PATIENT INFORMATION LEAFLET

Midazolam 1 mg/ml Solution for Injection or Infusion Midazolam 5 mg/ml Solution for Injection or Infusion

Midazolam

Read all of this leaflet carefully before you start using this medicine

•    Keep this leaflet. You may need to read it again.

•    If you have any further questions, ask your doctor or your pharmacist or nurse.

•    This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.

•    If you get any side effects, talk to your doctor or pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4

What is in this leaflet:

1.    What midazolam is and what it is used for

2.    What you need to know before you take midazolam

3.    How to use midazolam

4.    Possible side effects

5.    How to store midazolam

6.    Contents of the pack and other information

1. What midazolam is and what it is used for

Midazolam 1 mg/ml & 5 mg/ml Solution for Injection or Infusion contains Midazolam. Midazolam belongs to a group of medicines known as benzodiazepines (sedatives).

It is a short acting medicine that is used to induce sedation (a state of calm, drowsiness or sleep) and relieves anxiety, muscle tension. It has anticonvulsant effects and causes anterograde amnesia. This medicine is used for:

-    Conscious sedation (state of calm or drowsiness where you remain awake) in adults and children

-    Sedation in intensive care units in adults and children.

-    Anaesthesia in adults (premedication before induction, induction of anaesthesia, as a sedative component with other medicines in anaesthesia)

-    Premedication before induction of anaesthesia in children.

2. What you need to know before you take midazolam

Do not use midazolam

•    If you are allergic (hypersensitive) to midazolam, group of medicines known as benzodiazepines or any of the midazolam solution for injection

•    If you have severe difficulties with your breathing and that you are to undergo conscious sedation.

Take Special Care with midazolam

Midazolam should be used only when age- and size-appropriate resuscitation facilities are available. Administration of midazolam may depress myocardial contractility and cause apnoea (suspension of breathing). Severe cardio respiratory adverse events have occurred on rare occasions. These have included respiratory depression, apnea, respiratory and/or cardiac arrest. To avoid such incidents, the injection should be given slowly and the dose should be as low as possible.

Special care needs to be taken if midazolam is used in babies or children. Let your doctor know if your child has a cardiovascular disease. Your child will be carefully monitored and the dose will be adjusted specially. Patients under 6 months old in sedation in Intensive Care Unit are more likely to develop breathing problems, so they will be dosed very gradually and their breathing and oxygen levels observed.

When midazolam is given as a premedication, you will be checked closely to how you respond and to ensure you have received the right dose as the sensitivity varies depending of the patient.

The use of midazolam is not recommended in neonates and children up to 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. Possible Side Effects).

Let your doctor know if you:

-    are over 60 years of age

-    have a long term illness or are debilitated (for example, chronic respiratory problems, renal, hepatic or cardiac disorders).

-    have a myasthenia gravis (neuromuscular disease characterized by a muscle weakness).

-    have a history of alcohol or drug abuse.

-    are taking any other medicines including those not prescribed by your

doctor (for more information see section 'Using other medicines')

- are pregnant or think be pregnant.

Long term treatment

If you receive long-term midazolam, you may become tolerant (midazolam becomes less effective) or you may be become dependent upon this medicine. After treatment for a long time (such as in an intensive care unit) the following withdrawal symptoms may occur: headaches, muscle pain, anxiety, tension, restlessness, confusion, irritability, inability to sleep, mood changes, hallucinations and convulsions. Your doctor will reduce your dose gradually to avoid these effects happening to you.

Using other medicines:

Please tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

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 taking any of the following medicines:

•    tranquilisers (for anxiety or to help you sleep)

•    hypnotics (medicines to make you sleep)

•    sedatives (to make you feel calm or sleepy)

•    nefazodone and other antidepressants (medicines for depression)

•    narcotic analgesics (very strong pain killers)

•    antihistamines (used to treat allergies)

•    medicines to treat fungal infections (ketoconazole, voriconazole, fluconazole, itraconazole, posaconazole)

•    macrolide antibiotics (such as erythromycin, clarithromycin or roxithromycin)

•    diltiazem, verapamil (used to treat high blood pressure)

•    medicines for HIV called protease inhibitors (such as saquinavir)

•    atorvastatin (used to treat high cholesterol)

•    aprepitant (medicine for prevention of chemotherapy-induced nausea and vomiting)

•    rifampicin (used to treat mycobacterial infections such as tuberculosis)

•    carbamezapine or phenytoin (used to treat epileptic seizures and nerve pain)

•    efavirenz (used to treat Human immunodeficiency virus)

•    the herbal medicine St. John's Wort.

