Colistimethate Hikma

Package leaflet: Information for the user

Colistimetato Hikma 1 million International Units

Powder for injectable/infusion solution or nebulising solution
Colistimethate sodium
Generic medicine
Read this leaflet carefully before taking 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.
• This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor. See section 4.

Contents of this leaflet

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

1. What Colistimetate Hikma is and what it is used for

Colistimetate Hikma contains the active substance sodium colistimethate. Sodium colistimethate is an antibiotic. It belongs to a group of antibiotics called Polymyxins.
Colistimetate Hikma is administered by injection to treat certain types of serious infections caused by specific bacteria. Colistimetate Hikma is used when other antibiotics are not suitable.
Colistimetate Hikma is administered by inhalation to treat lung infections in patients with cystic fibrosis. Colistimetate Hikma is used when these infections are caused by specific bacteria called Pseudomonas aeruginosa.

2. What you should know before using Colistimetato Hikma

Do not use Colistimetato Hikma:

• If you are allergic (hypersensitive) to sodium colistimethate, colistin, or other polymyxins. Warnings and precautions Talk to your doctor before using Colistimetato Hikma
• If you suffer from porphyria
• If you have or have had kidney problems
• If you suffer from severe myasthenia
• If you suffer from asthma. Some people may experience a feeling of heaviness in the chest due to airway narrowing during inhalation of Colistimetato Hikma. Your doctor may prescribe other inhaled medicines immediately before or after using Colistimetato Hikma to prevent or treat this problem. Special caution is required when using Colistimetato Hikma in premature infants and newborns, as their kidneys are not yet fully developed.

Other medicines and Colistimetato Hikma
Inform your doctor if you are currently taking, have recently taken, or might take other
medicines.
If you are taking any of the following medicines, you may or may not be able to take
Colistimetato Hikma.
Sometimes treatment with other medicines must be interrupted (even temporarily), or a lower dose of Colistimetato Hikma may be required, or monitoring may be necessary while taking Colistimetato Hikma. In some cases, the level of Colistimetato Hikma in the blood may need to be measured periodically to ensure the correct dose.

• Medicines such as antibiotics called aminoglycosides (including gentamicin, tobramycin, amikacin, and netilmicin) and cephalosporins, which may affect kidney function. Administering these medicines together with Colistimetato Hikma 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) that may affect the nervous system. Administering these medicines together with Colistimetato Hikma may increase the risk of side effects in the ears and other parts of the nervous system (see section 4 of this leaflet).
• Medicines called muscle relaxants, often used during general anesthesia. Colistimetato Hikma may enhance the effects of these medicines. If you are undergoing general anesthesia, inform the anesthetist that you have taken Colistimetato Hikma. If you suffer from severe myasthenia and are taking other antibiotics called macrolides (such as azithromycin, clarithromycin, or erythromycin) or antibiotics called fluoroquinolones (such as ofloxacin, norfloxacin, and ciprofloxacin), taking Colistimetato Hikma further increases the risk of muscle weakness and breathing difficulties. Administering Colistimetato Hikma by intravenous infusion at the same time as inhaled Colistimetato Hikma may increase the risk of side effects.

Pregnancy and breastfeeding
It is not known whether Colistimetato Hikma causes harm to the unborn child, but, like all medicines, it will be administered to a pregnant woman only if truly necessary. If you are already pregnant, think you may be pregnant, or are planning to have a baby, ask your doctor for advice before taking this medicine.
Are you breastfeeding? Small amounts of Colistimetato Hikma pass into breast milk. If you cannot stop breastfeeding while taking Colistimetato Hikma, you should carefully monitor your baby for any signs of illness and inform your doctor if you notice any abnormalities.

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

3. How to use Colistimetate Hikma

Depending on the reason you are being given this medicine (see section 1 of this leaflet), Colistimetate Hikma may be administered by rapid injection (over 5 minutes via a special type of intravenous line) or by slow injection (infusion over approximately 30–60 minutes) into a vein. Colistimetate Hikma can also be delivered into the lungs as a fine mist using a device called a nebuliser. The droplets produced by nebulisation are small enough to reach the lungs so that Colistimetate Hikma can reach the site of bacterial infection.

Always use Colistimetate Hikma exactly as your doctor has told you. Check with your doctor if you are unsure.

For use in a nebuliser:

Dosing

• When Colistimetate Hikma is to be administered by inhalation using a nebuliser, the usual dose for adults, adolescents, and children aged 2 years and older is 1–2 million units two or three times a day (maximum 6 million units per day).
• The usual dose for children under 2 years of age is 0.5–1 million units twice a day (maximum 2 million units per day). Your doctor may decide to adjust the dose depending on individual circumstances. If you are also taking other inhaled medicines, your doctor will tell you in which order to take them.

