COLISTIMETHATE SODIUM 1MILLION INTERNATIONAL UNITS(IU) POWDER FOR SOLUTION FOR INJECTION OR INFUSION

Active substance: COLISTIMETHATE SODIUM

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Colistimethate sodium, 1 million International Units (IU), powder for solution for
injection or infusion.

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 injection or infusion
The powder is white to off white

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Colistimethate sodium 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
It is recommended that Colistimethate sodium 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.

4.2

Posology and method of administration
It is recommended that Colistimethate sodium should be administered under the
supervision of physicians with appropriate experience in its use.

Method of Administration
Administration is by injection or intravenous infusion. Each dose of Colistimethate
sodium 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.
The reconstituted solution is a clear colourless to pale yellow solution.
Solutions should be used immediately after reconstitution.
For instructions on dilution of the medical product before administration see section
6.6.

Posology
The dose regimen of Colistimethate sodium 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.
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 Colistimethate sodium to any patient with renal impairment due to the
limited information available on safety and appropriate dose regimens (see section
4.4).

Table 1: Suggested modification of dosage of Colistimethate sodium for adults
with impaired renal function
Degree of Renal Impairment
Normal
Creatinine
Clearance

Mild

Moderate

Severe

76 to 100

40 to 75

25 to 40

Less than 25

1.3 to 2

1 to 1.5

1

1 to 1.5

3

2

1 or 2

Every 36
hours

(% of normal)
Dose
Unit dose
(Million IU)
Frequency
(Times per day)

Total Daily Dose

4 to 6

2 to 3

1 to 2

0.6 to 1

(Million IU)

Hepatic impairment
It is not known whether the dose of Colistimethate sodium requires adjustment
in patients with hepatic impairment and therefore caution is advised.

4.3

Contraindications
Hypersensitivity to the active substance colistimethate sodium or other polymyxins

4.4

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

4.5

Interaction with other medicinal products and other forms of interaction
Due to the effects of colistimethate sodium on the release of acetylcholine, nondepolarising muscle relaxants should be used with extreme caution in patients
receiving Colistimethate sodium as their effects could be prolonged.
Concomitant use of colistimethate sodium with other medications that are
nephrotoxic or neurotoxic (eg. cephalothin sodium, aminoglycosides, nondepolarising 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.

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.

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 ( 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

Frequency

Reported adverse reaction

Immune system disorders

Not known

Hypersensitivity reactions
such as skin rash and
angioedema

Nervous system disorders

Very Common

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

Not known

Dizziness
Ataxia

Skin and subcutaneous
tissue disorders

Very Common

Pruritus

Renal and urinary
disorders

Very Common

Renal impairment
demonstrated by increased
blood creatinine and / or

urea and / or decreased
creatinine renal clearance
Rare
Not known

General disorders and
administration site
conditions

4.9

Renal failure
Injection site reaction

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.
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
a
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.

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

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
After administration to cystic fibrosis (CF) patients of 7.5 mg/kg/day in
divided doses given as 30 minute intravenous infusions to steady state the Cmax
was determined to be 23 (+6) mg/l and Cmin at 8 hr was 4.5 (+4) mg/l. In
another study in CF patients given 2 million units every 8 hours for 12 days
the Cmax was 12.9 mg/l (5.7 – 29.6 mg/l) and the Cmin was 2.76 mg/l (1.0 – 6.2
mg/l). In healthy volunteers given a bolus injection of 150 mg (approximately
2 million units) peak serum levels of 18 mg/l were observed 10 minutes after
injection.
Protein binding is low. Polymyxins persist in the liver, kidney, brain, heart and
muscle.
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 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

The main route of elimination of unchanged colistimethate sodium after
parenteral administration is by renal excretion with around 60% of a parenteral
dose recovered in the urine within 8 hours. Because colistimethate is largely
excreted in the urine, dosage reduction is required in renal impairment to
prevent accumulation. Refer to the table in Section 4.2. The free base colistin
is excreted by the non-renal route.
After intravenous administration to healthy adults the elimination half-life of
colistimethate sodium is around 1.5 hrs. In a study in CF patients given a
single intravenous infusion over 30 minutes the elimination half-life was 3.4 +
1.4 hrs.
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.
Colistimethate pharmacokinetics appear to be similar in children and adults,
including the elderly, provided renal function is normal. Limited data are
available on use in neonates that suggest that pharmacokinetics are similar to
children and adults but the possibility of higher peak serum levels and
prolonged half-life in these patients should be considered.

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.
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.

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:
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 8°C,
unless reconstitution/dilution has taken place in controlled and validated aseptic
conditions.

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 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.
Colistimethate sodium must be reconstituted, under aseptic conditions, with sodium
chloride solution 9 mg/ml (0.9%) or water for injections, 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).
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
20/05/2013

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Source: Medicines and Healthcare Products Regulatory Agency

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