Consumer medicine information

Midazolam Viatris

Midazolam

BRAND INFORMATION

Brand name

Midazolam Viatris

Active ingredient

Midazolam

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Midazolam Viatris.

SUMMARY CMI

MIDAZOLAM VIATRIS

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using MIDAZOLAM VIATRIS?

MIDAZOLAM VIATRIS contains the active ingredient Midazolam. MIDAZOLAM VIATRIS is used as a sedative during some short medical procedures.

For more information, see Section 1. Why am I using MIDAZOLAM VIATRIS? in the full CMI.

2. What should I know before I use MIDAZOLAM VIATRIS?

Do not use if you have ever had an allergic reaction to Midazolam or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use MIDAZOLAM VIATRIS? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with MIDAZOLAM VIATRIS and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How am I given MIDAZOLAM VIATRIS?

  • MIDAZOLAM VIATRIS may be given to you as an injection into a vein or muscle. It may also be given through an infusion set in an intensive care unit. Other medications may also be given at the same time.
  • Your doctor will adjust the dose necessary for you. This depends on which medical procedure you will be having, your age, weight and your general health. Elderly patients may need to receive less.

More instructions can be found in Section 4. How am I given MIDAZOLAM VIATRIS? in the full CMI.

5. What should I know while using MIDAZOLAM VIATRIS?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using MIDAZOLAM VIATRIS.
  • Tell your doctor if you are taking any other medicines or have any conditions listed in section 2 of the full CMI prior to taking MIDAZOLAM VIATRIS.
Things you should not do
  • Do not take any other medicines whether they require a prescription or not without first telling your doctor.
Driving or using machines
  • Do not drive or operate machinery until you know how MIDAZOLAM VIATRIS affects you.
  • MIDAZOLAM VIATRIS may cause drowsiness, dizziness, fatigue, confusion and affect alertness.
Drinking alcohol
  • Do not have any alcohol for at least 12 hours after you have been given MIDAZOLAM VIATRIS
Looking after your medicine
  • MIDAZOLAM VIATRIS will be stored in the pharmacy or on the ward.
  • It is kept in a cool dry place where the temperature stays below 25°C.
  • It should be protected from light.

For more information, see Section 5. What should I know while using MIDAZOLAM VIATRIS? in the full CMI.

6. Are there any side effects?

Tell your doctor or pharmacist as soon as possible if you do not feel well after you have received MIDAZOLAM VIATRIS, especially if you are over 60 years of age or have pre-existing heart and lung conditions. All medicines can have side effects. Sometimes they are serious, most of the time they are not. All medical procedures which involve the use of an anaesthetic have risk which your doctor will discuss with you. In elderly, or high-risk patients, death has resulted rarely due to heart attack or a slowdown of the heart and lungs. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

MIDAZOLAM VIATRIS

Active ingredient(s): midazolam

Consumer Medicine Information (CMI)

This leaflet provides important information about using MIDAZOLAM VIATRIS. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using MIDAZOLAM VIATRIS.

Where to find information in this leaflet:

1. Why am I using MIDAZOLAM VIATRIS?
2. What should I know before I use MIDAZOLAM VIATRIS?
3. What if I am taking other medicines?
4. How am I given MIDAZOLAM VIATRIS?
5. What should I know while using MIDAZOLAM VIATRIS?
6. Are there any side effects?
7. Product details

1. Why am I using MIDAZOLAM VIATRIS?

MIDAZOLAM VIATRIS contains the active ingredient midazolam. MIDAZOLAM VIATRIS belongs to a group of medicines called benzodiazepines. They are thought to work by their action on brain chemicals. MIDAZOLAM VIATRIS can cause sedation, hypnosis, amnesia and/or anaesthesia, depending on the dose.

MIDAZOLAM VIATRIS may be injected as a sedative during some short medical procedures.

MIDAZOLAM VIATRIS may be given to you by injection before an operation to produce sleepiness or drowsiness and to relieve anxiety.

If you are in an intensive care unit, you may receive an infusion of MIDAZOLAM VIATRIS over several hours or days as a sedative.

Your doctor, however, may have prescribed MIDAZOLAM VIATRIS for another purpose.

Ask your doctor if you have any questions about why MIDAZOLAM VIATRIS has been prescribed for you.

MIDAZOLAM VIATRIS is only given by a doctor trained to use this medicine. If you will be receiving MIDAZOLAM VIATRIS during surgery, your doctor will give you the medicine and closely follow your progress.

This medicine is available only with a doctor's prescription.

2. What should I know before I use MIDAZOLAM VIATRIS?

Warnings

Do not use MIDAZOLAM VIATRIS if:

  • you are allergic to midazolam, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.
  • you have severe muscle weakness, also known as myasthenia gravis
  • you have a condition called acute narrow angle glaucoma
  • you are suffering from shock, coma or acute alcoholic intoxication
  • you are less than eight years of age.
    The safety and effectiveness of MIDAZOLAM VIATRIS in children less than eight years of age has not been established.

Check with your doctor if you have any other medical conditions including:

  • liver, kidney, heart or lung disease
  • high or low blood pressure
  • mental disorders including; depression, psychosis or schizophrenia
  • epilepsy (fits or convulsions)
  • history of alcohol or drug abuse
  • are pregnant, intend to become pregnant or breastfeed
  • if you are allergic to any other medicines, foods, dyes or preservatives

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

MIDAZOLAM VIATRIS is not recommended for use in pregnant women, especially in the third (last) trimester or during labour unless there is no safer alternative.

MIDAZOLAM VIATRIS crosses the placenta and use in the third (last) trimester has resulted in serious and potentially fatal effects in newborns. These include irregular heart rates, muscle weakness, low body temperature, difficulty breathing, difficulty sucking. The newborn may also show signs of dependency and withdrawal after birth.

If there is a need to use MIDAZOLAM VIATRIS when you are pregnant, your doctor will discuss the risks and benefits to you and the unborn baby.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

If you are breastfeeding while taking MIDAZOLAM VIATRIS, monitor your baby for excessive sedation, poor feeding and poor weight gain, and seek medical attention if you notice these signs.

You should pump and discard breastmilk for at least 4 to 8 hours after receiving midazolam.

If you drink alcohol or use illicit (illegal) drugs regularly

  • MIDAZOLAM VIATRIS can cause physical dependency, especially if you have a history of drug or alcohol abuse, when used long-term. Your dose may be reduced gradually to overcome this effect.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and MIDAZOLAM VIATRIS may interfere with each other. These include:

  • other sleeping tablets, sedatives or tranquillisers
  • anaesthetics
  • fluvoxamine, nefazodone and other medicines for depression
  • medicines to control fits such as sodium valproate
  • medicines for allergies or colds such as antihistamines
  • pain relievers
  • chlorzoxazone and other muscle relaxants
  • cimetidine, a medicine used to treat ulcers
  • disulfiram, a medicine used in alcohol abuse
  • erythromycin and clarithromycin, common antibiotics
  • diltiazem, verapamil and atorvastatin, medicines used to treat high blood pressure or heart conditions
  • ketoconazole, fluconazole, posaconazole and itraconazole, medicines used to treat fungal infections
  • ritonavir, saquinavir and other HIV protease inhibitors, medicines used to treat HIV
  • bicalutamide, a medicine used in the treatment of prostate cancer and for excessive hair loss particularly in women
  • aprepitant, a medicine used for treatment of nausea (feeling sick) and vomiting associated with chemotherapy
  • goldenseal, a complementary medicine

These medicines may be affected by MIDAZOLAM VIATRIS or may affect how well MIDAZOLAM VIATRIS works.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect MIDAZOLAM VIATRIS.