Method of administration

If you are being treated at home, your doctor or nurse will show you how to use Colistimetate Hikma with the nebuliser when you start treatment. The following are general instructions:

1. Remove the plastic cap.
2. Using a syringe, draw up the required volume of solvent from the solvent container (sterile water or sterile physiological saline solution, or a 50:50 mixture of sterile water and sterile 0.9% saline solution) to dissolve the powder as follows:
   One vial of 1 million units: 3 ml of sterile water or 3 ml of sterile 0.9% saline solution or 1.5 ml of sterile water and 1.5 ml of sterile 0.9% saline solution.
3. Pierce the centre of the vial stopper with the syringe and slowly inject the solvent into the vial.
4. Gently invert the vial twice.
5. Gently rotate the vial between your hands to dissolve all visible Colistimetate Hikma powder on the bottom and sides of the vial. Do not shake the vial too vigorously, as this may cause foaming of the solution.
6. Invert the vial and use the syringe to withdraw the final solution.
7. Remove the needle from the syringe and pour the solution into the nebuliser. Then inhale as usual. Use the nebuliser according to the manufacturer’s instructions.

IMPORTANT: Do not mix Colistimetate Hikma with other nebulisation products at the same time.

For intravenous infusion or injection:

Dosing

Colistimetate Hikma will be administered by your doctor as an intravenous infusion over 30–60 minutes.

The daily dose for adults is 9 million units, divided into two or three doses. If you are particularly unwell, you may initially receive a single dose of up to 9 million units at the start of treatment.

In some cases, your doctor may decide to give a daily dose of up to 12 million units.

The usual daily dose for children weighing up to 40 kg is 75,000 to 150,000 units per kilogram of body weight, divided into three doses.

Higher doses have sometimes been used in cystic fibrosis.

Children and adults with kidney problems, including those on dialysis, are generally treated with lower doses.

Your doctor will regularly monitor your kidney function while you are receiving Colistimetate Hikma.

Method of administration

Colistimetate Hikma is administered by injection, primarily in hospitals. If you are being treated at home, your doctor or nurse will show you how to reconstitute the powder and administer the correct dose of solution.

Duration of treatment

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

If you use more Colistimetate Hikma than you should

If you think you have been given too much Colistimetate Hikma, contact your doctor or nurse immediately for advice, or if they are not available, contact or go to the hospital emergency department. If you have accidentally been given too much Colistimetate Hikma, side effects may be serious and may include kidney problems, muscle weakness, and breathing difficulties (or even respiratory arrest).

If you are being treated in hospital or at home by a doctor or nurse and you think you have missed a dose or received too much Colistimetate Hikma, please speak to your doctor, nurse, or pharmacist.

If you forget to take Colistimetate Hikma

If you are self-administering and you forget a dose, take the missed dose as soon as you remember, then take the next dose 8 hours later if you are taking Colistimetate Hikma three times a day, or 12 hours later if you are taking it twice a day. After that, continue as directed.

Do not take a double dose to make up for a missed dose.

If you stop using Colistimetate Hikma

Do not stop treatment early unless your doctor tells you it is safe to do so. Your doctor will decide how long your treatment should last. If you have any further questions about the use of this medicine, ask your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Allergic reactions
If Colistimethate Hikma is administered intravenously or by inhalation, an allergic reaction may occur. Allergic reactions can happen 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, you must seek urgent medical advice.
Less severe allergic reactions include skin rashes that appear later during treatment.

Side effects associated with intravenous injection of Colistimethate Hikma
Nervous system-related side effects are more likely when the dose of Colistimethate Hikma is too high, in people with weak kidneys, or in those also taking muscle relaxants or other medicines with similar effects on nerve function.
The most serious of these possible nervous system side effects is the inability to breathe due to paralysis of the chest muscles. If you experience breathing difficulties, you must seek urgent medical advice.
Other possible side effects include numbness or tingling (particularly around the face), dizziness or loss of balance, rapid changes in blood pressure or blood flow (including weakness and hot flushes), difficulty speaking, vision problems, confusion and mental disturbances (including loss of touch with reality). There may also be reactions at the injection site, such as irritation.
Kidney problems may also occur. These are particularly likely in people who already have weak kidneys, in those who have received Colistimethate Hikma at the same time as other medicines that may cause kidney-related side effects, or in those receiving too high a dose. These problems usually improve if treatment is stopped or if the dose of Colistimethate Hikma is reduced.
If you experience any side effects, including any not listed in this leaflet, talk to your doctor.

