Colobreathe

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Colobreathe 1,662,500 IU inhalation powder, hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each capsule contains 1,662,500 IU, which is approximately equal to 125 mg of colistimethate 
sodium.  
 
 
3. PHARMACEUTICAL FORM 
 
Inhalation powder, hard capsule (inhalation powder) 
Hard transparent PEG-gelatin capsules containing a fine white powder. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Colobreathe is indicated for the management of chronic pulmonary infections due to Pseudomonas 
aeruginosa in patients with cystic fibrosis (CF) aged 6 years and older (see  section 5.1). 
Consideration should be given to official guidance on the appropriate use of antibacterial active 
substances. 
 
4.2 Posology and method of administration 
 
Posology 
 
Adults and children of 6 years of age and older 
One capsule to be inhaled twice daily. 
The dose interval should be as close as possible to 12 hours.  
 
The efficacy of Colobreathe has been demonstrated in a study of 24-weeks duration. Treatment may be 
continued for as long as the physician considers that the patient is obtaining clinical benefit. 
 
Renal impairment   
No dose adjustment is considered to be necessary (see section 5.2). 
 
Hepatic impairment  
No dose adjustment is considered to be necessary (see section 5.2). 
 
Paediatric population 
 
The safety and efficacy of Colobreathe in children under 6 years of age have not been established. No data 
are available. 
 
Method of administration 
 
For inhalation use only. 
Colobreathe capsules are to be used only with the Turbospin powder inhaler. 
The capsules must not be swallowed. 
 



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To ensure proper administration of the medicinal product, the patient should be shown how to use the 
inhaler by a physician or other health professional, with the first dose being given under medical 
supervision. 
 
If other treatments are being taken, they should be taken in the following order: 
Inhaled bronchodilators 
Chest physiotherapy 
Other inhaled medicinal products 
Colobreathe 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance, colistin sulphate or polymyxin B. 
 
4.4 Special warnings and precautions for use 
 
Bronchospasm and coughing 
 
Bronchospasm or coughing may occur on inhalation. These reactions usually disappear or 
significantly diminish with continued use and may be ameliorated by appropriate treatment with beta2-
agonists prior to or following dry powder colistimethate sodium inhalation. If bronchospasm or 
coughing remain problematic, withdrawal of treatment should be considered. 
 
Haemoptysis  
 
Haemoptysis is a complication in cystic fibrosis and is more frequent in adults. The use 
of colistimethate sodium in patients with clinically significant haemoptysis should be undertaken or 
continued only if the benefits of treatment are considered to outweigh the risks of inducing further 
haemorrhage. 
 
Acute respiratory exacerbation 
 
If acute respiratory exacerbations develop additional intravenous or oral antibacterial agent therapy should 
be considered. 
 
Oral fungal super-infection 
 
After each inhalation of Colobreathe, the mouth should be rinsed with water.  The rinse should not be 
swallowed.  Rinsing may reduce the risk of developing oral fungal super-infection during treatment 
and may also reduce the unpleasant taste associated with colistimethate sodium. 
 
Nephrotoxicity/neurotoxicity 
 
There is very low transpulmonary absorption of colistimethate after inhalation of Colobreathe (see 
section 5.2). Care should still be taken in administering Colobreathe to patients who are known to have 
a propensity for nephrotoxic or neurotoxic events.  
 
Caution should be taken with concomitant use of Colobreathe and parenteral or nebulised 
colistimethate sodium.  
 
Caution should be taken with concomitant use of colistimethate sodium and potential nephrotoxic or 
neurotoxic medicinal products, including non-depolarising muscle relaxants (see section 4.5).  



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Other 
 
Colobreathe should be used with extreme caution in patients with myasthenia gravis because of 
potential for drug induced neuromuscular blockade. 
 
Colistimethate sodium should be used with extreme caution in patients with porphyria. 
 
Safety and efficacy have been assessed in controlled studies for up to 24 weeks. (see section 5.1). 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
There is no experience of using Colobreathe concurrently with other inhaled antibacterial agents. 
 
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.  
 
Colistimethate sodium and colistin have been investigated in vitro to determine the effects on the 
expression of cytochrome P450 (CYP) enzymes on treating primary cultures of fresh human 
hepatocytes.  Treatment with colistimethate sodium or colistin did not induce the activity of any 
enzyme tested (CYP1A2, 2B6, 2C8, 2C9, 2C19 and 3A4/5).  
 
Concomitant use of inhaled colistimethate sodium with other medicinal products that are potentially 
nephrotoxic or neurotoxic, such as aminoglycosides, or neuromuscular blocking products, such as 
curariform agents should be undertaken with caution. 
 
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 
 
Pregnancy 
 
There are no or limited amount of data from the use of inhaled colistimethate sodium in pregnant 
women. Studies in animals using parenteral administration have shown reproductive toxicity (see 
section 5.3). Single dose intravenous studies in human pregnancy show that colistimethate sodium 
crosses the placenta and consequently there is potential for foetal toxicity if administered during 
pregnancy.  
Colistimethate sodium is not recommended during pregnancy and in women of childbearing potential 
not using contraception. 
 
