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COLOMYCIN INJECTION 1 MILLION INTERNATIONAL UNITS. POWDER FOR SOLN FOR INJ INFUSION OR INHALATION

Active substance(s): COLISTIMETHATE SODIUM

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Colomycin Injection 1 million International Units.
Powder for solution for injection, infusion or inhalation.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 1 million International Units Colistimethate Sodium.
For excipients, see 6.1

3

PHARMACEUTICAL FORM
Powder for solution for injection, infusion or inhalation.
Sterile white powder in a 10ml colourless glass vial with a red ‘flip-off’ cap.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Colomycin by intravenous administration 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).
Colomycin by inhalation is also indicated for the management of adult and paediatric
chronic pulmonary infections due to Pseudomonas aeruginosa in patients with cystic
fibrosis (see section 5.1).
Consideration should be given to official guidance on the appropriate use of
antibacterial agents.

4.2

Posology and method of administration

SYSTEMIC TREATMENT

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 population-pharmacokinetic
data in critically ill patients (see section 4.4):
Adults and adolescents
Maintenance dose 9 million IU/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 is 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)

Daily dose

< 50- 30

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
Colomycin 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
IU
12 500
150 000
1 000 000
4 500 000
9 000 000

≈ mg CBA
0.4
5
34
150
300

≈ mass of
CMS (mg) *
1
12
80
360
720

* Nominal potency of the drug substance = 12,500 IU/mg
AEROSOL INHALATION
It is recommended that colistimethate sodium (CMS) should be administered under the
supervision of physicians with appropriate experience in its use.
Posology
The dosage can be adjusted depending on the severity of the condition and clinical response.
Recommended dose range:
Administration via inhalation
Adults, adolescents and children ≥ 2 years
1-2 MIU two to three times per day (max 6 MIU/day)
Children < 2 years
0.5-1 MIU twice daily (max 2 MIU/ day)
Relevant clinical guidance on treatment regimens, including duration of treatment, periodicity
and co-administration of other antibacterial agents should be adhered to.
Elderly
Dose adjustment is not considered necessary
Renal impairment
Dose adjustment is not considered necessary, however caution is advised in patients with
renal impairment (see sections 4.4 and 5.2).
Hepatic impairment
Dose adjustment is not considered necessary.
Method of administration
For inhalation use.

Colistimethate sodium undergoes hydrolysis to the active substance colistin in aqueous
solution. For special precautions for disposal and handling of reconstituted solutions, see
section 6.6.
If other treatments are being taken, they should be taken in the order recommended by the
physician.
See above for Dose conversion table.

4.3

Contraindications

Hypersensitivity to colistimethate sodium (colistin) or to polymyxin B.

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).
Bronchospasm may occur on inhalation of antibiotics. This may be prevented or
treated with appropriate use of beta2-agonists. If troublesome, treatment should be
withdrawn.

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 Colomycin 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

Pregnancy and lactation
There are no adequate data from the use of colistimethate sodium in pregnant
women.
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. Animal studies are insufficient
with respect to the effect of colistimethate sodium on reproduction and
development (see Section 5.3 – Preclinical safety data).
Colistimethate sodium should be used in pregnancy only if the benefit to the
mother outweighs the potential risk to the fetus.
Colistimethate sodium is secreted 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
During parenteral treatment with colistimethate sodium neurotoxicity may
occur with the possibility of dizziness, confusion or visual disturbance.
Patients should be warned not to drive or operate machinery if these effects
occur.

