Midazolam 1 mg/ml solution for injection/infusion – patient leaflet, side effects, dosage

1. What Midazolam is and what it is used for

Midazolam belongs to a class of

medicines called benzodiazepines

(sedatives). It is a short-acting

medicine that is used to induce

sedation (a state of calm, drowsiness

or sleep) and relieves anxiety and

muscle tension. This drug is used for:

• Conscious sedation (an awake

  state of calm or drowsiness) in

  adults and children.

• Sedation of adults and children,

  in intensive care units.

• Anaesthesia in adults

  (premedication before induction,

  induction of anaesthesia, as

  a sedative component with other

  medicines for maintenance of

  anaesthesia).

• Premedication before induction

  of anaesthesia in children.

2. What you need to know before you are given Midazolam

You should not be given

Midazolam:

• if you are allergic to midazolam,

  other benzodiazepines or any of

  the other ingredients of this

  medicine (listed in section 6),

• for conscious sedation, if you

  have severe breathing difficulties.

Warnings and precautions

Talk to your doctor or nurse before

you are given Midazolam if you:

• are over 60 years of age,

• have a long-term illness or are

  debilitated (e.g. chronic respiratory

  problems, kidney, liver or heart

  diseases),

• have myasthenia gravis

  (a neuromuscular disease

  characterized by muscle weakness),

• have a history of alcohol or drug

  abuse,

• are using other medicines,

  including those not prescribed by

  your attending physician (see

  section “Other medicines and

  Midazolam”),

• if your breathing sometimes stops

  while you are sleeping,

• are pregnant or if you suspect

  pregnancy.

Midazolam should be used only

when age- and size-appropriate

resuscitation facilities are available.

Administration of midazolam may

depress myocardial contractility

and cause apnoea (pauses in

breathing). In rare cases severe

cardiorespiratory complications

have occurred, including respiratory

depression, apnoea, respiratory

and/or cardiac arrest. To avoid such

complications the medicine should be

injected slowly and the administered

dose must be as low as possible.

Special caution is required when

using midazolam in infants or

children. Let your doctor know if

your child has a cardiovascular

disease or breathing problems.

Your child will be monitored and

the dose will be specially adjusted.

Patients under 6 months of age

undergoing sedation in an intensive

care unit are more likely to develop

breathing problems, so their dosing

will be increased very slowly and

their breathing and oxygen levels

will be observed.

When midazolam is used for

premedication, your response to the

drug will be checked and the correct

dosage for you will be ascertained,

as sensitivity varies between

patients. Midazolam is not

recommended for new-borns or

children under 6 months of age.

Paradoxical reactions and

anterograde amnesia (loss of

memory for recent events) have

been reported to occur with

midazolam (see section 4).

Long-term treatment

If you receive midazolam for

a longer period, you may become

tolerant (midazolam becomes less

effective) or dependent upon this

medicine.

After long-term treatment (e.g. in

intensive care unit) the following

withdrawal symptoms may occur:

headaches, diarrhoea, muscle pain,

anxiety, tension, restlessness,

confusion, irritability, sleep

disturbances, mood changes,

hallucinations and convulsions. In

severe cases, depersonalisation,

numbness and tingling of the

extremities, hypersensitivity to

light, noise and physical contact

may occur. In order to avoid getting

such adverse reactions your doctor

will reduce the dosage gradually.

Other medicines and Midazolam

Tell your doctor or nurse if you are

taking, have recently taken or might

take any other medicines.

This is extremely important, as

using more than one medicine at

the same time can strengthen or

weaken the effect of the medicines

involved.

In particular, tell your doctor or

nurse if you are using any of the

following medicines:

• tranquilisers (for anxiety or to

  help you sleep),

• sedatives (to make you feel calm

  or sleepy),

• hypnotics (sleep medicines),

• antidepressants (medicines for

  depression, e.g. nefazodone),

• narcotic analgesics (very strong

  pain killers, e.g. fentanyl),

• anaesthetics (e.g. propofol),

• some antihistamines (allergy

  drugs),

• antifungal medicines

  (ketoconazole, voriconazole,

  fluconazole, itraconazole, posaconazole),

  • antibiotics (erythromycin, clarithromycin, telithromycin, roxithromycin),
  • blood pressure drugs, calcium channel blocker like diltiazem, verapamil,
  • medicines for HIV (human immunodeficiency virus) (efavirenz or saquinavir, lopinavir and other protease inhibitors),
  • medicines for treatment of hepatitis C virus (simeprevir, boceprevir and telaprevir),