Your doctor or pharmacist can tell you what to do if you are taking any of these medicines. They also know of other medicines to be careful with or avoid while using MIDAZOLAM VIATRIS.

4. How am I given MIDAZOLAM VIATRIS?

How MIDAZOLAM VIATRIS is given

  • MIDAZOLAM VIATRIS may be given to you as an injection into a vein or muscle. It may also be given through an infusion set in an intensive care unit. Other medications may also be given at the same time.

How much is given

Your doctor will adjust the dose necessary for you. This depends on which medical procedure you will be having, your age, weight and your general health. Elderly patients may need to receive less.

When and how long is MIDAZOLAM VIATRIS given

  • MIDAZOLAM VIATRIS may be given once before a medical procedure, or continuously by infusion for patients in an intensive care unit.
  • MIDAZOLAM VIATRIS will be stopped once there is no further need for sedation.

If have been given too much MIDAZOLAM VIATRIS

If you think that you have been given too much MIDAZOLAM VIATRIS, you may feel drowsy, tired, confused, dizzy, feel weak or become unconscious. If used in combination with other similar medicines, the effects of overdose may be serious and potentially fatal. You may need urgent medical attention.

You should immediately:

  • tell the doctor or nurse on duty if you think you have been given too much of MIDAZOLAM VIATRIS, or
  • phone the Poisons Information Centre
    (Australia telephone 13 11 26) for advice, or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

Ask your doctor if you have any concerns.

Your doctor has information on how to recognise and treat an overdose.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using MIDAZOLAM VIATRIS?

Things you should do

Call your doctor straight away if you:

  • feel MIDAZOLAM VIATRIS is not helping you
  • experience serious side effects listed in section 6

Remind any doctor, dentist or pharmacist you visit that you are using MIDAZOLAM VIATRIS.

Things you should not do

  • Do not take any other medicines whether they require a prescription or not without first telling your doctor.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how MIDAZOLAM VIATRIS affects you.

MIDAZOLAM VIATRIS may cause dizziness, drowsiness, dizziness, fatigue, confusion and forgetfulness in some people and therefore may affect alertness. Make sure you know how you react to MIDAZOLAM VIATRIS before you drive a car or operate machinery, or do anything else that could be dangerous if you are drowsy, dizzy or not alert.

Drinking alcohol

Tell your doctor if you drink alcohol.

Do not have any alcohol for at least 12 hours after you have been given MIDAZOLAM VIATRIS.

Alcohol may increase the risk of fall and fracture due to dizziness and unsteadiness, a possible side effect of MIDAZOLAM VIATRIS.

Looking after your medicine

  • MIDAZOLAM VIATRIS will be stored in the pharmacy or on the ward.
  • It is kept in a cool dry place where the temperature stays below 25°C. It should not be stored in the refrigerator.
  • It should be protected from light.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

In elderly, or high-risk patients, death has resulted on rare occasions, due to heart attack or a slowdown of the heart and lungs. These life-threatening diseases are more common in adults over 60 years of age and with pre-existing heart and lung conditions when a high dose of MIDAZOLAM VIATRIS is administered or when the injection is given too rapidly. If you belong to these high-risk groups seek medical attention immediately if you notice heart or breathing issues.

Less serious side effects

Less serious side effectsWhat to do
  • drowsiness, tiredness, reduced alertness
  • dizziness, unsteadiness – there is a risk of fall and fracture which is increased in those taking sedatives, alcohol and in the elderly
  • loss of memory, inattentiveness, confusion, lack of concentration, lethargy
  • headache, hangover feeling in the morning
  • slurred speech
  • unpleasant dreams
  • blurred vision
  • pain, redness or hardness at the injection site
  • muscle stiffness or inflammation of the vein
  • coughing, hiccups
  • constipation
  • nausea/feeling sick with or without vomiting
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • difficulty breathing or wheezing
  • changes in pulse rate and blood pressure
  • sudden anxiety, excitation or agitation, involuntary movements such as muscle tremors
  • hallucinations, unusual mood or delusions
  • severe sleep disturbances
  • allergic reaction - sudden signs such as rash, itching or hives on the skin, swelling of the face, lips, tongue which may cause difficulty in swallowing or breathing and other parts of the body
  • withdrawal symptoms including withdrawal convulsions
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What MIDAZOLAM VIATRIS contains

Active ingredient
(main ingredient)		midazolam
Other ingredients
(inactive ingredients)
  • sodium chloride
  • water for injections
  • small amounts of hydrochloric acid and sodium hydroxide to adjust the acidity of the solution.

Do not take this medicine if you are allergic to any of these ingredients.

What MIDAZOLAM VIATRIS looks like

MIDAZOLAM VIATRIS is a clear colourless solution and available in the following strengths:

  • MIDAZOLAM VIATRIS 5 mg/ 5 mL - AUST R 160206
  • MIDAZOLAM VIATRIS 5 mg/mL - AUST R 160207
  • MIDAZOLAM VIATRIS 15 mg/ 3 mL - AUST R 160205
  • MIDAZOLAM VIATRIS 50 mg/ 10mL - AUST R 160208

Who distributes MIDAZOLAM VIATRIS

Alphapharm Pty Ltd trading as Viatris
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

This leaflet was prepared in January 2024.

MIDAZOLAM VIATRIS_cmi\Jan24/00

Published by MIMS March 2024

BRAND INFORMATION

Brand name

Midazolam Viatris

Active ingredient

Midazolam

Schedule

S4

 

1 Name of Medicine

Midazolam.

2 Qualitative and Quantitative Composition

Midazolam Viatris, midazolam solution for injection is available as a 5 mg/5 mL, 5 mg/1 mL, 15 mg/3 mL and 50 mg/10 mL solution.

Midazolam Viatris 5 mg/5 mL.

Each mL contains 1 mg of midazolam.
One 5 mL ampoule contains 5 mg of midazolam.

Midazolam Viatris 5 mg/1 mL.

Each mL contains 5 mg of midazolam.
One 1 mL ampoule contains 5 mg of midazolam.
One 3 mL ampoule contains 15 mg of midazolam.
One 10 mL ampoule contains 50 mg of midazolam.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
Clear, colourless solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Intravenously (IV) as an agent for:
conscious sedation prior to short surgical, diagnostic, therapeutic or endoscopic procedures such as bronchoscopy, gastroscopy, cystoscopy, coronary angiography and cardiac catheterisation, either alone or in conjunction with an opioid;
induction of anaesthesia preliminary to administration of other anaesthetic agents. With the use of an opioid premedicant, induction of anaesthesia can be attained with a narrower dose range and in a shorter period of time.
Intermittent IV administration or continuous infusion for:
sedation in intensive care units, intermittent administration or continuous infusion.
Intramuscularly (IM) for:
preoperative sedation (induction of sleepiness or drowsiness and relief of apprehension) and to impair memory of perioperative events.

