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

Active substance(s): COLISTIMETHATE SODIUM / COLISTIMETHATE SODIUM / 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.
Excipients with known effect: None
For the full list of excipients, see section 6.1.

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 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.).
Consideration should be given to official guidance on the appropriate use of
antibacterial agents.
4.2

Posology and method of administration
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.

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.
Posology
The following dose recommendations are made based on limited populationpharmacokinetic data in critically ill patients (see also section 4.4):
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 administered.
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 are very limited.
The following dose adjustments are suggested as guidance.
Dose reductions are recommended for patients with creatinine clearance < 50 ml/min:
Twice daily dosing is recommended.
Creatinine clearance (ml/min)
< 50- 30

Daily dose
5.5- 7.5 MIU

<30- 10

4.5- 5.5 MIU

<10

3.5 MIU

MIU = million IU
Haemodialysis and continuous haemo(dia)filtration
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 considered.
Haemodialysis
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
Twice daily dosing is recommended.
CVVHF/ CVVHDF
As in patients with normal renal function. Three times daily dosing is recommended.

Hepatic impairment
There are no data in patients with hepatic impairment. Caution is advised when
administering colistimethate sodium in these patients.
Elderly
No dose adjustments in older patients with normal renal function are considered
necessary.
Paediatric population
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.
Intrathecal and intraventricular administration
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.

Method of administration
Colistimethate sodium is administered intravenously as a slow infusion over 30 – 60
minutes.
Patients with a totally implantable venous access device (TIVAD) in place may
tolerate a bolus injection of up to 2 million units in 10ml given over a minimum of 5
minutes (see section 6.6).
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).

Dose conversion table:
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.
CMS conversion table
Potency
≈ mass of CMS (mg)*
IU
≈ mg CBA
12.500
0.4
1
150.000
5
12
1.000.000
34
80
4.500.000
150
360
9.000.000
300
720
*Nominal potency of the drug substance = 12.500 IU/mg

4.3

Contraindications
Hypersensitivity to the active substance colistimethate sodium or other polymyxins

4.4

Special warnings and precautions for use
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.
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 (> 6MIU/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 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).
Concomitant use of colistimethate sodium with other medicinal products of
neurotoxic and/or nephrotoxic potential should be avoided. These include the
aminoglycoside antibiotics such as gentamicin, amikacin, netilmicin and
tobramycin. There may be an increased risk of nephrotoxicity if given
concomitantly with cephalosporin antibiotics.
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). Single dose
studies in human pregnancy show that colistimethate sodium crosses the placental
barrier and there may be a risk of foetal toxicity if repeated doses are given to
pregnant patients. 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. Colistimethate sodium should be
administered to breastfeeding women only when clearly needed.

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 likelihood of adverse events may be related to the age, renal function and
condition of the patient.
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.
In cystic fibrosis patients treated within the recommended dosage limits,
nephrotoxicity appears to be rare (less than 1%). In seriously ill hospitalized non-CF
patients, signs of nephrotoxicity have been reported in approximately 20% of patients.
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.
In cystic fibrosis patients neurological events have been reported in up to 27% of
patients. These are generally mild and resolve during or shortly after treatment.
Hypersensitivity reactions such as skin rash, drug fever 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, drug fever and angioedema

Nervous system

Very Common

Neurotoxicity such as, facial, mouth

Body System

Frequency

disorders

Reported adverse reaction
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

Renal failure

Not known

Injection site reaction

General disorders and
administration site
conditions

Reporting of suspected adverse reactions
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 the Yellow Card Scheme (Website: www.mhra.gov.uk/yellowcard).

4.9

Overdose
Overdose can result in neuromuscular blockade that can lead to muscular weakness,
apnoea and possible respiratory arrest. Overdose can also cause renal insufficiency or
acute renal failure characterised by decreased urine output and increased serum
concentration of BUN and creatinine. Overdose may cause 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, but the effectiveness in
unknown.

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
Burkholderia 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.
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.
EUCAST Breakpoints
Susceptible (S) Resistant (R) a
Acinetobacter

S≤2

R>2 mg/L

Enterobacteriaceae

S≤2

R>2 mg/L

R>4 mg/L
Pseudomonas spp
S≤4
a
Breakpoints apply to dosage of 2-3 million IU x 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.

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

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.
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:
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
IU/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 IU/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.

For bolus injection, 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
10/02/2017

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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