Breast-feeding 
 
Physico-chemical data suggest excretion of colistimethate sodium in human milk. A risk to the 
newborns/infants cannot be excluded.  A decision must be made whether to discontinue breastfeeding 
or to discontinue/abstain from colistimethate sodium therapy taking into account the benefit of 
breastfeeding for the child and the benefit of therapy for the woman.  
 
Fertility 
 
Colistimethate sodium has no notable effects on fertility in male or female rats or mice. 
 



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4.7 Effects on ability to drive and use machines 
 
Based on the safety profile of colistimethate sodium, neurotoxity may occur with the possibility of 
dizziness, confusion or visual disturbances.  Patients should be warned not to drive or operate 
machines if this occurs. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The safety of Colobreathe has been assessed in a total of 237 subjects (225 cystic fibrosis patients and 
12 healthy volunteers).  Of these, 187 patients aged 6 years and above were exposed to Colobreathe 
one capsule twice daily in a 24-week, phase 3 comparative study.  There were 32 patients aged 6-12 
years, 41 patients aged 13-17 years and 114 patients aged 18 years and older.  The most commonly 
reported adverse reactions as a percent of all Colobreathe treated patients were: unpleasant taste 
(62%), cough (59.4%), throat irritation (43.9%), dyspnoea (16.6%) and dysphonia (10.7%). Inhalation 
may induce coughing or bronchospasm which may be controlled by pre-treatment with inhaled beta2 
agonists.  
 
Sore throat or mouth has been reported with nebulised colistimethate sodium and may occur with 
Colobreathe.  This may be related to Candida albicans infection or hypersensitivity.  Skin rash may 
also indicate hypersensitivity and if this occurs treatment should be withdrawn.  
 
Tabulated list of adverse reactions 
 
In the 24 week clinical study, the following adverse reactions were observed across all ages. 
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), very rare <1/10,000), not known (cannot be estimated from 
the available data).  Within each frequency grouping, adverse reactions are presented in order of 
decreasing seriousness. 
 
System Organ Class Very Common Common Uncommon 
Immune system 
disorders 

  Drug 
hypersensitivity 

Metabolism and 
nutrition disorders 

  Weight fluctuation, 
decreased appetite 

Psychiatric disorders   Anxiety 
Nervous system 
disorders 

 Balance disorder, 
headache 

Convulsions, 
somnolence  

Ear and labyrinth 
disorders 

 Tinnitus Ear congestion 

Respiratory, thoracic 
and mediastinal 
disorders 

Dyspnoea, 
cough,  
dysphonia, 
throat irritation 

Haemoptysis, 
bronchospasm,  
asthma,  
wheezing,  
chest discomfort,  
lower respiratory tract 
infection,  
productive cough, 
crackles lung 

Chest pain, 
dyspnoea 
exacerbated,   
pharyngolaryngeal 
pain, 
epistaxis, 
sputum purulent, 
abnormal chest 
sound, 
increased upper 
airway secretion 



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Gastrointestinal 
disorders 

Dysgeusia Vomiting,  nausea  Diarrhoea, 
toothache, 
salivary 
hypersecretion, 
flatulence 

Musculoskeletal and 
connective tissue 
disorders 

  Arthralgia  

Renal and urinary 
disorders 

  Proteinuria 

General disorders and 
administration site 
conditions 

 Pyrexia, asthenia, 
fatigue 

Thirst 

Investigations  Forced expiratory 
volume decreased 

 

Injury, poisoning and 
procedural 
complications 

  Medication error 

 
Paediatric population 
 
In the 24-week clinical study, where Colobreathe was administered twice daily to adults and children 
aged 6-17, the adverse reactions identified in the paediatric population were similar to that for the 
overall population. The most commonly reported adverse reactions as a percent of Colobreathe treated 
patients were: cough (55%), unpleasant taste (51%), throat irritation (34%), dyspnoea (10%) and 
dysphonia (10%). 
 
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 national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Symptoms 
 
Currently there is no experience of overdose with the use of Colobreathe.  However, overdose may 
possibly result in higher systemic exposure. 
 
Overdose is unlikely by the inhaled route but has been recognised after systemic use. More common 
signs and symptoms of intravenous overdose include unsteadiness, paraesthesia and dizziness.  It can 
also 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. 
 
Management 
 
There is no specific antidote, therefore management should be done by supportive treatment. Measures 
to increase the rate of elimination of colistimethate sodium e.g. mannitol diuresis, prolonged 
haemodialysis or peritoneal dialysis may be tried, but effectiveness is unknown. 
 
  

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: antibacterials for systemic use, other antibacterials.  
ATC Code: J01XB01 
 
Mechanism of action 
 
Colistimethate sodium (CMS) is a cyclic polypeptide antibacterial active substance that is derived 
from Bacillus polymyxa var. colistinus and belongs 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 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 
 
Cross resistance between colistimethate sodium 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.  
 