4.2 Dose and Method of Administration

Dose.

Dosage should be individualised and drug should be administered slowly.
Lower doses may be required in elderly or debilitated patients or in patients with hepatic or renal insufficiency. Because serious and life-threatening cardiorespiratory adverse events have been reported, provision for monitoring, detection and correction of these reactions must be made for every patient to whom midazolam injection is administered, regardless of health status or age. The dosage of midazolam administered should be modified according to the type and amount of premedication used.
This product is for single patient use only. Use once and discard any residue. The solution should be visually inspected prior to use. Only clear solutions without particles should be used.
IV administration. Midazolam should be administered slowly.

Conscious sedation.

Endoscopic or cardiovascular procedures: For conscious sedation, midazolam can be used either alone or together with an opioid immediately before the procedure with supplemental doses to maintain the desired level of sedation throughout the procedure. For per oral procedures, the use of an appropriate topical anaesthetic is recommended. For bronchoscopic procedures, the use of an opioid premedicant is recommended. Individual response will vary with age, physical status and concomitant medications, but may also vary independent of these factors.
Titrate dosage to desired sedative end point, such as slurring of speech, with slow administration immediately prior to the procedure. The initial dose should be given over a period of at least 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. When titrating the dose, 2 or more minutes should be allowed after each increment.
In healthy adults the initial dose is approximately 2.5 mg. Some patients may respond to as little as 1 mg. Further doses of 1 mg may be given if necessary. A total dose greater than 5 mg is not usually necessary to reach the desired end point.
In cases of severe illness and in elderly patients the initial dose must be reduced to 1 - 1.5 mg. Total doses greater than 3.5 mg are not usually necessary. Special caution is required for the indication of conscious sedation in patients with impaired respiratory function (see Section 4.4 Special Warnings and Precautions for Use).
If an opioid premedicant or other CNS depressant is used the dose of midazolam should be lowered by 25% to 30%.

Induction of anaesthesia.

The dosage of midazolam should be determined by the response of the individual patient.
Administration should be by slow IV injection until the consciousness is lost using approximately 0.15-0.2 mg/kg (10-15 mg) administered at a rate of approximately 2.5 mg per 10 seconds. Maximum sedation is usually reached after 2-3 minutes, but if required a further dose up to a total of 0.35 mg/kg may be administered. The onset of sedation has not been found to be dose-dependent but the time to recovery is related to the amount of drug administered.
Midazolam should be used with opioid analgesics as it does not have analgesic properties and opioid analgesics increases its anaesthetic-inducing properties.

IV sedation in intensive care units (ICU).

For sedation in ICU, the recommended infusion rate is 0.03-0.2 mg/kg/hour. The dosage should be individualised and midazolam titrated to the desired state of sedation according to the clinical need, physical status, age and concomitant medication. It may be possible to reduce the dose (infusion rate) once the therapeutic effect has been obtained.
The dosage should be reduced in hypovolemic, vasoconstricted, and hypothermic patients.
After prolonged IV administration of midazolam, abrupt discontinuation of the product may be accompanied by withdrawal symptoms. Therefore, a gradual reduction of midazolam is recommended. Midazolam can be used in neurosurgical patients with increased intracranial pressure.
IM administration. For preoperative sedation (induction of sleepiness or drowsiness and relief of apprehension) and to impair memory of preoperative events.
For IM use, midazolam should be injected deep in a large muscle mass.
The recommended premedication dose of midazolam for low-risk adult patients below the age of 60 years is 0.07 - 0.08 mg/kg IM (approximately 5 mg IM) administered approximately one hour prior to surgery.
The dose must be individualised and reduced when IM midazolam is administered to patients with chronic obstructive pulmonary disease, other higher risk surgical patients, patients 60 or more years of age, and patients who have received concomitant opioids or other CNS depressants (see Section 4.8 Adverse Effects (Undesirable Effects)). In a study of patients 60 years or older who did not receive concomitant administration of opioids, 2 - 3 mg (0.02 - 0.05 mg/kg) of midazolam produced adequate sedation during the preoperative period. In approximately 25% of patients, 1 mg provided satisfactory sedation. As with any potential respiratory depressant, these patients require special observation for signs of cardio-respiratory depression after receiving IM midazolam.
Onset is within 15 minutes, peaking at 30 - 60 minutes. It can be administered concurrently with atropine sulfate or hyoscine hydrobromide and reduced doses of opioids.

Special dosage instructions.

Patients with renal impairment.

In patients with severe renal impairment, midazolam may be accompanied by more pronounced and prolonged sedation, possibly including clinically relevant respiratory and cardiovascular depression. Midazolam should therefore be dosed carefully in this patient population and titrated for the desired effect (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).

Hepatic impairment.

The clinical effects in patients with hepatic impairment may be stronger and prolonged. The dose of midazolam may have to be reduced and vital signs should be monitored (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment; Section 5.2 Pharmacokinetic Properties).

Dilution and admixture.

Midazolam may be mixed in the same syringe with frequently used premedicants: morphine sulfate, pethidine, atropine sulfate or hyoscine. Midazolam is compatible with normal saline, glucose 5% and 10% in water, fructose IV infusion (levulose 5%), potassium chloride, sodium chloride and calcium chloride IV infusion (Ringer's solution) and compound sodium lactate IV infusion (Hartmann's solution).
The 15 mg/3 mL, 5 mg/1 mL and 5 mg/5 mL formulations may be diluted to facilitate slow injection.
The 50 mg/10 mL ampoules may be added to the infusion solutions in a mixing ratio of 15 mg midazolam per 100-1000 mL infusion solution.
The product and its admixtures contain no antimicrobial agent. In order to reduce microbiological hazards, it is recommended that further dilution be effected immediately prior to use and infusion commenced as soon as practicable after preparation of the admixture.
Infusion should be completed within 24 hours of preparation and the residue discarded, however infusion with calcium chloride IV infusion (Ringer's solution) and compound sodium lactate IV infusion (Hartmann's solution) should be completed within 4 hours as the potency of midazolam is known to decrease. Any storage of diluted solution should be at 2°C - 8°C.

4.3 Contraindications

Patients with a hypersensitivity to benzodiazepines or any of the formulation excipients in Midazolam Viatris.
Patients in shock, coma or in acute alcoholic intoxication with depression of vital signs.
Patients with acute narrow angle glaucoma. Benzodiazepines may be used in patients with open angle glaucoma only if they are receiving appropriate therapy. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction with midazolam. Patients with glaucoma have not been studied.
Myasthenia gravis.

4.4 Special Warnings and Precautions for Use

IV midazolam should only be used in settings with equipment and skilled personnel for continuous monitoring of cardio-respiratory function and resuscitation procedures.
Midazolam must never be used without individualisation of dosage. Midazolam should not be administered by rapid or single bolus IV administration (see Section 4.2 Dose and Method of Administration). Extravasation should also be avoided. The hazards of intra-arterial injection of midazolam solutions into humans are unknown; therefore, precautions against unintended intra-arterial injection should be taken.
Patients should be continuously monitored for early signs of under-ventilation or apnoea. Vital signs should continue to be monitored during the recovery period. During IV application of midazolam, respiratory depression, apnoea, respiratory arrest and/or cardiac arrest have occurred. In some cases where this was not recognised promptly and treated, hypoxic encephalopathy or death has resulted. These life-threatening incidents may occur, especially if the injection is given too rapidly or with excessive doses. Particular care must be used in administering the drug, by the IV route, to the elderly, to very ill patients, high risk surgical patients and to those with significant hepatic impairment (benzodiazepines may precipitate or exacerbate encephalopathy in patients with severe hepatic impairment), chronic renal insufficiency, congestive heart failure, or with limited pulmonary reserve because of the possibility that apnoea or respiratory depression may occur. These patients require lower doses whether premedicated or not.
Benzodiazepines are not recommended for the primary treatment of psychotic illness.