Side effects associated with inhalation of Colistimethate Hikma (nebulisation)
The risk of side effects is usually much lower when administered by inhalation because usually very little Colistimethate Hikma reaches the bloodstream when given this way.
Possible side effects include cough, chest tightness due to narrowing of the airways, mouth or throat pain, and mouth or throat infections (Candida).

Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, talk to your doctor. You can also report side effects directly via the national reporting system:
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 Colistimetate Hikma

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 after EXP. The expiry date refers to the last day of the stated month.
Do not store above 25°C.
Keep the vials in the outer carton to protect the medicine from light.
Solutions of Colistimetate Hikma for injection must be used immediately after preparation. If this is not possible, prepared solutions must not be stored for longer than 6 hours in a refrigerator or 2 hours at room temperature. Any unused solution must be discarded.
Solutions of Colistimetate Hikma for inhalation must be administered immediately. If this is not possible, solutions must not be stored for longer than 6 hours in a refrigerator or 2 hours at room temperature. Any unused solution must be discarded.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist to dispose of medicines you no longer use. These measures will help protect the environment.

6. Package contents and other information

What Colistimetate Hikma contains
Each vial contains 1 million International Units of colistimethate sodium
(approximately 80 mg of powder).
There are no other ingredients.

What Colistimetate Hikma looks like and contents of the pack
Colistimetate Hikma, a powder for solution for injection or infusion, or for nebuliser solution, is supplied as a white powder in single-dose vials.
Each carton contains 1 or 10 vials.

Marketing Authorisation Holder and manufacturer
Marketing Authorisation Holder
Hikma Farmacêutica (Portugal), S.A.
Estrada do Rio da Mó, nº8, 8A/8B
Fervença
2705-906 Terrugem SNT
Portugal

Manufacturer
Hikma Italia S.p.A.
Viale Certosa, 10,
27100 Pavia
Italy

This medicinal product is authorised in the EEA Member States under the following names:
Germany: Colistimethat-Natrium Hikma 1 Million I.E. Pulver zur Herstellung einer Injektions-/Infusionslösung oder einer Lösung für einen Vernebler
Italy: Colistimetato Hikma
Portugal: Colistimetato de sódio Hikma

This leaflet was last reviewed MM/YYYY
The following information is intended for healthcare professionals only

Posology and method of administration
For injection or infusion
The dose to be administered and the duration of treatment should take into account the severity of the infection and the clinical response. Therapeutic guidelines must be followed.
The dose is expressed in International Units (IU) of colistimethate sodium (CMS). A conversion table from CMS IU to mg of CMS and mg of colistin base activity (CBA) is included at the end of this section.

Posology
The dosage recommendations below are based on limited population pharmacokinetic data in critically ill patients (see section 4.4):

Adults and adolescents
Maintenance dose: 9 million IU/day (MIU/day) divided into 2–3 doses.
A loading dose of 9 MIU should be administered in severely ill patients.
The optimal timing for the first maintenance dose has not been established.
Models suggest that loading and maintenance doses up to 12 MIU may be required in some patients with good renal function. However, clinical experience with such doses is extremely limited, and safety has not been established.
The loading dose applies to patients with normal and impaired renal function, including those on renal replacement therapy.

Renal impairment
Dosage adjustments are required in cases of renal impairment, but available pharmacokinetic data in patients with impaired renal function are very limited.
The following dosage adjustments are suggested as guidance.
Dose reductions are recommended for patients with creatinine clearance <50 ml/min:
Dosing regimens with two administrations per day are recommended.

