MIDAZOLAM 2MG/ML SOLUTION FOR INJECTION OR INFUSION

Active substance: MIDAZOLAM

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PACKAGE LEAFLET
INFORMATION FOR THE USER

Midazolam 2mg/ml Solution for Injection
or Infusion
Midazolam

Read all of this leaflet carefully before you start
using this medicine.
- Keep this leaflet. You may need to read it again.
- If you have further questions, please ask your doctor
or nurse.
- This medicine has been prescribed for you personally
and you should not pass it on to others. It may harm
them, even if their symptoms are the same as yours.
The name of your medicine is Midazolam 2mg/ml
Solution for Injection or Infusion. In the rest of this leaflet
it is called Midazolam Injection.
In this leaflet:
1. What Midazolam Injection is and what it is used for
2. Before you are given Midazolam Injection
3. How Midazolam Injection should be given
4. Possible side effects
5. How to store Midazolam Injection
6. Further information
1. WHAT MIDAZOLAM INJECTION IS
AND WHAT IT IS USED FOR
The active ingredient in Midazolam Injection is
midazolam which belongs to a group of sedative
medicines called benzodiazepines.
Midazolam Injection is used:
• for sedation before and during minor medical, dental
or surgical procedures
• for sedation of patients in intensive care
• at the start of a general anaesthetic

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Special care should be taken if the patient is in a coma.
Taking other medicines
Taking another medicine while you are being given
Midazolam Injection can affect how it or the other
medicine works. Please inform your doctor or nurse if
you are taking or have recently taken any other
medicines, drugs or herbal products, including those
you may have bought yourself without a prescription.

If your doctor has decided that you should be given this
medicine during labour, your baby might have a low
body temperature, floppiness, an abnormal heart rate
and breathing or feeding difficulties.
If you wish to become pregnant, you should speak to
your doctor about the use of Midazolam Injection.
Midazolam can enter breast milk. You should not be
given Midazolam Injection if you are breast-feeding or
wish to breast-feed.

Please check with your doctor if you are taking or have
been given any of the following (or any other medication): Driving and operating machines
You should not drive or operate machinery for at least
Alcohol and smoking:
twelve hours after receiving Midazolam Injection. You
• alcohol
should speak to your doctor about driving if you also
• disulfiram, a drug used for alcohol dependence
take other medicines that can cause sedation.
• nicotine, from smoking
Alcohol and Midazolam Injection
Other medicines that cause sedation:
You should not drink alcohol for at least eight hours
• sleeping tablets
before or after having an injection of midazolam.
• medicines used to treat anxiety e.g. other
benzodiazepines
Important information about the sodium content of
• medicines used to treat depression, such
Midazolam Injection
as nefazodone
This medicinal product contains less than 1 mmol
• medicines for epilepsy, such as phenytoin
sodium (23mg) per ampoule, i.e. it is essentially
• some antihistamines, used to treat hayfever
‘sodium-free’.
• medicines used for mental illness, such
as clozapine
3. HOW MIDAZOLAM INJECTION
• nabilone, used to treat vomiting due to
SHOULD BE GIVEN
cancer therapy
You will only be given Midazolam Injection in places
with adequate resuscitation equipment and when
Medicines used during operations:
there is a second member of staff present to help your
• anaesthetics
doctor. Midazolam Injection will be given into a vein in
• certain pain killers (e.g. fentanyl) – If you take or are your arm (intravenous injection) whilst you are lying
given these drugs you should have them before you down. Your doctor will decide which dose is suitable
receive your Midazolam Injection and will need to be for you. The dose used will depend on what the
carefully monitored for problems with your breathing injection is being given for and on your general physical
and your heart
condition, age, weight, what other medicines you are
• medicines used to relax your muscles during an
taking and your response to the drug.
operation (e.g. baclofen)
For sedation before and during minor surgery or
Medicines that fight infections:
dental procedures
• antibiotics, used to treat bacterial infections, such as
erythromycin, clarithromycin, quinupristin with
Adults
dalfopristin
The usual adult dose for sedation of adults before and
• drugs used to treat fungal infections, such as
during minor surgery or dental procedures is 2mg
ketoconazole, itraconazole or fluconazole
given into a vein over a period of 30 seconds. Further
• drugs used to treat virus infections, such as
injections of 0.5 - 1mg may be given every two
amprenavir or ritonavir used for HIV
minutes until you are properly sedated. The total dose
• drugs used for tuberculosis, such as isoniazid or
required is usually 2.5 to 7.5mg.
rifampicin
Elderly
Other medicines:
The usual dose for the elderly is 1 to 1.5mg, given into
• medicines to lower your blood pressure, such as to a vein over a period of 30 seconds. Further 0.5 - 1mg
diltiazem, verapamil or moxonidine
injections may be given every two minutes until you
• medicines used for pain relief and inflammation such are properly sedated.
as aspirin
• medicines used to treat stomach ulcers, such as
Children
cimetidine, ranitidine or omeprazole
Midazolam Injection is not used in this way in
• levodopa, a drug used in the treatment of
children.
Parkinson's disease
• theophylline, a drug used for asthma and lung
If you have kidney or liver disease
disease
If you have kidney or liver disease you will be given a
• probenecid, used for gout.
lower dose.