Preoperative sedation.

Adequate observation of the patient after preoperative sedation of midazolam is mandatory as individual sensitivity varies and symptoms of overdose may occur.
Patients with chronic obstructive pulmonary disease are unusually sensitive to the respiratory depressant effect of midazolam.
Elderly patients frequently have inefficient function of one or more organ systems and dosage requirements have been shown to be reduced with age. Patients with chronic renal failure and patients with congestive heart failure eliminate midazolam more slowly.
In some intensive care patients, and in some elderly patients given midazolam by IV infusion for prolonged sedation, the elimination half-life was found to increase by up to four times (see Section 5.2 Pharmacokinetic Properties).
Particular care should be exercised in the use of IV midazolam in patients with uncompensated acute illnesses, such as severe fluid or electrolyte disturbances.
There have been rare reports of hypotensive episodes requiring treatment during or after diagnostic or surgical manipulations in patients who have received midazolam. Hypotension occurred more frequently in the conscious sedation studies in patients premedicated with a narcotic.
After prolonged IV administration of midazolam, abrupt discontinuation of the product may be accompanied by withdrawal symptoms. Therefore, a gradual reduction of midazolam is recommended. The following withdrawal symptoms may occur: headaches, diarrhoea, muscle pain, extreme anxiety, tension, sleep disturbances, restlessness, confusion, irritability, mood changes, hallucinations and convulsions. In severe cases the following symptoms may occur: depersonalisation, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact.
Reactions such as restlessness, agitation, irritability, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity, combativeness, delusion, anger, aggressiveness, anxiety, nightmares, hallucinations, psychoses, inappropriate behaviour or other adverse behavioural effects have been reported. These reactions may be due to inadequate or excessive dosing or improper administration of midazolam; however, consideration should be given to the possibility of cerebral hypoxia or true paradoxical reactions. If midazolam is the suspected cause, the use of the drug should be discontinued and all other drugs, including local anaesthetics, should be evaluated before proceeding.
Concomitant use of barbiturates, alcohol or other central nervous system depressants increases the risk of under-ventilation or apnoea and/or cardio-ventricular depression and may contribute to a profound and/or prolonged drug effect that could result in coma or death. When midazolam is used with a narcotic analgesic, the dosage of both agents should be reduced. Narcotic premedication also reduces the ventilatory response to carbon dioxide stimulation.
Midazolam does not protect against the increase in intracranial pressure or against the heart rate rise and/or blood pressure rise associated with endotracheal intubation under light general anaesthesia.
Since an increase in cough reflex and laryngospasm may occur with per oral endoscopic procedures, the use of a topical anaesthetic agent and the availability of necessary counter measures are recommended. The use of a narcotic premedicant is recommended for bronchoscopies.
Administration of a muscle relaxant may sometimes be necessary to overcome midazolam-associated hiccoughs.
As with other benzodiazepines, midazolam may have the potential to cause dependence. Benzodiazepines should be avoided in patients with a history of alcohol or drug abuse. The risk of dependence increases with the duration of treatment; it is also greater in patients with a medical history of alcohol and/or drug abuse.
Midazolam ampoules should be used with extreme caution in patients with sleep apnoea syndrome and patients should be regularly monitored.
After parenteral administration of midazolam, patients should not be discharged from hospital for at least 3 hours, and responsibility for medical supervision of discharge shall lie with a physician (preferably the treating physician) and then, if possible, only if accompanied by a responsible person. The decision as to when patients may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualised. Gross tests of recovery from the effects of midazolam cannot be relied upon to predict reaction time under stress. When midazolam is used with other drugs during anaesthesia, the contribution of these can vary and should also be considered.

Use in 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 have to be reduced and proper monitoring of vital signs should be established. (See Section 4.2 Dose and Method of Administration, Special dosage instructions; Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations).

Use in renal impairment.

There is a greater likelihood of adverse drug reactions in patients with severe renal impairment (see Section 4.2 Dose and Method of Administration, Special dosage instructions; Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations).

Use in the elderly.

There have been reports of falls and fractures in benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.

Paediatric use.

The safety and effectiveness of midazolam in children under the age of 8 have not been established. Pharmacokinetics in children have not been established and may differ from adults.
Some published studies in children have observed cognitive deficits after repeated or prolonged exposures to anaesthetic agents early in life. These studies have substantial limitations, and it is not clear if the observed effects are due to the anaesthetic/analgesic/sedation drug administration or other factors such as the surgery or underlying illness.
Published animal studies of some anaesthetic/analgesic/sedation drugs have reported adverse effects on brain development in early life and late pregnancy. The clinical significance of these nonclinical finding is yet to be determined.

Effects on laboratory tests.

Midazolam has not been shown to interfere with results obtained in clinical laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Specific interaction studies.

Midazolam can enhance the central sedative effect of neuroleptics, tranquillisers, antidepressants, sleep-inducing drugs, analgesics, anaesthetics, antipsychotics, anxiolytics, antiepileptic drugs and sedative antihistamines. This potentiation of effect can in certain cases be therapeutically advantageous.
There is potentially relevant interaction between midazolam and compounds which inhibit or induce certain hepatic enzymes (particularly cytochrome CYP3A). Data clearly indicate that these compounds influence the pharmacokinetics of midazolam and this may lead to prolonged sedation. At present, enzyme induction is known to occur in vivo with rifampicin, carbamazepine and phenytoin, and enzyme inhibition occurs with cimetidine, erythromycin, diltiazem, verapamil, ketoconazole, fluconazole, itraconazole, ritonavir and saquinavir.
Therefore, patients receiving the above compounds or others which inhibit CYP3A together with midazolam should be monitored carefully for the first few hours after administration of midazolam. During long-term midazolam infusions, a reduction of up to 50% of the initial dose followed by careful titration is recommended. Studies have shown that ranitidine has no influence on the pharmacokinetics of parenterally given midazolam.
In some patients the mutual potentiation of alcohol and midazolam can produce unforeseeable reactions (no alcoholic beverages for at least 12 hours after parenteral administration).
The sedative effect of IV midazolam is accentuated by premedication. Consequently, the dosage of midazolam should be adjusted according to the type and amount of premedication administered.
The plasma concentration of midazolam, following oral administration, has been shown to increase when used in combination with erythromycin and this results in a potentiation of midazolam's sedative effect. A much smaller change in plasma concentration with no observed increase of the sedative effects was observed following IV administration of midazolam, however, caution is advised.
A moderate reduction in induction dosage requirements of thiopentone (about 15%) has been noted following use of IM midazolam for premedication.
Simultaneous administration of cimetidine (but not ranitidine) has been reported to reduce clearance of midazolam.
Displacement of midazolam from its plasma protein binding sites by sodium valproate may increase the response to midazolam and, therefore, care should be taken to adjust the midazolam dosage in patients with epilepsy.
The IV administration of midazolam decreases the minimum alveolar concentration (MAC) of halothane required for general anaesthesia. This decrease correlates with the dose of midazolam administered.
The effects of midazolam can be reversed by the benzodiazepine antagonist flumazenil.

