Colistimethate sodium noridem

PACKAGE LEAFLET

Package leaflet: Information for the patient

Colistimethatum natricum Noridem, 1 000 000 IU, powder for solution for
injection/infusion
Colistimethatum natricum Noridem, 2 000 000 IU, powder for solution for
injection/infusion
Colistimethatum natricum
Before taking this medicine, carefully read this leaflet as it contains important information for
you.

• Keep this leaflet as you may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• If you experience any side effects, talk to your doctor. This includes any side effects not listed in this leaflet. See section 4.

Leaflet contents

1. What Colistimethatum natricum Noridem is and what it is used for
2. Important information before using Colistimethatum natricum Noridem
3. How to use Colistimethatum natricum Noridem
4. Possible side effects
5. How to store Colistimethatum natricum Noridem
6. Contents of the pack and other information

1. What Colistimethatum natricum Noridem is and what it is used for

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

2. Important information before using Colistimethatum natricum Noridem

Do not use Colistimethatum natricum Noridem if:

• you are allergic to sodium colistimethate, colistin, or other polymyxins.

Warnings and precautions
Before starting treatment with Colistimethatum natricum Noridem, consult your doctor, pharmacist, or nurse if you:

• have or have had kidney function disorders
• suffer from myasthenia gravis
• suffer from porphyria
• suffer from asthma

If you experience muscle cramps, fatigue, or increased urine output, contact your doctor immediately, as these symptoms may be related to a condition known as pseudobartter syndrome.

Children
Particular caution should be exercised when administering Colistimethatum natricum Noridem to premature infants and newborns, as their kidneys are not yet fully developed.

Colistimethatum natricum Noridem and other medicines
Inform your doctor about all medicines you are currently taking, have recently taken, or plan to take.
Depending on the medicines you are taking, you may or may not be able to use them concurrently with Colistimethatum natricum Noridem. In some cases, your doctor may decide to temporarily discontinue other medicines, reduce the dose of Colistimethatum natricum Noridem, or monitor you during treatment. In certain cases, monitoring blood levels of Colistimethatum natricum Noridem may be necessary to ensure you are receiving the correct dose.

• Aminoglycoside antibiotics (such as gentamicin, tobramycin, amikacin, and netilmicin) and cephalosporins may affect kidney function. Concurrent use of these medicines with Colistimethatum natricum Noridem 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. Concurrent use of these medicines with Colistimethatum natricum Noridem may increase the risk of side effects affecting the auditory organ and other parts of the nervous system (see section 4 of this leaflet).
• Muscle relaxants, often used during general anesthesia. Colistimethatum natricum Noridem may enhance the effect of these medicines. If you are undergoing general anesthesia, inform the anesthesiologist that you are receiving Colistimethatum natricum Noridem.

If you suffer from myasthenia gravis (muscle weakness) and are also taking other antibiotics called macrolides (such as azithromycin, clarithromycin, or erythromycin) or antibiotics called fluoroquinolones (such as ofloxacin, norfloxacin, and ciprofloxacin), taking Colistimethatum natricum Noridem may further increase the risk of muscle weakness and breathing difficulties.
Concurrent intravenous infusion and inhalation of Colistimethatum natricum Noridem may increase the risk of adverse effects.

Pregnancy, breastfeeding, and fertility
If you are pregnant or breastfeeding, suspect you may be pregnant, or are planning to have a child, consult your doctor or pharmacist before using this medicine.
Small amounts of Colistimethatum natricum Noridem pass into breast milk; therefore, breastfeeding is not contraindicated during treatment. However, if you cannot discontinue breastfeeding while taking Colistimethatum natricum Noridem, carefully monitor the infant for any symptoms and inform your doctor if you notice any concerning signs.
There is no data on the effect of sodium colistimethate on human fertility.

Driving and operating machinery
When Colistimethatum natricum Noridem is administered intravenously, side effects such as dizziness, confusion, or visual disturbances may occur. If you experience any side effects, do not drive or operate machinery.

Colistimethatum natricum Noridem contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per vial, meaning it is considered "sodium-free".

3. How to use Colistimethatum natricum Noridem

This medicine should always be used exactly as prescribed by your doctor or pharmacist. If in doubt, consult your doctor or pharmacist.