The epidemiological cut off value for colistimethate sodium for Pseudomonas aeruginosa, 
distinguishing the wild type population from isolates with acquired resistance traits, is 4 mg/l. 
 
Clinical efficacy 
 
The Phase 3 clinical study was a randomised, open-label active comparator study comparing the 
efficacy of colistimethate sodium 1,662,500 IU dry powder for inhalation to tobramycin nebuliser 
solution for inhalation, 300 mg/5 ml, in 380 subjects with documented cystic fibrosis complicated by 
chronic pulmonary infection with Pseudomonas aeruginosa. The subjects were aged 6 years and 
above and had an FEV1% predicted of 25-75%. All subjects were also required to have successfully 
completed a minimum of two cycles of nebulised tobramycin solution run-in prior to randomisation. 
Subjects were randomised to receive either one 1,662,500 IU capsule of colistimethate sodium twice 
daily, or 300 mg of tobramycin, twice daily. It should be noted that treatment was not interrupted 
when patients received concomitant parenteral antibacterial active substances. 
 
Efficacy was measured by the change in FEV1 % predicted compared to baseline after a 24-week 
treatment period.  
 
The results of the Intent-To-Treat (ITT) population for the primary efficacy outcome are shown below: 
 
Change in FEV1 (% predicted) from baseline at Week 24 (ITT Population) 

Patient group Colobreathe 
( Mean) 

Tobramycin  
( Mean) 

Adjusted 
Treatment 
difference 

95% CI 

All patients 
using LOCF 

-0.90 (n=183) 0.35  (n=190) -0.97 -2.74, 0.86 

Completed 0.39  (n=153) 0.78  (n=171) -0.29 -2.21, 1.71 



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patients 
The data from the primary outcome parameter, change in FEV1 % predicted, are not normally distributed. The adjusted treatment difference 
and 95% confidence interval have been back transformed from log transformed data.  The ITT population excluded patients who had been 
treated but demonstrated no evidence of chronic infection. 
 
The European Medicines Agency has deferred the obligation to submit the results of studies 
with Colobreathe  in one or more subsets of the paediatric population in Pseudomonas aeruginosa 
pulmonary infection/colonisation in patients with cystic fibrosis (see section 4.2 for information on 
paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
Colistimethate is not significantly absorbed from the lung after inhalation of Colobreathe.  After 
administration of 1,662, 500IU twice daily for 7 days in adult, adolescent and paediatric cystic fibrosis 
patients mean C max values of total colistimethate of up to 455ng/ml (adult mean) were observed.  Tmax for 
total colistimethate occurred between 0.5 and 1 hour post-dose. Although the population PK analysis 
showed that age is a statistically significant covariate, the AUC 0-6 and dose adjusted AUC0-6 (AUC 0-6  /D) 
for total CMS and total free colistin were similar between children and adolescents, while higher AUC 0-6  
was observed in the adult group. When AUC 0-6  was adjusted by dose and body weight, a slightly higher 
AUC 0-6 /D/W for total CMS and total free colistin was observed in children. High PK variability was 
observed in all three groups. Therefore, dose adjustment in low age groups is considered not necessary. 
 
High concentrations of total free colistin (mean 23.5mg/L) and total colistimethate (mean 178mg/L) were 
observed in sputum at 1 hour post-dose on Day 8 following BID dosing for 7 days across all age groups.  
 
Absorption of colistimethate from the gastro-intestinal tract does not occur to any appreciable extent in the 
normal individual. 
 
Distribution 
 
Protein binding is low.  Polymyxins persist in the liver, kidney, brain, heart and muscle.  One study in 
cystic fibrosis patients gives the steady-state volume of distribution as 0.09 l/kg. 
 
Biotransformation 
 
Colistimethate sodium is converted to the base in vivo.  As 80% of a parenteral dose can be recovered 
unchanged in the urine, and there is no biliary excretion, it can be assumed that the remaining drug is 
inactivated in the tissues.  The mechanism is unknown. 

 
Elimination 
 
A systemic absorption study showed minimal urinary excretion with less than 3% of the dose of 
Colobreathe excreted in the urine as colistimethate sodium and colistin. Therefore, dose adjustment in 
patients with renal impairment is not considered necessary.  The estimated mean terminal half-lives for 
total CMS and total free colistin were 3.0 and 6.4 h, respectively.   
 
5.3 Preclinical safety data 
 
Nonclinical data reveal no special hazard for humans based on conventional studies of genotoxicity. 
Animal studies of safety pharmacology, repeated dose toxicity or toxicity to reproduction, employing 
routes assuring systemic exposure, showed no particular hazard.  There were no notable effects on 
fertility or general reproductive performance in male or female rats or mice.  In embryo-fetal 
development studies in mice, resorptions and reduced ossification were seen, and in rats reduced fetal 
weights, reduced ossification and at the high dose of 10 mg colistin base per day, reduced post-natal 



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survival.  An embryo-fetal study in rabbits reported no effects at intravenous doses up to 80 mg/kg 
colistimethate sodium (32 mg colistin base/kg).   