Pharmacokinetic drug-drug interaction (DDI).

Midazolam is almost exclusively metabolized by CYP3A (primarily CYP 3A4 and also CYP 3A5). Inhibitors and inducers of CYP3A have the potential to increase and decrease the plasma concentrations and, subsequently, the pharmacodynamic effects of midazolam. No mechanism other than modulation of CYP3A activity has been proven as a source for a clinically relevant pharmacokinetic DDI with midazolam. However, acute protein displacement from albumin is a theoretical possibility of drug interaction with drugs that have high therapeutic serum concentrations, as has been hypothesized for valproic acid (see below). Midazolam is not known to change the pharmacokinetics of other drugs.
When co-administered with a CYP3A-inhibitor, the clinical effects of midazolam may be stronger and also longer lasting and a lower dose may be required. Conversely, the effect of midazolam may be weaker and the duration of effect shorter when co-administered with a CYP3A-inducer and a higher dose may be required.
In case of CYP3A induction and irreversible inhibition (so-called mechanism based inhibition), the effect on the pharmacokinetics of midazolam may persist for a period of several days up to several weeks after administration of the CYP3A modulator. Examples of mechanism based CYP3A inhibitors include antibacterials (e.g. clarithromycin, erythromycin, isoniazid); anti-retroviral agents (e.g. HIV protease inhibitors, such as ritonavir (including ritonavir-boosted protease inhibitors), delavirdine); calcium channel blockers (e.g. verapamil, diltiazem); tyrosine kinase inhibitors (e.g. imatinib, lapatinib, idelalisib, or the estrogen receptor modulator, raloxifene, and several herbal constituents (e.g. bergamottin). In contrast to other mechanism based inhibitors, ethinylestradiol combined with norgestrel or gestodene (used for oral contraception) and grapefruit juice (200 mL) did not modify exposure to midazolam to a clinically significant degree.
The range of the inhibiting/inducing potency of drugs is wide. The antifungal ketoconazole, a very potent CYP3A inhibitor, increased the plasma concentration of IV midazolam by approximately 5-fold. The tuberculostatic drug, rifampicin, belongs to the strongest inducers of CYP3A and its co-administration resulted in a decrease in the AUC0-∞ of IV midazolam by approximately 60%.
The administration route of midazolam also determines the magnitude of change in its pharmacokinetics due to CYP3A modulation:
The change in plasma concentration is expected to be less for IV administration compared with oral administration of midazolam. This is because CYP3A modulation not only affects the systemic clearance, but also the bioavailability of oral midazolam.
There are no studies available investigating the effect of CYP3A modulation on the pharmacokinetics of midazolam after either rectal or IM administration. After rectal administration the drug partially bypasses the liver and the expression of CYP3A is lower in the colon compared with the upper gastrointestinal tract. Therefore, it is expected that the change in midazolam plasma concentration, due to CYP3A modulation, will be less for the rectal than for the oral route of administration. After IM administration, the drug directly enters the systemic circulation. Therefore, it is expected that the effect of CYP3A modulation will be similar to that for IV administration of midazolam.
In line with pharmacokinetic principles, clinical studies have shown that after a single IV dose of midazolam, in the presence of CYP3A inhibition, the change in maximal clinical effect due to CYP3A modulation will be minor, whereas the duration of effect may be prolonged. However, after prolonged dosing of midazolam, both the magnitude and duration of effect may be increased.
The following listing gives examples of clinical pharmacokinetic drug-drug interactions with midazolam after IV administration. Importantly, any drug shown to possess CYP3A-modulating effects, either in vitro or in vivo has the potential to change the plasma concentration of midazolam, and therefore its effects. The listing includes information from clinical drug-drug interaction studies for oral midazolam. As outlined above, the change in plasma concentration is expected to be less for IV compared with oral midazolam.

Drugs that inhibit CYP3A.

Patients receiving compounds which inhibit CYP3A should not be administered midazolam whenever possible. Otherwise, the dose of midazolam should be adjusted and the patient kept under careful surveillance. There is a potential interaction with the following.
Azole antifungals.

Ketoconazole and voriconazole.

Increased the AUC0-∞ of IV midazolam by 5-fold and 3-4 fold, respectively, while the terminal half-life increased by approximately 43-fold.

Fluconazole and itraconazole.

Both increased the AUC0-∞ of IV midazolam, which was associated with a 2.4-fold and 1.5-fold increase in terminal half-life for itraconazole and fluconazole, respectively. A 100 - 300% increase in plasma midazolam at 48 hours after receiving fluconazole was commonly (3/10) seen in intensive care unit patients with a midazolam infusion. Orally, fluconazole increased Cmax 1.7-fold and AUC0-∞ 3.6-fold, while for itraconazole they increased 2.5- and 6.6-fold, respectively.

Posaconazole.

Increased the AUC(tf) (AUC zero to last measurable concentration) of IV midazolam by 1.8-fold.
Macrolide antibiotics.

Erythromycin.

Resulted in an increase in the AUC(tf) of IV midazolam and was associated with a 1.4 - 1.8 fold increase in the terminal half-life of midazolam.

Clarithromycin.

Increased the AUC of IV midazolam by approximately 2.5-fold and was associated with a 2.7-fold increase in terminal half-life.

Additional information from oral midazolam.

Telithromycin increased the plasma levels of oral midazolam 6-fold.
Roxithromycin has less of an effect on the pharmacokinetics of midazolam than erythromycin or clarithromycin. After oral administration with roxithromycin the maximum plasma concentration (Cmax) of midazolam increased approximately 40% compared with increases of 2.7-fold caused by erythromycin and 2.8-fold with clarithromycin, while the 40% increase in AUC0-∞ is matched by 4.4-fold and 7-fold increases, respectively. The mild effect on the terminal half-life of midazolam (~ 30%) indicated that the effects of roxithromycin on IV midazolam may be minor.
IV anaesthetics. Disposition of IV midazolam was also changed by IV propofol (AUC and half-life increased by 1.6-fold).
Protease inhibitors.

Saquinavir and other HIV protease inhibitors.

If parenteral midazolam is co-administered with HIV protease inhibitors, treatment setting should follow the description in the section above for ketoconazole within azole antifungals.

HCV protease inhibitors.

Boceprevir and telaprevir reduce midazolam clearance. This effect resulted in a 3.4-fold increase of midazolam AUC after i.v. administration and prolonged its elimination half-life 4-fold.
Histamine receptor 2 antagonists. Cimetidine increased the steady state plasma concentration of midazolam by 26%.
Calcium-channel blockers.

Diltiazem.

After pretreatment with lorazepam and a single dose of diltiazem, on cessation of an IV infusion of midazolam, the AUC from cessation for 23 h increased approximately 25% and the terminal half-life was prolonged approximately 43%.

Additional information from oral midazolam.

