COLISTIMETHATUM 2000000 IU Powder

Contents of the leaflet

1. LEAFLET INCLUDED IN THE PACKAGE
2. Leaflet included in the package: Information for the patient
   1. Before taking the medicine, carefully read the contents of the leaflet, as it contains important information for the patient.
   2. Table of contents of the leaflet
3. What is Colistimethate sodium Noridem and what is it used for
4. Important information before taking Colistimethate sodium Noridem
   1. When not to take Colistimethate sodium Noridem
   2. Warnings and precautions
   3. Children
   4. Colistimethate sodium Noridem and other medicines
   5. Pregnancy, breastfeeding, and fertility
   6. Driving and using machines
   7. Colistimethate sodium Noridem contains sodium
5. How to take Colistimethate sodium Noridem
   1. Using a higher dose of Colistimethate sodium Noridem than recommended
   2. Missing a dose of Colistimethate sodium Noridem
   3. Stopping treatment with Colistimethate sodium Noridem
6. Possible side effects
   1. In case of allergic reactions, the patient should immediately seek medical attention.
   2. In case of breathing difficulties, the patient should immediately seek medical attention.
   3. Reporting side effects
7. How to store Colistimethate sodium Noridem
8. Contents of the package and other information
   1. What Colistimethate sodium Noridem contains
   2. What Colistimethate sodium Noridem looks like and contents of the package
   3. Marketing authorization holder:
   4. Manufacturer:
   5. This medicine is authorized in the Member States of the European Economic Area under the following names:
   6. Date of last revision of the leaflet:
   7. Preparation and handling
   8. Instructions for preparing the solution for injection/infusion
   9. Incompatibilities
   10. Dosage and administration
   11. Conversion table:
   12. Colistimethate sodium conversion table
   13. Overdose

LEAFLET INCLUDED IN THE PACKAGE

Leaflet included in the package: Information for the patient

Colistimethate sodium Noridem, 1,000,000 IU, powder for solution for injection/infusion
Colistimethate sodium Noridem, 2,000,000 IU, powder for solution for injection/infusion
Colistimethate sodium

Before taking the medicine, carefully read the contents of the leaflet, as it contains important information for the patient.

• You should keep this leaflet, so you can read it again if you need to.
• In case of any doubts, you should consult a doctor or pharmacist.
• If the patient experiences any adverse reactions, they should contact their doctor. This also applies to any adverse reactions not listed in this leaflet. See section 4.

Table of contents of the leaflet

• 1. What is Colistimethate sodium Noridem and what is it used for
• 2. Important information before taking Colistimethate sodium Noridem
• 3. How to take Colistimethate sodium Noridem
• 4. Possible side effects
• 5. How to store Colistimethate sodium Noridem
• 6. Contents of the package and other information

1. What is Colistimethate sodium Noridem and what is it used for

This medicine contains the active substance colistimethate sodium. Colistimethate sodium is an antibiotic belonging to a group of antibiotics called polymyxins.
This medicine is given by injection to treat certain types of severe infections caused by specific bacteria. The medicine is used when other antibiotics are not indicated.

2. Important information before taking Colistimethate sodium Noridem

When not to take Colistimethate sodium Noridem

• -if the patient is allergic to colistimethate sodium, colistin, or other polymyxins .

Warnings and precautions

Before starting treatment with Colistimethate sodium Noridem, the patient should discuss it with their doctor, pharmacist, or nurse if:

• the patient has or has had kidney function disorders
• the patient has myasthenia gravis
• the patient has porphyria
• the patient has asthma

If the patient experiences muscle spasms, fatigue, or increased urine production, they should immediately inform their doctor, as these events may be related to a condition known as pseudo-Bartter syndrome.

Children

In premature infants and newborns, special caution should be exercised when using Colistimethate sodium Noridem, as their kidneys are not yet fully developed.

Colistimethate sodium Noridem and other medicines

The patient should tell their doctor about all medicines they are currently taking or have recently taken, as well as any medicines they plan to take.
If the patient is taking any of the listed medicines, they may or may not be able to take them at the same time as Colistimethate sodium Noridem. In some cases, the doctor may decide to discontinue the use of other medicines (for a certain period) or may reduce the dose of Colistimethate sodium Noridem; it may also be necessary to monitor the patient during treatment with this medicine. In some cases, it may be necessary to control the concentration of Colistimethate sodium Noridem in the blood to ensure that the patient is taking the correct dose.