Depending on the indication (see section 1 of this leaflet), Colistimethatum natricum Noridem may be administered as a rapid injection (over more than 5 minutes into a special tube in a vein) or as a slow injection (infusion lasting approximately 30 to 60 minutes) into a vein. In some cases, Colistimethatum natricum Noridem may be administered by injection into the spinal canal or brain ventricle (intrathecal or intraventricular administration).

The usual daily dose for adults is 9 000 000 IU given in 2–3 divided doses. In severe cases, an initial higher dose of 9 million IU may be administered.

In some cases, your doctor may decide to administer a higher daily dose of up to 12 million IU.

The usual daily dose for children weighing up to 40 kg is 75 000 to 150 000 IU per kg of body weight, divided into 3 doses. Higher doses have sometimes been used in cystic fibrosis.

Lower doses are usually administered to children and adults with impaired kidney function, including dialysis patients. During treatment with Colistimethatum natricum Noridem, your doctor will regularly monitor your kidney function.

Method of administration
Intravenous, intrathecal, or intraventricular administration
Colistimethatum natricum Noridem is administered by a doctor as an intravenous infusion over 30–60 minutes or as an intravenous injection over at least 5 minutes. Colistimethatum natricum Noridem is primarily administered in hospitals. If you are self-administering at home, your doctor or nurse should demonstrate how to reconstitute the powder and inject the correct dose of solution.

Duration of treatment
Your doctor will decide how long treatment should last, depending on the severity of the infection.
In treating bacterial infections, it is important to complete the full course of treatment to prevent worsening of the existing infection.

Use of a higher than recommended dose of Colistimethatum natricum Noridem
If you think you have taken more Colistimethatum natricum Noridem than recommended, contact your doctor or nurse immediately. If you cannot contact your doctor or nurse, go to the nearest emergency department or hospital emergency unit.
Accidental administration of too high a dose of Colistimethatum natricum Noridem may cause serious side effects such as kidney dysfunction, muscle weakness, and breathing difficulties (or even respiratory arrest).

Missed dose of Colistimethatum natricum Noridem
If you miss a dose while self-treating, take the missed dose as soon as possible, then take the next dose after 8 hours if Colistimethatum natricum Noridem is administered three times daily, or after 12 hours if administered twice daily. Then continue with your regular dosing schedule. Do not take a double dose to make up for a missed dose.

If you are being treated in hospital or at home by a doctor or nurse and think you may have missed a dose or received too high a dose of Colistimethatum natricum Noridem, ask your doctor or nurse.

Stopping treatment with Colistimethatum natricum Noridem
Do not stop treatment prematurely unless instructed by your doctor. Your doctor will decide how long treatment should continue.

If you have any further questions about the use of this medicine, consult your doctor.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
Allergic reactions
After intravenous administration of Colistimethatum natricum Noridem, patients may experience allergic reactions.
Severe allergic reactions may occur shortly after the first dose and may include symptoms such as sudden onset of rash, swelling of the face, tongue and neck, difficulty breathing due to bronchospasm, and loss of consciousness.
If an allergic reaction occurs, seek immediate medical help.
Milder hypersensitivity reactions include skin rashes, which may appear later during treatment.

The following symptoms may occur after intravenous administration and may be related to a condition known as pseudohyperaldosteronism (see section 2):

• muscle cramps
• increased urination
• fatigue

Nervous system adverse reactions are more likely when the dose of Colistimethatum natricum Noridem is too high, in patients with renal impairment, or in patients receiving concomitant muscle relaxants or other medicines with similar effects on the nervous system. The most serious adverse effect affecting the nervous system is inability to breathe due to paralysis of the muscles of the chest wall.
If any difficulty in breathing occurs, seek immediate medical help.

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 flushes), slurred speech, vision problems, confusion, and psychiatric problems (including loss of touch with reality). Allergic reactions such as irritation may occur at the injection site.

Kidney function disorders may also occur. The likelihood is particularly high in patients who already have impaired kidney function, in patients receiving Colistimethatum natricum Noridem together with other medicines that may cause kidney-related adverse reactions, or in patients receiving too high a dose. These problems usually resolve after discontinuation or dose reduction of Colistimethatum natricum Noridem.

Reporting of adverse reactions
If any adverse reactions occur, including any not listed in this leaflet, inform your doctor or pharmacist. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products,
Al. Jerozolimskie 181C
PL-02 222 Warsaw,
Tel.: + 48 22 49 21 301
Fax: + 48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl .
Adverse reactions can also be reported to the marketing authorization holder. Reporting adverse reactions helps provide more information on the safety of the medicine.