Verapamil: Increased the Cmax of oral midazolam 2-fold, while AUC0-∞ increased 3- and 4-fold, respectively. The terminal-half-life of midazolam increased 41%.
Various drugs/herbs.

Atorvastatin.

Increased the AUC of IV midazolam by approximately 1.4-fold compared with control group.

Intravenous fentanyl.

Intravenous fentanyl is a weak inhibitor of midazolam's elimination: AUC and half-life of i.v. midazolam were increased by 1.5-fold in presence of fentanyl.

Additional information from oral midazolam.

Fluvoxamine: Increased the AUC0-∞ and Cmax of oral midazolam 40% and doubled the terminal half-life.
Nefazodone: Increased the AUC0-∞ of oral midazolam 4.6-fold with an increase in Cmax of 1.8-fold and in terminal half-life of 1.6-fold.
Tyrosine kinase inhibitors have been shown either in vitro (imatinib, lapatinib), or after oral administration in vivo (idelalisib) to be potent inhibitors of CYP3A4. After concomitant administration of idelalisib, oral midazolam exposure was increased on average 5.4-fold.
NK1 receptor antagonists (aprepitant, netupitant, casoprepitant): Dose-dependently increased the AUC of oral midazolam up to approximately 2.5-3.5 fold and increased terminal half-life by approximately 1.5-2-fold.
Chlorzoxazone: Decreased the ratio of the CYP3A-generated metabolite α-hydroxymidazolam to midazolam, indicating a CYP3A-inhibiting effect of chlorzoxazone.
For a number of drugs or herbal medicines, a weak interaction with midazolam's elimination was observed with concomitant changes in its exposure (< 2-fold change in AUC) (bicalutamide, everolimus, cyclosporine, simeprevir, propiverine, berberine as also contained in goldenseal). These weak interactions are expected to be further attenuated after i.v. administration.

Drugs that induce CYP3A.

Rifampicin (600 mg o.d.) decreased the AUC of IV midazolam by approximately 60% after 7 days. The terminal half-life decreased by approximately 50 - 60%.
Ticagrelor is a weak CYP3A activator in vitro but has only small effects on IV administered midazolam (-12%) and 4-hydroxy-midazolam (-23%) exposures.

Additional information from oral midazolam.

Carbamazepine and phenytoin: Repeat dosages of carbamazepine or phenytoin resulted in a decrease in the AUC and Cmax of oral midazolam by over 90% and a shortening of the terminal half-life by almost 60%.
The very strong CYP3A4 induction seen after mitotane or enzalutamide resulted in a profound and long-lasting decrease of midazolam levels in cancer patients. AUC of orally administered midazolam was reduced to 5% and 14% of normal values, respectively.
Clobazam and efavirenz: are weak inducers of midazolam metabolism and reduce the AUC of the parent compound by approximately 30%. There is a resulting 4-5-fold increase in the ratio of the active metabolite (α-hydroxy-midazolam) to the parent compound but the clinical significance of this is unknown.
Vemurafenib modulates CYP isozymes and inhibits CYP3A4 mildly: repeat-dose administration resulted in a mean decrease of oral midazolam exposure of 39% (up to 80% in individuals).

Herbs and food.

Echinacea purpurea root extract.

Decreased the AUC of IV midazolam 20% and was associated with a decrease in half-life approximately 42%.

St John's wort.

Decreased the AUC of IV midazolam by approximately 20% and AUC of oral midazolam by 50% with Cmax decreased by 40 - 50%. It was associated with a decrease in terminal half-life by approximately 16 - 19%.

Additional information from oral midazolam.

Quercetin (also contained in Gingko biloba) and Panax ginseng both have weak enzyme inducing effects and reduced exposure to midazolam after its oral administration to the extent of 20-30%.

Acute protein displacement.

Valproic acid.

Increased concentrations of free midazolam due to displacement from plasma protein binding sites by valproic acid cannot be excluded although the clinical relevance of such an interaction is not known.

Pharmacodynamic drug-drug interactions (DDI).

The co-administration of midazolam with other sedative/hypnotic agents, including alcohol, is likely to result in increased sedative/hypnotic effects. Examples include opiates/opioids (when they are used as analgesics, antitussives or substitutive treatments), antipsychotics, other benzodiazepines (used as anxiolytics or hypnotics), barbiturates, propofol, ketamine, etomidate, sedative antidepressants, antihistaminics and centrally acting antihypertensive drugs. Midazolam decreased the minimum alveolar concentration (MAC) of halothane.
Enhanced effects such as sedation and cardio-respiratory depression may also occur when midazolam is co-administered with any centrally acting depressants including alcohol. Therefore, adequate monitoring of vital signs should be established. Alcohol should be avoided in patients receiving midazolam (see Section 4.4 Special Warnings and Precautions for Use; Section 4.9 Overdose for warning of other CNS depressants, including alcohol).
It has been shown that high spinal anaesthesia can increase the sedative effect of IV midazolam. The midazolam dose may therefore have to be reduced. When either lidocaine or bupivacaine were administered IM, the dose of IV midazolam required for sedation was reduced.
Drugs increasing alertness/memory such as the acetylcholinesterase inhibitor physostigmine, reversed the hypnotic effects of midazolam. Similarly, 250 mg of caffeine partly reversed the sedative effects of midazolam.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

A reproduction study in male and female rats did not show any impairment of fertility at dosages up to 10 times the human IV dose of 0.35 mg/kg.
(Category C)
Benzodiazepines should be avoided during pregnancy unless there is no safer alternative. Midazolam crosses the placenta and the administration of midazolam in the last weeks of pregnancy or at high doses during labour have resulted in neonatal CNS depression and can be expected to cause irregularities in the foetal heart rate, hypothermia, hypotonia, poor sucking and moderate respiratory depression due to the pharmacological action of the product. Moreover, infants born to mothers who received benzodiazepines chronically during the latter stage of pregnancy may have developed physical dependence, and may be at some risk of developing withdrawal symptoms in the postnatal period. Midazolam is therefore not recommended for obstetric use.
Published animal studies of some anaesthetic/analgesic/sedation drugs have reported adverse effects on brain development in early life and late pregnancy.
Published studies in pregnant and juvenile animals demonstrate that the use of anaesthetic/analgesic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of rapid brain growth or synaptogenesis may result in neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis when used for longer than 3 hours. These studies included anaesthetic agents from a variety of drug classes.
Teratological studies with midazolam in a number of animal species have not shown association between administration of the drug and disturbances of foetal development, nor has clinical experience so far yielded any evidence of such an association. however, like any other drug, midazolam should not be used in the first three months of pregnancy unless considered absolutely necessary by the physician.
An increased risk of congenital malformation associated with the use of benzodiazepines during the first trimester of pregnancy has been suggested.
 Midazolam is excreted in human breast milk, and may cause drowsiness, feeding difficulties and poor weight gain in the infant. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for midazolam and any potential adverse effects on the breastfed infant from midazolam or from the underlying maternal condition.
A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment for a range of at least 4 to 8 hours after midazolam administration in order to minimize drug exposure to a breastfed infant. Infants exposed to midazolam through breast milk should be monitored for sedation, poor feeding and poor weight gain.

