Colistimethate sodium Noridem Ltd.

PACKAGE LEAFLET

Package leaflet: Information for the user

Colistimethate Sodium Noridem Ltd 1 million IU powder for solution for injection/infusion
Colistimethate Sodium Noridem Ltd 2 million IU powder for solution for injection/infusion
Colistimethate sodium
Please read all of this leaflet carefully before you start 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 pharmacist.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of this leaflet

1. What Colistimethate Sodium Noridem Ltd is and what it is used for
2. What you need to know before you use Colistimethate Sodium Noridem Ltd
3. How Colistimethate Sodium Noridem Ltd is given
4. Possible side effects
5. How to store Colistimethate Sodium Noridem Ltd
6. Contents of the pack and other information

1. What Colistimetato sodico Noridem Ltd is and what it is used for

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

2. What you need to know before using Colistimetato sodico Noridem Ltd

Colistimetato sodico Noridem Ltd must not be administered

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

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before taking Colistimetato sodico Noridem Ltd if:

• you have or have had kidney problems
• you suffer from myasthenia gravis
• you suffer from porphyria
• you suffer from asthma

Children
Particular caution should be exercised when using Colistimetato sodico Noridem Ltd in neonates and premature infants, as their kidneys are not yet fully developed.

Other medicines and Colistimetato sodico Noridem Ltd
Inform your doctor if you are taking, have recently taken, or might take any other medicine.
If you are taking any of the following medicines, you may or may not be able to take Colistimetato sodico Noridem Ltd. Sometimes other medicines may need to be discontinued (even if only temporarily), or you may require a lower dose of Colistimetato sodico Noridem Ltd, or you may need to be monitored while receiving treatment with this medicine.
In some cases, it may be necessary to periodically measure your blood levels of Colistimetato sodico Noridem Ltd to ensure you are receiving the correct dosage.

• Medicines such as antibiotics called aminoglycosides (including gentamicin, tobramycin, amikacin, and netilmicin) and cephalosporins, which may affect your kidney function. Taking these medicines together with Colistimetato sodico Noridem Ltd may increase the risk of kidney damage (see section 4 of this leaflet).
• Medicines such as antibiotics called aminoglycosides (including gentamicin, tobramycin, amikacin, and netilmicin), which may affect your nervous system. Taking these medicines together with Colistimetato sodico Noridem Ltd may increase the risk of adverse effects on the ear and other parts of your nervous system (see section 4 of this leaflet).
• Medicines called muscle relaxants, often used during general anesthesia. Colistimetato sodico Noridem Ltd may enhance the effect of these medicines. If you are undergoing general anesthesia, inform your anesthetist that you are taking Colistimetato sodico Noridem Ltd. 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 Colistimetato sodico Noridem Ltd may further increase the risk of muscle weakness and breathing difficulties.

Administering Colistimetato sodico INH Noridem by infusion at the same time as inhaled Colistimetato sodico INH Noridem may increase the risk of adverse effects.

Pregnancy, breastfeeding, and fertility
If you are pregnant, suspect you may be pregnant, are planning to become pregnant, or are breastfeeding, consult your doctor before taking this medicine.
Small amounts of Colistimetato sodico Noridem Ltd are excreted in breast milk; therefore, breastfeeding is not recommended. If you cannot stop breastfeeding while taking Colistimetato sodico Noridem Ltd, you must closely monitor your baby for any signs of illness and inform your doctor if you notice any abnormalities.
There are no data available on the potential impact of colistimethate sodium on human fertility.

Driving and using machines
When Colistimetato sodico Noridem Ltd is administered intravenously, adverse effects such as dizziness, confusion, or vision problems may occur. If these occur, you must not drive or operate machinery.

Colistimetato sodico Noridem Ltd contains sodium
This medicine contains less than 1 mmol of sodium (23 mg) per vial, i.e. it is essentially ‘sodium-free’.

