Midazolam Kalceks

Package leaflet: Information for the user

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

Generic Medicine
midazolam
Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or nurse.
• If you experience any side effects, including those not listed in this leaflet, contact your doctor or nurse. See section 4.

Contents of this leaflet:

1. What Midazolam Kalceks is and what it is used for
2. What you need to know before being given Midazolam Kalceks
3. How Midazolam Kalceks is administered
4. Possible side effects
5. How to store Midazolam Kalceks
6. Contents of the pack and other information

1. What Midazolam Kalceks is and what it is used for

Midazolam belongs to a class of medicines called benzodiazepines (sedatives). It is a short-acting medicine used to induce sedation (a state of calmness, drowsiness or sleep) and to relieve anxiety and muscle tension. This medicine is used for:

• Conscious sedation (a state of wakefulness characterized by calmness and 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 should know before receiving Midazolam Kalceks

Midazolam Kalceks must not be administered to you if:

• you are allergic to midazolam, to other benzodiazepines, or to any of the other ingredients of this medicine (listed in section 6),
• for conscious sedation, if you have severe respiratory difficulties.

Warnings and precautions
Please consult your doctor or nurse before receiving Midazolam Kalceks if:

• you are over 60 years of age,
• you have a long-term illness or are debilitated (e.g. chronic respiratory problems, kidney, liver or heart disease),
• you suffer from severe myasthenia (a neuromuscular disease characterized by muscle weakness),
• you have a history of alcohol or substance abuse,
• you are taking other medicines, including those not prescribed by your doctor (see section “Other medicines and Midazolam Kalceks”),
• your breathing sometimes stops while you sleep,
• you are pregnant or suspect you may be pregnant.

Midazolam Kalceks must only be used when appropriate resuscitation facilities are available, suitable for the patient's age and body size. Administration of midazolam may depress myocardial contractility and cause apnea (pauses in breathing). Rarely, serious cardiorespiratory complications have occurred, including respiratory depression, apnea, respiratory arrest, and/or cardiac arrest. To avoid such complications, the medicine must be injected slowly and the administered dose should be as low as possible.
The use of midazolam in neonates or children requires particular caution. Inform your doctor if your child suffers from cardiovascular disease or respiratory problems. Your child will be closely monitored and the dose will be specifically adjusted.
Infants under 6 months of age undergoing sedation in an intensive care unit have a higher risk of developing respiratory problems; therefore, the dose will be increased very slowly and breathing and oxygen levels will be closely monitored.
When midazolam is used for premedication, your response to the drug will be monitored and the correct dose for you will be determined, as sensitivity varies from patient to patient. Midazolam is not recommended for neonates or children under 6 months of age.
Paradoxical reactions and anterograde amnesia (loss of memory for recent events) have been reported with midazolam (see section 4).

Long-term treatment
If you receive midazolam for a prolonged period, you may develop tolerance (midazolam becomes less effective) or become dependent on this medicine.
After long-term treatment (e.g. in intensive care units), the following withdrawal symptoms may occur: headache, diarrhea, muscle pain, anxiety, tension, restlessness, confusion, irritability, sleep disturbances, mood changes, hallucinations, and seizures. In severe cases, the following symptoms may appear: depersonalization, numbness and tingling in the limbs, and hypersensitivity to light, noise, and physical contact. To prevent these adverse reactions, your doctor will gradually reduce the dose.

Other medicines and Midazolam Kalceks
Inform your doctor or nurse if you are taking, have recently taken, or might take any other medicines.
This is extremely important because using more than one medicine at the same time may strengthen or weaken the effects of the medicines.
In particular, inform your doctor or nurse if you are taking any of the following medicines:

• medicines for anxiety or sleep (tranquilizers),
• sedatives (to induce calmness or drowsiness),
• hypnotics (medicines for sleep),
• antidepressants (medicines for depression, e.g. nefazodone),
• narcotic analgesics (strong painkillers, e.g. fentanyl),
• anesthetics (e.g. propofol),
• certain antihistamines (allergy medications),
• antifungal medicines (ketoconazole, voriconazole, fluconazole, itraconazole, posaconazole),
• antibiotics (erythromycin, clarithromycin, telithromycin, roxithromycin),
• blood pressure medicines, calcium channel blockers such as diltiazem, verapamil,
• HIV medicines (human immunodeficiency virus) (efavirenz or saquinavir, lopinavir and other protease inhibitors),
• medicines for hepatitis C virus (simeprevir, boceprevir and telaprevir),
• medicines for epilepsy (carbamazepine, phenytoin or valproic acid),
• atorvastatin (used to treat high cholesterol levels),
• rifampicin (used to treat mycobacterial infections, such as tuberculosis),
• ticagrelor (used to prevent heart attack),
• aprepitant, netupitant, casoprepitant (used to prevent nausea or vomiting),
• certain anticancer medicines (e.g. imatinib, lapatinib, idelalisib, vemurafenib),
• 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 painkillers, medicines for substitution therapy, and some cough medicines) increases the risk of drowsiness, breathing difficulties (respiratory depression), coma, and may be fatal. Therefore, concomitant use should only be considered when no other treatment options are possible.
However, if your doctor prescribes midazolam together with opioids, your doctor must limit the dose and duration of concomitant opioid treatment.
Inform your doctor about all opioid-containing medicines you are taking and carefully follow the doses recommended by your doctor. It may be helpful to inform friends or family members so they are aware of the signs and symptoms listed above. Contact your doctor if these symptoms occur.