4.8

Undesirable effects
Systemic treatment
The likelihood of adverse events may be related to the age, renal function and
condition of the patient.
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.
Neurotoxicity may be associated with overdose, failure to reduce the dose in
patients with renal insufficiency and concomitant use of either neuromuscular
blocking drugs or other drugs with similar neurological effects. Reducing the
dose may alleviate symptoms. Effects may include apnoea, transient sensory
disturbances (such as facial paraesthesia and vertigo) and, rarely, vasomotor
instability, slurred speech, visual disturbances, confusion or psychosis.
Adverse effects on renal function have been reported, 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 during
concomitant use of other nephrotoxic drugs. The effects are usually reversible
on discontinuation of therapy.
In cystic fibrosis patients treated within the recommended dosage limits,
nephrotoxicity appears to be rare (less than 1%). In seriously ill hospitalised
non-CF patients, signs of nephrotoxicity have been reported in approximately
20% of patients.
Hypersensitivity reactions including skin rash and drug fever have been
reported. If these occur treatment should be withdrawn.
Local irritation at the site of injection may occur.
Inhalation treatment
Inhalation may induce coughing or bronchospasm.
Sore throat or mouth has been reported and may be due to Candida albicans
infection or hypersensitivity. Skin rash may also indicate hypersensitivity, if
this occurs treatment should be withdrawn.

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
acute renal failure characterised by decreased urine output and increased
serum concentrations of BUN and creatinine.
There is no specific antidote, manage by supportive treatment. Measures to
increase the rate of elimination of colistin e.g. mannitol diuresis, prolonged
haemodialysis or peritoneal dialysis may be tried, but effectiveness is
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 aerobic Gramnegative 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
Acinetobacter
Enterobacteriaceae
Pseudomonas spp
a

Susceptible (S)
S≤2
S≤2
S≤4

Resistant (R) a
R>2 mg/L
R>2 mg/L
R>4 mg/L

Breakpoints apply to dosage of 2-3 MIU x 3. A loading dose (9 MIU) 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 baumannii
Haemophilus influenza
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 species
Providencia species
Serratia species

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.
When given by nebulisation, variable absorption has been reported that may depend on
the aerosol particle size, nebuliser system and lung status. Studies in healthy volunteers
and patients with various infections have reported serum levels from nil to potentially
therapeutic concentrations of 4mg/l or more. Therefore, the possibility of systemic
absorption should always be borne in mind when treating patients by inhalation.
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 teratogenic
properties. However, colistimethate sodium given intramuscularly during
organogenesis to rabbits 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.
There are no other preclinical safety data of relevance to the prescriber which
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
Mixed infusions, injections and nebuliser solutions involving colistimethate
sodium should be avoided.

6.3

Shelf life

Before opening:
3 years.
Reconstituted solutions:
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 or nebulisation, 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.
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 solutions for intrathecal and intraventricular administration, the reconstituted
product should be used immediately.

6.4

Special precautions for storage
Do not store above 25°C.
Keep the vials in the outer carton in order to protect from light.
For storage of solutions following reconstitution refer to 6.3.

6.5

Nature and contents of container

1 million IU/vial:
2 million IU/vial:

6.6

Type I, 10 ml nominal capacity glass vial with red ‘flip-off’ cap
supplied in cartons of ten vials.
Type I, 10 ml nominal capacity glass vial with lilac ‘flip-off’
cap supplied in cartons of ten vials.

Special precautions for disposal

For bolus injection:
Reconstitute the contents of the vial with not more than 10ml water for injection or
0.9% sodium chloride.
For infusion:
The contents of the reconstituted vial may be diluted, usually with 50ml 0.9% sodium
chloride.
When the intrathecal and intraventricular routes of administration are used, the
volume administered should not exceed 1 ml (reconstituted concentration 125,000
IU/ml).
For inhalation by nebuliser:
Reconstitute the contents of the vial with either water for injections to produce a
hypotonic solution or a 50:50 mixture of water for injections and 0.9% sodium

chloride to produce an isotonic solution or with 0.9% sodium chloride to produce a
hypertonic solution.
The volume of reconstitution should be according to the instructions for use of
nebuliser administration device, and is normally not more than 4ml.
The output from the nebuliser may be vented to the open air or a filter may be fitted.
Nebulisation should take place in a well ventilated room.
During reconstitution swirl gently to avoid frothing.
Solutions are for single use only and any remaining solution should be discarded.

7

MARKETING AUTHORISATION HOLDER
Forest Laboratories UK Limited
Whiddon Valley
Barnstaple
North Devon
EX32 8NS
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 00108/5006R

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
June 1986 / November 2006

10

DATE OF REVISION OF THE TEXT
03/02/2016

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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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