PROMIXIN 1 MILLION INTERNATIONAL UNITS (IU) POWDER FOR SOLUTION FOR INFUSION

In this leaflet
1. What Promixin is and what it is used for 2. Before you are given Promixin 3. How you will be given Promixin 4. Possible side effects 5. How to store Promixin 6. Further information

1. WHAT PROMIXIN IS AND WHAT IT IS USED FOR
Promixin contains colistimethate sodium. It is an antibiotic that fights serious bacterial infections, especially chest infections and infections of the urinary tract. Promixin is used when other more common antibiotics no longer work or cannot be used.

2. BEFORE YOU ARE GIVEN PROMIXIN
In certain circumstances your doctor may decide not to prescribe Promixin.

Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including nonprescription medicines. These medicines may interfere with the effects of Promixin. If you are taking any medicines that may affect your kidneys including other antibiotics such as cephalothin sodium, gentamicin, amikacin, netilmicin and tobramycin, please tell your doctor. Taking Promixin at the same time as these other medicines could increase your risk of kidney problems. Promixin could prolong the effects of muscle relaxing medicines, which may be used as part of a general anaesthetic if you have an operation. If you need to have a general anaesthetic, tell the anaesthetist that you are being given Promixin.

Pregnancy and breastfeeding
You may be given Promixin 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 Promixin may harm your unborn baby. It is not recommended that you breast-feed while you are taking this medicine as Promixin can pass into breast milk.

3. HOW YOU WILL BE GIVEN PROMIXIN
Your treatment with Promixin has been prescribed by and will be given to you under the supervision of a doctor or nurse. The dose of Promixin is dependent on how ill you are, how well your kidneys are working and your weight. The usual dose for adults and children who weigh up to 60 Kg is 50,000 to 75,000 International Units (IU) for each kilogram of body weight each day. This will be divided into 3 equal doses and given at 8 hourly intervals. The usual dose for adults and children who weigh over 60 Kg is 1-2 million International Units given every 8 hours. Your doctor may decide you need a higher dose.

PACKAGE LEAFLET: INFORMATION FOR THE USER

Promixin
colistimethate sodium



Do not have Promixin and tell your doctor if:
you are allergic (hypersensitive) to the active substance in Promixin (colistimethate sodium) or other polymyxins; If this applies to you, tell your doctor before you are given Promixin.

1 million International Units (IU) Powder for Solution for Infusion

Read all of this leaflet carefully before you are given this medicine
Keep this leaflet. You may need to read it again. If you have further questions, please ask your doctor, nurse or pharmacist. If any of the side effects gets serious, or you notice any side effects not listed in this leaflet, please tell your doctor, nurse or pharmacist.

Driving and using machines
Promixin 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.

Take special care with Promixin and tell your doctor if:
you have or have had kidney problems; you suffer from myasthenia gravis (a rare disease where your muscles are extremely weak and get tired very quickly); you suffer from porphyria (a rare metabolic disease that some people are born with). If any of these apply to you, tell your doctor.

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3. HOW YOU WILL BE GIVEN PROMIXIN continued...
If you have problems with your kidneys you will usually be given a lower dose of Promixin fewer times a day. Your doctor will work out the correct dose for you. You will be given Promixin 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 Promixin over a shorter time. Before Promixin can be given it must be dissolved in sterile saline (salt water). The correct dose of Promixin will then be further diluted in a suitable volume (usually 50 mL). Usually you will be treated for at least 5 days.

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 Promixin 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

Stopping Promixin
Your doctor will decide how long you should be given Promixin. 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 product, ask your doctor.

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

5. HOW TO STORE PROMIXIN
Keep Promixin out of the reach and sight of children. Do not use Promixin after the expiry date which is stated on the vial or carton. The expiry date refers to the last day of that month. Promixin does not require any special storage conditions. Promixin contains no preservatives. Once prepared, Promixin should be used immediately. Your doctor or nurse will dispose of any unused medicine safely. These measures will help to protect the environment.

6. FURTHER INFORMATION What Promixin 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.

Marketing Authorisation Holder Profile Pharma Limited Chichester Business Park City Fields Way Tangmere Chichester West Sussex PO20 2FT UK Tel: Fax: Email: +44 (0) 800 1300 855 +44 (0) 800 1300 856 info@profilepharma.com

4. POSSIBLE SIDE EFFECTS
Like all medicines, Promixin can cause side effects, although not everybody gets them. Promixin 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 Promixin treatment will be stopped immediately. Promixin can also affect your kidneys, especially if the dose is high or you are taking other medicines that may affect your kidneys.

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

What Promixin looks like and contents of the pack
Promixin is supplied as a powder in a glass vial. The powder must be made into a solution for infusion. Promixin is supplied in packs containing 10 vials.

Manufacturer Xellia Pharmaceuticals ApS Dalslandsgade 11 DK-2300 Copenhagen S Denmark This medicinal product is authorised in the Member States of the EEA under the following names: Austria, The Netherlands, Sweden: Tadim Germany, Denmark, Norway, United Kingdom: Promixin This leaflet was last approved in August 2011

Other side effects can include:
dizziness difficulty in controlling movements soreness at the site of injection If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor, nurse or pharmacist.

If you were not given Promixin when expected
If you think that you have missed a dose of Promixin 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.

If you are given too much Promixin
As a doctor or nurse will be giving you Promixin, it is unlikely that you will receive an incorrect dose.

PL393 Issue 4

The following information is intended for medical or healthcare professionals only:

Summary Of Product Characteristics for

It is recommended that Promixin should be selected when antibacterial agents that are commonly used to treat these infections are not considered to be appropriate for the individual patient and/or the causative pathogen(s) (see sections 4.4 and 5.1). Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Table 1: Suggested modification of dosage of Promixin for adults with impaired renal function
Degree of Renal Impairment Normal Creatinine Clearance (% of normal) Dose Unit dose (Million IU) Frequency (Times per day) Total Daily Dose (Million IU)
Posology The dose regimen of Promixin that is selected should take into account factors such as the susceptibility of the pathogen(s), the severity and type of infection, and the ideal body weight and renal function of the patient. The duration of treatment is usually at least 5 days. Standard dose recommendations are as follows: Up to 60 Kg: 50,000 IU/Kg (4 mg/Kg) bodyweight, to a maximum of 75,000 IU/Kg (6 mg/Kg), in 24 hours. The total daily dose should be administered as three equal doses at 8 hourly intervals. Over 60 Kg: 1-2 million IU every 8 hours. The maximum standard dose is 6 million IU (480 mg) in 24 hours.

Mild 40 to 75

Moderate 25 to 40

Severe Less than 25

76 to 100

Nephrotoxicity or neurotoxicity may occur especially if the recommended dose is exceeded (see also Section 4.5). There are limited safety data when colistimethate sodium is used in doses exceeding 6 million IU/day. Monitoring of renal function should be performed before initiating treatment with Promixin. Monitoring of serum creatinine must continue at regular intervals (at least daily) during therapy. Particular caution should be exercised when administering doses greater than 6 million IU/day. The dose of Promixin may have to be reduced if serum creatinine concentrations rise or exceed the upper limit of normal. There is evidence that it is the total cumulative dose (not the daily dose) of colistimethate sodium that may be associated with risk of nephrotoxicity. Do not use concomitantly with other medications with nephrotoxic or neurotoxic effects except with the greatest caution. Colistimethate sodium is known to reduce the amount of acetylcholine released from the pre-synaptic neuromuscular junction and therefore should not be used in patients with myasthenia gravis, unless in life-threatening situations. Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. Therefore, it is important to consider this diagnosis in patients who

Promixin

present with diarrhoea during or subsequent to the administration of colistimethate sodium. Discontinuation of therapy with colistimethate sodium and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given. Use with extreme caution in patients with porphyria.

4.6 Fertility, pregnancy and lactation
Fertility There are no data on the effects of colistimethate sodium on human fertility. Effects on male and female fertility have not been evaluated in animal studies. Pregnancy Safety in human pregnancy has not been established. Animal studies are insufficient with respect to effects on reproduction. There is evidence that colistimethate sodium crosses the placenta and consequently there is potential for foetal toxicity if administered during pregnancy. Hence, Promixin should only be given during pregnancy if the benefits outweigh any potential risk. Lactation Colistimethate sodium is excreted in breast milk; breast feeding is not recommended during therapy.

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 (1/1,000 to <1/100): rare (1/10,000 to <1/1,000) and very rare (<1/10,000), not known (cannot be estimated from the available data).



1.3 to 2 3

1 to 1.5 2

1 1 or 2

1 to 1.5 Every 36 hours

1 million International Units (IU) Powder for Solution for Infusion

4.2 Posology and method of administration
It is recommended that Promixin should be administered under the supervision of physicians with appropriate experience in its use. Method of Administration Administration is by intravenous infusion. Each dose of Promixin can be diluted in 50 mL and administered by intravenous infusion over 30 minutes. Patients fitted with a totally implantable venous access device (TIVAD) may tolerate an injection of up to 2 million IU in 10 mL given over a minimum of 5 minutes. Solutions should be used immediately after reconstitution. For instructions on dilution of the product before administration see section 6.6.

1. NAME OF THE MEDICINAL PRODUCT
Promixin, 1 million International Units (IU), Powder for Solution for Infusion.

4 to 6

2 to 3

1 to 2

0.6 to 1

4.5 Interaction with other medicinal products and other forms of interaction
Due to the effects of colistimethate sodium on the release of acetylcholine, non-depolarising muscle relaxants should be used with extreme caution in patients receiving Promixin as their effects could be prolonged. Concomitant use of colistimethate sodium with other medications that are nephrotoxic or neurotoxic (eg. cephalothin sodium, aminoglycosides, non-depolarising muscle relaxants) should only be undertaken with the greatest caution. The potential of colistimethate sodium to affect the pharmacokinetics of other medicinal products has not been evaluated. Caution is recommended if colistimethate sodium is combined with medicinal products with a narrow therapeutic index.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 1 million International Units (IU) which is approximately equivalent to 80 mg of colistimethate sodium.

3. PHARMACEUTICAL FORM
Powder for solution for infusion The powder is white to off white

Limited pharmacokinetic data from critically ill patients suggest that use of a loading dose and higher than standard doses may be appropriate (see Section 5.2). For severe infections and in critically ill patients doses up to 9 million IU per day in divided doses, have been reported in the literature. Clinical efficacy and safety data with these regimens are very limited and caution is advised (see sections 4.4 and 5.2). Paediatric population Dose recommendations are the same in adults and all paediatric sub groups. Renal impairment The suggested dose recommendations in Table 1 for patients with renal impairment are based on the standard total daily dose of 3-6 million IU/day. For patients with renal impairment in whom higher doses (e.g. up to 9 million IU/day) would be considered if their renal function

was normal, corresponding proportional adjustments should be considered when calculating the dose. Caution is advised when administering Promixin to any patient with renal impairment due to the limited information available on safety and appropriate dose regimens (see section 4.4). Hepatic impairment It is not known whether the dose of Promixin requires adjustment in patients with hepatic impairment and therefore caution is advised.

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. CLINICAL PARTICULARS 4.1 Therapeutic indications
Promixin is indicated for treatment of the following infections caused by susceptible aerobic Gram-negative bacteria (see section 5.1): - Hospital acquired pneumonia (HAP) - Complicated urinary tract infections

4.3 Contraindications
Hypersensitivity to the active substance colistimethate sodium or other polymyxins.

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,

4.4 Special warnings and precautions for use
Use with caution in patients with renal impairment as colistimethate sodium is renally excreted.

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Body System Immune system disorders Nervous system disorders

Frequency Not known Very Common

Reported adverse reaction Hypersensitivity reactions such as skin rash and angioedema Neurotoxicity such as, facial, mouth and peri-oral paraesthesia, headache, and muscle weakness Dizziness Ataxia Pruritus Renal impairment demonstrated by increased blood creatinine and / or urea and / or decreased creatinine renal clearance Renal failure Injection site reaction

EUCAST Breakpoints Acinetobacter Enterobacteriaceae Pseudomonas Spp
a

Susceptible (S) Resistant (R)a S2 R>2 mg/L S2 R>2 mg/L S4 R>4 mg/L

9 million IU has been suggested, especially in critically ill patients. In critically ill patients given colistimethate sodium 2 million IU and 3 million IU three times a day intravenously, peak colistin plasma concentrations of 2.21 and 2.93 mg/L, respectively, were observed. Biotransformation Colistimethate sodium undergoes conversion to polymyxin E1 and polymyxin E2 (colistin) in vivo. It has been estimated that approximately 30% of the colistimethate sodium is converted to colistin. Elimination Colistimethate sodium is primarily excreted unchanged in the urine where the hydrolysis to the active moiety continues. Following intravenous administration 62% of a dose is recovered in the urine within 8 hours. Colistin is excreted by the non-renal route. The half-life of colistin following administration of colistimethate sodium in healthy volunteers and in patients with cystic fibrosis has been reported to be 3 hours and 4.2 hours respectively. The half-life of colistin following administration of colistimethate sodium has been reported to increase when administered to critically ill patients compared to healthy volunteers and mean half life is estimated to range from approximately 5.9 hours to 7.4 hours following intravenous administration to critically ill patients. In patients with renal impairment, colistimethate sodium excretion is reduced and a higher proportion may be converted to colistin, leading to increased plasma colistin concentrations.

5.3 Preclinical safety data
Animal studies are insufficient with respect to effects on reproduction. 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.

6.4 Special precautions for storage
No special precautions for storage. For storage conditions of the reconstituted/diluted product see section 6.3.

7. MARKETING AUTHORISATION HOLDER
Profile Pharma Limited Chichester Business Park City Fields Way Tangmere Chichester West Sussex PO20 2FT United Kingdom

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

Mechanisms of resistance Acquired resistance to Colistimethate sodium in Pseudomonas aeruginosa appears to be related to alterations in the bacterial outer membrane. In-vitro studies with Salmonella and E. coli have shown that resistance may occur due to modification of the cell wall lipopolysaccharide phosphate groups. Modification is achieved by substitution of the phosphate groups with ethanolamine or aminoarabinose. Proteus mirabilis, Burkholderia cepacia and other naturally resistant Gram-negative bacteria, show complete substitution of their lipopolysaccharide groups. Polymyxins including colistimethate sodium differ in their mechanism of action compared with other antibiotics and there is evidence to show that Gram-negative bacteria resistant to other antibiotics may be susceptible to colistimethate sodium. There is no co- resistance between polymyxins and other groups of antibiotics. 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. 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.

Not known

Commonly susceptible species Acinetobacter species Klebsiella species Pseudomonas aeruginosa Species for which acquired resistance may be a problem Stenotrophomonas maltophilia Achromobacter xylosoxidans Inherently resistant organisms Burkholderia cepacia and related species Proteus spp Providencia spp Serratia spp

6.5 Nature and contents of container
The product is supplied in clear type I glass vials 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.

Skin and subcutaneous tissue disorders Renal and urinary disorders

Very Common Very Common

6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients
None

8. MARKETING AUTHORISATION NUMBER(S)
PL 19419/0002

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

Rare General disorders and administration site conditions Not known

6.6 Special precautions for disposal and other handling
For single use only. Promixin must be reconstituted, under aseptic conditions, with sodium chloride solution 9 mg/mL (0.9%) to produce a clear colourless to pale yellow solution. 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. 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. Solutions should be used immediately after reconstitution (see section 4.2). Discard any unused solution. Waste material should be disposed of in accordance with local requirements.

9. DATE OF FIRST AUTHORISATION/ RENEWAL OF THE AUTHORISATION
Date of first authorisation: 24th June 2003 Date of latest renewal: 13th March 2009

5.2 Pharmacokinetic properties
Absorption Absorption of colistimethate sodium from the gastrointestinal tract does not occur to any appreciable extent in the normal individual. Distribution The volume of distribution of colistin following administration of colistimethate sodium in healthy volunteers and in patients with cystic fibrosis has been reported to be 12.4L and 20.4L respectively. In comparison the volume of distribution for colistin following administration of colistimethate sodium has been shown to be between 90.6 L and 139.9 L in critically ill patients. The increase in the volume of distribution in critically ill patients, may lead to a delay in reaching effective plasma concentrations. Therefore the use of an initial loading dose of up to

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: other antibacterials, Polymyxins ATC code: J01XB01 General properties Mode of action The polymyxin antibiotics are surface active agents and act by binding to and changing the permeability of bacterial cell membrane causing bacterial cell death. Polymyxins are bactericidal against Gram-negative bacteria with a hydrophobic outer membrane.

PK/PD relationship Polymyxins have been reported to have a concentration-dependent bactericidal effect on susceptible bacteria.

6.3 Shelf life
Unopened: Two years After reconstitution: Chemical and physical in-use stability has been demonstrated for up to 8 hours at room temperature. From a microbiological point of view solutions should be used immediately. If not used immediately in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

10. DATE OF REVISION OF THE TEXT
30th August 2011

11. LEGAL CATEGORY
POM

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