If any of the above apply to you, or if you are not sure, talk to your doctor or nurse before you are given Midazolam.

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.

Using midazolam with food and drink

While you are using midazolam you must not drink any alcohol, since alcohol can markedly increase the sedative effect of midazolam.

Pregnancy and breast-feeding and fertility:

•    If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. If your doctor decides that you should be given this medicine during late pregnancy, labour or caesarean section, you might have an inhalation risk and your baby might have an irregular heart beat, hypotonia (state of low muscle tone), feeding difficulties, a low body temperature and respiratory depression.

•    If you have passed through prolonged treatment during last phase of pregnancy with this medicine, your baby may develop physical dependence and risk of withdrawal symptoms after birth.

•    Midazolam may pass into breast milk, therefore, if you are breast feeding you should not do so for 24 hours after receiving this medicine.

Driving and using machines:

This medicine may make you sleepy, forgetful, dizzy or affect your concentration and co-ordination.

•    Do not drive while taking this medicine until you know how it affects you.

This may affect your performance at skilled tasks, e.g. driving or operating machinery.

•    After midazolam administration you should not drive a vehicle or operate a machine until completely recovered. Your doctor should advise you when you can start these again.

•    You should always be accompanied to home by a responsible adult after your treatment.

•    It is an offence to drive if this medicine affects your ability to drive.

•    However, you would not be committing an offence if:

-    The medicine has been prescribed to treat a medical or dental problem and

-    You have taken it according to the instructions given by the prescriber or in the information provided with the medicine and

-    It was not affecting your ability to drive safely

Talk to your doctor or pharmacist if you are not sure whether it is safe for you to drive while taking this medicine.

Important information about some of the ingredients of midazolam solution for injection

This medicinal product contains less than 1 mmol sodium (23 mg) per dose i.e. essentially 'sodium free'.

3. How to use midazolam

Midazolam should be administered only by experienced physicians in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function and by persons specifically trained in the recognition and management of expected adverse events.

Instructions for proper use

Midazolam is compatible with the following infusion solutions:

-    sodium chloride 9 mg/ml (0.9 %) solution

-    5 % dextrose solution

-    10 % dextrose solution

-    Fructose 50 mg/ml (5 %) solution

-    Ringer solution

-    Hartmann's solution

Do not dilute midazolam solutions with 6% w/v dextran (with 0.9% sodium chloride) in dextrose.

Do not mix midazolam ampoule solutions in alkaline injections.

Midazolam precipitates in sodium bicarbonate.

To avoid potential incompatibility with other solutions, midazolam ampoule solution must not be mixed with other solutions except those mentioned above.

Dosage and route of administration

Your doctor will decide on a suitable dose for you. Doses vary considerably and will depend on the planned treatment and the sedation required. Your weight, age, general condition of health, concomitant medication, response to the drug and whether other medicines are required at the same time will also influence the dose that you receive.

If you are to receive strong painkillers, you will receive these first and then have your midazolam dose adjusted specially for you.

Midazolam is given slowly, by injection into a vein (intravenously), by a drip (infusion), injection into a muscle (intramuscular) or via rectal administration.

Midazolam ampoules are for single use only. Discard any unused solution.

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

If you use more midazolam than you should

Your medicine will be given by a doctor.

If you accidentally got an overdose, this could lead to sleepiness, ataxia (in coordination of voluntary muscular action), dysarthria (speech disorder) and nystagmus (involuntary eye movements), loss of reflexes, apnoea (suspension of breathing), hypotension (low blood pressure), cardio respiratory depression and coma. Overdose may require intense vital sign monitoring and symptomatic treatment of cardio respiratory effects and use of benzodiazepine antagonist.

If you stop using midazolam

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

For further information on preparation of the medicinal product before use please refers the end of the PIL 'The following information is intended for medical or healthcare professionals only'.

4. Possible side effects

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

Not known (Frequency cannot be estimated):

Immune System Disorders:

General allergic reactions

•    skin reactions

•    heart and blood system reactions

•    wheezing

•    anaphylactic shock (a life-threatening allergic reaction)

The following information is intended for medical or healthcare professionals only

Preparation of solution for infusion

Midazolam injection can be diluted with 0.9% sodium chloride solution, 5% or 10% dextrose solution, or Ringer or Hartmann solution at a ratio of 15 mg of

midazolam to 100-1,000 ml of infusion solution. These solutions remain stable for 24 hours at room temperature, and 3 days at 5°C. Midazolam injection must not be mixed with any solution other than those listed above. In particular, midazolam injection must not be diluted with 6% w/v dextran (with 0.9% sodium chloride) in dextrose or mixed with alkaline injection injections. Midazolam precipitates in sodium bicarbonate.

The solution for injection should be examined visually before administration. Only solutions without visible particles should be used.

Shelf Life and storage

Midazolam Injection ampoules are intended for single use only.

Psychiatric disorders:

•    confusion

•    euphoria

•    hallucinations

•    mood change

•    Paradoxical reactions (the opposite to those expected) were observed in the case of children and elderly people. These took the form of following:

-    agitation

-    aggressiveness

-    hyperactivity

-    hostility

-    violence

-    involuntary movements (including regular and jerky muscle spasms and muscular tremor)

-    paroxysmal excitement

-    rage reactions

•    These have been observed more when a high dose has been given, or administered too quickly. Children and the elderly are more susceptible to these reactions.

•    Dependence: Patients can become dependant on midazolam, even in therapeutic doses. After prolonged use, doses of midazolam will reduce gradually to avoid withdrawal symptoms including convulsions (see section 2 'BEFORE YOU USE midazolam - Long term treatment').

Nervous system disorders:

•    fatigue

•    headache

•    difficulty co-ordinating muscles

•    dizziness

•    reduced alertness

•    somnolence

•    prolong sedation

•    Temporary memory loss has been reported. How long this lasts will depend on how much midazolam solution for injection you were given and you may experience this after your treatment. In isolated cases this has been prolonged.

•    Convulsions have been reported in premature infants and new-born babies. Cardiac disorders:

•    severe events have occurred and include heart attack (cardiac arrest)

•    low blood pressure

•    slow heart rate

•    vasodilating effects (for example flushing, fainting and headache)

Respiratory, thoracic and mediastinal disorders:

•    breathing complications (sometimes causing the breathing to stop)

•    shortness of breath

•    sudden blockage of the airway (laryngospasm)

•    hiccoughs

•    Life-threatening incidents are more likely to occur in adults over 60 years of age and those already experiencing breathing difficulties or heart problems, particularly when the injection is given too rapidly or at a high dose (see section “Take special care”)

Gastrointestinal disorders:

•    nausea

•    vomiting

•    constipation

•    dry mouth.

Skin and subcutaneous tissue disorders:

•    redness of the skin (rash)

•    itching weals (urticaria)

•    itching skin with a compulsion to scratch (pruritus)

General disorders and administration site conditions:

•    fatigue

•    redness and pain at injection site (erythema - redness of skin)

•    swelling of skin

•    blood clots (thrombosis) and inflammation due to blood clot (thrombophlebitis)

•    An increased risk for falls and fractures has been recorded in elderly users of benzodiazepines (medicines that induce a state of calm, drowsiness or sleep).

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store midazolam

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

•    Do not use midazolam after the expiry date (EXP) which is stated on the carton and ampoule. The expiry date refers to the last day of that month.

•    Store in the original package in order to protect from light.

Shelf life after dilution

Chemical and physical in-use stability of the dilutions has been demonstrated for 24 hours at room temperature (15 - 25°C) or for 3 days at +2 to +8 °C.

From the microbiological point of view, the dilutions should be used immediately.

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

•    The product is for single used and any remaining solution should be discarded. (The injection solution contains no preservatives).

•    Do not use midazolam solution for injection or infusion if container is found leaking, solution is not clear with visible particles or any discoloration of the solution.

•    Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

6. Contents of the pack and other information

What midazolam contains:

The active ingredient is midazolam (as hydrochloride).

For 1 mg/ml

Each ml of solution for injection contains 1 mg of midazolam (as midazolam hydrochloride)

Presentations    5    ml

Amount of midazolam    5 mg

For 5 mg/ml

Each ml of solution for injection contains 5 mg of midazolam (as midazolam hydrochloride)

Presentations    1    ml    3 ml    10 ml

Amount of midazolam    5 mg    15 mg    50 mg

The other ingredients include water for injections, sodium chloride,

sodium hydroxide (for pH adjustment) and concentrated hydrochloric acid

(for pH adjustment).

What midazolam solution for injection looks like and contents of the pack:

Midazolam solution for injection is a clear colourless to pale yellow solution filled in a clear glass ampoule.

Midazolam solution for injection is available in pack of 10 X 5 ml ampoules for 1 mg/ml formulation.

Midazolam solution for injection is available in pack of 10 X 1ml, 10 X 3 ml, 10 X 10 ml and 1 X 10 ml ampoules for 5 mg/ml formulation.

The ampoule are available in blister/ tray pack.

Not all pack sizes may be marketed.