2. BEFORE YOU ARE GIVEN MIDAZOLAM
INJECTION
You should not be given Midazolam Injection if you:
• are allergic to midazolam or any of the other
ingredients contained in Midazolam Injection (see list
under heading ‘What Midazolam Injection contains’
in section 6)
• have severe breathing problems
• have severe liver problems.
If you have any doubts about whether you should be
If any of the above statements apply to you, you should given this medicine then discuss matters with your
doctor.
not be given Midazolam Injection.
Pregnancy and breast-feeding
Speak to your doctor before you are given
You should not usually be given Midazolam Injection if
Midazolam Injection if you:
you are pregnant. If Midazolam Injection is given to
• are elderly
women in the first three months of pregnancy, there is
• are very run down and lack strength
a small risk of congenital malformation in the baby
• have problems with your liver, kidneys or lungs
particularly a split in the mouth (cleft palate). Infants
• have a condition called myasthenia gravis which
born to mothers who are given Midazolam Injection
causes very weak muscles
during the late stages of pregnancy may experience
• have a personality disorder, depression, aggressive
withdrawal symptoms or slow development.
tendencies or if you feel suicidal
• have had problems with addiction to drugs or alcohol

If you are in intensive care
Adults, Elderly and Children
Small doses of 1 to 2mg may be given directly into a
vein and repeated until sedation is achieved. For the
elderly even smaller doses of 0.5 to 1mg may be
adequate.
Alternatively you may be given 0.03 to 0.3mg/kg body
weight over five minutes, followed by 0.03 to 0.2mg/kg
body weight every hour given by continuous
intravenous infusion (a continuous injection into a vein
in your arm).

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Product Summary
1.NAME OF THE MEDICINAL PRODUCT
Midazolam 2mg/ml Solution for Injection or Infusion
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Midazolam 2mg/ml. Each 5ml ampoule contains 10mg
midazolam. Contains less than 1mmol sodium (23mg) per
5ml ampoule.
3. PHARMACEUTICAL FORM
Solution for injection or infusion
4. CLINICAL PARTICULARS
4.1 Therapeutic indication
Midazolam may be used as an intravenous sedative
before and during minor medical, dental and surgical
procedures.

impairment.
central nervous system depressants (e.g. potent
analgesics) recovery may be prolonged. Patients should
therefore be assessed carefully before being allowed to go Midazolam injection and an opioid
When opioid analgesics are used, the rate of infusion of
home or resume normal activities.
midazolam should be titrated carefully to the sedative
needs of the patient. Low doses of midazolam 0.01 to
Sedation in the critically ill patient:Midazolam injection can be given intravenously by two
0.1mg/kg/hour may be used to start.
methods for this purpose, either by continuous infusion or
by intermittent bolus dose. Both have their own
The use of these two groups of drugs can increase the
advantages and disadvantages and the appropriate
risk of respiratory depression. If the patient is being given
method of giving midazolam injection will need to be
ventilatory support using a mode that depends upon
determined for each patient.
some spontaneous effort by the patient, then the minute
volume may decrease.
The dose of midazolam injection needed to sedate
critically ill patients varies considerably between patients. Whenever a continuous infusion of midazolam is used
The dose should be titrated to the desired state of
(with or without an opioid analgesic), its need should be
sedation. This will depend on clinical need, physical
assessed on a daily basis in order to reduce the risk of
accumulation and prolonged recovery. Each day the
status, age and concomitant medication.
infusion of midazolam should be stopped or its rate
Midazolam injection can also be given in combination with reduced and the patient seen to recover from its effect. If
an opioid. The opioid may be used for its analgesic effects recovery is prolonged (>2 hours) a lower dose should be
or as an antitussive agent to help the patient tolerate the
used when it is restarted. A sedation score should be
tracheal tube and ventilatory support.
used routinely.

