml of solution.
• MIDAZOLAM 2 mg/ml Solution for Injection:
Each ampoule (small glass bottle) contains 10 mg of
midazolam in 5 ml of liquid.
• MIDAZOLAM 5 mg/ml Solution for Injection:
Each ampoule (small glass bottle) contains 10 mg of
midazolam in 2 ml of liquid.

General:
• tiredness (fatigue).

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. After receiving midazolam
parenterally, patients should be discharged from hospital or consulting room
only if accompanied by an attendant.

Altered elimination of midazolam
Midazolam elimination may be altered in patients receiving compounds that
inhibit or induce CYP3A4 and the dose of midazolam may need to be
adjusted accordingly (see section 4.5).

Breathing problems:
• shortness of breath
• hiccup.

Immune system problems:
• general allergic reactions (skin reactions, heart and blood
system reactions, wheezing)

Use in Special Populations
Renal Impairment
In patients with renal impairment (creatinine clearance < 10 ml/min) the
pharmacokinetics of unbound midazolam following a single IV dose is similar
to that reported in healthy volunteers. However, after prolonged infusion in
intensive care unit (ICU) patients, the mean duration of the sedative effect in
the renal failure population was considerably increased most likely due to
accumulation of α-hydroxymidazolam glucuronide.

Hepatic Impairment
Hepatic impairment reduces the clearance of i.v. midazolam with a
subsequent increase in terminal half-life. Therefore the clinical effects may be
stronger and prolonged. The required dose of midazolam may be reduced
and proper monitoring of vital signs should be established. (See section 4.4).

Heart and circulation problems:
• low blood pressure
• slow heart rate
• redness of the face and neck (flushing), fainting or headache.

MIDAZOLAM Injection is supplied in cartons of 5 or 10
ampoules containing either 2 mg/ml or 5 mg/ml.

If any of the side effects gets serious, or if you notice
any side effects not listed in this leaflet, please tell
your doctor, nurse or pharmacist.

5. Storing MIDAZOLAM

Not all pack sizes may be marketed.
Marketing authorisation holder:
Auden Mckenzie (Pharma Division) Ltd.,
Mckenzie House,
Bury Street, Ruislip, Middlesex
HA4 7TL, UK
Manufacturer:
SNS Pharmaceuticals Ltd.,
Mckenzie House,
Bury Street, Ruislip, Middlesex
HA4 7TL, UK

Keep out of the reach and sight of children.

This leaflet was last approved in May 2011.

Do not use MIDAZOLAM Injection after the expiry date on
the carton or the ampoule. The expiry date refers to the last
day of that month.

For information in large print, on tape, on CD or in
Braille, phone +44 (0) 1895 627 420.

Your doctor or pharmacist is responsible for storing
MIDAZOLAM. They are also responsible for disposing of any
unused MIDAZOLAM correctly.
Keep the ampoules (small glass bottle) in the outer carton in
order to protect from light.

Nervous System Disorders: Prolonged sedation, decreased alertness,
somnolence, 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.
Convulsions have been reported in premature infants and neonates.
Cardiac Disorders: Severe cardiorespiratory adverse events have occurred.
These have included cardiac arrest, hypotension, bradycardia, vasodilating
effects. 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).
Respiratory Disorders: Severe cardiorespiratory adverse events including
respiratory depression, apnoea, respiratory arrest, dyspnoea, laryngospasm
have been reported. 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).
Hiccup.
Gastrointestinal System Disorders: Nausea, vomiting, constipation, dry
mouth.
Skin and Appendages Disorders: Skin rash urticaria, pruritus.
General and Application Site Disorders: Fatigue, erythema and pain on
injection site, thrombophlebitis, thrombosis.
Injury, Poisoning and Procedural Complications: An increased risk for falls
and fractures has been recorded in elderly benzodiazepine users.
4.9 Overdose
Symptoms
Like other benzodiazepines, midazolam commonly causes drowsiness, ataxia,
dysarthria and nystagmus. Overdose of midazolam is seldom life-threatening
if the drug is taken alone, but may lead to areflexia, apnoea, hypotension,
cardiorespiratory depression and in rare cases to coma. Coma, if it occurs,
usually lasts a few hours but it may be more protracted and cyclical,
particularly in elderly patients. Benzodiazepine respiratory depressant effects
are more serious in patients with respiratory disease.
Benzodiazepines increase the effects of other central nervous system
depressants, including alcohol.