MUI = million IU
Haemodialysis and haemo(dia)filtration continuous
Colistimethate appears to be dialysable through conventional haemodialysis and continuous
venovenous filtration (CVVHF, CVVHDF). There are extremely limited population PK study data from a very small number of patients on renal replacement therapy. Fixed dosing recommendations cannot be made. The following regimens may be considered.
Haemodialysis
Non-HD days: 2.25 million IU/day (2.2–2.3 million IU/day).
HD days: 3 million IU/day on haemodialysis days, to be administered after the HD session.
Twice-daily dosing is recommended.
CVVHF/CVVHDF
As in patients with normal renal function. Three times daily dosing is recommended.
Hepatic impairment
There are no data in patients with hepatic impairment. Caution should be exercised when administering sodium colistimethate in these patients.
Elderly
Dose adjustment is not considered necessary in elderly patients with normal renal function.
Paediatric population
Data supporting the dosing regimen in paediatric patients are very limited. Renal maturity should be taken into account when selecting the dose. The dose should be calculated based on body weight.
Children ≤ 40 kg
75,000–150,000 IU/kg/day divided into 3 doses.
For children with body weight above 40 kg, the adult dose recommendation 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 size of a loading dose in critically ill children.
Dose recommendations have not been established in children with impaired renal function.
Intrathecal and intraventricular administration
Based on limited data, the following dose is recommended in adults:
Intraventricular route
125,000 IU/day
Intrathecal doses administered should not exceed those recommended for intraventricular use.
No specific recommendations can be made for dosing in children via intrathecal and intraventricular routes.
Method of administration
Colistimethate Hikma is administered intravenously as a slow infusion over 30–60 minutes.
Patients with a totally implanted venous access device (TIVAD) may tolerate a bolus injection of up to 2 million IU in 10 ml administered over a minimum of 5 minutes (see section 6.6).
Sodium colistimethate undergoes hydrolysis to the active substance colistin in aqueous solution. For dose preparation, especially where combination of multiple vials is required, reconstitution of the required dose must be performed using strict aseptic technique (see section 6.6).
Nebulised solution
It is recommended that sodium colistimethate (CMS) be administered under the supervision of physicians experienced in its use.
Dosage
Dosing may be adjusted according to the severity of the condition and clinical response.
Recommended dosage range:
Inhalation administration
Adults, adolescents and children ≥ 2 years
1–2 million IU two or three times daily (max 6 million IU/day)
Children < 2 years
0.5–1 million IU twice daily (max 2 million IU/day)
Relevant clinical guidelines regarding treatment regimens, duration of treatment, frequency and co-administration of other antibacterial agents should be followed.
Elderly
Dose adjustment is not considered necessary.
Renal impairment
Dose adjustment is not considered necessary; however, caution should be exercised in patients with renal impairment (see sections 4.4 and 5.2).
Hepatic impairment
Dose adjustment is not considered necessary.
Method of administration
For inhalation use
Sodium colistimethate undergoes hydrolysis to the active substance colistin in aqueous solution.
For special precautions regarding disposal and handling of reconstituted solutions, see section 6.6.
If other treatments have been initiated, they should be followed in the order recommended by the physician.
Dose conversion table
In the EU, the dose of sodium colistimethate (CMS) must be prescribed and administered only in International Units (IU). The product label indicates the number of IU per vial.
Confusion and medication errors have occurred due to different expressions of dose in terms of potency. The dose is expressed in the United States and other parts of the world as milligrams of colistin base activity (mg CBA).
The following conversion table is provided for information only, and values should be considered nominal and approximate.
CMS conversion table

*Nominal potency of the active substance = 12,500 IU/mg
Special precautions for disposal and other handling
For bolus injection:
Reconstitute the contents of the vial with no more than 10 ml of water for injections or with 0.9% sodium chloride.
For infusion:
The reconstituted vial contents may be diluted, usually with 50 ml of 0.9% sodium chloride.
When intrathecal and intraventricular routes of administration are used, the administered volume must not exceed 1 ml (reconstituted concentration 125,000 IU/ml).
Inhalation:
Reconstitute the contents of the vial with water for injections to produce a hypotonic solution, or with a 50:50 mixture of water for injections and 0.9% sodium chloride to produce an isotonic solution, or with 0.9% sodium chloride to produce a hypertonic solution.
The reconstitution volume must comply with the nebulizer’s instructions for use and normally does not exceed 4 ml.
Nebulizer delivery may be performed in open air or with a filter attached.
Nebulization should be carried out in a well-ventilated room.
During reconstitution, gently swirl to avoid foaming.
The solution is for single use only, and any remaining solution must be discarded.
Reconstituted solutions:
Solutions for injection or infusion:
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 must be used immediately.
For solutions for bolus injection or nebulization, chemical and physical in-use stability of the reconstituted solution in the original vial at a concentration ≥ 80,000 IU/mL has been demonstrated for 6 hours at 2–8°C.
From a microbiological standpoint, unless the method of opening/reconstitution/dilution prevents the risk of microbial contamination, the product should be used immediately.
If not used immediately, the duration and conditions of storage during use are the responsibility of the user.
Solutions for infusion that have been diluted beyond the original vial volume and/or to a concentration <80,000 IU/mL must be used immediately.
For solutions intended for intrathecal and intraventricular administration, the reconstituted product must be used immediately.

Package leaflet: information for the user

Colistimetato Hikma 2 000 000 UI

Powder for injectable/infusion solution or for nebuliser solution
Colistimethate sodium
Generic medicine
Please read this leaflet carefully before taking 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.
• This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any side effect, including those not listed in this leaflet, consult your doctor. See section 4.

Contents of this leaflet

1. What Colistimetato Hikma is and what it is used for
2. What you need to know before using Colistimetato Hikma
3. How to use Colistimetato Hikma
4. Possible side effects
5. How to store Colistimetato Hikma
6. Package contents and other information

2. What Colistimetato Hikma is and what it is used for

Colistimetato Hikma contains the active substance sodium colistimethate. Sodium colistimethate is an antibiotic. It belongs to a group of antibiotics called Polymyxins.
Colistimetato Hikma is administered by injection to treat certain types of serious infections caused by specific bacteria. Colistimetato Hikma is used when other antibiotics are not suitable.
Colistimetato Hikma is administered by inhalation to treat lung infections in patients with cystic fibrosis. Colistimetato Hikma is used when these infections are caused by specific bacteria called Pseudomonas aeruginosa.

2. What you need to know before using Colistimetato Hikma

Do not use Colistimetato Hikma:

• If you are allergic (hypersensitive) to colistimethate sodium, colistin, or other polymyxins.
• Warnings and precautions Talk to your doctor before using Colistimetato Hikma
• If you have porphyria
• If you have or have had kidney problems
• If you have severe myasthenia gravis
• If you have asthma

Some people may experience a feeling of chest heaviness due to narrowing of the airways during inhalation of Colistimetato Hikma. Your doctor may prescribe other inhaled medications immediately before or after using Colistimetato Hikma to prevent or treat this problem.
Particular caution should be exercised when using Colistimetato Hikma in premature infants and newborns, as their kidneys are not yet fully developed.
Other medicines and Colistimetato Hikma
Inform your doctor if you are taking, have recently taken, or might take any other medicines.
If you are taking any of the following medicines, you may or may not be able to take Colistimetato Hikma.
Sometimes treatment with other medicines may need to be stopped (even if only temporarily), or a lower dose of Colistimetato Hikma may be required, or you may need to be monitored while taking Colistimetato Hikma.
In some cases, blood levels of Colistimetato Hikma may need to be measured periodically to ensure you are receiving the correct dose.

• Medicines such as antibiotics known as aminoglycosides (including gentamicin, tobramycin, amikacin, and netilmicin) and cephalosporins, which can affect kidney function. Administering these medicines together with Colistimetato Hikma may increase the risk of kidney damage (see section 4 of this leaflet).
• Medicines such as antibiotics known as aminoglycosides (including gentamicin, tobramycin, amikacin, and netilmicin) that can affect the nervous system. Administering these medicines together with Colistimetato Hikma may increase the risk of side effects in the ears and other parts of the nervous system (see section 4 of this leaflet).
• Medicines known as muscle relaxants, often used during general anesthesia. Colistimetato Hikma may enhance the effects of these medicines. If you are undergoing general anesthesia, inform the anesthetist that you have taken Colistimetato Hikma.

If you have severe myasthenia gravis and are taking other antibiotics known as macrolides (such as azithromycin, clarithromycin, or erythromycin) or antibiotics known as fluoroquinolones (such as ofloxacin, norfloxacin, and ciprofloxacin), taking Colistimetato Hikma may further increase the risk of muscle weakness and breathing difficulties.
Receiving Colistimetato Hikma by intravenous infusion at the same time as inhaled Colistimetato Hikma may increase the risk of side effects.
Pregnancy and breastfeeding
If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, consult your doctor or pharmacist before using this medicine.
There is no information available on the safety of Colistimetato Hikma in pregnant women.
Before using Colistimetato Hikma, your doctor must inform you whether the benefits of the medicine outweigh the risks.
Colistimethate sodium may be excreted in breast milk. Discuss the use of Colistimetato Hikma with your doctor.
Driving and using machines
When Colistimetato Hikma is administered intravenously, side effects such as dizziness, confusion, or vision problems may occur. If these occur, you must not drive or operate machinery.

4. How to use Colistimetate Hikma

Depending on the reason for which you are being administered this medicine (see section 1 of this leaflet), Colistimetate Hikma may be given either as a rapid injection (over 5 minutes via a special type of intravenous line) or as a slow injection (infusion over approximately 30–60 minutes) into a vein. Colistimetate Hikma may also be nebulised into the lungs as a fine mist using a device called a nebuliser. The droplets produced by nebulisation are small enough to enter the lungs so that Colistimetate Hikma can reach the site of bacterial infection.
Always use Colistimetate Hikma exactly as your doctor has told you. Check with your doctor if you are unsure.

For use in a nebuliser:
Dosing

• When Colistimetate Hikma is to be administered by inhalation using a nebuliser, the usual dose for adults, adolescents and children aged 2 years or older is 1–2 million units two or three times daily (maximum 6 million units per day).
• The usual dose for children under 2 years of age is 0.5–1 million units twice daily (maximum 2 million units per day). Your doctor may decide to adjust the dose depending on circumstances. If you are also taking other inhaled medicines, your doctor will tell you the order in which to take them.

Method of administration
If you are being treated at home, your doctor or nurse will show you how to use Colistimetate Hikma with the nebuliser when you start treatment. The following are general instructions.

1. Remove the plastic cap
2. Using a syringe, withdraw the required volume of solvent from the solvent container
(- water for injections to produce a hypotonic solution, or

• a 50:50 mixture of water for injections and 0.9% saline solution, to produce an isotonic solution, or
• 0.9% saline solution, to produce a hypertonic solution) to dissolve the powder as follows: 1 vial of 2 million units in:
• 4 ml of sterile water, or
• 2 ml of sterile water and 2 ml of sterile 0.9% saline solution, or
• 4 ml of sterile 0.9% saline solution

3. Pierce the centre of the vial stopper with the syringe and slowly inject the solvent into the vial.
4. Gently invert the vial twice.
5. Gently rotate the vial between your hands to dissolve all visible Colistimetate Hikma powder on the bottom and sides of the vial. Do not shake the vial vigorously, as this may cause the solution to foam.
6. Invert the vial and use the syringe to withdraw the final solution.
7. Remove the needle from the syringe and pour the solution into the nebuliser. Then inhale as usual. Use the nebuliser according to the manufacturer's instructions.
IMPORTANT: Do not mix Colistimetate Hikma with other nebulisation products at the same time.

For intravenous infusion or injection:
Dosing
Colistimetate Hikma will be administered by your doctor as an intravenous infusion over 30–60 minutes.
The usual daily dose in adults is 9 million units, divided into two or three doses. If you are particularly unwell, you may initially receive a higher dose of 9 million units once at the start of treatment.
In some cases, your doctor may decide to administer a daily dose of up to 12 million units.
The usual daily dose for children weighing up to 40 kg is 75,000 to 150,000 units per kilogram of body weight, divided into three doses.
Higher doses have sometimes been used in cystic fibrosis.
Children and adults with kidney problems, including those on dialysis, are generally treated with lower doses.
Your doctor will regularly monitor your kidney function while you are receiving Colistimetate Hikma.

Method of administration
Colistimetate Hikma is administered by injection, primarily in hospital settings. If you are to be treated at home, your doctor or nurse will show you how to reconstitute the powder and administer the correct dose of solution.

Duration of treatment
Your doctor will decide how long your 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.

If you use more Colistimetate Hikma than you should
If you think you have been given too much Colistimetate Hikma, contact your doctor or nurse immediately for advice, or if they are not available, contact or go to the nearest hospital emergency department or emergency unit. If you have accidentally been given too much Colistimetate Hikma, side effects may be severe and may include kidney problems, muscle weakness, and breathing difficulties (or even respiratory arrest).
If you are being treated in hospital or at home by a doctor or nurse and you think you have missed a dose or received too much Colistimetate Hikma, please discuss this with your doctor, nurse or pharmacist.

If you forget to take Colistimetate Hikma
If you are self-administering and have missed a dose, take the missed dose as soon as you remember, then take the next dose 8 hours later if you are using Colistimetate Hikma three times daily, or 12 hours later if you are using it twice daily. Continue as directed thereafter.
Do not take a double dose to make up for a missed dose.

If you stop using Colistimetate Hikma
Do not stop treatment early unless your doctor tells you to do so. Your doctor will decide how long your treatment should last. If you have any further questions about the use of this medicine, ask your doctor.

4. Possible side effects

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

Allergic reactions
If Colistimethate Hikma is administered intravenously or by inhalation, an allergic reaction may occur. Allergic reactions can happen even after the first dose and may include a 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, you must seek urgent medical advice.
Less severe allergic reactions may include skin rashes appearing later during treatment.

Side effects associated with intravenous injection of Colistimethate Hikma
Nervous system side effects are more likely when the dose of Colistimethate Hikma is too high, in people with impaired kidney function, or in those also taking muscle relaxants or other medicines with similar effects on nerve function.
The most serious of these possible nervous system side effects is the inability to breathe due to paralysis of the chest muscles. If you experience breathing difficulties, you must seek urgent medical advice.
Other possible side effects include numbness or tingling (particularly around the face), dizziness or loss of balance, rapid changes in blood pressure or blood flow (including weakness and hot flushes), difficulty speaking, vision problems, confusion, and 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 people who already have impaired kidney function, in whom Colistimethate Hikma has been administered concomitantly with other medicines that may cause kidney-related side effects, or who are receiving too high a dose. These problems usually improve if treatment is stopped or if the dose of Colistimethate Hikma is reduced.

If you experience any side effects, including any not listed in this leaflet, speak to your doctor.

Side effects associated with inhalation of Colistimethate Hikma (nebulisation)
The risk of side effects is usually much lower when administered by inhalation, because usually very little Colistimethate Hikma reaches the bloodstream when given this way.
Possible side effects include cough, chest tightness due to narrowing of the airways, mouth or throat pain, and mouth or throat infections (Candida).

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, speak to your doctor. You may also report side effects directly via the national reporting system at the following address:
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 Colistimetate Hikma

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the label of the vial after EXP. The expiry date refers to the last day of the month.
Do not store above 25°C.
Keep the vials in the outer carton to protect the medicine from light.
Colistimetate Hikma solutions for injection should be used immediately after preparation. If this is not possible, the solutions should be stored in a refrigerator for no more than 24 hours. Any remaining solution must be discarded.
Colistimetate Hikma solutions for inhalation should preferably be administered immediately. If this is not possible, the solutions should be stored in a refrigerator for no more than 24 hours. Any remaining solution must be discarded.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist to dispose of medicines you no longer use. These measures will help protect the environment.

6. Package contents and other information

What Colistimetate Hikma contains
Each vial contains 2 million International Units of colistimethate sodium.
There are no other ingredients.

Appearance of Colistimetate Hikma and contents of the pack
Colistimetate Hikma, a powder for solution for injection or infusion, or for nebuliser solution, is supplied as a white powder in single-dose vials.
Each carton contains 1 or 10 vials.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Hikma Farmacêutica (Portugal), S.A.
Estrada do Rio da Mó, nº8, 8A/8B
Fervença
2705-906 Terrugem SNT
Portugal

Manufacturer
Hikma Italia S.p.A.
Viale Certosa, 10,
27100 Pavia
Italy

This medicinal product is authorised in the EEA Member States under the following names:
Germany: Colistimethat-Natrium Hikma 2 Millionen I.E. Pulver zur Herstellung einer Injektions-/Infusionslösung oder einer Lösung für einen Vernebler
Italy: Colistimetato Hikma
Portugal: Colistimetato de sódio Hikma

This leaflet was last reviewed on
The following information is intended for healthcare professionals only

Dosage and method of administration
For injection or infusion
The dose to be administered and the duration of treatment should take into account the severity of the infection and the clinical response. Therapeutic guidelines must be followed.
The dose is expressed in International Units (IU) of colistimethate sodium (CMS). A conversion table from CMS IU to mg of CMS and mg of colistin base activity (CBA) is included at the end of this section.

Dosage
The dosage recommendations below are based on limited population pharmacokinetic data in critically ill patients (see section 4.4):

Adults and adolescents
Maintenance dose: 9 million IU/day (MIU/day) divided into 2–3 doses.
In severely ill patients, a loading dose of 9 MIU should be administered.
The optimal timing for the first maintenance dose has not been established.
Models suggest that in patients with good renal function, loading and maintenance doses up to 12 MIU may be required in some cases. However, clinical experience with such doses is extremely limited and safety has not been established.
The loading dose applies to patients with normal and impaired renal function, including those on renal replacement therapy.

Renal impairment
Dosage adjustments are required in cases of renal impairment, but pharmacokinetic data available for patients with impaired renal function are very limited.
The following dosage adjustments are suggested as guidance.
Dose reductions are recommended for patients with creatinine clearance <50 mL/min:
Dosing regimens with two administrations per day are recommended.

MUI = million IU
Haemodialysis and continuous haemo(dia)filtration
Colistin appears to be dialysable by conventional haemodialysis and continuous
venovenous haemo(dia)filtration (CVVHF, CVVHDF). Extremely limited data are available from
population pharmacokinetic studies involving very small numbers of patients undergoing
renal replacement therapy.
It is not possible to formulate definitive dosage recommendations.
The following therapeutic regimens may be considered.

Haemodialysis
Non-HD days: 2.25 million IU/day (2.2–2.3 million IU/day).
HD days: 3 million IU/day on haemodialysis days, to be administered after the HD session.
Twice-daily dosing is recommended.