3. How to use Colistimetate Sodium Noridem Ltd

Use this medicine exactly as instructed by your doctor or pharmacist. If you have
any doubts, consult your doctor or pharmacist.
Depending on the reason (see section 1 of this leaflet), Colistimetate Sodium Noridem Ltd may be
administered as a rapid injection (over more than 5 minutes using a special tube into a vein) or as a slow
injection (infusion lasting from more than 30 minutes up to 60 minutes) into a vein. Colistimetate
Sodium Noridem Ltd may occasionally be administered by injection into the brain or spinal cord.
The recommended daily dose in adults is 9 million units, divided into two or three doses. If you are
seriously ill, you will initially be given a higher dose of 9 million units.
In some cases, your doctor may decide to administer a higher daily dose of up to
12 million units.
The recommended dose for children up to 40 kg body weight is 75,000 to 150,000 units per kg of body
weight, divided into three doses. Higher doses have occasionally been administered in cases of
cystic fibrosis.
Children and adults with kidney problems, including patients on dialysis, typically receive lower doses.
Your doctor will regularly monitor your kidney function while you are receiving Colistimetate Sodium Noridem Ltd.
Method of administration
For intravenous, intrathecal, or intracerebroventricular use.
Colistimetate Sodium Noridem Ltd will be administered by your doctor as an intravenous infusion over
30–60 minutes or by injection over a minimum of 5 minutes. Colistimetate Sodium Noridem Ltd is
primarily administered in a hospital setting. If you are self-medicating at home, your doctor or
nurse will show you how to dissolve the powder and inject the correct dosage of the solution.
Duration of treatment
Your doctor will decide how long your treatment should last, based on the severity of the infection.
When treating bacterial infections, it is important to complete the entire course of treatment to
prevent worsening of the existing infection.
If you take more Colistimetate Sodium Noridem Ltd than you should
If you think you have taken too much Colistimetate Sodium Noridem Ltd, contact your doctor or
nurse immediately for advice, or if they are not available, contact or go to the nearest
emergency department.
If too much Colistimetate Sodium Noridem Ltd is accidentally administered, side effects may be
serious and may include kidney problems, muscle weakness, and difficulty breathing (or even respiratory arrest).
If you forget to take Colistimetate Sodium Noridem Ltd
If you are taking the medicine yourself and miss a dose, take the missed dose as soon as you remember, then take the next dose 8 hours later if you are using Colistimetate Sodium Noridem Ltd three times a day, or 12 hours later if you are taking Colistimetate Sodium Noridem Ltd twice a day. Continue as directed thereafter. Do not take a double dose to make up for a missed dose.
If you are receiving treatment in hospital or at home from a doctor or nurse and think you may have missed a dose or received too much Colistimetate Sodium Noridem Ltd, please ask your doctor or nurse for clarification.
If you stop treatment with Colistimetate Sodium Noridem Ltd
Do not stop treatment early unless instructed by your doctor. Your doctor will decide the duration of treatment.
If you have any questions about how to use this medicine, consult your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them.

Allergic reactions
When Colistimethate Sodium Noridem Ltd is administered intravenously, an allergic reaction may occur.
Severe allergic reactions can occur even after the first dose and may include rapid onset of skin rashes, swelling of the face, tongue and neck, difficulty breathing due to narrowing of the airways, and loss of consciousness.
If you experience signs of an allergic reaction, seek immediate medical attention.
Less severe allergic reactions may include skin rashes appearing later during treatment.

Nervous system side effects
Side effects affecting the nervous system are more likely to occur when the dose of Colistimethate Sodium Noridem Ltd is too high, in patients with poor kidney function, or in those also taking muscle relaxants and other medicines with similar effects on nerve function. The most serious of these possible nervous system side effects is inability to breathe due to paralysis of the chest muscles.
If you have difficulty breathing, seek immediate medical attention.

Other possible side effects may include numbness or tingling (especially in the face), dizziness or loss of balance, rapid changes in blood pressure or blood flow (including fainting and flushing), slurred speech, confusion and other mental disturbances (including loss of sense of reality). Injection site reactions such as irritation may also occur.