4.7 Effects on Ability to Drive and Use Machines

After administration of midazolam, patients should not be discharged from hospital for at least three hours and then, if possible, only if accompanied by a responsible person. The decision as to when patients may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualised. Gross tests of recovery from the effects of midazolam cannot be relied upon to predict reaction time under stress. When midazolam is used with other drugs during anaesthesia, the contribution of these can vary and should be considered accordingly.
Patients should be warned to take extra care as a pedestrian and not to drive a vehicle or operate machinery until effects such as drowsiness, have subsided or until the day after anaesthesia and surgery, whichever is longer. The physician should decide when activities such as driving a vehicle or operating a machine may be resumed. The patient's attendants should be made aware that anterograde amnesia may persist longer than the sedation and therefore patients may not carry out instructions even though they appear to acknowledge them.
If sleep duration is insufficient or alcohol is consumed, the likelihood of impaired alertness may be increased (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.8 Adverse Effects (Undesirable Effects)

(See Section 4.4 Special Warnings and Precautions for Use.)
Fluctuations in vital signs that have been observed following parenteral administration of midazolam include:
respiratory depression (22.9% following IV administration and 10.8% of patients following IM administration);
apnoea (19% following IV administration);
variations in blood pressure and pulse rate.
These common occurrences during anaesthesia and surgery are affected by the lightening or deepening of anaesthesia, instrumentation, intubation and use of concomitant drugs. Administration of IM midazolam to elderly and/or higher risk surgical patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression. In most of these cases, the patients also received other central nervous system depressants capable of depressing respiration, especially narcotics (see Section 4.2 Dose and Method of Administration).
The following additional adverse effects were reported after IM administration:
local effects at IM injection site: pain (3.7%); headache (1.3%); induration (0.5%); redness (0.5%); muscle stiffness (0.3%).
The following additional adverse effects were reported after IV administration:
local effects at the IV site: tenderness (7%); pain during injection (6.2%); hiccough (5.5%); redness (3.8%); nausea (3%); vomiting (2.9%); coughing (1.9%); induration (1.9%); drowsiness (1.3%); oversedation (1%); phlebitis (0.5%).
Other adverse experiences, observed mainly following IV injection and occurring at an incidence of less than 1%, are as follows.

Respiratory.

Laryngospasm, bronchospasm, dyspnoea, hyperventilation, wheezing, shallow respiration, airway obstruction, tachypnoea.

Cardiovascular.

Bigeminy, premature ventricular contractions, tachycardia, nodal rhythm, cardiovascular collapse, vasovagal episode, cardiac arrest.

Gastrointestinal.

Acid taste, excessive salivation, retching.

CNS/neuromuscular.

Anterograde amnesia (the duration and risk of which is directly related to the administered dose, with the risk increasing at higher doses. Anterograde amnesia may still be present at the end of the procedure and in isolated cases prolonged amnesia has been reported), headache, euphoria, confusion, argumentativeness, nervousness, agitation, anxiety, grogginess, irritability, restlessness, emergence delirium or agitation, prolonged emergence from anaesthesia, dreaming during emergence, sleep disturbance, insomnia, nightmares, tonic/clonic movements, muscle tremor, involuntary movements, athetoid movements, dizziness, ataxia, dysphoria, slurred speech, dysphonia, paraesthesia.

Ophthalmic.

Blurred vision, diplopia, nystagmus, pinpoint pupils, cyclic movements of eyelids, difficulty in focusing.

Integumentary.

Hives, hive-like elevation at injection site, swelling or feeling of burning, warmth or coldness at injection site, erythema, rash, pruritus.

Hypersensitivity.

In isolated cases, generalised hypersensitivity - including anaphylactic reactions and skin reactions - has been reported.

Miscellaneous.

Yawning, lethargy, chills, weakness, continued phonation, ears blocked, loss of balance, light-headedness, toothache, faint feeling, haematoma.

Post-marketing experience.

The following additional adverse effects were reported subsequent to IV administration of midazolam.

Immune system disorders.

Cardiovascular reactions, angioedema, anaphylactic shock.

Psychiatric disorders.

Disorientation, emotional and mood disturbances, hallucinations, changes in libido.

Paradoxical reactions.

Hyperactivity, hostility, anger, aggressiveness, abnormal dreams, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects, tension, mood changes, paroxysmal excitement and assault, have been reported, particularly among children and the elderly. In these cases, discontinuation of the drug should be considered.

Dependence.

Use of midazolam, even in therapeutic doses, may lead to the development of physical dependence. After prolonged IV administration, discontinuation, especially abrupt discontinuation of the product, may be accompanied by withdrawal symptoms including withdrawal convulsions. Abuse has been reported in poly-drug abusers.

Nervous system disorder.

Prolonged sedation, decreased alertness, dreaming during sleep, postoperative sedation.
Convulsions have been reported in premature infants and neonates.

Cardiac disorders.

Severe cardio-respiratory adverse effects have occurred on rare occasions. These have included 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 Special Warnings and Precautions for Use).

Respiratory disorders.

Severe cardio-respiratory adverse effects have occurred on rare occasions. These have included respiratory depression, apnoea, respiratory arrest. 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 Special Warnings and Precautions for Use).

Gastrointestinal system disorders.

Constipation, dry mouth.

Skin and appendages disorders.

Skin rash, urticaria.

General and application site disorders.

Erythema and pain on injection site, thrombophlebitis, thrombosis.

Injury, poisoning and procedural complications.

There have been reports of falls and fractures in benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

The manifestations of midazolam overdosage are similar to those observed with other benzodiazepines ranging from drowsiness to coma. Overdose of midazolam is seldom life-threatening if the medicine is taken alone, but in mild cases, may lead to symptoms including drowsiness, mental confusion and lethargy. In more serious cases, symptoms may include ataxia, areflexia, apnoea, hypotonia, hypotension, respiratory depression, coma and very rarely death. Coma 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. When combined with other CNS depressants, the effects of overdosage are likely to be severe and may prove fatal.

Treatment.

Treatment of midazolam overdose is the same as that followed for overdosage with other benzodiazepines. Respiration, pulse rate and blood pressure should be monitored and general supportive measures should be employed. In adults or children who have taken an overdose of benzodiazepines within 1 - 2 hours, consider activated charcoal with airway protection if indicated.
Flumazenil can be used to reverse the effects of midazolam (refer to Flumazenil Product Information) if CNS depression is severe. IV fluids should be administered and an adequate airway maintained. Hypotension may be combated by the judicious use of other accepted antihypotensive measures. There is no information as to whether peritoneal dialysis, forced diuresis or haemodialysis are of any value in the treatment of overdosage. Hepatic function should be monitored.
Haemoperfusion and haemodialysis are not useful in benzodiazepine intoxication.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Hypnotics and sedatives (benzodiazepine derivatives), ATC code: N05CD08.
Short-acting sleep inducing agent for sedation for short procedures, induction of anaesthesia, and for prolonged sedation in intensive care units.
Midazolam Viatris is a benzodiazepine from the imidazobenzodiazepine group.

Mechanism of action.

Midazolam is a short-acting central nervous system depressant which induces sedation, hypnosis, anaesthesia and amnesia. Like all benzodiazepines, midazolam also induces muscle relaxation. Pharmacokinetic and pharmacodynamic data in chronic IV usage are not available beyond 15 days.

Pharmacodynamic effect.