• Aminoglycoside antibiotics (such as gentamicin, tobramycin, amikacin, and netilmicin) and cephalosporins may affect kidney function. Taking these medicines and Colistimethate sodium Noridem at the same time may increase the risk of kidney damage (see section 4 of this leaflet).
• Aminoglycoside antibiotics (including gentamicin, tobramycin, amikacin, and netilmicin) and cephalosporins may affect the nervous system. Taking such medicines at the same time as Colistimethate sodium Noridem may increase the risk of adverse reactions in the ear and other parts of the nervous system (see section 4 of this leaflet).
• Muscle relaxants, often used during general anesthesia. Colistimethate sodium Noridem may enhance the effect of these medicines. If the patient is to undergo general anesthesia, they should inform the anesthesiologist that they are taking Colistimethate sodium Noridem.

If the patient has myasthenia gravis (muscle weakness) and is also taking other antibiotics called macrolides (such as azithromycin, clarithromycin, or erythromycin) or antibiotics called fluoroquinolones (such as ofloxacin, norfloxacin, and ciprofloxacin), taking Colistimethate sodium Noridem increases the risk of muscle weakness and breathing difficulties.
Taking Colistimethate sodium Noridem by infusion at the same time as taking Colistimethate sodium Noridem by inhalation may increase the risk of adverse reactions.

Pregnancy, breastfeeding, and fertility

If the patient is pregnant or breastfeeding, thinks they may be pregnant, or plans to have a child, they should consult their doctor or pharmacist before taking this medicine.
Small amounts of Colistimethate sodium Noridem pass into breast milk, so breastfeeding is not contraindicated during treatment. If the patient cannot stop breastfeeding while taking Colistimethate sodium Noridem, they should carefully observe their child for signs of illness and inform their doctor if they notice any worrying symptoms.
There is no data on the effect of colistimethate sodium on human fertility.

Driving and using machines

When Colistimethate sodium Noridem is administered intravenously, adverse reactions such as dizziness, confusion, or vision disturbances may occur. If such adverse reactions occur, the patient should not drive or operate machinery.

Colistimethate sodium Noridem contains sodium

The medicine contains less than 1 mmol (23 mg) of sodium per vial, which means the medicine is considered "sodium-free).

3. How to take Colistimethate sodium Noridem

This medicine should always be used as directed by the doctor or pharmacist. In case of doubts, the patient should consult their doctor or pharmacist.
Depending on the indication (see section 1 of this leaflet), Colistimethate sodium Noridem can be administered by rapid injection (lasting over 5 minutes into a special tube in the vein) or slow injection (infusion lasting about 30 to 60 minutes) into the vein. In some cases, Colistimethate sodium Noridem may be administered by injection into the spinal canal or brain (intrathecal administration).
The usual daily dose for adults is 9,000,000 IU in 2-3 divided doses. In cases of severe illness, a larger initial dose of 9 million units is given at the beginning of treatment.
In some cases, the doctor may decide to administer a higher daily dose of up to 12 million units.
The usual daily dose in children with a body weight of up to 40 kg is 75,000 to 150,000 IU/kg body weight, divided into 3 doses. In cases of cystic fibrosis, higher doses have sometimes been administered.
Children and adults with kidney function disorders, including those undergoing dialysis, usually receive lower doses. While taking Colistimethate sodium Noridem, the doctor will regularly check the patient's kidney function.
Administration method
Intravenous, intrathecal, or intracranial administration
Colistimethate sodium Noridem is administered by a doctor through intravenous infusion over 30-60 minutes or by intravenous injection over at least 5 minutes. Colistimethate sodium Noridem is mainly administered in hospitals. If the patient is being treated at home, the doctor or nurse should demonstrate how to dilute the powder and inject the correct dose of the solution.
Duration of treatment
The doctor will decide how long the treatment should last, depending on the severity of the infection.
In the treatment of bacterial infections, it is essential to complete the full treatment cycle to prevent the worsening of the existing infection.

Using a higher dose of Colistimethate sodium Noridem than recommended

If the patient thinks they have taken a dose of Colistimethate sodium Noridem higher than recommended, they should immediately inform their doctor or nurse. If it is not possible to contact the doctor or nurse, the patient should contact the nearest emergency department or go to the nearest hospital emergency department.
Unintentional administration of too high a dose of Colistimethate sodium Noridem may cause serious adverse reactions, such as kidney function disorders, muscle weakness, and breathing difficulties (or even cessation of breathing).

Missing a dose of Colistimethate sodium Noridem

In case of missing a dose during self-treatment, the patient should take the missed dose as soon as possible and then take the next dose after 8 hours if Colistimethate sodium Noridem is administered in three doses per day, or after 12 hours if Colistimethate sodium Noridem is administered in two doses per day.
Then, the patient should continue with the regular administration of the medicine. The patient should not take a double dose to make up for the missed dose.
If the patient is being treated in a hospital or at home by a doctor or nurse and thinks they may have missed a dose or taken too high a dose of Colistimethate sodium Noridem, they should ask their doctor or nurse about it.

Stopping treatment with Colistimethate sodium Noridem

The patient should not stop treatment prematurely unless their doctor advises them to do so. The doctor will decide how long the treatment should last.
In case of any further doubts related to the use of this medicine, the patient should consult their doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Allergic reactions
After intravenous administration of Colistimethate sodium Noridem, patients may experience allergic reactions.
Severe allergic reactions may occur immediately after the first dose of the medicine and may include symptoms such as sudden development of a rash, swelling of the face, tongue, and throat, difficulty breathing due to constriction of the airways, and loss of consciousness.

In case of allergic reactions, the patient should immediately seek medical attention.

Milder hypersensitivity reactions include skin rashes, which may appear later in the course of treatment.
After intravenous administration, the following symptoms may occur, which may be related to a condition known as pseudo-Bartter syndrome (see section 2):

• muscle spasms
• increased urine production
• fatigue

Adverse reactions affecting the nervous system are more likely to occur when the dose of Colistimethate sodium Noridem is too high, in patients with kidney function disorders, or in patients taking muscle relaxants or other medicines with a similar effect on the nervous system. The most serious adverse reaction affecting the nervous system is the inability to breathe due to paralysis of the chest muscles.

In case of breathing difficulties, the patient should immediately seek medical attention.

Other possible adverse reactions: numbness or tingling (especially around the face), dizziness or loss of balance, sudden changes in blood pressure or blood flow (including fainting and hot flashes), slurred speech, vision problems, confusion, and mental problems (including loss of touch with reality). At the injection site, allergic reactions such as irritation may occur.
Kidney function disorders may also occur. The likelihood of their occurrence is particularly high in patients who already have poor kidney function or are taking Colistimethate sodium Noridem with other medicines that may cause adverse reactions in the kidneys or are taking too high a dose. These problems usually resolve after discontinuation of treatment or reduction of the Colistimethate sodium Noridem dose.

Reporting side effects

If the patient experiences any side effects, including any side effects not listed in this leaflet, they should inform their doctor or pharmacist. Side effects can be reported directly to the Department of Adverse Reaction Monitoring, Office of Registration of Medicinal Products, Medical Devices, and Biocidal Products,
Jerozolimskie Avenue 181C
02-222 Warsaw,
Phone: +48 22 49 21 301
Fax: +48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl .
Side effects can also be reported to the marketing authorization holder. By reporting side effects, more information can be collected on the safety of the medicine.

5. How to store Colistimethate sodium Noridem

The medicine should be stored out of sight and reach of children.
Do not use this medicine after the expiry date stated on the vial and carton after the expiry date (EXP). The expiry date refers to the last day of the specified month.
This medicine does not require any special storage conditions.
Reconstituted/diluted solution:
Hydrolysis of colistimethate is significantly increased after dissolution and dilution below the critical micellar concentration of approximately 80,000 IU/ml. Solutions below this concentration should be used immediately.
In the case of injection solutions in bolus, the chemical and physical stability of the solution after reconstitution has been demonstrated in the original vial, at a concentration of ≥80,000 IU/ml for:

• 1,000,000 IU for 3 hours at a temperature of 2-8°C after dilution in 10 ml of sodium chloride injection solution at a concentration of 9 mg/ml (0,9%) or water for injection.
• 2,000,000 IU for 3 hours at a temperature of 2-8°C after dilution in 10 ml of sodium chloride injection solution at a concentration of 9 mg/ml (0,9%) or water for injection.