 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Components of the PEG-gelatin hard capsules: 
 
Gelatin 
Polyethylene glycol 
Purified water 
Sodium lauryl sulfate 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
Do not store above 25°C. 
 
Store in the original package until immediately before use in order to protect from moisture. 
 
6.5 Nature and contents of container 

 
The capsules are contained in oPA/aluminium/pvc blisters with a peelable lidding foil composed of 
polyester/aluminium of either 8 or 14 hard capsules in each blister.   
 
Colobreathe is available in packs containing either 8 or 56 hard capsules. 
 
Each 56 capsule pack contains one Turbospin powder inhaler device and 7 blisters of 8 capsules or 
one Turbospin powder inhaler device and 4 blisters of 14 capsules (56 hard capsules) sufficient for 4 
weeks use.  
 
Each 8 capsule pack contains one Turbospin powder inhaler device and 1 blister of 8 hard capsules 
sufficient for 4 days use. 
 
Not all pack sizes may be marketed. 
 
 
6.6 Special precautions for disposal and other handling  
 
Capsules: no special requirements for disposal.  The Turbospin device should be discarded after 
completion of the treatment pack. 
 
Colobreathe capsules should only be administered using the Turbospin inhaler device.   
 
Taking Colobreathe using the Turbospin inhaler 
 
The following instructions should be adhered to by the patient when taking Colobreathe: 



10 

 
 
Preparing the Turbospin 
 

1. Remove the cap. It comes away with a gentle pull. 
2. Unscrew the mouthpiece, exposing the chamber of the Turbospin inhaler. 
3. Remove a single capsule from the blister pack. Once you have removed the capsule it must be 

used immediately. 
4. Gently insert the capsule into the chamber with the widest end first. No force is required.  
5. Now replace the mouthpiece by screwing it back into place. 

 
Piercing the capsule and inhaling the medicine 
 

6. To pierce the capsule: 
• Hold the inhaler with the mouthpiece upright, gently push the piston upwards until the 

visible line is reached – you will feel resistance at this point and this will lock the capsule in 
place ready for piercing. Hold that position before continuing to follow through with the 
piercing. 

• Now, with the capsule locked in place, continue pushing the piston as far as it will go and 
then release. 

• The capsule is now pierced and the contents can be inhaled. 
• Do not pierce the capsule more than once. You may see a small amount of powder released 

from the capsule chamber after the capsule is pierced, this is normal. 
7. Breathe out slowly. Place the mouthpiece between your lips and teeth. Ensure there is a seal 

between your lips and the mouthpiece. Take care not to cover the air slits with your fingers or 
mouth during inhalation.  

8. Then, breathe in slowly and deeply through your mouth at a rate sufficient for you to hear or 
feel the capsule spinning.   

9. Remove the Turbospin inhaler from your mouth and hold your breath for about 10 seconds or 
for as long as is comfortable, then breathe out slowly.   

10. If you do not hear the capsule spinning, the capsule may be stuck in the compartment.  If this 
occurs, you can loosen the capsule by gently tapping the chamber of the inhaler. Do not try to 
loosen the capsule by repeatedly pressing the piston.  If the capsule cannot be loosened and 
the powder cannot be inhaled, dispose of the broken capsule and any powder remaining in it 
and use another. 

11. Inhale the medicine again by repeating Steps 7 and 8 to ensure you have emptied the capsule. 
12. You can check whether the capsule is empty by unscrewing the mouthpiece and checking the 

capsule. If it is not empty, repeat steps 7, 8 and 9 until you have inhaled all of the contents.  
13. Once all the contents have been inhaled, rinse your mouth out well with water and spit out. 

 
Removing the empty capsule from the Turbospin 
 

14. When the capsule is empty, unscrew the mouthpiece, then remove and discard the empty 
capsule.   

 
Additional information  
 
As you breathe in slowly, you suck air through the body of the Turbospin inhaler into the capsule 
chamber. The tiny particles of medicine in the capsule are picked up by the airflow and carried down 
your airway into your lungs. 
 
Occasionally, very small pieces of the capsule shell can get into your mouth or airways.  
• If this happens, you may be able to feel these pieces on your tongue or in your airways.  
• The capsule shell is made of gelatin, which is harmless to humans if swallowed or inhaled. 
• The chances of the capsule breaking into pieces are increased if the capsule is pierced more than 

once during Step 6. 



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7. MARKETING AUTHORISATION HOLDER 
 
Teva B.V.  
Swensweg 5  
2031 GA Haarlem  
The Netherlands. 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/11/747/001 56 hard capsules (4 blisters of 14 capsules) 
EU/1/11/747/002 8 hard capsules (1 blister of 8 capsules) 
EU/1/11/747/003 56 hard capsules (7 blisters of 8 capsules) 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 13/02/2012 
Date of latest renewal: 26/09/2016 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http:/www.ema.europa.eu. 
 