P0030-31-10-01/1

Auden Mckenzie

5.2 Pharmacokinetic properties

6.2 Incompatibilities

Absorption after i.m. injection
Absorption of midazolam from muscle tissue is rapid and complete.
Maximum plasma concentrations are reached within 30 minutes. The
absolute bioavailability after i.m. injection is over 90%.

This medicinal product must not be diluted with other solutions for
parenteral use than those mentioned in section 6.6 Special precautions for
disposal and other handling.

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%.
Distribution
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 - 1.2 l/kg. 96 - 98% of midazolam is bound to plasma
proteins. The major fraction of plasma protein binding is due to 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.
Metabolism
Midazolam is almost entirely eliminated by biotransformation. The fraction of
the dose extracted by the liver has been estimated to be 30 - 60%.
Midazolam is hydroxylated by the cytochrome P4503A4 isozyme and the
major urinary and plasma metabolite is alpha-hydroxymidazolam. Plasma
concentrations of alpha-hydroxymidazolam are 12% of those of the parent
compound. Alpha-hydroxymidazolam is pharmacologically active, but
contributes only minimally (about 10%) to the effects of intravenous
midazolam.
Elimination
In healthy volunteers, the elimination half-life of midazolam is between 1.5 2.5 hours. Plasma clearance is in the range of 300 - 500ml/min. Midazolam is
excreted mainly by renal route (60 - 80% of the injected dose) and
recovered as glucuroconjugated alpha-hydroxymidazolam. Less than 1% of
the dose is recovered in urine as unchanged drug. The elimination half-life of
alpha-hydroxy-midazolam is shorter than 1 hour. When midazolam is given
by i.v. infusion, its elimination kinetics do not differ from those following
bolus injection.
Pharmacokinetics in Special Populations
Elderly
In adults over 60 years of age, the elimination half-life may be prolonged up
to four times.

Midazolam is incompatible with alkaline solutions (due to reduced solubility
and precipitation of midazolam) and some medicines. Compatibility must be
checked before administration, if intended to be mixed with other drugs.
Published data show that midazolam injection is incompatible with alkaline
injections such as some antibiotic and steroid injections, bumetanide,
furosemide, omeprazole sodium, sodium bicarbonate and thiopental sodium.
It is also incompatible with aciclovir, albumin, amoxicillin sodium, ampicillin
sodium, alteplase, acetazolam disodium, ceftazidime, dexamethasone sodium
phosphate, diazepam, enoximone, flecainide acetate, flucloxacillin sodium,
fluorouracil, hydrocortisone sodium succinate, imipenem, mezlocillin sodium,
nafcillin, phenobarbital sodium, phenytoin sodium, potassium canrenoate,
sulbactam sodium, theophylline, trometamol, urokinase, dimenhydrinate,
foscarnet sodium, imipenem with cilastin, pentobarbital sodium, clonidine
hydrochloride, perphenazine, prochlorperazine, ranitidine,
trimethoprim-sulfamethoxazole, methotrexate sodium and certain
parenteral solutions, including parenteral nutrition solutions.
Mixture or dilution with Hartmann's solution is not recommended, as the
potency of midazolam decreases.
6.3 Shelf life
24 months (unopened)
24 hours (dilutions)
6.4 Special precautions for storage
Keep the ampoules in the original carton to protect from light.
6.5 Nature and contents of container
2 mg/ml: Type I clear glass ampoules containing 5 ml.
5 mg/ml: Type I clear glass ampoules containing 2 ml.
5 or 10 ampoules per carton.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
The injection is for single use only and should be used immediately after
opening. The injection should not be used if particles are present.
Any unused portion should be discarded.
Midazolam ampoule solution is stable, both physically and chemically, for up
to 24 hours at room temperature when mixed with 500ml infusion fluids
containing Dextrose 4% with Sodium Chloride 0.18%, Dextrose 5% or
Sodium Chloride 0.9%.