4.4 Special warnings and precautions for use
Midazolam injection should be used with caution in
patients with renal or hepatic dysfunction (see 4.2
Posology and Method of Administration), chronic
pulmonary insufficiency, myasthenia gravis, coma, or a
known history of drug or alcohol abuse.
Midazolam may enhance the effects of other CNS
depressants and may result in severe respiratory or
cardiovascular depression. Their concurrent use should be
avoided. Elderly or debilitated patients are more prone to
the CNS effects of benzodiazepines and, therefore, lower
doses are required (see 4.2 Posology and Method of
Administration).

Dependence and withdrawal symptoms
The dependence potential of midazolam increases with
dose and duration of treatment and is greater in patients
with a history of alcohol or drug abuse. It is low when
limited to short term use. Due to the possibility of
As an intravenous sedative, (either by continuous infusion
withdrawal symptoms, midazolam should be gradually
or intermittent bolus injection) in critically ill patients in
reduced following a prolonged iv administration; abrupt
intensive care.
discontinuation should be avoided. Withdrawal symptoms
As an alternative intravenous agent for the induction of
may occur with benzodiazepines following normal use of
anaesthesia in high risk and elderly patients where
therapeutic doses for only short periods and may be
Patients receiving midazolam injection for sedation in the When midazolam has been given for a number of days
cardiovascular stability is of particular importance.
intensive care situation should receive ventilatory support. and then gradually withdrawn, patients may be awake but associated with physiological and psychological sequelae
Induction is more reliable when heavy opiate medication
(see Section 4.8 Undesirable effects). This should be
show signs of residual sedation for the next 12 to 24
has been administered or when midazolam injection is
Safe use for midazolam for periods of over 14 days in
considered when treating patients for more than a few
hours. This can cause difficulties because patients may
given with a narcotic analgesic such as fentanyl.
duration has not been established in clinical trials.
days.
not cough and expectorate well if they are then weaned
from ventilatory support. However, while recovering from
4.2 Posology and method of administration
Potential drug interactions:the effects of midazolam, patients may not be sufficiently As with other benzodiazepines, extreme caution should be
The critically ill patient is exposed to many drugs.
Dosage depends on the individual response, age and
used if prescribing midazolam for patients with personality
sedated to tolerate ventilatory support. In such
weight. Midazolam 2mg/ml may be given by intravenous Because of this, there is a potential for drug interactions.
disorders. The disinhibiting effects of benzodiazepines
circumstances sedation may be provided with a shorter
(Refer to Section 4.5 Interactions with other medicaments acting agent while there is recovery from the effects of
or slow intravenous injection.
may be manifested as the precipitation of suicide in
and other forms of interaction).
patients who are depressed or show aggressive
midazolam.
Intravenous sedation
behaviour towards self and others.
After prolonged iv administration of midazolam injection,
One or more intravenous injections to be administered
The recommended concentration of a solution for infusion
abrupt discontinuation may be accompanied by
over a single operating session.
This medicinal product contains 0.15mmol sodium per
in a critically ill adult patient is 1mg/ml.
withdrawal symptoms, therefore a gradual reduction of
ampoule. To be taken into consideration by patients on a
the drug is recommended.
Dosage should be titrated according to an individual's
controlled sodium diet.
Induction of anaesthesia by slow intravenous injection
One or more bolus intravenous injections should be
response, age and weight. The end-point of this titration is
administered over a single anaesthetic session.
dependent on the procedure. Full sedation will be evident Sedation by intermittent bolus dose in intensive care
4.5 Interactions with other medicinal products and
by drowsiness and slurred speech, although a response to
other forms of interaction
Adults
Midazolam injection only
commands will be maintained.
Alcohol: Alcohol should be avoided for at least eight hours
The exact dose of midazolam needs to be titrated to the
The dose should be titrated against the individual
before and after the administration of midazolam due to
response of the patient. Midazolam injection should be
Adults: 2mg, (1ml of 2mg/ml midazolam injection solution) individual patient response. Small doses of midazolam
increased sedative effects.
1.0-2.0mg can be given, and repeated, until the required
given by slow intravenous injection until there is a loss of
over a period of 30 seconds initially
degree of sedation is reached.
eyelid reflex, response to commands and voluntary
Anaesthetics and narcotic analgesics: Enhanced sedation
movements.
Elderly: 1 to 1.5mg (0.5-0.75ml of 2mg/ml midazolam
or respiratory and cardiovascular depression. If such
Midazolam injection and an opioid
injection solution) over a period of 30 seconds initially.
centrally acting depressant drugs are given parenterally in
When midazolam and an opioid are used together, the
In anticipating the required dose of midazolam, both the
conjunction with intravenous midazolam, severe
