Package leaflet: Information for the user

Colistimethate sodium 1 million International Units (IU) powder for solution for injection or infusion

colistimethate sodium

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 further questions, ask your doctor, pharmacist or nurse.

•    If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

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

2.    What you need to know before you use Colistimethate sodium

3.    How to use Colistimethate sodium

4.    Possible side effects

5.    How to store Colistimethate sodium

6.    Contents of the pack and other information

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

Colistimethate sodium contains colistimethate sodium. It is an antibiotic that fights serious bacterial infections, especially chest infections and infections of the urinary tract.

Colistimethate sodium is given by injection to treat some types of serious infections caused by certain bacteria. Colistimethate sodium is used when other antibiotics are not suitable.

2.    What you need to know before you use Colistimethate sodium

In certain circumstances your doctor may decide not to prescribe Colistimethate sodium.

Do not use Colistimethate sodium

•    If you are allergic (hypersensitive) to colistimethate sodium, colistin or to other polymyxins

If this applies to you, tell your doctor before you are given Colistimethate sodium.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before using Colistimethate sodium:

•    If you have or have had kidney problems

•    If you suffer from myasthenia gravis

•    If you suffer from porphyria

If any of these apply to you, tell your doctor.

In premature and new-born babies, special care should be taken when using Colistimethate sodium as the kidneys are not yet fully developed.

Other medicines and Colistimethate sodium

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including non-prescription medicines. These medicines may interfere with the effects of Colistimethate sodium.

•    medicines which can affect how your kidneys function. Taking such medicines at the same time as Colistimethate sodium can increase the risk of damage to the kidneys.

•    medicines which can affect your nervous system. Taking such medicines at the same time as Colistimethate sodium can increase the risk of side effects in your nervous system

•    medicines called muscle relaxants, often used during general anaesthesia. Colistimethate sodium can increase the effects of these medicines. If you have a general anaesthetic, let your anaesthetist know that you are having Colistimethate sodium.

If you suffer from myasthenia gravis 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 Colistimethate sodium further increases the risk of muscle weakness and breathing difficulties.

Having Colistimethate sodium as an infusion at the same time as receiving Colistimethate sodium as an inhalation can increase your risk of side effects.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking Colistimethate sodium.

You may be given Colistimethate sodium if you are pregnant or trying to get pregnant if your doctor considers the benefits are greater than the possible risks. It is unknown if having Colistimethate sodium may harm your unborn baby.

It is not recommended that you breast-feed while you are taking this medicine as Colistimethate sodium can pass into breast milk.

Driving and using machines

Colistimethate sodium may make you feel dizzy, confused or have problems with your sight, such as blurred vision. If this happens to you, do not drive or use any tools or machines.

3.    How to use Colistimethate sodium

Your treatment with Colistimethate sodium has been prescribed by and will be given to you under the supervision of a doctor or nurse.

The dose of Colistimethate sodium is dependent on how ill you are, how well your kidneys are working and your weight.

Colistimethate sodium is given to you by your doctor as an infusion into a vein over 30-60 minutes.

The usual daily dose in adults is 9 million units, divided into two or three doses. If you are quite unwell, you will be given a higher dose of 9 million units once at the start of treatment.

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

The usual daily dose in children weighing up to 40 kg is 75.000 to 150.000 units per kilogram body weight, divided into three doses.

Higher doses have occasionally been given in cystic fibrosis.

Children and adults with kidney problems, including those on dialysis, are usually given lower doses.

Your doctor will monitor your kidney function regularly while you receive Colistimethate sodium.

If you have problems with your kidneys you will usually be given a lower dose of Colistimethate sodium fewer times a day. Your doctor will work out the correct dose for you.

•    You will be given Colistimethate sodium by a slow injection (infusion) into a vein over 30 minutes.

•    If you have been fitted with a Totally Implantable Venous Access Device (TIVAD) you may be given a smaller volume of Colistimethate sodium over a shorter time.

•    Before Colistimethate sodium can be given it must be dissolved in sterile saline (salt water) or water for injection.

•    The correct dose of Colistimethate sodium will then be further diluted in a suitable volume (usually 50 ml).

•    Usually you will be treated for at least 5 days.

If you are given too much Colistimethate sodium

As a doctor or nurse will be giving you Colistimethate sodium, it is unlikely that you will receive an incorrect dose. Tell your doctor or nurse if you have any concerns about the amount of medicine that you are given.

The symptoms of having too much Colistimethate sodium can include:

•    dizziness and spinning sensation (vertigo)

•    slurred speech

•    visual disturbance

•    confusion

•    mental disturbance

•    flushing (reddening of the face)

•    kidney problems

•    muscle weakness

•    feeling as though you cannot breathe

If you were not given Colistimethate sodium when expected

If you think that you have missed a dose of Colistimethate sodium and it is less than 3 hours since you should have been given the dose, tell your doctor or nurse.

If it is more than 3 hours after the missed dose the doctor or nurse will wait for your next dose.

Stopping Colistimethate sodium

Your doctor will decide how long you should be given Colistimethate sodium. It is important that your treatment is completed as advised by your doctor or your symptoms may get worse.

If you have any further questions on the use of this medicine, ask your doctor.

4.    Possible side effects

Like all medicines, Colistimethate sodium can cause side effects, although not everybody gets them.

Colistimethate sodium can sometimes cause allergic reactions like skin rash or red and lumpy skin rash, swollen eyelids, face, lips, mouth or tongue, itching, difficulty breathing or swallowing. If this happens, your Colistimethate sodium treatment will be stopped immediately.

Colistimethate sodium can also affect your kidneys, especially if the dose is high or you are taking other medicines that may affect your kidneys.

Very common side effects (affecting more than 1 person in 10):

•    blood tests may show changes in the way the kidneys are working

•    headache

•    tingling or numbness around the mouth, lips and face

•    itching

•    muscle weakness

Rare side effects (affecting less than 1 person in 1 000):

•    kidney failure

Other side effects can include:

•    dizziness

•    difficulty in controlling movements

•    soreness at the site of injection

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report any side effects directly via Yellow card scheme:

Tel: Free phone 0808100 3352 www.mhra.gov.uk/yellowcard

By reporting side effects you can help provide more information on the safety of this medicine.

5.    How to store Colistimethate sodium

Keep Colistimethate sodium out of the sight and reach of children.

Do not use Colistimethate sodium after the expiry date which is stated on the vial or carton as "EXP". The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Colistimethate sodium contains no preservatives. Once prepared, Colistimethate sodium should be used immediately.

Your doctor or nurse will dispose of any unused medicine safely. These measures will help to protect the environment.

6.    Contents of the pack and other information What Colistimethate sodium contains

-    The active substance is colistimethate sodium.

Each vial contains 1 million International Units (IU) of colistimethate sodium, which weighs about 80 milligrams (mg).

-    There are no other ingredients.

This medicinal product containes less than 1 mmol sodium (23 mg) per vial, i.e. essentially 'sodium-free'.

What Colistimethate sodium looks like and contents of the pack

Colistimethate sodium is a white to off white powder supplied in a glass vial.

The powder must be made into a solution for injection or infusion.

Colistimethate sodium is supplied in packs containing 10 vials.

Marketing Authorisation Holder and Manufacturer

Xellia Pharmaceuticals ApS, Dalslandsgade 11,2300 Copenhagen S, Denmark

This medicinal product is authorised in the Member States under the following names:

This leaflet was last revised in 01/2015.

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4 Pia: 1908-B 15-02-04 Font Size 9pt, Format: 330 x 320 mm, Black, Profile

The following information is intended for healthcare professionals only

Colistimethate sodium,

1 million International Units (IU), powder for solution for injection or infusion

colistimethate sodium

Dose reductions are recommended for patients with creatinine clearance < 50 ml/min: Twice daily dosing is recommended.

Colistimethate sodium should only be used when other, more commonly prescribed antibiotics are not effective or not appropriate.

Renal function monitoring should be performed at the start of treatment and regularly during treatment in all patients. The dose of colistimethate sodium should be adjusted according to creatinine clearance (see section 4.2). Patients who are hypovolaemic or those receiving other potentially nephrotoxic drugs are at increased risk of nephrotoxicity from colistin (see sections 4.5 and 4.8). Nephrotoxicity has been reported to be associated with cumulative dose and treatment duration in some studies. The benefit of prolonged treatment duration should be balanced against the potentially increased risk of renal toxicity.

Caution is advised when administering colistimethate sodium to infants < 1 year of age as renal function is not fully mature in this age group. Further, the effect of immature renal and metabolic function on the conversion of colistimethate sodium to colistin is not known.

In case of an allergic reaction, treatment with colistimethate sodium must be discontinued and appropriate measures implemented.

High serum concentrations of colistimethate sodium, which may be associated with overdosage or failure to reduce the dosage in patients with renal impairment, have been reported to lead to neurotoxic effects such as facial paraesthesia, muscle weakness, vertigo, slurred speech, vasomotor instability, visual disturbances, confusion, psychosis and apnoea. Monitoring should be performed for perioral paraesthesia and paraesthesia in the extremities, which are signs of overdose (see section 4.9).

Colistimethate sodium is known to reduce the presynaptic release of acetyl-choline at the neuro-muscular junction and should be used in patients with myasthenia gravis with the greatest caution and only if clearly needed.

Respiratory arrest has been reported following intramuscular administration of colistimethate sodium. Impaired renal function increases the possibility of apnoea and neuromuscular blockade following administration of colistimethate sodium.

Colistimethate sodium should be used with extreme caution in patients with porphyria.

Antibiotic-associated colitis and pseudomembranous colitis have been reported with nearly all anti-bacterial agents and may occur with colistimethate sodium. They may range from mild to life-threatening in severity. It is important to consider this diagnosis in patients who develop diarrhoea during or after the use of colistimethate sodium (see section 4.8). Discontinuation of therapy and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

Intravenous colistimethate sodium does not cross the blood brain barrier to a clinically relevant extent. The use of intrathecal or intraventricular administration of colistimethate sodium in the treatment of meningitis was not systematically investigated in clinical trials and is supported by case reports only. Data supporting the posology are very limited. The most commonly observed adverse effect of CMS administration was aseptic meningitis (see section 4.8).

4.5    Interaction with other medicinal products and other forms of interaction

Concomitant use of intravenous colistimethate sodium with other medications that are potentially nephrotoxic or neurotoxic should be undertaken with great caution.

Caution should be taken with concomitant use with other formulations of colistimethate sodium as there is little experience and there is a possibility of summative toxicity.

No in vivo interaction studies have been performed. The mechanism of conversion of colistimethate sodium to the active substance, colistin, is not characterised. The mechanism of colistin clearance, including renal handling, is equally unknown. Colistimethate sodium or colistin did not induce the activity of any P 450 (CYP) enzyme tested (CYP1A2,2B6,2C8,2C9,2C19 and 3A4/5) in in vitro studies in human hepatocytes.

The potential for drug-drug interactions should be borne in mind when Colistimethate sodium is co-administered with drugs known to inhibit or induce drug metabolising enzymes or drugs known to be substrates for renal carrier mechanisms.

Due to the effects of colistin on the release of acetylcholine, non-depolarising muscle relaxants should be used with caution in patients receiving colistimethate sodium as their effects could be prolonged (see section 4.4).

Co-treatment with colistimethate sodium and macrolides such as azithromycin and clarithromycin, or fluoroquinolones such as norfloxacin and ciprofloxacin should be undertaken with caution in patients with myasthenia gravis (see section 4.4).

4.6    Fertility, pregnancy and lactation Fertility

There are no data on the effects of colistimethate sodium on human fertility. Animal studies do not indicate effects with respect to fertility (see section 5.3).

Pregnancy

Safety in human pregnancy has not been established. Animal studies are insufficient with respect to effects on reproduction and development (see section 5.3). There is evidence that colistimethate sodium crosses the placenta and consequently there is potential for foetal toxicity if administered during pregnancy. Hence, Colistimethate sodium should only be given during pregnancy if the benefits outweigh any potential risk.

Breast-feeding

Colistimethate sodium is excreted in breast milk; hence breast feeding is not recommended during therapy.

PK/PD relationship

Polymyxins have been reported to have a concentration-dependent bactericidal effect on susceptible bacteria. fAUC/ MIC is considered to be correlated with clinical efficacy.

There are no other preclinical safety data of relevance to the prescriber that are additional to safety data derived from patient exposure and already included in other sections of the SPC.

4.7    Effects on ability to drive and use machines

Neurotoxicity, characterised by dizziness, confusion or visual disturbances have been reported following parenteral administration of colistimethate sodium. If these effects occur patients should be warned against driving or operating machinery.

4.8    Undesirable effects

The most commonly reported adverse reaction is renal function impairment, and more rarely renal failure, usually following use of higher than recommended doses in patients with normal renal function, or failure to reduce the dosage in patients with renal impairment or when used concomitantly with other nephrotoxic antibiotics. The effect is usually reversible on discontinuation of therapy, but rarely intervention (renal replacement therapy) may be required.

High serum concentrations of colistimethate sodium, which may be associated with overdosage or failure to reduce the dosage in patients with renal impairment, have been reported to lead to neurotoxic effects such as facial paraesthesia, muscle weakness, vertigo, slurred speech, vasomotor instability, visual disturbances, confusion, psychosis and apnoea. Concomitant use with either non-depolarising muscle relaxants or antibiotics with similar neurotoxic effects can also lead to neurotoxicity. Dose reduction of colistimethate sodium may relieve symptoms.

Hypersensitivity reactions such as skin rash and angioedema have been known to occur. In the event such reactions occur, treatment with colistimethate sodium should be withdrawn.

Adverse reactions are tabulated below by system organ class and frequency. Frequencies are defined as Very common (>1/10): common (>1/100 to <1/10): uncommon (2:1/1,000 to <1/100): rare (2:1/10,000 to <1/1,000) and very rare (<1/10,000), not known (cannot be estimated from the available data).

EUCAST Breakpoints

Susceptible (S) Resistant (R)^a Acinetobacter    S<2    R>2    mg/L

Enterobacteriaceae    S<2    R>2    mg/L

Pseudomonas spp    S<4    R>4    mg/L

³ Breakpoints apply to dosage of 2-3 million lUx 3. A loading dose (9 million IU) may be needed.

Susceptibility

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent, in at least some types of infections, is questionable.

4.9 Overdose

Overdosage may cause renal insufficiency, renal failure, apnoea, muscle weakness, vertigo, slurred speech, vasomotor instability, visual disturbances, confusion and psychosis.

No antidote is available.

Management of overdose is by means of supportive treatment and measures designed to increase clearance of colistimethate sodium such as inducing an osmotic diuresis with mannitol, peritoneal dialysis or prolonged haemodialysis

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antibacterials for systemic use, other antibacterials, polymyxins

ATC Code: J01XB01

Mechanism of action

Colistin is a cyclic polypeptide antibacterial agent belonging to the polymyxin group. Polymyxins work by damaging the cell membrane and the resulting physiological effects are lethal to the bacterium. Polymyxins are selective for aerobe Gram-negative bacteria that have a hydrophobic outer membrane.

Resistance

Resistant bacteria are characterised by modification of the phosphate groups of lipopolysaccharide, which become substituted with ethanolamine or aminoarabinose. Naturally resistant Gram-negative bacteria, such as Proteus mirabilis and Burkholde-ria cepacia, show complete substitution of their lipid phosphate by ethanolamine or aminoarabinose.

Cross resistance between colistin (polymyxin E) and polymyxin B is expected. Since the mechanism of action of the polymyxins is different from that of other antibacterial agents, resistance to colistin and polymyxin by the above mechanism alone would not be expected to result in resistance to other drug classes.

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Commonly susceptible species_

Acinetobacter baumanii_

Haemophilus influenzae_

Klebsiella spp_

Pseudomonas aeruginosa_

Species for which acquired resistance may be a problem

Stenotrophomonas maltophilia_

Achromobacter xylosoxidans (formerly Alcaligenes xylosoxidans) Inherently resistant organisms

Burkholderia cepacia and related species_

Proteus spp_

Providencia spp_

Serratia spp

5.2    Pharmacokinetic properties

The information on the pharmacokinetics of colistimethate sodium (CMS) and colistin is limited. There are indications that pharmacokinetics in critically ill patients differ from those in patients with less severe physiological derangement and from those in healthy volunteers. The following data are based on studies using HPLC to determine CMS/ colistin plasma concentrations.

After infusion of colistimethate sodium the inactive pro-drug is converted to the active colistin. Peak plasma concentrations of colistin have been shown to occur with a delay of up to 7 hours after administration of colistimethate sodium in critically ill patients.

Distribution

The volume of distribution of colistin in healthy subjects is low and corresponds approximately to extracellular fluid (ECF). The volume of distribution is relevantly enlarged in critically ill subjects. Protein binding is moderate and decreases at higher concentrations. In the absence of meningeal inflammation, penetration into the cerebrospinal fluid (CSF) is minimal, but increases in the presence of meningeal inflammation.

Both CMS and colistin display linear PK in the clinically relevant dose range.

Elimination

It is estimated that approximately 30% of colistimethate sodium is converted to colistin in healthy subjects, its clearance is dependent on creatinine clearance and as renal function decreases, a greater portion of CMS is converted to colistin. In patients with very poor renal function (creatinine clearance <30 ml/min), the extent of conversion could be as high as 60 to 70%. CMS is eliminated predominantly by the kidneys via glomerular filtration. In healthy subjects, 60% to 70% of CMS is excreted unchanged in the urine within 24 hours.

The elimination of the active colistin is incompletely characterised. Colistin undergoes extensive renal tubular reabsorption and may either be cleared non-renally or undergo renal metabolism with the potential for renal accumulation. Colistin clearance is decreased in renal impairment, possibly due to increased conversion of CMS.

Half-life of colistin in healthy subjects and those with cystic fibrosis is reported to be around 3h and 4h, respectively, with a total clearance of around 3L/h. In critically ill patients, half-life has been reported to be prolonged to around 9-18h.

5.3    Preclinical safety data

Data on potential genotoxicity are limited and carcinogenicity data for colistimethate sodium are lacking. Colistimethate sodium has been shown to induce chromosomal aberrations in human lymphocytes, in vitro. This effect may be related to a reduction in mitotic index, which was also observed.

Reproductive toxicity studies in rats and mice do not indicate a potential for teratogenicity. However, in the rabbit, colistimethate sodium given intramuscularly during organogenesis at 4.15 and 9.3 mg/kg resulted in talipes varus in 2.6 and 2.9% of fetuses respectively. These doses are 0.5 and 1.2 times the maximum daily human dose. In addition, increased resorption occurred at 9.3 mg/kg.

No effects were seen on mouse or rat fertility at intravenous doses of up to 25 mg/kg/day.

6.    PHARMACEUTICAL PARTICULARS

6.1    List of excipients None.

6.2    Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3    Shelf life Unopened:

2 years

After reconstitution:

Hydrolysis of colistimethate is significantly increased when reconstituted and diluted below its critical micelle concentration of about 80,000 IU per ml.

Solutions below this concentration should be used immediately.

For solutions for bolus injection, the chemical and physical in-use stability of reconstituted solution in the original vial, with a concentration > 80,000 lU/mL, has been demonstrated for 24 hours at 2 to 8°C.

From a microbiological point of view, unless the method of opening/ reconstitution/ dilution precludes the risk of microbial contamination, the product should be used immediately.

If not used immediately, in-use storage times and conditions are the responsibility of user.

For solutions for infusion, which have been diluted beyond the original vial volume and / or with a concentration < 80,000 lU/mL, should be used immediately.

For the intrathecal and intraventricular routes of administration, the reconstituted product should be used immediately.

6.4    Special precautions for storage

This medicinal product does not require any special storage conditions.

For storage conditions after reconstitution/dilution of the medical product see section 6.3.

6.5    Nature and contents of container

The product is supplied in clear type I glass vials, 10 ml, sealed with a siliconised chlorobutyl type I rubber stopper and protected by a 20 mm aluminium tear-off cap incorporating a red flip-up central plastic top. The product is supplied in pack sizes of 10 vials.

6.6    Special precautions for disposal

For single use only and any remaining solution should be discarded.

Colistimethate sodium must be reconstituted, under aseptic conditions, with not more than 10 ml of sodium chloride solution 9 mg/ml (0.9%) or water for injection, to produce a clear colourless to pale yellow solution.

During reconstitution swirl gently to avoid frothing.

If used for infusion, following reconstitution, the solution should be diluted to a suitable volume for infusion over 30 minutes with sodium chloride solution 9 mg/ml (0.9%) for infusion (usually 50 ml of 0.9% sodium chloride).

The solution should be inspected visually for particulate matter and discoloration prior to administration. The solution should only be used if the solution is clear and free from particles.

For the intrathecal and intraventricular routes of administration, the volume administered should not exceed 1 ml (reconstituted concentration 125,000 IU/ml).The reconstituted product should be used immediately.

Solutions should be used immediately after reconstitution (see section 4.2).

For information related to stability of the reconstituted product see section 6.3.

Discard any unused solution. Waste material should be disposed of in accordance with local requirements.

7.    MARKETING AUTHORISATION HOLDER

Xellia Pharmaceuticals ApS, Dalslandsgade 11,2300 Copenhagen S, Denmark

8.    MARKETING AUTHORISATION NUMBER(S)

PL 17815/0062

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

20/05/2013

10. DATE OF REVISION OF THE TEXT

29/10/2015

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