CVVHF/CVVHDF
Same as in patients with normal renal function. Three times daily dosing is recommended.

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

Elderly
Dose adjustment is not considered necessary in elderly patients with normal renal function.

Paediatric population
Data supporting dosage regimens in paediatric patients are very limited. Renal maturity should be taken into account when selecting the dose. The dose should be calculated based on body weight.

Children ≤ 40 kg
75,000–150,000 IU/kg/day divided into 3 doses.

For children with body weight above 40 kg, the adult dosage recommendation 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 size of a loading dose in severely ill children.

Dosage recommendations have not been established in children with impaired renal function.

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

Intraventricular route
125,000 IU/day

Doses administered intrathecally should not exceed those recommended for intraventricular use.

No specific dosage recommendations can be made for children receiving intrathecal or intraventricular administration.

Method of administration
Colistimethate Hikma is administered intravenously as a slow infusion over 30–60 minutes.

Patients with a totally implanted venous access device (TIVAD) may tolerate a bolus injection of up to 2 million units in 10 ml administered over at least 5 minutes (see section 6.6).

Colistimethate sodium is hydrolysed to colistin, the active substance, in aqueous solution. For dose preparation, particularly when combined use of multiple vials is required, reconstitution of the required dose must be performed using strict aseptic technique (see section 6.6).

Nebuliser solution
It is recommended that colistimethate sodium (CMS) be administered under the supervision of physicians experienced in its use.

Dosage
Dosage may be adjusted according to the severity of the condition and clinical response.

Recommended dosage interval:

Inhalation administration

Adults, adolescents and children ≥ 2 years
1–2 million IU two or three times daily (maximum 6 million IU/day)

Children < 2 years
0.5–1 million IU twice daily (maximum 2 million IU/day)

Applicable clinical guidelines regarding treatment regimens, duration of treatment, frequency and co-administration with other antibacterial agents should be followed.

Elderly
Dosage adjustment is not considered necessary.

Renal impairment
Dosage adjustment is not considered necessary; however, caution should be exercised in patients with renal impairment (see sections 4.4 and 5.2).

Hepatic impairment
Dosage adjustment is not considered necessary.

Method of administration
For inhalation use
Colistimethate sodium undergoes hydrolysis to colistin, the active substance, in aqueous solution.

For special precautions regarding disposal and handling of reconstituted solutions, see section 6.6.

If other treatments have been initiated, they should be followed in the order recommended by the physician.

Dose conversion table
In the EU, the dose of colistimethate sodium (CMS) must be prescribed and administered only in International Units (IU). The product label indicates the number of IU per vial.

Confusion and medication errors have occurred due to different expressions of dose in terms of potency. In the United States and other parts of the world, the dose is expressed as milligrams of colistin base activity (mg CBA).

The following conversion table is provided for information purposes only, and values should be considered nominal and approximate.

CMS conversion table

*Potency of the active substance = 12,500 IU/mg
Special precautions for disposal and other handling
For bolus injection:
Reconstitute the vial contents with no more than 10 ml of water for injections
or with 0.9% sodium chloride.
For infusion:
The reconstituted vial contents may be diluted, usually with 50 ml of 0.9% sodium chloride.
When intrathecal and intraventricular routes of administration are used, the administered volume
must not exceed 1 ml (reconstituted concentration 125,000 IU/ml).
Inhalation:
Reconstitute the vial contents with water for injections to produce a hypotonic solution, or with a 50:50 mixture of water for injections and 0.9% sodium chloride to produce an isotonic solution, or with 0.9% sodium chloride to produce a hypertonic solution.
The reconstitution volume must comply with the nebulizer’s instructions for use and normally does not exceed 4 ml.
Nebulization can be performed in open air or with a filter attached.
Nebulization should be carried out in a well-ventilated room.
During reconstitution, gently swirl to avoid foam formation.
The solution is for single use only and any remaining solution must be discarded.
Reconstituted solutions:
Solutions for injection or infusion:
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 must be used immediately.
For solutions for bolus injection or for nebulization, chemical and physical in-use stability of the reconstituted solution in the original vial at a concentration ≥ 80,000 IU/mL has been demonstrated for 24 hours at 2–8 °C.
From a microbiological standpoint, unless the method of opening/reconstitution/dilution prevents the risk of microbial contamination, the product should be used immediately.
If not used immediately, the times and conditions of storage during use are the responsibility of the user.
Solutions for infusion that have been diluted beyond the original vial volume and/or to a concentration <80,000 IU/mL must be used immediately.
For solutions intended for intrathecal and intraventricular administration, the reconstituted product must be used immediately.