Kidney problems may also occur. These are particularly likely in patients who already have kidney disease, or who are receiving Colistimethate Sodium Noridem Ltd together with other medicines that may cause kidney-related side effects, or who are being treated with excessively high doses. These problems usually improve when treatment is stopped or when the dose of Colistimethate Sodium Noridem Ltd is reduced.

Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, consult your doctor or pharmacist. You may also report side effects directly through the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Colistimethate Sodium Noridem Ltd

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial label and on the
packaging after “EXP”. The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.

Reconstituted/diluted solution:
Hydrolysis of colistimethate is significantly increased when reconstituted and diluted below its critical micellar concentration of approximately 80,000 IU per ml. Solutions below this concentration should be used immediately.

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

• 1 MIU for 3 hours at 2-8°C when dissolved in 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection or water for injection.
• 2 MIU for 3 hours at 2-8°C when dissolved in 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection or water for injection.

From a microbiological standpoint, unless the method of opening/reconstitution/dilution excludes the risk of microbial contamination, the product should be used immediately.
If not used immediately, the user is responsible for the duration and conditions of storage.
Infusion solutions that have been diluted beyond the original vial volume and/or with a concentration < 80,000 IU/ml must be used immediately.
For intrathecal and intracerebroventricular administration, the reconstituted medicinal product must be used immediately.

Visually inspect the solution for the presence of particulate matter before administration. Only a clear solution practically free from visible particles should be used.
Any remaining solution should be discarded.
Do not dispose of medicines via wastewater. 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 Colistimethate Sodium Noridem Ltd Contains
The active substance is colistimethate sodium.
Each vial contains 1 million IU of colistimethate sodium.
Each vial contains 2 million IU of colistimethate sodium.
There are no other ingredients.

Description of the Appearance of Colistimethate Sodium Noridem Ltd and Contents of the Package
Colistimethate Sodium Noridem Ltd powder for solution for injection/infusion is supplied as white or off-white powder in single-dose vials.

For 1 million IU: Clear type I glass vial closed with a 20 mm bromobutyl rubber stopper of type I and sealed with a 20 mm white flip-off cap and aluminum seal.
For 2 million IU: Clear type I glass vial closed with a 20 mm bromobutyl rubber stopper of type I and sealed with a 20 mm orange plastic flip-off cap and aluminum seal.
Pack sizes: 1, 10 and 30 vials.
Not all pack sizes may be marketed.

Marketing Authorization Holder:
Noridem Enterprises Limited
Evagorou & Makariou, Mitsi Building 3, Office 115,
1065 Nicosia, Cyprus

Manufacturer:
DEMO S.A. PHARMACEUTICAL INDUSTRY,
14568 Krioneri, Attiki, Greece,
T: +30 210 8161802, F: +30 210 8161587.

This medicinal product is authorized in the European Economic Area Member States 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

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

The following information is intended exclusively for physicians or healthcare professionals:

Preparation and Handling
Instructions for Preparing the Solution for Injection / Infusion

For bolus injection:
Reconstitute the vial contents with no more than 10 ml of water for injections or sodium chloride 9 mg/ml (0.9%) solution for injection.

For infusion:
The reconstituted vial contents may be further diluted, typically with 50 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.

For intrathecal / intraventricular administration:
When intrathecal or intraventricular routes of administration are used, the administered volume must not exceed 1 ml (reconstituted concentration 125,000 IU/ml).

After reconstitution, the solution should be clear and colorless or not more intensely colored than a Y6 solution, free from visible particles.
The solutions are for single use only, and any residual solution must be discarded.
The medicinal product must be visually inspected before use (including after dilution). Only clear solutions practically free from visible particles should be used.

Incompatibilities
Mixing colistimethate sodium in infusion or injection solutions with other medicinal products is not recommended.