Manufacturing authorisation holder and manufacturer:

Accord Healthcare Limited Sage House,

319 Pinner Road,

North Harrow,

Middlesex, HA1 4HF, UK

This medicinal product is authorized in the Member States of the EEA under the following names:

Name of the Name of the medicinal product member state

Austria    Midazolam Accord 1 mg/ml, Injektionslosung

oder Infusionslosung

Midazolam Accord 5 mg/ml, Injektionslosung oder Infusionslosung

Belgium    Midazolam Accord Healthcare 1 mg/ml, solution

pour injection ou perfusion/ oplossing voor injectie of infusie/ Losung zur Injektion oder Infusion Midazolam Accord Healthcare 5 mg/ml, solution pour injection ou perfusion/ oplossing voor injectie of infusie/ Losung zur Injektion oder Infusion Cyprus    Midazolam Accord 1 mg/ml, svsaipo SiaAupa q

SiaAupa Yia SYXuaq

Midazolam Accord 5 mg/ml, svsaipo SiaAupa q SiaAupa Yia SYXuaq

Czech Republic Midazolam Accord 1 mg/ml, injekcm roztok nebo infuzi Midazolam Accord 5 mg/ml, injekcm roztok nebo infuzi Germany    Midazolam Accord 1 mg/ml Injektionslosung oder

Infusionslosung

Midazolam Accord 5 mg/ml Injektionslosung oder Infusionslosung

Denmark    Midazolam Accord 1 mg/ml, injektions og

infusionsv^ske, oplosning Midazolam Accord 5 mg/ml, injektions og infusionsv^ske, oplosning

Estonia    Midazolam Accord 1 mg/ml, injekcinis ar infuzinis tirpalas

Midazolam Accord 5 mg/ml, injekcinis ar infuzinis tirpalas Greece    Midazolam Accord 1 mg/ml, svsaipo SiaAupa q

SiaAupa Yia SYXuaq

Midazolam Accord 5 mg/ml, svsaipo SiaAupa q SiaAupa Yia SYXuaq

Spain    Midazolam Accord 1 mg/ml, para inyeccion o infusion

Midazolam Accord 5 mg/ml, para inyeccion o infusion Finland    Midazolam Accord 1 mg/ml, injektio- tai

infuusioneste/ Losning for injektion och infusion Midazolam Accord 5 mg/ml, injektio- tai infuusioneste/ Losning for injektion och infusion Hungary    Midazolam Accord 1 mg/ml, oldatos injekcio/ infuzio

Midazolam Accord 5 mg/ml, oldatos injekcio/ infuzio Ireland    Midazolam 1 mg/ml, Solution for Injection or Infusion

Midazolam 5 mg/ml, Solution for Injection or Infusion Italy    Midazolam Accord 1 mg/ml, Soluzione per

Iniezione o Infusione

Midazolam Accord 5 mg/ml, Soluzione per Iniezione o Infusione

Latvia    Midazolam Accord 1 mg/ml, skfdums injekcijam

vai infuzijam

Midazolam Accord 5 mg/ml, skfdums injekcijam vai infuzijam

Malta    Midazolam 1 mg/ml, Solution for Injection or Infusion

Midazolam 5 mg/ml, Solution for Injection or Infusion The Netherlands Midazolam Accord 1 mg/ml, oplossing voor injectie of infusie

Midazolam Accord 5 mg/ml, oplossing voor injectie of infusie

Midazolam Accord 1 mg/ml, opplosning til injeksjon og infusjon

Midazolam Accord 5 mg/ml, opplosning til injeksjon og infusjon Midazolam Accord Midazolam Accord

Midazolam Accord 1 mg/ml, Losning for injektion och infusion

Midazolam Accord 5 mg/ml, Losning for injektion och infusion

Midazolam Accord 1 mg/ml, raztopina za injiciranje ali infundiranje Midazolam Accord 5 mg/ml, raztopina za injiciranje ali infundiranje

Slovak Republic Midazolam Accord 1 mg/ml, injekcny alebo infuzny roztok

Midazolam Accord 5 mg/ml, injekcny alebo infuzny roztok

Midazolam 1 mg/ml, Solution for Injection or Infusion Midazolam 5 mg/ml, Solution for Injection or Infusion

This leaflet was last revised in 12/2014.

Ampoule before opening

Store in the original package in order to protect from light Ampoule after dilution

Chemical and physical in-use stability of the dilutions has been demonstrated for 24 hours at room temperature (15 - 25°C) or for 3 days at 5°C.

From the microbiological point of view, the dilutions should be used immediately.

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

In case of continuous intravenous infusion, midazolam injection solution may be diluted in the range of 0.015 to 0.15 mg with one of the solution mentioned above.

Disposal of waste

Any unused product or waste material should be disposed of in accordance with local requirements.