Treatment
Monitor the patient's vital signs and institute supportive measures as
indicated by the patient's clinical state. In particular, patients may require
symptomatic treatment for cardiorespiratory effects or central nervous
system effects.

Children
The rate of rectal absorption in children is similar to that in adults but the
bioavailability is lower (5 - 18%). The elimination half-life after i.v. and rectal
administration is shorter in children 3 - 10 years old (1 - 1.5 hours) as
compared with that in adults. The difference is consistent with an increased
metabolic clearance in children.

If taken orally further absorption should be prevented using an appropriate
method e.g. treatment within 1-2 hours with activated charcoal. If activated
charcoal is used airway protection is imperative for drowsy patients. In case
of mixed ingestion gastric lavage may be considered, however not as a
routine measure.

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).

Chemical and physical in-use stability has been demonstrated for 24 hours
at 25°C.

Obese
The mean half-life is greater in obese than in non-obese patients (5.9 vs 2.3
hours). This is due to an increase of approximately 50% in the volume of
distribution corrected for total body weight. The clearance is not significantly
different in obese and non-obese patients.

From a microbiological point of view, the product should be used
immediately. If not used immediately, in-use storage times and conditions
prior to use are the responsibility of the user and would normally not be
longer than 24 hours at 2-8°C, unless dilution has taken place in controlled
and validated aseptic conditions.

Patients with hepatic impairment
The elimination half-life in cirrhotic patients may be longer and the clearance
smaller as compared to those in healthy volunteers (see section 4.4).

7. MARKETING AUTHORISATION HOLDER
Auden Mckenzie (Pharma Division) Ltd
Mckenzie House
Bury Street
Ruislip
Middlesex
HA4 7TL
UK

If CNS depression is severe consider the use of flumazenil, a benzodiazepine
antagonist. This should only be administered under closely monitored
conditions. It has a short half-life (about an hour), therefore patients
administered flumazenil will require monitoring after its effects have worn
off. Flumazenil is to be used with extreme caution in the presence of drugs
that reduce seizure threshold (e.g. tricyclic antidepressants). Refer to the
prescribing information for flumazenil, for further information on the correct
use of this drug.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group:
Hypnotics and sedatives (benzodiazepine derivatives), ATC code: N05CD08.
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 the active ingredient of midazolam to form water-soluble salts with
acids. These produce a stable and well tolerated injection solution.
The pharmacological action of midazolam is characterised by short duration
because of rapid metabolic transformation. Midazolam has a 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 remember events that occurred during the maximal
activity of the compound).

Patients with renal impairment
The elimination half-life in patients with chronic renal failure is similar to that
in healthy volunteers.
Critically ill patients
The elimination half-life of midazolam is prolonged up to six times in the
critically ill.
Patients with cardiac insufficiency
The elimination half-life is longer in patients with congestive heart failure
compared with that in healthy subjects (see section 4.4).
5.3 Preclinical safety data

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

8. MARKETING AUTHORISATION NUMBER(S)
UK: 5 mg/ml: PL 17507/0030
2 mg/ml: PL 17507/0031
IE:

5 mg/ml: PA 1532/14/1
2 mg/ml: PA 1532/14/2

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION

There are no preclinical data of relevance to the prescriber that are
additional to those already included in other sections of the SPC.

10. DATE OF REVISION OF THE TEXT

6. PHARMACEUTICAL PARTICULARS

Legal category POM

6.1 List of excipients

This healthcare professional leaflet was last approved in May 2011.

Sodium Chloride
Hydrochloric Acid
Sodium Hydroxide (pH adjustment)
Water for Injections
P0030-31-10-01/1

Auden Mckenzie

350mm high

Do not use MIDAZOLAM if:
• You are allergic (hypersensitive) to any of the
ingredients of the medicine (see section 6, Further
information).
• You are allergic to other benzodiazepine medicines,
such as diazepam or nitrazepam.
• You have severe breathing problems and you are going
to have MIDAZOLAM for conscious sedation

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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