  • medicines for epilepsy

    (carbamazepine, phenytoin or valproic acid),

  • atorvastatin (used to treat high cholesterol),
  • rifampicin (used to treat mycobacterial infections such as tuberculosis),
  • ticagrelor (used to prevent heart attack),

  • aprepitant, netupitant,

    casoprepitant (used to stop you feeling or being sick),

  • some medicines to treat cancer (e.g. imatinib, lapatinib, idelalisib, vermurafenib),
  • everolimus, ciclosporin (used to prevent organ transplant rejection),
  • propiverine (used for urinary incontinence),
  • herbal medicines (e.g. St John’s Wort, Ginkgo biloba or ginseng).

Concomitant use of midazolam and opioids (strong pain killers, medicines for substitution therapy and some cough medicines) increases the risk of drowsiness, difficulties in breathing (respiratory depression), coma and may be life-threatening. Because of this, concomitant use should only be considered when other treatment options are not possible.

However if your doctor does prescribe midazolam together with opioids the dose and duration of concomitant treatment should be limited by your doctor.

Please tell your doctor about all opioid medicines you are taking, and follow your doctor’s dose recommendation closely. It could be helpful to inform friends or relatives to be aware of the signs and symptoms stated above. Contact your doctor when experiencing such symptoms.

Operations

If you are going to have an inhaled anaesthetic (one that you breathe in) for an operation or for dental treatment, it is important to tell your doctor or dentist that you have been given Midazolam.

Midazolam with alcohol

Alcohol may strengthen the sedative (calming) effect of midazolam therefore you should avoid any alcohol intake.

Pregnancy and breast-feeding

If you are pregnant or

breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before this medicine is given to you. Your doctor will decide if this medicine should be given to you or not.

After you have been given Midazolam, do not breastfeed for 24 hours. This is because midazolam may pass into your breast milk.

Driving and using machines

Midazolam has a major influence on the ability to drive and use machines.

This medicine may cause sleepiness and forgetfulness, and affect your concentration and co-ordination. This may affect your performance at skilled tasks such as driving or using machines. After midazolam administration you should not drive or operate machines until completely recovered. The doctor will tell you when you can recommence these activities. You should always be taken home by a responsible adult after your treatment.

If insufficient sleep occurs or alcohol is consumed, the likelihood of impaired alertness may be increased.

Midazolam contains sodium

Midazolam 1 mg/ml

In daily dose up to 6.5 ml this medicine contains less than 1 mmol sodium (23 mg), that is to say essentially ‘sodium-free’. If daily dose 6.6 ml or more is administered (equivalent to more than 1 mmol sodium) the following should be taken into account: This medicine contains 3.5 mg sodium (main component of cooking/table salt) in each ml of solution. This is equivalent to 0.18 % of the recommended maximum daily dietary intake of sodium for an adult.

Midazolam 5 mg/ml

In daily dose up to 7.3 ml this medicine contains less than 1 mmol sodium (23 mg), that is to say essentially ‘sodium-free’. If daily dose 7.4 ml or more is administered (equivalent to more than 1 mmol sodium) the following should be taken into account: This medicine contains 3.15 mg sodium (main component of cooking/table salt) in each ml of solution. This is equivalent to 0.16 % of the recommended maximum daily dietary intake of sodium for an adult.

3. How Midazolam is given

This medicine should be

administered only by experienced physicians in a place that has the equipment needed to monitor and support the respiratory and cardiovascular function, or by persons specifically trained in the recognition and management of adverse reactions.

Dosage and route of administration Your doctor will decide on a suitable dose for you. The dosages vary depending on the treatment planned and the required sedation. The dose you will receive depends on your weight, age, general condition of health, concomitant medication, response to the drug and whether other medicines are required at the same time.

If you need strong pain killers, you will receive these first and then have your Midazolam dose adjusted specially for you.

This medicine will be injected directly into your vein

(intravenously), administered by

The following information is intended for healthcare professionals only:

Instructions for use

Midazolam is compatible with the

following solutions for infusion:

• sodium chloride 0.9 % solution
• glucose 5 % solution
• glucose 10 % solution
• Ringer's solution
• Hartmann's solution

For intravenous infusion, the content

of Midazolam ampoules may be

diluted with one of the solution

mentioned above in a ratio of 15 mg

midazolam per 100 to 1000 ml of

infusion solution.