  



12 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURERS RESPONSIBLE FOR BATCH 
RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

  C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D.  CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
 
 



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A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Penn Pharmaceutical Services Ltd. 
23-24 Tafarnaubach Industrial Estate 
Tredegar, Gwent NP2 3AA 
United Kingdom 
 
Teva Pharmaceuticals Europe BV  
Swensweg 5  
2031 GA Haarlem  
The Netherlands 
 
Millmount Healthcare Limited 
Block 7, City North Business Campus 
Stamullen 
Co Meath 
K32 YD60 
Ireland 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to medical prescription 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports  
 
The requirements for submission of periodic safety update reports for this medicinal product are 
set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of 
Directive 2001/83/EC and any subsequent updates published on the European medicines web-
portal. 
 
 
D.  CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP)  
 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in 
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 
subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk 



14 

profile or as the result of an important (pharmacovigilance or risk minimisation) 
milestone being reached. 

 
• Additional risk minimisation measures 

The Marketing Authorisation Holder shall agree the format and content of the healthcare professional 
and patient educational pack with the National Competent Authority prior to launch in the Member 
State.  

The Marketing Authorisation Holder shall ensure that all physicians who are expected to prescribe or 
use Colobreathe are provided with a healthcare professional and patient educational pack containing 
the following: 

• The Summary of Product Characteristics 

• The Patient Information Leaflet 

• The “Physician DVD” 

• The “Patient DVD” 

• “Physician DVD” information in “leaflet form” for those physicians who do not have access to a 
DVD player 

• “Patient DVD” information in “leaflet form” for those patients who do not have access to a DVD 
player 

The Physician and patient “DVDs/leaflet forms” should contain the following key elements and 
messages: 

• Introduction to the product: provide information on the contents of the box ie that 28 days 
treatment is 56 capsules and 1 device. Explain that the device should be discarded after 28 days. 
Explanation of the Turbospin and how it works. 

• Information on the need to comply with the treatment in order to maximise the potential benefits. 
Explanation that using inhaled antibiotics can reduce the need for intravenous antibiotics. 

• Detailed instructions about how to use the medication: starting from unpacking of the product and 
finishing with disposal of the used capsule and device. Some detail about cleaning the Turbospin 
device. 

• Discussion about common side effects and in particular cough and taste abnormality: Explanation 
that: 

− these are only of nuisance value for most patients 

− emphasise that patients should persist with the treatment. 

− that cough decreases with repeated use of the product and should stabilize after the first month 
or so.  

 
 

  



15 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 

 
  



16 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 
 

  



17 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Colobreathe 1,662,500 IU inhalation powder, hard capsules 
colistimethate sodium 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains 1,662,500 IU (approximately equal to 125 mg) of colistimethate sodium 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Inhalation powder, hard capsule. 
8 capsules with 1 Turbospin inhaler (1 strip of 8 capsules) 
56  capsules with 1 Turbospin inhaler (4 strips of 14 capsules) 
56 capsules with 1 Turbospin inhaler (7 strips of 8 capsules)  
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Inhalation use only. 
Use as directed by the physician. 
Do not swallow the capsules. 
For use with the Turbospin inhaler only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C. 
Store in the original package until immediately before use in order to protect from moisture. 
 
 



18 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Teva B.V.  
Swensweg 5 
2031 GA Haarlem 
The Netherlands. 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/11/747/001 56 hard capsules (4 strips of 14 capsules) 
EU/1/11/747/002 8 hard capsules (1 strip of 8 capsules) 
EU/1/11/747/003 56 hard capsules (7 strips of 8 capsules) 
 
 
13. BATCH NUMBER 
 
Lot 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Colobreathe 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
  



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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Colobreathe 1,662,500 IU inhalation powder 
colistimethate sodium  
Inhalation use 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Teva B.V.  
 
3. EXPIRY DATE 
 
EXP  
 
4. BATCH NUMBER 
 
Lot  
 
 
5. OTHER 
 

  



20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
 

 
 
 
 
 
 



21 

Package leaflet: Information for the user 
 

Colobreathe 1,662,500 IU inhalation powder, hard capsules 
Colistimethate sodium 

 
 

Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
- Keep this leaflet.  You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only.  Do not pass it on to others.  It may harm them, 

even if their signs of illness are the same as yours.   
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
 
What is in this leaflet 
1. What Colobreathe is and what it is used for 
2. What you need to know before you use Colobreathe 
3. How to use Colobreathe 
4. Possible side effects 
5. How to store Colobreathe 
6. Contents of the pack and other information 
 
 
1. What Colobreathe is and what it is used for 
 
Colobreathe contains colistimethate sodium, a type of antibiotic called a polymyxin.  
 
Colobreathe is used to control persistent lung infections caused by the bacterium Pseudomonas 
aeruginosa in adult patients and children aged 6 years and older with cystic fibrosis.  Pseudomonas 
aeruginosa is a very common bacterium that infects nearly all cystic fibrosis patients at some time 
during their lives. Some people will get this infection whilst very young but for others it will be much 
later. If this infection is not properly controlled it will cause damage to the lungs.  
 
How it works 
Colobreathe works by destroying the bacterial cell membrane, having a lethal effect on them.  
 
 
2. What you need to know before you use Colobreathe 
 
Do not use Colobreathe: 
• if you/your child are allergic to colistimethate sodium, colistin sulphate or polymyxins. 

 
Warnings and precautions 
 
Tell your doctor if you/your child has ever had any of the following conditions: 

• have reacted badly to inhaled dry powder medicines previously unless this has already been 
discussed with your doctor. 

• already have a muscle condition known as myasthenia gravis or the inherited condition,  
porphyria 

• blood in your sputum (the substance you cough up) 
 
After each inhalation of Colobreathe, the mouth should be rinsed with water.  The rinse should not be 
swallowed.  Rinsing may reduce the risk of developing oral fungal super-infection during treatment 
and may also reduce the unpleasant taste associated with colistimethate sodium. 



22 

 
When you/your child start using Colobreathe, you/your child may find they have cough, 
breathlessness, tightness of chest or wheezing. The number of these side-effects may reduce as you 
continue to use the inhaler or your doctor may prescribe a bronchodilator to use before or after taking 
Colobreathe. If any of these effects become a problem, please contact your doctor who may change 
your treatment. 
 
If you/your child has any problems with your kidneys or nerves, care should be taken when 
administering Colobreathe but your doctor should be aware of this. 
 
If you/your child needs to have other forms of colistimethate either by injection or nebulisation 
caution should be used but your doctor should be aware of this. 
 
Children 
Do not give Colobreathe to children under the age of 6 years as it is not suitable for them. 
 
Other medicines and Colobreathe 
Tell your doctor if you/your child are taking, have recently taken or might use any other medicines, 
and in particular: 

  
• if you/your child are taking aminoglycoside antibiotics used to treat infections caution must be 

taken; 
• if you/your child suffer from myasthenia gravis and are taking macrolide type antibiotics such 

as azithromycin and clarithromycin, or fluoroquinolones such as norfloxacin and 
ciprofloxacin.  Taking these at the same time as Colobreathe may cause problems with muscle 
weakness; 

• if you/your child are taking colistimethate by injection or nebulisation caution must be taken; 
• if you/your child need to have a general anaesthetic caution must be taken. 

 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before using this medicine. 
 
There is no information about the safety of Colobreathe in pregnant women. Your doctor should 
advise you before using Colobreathe whether the benefits of the medicine exceed the risks. 
 
Colistimethate sodium may be secreted in the breast milk. Please discuss the use of Colobreathe with 
your doctor. 
 
Driving and using machines 
It is possible while using Colobreathe that you may experience dizziness, confusion or have problems 
with your sight. Do not drive or use any machines until the symptoms have gone away. 
 
 
3. How to use Colobreathe 
 
Always use this medicine exactly as your doctor has told you. Check with your doctor if you/your 
child are not sure. 
 
The first dose should be given under medical supervision. 
 



23 
 

 
Dosage 
 
Adults and children 6 years of age and older 
 

• The contents of one Colobreathe capsule should be inhaled twice a day using the Turbospin 
inhaler. 

• There should be a 12 hour gap between doses. 
 
The order in which other treatments should be taken or carried out 
If you/your child are taking other treatments for cystic fibrosis you/your child should take them in the 
following order: 

• Inhaled bronchodilators 
• Chest physiotherapy  
• Other inhaled medicines 
• Then Colobreathe  
 

You/your child should confirm the order of your treatments with your doctor. 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Method of administration 
 
Colobreathe is inhaled into the lungs as a powder from the capsule using the hand-held inhaler called 
the Turbospin. Colobreathe can only be administered using this device. 
 
Do not swallow Colobreathe capsules.  
 
To inhale Colobreathe from the capsule through the Turbospin inhaler follow the procedure described 
below. Your doctor, pharmacist or nurse should show you/your child how to inhale the medicine when 
you/your child first start treatment: 
 
Taking Colobreathe using the Turbospin inhaler 
 
Preparing the Turbospin 
 
 



24 

 
 

1. Remove the cap. It comes away with a gentle pull. 
 

 

 
 

2. Unscrew the mouthpiece, exposing the chamber of the Turbospin inhaler. 
 

 

 
 
 

3. Remove a single capsule from the blister. Once you have removed the capsule it must be used 
immediately. 

 
 

 
 

4. Gently insert the capsule into the chamber with the widest end first. No force is required.  
 

 
 
 

5. Now replace the mouthpiece by screwing it back into place. 
 
 



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Piercing the capsule and inhaling the medicine 
 

 
 
 

6. To pierce the capsule: 
• Hold the inhaler with the mouthpiece upright, gently push the piston upwards until the 

visible line is reached – you will feel resistance at this point and this will lock the capsule 
in place ready for piercing. Hold that position before continuing to follow through with 
the piercing. 

• Now, with the capsule locked in place, continue pushing the piston as far as it will go and 
then release. 

• The capsule is now pierced and the contents can be inhaled. 
• Do not pierce the capsule more than once. You may see a small amount of powder 

released from the capsule chamber after the capsule is pierced, this is normal. 
 