Dosage and Administration
Dosage
The dose is expressed in International Units (IU) of colistimethate sodium (CMS). A conversion table from CMS IU to mg of CMS, as well as to mg of colistin base activity (CBA), is included 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 of 9 million IU/day divided into 2–3 doses.
In critically ill patients, a loading dose of 9 million IU should be administered.
The optimal time interval until the first maintenance dose has not been established.
Models suggest that loading and maintenance doses up to 12 million IU may be required in some cases, particularly in patients with good renal function. However, clinical experience with such doses is extremely limited, and safety has not been established.
The recommended loading dose applies to patients with normal and impaired renal function, including those receiving renal replacement therapy.

Special Populations

Elderly
No dosage adjustment is considered necessary in elderly patients with normal renal function.

Renal impairment
Dosage adjustment is required in case of renal impairment, but available pharmacokinetic data in patients with renal impairment are very limited.
The following dosage adjustments are suggested as guidance.
A reduced dosage is recommended for patients with creatinine clearance < 50 ml/min:
A twice-daily dose is recommended.

Hemodialysis and continuous hemodiafiltration
Colistin appears to be dialyzable by conventional hemodialysis and continuous venovenous hemofiltration (CVVHF, CVVHDF). Extremely limited data are available from population PK studies in a very small number of patients receiving renal replacement therapy. Solid recommendations cannot be provided. The following regimens should be considered.

Hemodialysis (HD)
Days without HD: 2.25 million IU/day (2.2–2.3 million IU/day).
HD days: 3 million IU/day on hemodialysis days, to be administered after the HD session.
A twice-daily dosing regimen is recommended.

CVVHF/CVVHDF
Same as in patients with normal renal function. A three-times-daily dosing regimen is recommended.

Hepatic impairment
There are no data in patients with hepatic impairment. Caution is recommended when sodium colistimethate is administered in these patients.

Paediatric population
Data supporting dosing regimens in paediatric patients are very limited. Renal maturity must be taken into account when selecting the dosage. Dosing should be based on lean body mass.

Children ≤ 40 kg
75,000–150,000 IU/kg/day divided into three doses.
For children weighing more than 40 kg, adult dosing recommendations should be considered.
Doses >150,000 IU/kg/day have been reported in children with cystic fibrosis.
There are no data regarding the use or amount of initial dose in critically ill children.
Dosing recommendations in children with renal impairment have not been established.

Intrathecal and intracerebroventricular administration
Based on limited data, the following dose is recommended in adults:

Intracerebroventricular route:
125,000 IU/day

Intrathecal doses should not exceed those recommended for intracerebroventricular use.
Specific dosage recommendations for children cannot be provided for intrathecal and intracerebroventricular administration routes.

Method of administration
Sodium colistimethate Noridem Ltd is administered intravenously as a slow infusion over 30–60 minutes.
Patients with an implanted totally implantable venous access device (TIVAD) may tolerate bolus injections of up to 2 million IU in 10 ml administered over a minimum period of 5 minutes.

Sodium colistimethate undergoes hydrolysis in aqueous solution to form the active substance colistin. For dose preparation, especially when combining multiple vials is required, reconstitution of the required dose must be performed using strict aseptic techniques.

Dosage conversion table:
In the EU, the dose of sodium colistimethate (CMS) must be prescribed and administered exclusively in IU. The product label indicates the number of IU per vial.
Confusion and medication errors have occurred due to different expressions of dosage in terms of potency. In the USA and other parts of the world, dosage is expressed in milligrams of colistin base activity (mg CBA).
The following conversion table has been prepared for informational purposes only, and the values should be considered nominal and approximate.

CMS conversion table

*Nominal potency of the active substance = 12,500 IU/mg
Overdose
Symptoms
Overdose may result in neuromuscular blockade that can lead to muscle weakness,
apnea, and possible respiratory arrest. Overdose may also cause acute renal failure
characterized by decreased urine output and increased serum concentrations of
BUN and creatinine.
Treatment
There is no specific antidote; manage with supportive treatment. Measures to
increase the elimination rate of colistin may be attempted, e.g. mannitol-induced diuresis, prolonged hemodialysis, or peritoneal dialysis, but efficacy is unknown.