Midazolam solution for

injection/infusion must not be diluted with Macrodex 6 % solution in glucose.

Midazolam solution for

injection/infusion must not be mixed with alkaline solutions for injection. Midazolam precipitates in solutions containing hydrogen carbonate.

To avoid potential incompatibility, Midazolam solution for

injection/infusion must not be mixed with other solutions except those mentioned above.

Midazolam solution for

injection/infusion is intended for single use.

05.06.2024. MUK/I/0/1

Place for bleedmarks

infusion, injected into the muscle (intramuscularly) or administered rectally.

Children and neonates

In neonates and infants under 6 months of age midazolam is only recommended for sedation in intensive care units. The dose will be given gradually into a vein.

Children 12 years and under will usually be given midazolam into a vein. When this medicine is used for premedication (to cause

relaxation, calm and drowsiness before an anaesthetic) it may be given into the back passage (rectum).

If you are given more Midazolam than you should

The medicine is administered by the doctor or nurse.

If you are accidentally given too much midazolam, this could lead to drowsiness, ataxia (coordination disorders of voluntary muscular action), dysarthria (speech disorder) and nystagmus (involuntary eye movements), loss of reflexes, apnoea (suspension of breathing), hypotension (low blood pressure), cardiac and respiratory depression, and coma. In case of overdose careful monitoring of vital signs, symptomatic treatment of cardiorespiratory effects and use of benzodiazepine antagonist may be required.

If you stop using Midazolam

Sudden discontinuation of treatment can be accompanied by withdrawal symptoms such as headache, muscular pain, anxiety, tension, restlessness, confusion, mood swings, hallucinations and convulsions, rebound insomnia, irritability. Since the risk of withdrawal symptoms occurring is greater if treatment is discontinued abruptly, dose should be reduced gradually when treatment is being discontinued.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell a doctor straight away if you notice any of the following side effects. They can be life-threatening and you may need urgent medical treatment:

• Anaphylactic shock

  (a life-threatening allergic reaction). Signs may include a sudden rash, itching or lumpy rash (hives) and swelling of the face, lips, tongue or other parts of the body. You may also have shortness of breath, wheezing or trouble breathing, or a pale skin, a weak and rapid pulse, or feeling of loss of consciousness.

  Additionally, you may experience chest pain, which can be a sign of a potentially serious allergic reaction called Kounis syndrome.

• Heart attack (cardiac arrest). Signs may include chest pain which may spread to your neck and shoulders and down your left arm.

• Breathing problems or

  complications (sometimes causing the breathing to stop).

• Choking and sudden blockage of the airway (laryngospasm).

Life-threatening side effects are more likely to occur in adults over 60 years of age and those who already have breathing difficulties or heart problems, particularly if the injection is given too fast or at a high dose.

Other possible side effects:

The following side effects have been reported but their frequency is not known and cannot be estimated from the available data:

Immune system disorders: general allergic reactions (skin reactions, heart and vascular system reactions, wheezing).

Psychiatric disorders: confusion, disorientation, emotional and mood disturbances, changes in libido. Paradoxical reactions such as restlessness, agitation, irritability, nervousness, muscle spasms and tremors, hostility, delusion, anger, aggressiveness, anxiety, nightmares, abnormal dreams, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects, excitement and assault have been reported. These have mostly been observed if the injection is given too fast or at a high dose. The risk of the appearance of these symptoms is greater in children and elderly patients.

Dependence: midazolam may cause development of physical dependence, even if used in therapeutic doses. The withdrawal symptoms, including seizures, which may occur after prolonged administration of midazolam, can be avoided with gradual reduction in dosage (see section 2).

Nervous system disorders:

drowsiness and prolonged sedation, decreased alertness, somnolence, headache, dizziness, muscular coordination disorders. Temporary memory loss has been reported. Its duration depends on dosage administered and it may also occur after the treatment. In isolated cases the memory loss has been prolonged. Convulsions have been reported in preterm infants and new-born babies.

Cardiac disorders: severe adverse reactions have occurred, such as low blood pressure, slow heart rate, dilation of blood vessels (e.g. flushing, fainting and headache).

Gastrointestinal disorders: nausea, vomiting, constipation, dry mouth.

Skin disorders: skin rash, allergic reaction, itching.

