Colivia

Package leaflet: Information for the patient

Colivia, 1 000 000 IU, powder for solution for injection / infusion
Colivia, 2 000 000 IU, powder for solution for injection / infusion
Colivia, 3 000 000 IU, powder for solution for injection / infusion
Colistimethatum natricum
Please read this leaflet carefully before using this medicine, as it contains
important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, please ask your doctor or nurse.
• This medicine has been prescribed for a specific individual. Do not pass it on to others. This medicine may harm other people, even if their symptoms are the same.
• If you experience any adverse effects, including any not listed in this leaflet, tell your doctor or nurse. See section 4.

Contents of the leaflet

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

1. What Colivia is and what it is used for

Colivia contains colistimethate sodium (colistin) as the active substance, which belongs to a group of antibiotics called polymyxins.
Colivia 1 000 000 IU, 2 000 000 IU, and 3 000 000 IU is administered by injection to adults and children (including newborns) for the treatment of certain types of severe infections caused by specific bacteria. Colivia is used when other antibiotics are not suitable.
Colivia 1 000 000 IU and 2 000 000 IU are administered by inhalation to adults and children with cystic fibrosis for the treatment of chronic lung infections. Colivia is used when these infections are caused by a specific bacterium called Pseudomonas aeruginosa.
Colivia 1 000 000 IU, 2 000 000 IU, and 3 000 000 IU may also be administered intrathecally or intraventricularly in cases of central nervous system infections.

2. Important information before using Colivia

When not to use Colivia:

• if the patient is allergic (hypersensitive) to sodium colistimethate, colistin, or polymyxin B.

Warnings and precautions
Before starting treatment with Colivia, discuss with the doctor if:
✓ the patient has or has had kidney function disorders;
✓ the patient suffers from myasthenia gravis;
✓ the patient suffers from porphyria (a rare, usually hereditary metabolic disorder);
✓ the patient suffers from asthma.
If the patient experiences muscle cramps, fatigue, or increased urination, the doctor should be informed immediately, as these events may be related to a condition known as pseudohypoparathyroidism.
If the patient develops diarrhoea during or after treatment with sodium colistimethate, pseudomembranous colitis should be considered. In such a case, the doctor should be informed and may decide to discontinue treatment and initiate specific therapy against Clostridioides difficile. Do not take drugs that inhibit peristalsis/antidiarrhoeals.
Some patients may experience a feeling of chest tightness due to airway constriction during nebulization with Colivia. The doctor may then prescribe other nebulized medications to be used immediately before or after Colivia to prevent or treat this symptom.
Particular caution should be exercised when administering Colivia to premature infants, newborns, and infants, as their kidneys are not yet fully developed.

Colivia and other medicines
Inform the doctor about all medicines currently or recently taken by the patient, as well as any medicines the patient plans to take.
In particular, inform the doctor if the patient is taking any of the following medicines:

• medicines that may affect kidney function, such as aminoglycoside antibiotics (e.g. gentamicin, amikacin, tobramycin, netilmicin) and cephalosporins. Taking these medicines together with Colivia may increase the risk of kidney damage.
• medicines that may affect the nervous system, such as aminoglycoside antibiotics (e.g. gentamicin, amikacin, tobramycin, netilmicin) and cephalosporins. Taking these medicines together with Colivia may increase the risk of nervous system-related adverse effects.
• medicines known as muscle relaxants, often administered during general anaesthesia. Colivia may enhance the effect of these medicines. If the patient is to undergo general anaesthesia, the anaesthesiologist should be informed that the patient is taking Colivia.

Treatment with Colivia may not be recommended if the patient is taking any of the above-mentioned medicines. In some cases, the doctor may decide to discontinue their use (even temporarily), reduce the dose of Colivia, or monitor the patient during treatment with Colivia. In some cases, it may also be necessary to monitor blood levels of Colivia to ensure the correct dose is being administered.
If the patient suffers from myasthenia gravis and is simultaneously taking other antibiotics known as macrolides (such as azithromycin, clarithromycin or erythromycin) or antibiotics known as fluoroquinolones (such as ofloxacin, norfloxacin and ciprofloxacin), taking Colivia increases the risk of muscle weakness and breathing difficulties.
Concurrent use of Colivia with other forms of sodium colistimethate may increase the risk of adverse effects.

Pregnancy and breastfeeding
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to have a child, she should consult a doctor before using this medicine.
Harmful effects of Colivia on the unborn child have not been observed; however, as with all medicines, Colivia will be administered to a pregnant woman only if, in the doctor's opinion, it is absolutely necessary.
The drug passes into human milk. Colivia will be administered to a breastfeeding woman only if, in the doctor's opinion, it is absolutely necessary.