opioid should be administered first. Both drugs need to be premedication already given and the age of the patient are respiratory and cardiovascular depression may occur;
If adequate sedation is not achieved after two minutes,
titrated to the individual patient's response and to the level important. Young, fit unpremedicated patients may need
incremental doses of 0.5-1mg, (0.25-0.5ml of 2mg/ml
careful monitoring is required. When intravenous
of sedation thought to be necessary.
at least 0.3mg/kg bodyweight, whereas patients
midazolam injection solution) should be given until the
midazolam is to be administered concurrently with a
premedicated with an opiate usually need only 0.2mg/kg narcotic analgesic agent (e.g. fentanyl), it is recommended
desired level of sedation is achieved, usually at a total
Small doses of midazolam 1-2mg (0.5-1.0ml of 2mg/ml
bodyweight.
dose of 2.5-7.5mg (about 70 micrograms/kg) in adults.
that midazolam be given after the analgesic and that the
midazolam injection solution) can be given, and repeated,
dose be carefully titrated to meet the patient's needs.
until the required degree of sedation is reached. In the
Use in the elderly
Renal/hepatic impairment: Reduce dose
Fentanyl may reduce midazolam clearance.
elderly, smaller doses as little as 0.5-1.0mg (0.25-0.5ml of The elderly are more sensitive to the effects of
2mg/ml midazolam injection solution) may be adequate.
benzodiazepines. Induction may be adequate with
Children
Antibacterials: Agents that interfere with metabolism by
0.1mg/kg body weight in premedicated patients and
Not recommended. Midazolam injection has not been
hepatic enzymes (e.g. isoniazid, erythromycin,
The use of these two groups of drugs can increase the
0.2mg/kg body weight in unpremedicated patients.
evaluated as an intravenous sedative in children.
clarithromycin, quinupristin/dalfopristin) have been shown
risk of respiratory depression. If the patient is being given
to reduce the clearance of benzodiazepines and may
ventilatory support using a mode that depends upon
Renal/hepatic impairment: Reduce dose.
Combination therapy:potentiate their actions, whilst known inducers of hepatic
If analgesia is provided by a narcotic analgesic, the
some spontaneous effort by the patient, then the minute
Children over seven years
enzymes, for example, rifampicin, may increase the
analgesic should be administered first. The dose of
volume may decrease.
Midazolam injection has been shown to be an effective
clearance of benzodiazepines.
midazolam injection should then be carefully titrated. Low
agent for induction of anaesthesia in children over seven
total doses of 1-2mg may be adequate with lower total
Sedation by continuous infusion in intensive care
years of age, at a dose of 0.15mg/kg body-weight.
Antidepressants: Enhanced sedation or respiratory and
doses of 0.5-1mg in the elderly.
Midazolam injection only
cardiovascular depression. Midazolam plasma levels
Adults, Elderly and children
Mode of administration:increased by concomitant nefazodone.
For patients already sedated or anaesthetised after an
Mode of administration:For the administration of midazolam injection the patient
For the administration of midazolam injection the patient
operation, a loading dose of midazolam is unnecessary.
should be placed in a supine position and remain there
Antiepileptics: Enhanced sedation or respiratory or
should be placed in a supine position and remain there
throughout the procedure. Resuscitation facilities should
cardiovascular depression. Midazolam may interact with
In other situations a loading dose of 0.03-0.3mg/kg given always be available and a second person, fully trained in
throughout the procedure. Resuscitation facilities should
other hepatically metabolised drugs, e.g. phenytoin,
over a five minute period is recommended, depending on the use of such equipment, always be present. It is
always be available and a second person, fully trained in
causing potentiation.
the level of sedation required. The loading dose should be recommended that patients should remain under medical
the use of such equipment, always be present. It is
recommended that patients should remain under medical reduced or omitted in hypovolaemic, vasoconstricted or
supervision until at least one hour has elapsed from the
Antifungals: Ketoconazole, itraconazole, and possibly
hypothermic patients, renal or hepatic impairment.
supervision until at least one hour has elapsed from the
time of injection. They should always be accompanied
fluconazole, have been shown to reduce the clearance of
time of injection. They should always be accompanied
home by a responsible adult.
benzodiazepines and may potentiate their actions
Maintenance dose
home by a responsible adult.
A dose between 0.03-0.2mg/kg/hour is recommended,
4.3 Contraindications
Antihistamines: Enhanced sedation or respiratory and
Patients who have received only midazolam injection for iv starting at the lower dose.
Known hypersensitivity to benzodiazepines or any of the
cardiovascular depression with sedative antihistamines.
sedation prior to minor procedures, should be warned not
ingredients. Severe or acute respiratory
The dose should be reduced in hypovolaemic,
to drive or operate machinery for 12 hours. Where
insufficiency/depression.
Antihypertensives: Enhanced hypotensive effect.
vasoconstricted or hypothermic patients, renal or hepatic
midazolam injection is used concurrently with other
Severe hepatic insufficiency
Enhanced sedative effect possible with moxonidine.

Patients who have kidney or liver disease, who
have a low body temperature, or who are severely
dehydrated
A smaller dose should be given.
Patients who are receiving certain pain killers (e.g.
fentanyl)
If you take or are given these drugs you should have
them before you are given your Midazolam Injection.
Low doses of Midazolam Injection (0.01 to 0.1mg/kg
body weight per hour) may be used to start.

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dizziness, ringing in your ears, loss of appetite, tremor,
sweating, irritability, increased sensation, abnormal
taste, feeling sick, being sick, stomach pains, rapid
heart beat, high blood pressure or low blood pressure
on standing. Rare and more serious withdrawal
symptoms include muscle twitching, confusion,
paranoia, fits, hallucinations, and delirium. Broken sleep
with vivid dreams may persist for some weeks after
withdrawal.

4. POSSIBLE SIDE EFFECTS
Like many medicines Midazolam Injection may cause
Monitoring of Response
side effects in some patients, although not everybody
Patients who receive Midazolam Injection for sedation gets them. The side effects are generally mild. If you
in intensive care should be on a ventilator. If you receive are elderly or very run-down you are more likely to
a continuous intravenous infusion of Midazolam
have side effects.
Injection, the infusion should be stopped / reduced
everyday to see how you recover from its effect. If
If you experience any of the following, you should
recovery takes more than two hours, a lower dose
contact your doctor or nurse immediately:
should be used.
• skin rashes or other allergic reactions (with swelling
of the face and eyes and difficulty breathing in severe
At the start of a general anaesthetic
cases)
One or more intravenous injections may be given until • problems breathing or if you stop breathing. This is
you are sedated.
more likely to occur if you are elderly or if your dose is
too high or it is given too quickly
Adults
• your heart stopping.
If you have not received any pre-medication the usual
adult dose is about 0.3mg/kg body weight. If you have Less serious side effects include:
received pre-mediation however, you may only need
Heart and circulation problems
about 0.2mg/kg body weight.
• slow pulse
• chest pain
Elderly
• low blood pressure
The elderly are more sensitive to Midazolam Injection
• inflammation of your veins
so the doses required tend to be lower than for adults.
If you have not received any pre-medication the usual Nervous system problems:
dose is about 0.2mg/kg body weight. However, if you
• dizziness, lack of coordination and over sedation with
have received pre-mediation you may only need about
a risk of falls and other accidents
0.1mg/kg body weight.
• headaches
• confusion
Children over seven years
• slurred speech
The usual dose for children over seven years is about
• drowsiness
0.15mg/kg body weight.
• tremor
• uncontrolled jerky movements
If you have kidney or liver disease
• reduced alertness
If you have kidney or liver disease you will be given a
• forgetfulness
lower dose.
Mental problems:
If you are given more Midazolam Injection than
• numbed emotions
you should
• depression
A doctor or nurse will give you this medicine. If you
• delirium after surgery
think that you have been given too much, inform your
doctor or nurse. Signs that you have been given too
Gut problems:
much Midazolam Injection include: confusion; reduction • dry mouth
in consciousness; feeling drowsy; breathing difficulties; • stomach problems
lack of co-ordination; speech impairment; low blood
pressure and muscle weakness. In the case of a severe Other side effects include:
overdose, coma can occur and you could stop
• fatigue
breathing. As the level of medicine falls in your blood
• hangover effect
you may get severe agitation; inability to sleep and
• pain on injection
possibly major fits.
• hiccups
• problems with your vision
If you think you have missed a dose of
• jaundice (a yellowing of the skin and whites of
Midazolam Injection
the eyes)
A doctor or nurse will give you this medicine. If you
• difficulty in passing water
think you have missed a dose, inform your doctor or
• incontinence (the inability to control when you go
nurse.
the toilet)
• changes in sexual desire
Stopping Midazolam Injection
• blood problems
If you are given Midazolam Injection for a long time,
there is a risk of becoming dependent on it in which
• some patients, particularly if they are children or
case you may have withdrawal symptoms when you
elderly, may become irritable, aggressive, hostile,
stop taking it. The dose should be reduced gradually to overexcited, uninhibited, overanxious or have
reduce the risk of withdrawal symptoms and you
hallucinations.
should never stop your Midazolam Injection abruptly.
Your doctor will decide when to stop your treatment
If any of the side effects get serious, or if you notice any
with Midazolam Injection.
side effects not listed in this leaflet, please contact your
doctor or nurse immediately.
Withdrawal symptoms include anxiety, depression,
impaired concentration, inability to sleep, headache,

5. HOW TO STORE MIDAZOLAM INJECTION
Keep out of the reach and sight of children.
This medicine should not be used if the expiry date on
the ampoule has passed. The expiry date refers to the
last day of that month.

This medicine should not be stored above 25°C.
Store the ampoule in the outer carton in order to protect
from light.
Medicines should not be disposed of via wastewater or
household waste. Ask your pharmacist how to dispose
of medicines no longer required. These measures will
help to protect the environment.
6. FURTHER INFORMATION
What Midazolam Injection contains
The active ingredient in Midazolam Injection is
midazolam. The injection is available in 5ml ampoules.
Each ampoule contains 10mg of the active ingredient in
5ml of solution.
The other ingredients are sodium chloride, hydrochloric
acid solution, sodium hydroxide solution and water for
injections.
What Midazolam Injection looks like and contents
of the pack
Midazolam Injection is a clear, colourless solution.
Midazolam Injection is available in cartons containing
10x5ml glass ampoules.
Marketing Authorisation Holder: Wockhardt UK Ltd,
Ash Road North, Wrexham, LL13 9UF, UK.
Manufacturer: CP Pharmaceuticals Ltd, Ash Road
North, Wrexham, LL13 9UF, UK.
Other formats:
To listen to or request a copy of this leaflet in Braille,
large print or audio please call, free of charge:
0800 198 5000 (UK Only)
Please be ready to give the following information:
Product Name

Reference Number

Midazolam 2mg/ml
Solution for Injection
or Infusion

29831/0140

This is a service provided by the Royal National Institute
of Blind People.
Date of leaflet preparation: July 2008

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Antipsychotics: Enhanced sedation or respiratory and
cardiovascular depression. Severe hypotension, collapse,
respiratory depression, potentially fatal respiratory arrest
and unconsciousness have been reported in a few
patients on benzodiazepines and clozapine. Caution is
advised when initiating clozapine therapy in patients
taking benzodiazepines.
Antivirals: Concomitant use of midazolam with
HIV-protease inhibitors (e.g. amprenavir, ritonavir) should
be avoided due to the risk of extreme sedation and
respiratory depression.
Anxiolytics and hypnotics: Enhanced sedation or
respiratory and cardiovascular depression with other
anxiolytics and hypnotics.
Calcium-channel blockers: Diltiazem and verapamil have
been shown to reduce the clearance of benzodiazepines
and may potentiate their actions.
Dopaminergic agents: Midazolam may cause inhibition of
levodopa.
Disulfiram: Has been shown to reduce clearance of
benzodiazepines and may potentiate their actions.
Muscle relaxants: e.g. baclofen Midazolam may cause
potentiation, with increased CNS depressant effects.
Nabilone: Enhanced sedation or respiratory and
cardiovascular depression.
Nicotine: Benzodiazepine metabolism is accelerated by
smoking.
Non-steroidal anti-inflammatory drugs: The induction of
anaesthesia with midazolam is more rapid in patients
pre-treated with aspirin.

4.7 Effects on ability to drive and use machines
The concurrent use of midazolam with other central
nervous system depressants, may result in a prolonged
recovery. A careful assessment should be undertaken
prior to allowing the patient to go home or resume normal
activities.
Patients treated with midazolam injection should not drive
or use machinery for twelve hours after receiving this
medicine.
4.8 Undesirable effects
Side-effects are usually mild.
Cardiovascular: Midazolam may cause bradycardia, chest
pain and decreases in cardiac output, stroke volume and
systemic vascular resistance. These effects are important
in those patients with a reduced myocardial oxygen
delivery capacity or suffering hypovolaemia. Also,
hypotension, particularly with high dosage, and cardiac
arrest. Local thrombophlebitis may occur.
CNS: Elderly or debilitated patients are particularly
susceptible to the CNS side effects of benzodiazepines. It
is recommended that dosage be limited to the smallest
effective dose and increased gradually, if necessary, to
decrease the possibility of development of ataxia,
dizziness and oversedation, which may lead to falls and
other accidents (see 4.2 Posology and method of
administration).
Disorders of the eye: Visual disturbances.
Gastrointestinal: dry mouth, gastrointestinal disturbances.
General: Fatigue and a hangover effect. Local pain on
injection. Hiccups.
Haematological: Blood dyscrasias.
Hepatic: Jaundice.
Immunological: Skin reactions and other hypersensitivity
reactions, including anaphylaxis, are rare.

Probenecid: May reduce midazolam clearance.
Sedatives: Enhanced sedation or respiratory and
cardiovascular depression.

Neurological: Headaches, confusion, slurred speech,
tremor, drowsiness, reduced alertness, anterograde
amnesia, extrapyramidal effects.

Ulcer-healing drugs: Cimetidine, ranitidine and omeprazole Psychiatric: Increased risk of postoperative delirium.
have been shown to reduce the clearance of
Numbed emotions. In susceptible patients, an unnoticed
benzodiazepines and may potentiate their actions.
depression may become evident. Paradoxical reactions
(including aggressive behaviour, hostility, hallucinations,
Xanthines: Benzodiazepine metabolism is accelerated by disinhibition, excitation, irritability and increased anxiety)
xanthines.
are known to occur with benzodiazepines and are more
likely in children and the elderly.
4.6 Pregnancy and lactation
There is no evidence regarding the safety of midazolam in Reproductive: Changes in libido
pregnancy. It should not be used, especially in the first
and third trimesters, unless the benefit is considered to
Respiratory: Midazolam can produce, respiratory
outweigh the risk.
depression, apnoea and may cause respiratory arrest
following iv administration, especially in the elderly with
If the product is prescribed to a woman of childbearing
pre-existing respiratory insufficiency or when the dose is
potential she should be warned to contact her physician
excessive or administered too rapidly.
regarding discontinuance of the product if she intends to
become or suspects that she is pregnant.
Urinary: urinary retention, incontinence.
There may be a small increase in the risk of congenital
malformation, particularly oral cleft, with the use of
benzodiazepines in the first trimester. In labour, high single
doses or repeated low doses have been reported to
produce effects on the neonate, such as hypothermia,
hypotonia, moderate respiratory depression, irregularities
in the foetal heart rate, and poor suckling in the neonate
(floppy infant syndrome).

Withdrawal symptoms:
Development of dependence is common after regular use,
even in therapeutic doses for short periods, particularly in
patients with a history of drug or alcohol abuse or marked
personality disorders. Discontinuation may be associated
with withdrawal symptoms or rebound phenomena (see
4.4 Special Warnings and Precautions for Use).
Symptoms of benzodiazepine withdrawal include anxiety,
depression, impaired concentration, insomnia, headache,
Infants born to mothers who take benzodiazepines
dizziness, tinnitus, loss of appetite, tremor, perspiration,
chronically during the latter stages of pregnancy may
irritability, perceptual disturbances such as hypersensitivity
develop physical dependence and may be at some risk for to physical, visual, and auditory stimuli and abnormal
developing withdrawal symptoms in the postnatal period. taste, nausea, vomiting, abdominal cramps, palpitations,
mild systolic hypertension, tachycardia, and orthostatic
A small number of children exposed in utero to
hypotension, Rare and more serious withdrawal
benzodiazepines have shown slow development in the
symptoms include muscle twitching, confusional or
early years but by four years of age have developed
paranoid psychosis, convulsions, hallucinations, and a
normally.
state resembling delirium tremens. Broken sleep with
vivid dreams and increased REM sleep may persist for
Since benzodiazepines are found in the breast milk,
some weeks after withdrawal of benzodiazepines.
benzodiazepines should not be given to breast-feeding
mothers.

4.9 Overdose
a) Symptoms
The symptoms of mild overdose may include confusion,
impairment of consciousness with somnolence or a
sleep-like state, little or no respiratory depression, ataxia,
dysarthria, hypotension and muscular weakness. Cardiac
rate and rhythm remain normal in the absence of anoxia
or severe hypotension.
In severe overdose, deep coma, or other manifestations of
severe depression of brainstem vital functions, particularly
the respiratory centre, may occur
As drug levels fall, severe agitation, insomnia and,
possibly, major convulsions may develop.
b) Treatment
Treatment is symptomatic. Respiration, heart rate, blood
pressure and body temperature should be monitored and
supportive measures taken to maintain cardiovascular
function. Ventilation should be used to support respiratory
function if appropriate.
Flumazenil is a specific antidote for use in midazolam
overdosage but expert advice is essential since adverse
effects may occur (e.g. convulsions in patients dependent
on benzodiazepines).
5. PHARMACOLOGICAL PROPERTIES
5.1Pharmacodynamic properties
Midazolam is a soluble benzodiazepine with marked
properties of suppression of tension, agitation and anxiety
as well as sedative and hypnotic effects. In addition,
midazolam demonstrates muscle relaxant and
anticonvulsive properties. In clinical use, the main action
is sleep induction.
Midazolam binds to specific receptors in the central
nervous system (CNS). The benzodiazepine receptors in
the CNS have a close functional connection with receptors
of the GABA-ergic transmitter system. After binding to the
benzodiazepine receptor, midazolam augments the
inhibitory effect of GABA-ergic transmission.
5.2 Pharmacokinetic properties
Midazolam is highly lipid soluble and crosses the blood
brain barrier. These properties qualify it for intravenous
use in short term anaesthetic procedures since it acts
promptly on the brain, and its initial effects decrease
rapidly as it is distributed into fat deposits and tissues.
Following the administration of 150 micrograms/kg
intravenously, plasma concentrations in the range
291-425 ng/ml are reached within five minutes.
Midazolam is almost completely absorbed following
intramuscular injection, peak plasma levels being attained
within 45 minutes.
Midazolam is extensively protein bound (94-98%). The
volume of distribution is between 0.8 and 1.7 litres/kg.
Midazolam crosses the placenta. It is not known whether
midazolam enters breast milk, but this is likely as it is
known to occur with other benzodiazepines.
Midazolam is extensively metabolised in the liver, involving
the P450 IIIA enzymes. The principal metabolite,
1-hydroxy midazolam, appears in the urine as a
glucuronide. The metabolite is less pharmacologically
active than midazolam and has a shorter half-life of about
one hour. Midazolam has a mean elimination half-life of
two to three hours. The half-life is short compared with
other benzodiazepines. Less than 1% midazolam is
excreted unchanged via the kidneys and the drug is
cleared virtually entirely by the liver. The half-life of
midazolam is prolonged in neonates, in the elderly and
patients with liver disorders.
5.3 Preclinical safety data
In vitro and in vivo microbial and mammalian test systems
have revealed no evidence of mutagenicity. No evidence
of carcinogenic potential was seen in rats or mice given
oral midazolam maleate in doses up to 25 times the
human recommended daily dose for two years.

In humans, the risk of congenital abnormalities from the
ingestion of therapeutic doses of benzodiazepines is slight,
although a few epidemiological studies have pointed to an
increased risk of cleft palate. There are case reports of
congenital abnormalities and mental retardation in
prenatally exposed children following overdosage and
intoxication with benzodiazepines.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium Chloride
Hydrochloric Acid Solution 3M
Sodium Hydroxide Solution 3M
Water for Injections
6.2 Incompatibilities
Midazolam is incompatible with alkaline solutions (due to
reduced solubility) and some medicines.
Published data show that midazolam injection is
incompatible with alkaline injections such as some
antibiotic and steroid injections, bumetanide, frusemide,
omeprazole sodium, sodium bicarbonate and thiopental
sodium. It is also incompatible with dimenhydrinate,
foscarnet sodium, imipenem with cilastin, pentobarbital
sodium, albumin, clonidine, perphenazine,
prochlorperazine, ranitidine and certain parenteral
solutions, including parenteral nutrition solutions.
Mixture or dilution with Hartmann's solution is not
recommended, as the potency of midazolam decreases.
Compatibility must be checked before administration, if
intended to be mixed with other drugs.
6.3 Shelf life
Three years.
6.4Special precautions for storage
Do not store above 25°C. Keep container in outer carton.
6.5 Nature and contents of container
Neutral glass ampoules Type I Ph Eur 5ml packed in 5 or
10s in an outer printed carton
6.6 Special precautions for disposal
The injection is for single patient use and should be used
immediately after opening. The injection should not be
used if particles are present. Any unused portion should
be discarded.
Midazolam for infusion may be prepared by dilution with
infusion fluids containing 5% glucose, 4% glucose with
0.18% sodium chloride or 0.9% sodium chloride.
Chemical and physical in-use stability has been
demonstrated for 24 hours at 25°C.
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.
7. MARKETING AUTHORISATION HOLDER
Wockhardt UK Ltd, Ash Road North
Wrexham, LL13 9UF
8. MARKETING AUTHORISATION NUMBER(S)
PL 29831/0140
9. DATE OF FIRST AUTHORISATION/RENEWAL OF
THE AUTHORISATION
27 March 2007
10. DATE OF REVISION OF THE TEXT
November 2007

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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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