The mechanism of action of the benzodiazepines is under continuous investigation. Benzodiazepines appear to intensify the physiological inhibitory mechanisms mediated by gamma-aminobutyric acid (GABA), which is the most common inhibitory neurotransmitter in the brain.
The effects of midazolam on the CNS are dependent on the dose administered, the route of administration and the presence or absence of other premedications. After IM administration, the onset time of sedative effects is 15 minutes. Peak sedation occurs 30 - 60 minutes following administration.
When used IV (as a sedative for endoscopic or other short therapeutic or diagnostic procedures), the end point of slurred speech is reached within 2.8 - 4.8 minutes. This end point is dependent on the total dose administered and whether or not it is preceded by opioid premedication. The time to induction of anaesthesia for surgical procedures is variable, occurring in approximately 1.5 minutes (0.3 - 8 minutes) subsequent to the administration of an opioid premedication and in 2 - 2.5 minutes without premedication or with a sedative premedication. Approximately two hours are required for full recovery from midazolam-induced anaesthesia. Duration of effect is dependent on the dose and the other drugs used. Induction of anaesthesia after administration of midazolam alone is ineffective in approximately 14% of patients, however, when given with an opioid it is ineffective in about 1% of patients.
At doses sufficient to induce sedation, IV midazolam decreases the sensitivity of the ventilatory response to elevated CO2 tension in normal subjects and in those with chronic obstructive lung disease, who are at special risk of hypoxia. Sedation with midazolam has no adverse effects on pulmonary compliance and does not cause bronchoconstriction or significantly affect functional residual capacity or residual volume.
Midazolam may cause a modest decrease in mean arterial pressure. Baroreceptor response is not affected and decreases in arterial pressure are accompanied by increases in heart rate. IV midazolam at doses of 0.15 - 0.2 mg/kg did not have a harmful effect on cardiac haemodynamics.
Unless the patient is intubated, IV administration of midazolam does not alter intracranial pressure. As with thiopentone, the intracranial pressure rises during intubation. Cerebral blood flow may be reduced by up to 35%, which is of the same order as caused by equivalent doses of diazepam. The effect on cerebral metabolism is not clearly established.
Midazolam reduces the intraocular pressure to the same degree as thiopentone and diazepam. However, the increase in intraocular pressure after succinylcholine administration or endotracheal intubation is not prevented by midazolam, thiopentone or diazepam.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Absorption after IM injection.

Absorption of midazolam from the muscle tissue is rapid and virtually complete.
The mean absolute bioavailability of midazolam is > 90%. The mean time of maximum midazolam plasma concentrations occurs within 45 minutes post-administration. Peak concentrations of midazolam as well as 1-hydroxymethyl midazolam after IM are about one-half of those achieved after equivalent IV doses.

Distribution.

The pharmacokinetic profile of midazolam in man is linear over the 0.05 - 0.4 mg/kg dose range. The volume of distribution of midazolam at steady state is 0.6 - 1.9 L/kg.
Midazolam is 97% plasma protein bound.

Metabolism.

Less than 0.03% is excreted in the urine unchanged. The drug is rapidly metabolised to the active metabolite, 1-hydroxymethyl midazolam, which is conjugated with subsequent excretion in the urine. The elimination half-life of the active metabolite is similar to that of parent drug. The concentration of midazolam is 10 - 30 times greater than that of 1-hydroxymethyl midazolam.

Excretion.

In normal subjects the mean elimination half-life of midazolam is between 1.4 - 2.4 h and the clearance is in the range of 220 - 470 mL/min. Midazolam is mainly excreted by renal route: 60 - 80% of the administered dose of midazolam is excreted in urine as glucoconjugated α-hydroxymidazolam. The elimination half-life of this metabolite is < 1 h.
Compounds that inhibit or induce cytochrome P450 3A4 (CYP3A) may alter patients' elimination of midazolam, and the dose may need to be adjusted accordingly (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Pharmacokinetics in special populations.

Elderly.

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

Renal impairment.

The free fraction of midazolam in chronic renal failure may be significantly higher than normal. After correcting for protein binding the pharmacokinetics of unbound midazolam is similar to that reported in healthy volunteers.

Critically ill.

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

Cardiac insufficiency.

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

Obese.

The elimination half-life of midazolam is prolonged in obese patients. The clearance is not altered.
In patient populations with prolonged elimination half-life, midazolam infusion at an unchanged rate resulted in higher plasma levels at steady state. Consequently, the infusion rate should be reduced once a satisfactory clinical response has been obtained.

5.3 Preclinical Safety Data

Genotoxicity.

The effects of midazolam on genotoxicity have not been established. Midazolam did not have mutagenic activity in Salmonella typhimurium (five bacterial strains), Chinese hamster lung cells (V79), human lymphocytes, or in the micronucleus test in mice.

Carcinogenicity.

Midazolam maleate was administered with diet in mice and rats for two years at dosages of 1, 9 and 80 mg/kg/day. In female mice in the highest dose group there was a distinct increase in the incidence of hepatic tumours. In high dose male rats there was a small but statistically significant increase in benign thyroid follicular cell tumours. Dosages of 9 mg/kg/day of midazolam maleate do not increase the incidence of tumours. The pathogenesis of induction of these tumours is unknown. These tumours were found after chronic administration, whereas human use will ordinarily be of single dose or of short duration.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium chloride (isotonic agent), hydrochloric acid, sodium hydroxide (for pH adjustment), water for injections.

6.2 Incompatibilities

To avoid potential incompatibility with other solutions, Midazolam Viatris must not be mixed with any solution except those mentioned in Section 4.2 Dose and Method of Administration, Dilution and admixture.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store in the original package below 25°C. Protect from light. Protect packaging against any physical damage.

6.5 Nature and Contents of Container

Container type: Type I Glass ampoule.
Pack sizes: midazolam injection 5 mg in 1 mL (sterile) (5 pack, 10 pack);
midazolam injection 5 mg in 5 mL (sterile) (5 pack, 10 pack);
midazolam injection 15 mg in 3 mL (sterile) (5 pack);
midazolam injection 50 mg in 10 mL (sterile) (5 pack).
Ready for injection.
Some strengths, pack sizes and/or pack types may not be marketed.

Australian register of therapeutic goods (ARTG).

AUST R 160205 - Midazolam Viatris 15 mg/ 3 mL midazolam solution for injection ampoule.
AUST R 160206 - Midazolam Viatris 5 mg/5 mL midazolam solution for injection ampoule.
AUST R 160207 - Midazolam Viatris 5 mg/1mL midazolam solution for injection ampoule.
AUST R 160208 - Midazolam Viatris 50 mg/ 10 mL midazolam solution for injection ampoule.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking it to your local pharmacy.

6.7 Physicochemical Properties

The active ingredient of Midazolam Viatris is 8-chloro-6- (2-fluorophenyl)-1-methyl-4H-imidazo [1,5-a][1,4] benzodiazepine (midazolam).
Molecular Formula: C18H13ClFN3 Molecular Weight: 325.8.
The free base of the active substance of Midazolam Viatris is a lipophilic substance with low solubility in water. The basic nitrogen in position 2 of the imidazobenzodiazepine ring enables the active substance, midazolam to form water-soluble salts with acids. These produce a stable injection solution.

Chemical structure.


CAS number.

59467-70-8.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes