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Active substance(s): COLISTIMETHATE SODIUM

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Summary of Product Characteristics for

1061604 Issue 6 UK

1 million International Units (IU)
Powder for Solution for Infusion
Summary of Product Characteristics for


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


Paediatric population

4.3 Contraindications

The following dose recommendations are made based on limited
population-pharmacokinetic data in critically ill patients (see section 4.4):

The data supporting the dose regimen in paediatric patients are very
limited. Renal maturity should be taken into consideration when
selecting the dose. The dose should be based on lean body weight.
Children ≤ 40kg: 75,000 - 150,000 IU/kg/day divided into 3 doses.
For children with a body weight above 40 kg, use of the dosing
recommendation for adults should be considered.
The use of doses >150,000 IU/kg/day has been reported in children
with cystic fibrosis.
There are no data regarding the use or magnitude of a loading dose in
critically ill children.
No dose recommendations have been established in children with
impaired renal function.

Hypersensitivity to the active substance colistimethate sodium or other

Adults and adolescents
Maintenance dose 9 MIU/day in 2-3 divided doses.
In patients who are critically ill, a loading dose of 9 MIU should be
The most appropriate time interval to the first maintenance dose has
not been established.
Modelling suggests that loading and maintenance doses of up to
12 MIU may be required in patients with good renal function in some
cases. Clinical experience with such doses is however extremely
limited and safety has not been established.
The loading dose applies to patients with normal and impaired renal
functions including those on renal replacement therapy.
Renal impairment


Dose adjustments in renal impairment are necessary, but
pharmacokinetic data available for patients with impaired renal function
is very limited.
The following dose adjustments are suggested as guidance.

Promixin, 1 million International Units (IU), Powder for Solution for


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

Creatinine clearance

Daily dose

< 50 - 30

5.5 - 7.5 MIU

< 30 - 10

4.5 - 5.5 MIU

< 10

3.5 MIU

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

Powder for solution for infusion
The powder is white to off white

4.1 Therapeutic indications
Promixin is indicated in adults and children including neonates for the
treatment of serious infections due to selected aerobic Gram-negative
pathogens in patients with limited treatment options (see sections 4.2,
4.4, 4.8 and 5.1).

MIU = million IU

Promixin is administered intravenously as a slow infusion over
30 - 60 minutes.
The volume administered in intrathecal or intraventricular use should
not exceed 1 mL. Patients fitted with a totally implantable venous
access device (TIVAD) may tolerate an injection of up to 2 MIU in 10 mL
given over a minimum of 5 minutes.
Colistimethate sodium undergoes hydrolysis to the active substance
colistin in aqueous solution. For dose preparation, particularly where
combination of multiple vials is needed, reconstitution of the required
dose must be performed using strict aseptic technique (see section 6.6).

Colistin appears to be dialyzable through conventional haemodialysis
and continuous venovenous haemo(dia)filtration (CVVHF, CVVHDF).
There are extremely limited data from population PK studies from very
small numbers of patients on renal replacement therapy. Firm dose
recommendations cannot be made. The following regimes could be

In the EU, the dose of colistimethate sodium (CMS) must be prescribed
and administered only as International Units (IU). The product label
states the number of IU per vial.
Confusion and medication errors have occurred because of the
different expressions of dose in terms of potency. The dose is
expressed in the US, and other parts of the world, as milligrams of
colistin base activity (mg CBA).
The following conversion table is prepared for information and the
values must be considered nominal and approximate only.

No-HD days: 2.25 MIU/day (2.2 - 2.3 MIU/day).
HD days: 3 MIU/day on haemodialysis days, to be given after the
HD session.

4.2 Posology and method of administration

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Method of administration

Dose conversion table:

Twice daily dosing is recommended.

The dose is expressed in international units (IU) of colistimethate sodium
(CMS). A conversion table from CMS in IU to mg of CMS as well as to
mg of colistin base activity (CBA) is included at the end of this section.

Based on limited data, the following dose is recommended in adults:
Intraventricular route: 125,000 IU/day
Intrathecally administered doses should not exceed those
recommended for intraventricular use.
No specific dosing recommendation can be made in children for
intrathecal and intraventricular routes of administration.

Haemodialysis and continuous haemo(dia)filtration:

Consideration should be given to official guidance on the appropriate
use of antibacterial agents.
The dose to be administered and the treatment duration should take
into account the severity of the infection as well as the clinical response.
Therapeutic guidelines should be adhered to.

Intrathecal and intraventricular administration

CMS conversion table

As in patients with normal renal function. Three times daily dosing is


≈ mg CBA

≈ mass of CMS




Hepatic impairment














There are no data in patients with hepatic impairment. Caution is
advised when administering colistimethate sodium in these patients.
Older people
No dose adjustments in older patients with normal renal function are
considered necessary.

* Nominal potency of the drug substance = 12,500 IU/mg

4.4 Special warnings and precautions for use

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.

Consideration should be given to co-administering intravenous
colistimethate sodium with another antibacterial agent whenever this
is possible, taking into account the remaining susceptibilities of the
pathogen(s) under treatment. As the development of resistance to
intravenous colistin has been reported in particular when it is used as
a monotherapy, co- administration with other antibacterial should also
be considered in order to prevent the emergence of resistance.

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).

There are limited clinical data on the efficacy and safety of intravenous
colistimethate sodium. The recommended doses in all subpopulations
are equally based on limited data (clinical and pharmacokinetic/
pharmacodynamics data). In particular there are limited safety data for
the use of high doses (> 6 MIU/day) and the use of a loading dose, and
for special populations (patients with renal impairment and the paediatric
population). Colistimethate sodium should only be used when other,
more commonly prescribed antibiotics are not effective or not

4.5 Interaction with other medicinal products and other
forms of interaction

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.

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.

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
acetylcholine at the neuromuscular 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

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

The potential for drug-drug interactions should be borne in mind when
Promixin is co-administered with drugs known to inhibit or induce drug
metabolising enzymes or drugs known to be substrates for renal carrier
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
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.
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.
Colistimethate sodium is excreted
in breast milk; breast feeding is not
recommended during therapy.

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4.7 Effects on ability to drive and use machines

Reporting of suspected adverse reactions


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.

Reporting suspected adverse reactions after authorisation of the medicinal
product is important. It allows continued monitoring of the benefit/risk
balance of the medicinal product. Healthcare professionals are asked to
report any suspected adverse reactions via;

4.8 Undesirable effects

Yellow Card Scheme

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.

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 (≥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).

Body System


Reported adverse reaction

Immune system

Not known

Hypersensitivity reactions
such as skin rash and

Nervous system

Very Common

Neurotoxicity such as,
facial, mouth and peri-oral
paraesthesia, headache, and
muscle weakness

Not known


Skin and
tissue disorders

Very Common


Renal and urinary

Very Common

Commonly susceptible species

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

Acinetobacter baumannii
Haemophilus influenzae
Klebsiella spp
Pseudomonas aeruginosa

No antidote is available.

Species for which acquired resistance may be a problem

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.

General disorders Not known
and administration
site conditions

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antibacterials for systemic use, other
antibacterials, polymyxins
ATC code: J01XB01
General properties
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 aerobic Gram-negative bacteria that have a hydrophobic
outer membrane.

Susceptible (S)
Acinetobacter S ≤ 2

R > 2 mg/L

Enterobacteriaceae S ≤ 2

R > 2 mg/L

Pseudomonas spp S ≤ 4

R > 4 mg/L


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Resistant (R) a

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

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

6.1 List of excipients
6.2 Incompatibilities


Two years

Absorption of colistimethate sodium from the gastrointestinal tract does
not occur to any appreciable extent in the normal individual.

After reconstitution:

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.

EUCAST Breakpoints

Reconstitute each vial necessary for the required dose with not more than
10mL water for injection or 0.9% sodium chloride solution.

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.

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 Burkholderia cepacia, show complete substitution of
their lipid phosphate by ethanolamine or aminoarabinose.

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

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.



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.

Promixin must be reconstituted, under aseptic conditions to produce a clear
colourless to pale yellow solution. 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.

5.2 Pharmacokinetic properties


Renal failure
Injection site reaction

Inherently resistant organisms
Burkholderia cepacia and related species
Proteus spp
Providencia spp
Serratia spp


PK/PD relationship

Renal impairment
demonstrated by increased
blood creatinine and / or urea
and / or decreased creatinine
renal clearance

Stenotrophomonas maltophilia
Achromobacter xylosoxidans (formerly Alcaligenes xylosoxidans)

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.

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

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

6.3 Shelf life

Hydrolysis of colistimethate sodium to the active substance colistin is
significantly increased when reconstituted and diluted below its critical
micelle concentration of about 80,000 IU per mL.
The chemical and physical in-use stability of reconstituted solution in the
original vial, with a concentration of ≥ 80,000 IU/mL, has been demonstrated
for 24 hours at 2 to 8ºC or for up to 8 hours at room temperature. Solutions
which have been diluted beyond the original vial volume and/or with a
concentration of < 80,000 IU/mL should be used immediately.

Bolus injection

Intrathecal and intraventricular use
Reconstitute the vial with 0.9% sodium chloride solution. The volume taken
for administration should not exceed 1 mL and the solution should be used
immediately after reconstitution. To achieve the recommended solution
concentration of 125,000 IU/mL reconstitute the vial with 8 mL of 0.9%
sodium chloride solution.
Reconstitute a sufficient number of vials to obtain the required dose by
adding an appropriate volume of water for injection or 0.9% sodium
chloride solution to each vial, not exceeding 10 mL per vial. Draw up the
content from each vial to make up the required dose which may then be
further diluted, usually with 50 mL of 0.9% sodium chloride solution, as
appropriate for the volume and method infusion. 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.

Profile Pharma Limited
Bicentennial Building
Southern Gate
West Sussex
PO19 8EZ
United Kingdom

PL 19419/0002

From a microbiological point of view unless the method of opening/
reconstitution/ dilution precludes the risk of microbial contamination, the
solution should be used immediately. If not used immediately in-use
storage times and conditions prior to use are the responsibility of the user.



6.4 Special precautions for storage

Date of latest renewal: 13th March 2009

Date of first authorisation: 24th June 2003

Do not store above 25ºC.


For storage conditions of the reconstituted/diluted product see section 6.3.

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.

6.5 Nature and contents of container
The product is supplied in a clear type I glass 10R ISO vial (nominal volume
10mL) 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 and other handling

XX November 2015


For single use only.
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Source: Medicines and Healthcare Products Regulatory Agency

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