Driving and operating machinery
Intravenous administration of Colivia may lead to adverse effects such as dizziness, disorientation, or visual disturbances. If these occur, the patient should not drive or operate machinery (see section 4. "Possible side effects").

Colivia contains sodium
Colivia contains less than 1 mmol (23 mg) of sodium per vial, meaning the medicine is considered "sodium-free".
Colivia contains approximately 63 mg of sodium per 12 million IU dose (loading dose administered intravenously), equivalent to 3.15% of the WHO-recommended maximum daily sodium intake of 2 g for adults. This should be taken into account in patients controlling sodium intake in their diet.

3. How to use Colivia

This medicine should always be used according to the instructions given by the doctor or pharmacist. If in doubt,
consult your doctor or pharmacist.
The doctor will determine the dose and duration of treatment depending on the severity of infection,
the susceptibility of the microorganism causing the infection, and the patient's health status, age, and body weight.
The dose is expressed in international units [IU] of sodium colistimethate. Information intended solely for healthcare professionals includes a table for converting the dose expressed in [IU] of sodium colistimethate into milligrams [mg] of sodium colistimethate and into active colistin base activity (CBA).

Colivia 1,000,000 IU, 2,000,000 IU, and 3,000,000 IU
Intravenous administration
Adults and adolescents
The usual daily dose in adults is 9 million IU, divided into two or three doses. In critically ill patients, an initial higher dose of 9 million IU may be administered once at the beginning of treatment.
In certain cases, the doctor may decide to administer a higher daily dose of up to 12 million IU.

Newborns, infants, and children with body weight of 40 kg or less
The usual daily dose in children with body weight up to 40 kg is 75,000 to 150,000 IU per kilogram of body weight, divided into three doses.
Higher doses have occasionally been used in cystic fibrosis.
For children with body weight greater than 40 kg, the doctor may consider applying adult dosing recommendations.

Special patient groups
In patients with impaired renal function, newborns, and patients with cystic fibrosis, the doctor will recommend frequent monitoring of colistin blood levels.
Children and adults with impaired renal function, including those undergoing dialysis, usually receive reduced doses.
The doctor will regularly monitor kidney function during treatment with Colivia.
Caution should be exercised when administering sodium colistimethate to patients with impaired liver function.

Method of administration
Colivia is primarily administered in hospitals, usually intravenously either as an injection or as a 30-60 minute intravenous infusion.
If the patient is self-administering at home, the doctor or nurse will instruct the patient on how to reconstitute the powder and administer the correct dose of solution.

Duration of treatment
The duration of treatment is determined by the doctor depending on the severity of infection. In bacterial infections, it is important to complete the entire course of treatment to prevent worsening of the existing infection.

Colivia 1,000,000 IU, 2,000,000 IU, and 3,000,000 IU
Intrathecal administration into cerebrospinal fluid (into the cerebral ventricle or intrathecally into the spinal subarachnoid space)
The dose recommended below is based on limited data in adults.

Dosing
125,000 IU/day.
For this route of administration, the single dose usually corresponds to the daily dose.
Specific dosing recommendations for intrathecal or intraventricular administration in children cannot be provided.

Method of administration
Intrathecal and intraventricular administration

Colivia 1,000,000 IU and 2,000,000 IU
Inhalation administration
The usual dose for adults, adolescents, and children aged 2 years or older is 1–2 million IU two to three times daily (maximum 6 million IU per day).
The usual dose for children under 2 years of age is 0.5–1 million IU twice daily (maximum 2 million IU per day).
The doctor may decide to modify the dose depending on the patient's health status. If the patient is using other inhaled medicines, the doctor will inform the patient about the order in which they should be taken.

Method of administration
For inhalation use. If the patient is self-administering, the doctor or nurse will instruct the patient at the beginning of treatment on how to use Colivia in a nebulizer. The patient should sit upright and breathe normally during nebulization.
To prepare the solution for nebulization, Colivia 1 million IU should be dissolved in 3 mL of 0.9% sodium chloride solution or water for injections, and Colivia 2 million IU should be dissolved in 4 mL of 0.9% sodium chloride solution or water for injections. To prevent foaming, gently shake the vial until the entire powder dissolves. The prepared solution should be poured into the nebulizer reservoir.
Colivia is intended for nebulization using an appropriate nebulizer (e.g., PARI LC Plus, PARI LC Sprint, eFlow rapid, Microlife NEB200). Before starting treatment, it is important to ensure that the nebulizer is functioning properly. Read the nebulizer user manual carefully for more information on operating the device.
The resulting solution for nebulization should be clear. If visible particles are observed in the prepared solution, the medicine should not be used. The solution must be used immediately after preparation. More information on storage conditions of the solution can be found in the section: "Information intended solely for healthcare professionals."
Nebulization should be performed in a well-ventilated room.
After nebulization with Colivia, the nebulizer should be cleaned and disinfected according to the manufacturer's instructions.
Colivia should not be mixed with any other medicine intended for nebulization.

Duration of treatment
The duration of treatment will be determined by the doctor.

Use of a higher than recommended dose of Colivia
If the patient believes they have taken more Colivia than recommended, they should inform their doctor, pharmacist, or nurse and seek advice. If unable to contact them, they should go to the nearest emergency department. Accidental overdose of Colivia may lead to serious adverse effects such as kidney problems, muscle weakness, and breathing difficulties (including respiratory arrest).
Patients treated in hospital or at home by a doctor or nurse who suspect they may have missed a dose or received too high a dose of Colivia should consult their doctor, nurse, or pharmacist.

Missed dose of Colivia
If the patient is self-administering and has missed a dose, they should take the missed dose as soon as they remember, then wait 8 hours before taking the next dose if taking Colivia three times daily, or wait 12 hours if taking Colivia twice daily. Continue as directed thereafter.
Do not use a double dose to make up for a missed dose.

Stopping treatment with Colivia
Do not stop treatment unless instructed by the doctor. The duration of treatment is determined by the doctor. If in any doubt about using this medicine, consult your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will experience them.
Allergic reaction
Regardless of whether Colivia is administered intravenously or by inhalation, an allergic reaction may occur.
Severe allergic reactions may occur after the first dose of the medicine and include rapidly developing rashes, swelling of the face, tongue and throat, breathing difficulties due to airway constriction, and loss of consciousness.
If an allergic reaction occurs, administration of the medicine must be stopped immediately and medical advice must be sought immediately.
Less serious allergic reactions include skin rash, which may appear during treatment.

Side effects that may occur after intravenous administration of Colivia injection
Nervous system side effects are more likely to occur if too high a dose of Colivia is administered to patients with renal impairment or to patients taking muscle relaxants or other medicines with similar effects on nerve function.
The most serious possible nervous system-related side effects include respiratory arrest due to paralysis of the chest muscles. If the patient begins to experience breathing difficulties, the medicine must be stopped immediately and medical advice must be sought immediately.
Other possible side effects include sensory disturbances or swelling (especially in the facial area), dizziness, loss of balance, rapid changes in blood pressure or blood flow (including nausea and skin flushing), slurred speech, vision problems, disorientation, and psychiatric symptoms (including loss of sense of reality). Reactions at the injection site, such as irritation, may also occur.

After intravenous administration, the following symptoms may occur, which could be related to a condition known as pseudohyperaldosteronism (frequency unknown – frequency cannot be estimated from available data) (see section 2):

• muscle cramps
• increased urination
• fatigue.

Kidney problems may occur. These are more likely in patients with impaired kidney function, in patients taking Colivia together with other medicines that may cause similar kidney function disturbances, or in patients receiving too high a dose of Colivia. These problems usually resolve after discontinuation of treatment or reduction of the Colivia dose.

Side effects that may occur after inhalation administration of Colivia (nebulizer).
Possible side effects include cough, feeling of tightness in the chest due to airway constriction, sore throat or mouth pain, which may be caused by hypersensitivity or Candida infection (Candida). Skin rash may also be a sign of hypersensitivity. If this occurs, treatment should be discontinued.

Reporting of side effects
If any side effects occur, including any side effects not listed in this leaflet, inform your doctor, pharmacist or nurse. Side effects 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, 02-222 Warsaw
Tel.: +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.
Reporting side effects helps provide more information on the safety of this medicine.

5. How to store the medicine Colivia

Keep the medicine out of the sight and reach of children.
Unopened vial: Store below 25°C.
Do not use the medicine after the expiry date stated on the outer carton and blister after EXP. The expiry date refers to the last day of the stated month.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. Such measures will help protect the environment.

6. Contents of the pack and other information

What Colivia contains
The active substance is colistimethate sodium (colistin).
One vial contains 1,000,000 i.u., 2,000,000 i.u., or 3,000,000 i.u. of colistimethate sodium.

What Colivia looks like and contents of the pack
Sterile, white or almost white powder.

Packaging:
Colivia is packed in 20 mL vials made of colourless type III glass.
The vials are closed with grey chlorobutyl rubber stoppers and sealed with aluminium caps. The vials are packed in cardboard boxes.
Pack sizes: 1 vial, 10 vials, or 20 vials.
Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer
Tarchomin Pharmaceutical Works "Polfa" Joint Stock Company
A. Fleminga 2 Street
03-176 Warsaw
Telephone number: 22 811-18-14

For further information about this medicinal product, please contact the Marketing Authorisation Holder.

