COLOBREATHE 1662500UI capsules with inhalation powder medication leaflet

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

Each capsule contains 1,662,500 IU, which is approximately equal to 125 mg of colistimethatesodium.

Inhalation powder, hard capsule (inhalation powder)

Hard transparent PEG-gelatin capsules containing a fine white powder.

Colobreathe is indicated for the management of chronic pulmonary infections due to Pseudomonasaeruginosa 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 activesubstances.

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 becontinued for as long as the physician considers that the patient is obtaining clinical benefit.

No dose adjustment is considered to be necessary (see section 5.2).

No dose adjustment is considered to be necessary (see section 5.2).

The safety and efficacy of Colobreathe in children under 6 years of age have not been established. No dataare available.

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 theinhaler by a physician or other health professional, with the first dose being given under medicalsupervision.

If other treatments are being taken, they should be taken in the following order:

Inhaled bronchodilators

Chest physiotherapy

Other inhaled medicinal products

Colobreathe

Hypersensitivity to the active substance, colistin sulphate or polymyxin B.

Bronchospasm and coughing

Bronchospasm or coughing may occur on inhalation. These reactions usually disappear orsignificantly 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 orcoughing remain problematic, withdrawal of treatment should be considered.

Haemoptysis

Haemoptysis is a complication in cystic fibrosis and is more frequent in adults. The useof colistimethate sodium in patients with clinically significant haemoptysis should be undertaken orcontinued only if the benefits of treatment are considered to outweigh the risks of inducing furtherhaemorrhage.

Acute respiratory exacerbation

If acute respiratory exacerbations develop additional intravenous or oral antibacterial agent therapy shouldbe considered.

Oral fungal super-infection

After each inhalation of Colobreathe, the mouth should be rinsed with water. The rinse should not beswallowed. Rinsing may reduce the risk of developing oral fungal super-infection during treatmentand may also reduce the unpleasant taste associated with colistimethate sodium.

Nephrotoxicity/neurotoxicity

There is very low transpulmonary absorption of colistimethate after inhalation of Colobreathe (seesection 5.2). Care should still be taken in administering Colobreathe to patients who are known to havea propensity for nephrotoxic or neurotoxic events.

Caution should be taken with concomitant use of Colobreathe and parenteral or nebulisedcolistimethate sodium.

Caution should be taken with concomitant use of colistimethate sodium and potential nephrotoxic orneurotoxic medicinal products, including non-depolarising muscle relaxants (see section 4.5).

Colobreathe should be used with extreme caution in patients with myasthenia gravis because ofpotential 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).

This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to sayessentially ‘sodium-free’.

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 asthere 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 theexpression of cytochrome P450 (CYP) enzymes on treating primary cultures of fresh humanhepatocytes. Treatment with colistimethate sodium or colistin did not induce the activity of anyenzyme tested (CYP1A2, 2B6, 2C8, 2C9, 2C19 and 3A4/5).

Concomitant use of inhaled colistimethate sodium with other medicinal products that are potentiallynephrotoxic or neurotoxic, such as aminoglycosides, or neuromuscular blocking products, such ascurariform agents should be undertaken with caution.

Co-treatment with colistimethate sodium and macrolides such as azithromycin and clarithromycin, orfluoroquinolones such as norfloxacin and ciprofloxacin should be undertaken with caution in patientswith myasthenia gravis (see section 4.4).

There are no or limited amount of data from the use of inhaled colistimethate sodium in pregnantwomen. Studies in animals using parenteral administration have shown reproductive toxicity (seesection 5.3). Single dose intravenous studies in human pregnancy show that colistimethate sodiumcrosses the placenta and consequently there is potential for foetal toxicity if administered duringpregnancy.

Colistimethate sodium is not recommended during pregnancy and in women of childbearing potentialnot using contraception.

Physico-chemical data suggest excretion of colistimethate sodium in human milk. A risk to thenewborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeedingor to discontinue/abstain from colistimethate sodium therapy taking into account the benefit ofbreastfeeding for the child and the benefit of therapy for the woman.

Colistimethate sodium has no notable effects on fertility in male or female rats or mice.

Based on the safety profile of colistimethate sodium, neurotoxity may occur with the possibility ofdizziness, confusion or visual disturbances. Patients should be warned not to drive or operate machinesif this occurs.

The safety of Colobreathe has been assessed in a total of 237 subjects (225 cystic fibrosis patients and12 healthy volunteers). Of these, 187 patients aged 6 years and above were exposed to Colobreatheone capsule twice daily in a 24-week, phase 3 comparative study. There were 32 patients aged 6-12years, 41 patients aged 13-17 years and 114 patients aged 18 years and older. The most commonlyreported 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%). Inhalationmay induce coughing or bronchospasm which may be controlled by pre-treatment with inhaled beta2agonists.

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 mayalso indicate hypersensitivity and if this occurs treatment should be withdrawn.

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 (≥1/1,000to <1/100), rare ((≥1/10,000 to <1/1,000), very rare <1/10,000), not known (cannot be estimated fromthe available data). Within each frequency grouping, adverse reactions are presented in order ofdecreasing seriousness.

System Organ Class Very Common Common Uncommon

Immune system Drugdisorders hypersensitivity

Metabolism and Weight fluctuation,nutrition disorders decreased appetite

Psychiatric disorders Anxiety

Nervous system Balance disorder, Convulsions,disorders headache somnolence

Ear and labyrinth Tinnitus Ear congestiondisorders

Respiratory, thoracic Dyspnoea, Haemoptysis, Chest pain,and mediastinal cough, bronchospasm, dyspnoeadisorders dysphonia, asthma, exacerbated,throat irritation wheezing, pharyngolaryngealchest discomfort, pain,lower respiratory tract epistaxis,infection, sputum purulent,productive cough, abnormal chestcrackles lung sound,increased upperairway secretion

System Organ Class Very Common Common Uncommon

Gastrointestinal Dysgeusia Vomiting, nausea Diarrhoea,disorders toothache,salivaryhypersecretion,flatulence

Musculoskeletal and Arthralgiaconnective tissuedisorders

Renal and urinary Proteinuriadisorders

General disorders and Pyrexia, asthenia, Thirstadministration site fatigueconditions

Investigations Forced expiratoryvolume decreased

Injury, poisoning and Medication errorproceduralcomplications

In the 24-week clinical study, where Colobreathe was administered twice daily to adults and childrenaged 6-17, the adverse reactions identified in the paediatric population were similar to that for theoverall population. The most commonly reported adverse reactions as a percent of Colobreathe treatedpatients were: cough (55%), unpleasant taste (51%), throat irritation (34%), dyspnoea (10%) anddysphonia (10%).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Currently there is no experience of overdose with the use of Colobreathe. However, overdose maypossibly result in higher systemic exposure.

Overdose is unlikely by the inhaled route but has been recognised after systemic use. More commonsigns and symptoms of intravenous overdose include unsteadiness, paraesthesia and dizziness. It canalso result in neuromuscular blockade that can lead to muscular weakness, apnoea and possiblerespiratory arrest. Overdose can also cause acute renal failure characterised by decreased urine outputand increased serum concentrations of BUN and creatinine.

There is no specific antidote, therefore management should be done by supportive treatment. Measuresto increase the rate of elimination of colistimethate sodium e.g. mannitol diuresis, prolongedhaemodialysis or peritoneal dialysis may be tried, but effectiveness is unknown.

Pharmacotherapeutic group: antibacterials for systemic use, other antibacterials.

ATC Code: J01XB01

Colistimethate sodium (CMS) is a cyclic polypeptide antibacterial active substance that is derivedfrom Bacillus polymyxa var. colistinus and belongs to the polymyxin group. Polymyxins work bydamaging 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.

Resistant bacteria are characterised by modification of the phosphate groups of lipopolysaccharide,which become substituted with ethanolamine or aminoarabinose. Naturally resistant Gram-negativebacteria, such as Proteus mirabilis and Burkholderia cepacia, show complete substitution of their lipidphosphate by ethanolamine or aminoarabinose.

Cross resistance between colistimethate sodium and polymyxin B is expected. Since the mechanism ofaction of the polymyxins is different from that of other antibacterial agents, resistance to colistin andpolymyxin by the above mechanism alone would not be expected to result in resistance to other drugclasses.

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.

The Phase 3 clinical study was a randomised, open-label active comparator study comparing theefficacy of colistimethate sodium 1,662,500 IU dry powder for inhalation to tobramycin nebulisersolution for inhalation, 300 mg/5 ml, in 380 subjects with documented cystic fibrosis complicated bychronic pulmonary infection with Pseudomonas aeruginosa. The subjects were aged 6 years andabove and had an FEV1% predicted of 25-75%. All subjects were also required to have successfullycompleted 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 twicedaily, or 300 mg of tobramycin, twice daily. It should be noted that treatment was not interruptedwhen patients received concomitant parenteral antibacterial active substances.

Efficacy was measured by the change in FEV1 % predicted compared to baseline after a 24-weektreatment 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 Tobramycin Adjusted 95% CI(Mean) (Mean) Treatmentdifference

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

LOCF

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 differenceand 95% confidence interval have been back transformed from log transformed data. The ITT population excluded patients who had beentreated but demonstrated no evidence of chronic infection.

The European Medicines Agency has deferred the obligation to submit the results of studieswith Colobreathe in one or more subsets of the paediatric population in Pseudomonas aeruginosapulmonary infection/colonisation in patients with cystic fibrosis (see section 4.2 for information onpaediatric use).

Colistimethate is not significantly absorbed from the lung after inhalation of Colobreathe. Afteradministration of 1,662, 500IU twice daily for 7 days in adult, adolescent and paediatric cystic fibrosispatients mean C max values of total colistimethate of up to 455ng/ml (adult mean) were observed. Tmax fortotal colistimethate occurred between 0.5 and 1 hour post-dose. Although the population PK analysisshowed 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 0-6was 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 wasobserved 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) wereobserved 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 thenormal individual.

Protein binding is low. Polymyxins persist in the liver, kidney, brain, heart and muscle. One study incystic fibrosis patients gives the steady-state volume of distribution as 0.09 l/kg.

Colistimethate sodium is converted to the base in vivo. As 80% of a parenteral dose can be recoveredunchanged in the urine, and there is no biliary excretion, it can be assumed that the remaining drug isinactivated in the tissues. The mechanism is unknown.

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 inpatients with renal impairment is not considered necessary. The estimated mean terminal half-lives fortotal CMS and total free colistin were 3.0 and 6.4 h, respectively.

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, employingroutes assuring systemic exposure, showed no particular hazard. There were no notable effects onfertility or general reproductive performance in male or female rats or mice. In embryo-fetaldevelopment studies in mice, resorptions and reduced ossification were seen, and in rats reduced fetalweights, reduced ossification and at the high dose of 10 mg colistin base per day, reduced post-natalsurvival. An embryo-fetal study in rabbits reported no effects at intravenous doses up to 80 mg/kgcolistimethate sodium (32 mg colistin base/kg).

Components of the PEG-gelatin hard capsules:

Gelatin

Polyethylene glycol

Purified water

Sodium lauryl sulfate

Not applicable.

3 years.

Do not store above 25°C.

Store in the original package until immediately before use in order to protect from moisture.

The capsules are contained in oPA/aluminium/pvc blisters with a peelable lidding foil composed ofpolyester/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 orone Turbospin powder inhaler device and 4 blisters of 14 capsules (56 hard capsules) sufficient for 4weeks use.

Each 8 capsule pack contains one Turbospin powder inhaler device and 1 blister of 8 hard capsulessufficient for 4 days use.

Not all pack sizes may be marketed.

Capsules: no special requirements for disposal. The Turbospin device should be discarded aftercompletion 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 Turbospin1. 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 beused 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 medicine6. To pierce the capsule:

* Hold the inhaler with the mouthpiece upright, gently push the piston upwards until thevisible line is reached - you will feel resistance at this point and this will lock the capsule inplace ready for piercing. Hold that position before continuing to follow through with thepiercing.

* Now, with the capsule locked in place, continue pushing the piston as far as it will go andthen 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 releasedfrom 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 sealbetween your lips and the mouthpiece. Take care not to cover the air slits with your fingers ormouth during inhalation.

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

9. Remove the Turbospin inhaler from your mouth and hold your breath for about 10 seconds orfor 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 thisoccurs, you can loosen the capsule by gently tapping the chamber of the inhaler. Do not try toloosen the capsule by repeatedly pressing the piston. If the capsule cannot be loosened and thepowder cannot be inhaled, dispose of the broken capsule and any powder remaining in it anduse 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 thecapsule. 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 Turbospin14. When the capsule is empty, unscrew the mouthpiece, then remove and discard the emptycapsule.

As you breathe in slowly, you suck air through the body of the Turbospin inhaler into the capsulechamber. The tiny particles of medicine in the capsule are picked up by the airflow and carried downyour 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 thanonce during Step 6.

Essential Pharma Limited,

Vision Exchange Building

Triq it-Territorjals, Zone 1,

Central Business District,

Birkirkara, CBD 1070, Malta

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)

Date of first authorisation: 13/02/2012

Date of latest renewal: 26/09/2016

Detailed information on this medicinal product is available on the website of the European Medicines

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