From a microbiological point of view, if the method of opening/reconstitution/dilution prevents the risk of microbial contamination, the product should be used immediately.
If the product is not used immediately, the user is responsible for the storage time and conditions.
Diluted infusion solutions and solutions with a concentration <80,000 IU/ml should be used immediately.
In the case of solutions for intrathecal or intracranial administration, the prepared medicinal product should be used immediately.
The solution should be carefully examined before use to ensure it does not contain solid particles. Only clear solutions without solid particles should be used.
Unused solution residues should be discarded.
Medicines should not be disposed of via wastewater or household waste. The patient should ask their pharmacist how to dispose of medicines they no longer use. This will help protect the environment.

6. Contents of the package and other information

What Colistimethate sodium Noridem contains

The active substance is colistimethate sodium.
One vial contains 1,000,000 IU of colistimethate sodium.
One vial contains 2,000,000 IU of colistimethate sodium.
There are no other ingredients.

What Colistimethate sodium Noridem looks like and contents of the package

Colistimethate sodium Noridem, powder for solution for injection/infusion, is a white or off-white powder in single-dose vials.
For 1,000,000 IU: Vial made of colorless glass (type I), with a 20 mm bromobutyl rubber stopper (type I) and a 20 mm white plastic cap with a pull-off mechanism and an aluminum seal.
For 2,000,000 IU: Vial made of colorless glass (type I), with a 20 mm bromobutyl rubber stopper (type I) and a 20 mm orange plastic cap with a pull-off mechanism and an aluminum seal.
Package sizes: 1, 10, and 30 vials
Not all package sizes may be marketed.

Marketing authorization holder:

Noridem Enterprises Limited, Evagorou & Makariou,
Mitsi Building 3, Office 115, Nikosia 1065, Cyprus

Manufacturer:

DEMO S.A. PHARMACEUTICAL INDUSTRY,
21st km National Road Athens-Lamia, 14568 Krioneri, Attiki, Greece,
T: +30 210 8161802, F: +30 2108161587.

This medicine is authorized in the Member States of the European Economic Area under the following names:

Germany
Colistimethat-Natrium Noridem 1 Million IU Powder for solution for injection/infusion
Colistimethat-Natrium Noridem 2 Million IU Powder for solution for injection/infusion
Ireland
Colistimethate sodium 1 million IU Powder for solution for injection/infusion
Colistimethate sodium 2 million IU Powder for solution for injection/infusion
Czech Republic
Colistimethate Noridem
Colistimethate Noridem
Greece
KOLELANG 1 MIU Powder for injection solution/infusion solution
KOLELANG 2 MIU Powder for injection solution/infusion solution
Austria
Colistimethat-Natrium DEMO 1 Mio. IU Powder for solution for injection/infusion
Colistimethat-Natrium DEMO 2 Mio. IU Powder for solution for injection/infusion
Italy
Colistimetato sodico Noridem Ltd
Colistimetato sodico Noridem Ltd
Poland
Colistimethatum natricum Noridem
Colistimethatum natricum Noridem
Slovakia
Colistimethate Noridem 1 MIU powder for injection/infusion solution
Colistimethate Noridem 2 MIU powder for injection/infusion solution

Date of last revision of the leaflet:

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Information intended for healthcare professionals only:

Preparation and handling

Instructions for preparing the solution for injection/infusion

For bolus injection:
Dissolve the contents of the vial in no more than 10 ml of water for injection or sodium chloride injection solution at a concentration of 9 mg/ml (0.9%).
For infusion:
After reconstitution, the contents of the vial should be diluted in 50 ml of sodium chloride injection solution at a concentration of 9 mg/ml (0.9%).
For intrathecal or intracranial administration
When administering intrathecally or intracranially, the administered volume should not exceed 1 ml (concentration after reconstitution 125,000 IU/ml)
After reconstitution, the solution is clear and colorless or not more intensely colored than a Y6 solution, without visible solid particles.
Solutions are for single use only, and any remaining solution should be discarded.
The medicinal product should be carefully examined before use (also after dilution). Only clear solutions without solid particles should be used.

Incompatibilities

Infusion solutions and injection solutions containing colistimethate sodium should not be mixed.

Dosage and administration

Dosage
The dose is expressed in International Units (IU) of colistimethate sodium (CMS).
The following dosage recommendations are based on limited pharmacokinetic data in critically ill patients:
Adults and adolescents
Maintenance dose 9,000,000 IU/day in 2-3 divided doses.
In critically ill patients, a loading dose of 9,000,000 IU is given.
It is not specified what the optimal interval between the loading dose and the first maintenance dose should be.
Modeling suggests that in some cases, in patients with good kidney function, it may be necessary to administer a loading dose and a maintenance dose of up to 12,000,000 IU. However, clinical experience with such doses is extremely limited, and the safety of their use has not been established.
The loading dose applies to patients with normal and impaired kidney function, including those undergoing renal replacement therapy.
Special patient groups
Elderly patients
It is considered that in elderly patients with normal kidney function, dose adjustment is not necessary.
Impaired kidney function
In impaired kidney function, dose adjustment is necessary, but pharmacokinetic data in patients with impaired kidney function are very limited.
The following dose adjustment is proposed as a guideline.
For patients with creatinine clearance <50 ml min, it is recommended to reduce the dose:
It is recommended to administer two doses per day.
Hemodialysis and continuous venovenous hemofiltration or hemodiafiltration
It appears that colistin is dialyzable by conventional hemodialysis and continuous venovenous hemofiltration or hemodiafiltration (CVVHF, CVVHDF). Available data come from

population pharmacokinetic studies with a very small number of patients undergoing renal replacement therapy, which are extremely limited. No specific dosage recommendations can be given.
It can be considered to use the following schemes.
Hemodialysis
Days without HD: 2.25 million IU/day (2.2 to 2.3 million IU/day).
Days with HD: 3,000,000 IU/day on days with hemodialysis, to be administered after the HD session.
It is recommended to administer two doses per day.
CVVHF/CVVHDF
Patients with normal kidney function. It is recommended to administer three doses per day.
Impaired liver function
There is no data on patients with impaired liver function. Caution should be exercised when administering colistimethate sodium to these patients.
Children
Data confirming the dosage regimen in children are very limited. When selecting a dose, the patient's renal maturity should be taken into account. The dose should be determined based on lean body weight.
Children with a body weight ≤ 40 kg
75,000 IU to 150,000 IU/kg body weight per day, divided into 3 doses.
For children with a body weight greater than 40 kg, the dosage recommendations for adults should be considered.
Doses >150,000 IU/kg body weight per day have been reported in children with cystic fibrosis
There is no data on the use or dosage in children in critical condition.
No dosage recommendations have been established for children with impaired kidney function.
Intrathecal and intracranial administration.
Based on limited data, the following dose is recommended for adults:
Intracranial administration
125,000 IU/day
Doses administered intrathecally should not exceed the doses recommended for intracranial administration.
No specific dosage recommendations can be given for children for intrathecal or intracranial administration.
Administration method
Intravenous, intrathecal, or intracranial administration
Colistimethate sodium Noridem is administered by slow intravenous infusion over 30-60 minutes. Patients with a permanently implanted venous port (TIVAD) may tolerate a single intravenous injection (bolus) of a dose of up to 2 million units in 10 ml of solution, administered over at least 5 minutes.
Colistimethate sodium in aqueous solution undergoes hydrolysis to the active substance, colistin. To prepare a dose, especially when combining multiple vials, reconstitution of the required dose should be performed using a strictly aseptic technique.

Conversion table:

In the European Union, the dose of colistimethate sodium must be prescribed and administered only in International Units (IU). The number of IU in the vial is indicated on the product labeling.
Due to different ways of expressing the dose in relation to potency, confusion and errors in treatment have occurred. In the United States and other parts of the world, the dose is expressed in milligrams of colistin base activity (mg CBA).
The following conversion table is prepared for informational purposes, and the values should be treated only as nominal and approximate.

Colistimethate sodium conversion table

* Nominal potency of the active substance = 12,500 IU/mg

Overdose

Symptoms
Overdose may result in neuromuscular blockade, which can lead to muscle weakness, apnea, and potentially respiratory arrest.
Additionally, colistimethate overdose may cause acute kidney injury, manifested by decreased urine output, increased blood urea nitrogen, and creatinine levels.
Treatment
There is no specific antidote, so symptomatic treatment should be used. Measures to increase the elimination of colistin, such as forced diuresis with mannitol, prolonged hemodialysis, or peritoneal dialysis, may be used, but their effectiveness is unknown.