This information is intended for use by health professionals

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.

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).

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.

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

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store..

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.

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 patients

0.39 (n=153)

0.78 (n=171)

-0.29

-2.21, 1.71

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 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:

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.

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

24/03/2017

Detailed information on this medicinal product is available on the website of the European Medicines Agency http:/www.ema.europa.eu.