Information intended exclusively for healthcare professionals

For additional information, see the Summary of Product Characteristics.
Dosing in adult patients with renal impairment
Dosing recommendations in pediatric patients with renal impairment have not been established.
In adult patients with renal impairment, dose adjustment is necessary, but pharmacokinetic data available in patients with renal impairment are very limited.
The following dosing recommendations are proposed as a guideline.
In patients with creatinine clearance <50 mL/min, a dose reduction is recommended.
It is recommended to administer the drug twice daily.

mln IU = million IU
Hemodialysis and continuous hemofiltration or hemodiafiltration
Colistin appears to be dialyzed during conventional hemodialysis and continuous venovenous
hemofiltration or hemodiafiltration (CVVHF, 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
Days without HD: 2.25 million IU/day (2.2 to 2.3 million IU/day).
HD days: 3 million IU on hemodialysis days, to be administered after the HD session.
Administration twice daily is recommended.
CVVHF or CVVHDF
As in patients with normal renal function. Administration three times daily is recommended.
Method of administration and preparation of solutions
The solution may be administered only if it is clear and practically free from particles visible to the
naked eye.
Colivia 1 000 000 IU, 2 000 000 IU, and 3 000 000 IU
Intravenous administration
Intravenous injection solution
The content of the vial (1 million IU, 2 million IU, or 3 million IU) should be dissolved in no more than
10 mL of water for injections or 0.9% sodium chloride. The prepared solution should be administered
by slow intravenous injection (over 3 to 5 minutes).
Infusion solution
After reconstitution, the content of the vial (1 million IU, 2 million IU, or 3 million IU) may be diluted,
typically in 50 mL of 0.9% sodium chloride. The solution should be prepared in a polyolefin bag or container.
Colivia 1 000 000 IU, 2 000 000 IU, and 3 000 000 IU
Intrathecal and intraventricular administration
The volume of the prepared solution must not exceed 1 mL, and the concentration after dissolution must not
be higher than 125,000 IU/mL.
The appropriate solvent for solution preparation is 0.9% sodium chloride solution.
Colivia 1 000 000 IU and 2 000 000 IU
Inhalation administration
Nebulized solution
The content of the vial should be dissolved in water for injections or 0.9% sodium chloride solution.
Sodium colistimethate is very well soluble in the reconstitution medium.
The content of the 1 million IU vial should be dissolved in 3 mL of water for injections or 0.9% sodium
chloride solution. The content of the 2 million IU vial should be dissolved in 4 mL of water for injections or
0.9% sodium chloride solution. Administer via nebulizer.
Due to the possibility of foaming, vigorous shaking should be avoided. The resulting nebulized solution should
be clear and carefully transferred into the nebulizer drug reservoir.
Nebulization should be performed in a well-ventilated room.
Dose conversion table
In the EU, the dose of sodium colistimethate 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 dose in terms of potency, confusion and medication errors have
occurred. In the United States and other parts of the world, the dose is expressed in milligrams referring to
the active form of colistin (mg CBA).
Both IU and mg CBA do not represent the quantity or weight of colistin, but rather its antibacterial activity
measured by microbiological methods. The unit of active colistin is defined as the minimum concentration
that inhibits the growth of Escherichia coli 95 I.S.M.* in 1 mL of broth at pH 7.2. Pure colistin has been
assigned a potency of 1000 µg base activity/mg (30,000 IU/mg).
*(In Situ Microscopy (ISM) is an optical, non-invasive technique for monitoring cells in biological processes in real time).
The following conversion table is provided for informational purposes only, and values should be considered nominal and approximate.
Sodium colistimethate conversion table

* Nominal active substance potency = 12,500 IU/mg
Special precautions during storage
Shelf-life after reconstitution
The hydrolysis of colistimethate increases significantly after reconstitution and dilution below the critical micelle concentration of approximately 80,000 IU/mL.
For infusion solutions that have been diluted to a volume greater than the original vial volume and/or to a concentration < 80,000 IU/mL, and for intrathecal and intraventricular administration, the solution should be used immediately after preparation.
From a microbiological perspective, solutions should be used immediately after preparation. If the solution is not used immediately, the user is responsible for the storage period and conditions after opening, which should not exceed 8 hours at 2–8°C, unless reconstitution/dilution was carried out under controlled and validated aseptic conditions.
Special precautions for disposal of medicinal product
Any unused residues of the medicinal product or waste materials should be disposed of in accordance with local regulations.
Pharmaceutical incompatibilities
Care should be taken to avoid mixing infusions, injections, and nebulization solutions containing sodium colistimethate.