General disorders and

administration site conditions: tiredness, redness, swelling of the skin, blood clots and pain at the injection site (erythema,

thrombophlebitis and thrombosis). Patients taking benzodiazepines are at a higher risk of falling and breaking bones, especially the elderly and those taking other sedatives (including alcoholic beverages).

Patients with severe kidney disease are more likely to experience side effects.

Reporting of side effects

If you get any side effects, talk to your anaesthetist or other doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via: Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Midazolam

This medicine does not require any special temperature storage conditions. Keep the ampoules in the outer carton in order to protect from light.

Keep this medicine out of the sight and reach of children.

After opening the ampoule the product should be used immediately.

Chemical and physical in-use stability has been demonstrated 24 hours at 25 °C and 3 days at 2 - 8 °C temperature with following infusion solutions: sodium chloride 0.9 %, glucose 5 % and 10 %, Ringer`s solution and Hartmann`s solution. From a microbiological point of view, the dilutions 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 °C to 8 °C, unless dilution has taken place in controlled and validated aseptic conditions.

Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Midazolam contains

• The active substance is midazolam.

Midazolam 1 mg/ml

1 ml of solution contains 1 mg of midazolam.

One ampoule with 5 ml of solution contains 5 mg of midazolam.

Midazolam 5 mg/ml

1 ml of solution contains 5 mg of midazolam.

One ampoule with 1 ml of solution contains 5 mg of midazolam. One ampoule with 3 ml of solution contains 15 mg of midazolam. One ampoule with 10 ml of solution contains 50 mg of midazolam.

• The excipients are: hydrochloric acid concentrated, sodium chloride, sodium hydroxide (for pH adjustment), water for injections.

What Midazolam looks like and contents of the pack

Clear, colourless solution for injection/infusion of 1 ml, 3 ml or 10 ml (for 5 mg/ml) and 5 ml solution (for 1 mg/ml) filled in Type I colourless glass ampoules with one point cut.

Pack size: 5 or 10 ampoules. Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

AS KALCEKS

Krustpils iela 71E, Rīga, LV-1057, Latvia

This medicine is authorised in the Member States of the European Economic Area and in the United Kingdom (Northern Ireland) under the following names:

Estonia, Czech Republic, Poland, Italy, Sweden Midazolam Kalceks Austria Midazolam Kalceks

1 mg/ml, 5 mg/ml Injektions-/

Infusionslösung Belgium Midazolam Kalceks

1 mg/ml, 5 mg/ml solution

injectable/pour perfusion Midazolam Kalceks 1 mg/ml, 5 mg/ml oplossing voor injectie/infusie Midazolam Kalceks 1 mg/ml, 5 mg/ml Injektions-/

Infusionslösung Bulgaria Midazolam Kalceks

1 mg/ml, 5 mg/ml инжекционен/ инфузионен разтвор Croatia Midazolam Kalceks

1 mg/ml, 5 mg/ml otopina za injekciju/infuziju France MIDAZOLAM

KALCEKS 1 mg/mL, 5 mg/mL, solution injectable/pour perfusion

Germany Midazolam Kalceks

1 mg/ml Injektions-/ Infusionslösung Midazolam

Ethypharm Kalceks 5 mg/ml Injektions-/ Infusionslösung Hungary Midazolam Kalceks

1 mg/ml, 5 mg/ml oldatos injekció vagy infúzió

Ireland Midazolam 1 mg/ml,

5 mg/ml solution for injection/infusion Latvia Midazolam Kalceks

1 mg/ml, 5 mg/ml šķīdums

injekcijām/infūzijām Lithuania Midazolam Kalceks

1 mg/ml, 5 mg/ml injekcinis ar infuzinis tirpalas

The Netherlands Midazolam Kalceks

1 mg/ml, 5 mg/ml oplossing voor injectie/infusie Slovakia Midazolam Kalceks

1 mg/ml, 5 mg/ml injekčný/infúzny roztok

United Kingdom (Northern Ireland)

Midazolam 1 mg/ml, 5 mg/ml solution for injection/infusion

This leaflet was last revised in 05/2024

The solution should be examined visually before administration. Only clear solution without visible particles may be used.

Instruction of ampoule opening:

1. 1) Turn the ampoule with coloured point up. If there is any solution in the upper part of the ampoule, gently tap with your finger to get all the solution to the lower part of the ampoule.
2. 2) Use both hands to open; while holding the lower part of the ampoule in one hand, use the other hand to break off the upper part of the ampoule in the direction away from the coloured point (see the pictures below).