Surgical procedures
If you are to receive an inhaled anesthetic (i.e. one that is inhaled) for a surgical or dental procedure, it is important to inform your doctor or dentist that you have received Midazolam Kalceks.

Midazolam Kalceks and alcohol
Alcohol may enhance the sedative (calming) effect of midazolam; therefore, you must avoid consuming alcohol.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding, consult your doctor before receiving this medicine. Your doctor will decide whether you should receive this medicine.
After receiving Midazolam Kalceks, you must not breastfeed for 24 hours, as midazolam may pass into breast milk.

Driving and using machines
Midazolam impairs your ability to drive vehicles and operate machinery.
This medicine may cause drowsiness and forgetfulness and may affect your concentration and coordination. This may impair your ability to perform tasks requiring skill, such as driving vehicles or operating machinery. After administration of midazolam, you must not drive or operate machinery until you have fully recovered. Your doctor will advise you when you may resume these activities. After treatment, you must always be accompanied home by a responsible adult.
Insufficient sleep or alcohol consumption may increase the likelihood of impaired alertness.

Midazolam Kalceks contains sodium
Midazolam Kalceks 1 mg/ml
At daily doses up to 6.5 ml, this medicine contains less than 1 mmol (23 mg) of sodium, i.e. essentially “sodium-free”. If a daily dose equal to or greater than 6.6 ml (equivalent to or greater than 1 mmol of sodium) is administered, the following should be considered: This medicine contains 3.5 mg of sodium (the main component of table salt) per ml of solution. This corresponds to 0.18% of the maximum daily dietary intake recommended for an adult.

Midazolam Kalceks 5 mg/ml
At daily doses up to 7.3 ml, this medicine contains less than 1 mmol (23 mg) of sodium, i.e. essentially “sodium-free”. If a daily dose equal to or greater than 7.4 ml (equivalent to or greater than 1 mmol of sodium) is administered, the following should be considered: This medicine contains 3.15 mg of sodium (the main component of table salt) per ml of solution. This corresponds to 0.16% of the maximum daily dietary intake recommended for an adult.

3. How Midazolam Kalceks is administered

This medicine must be administered only by experienced physicians, in a setting where equipment necessary for monitoring and supporting respiratory and cardiovascular function is available, or by personnel specifically trained in the recognition and management of adverse reactions.

Dosage and route of administration
Your doctor will determine the appropriate dose for you. Doses vary depending on the intended treatment and the level of sedation required. The dose you will receive depends on your body weight, age, general health status, concomitant medications, response to the drug, and the possible need for other medicines administered at the same time.

If you require strong painkillers, you will receive them first, and then the dose of Midazolam Kalceks will be specifically adjusted for you.

This medicine will be injected directly into a vein (intravenous route), administered by infusion, injected into muscle (intramuscular route), or given rectally.

Children and newborns
In newborns and children under 6 months of age, midazolam is recommended only for sedation in intensive care units. The dose will be administered gradually into a vein.

In children aged 12 years and younger, midazolam is generally administered into a vein.
When this medicine is used for premedication (to induce relaxation, calmness, and drowsiness before anesthesia), it may be administered rectally.

If you receive more Midazolam Kalceks than you should
The medicine is administered by a doctor or nurse.
If you are accidentally given an excessive amount of midazolam, symptoms such as drowsiness, ataxia (disorders in coordination of voluntary muscle activity), dysarthria (speech disorders), nystagmus (involuntary eye movements), loss of reflexes, apnea (cessation of breathing), hypotension (low blood pressure), cardiac and respiratory depression, and coma may occur. In case of overdose, careful monitoring of vital signs, symptomatic treatment of cardiorespiratory effects, and use of a benzodiazepine antagonist may be required.

If you stop Midazolam Kalceks treatment
Sudden discontinuation of treatment may be accompanied by withdrawal symptoms such as headache, muscle pain, anxiety, tension, restlessness, confusion, mood swings, hallucinations and seizures, rebound insomnia, and irritability. Since the risk of withdrawal symptoms is higher with abrupt termination of treatment, the dose should be gradually reduced when stopping therapy.

If you have any doubts about the use of this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
Stop receiving midazolam and contact your doctor immediately if you experience any of the
following side effects. These may be life-threatening and require urgent medical treatment:

• Anaphylactic shock (a severe allergic reaction that may be life-threatening). Signs may include sudden rash, itching or skin rash with lumps (urticaria), swelling of the face, lips, tongue or other parts of the body. Breathing difficulties, wheezing or shortness of breath, pale skin, weak and rapid pulse, or feeling faint may also occur. Chest pain may also occur, which could 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 the neck and shoulders and radiate down the left arm.
• Breathing problems or complications (sometimes leading to respiratory arrest).
• Choking and sudden blockage of the airways (laryngospasm).