 
 

7. Breathe out slowly.  Place the mouthpiece between your lips and teeth. Ensure there is a seal 
between your lips and the mouthpiece. Take care not to cover the air slits with your fingers or 
mouth during inhalation.  

8. Then, breathe in slowly and deeply through your mouth at a rate sufficient for you to hear or 
feel the capsule spinning.   

9. Remove the Turbospin inhaler from your mouth and hold your breath for about 10 seconds or 
for as long as is comfortable, then breathe out slowly.   

10. If you do not hear the capsule spinning, the capsule may be stuck in the compartment.  If this 
occurs, you can loosen the capsule by gently tapping the chamber of the inhaler. Do not try to 
loosen the capsule by repeatedly pressing the piston.  If the capsule cannot be loosened and 
the powder cannot be inhaled, dispose of the broken capsule and any powder remaining in it 
and use another. 

11. Inhale the medicine again by repeating Steps 7 and 8 to ensure you have emptied the capsule. 
12. You can check whether the capsule is empty by unscrewing the mouthpiece and checking the 

capsule. If it is not empty, repeat steps 7, 8 and 9 until you have inhaled all of the contents.  
13. Once all the contents have been inhaled, rinse your mouth out well with water and spit out. 

 
Removing the empty capsule from the Turbospin 
 

14. When the capsule is empty, unscrew the mouthpiece, then remove and discard the empty 
capsule.   

 
Additional information  
 



26 

As you breathe in slowly, you suck air through the body of the Turbospin inhaler into the capsule 
chamber. The tiny particles of medication in the capsule are picked up by the airflow and carried down 
your airway into your lungs. 
 
Occasionally, very small pieces of the capsule shell can get into your mouth or airways.  
• If this happens, you may be able to feel these pieces on your tongue or in your airways.  
• The capsule shell is made of gelatin, which is harmless to humans if swallowed or inhaled. 
• The chances of the capsule breaking into pieces are increased if the capsule is pierced more than 

once during Step 6. 
 
Cleaning the Turbospin device 
 
Clean the Turbospin inhaler after each dose using the following procedure: 

1. Deeply press the piston a few times whilst keeping the chamber turned upside down. 
2. Clean the chamber using a tissue or cotton bud. Do not use water. 
3. Screw the mouthpiece firmly back into place, put the cap back on and the inhaler is ready to 

be used for your next dose.   
 
If you/your child use more Colobreathe than you/your child should, or have accidentally 
swallowed the capsule, contact your doctor immediately for advice. 
 
If you/your child forget to use Colobreathe 
 
If you/your child forget to take a dose of Colobreathe then you/your child should take your missed 
dose as soon as you/your child remember. You/your child must not take 2 doses within 12 hours. 
Carry on from there as instructed. 
 
If you/your child stop using Colobreathe 
 
Do not stop your treatment early unless your doctor says you can. Your doctor will decide how long 
you/your child’s treatment should last.   
 
If you/your child have any further questions on the use of this medicine, ask your doctor. 
 
 
4. Possible side effects 
 
Like all medicines this medicine can cause side effects, although not everyone gets them.   
 
Allergic reactions 
An allergic reaction with Colobreathe is possible (typically serious allergic reactions may cause 
rashes, swelling of the face, tongue and neck, inability to breathe due to narrowing of the airways and 
loss of consciousness).  If you/your child experience signs of an allergic reaction you should seek 
urgent medical attention.   
 
Other possible side effects 
 
You/your child may get an unpleasant taste in your mouth after inhaling Colobreathe.  
 
Very common: may affect more than 1 in 10 people 

• Difficulty in breathing 
• Cough, throat irritation  
• Hoarse or weak, or even  loss of the voice 
• Unpleasant taste 

 
Common: may affect up to 1 in 10 people 



27 

• Headache 
• Ringing or buzzing noises in the ear, problems with balance  
• Coughing up blood, wheezing, chest discomfort,  asthma, productive cough (a cough 

which brings up mucus), infection of the lungs, lung crackles (your doctor would hear this 
when listening to your lungs using a stethoscope) 

• Vomiting, nausea 
• Changes in how your lungs function (found by testing) 
• Joint pains 
• Lack of energy, tiredness 
• Raised temperature 

 
Uncommon: may affect up to 1 in 100 people 

• Allergic (hypersensitivity) reactions, the signs may include rash and itching 
• Weight fluctuations, decreased appetite  
• Anxiety 
• Fits 
• Sleepiness 
• Blockage in the ears 
• Chest pain 
• Shortness of breath 
• Nose bleeds, catarrh (mucus in your nose, which may make you feel blocked up), 

coughing up thick green mucus, pain in the throat and sinuses 
• Unusual noises in the chest (your doctor would hear this when listening to your lungs with 

a stethoscope) 
• Diarrhoea, wind 
• Excessive production of saliva 
• Toothache 
• Protein in the urine (found by testing) 
• Thirst 

 
The above side effects have been seen in people of all ages with similar frequency. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
  
 
5. How to store Colobreathe 
 
Keep this medicine out of the sight and reach of children.  
 
Do not use this medicine after the expiry date, which is stated on the outer carton and blister after 
EXP.  The expiry date refers to the last date of that month.     
 