5. How to store Colistimethatum natricum Noridem

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial and outer carton box,
after the expiry date (EXP). The expiry date refers to the last day of the stated 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.

For intravenous bolus injection solutions, chemical and physical in-use stability has been demonstrated
for the reconstituted solution stored in the original vial at a concentration ≥80,000 IU/mL for:

• 1,000,000 IU for 3 hours at 2–8°C after dilution in 10 mL of sodium chloride solution for injection 9 mg/mL (0.9%) or water for injections.
• 2,000,000 IU for 3 hours at 2–8°C after dilution in 10 mL of sodium chloride solution for injection 9 mg/mL (0.9%) or water for injections.

From a microbiological point of view, if the method of opening/reconstitution/dilution
prevents the risk of microbiological contamination, the medicinal product should be used
immediately.
If the product is not used immediately, the responsibility for storage duration and conditions
lies with the user.

Solutions for infusion diluted beyond the original vial volume and/or at a concentration <80,000 IU/mL
should be used immediately.
For solutions intended for intrathecal and intraventricular administration, the prepared medicinal product
should be used immediately.

The solution should be carefully inspected before use to ensure that no particulate matter is present.
Only clear, particle-free solutions should be used.
Any unused portion of the solution should be discarded.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist
how to dispose of medicines no longer in use. Such measures will help protect
the environment.

6. Contents of the pack and other information

What Colistimethatum natricum 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.
No other ingredients.

What Colistimethatum natricum Noridem looks like and contents of the pack
Colistimethatum natricum Noridem, powder for solution for injection/infusion,
is supplied as a white or off-white powder in single-dose vials.

For 1,000,000 IU: A vial made of colourless glass (Type I), with a 20 mm bromobutyl rubber stopper (Type I), a 20 mm plastic pull-off cap in white colour, and an aluminium seal.
For 2,000,000 IU: A vial made of colourless glass (Type I), with a 20 mm bromobutyl rubber stopper (Type I), a 20 mm plastic pull-off cap in orange colour, and an aluminium seal.

Pack sizes: 1, 10 and 30 vials.
Not all pack sizes may be marketed.

Marketing Authorisation Holder:
Noridem Enterprises Limited, Evagorou & Makariou,
Mitsi Building 3, Office 115, Nicosia 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 medicinal product is authorised in the European Economic Area under the following names:
Germany Colistimethat-Natrium Noridem 1 Million I.E. Pulver zur Herstellung einer Injektions-/Infusionslösung
Colistimethat-Natrium Noridem 2 Millionen I.E. Pulver zur Herstellung einer Injektions-/Infusionslösung
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 Κόνις για ενέσιμο διάλυμα/ διάλυμα προς έγχυση
KOLELANG 2 MIU Κόνις για ενέσιμο διάλυμα/ διάλυμα προς έγχυση
Austria Colistimethat-Natrium DEMO 1 Mio. I.E. Pulver zur Herstellung einer Injektions-/Infusionslösung
Colistimethat-Natrium DEMO 2 Mio. I.E. Pulver zur Herstellung einer Injektions-/Infusionslösung
Italy Colistimetato sodico Noridem Ltd
Colistimetato sodico Noridem Ltd
Poland Colistimethatum natricum Noridem
Colistimethatum natricum Noridem
Slovakia Colistimethate Noridem 1 MIU prášok na injekčný/infúzny roztok
Colistimethate Noridem 2 MIU prášok na injekčný/infúzny roztok

Information intended exclusively for healthcare professionals:

Preparation and handling
Instructions for preparing the injection/infusion solution
For intravenous bolus injection:
Dissolve the contents of the vial in no more than 10 mL of water for injections or sodium chloride solution for injections at a concentration of 9 mg/mL (0.9%).
For infusion:
After dissolution, dilute the vial contents in 50 mL of sodium chloride solution for injections at a concentration of 9 mg/mL (0.9%).
For intrathecal or intraventricular administration:
When administered intrathecally or intraventricularly, the volume administered 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 solution Y6, and free from visible solid particles.
Solutions are for single use only, and any unused portion must be discarded.
The medicinal product should be carefully inspected visually before use (including after dilution). Only clear solutions free from particulate matter should be used.
Pharmaceutical incompatibilities
Infusion solutions and injection solutions containing colistimethate sodium should not be mixed.
Dosage and administration
Dosage
The dosage is expressed in international units (IU) of colistimethate sodium (CMS).
A conversion table for colistimethate sodium from IU to mg and from mg to mg of colistin base activity (CBA) is provided at the end of this section.
The following dosage recommendations are based on limited population pharmacokinetic data in critically ill patients:
Adults and adolescents
Maintenance dose: 9,000,000 IU/day given in 2–3 divided doses.
In critically ill patients, a loading dose of 9,000,000 IU should be administered.
The optimal time interval before the first maintenance dose has not been established.
Modeling suggests that in some cases, in patients with good renal function, doses of up to 12,000,000 IU (loading and maintenance) may be required. However, clinical experience with such doses is extremely limited, and safety has not been established.
The loading dose applies to patients with normal renal function as well as those with renal impairment, including patients undergoing renal replacement therapy.
Special patient groups
Elderly patients
Dosage adjustment is not considered necessary in elderly patients with normal renal function.
Renal impairment
Dosage adjustment is required in patients with renal impairment, but pharmacokinetic data in patients with renal impairment are very limited.
The following dosage adjustment approach is recommended as a guideline.
In patients with creatinine clearance <50 mL/min, dose reduction is recommended:
Administration of two divided doses per day is advised.

Hemodialysis and continuous hemofiltration or hemodiafiltration
Colistin appears to be dialyzed during conventional hemodialysis and
continuous venovenous hemofiltration or hemodiafiltration (CVVH, CVVHDF). Available data from
population pharmacokinetic studies involving a very small number of patients undergoing
renal replacement therapy are extremely limited. Precise dosing recommendations cannot be provided.
The following regimens may be considered.

Hemodialysis
Non-HD days: 2.25 million IU/day (2.2 to 2.3 million IU/day).
HD days: 3,000,000 IU/day on hemodialysis days, to be administered after HD session.
It is recommended to administer two doses per day.

CVVHF / CVVHDF
Patients with normal renal function: administration of three doses per day is recommended.

Hepatic impairment
There are no data available in patients with hepatic impairment. Caution should be exercised when administering colistimethate sodium in these patients.

Children
Data supporting dosing regimens in children are very limited. Dose selection should take into account renal maturity. The dose should be based on lean body weight.

Children with body weight ≤ 40 kg
75,000 IU to 150,000 IU/kg body weight/day, divided into three doses.
In children with body weight greater than 40 kg, consideration should be given to using adult dosing recommendations.
Doses exceeding 150,000 IU/kg body weight/day have been reported in children with cystic fibrosis.
There are no data on the use or size of loading doses in critically ill children.
Dosing recommendations in children with renal impairment have not been established.

Intrathecal and intraventricular administration
Based on limited data, the following dose is recommended in adults:
Intraventricular administration: 125,000 IU/day.
Intrathecal doses should not exceed the doses recommended for intraventricular administration.
Specific dosing recommendations for intrathecal and intraventricular administration in children cannot be provided.

Method of administration
Intravenous, intrathecal, or intraventricular administration.
Colistimethatum natricum Noridem is administered as a slow intravenous infusion over 30–60 minutes.
Patients with a permanently implanted intravenous access port (TIVAD) may tolerate a single intravenous bolus injection of up to 2 million IU in 10 mL solution administered over at least 5 minutes.

Colistimethate sodium in aqueous solution undergoes hydrolysis to the active substance, colistin. To prepare the dose, especially when combining multiple vials, reconstitution should be performed using strict aseptic technique.

Dosage conversion table:
In the European Union, colistimethate sodium dosage must be prescribed and administered exclusively in international units (IU). The number of IU per vial is indicated on the product label.
Due to different methods of expressing dosage in terms of potency, confusion and medication errors have occurred. In the United States and other parts of the world, dosage is expressed in milligrams of colistin base activity (mg CBA).

The following conversion table is provided for informational purposes only, and values should be considered 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 in turn may lead to muscle weakness, respiratory depression, and potentially respiratory arrest.
In addition, overdose with colistimethate may cause acute renal failure manifested by decreased urine output, and increased serum concentrations of urea and creatinine.
Treatment
There is no specific antidote; therefore, symptomatic treatment should be administered. Measures to enhance colistin elimination may be used, such as forced diuresis with mannitol, prolonged hemodialysis, or peritoneal dialysis, although their effectiveness remains unknown.