The occurrence of life-threatening side effects is more likely in adults over 60 years of age and in those who already have breathing difficulties or heart problems, particularly if the injection is administered too rapidly or at a high dose.
Other possible side effects:
The following side effects have been reported, but their frequency is unknown 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 have been reported, such as restlessness, agitation, irritability, nervousness, muscle spasms and tremors, hostility, delirium, rage, aggression, anxiety, nightmares, abnormal dreams, hallucinations, psychosis, inappropriate behaviour and other adverse behavioural effects, excitement and aggression. These reactions have been observed mainly when the injection is administered too rapidly or at a high dose. The risk of these symptoms is higher in children and elderly patients.
Dependence: midazolam may lead to physical dependence, even when used at therapeutic doses. Withdrawal symptoms, including seizures, which may occur after prolonged administration of midazolam, can be avoided by gradually reducing the dose (see section 2).
Nervous system disorders: drowsiness and prolonged sedation, reduced alertness, stupor, headache, dizziness, impaired muscle coordination. Temporary memory loss has been reported, the duration of which depends on the dose administered and may occur even after treatment has ended. In isolated cases, memory loss has been prolonged. Seizures have been reported in premature infants and newborns.
Cardiac disorders: serious adverse reactions have occurred, such as low blood pressure, slowed heart rate, and blood vessel dilation (e.g. flushing, fainting, and headache).
Gastrointestinal disorders: nausea, vomiting, constipation, dry mouth.
Skin disorders: rash, allergic reaction, itching.
General disorders and administration site conditions: fatigue, redness, swelling of the skin, blood clots, and injection site pain (erythema, thrombophlebitis, and thrombosis).
Patients taking benzodiazepines have an increased risk of falls and fractures, especially the elderly and those using other sedatives (including alcoholic beverages).
Patients with severe kidney disease are more likely to experience side effects.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, contact your doctor. You can also report side effects directly via the national reporting system at the following address: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse .
Reporting side effects helps provide more information on the safety of this medicine.

5. How to store Midazolam Kalceks

This medicine does not require any special storage temperature.
Keep the vials in the outer packaging to protect the medicine from light.
Keep this medicine out of the sight and reach of children.
After opening the vial, the product must be used immediately.
Chemical and physical in-use stability has been demonstrated for 24 hours at a temperature of 25°C and for
3 days at a temperature of 2–8°C with the following infusion solutions: 0.9% sodium chloride,
5% and 10% glucose, Ringer's solution, and Hartmann's solution.
From a microbiological standpoint, diluted solutions should be used immediately. If not used immediately,
the in-use storage times and conditions prior to use are the responsibility of the user and should normally not exceed 24 hours at 2°C–8°C, unless the dilution has been carried out under controlled and validated aseptic conditions.
Do not use this medicine after the expiry date stated on the carton after (Exp.). The expiry date refers to the last day of that month.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Midazolam Kalceks contains

• The active substance is midazolam.

Midazolam Kalceks 1 mg/ml
1 ml of solution contains 1 mg of midazolam.
A 5 ml vial of solution contains 5 mg of midazolam.
Midazolam Kalceks 5 mg/ml
1 ml of solution contains 5 mg of midazolam.
A 1 ml vial of solution contains 5 mg of midazolam.
A 3 ml vial of solution contains 15 mg of midazolam.
A 10 ml vial of solution contains 50 mg of midazolam.

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

Description of the appearance of Midazolam Kalceks and contents of the pack
Clear, colourless injectable/infusion solution, in 1 ml, 3 ml or 10 ml (for 5 mg/ml) and
5 ml (for 1 mg/ml) vials made of colourless glass of type I, with OPC snap-off system.
Pack sizes: 5 or 10 vials.
It is possible that not all pack sizes are marketed.

Marketing Authorisation Holder and Manufacturer
AS KALCEKS
Krustpils iela 71E, Rīga, LV-1057, Latvia

The following information is intended for healthcare professionals only:

Instructions for use

Midazolam Kalceks is compatible with the following infusion solutions:

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

For intravenous infusion, the contents of Midazolam Kalceks vials may be diluted with one of the above-mentioned solutions, at a ratio of 15 mg midazolam per 100–1000 mL of infusion solution.
Midazolam Kalceks injectable solution/for infusion must not be diluted with Macrodex 6% in glucose solution.
Midazolam Kalceks injectable solution/for infusion must not be mixed with alkaline injectable solutions. Midazolam precipitates in solutions containing bicarbonate.
To avoid potential incompatibilities, Midazolam Kalceks injectable solution/for infusion must not be mixed with solutions other than those listed above.
Midazolam Kalceks injectable solution/for infusion is for single use only.
The solution should be inspected visually prior to administration. Only a clear solution free from visible particles should be used.

Instructions for opening the vial:

1. Turn the vial with the coloured tip upwards. If any solution is present in the upper part of the vial, gently tap with the finger to bring all the solution to the lower part of the vial.
2. Use both hands to open the vial; holding the lower part of the vial in one hand, use the other hand to break the top part of the vial in the direction opposite to the coloured mark (see figures below).