Do not store Colobreathe above 25oC. 
   
Store in the original package until immediately before use in order to protect from moisture. 
 
If you/your child accidentally peel back the foil, and any capsules become exposed, please discard 
these capsules. 
 
Discard the Turbospin inhaler after the completion of a treatment pack. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


28 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.   
 
 
6. Contents of the pack and other information 
 
What Colobreathe contains 
The active substance is colistimethate sodium. Each capsule contains 1,662,500 IU (approximately 
equivalent to 125 mg) of colistimethate sodium. 
 
The other ingredients are: 
Capsule Shell 
Gelatin 
polyethylene glycol 
sodium lauryl sulfate 
purified water 
 
What Colobreathe looks like and contents of the pack 
Colobreathe inhalation powder, hard capsule (inhalation powder) is supplied as small, hard, 
transparent gelatin capsules containing a fine white powder.  
 
The Turbospin is an inspiratory flow driven dry powder inhaler made of polypropylene and stainless 
steel. 
 
The capsules are packed in blister packs supplied in cartons containing: 
 

• 56 hard capsules and one Turbospin powder inhaler device sufficient for 4 weeks use. 
• 8 hard capsules and one Turbospin inhaler device sufficient for 4 days use. 
 

Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Teva B.V. 
Swensweg 5 
2031 GA Haarlem 
The Netherlands. 
 
 
Manufacturer 
Penn Pharmaceutical Services Limited 
Tafarnaubach Industrial Estate 
Tredegar 
Gwent 
NP22 3AA 
United Kingdom 
 
Teva Pharmaceuticals Europe BV 
Swensweg 5 
2031 GA Haarlem 
The Netherlands 
 



29 

Millmount Healthcare Limited 
Block 7, City North Business Campus 
Stamullen 
Co Meath 
K32 YD60 
Ireland



30 
 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Teva Pharma Belgium N.V./S.A. /AG  
Tel/Tél: +32 3 820 73 73 
 

Lietuva 
UAB “Sicor Biotech” 
Tel: +370 5 266 02 03 
 

България 
Актавис ЕАД 
Teл: +359 2 489 95 82 
 

Luxembourg/Luxemburg 
Teva Pharma Belgium S.A. /AG  
Tel/Tél: +32 3 820 73 73 
 

Česká republika 
Teva Pharmaceuticals CR, s.r.o. 
Tel: +420 251 007 111 
 

Magyarország 
Teva Gyógyszergyár Zrt. 
Tel: +36 1 288 64 00 

Danmark 
Teva Denmark A/S 
Tlf: +45 44 98 55 11 
 

Malta 
Actavis Ltd.  
Tel: +35621693533 
 

Deutschland 
TEVA GmbH  
Tel: +49 731 402 08  
 

Nederland 
Teva Nederland B.V. 
Tel: +31 800 0228 400 
 

Eesti 
UAB "Sicor Biotech" Eesti filiaal 
Tel: +372 661 0801 
 

Norge 
Teva Norway AS 
Tlf: +47 66 77 55 90 

Ελλάδα 
Specifar ABEE 
Τηλ: +30 210 5401500 
 

Österreich 
ratiopharm Arzneimittel Vertriebs-GmbH   
Tel: +43 1 97 007 
 

España 
Teva Pharma, S.L.U. 
Tél: +34 91 387 32 80 

Polska 
Teva Pharmaceuticals Polska Sp. z o.o. 
Tel: +48 22 345 93 00 
 

France 
Teva Santé 
Tél: +33 1 55 91 78 00 
 

Portugal 
Teva Pharma – Produtos Farmacêuticos, Lda. 
Tel:+351 214 767 550 

Hrvatska 
Pliva Hrvatska d.o.o 
Tel: + 385 1 37 20 000 
 

România 
Teva Pharmaceuticals S.R.L. 
Tel: +4021 230 65 24 

Ireland 
Teva Pharmaceuticals Ireland 
Tel: +353 51 321 740 
 

Slovenija 
Pliva Ljubljana d.o.o. 
Tel: +386 1 58 90 390 

Ísland 
Actavis Group PTC ehf. 
Sími: +354 550 3300 
 

Slovenská republika 
TEVA Pharmaceuticals Slovakia s.r.o 
Tel: +421 2 57 26 79 11 
 

Italia 
Teva Italia S.r.l 
Tel:. +39 02 89 17 98 1 

Suomi/Finland 
Teva Finland 
Puh/Tel: +358 20 180 5900 
 

  

tel:+351


31 

Κύπρος 
Specifar ABEE 
Τηλ: +30 210 5401500 
 

Sverige 
Teva Sweden AB 
Tel: +46 42 12 11 00 
 

Latvija 
UAB "Sicor Biotech" filiāle Latvijā 
Tel: +371 673 23 666 
 

United Kingdom 
Teva UK Limited 
Tel:  +44 1977 628500 
 

 
 
This leaflet was last revised in  
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.  There are also links to other websites about rare diseases and treatments. 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D.  CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET