Bronchitol

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX I 

 

   SUMMARY OF PRODUCT CHARACTERISTICS 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



 

2 

1. NAME OF THE MEDICINAL PRODUCT 

 

Bronchitol 40 mg inhalation powder, hard capsules 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each hard capsule contains 40 mg mannitol. 

 

Mean delivered dose per capsule is 32.2 mg. 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Inhalation powder, hard capsule. 

 

Clear colourless hard capsules marked with ‘PXS 40 mg’ and containing white or almost white 

powder. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Bronchitol is indicated for the treatment of cystic fibrosis (CF) in adults aged 18 years and above as 

an add-on therapy to best standard of care. 

 

4.2 Posology and method of administration 

 

Posology 

 

Initiation dose assessment 

Before commencing treatment with Bronchitol all patients should be assessed for bronchial 

hyperresponsiveness to inhaled mannitol during administration of their initiation dose (see sections 

4.4 and 5.1). 

The patient’s initiation dose of Bronchitol must be used under the supervision and monitoring of an 

experienced physician or another health care professional appropriately trained and equipped to 

perform spirometry, monitor oxygen saturation (SpO2), and manage acute bronchospasm (see sections 

4.4 and 4.8) including appropriate use of resuscitation equipment. 

 

 

The patient should be pre-medicated with a bronchodilator 5-15 minutes prior to the initiation dose 

but after the baseline FEV1 and SpO2 (Oxygen saturation in the blood) measurement. All FEV1 

measurements and SpO2 monitoring should be performed 60 seconds after dose inhalation. 

 

Training the patient to practice correct inhaler technique during the initiation dose assessment is 

important. 

 

The initiation dose assessment must be performed according to the following steps: 

 

 Step 1: Patients baseline FEV1 and SpO2 is measured prior to the initiation dose 

 Step 2: Patient inhales 40 mg (1x40 mg capsules) and SpO2 is monitored 

 Step 3: Patient inhales 80 mg (2x40 mg capsules) and SpO2 is monitored 

 Step 4: Patient inhales 120 mg (3x40 mg capsules), FEV1 is measured and SpO2 is monitored 



 

3 

 Step 5: Patient inhales 160 mg (4x40 mg capsules), FEV1 is measured and SpO2 is monitored 

 Step 6: Patients FEV1 is measured 15 minutes post initiation dose. 

 

Patients with asthma may experience reversible temporary mild bronchospasm after passing the 

initiation dose assessment and therefore all patients should be monitored until their FEV1 has returned 

to baseline levels. 

 

Therapeutic dose regimen 

The therapeutic dose regimen should not be prescribed until the initiation dose assessment has been 

performed. The patient must complete and pass the initiation dose assessment before starting 

treatment with Bronchitol. 

 

 

A bronchodilator must be administered 5-15 minutes before each dose of Bronchitol. 

 

The recommended dose of Bronchitol is 400 mg twice a day. This requires the inhalation of the 

contents of ten capsules via the inhaler device twice a day. 

The doses should be taken morning and night with the evening dose taken 2-3 hours before bedtime. 

 

For patients receiving several respiratory therapies, the recommended order is: 

 

1. Bronchodilator   

2. Bronchitol 

3. Physiotherapy/exercise 

4. Dornase alfa (if applicable) 

5. Inhaled antibiotics (if applicable) 

 

 

Special populations 

 

Elderly patients (≥65 years) 

There are insufficient data in this population to support a recommendation for or against dose 

adjustment. 

 

Renal or hepatic impairment 

Bronchitol has not formally been studied in patients with impaired renal and hepatic function. 

Available data from studies DPM-CF-301 and 302 suggest that no dose adjustments are required for 

these patient populations. 

 

Paediatric population  

The safety and efficacy of Bronchitol in children and adolescents aged 6 to 18 years has not yet been 

established. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation 

on a posology can be made. 

 

The safety and efficacy of Bronchitol in children aged less than 6 years has not been established. No 

data are available. 

 

Method of administration 

Bronchitol is for inhalation use, using the inhaler provided in the pack. It must not be administered by 

any other route or using any other inhaler. The capsules must not be swallowed. 

 

Each of the capsules is loaded into the device separately. The contents of the capsules are inhaled via 

the inhaler device with one or two breaths. After inhalation, each empty capsule is discarded before 

inserting the next capsule into the inhaler device with as little delay as possible between capsules. 

 



 

4 

The inhaler device is to be replaced after one week of use. If the inhaler does require cleaning, it must 

be ensured that the device is empty, then it should be washed in warm water and before re-use,the 

inhaler should be allowed to thoroughly air dry. 

 

Detailed instructions on how to use the inhaler can be found in the patient information leaflet. Patients 

should be advised to carefully read them. 

 

4.3 Contraindications 

 

Hypersensitivity to the active substance. 

 

Bronchial hyperresponsiveness to inhaled mannitol (see section 4.4).  

 

4.4 Special warnings and precautions for use 

 

Hyperresponsiveness to mannitol 

Patients must be monitored for bronchial hyperresponsiveness to inhaled mannitol during their 

initiation dose assessment before commencing the therapeutic dose regimen of Bronchitol.If the 

patient is unable to perform spirometry or complete the initiation dose assessment, they must not be 

prescribed Bronchitol. Hyperresponsive patients should not be prescribed the therapeutic dose 

regimen of Bronchitol (see section 4.3).The usual precautions regarding bronchial 

hyperresponsiveness monitoring apply (see section 4.2).  

 

A patient is defined as hyperresponsive to inhaled mannitol and must not be prescribed the therapeutic 

dose regimen if they experience any of the following during the initiation dose assessment: 

 

- ≥10% fall from baseline in SpO2 at any point of the assessment; 

- FEV1 fall from baseline is ≥20% at 240 mg cumulative dose; 

- FEV1 has fallen 20-<50% (from baseline) at the end of the assessment and does not return to 

<20% within 15 minutes; 

- FEV1 has fallen ≥50% (from baseline) at the end of the assessment. 

 

If a therapy induced hyperresponsive reaction is suspected, Bronchitol should be discontinued. 

All patients should be monitored until their FEV1 has returned to baseline levels. 

 

Bronchospasm 

Bronchospasm can occur with inhalation of medicinal product and has been reported with Bronchitol 

in clinical studies, even in patients who were not hyperresponsive to the initiation dose of inhaled 

mannitol (see section 4.8). Bronchospasm should be treated with a bronchodilator or as medically 

appropriate. 

 

If there is evidence of therapy induced bronchospasm, the physician should carefully evaluate whether 

the benefits of continued use of Bronchitol outweigh the risks to the patient. 

 

All patients should be formally reviewed after approximately six weeks of Bronchitol treatment to 

assess for signs and symptoms suggestive of active substance induced bronchospasm. The initiation 

dose assessment described in section 4.2 should be repeated if uncertainty exists. 

 

Asthma 

The safety/efficacy of Bronchitol in patients with asthma has not been formally studied. Patients with 

asthma must be carefully monitored for worsening signs and symptoms of asthma after the initiation 

dose of Bronchitol. 

 

Patients must be advised to report worsening signs and symptoms of asthma during therapeutic use 



 

5 

to their physician. If there is evidence of therapy induced bronchospasm, the physician should 

carefully evaluate whether the benefits of continued use of Bronchitol outweigh the risks to the 

patient. Bronchospasm should be treated with a bronchodilator or as medically appropriate. 

 

Haemoptysis 

Haemoptysis has been commonly reported with Bronchitol in clinical studies. Bronchitol has not been 
studied in patients with a history of significant episodes of haemoptysis (>60 ml) in the previous three 

months. As a consequence, these patients should be carefully monitored, and Bronchitol should be 

withheld in the event of massive haemoptysis. A massive/serious haemoptysis is considered to be: 

 acute bleeding ≥240 ml in a 24-hour period 

 recurrent bleeding ≥100 ml/day over several days  

The reinstitution or withholding of Bronchitol following smaller episodes of haemoptysis should be 

based on clinical judgement. 

 

Cough 

Cough was  commonly reported with use of Bronchitol in clinical studies (see section 4.8). Patients 

should be trained to practice correct inhaler technique during treatment and advised to report 

persistent cough with the use of Bronchitol to their physician. 

  

Impaired lung function 

Safety and efficacy have not been demonstrated in patients with a FEV1 of less than 30% of predicted 

(see section 5.1). The use of Bronchitol is not recommended in these patients. 

 

Non-CF Bronchiectasis 

Efficacy and safety have not been established in non-CF bronchiectasis patients. Therefore, treatment 

with Bronchitol is not recommended. 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

No formal interaction studies have been conducted. 

However, Bronchitol has been used in clinical studies in conjunction with standard cystic fibrosis 

therapies such as mucolytics, antibiotics (including tobramycin and colistimethate sodium), 

bronchodilators, pancreatic enzymes, vitamins, inhaled and systemic corticosteroids, and analgesics. 

 

There are no data on concomitant use of hypertonic saline with Bronchitol as it was excluded from the 

Phase 3 studies. 

 

4.6 Fertility, pregnancy and lactation 

 

Pregnancy 

There are limited data from the use of mannitol in pregnant women. Animal studies do not indicate 

direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As the effects 

of a possible hyperresponsive reaction on the mother and/or foetus are unknown, caution should be 

exercised when prescribing Bronchitol to pregnant women. As a precautionary measure, it is 

preferable to avoid the use of Bronchitol during pregnancy. 

 

Breastfeeding 

It is unknown whether mannitol is excreted in human milk. The excretion of mannitol in milk has not 

been studied in animals. A risk to the newborns/infants cannot be excluded. A decision must be made 

whether to discontinue breast feeding or to discontinue Bronchitol therapy taking into account the 

benefit of breast feeding for the child and the benefit of Bronchitol therapy for the woman. 

 

Fertility 

For mannitol no clinical data on fertility is available. Animal reproduction studies have not been 

carried out with inhaled mannitol. However, studies with orally administered mannitol indicate no 

fertility effects (see section 5.3). 



 

6 

 

4.7 Effects on ability to drive and use machines 

 

Bronchitol has no or negligible influence on the ability to drive and use machines. 

 

4.8 Undesirable effects 

 

Summary of the safety profile 

  The safety profile of Bronchitol has been evaluated in clinical studies involving more than 1200 

patients. (See Table 1). 

 

Initiation dose assessment 

The most commonly observed adverse reaction associated with the use of Bronchitol during the 

initiation dose assessment is cough (2.9% of patients), (see section 4.4).  

 

The most important adverse reaction associated with the use of Bronchitol during the initiation dose 

assessment is bronchospasm (see section 4.4).  

 

Therapeutic dose regimen 

The most commonly observed adverse reaction associated with the use of Bronchitol is cough (see 

section 4.4). This was observed in 8.3% of patients compared to 4.0% of patients in the control arm. 

Cough which led to cessation of treatment was also commonly experienced and was observed in 4.0% 

of patients in the Bronchitol treatment arm. 

 

The most important adverse reaction associated with the use of Bronchitol is haemoptysis. The 

proportion of patients who experienced haemoptysis as an adverse reaction was 7.3%, 3.3% and 3.4% 

in the Bronchitol arms for studies 301, 302 and 303 respectively vs. 3.4%, 0% and 5.6% in the control 

arms. The proportion of patients who experienced haemoptysis  including haemoptysis reported 

during exacerbation was 7.0% in the mannitol arm and 7.7% in the control arm (see section 4.4).  

 

Tabulated list of adverse reactions 

The safety profile of Bronchitol is based on the safety data from Phase III clinical studies (including 

data from the initiation dose assessment). 

 

 

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 (≥1/100,000 to <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. 

 

 

 



 

7 

 

Table 1: Frequency of adverse reactions with Bronchitol in the phase 3 studies (initiation dose 

assessment and/or treatment phase)  

System organ class Frequency Adverse Reaction 

Infections and infestations Uncommon Bacterial disease carrier, Bronchitis, 

Bronchopneumonia, Lung infection, Oral 

candidiasis, Pharyngitis, Staphylococcal 

infection, Upper respiratory tract infection 

Metabolism and nutrition 

disorders 

Uncommon Decreased appetite, CF related diabetes, 

Dehydration 

Psychiatric disorders Uncommon Initial insomnia, Morbid thoughts 

Nervous system disorders Common Headache 

Uncommon Dizziness 

Ear and labyrinth disorders Uncommon Ear pain 

Respiratory, thoracic and 

mediastinal disorders 

 

Common Cough, Haemoptysis,  

Oropharyngeal pain, Wheezing 

Uncommon Productive cough, Throat irritation,  

Asthma, Bronchospasm, Forced expiratory 

volume decreased, Rhinorrhoea, Dyspnoea, 

Dysphonia, Hyperventilation, Obstructive 

airways disorder, Respiratory tract congestion, 

Sputum discoloured, Hypoxia 

Gastrointestinal disorders Common Post-tussive vomiting, Vomiting 

Uncommon Nausea, Diarrhoea, Eructation, 

Flatulence, Gastrooesophageal reflux disease, 

Glossodynia, Retching, Stomatitis, Abdominal 

pain upper, Aphthous Stomatitis, Odynophagia  

  

Skin and subcutaneous tissue 

disorders 

Uncommon Acne, Cold sweat, Pruritus, Rash, Rash pruritic 

Musculoskeletal and 

connective tissue disorders 

Uncommon Musculoskeletal chest pain, Arthralgia, Back 

pain, Joint stiffness, Musculoskeletal pain 

Renal and urinary disorders Uncommon Urinary incontinence 

General disorders and 

administration site 

conditions 

Common Condition aggravated, Chest discomfort 

Uncommon Pyrexia, Fatigue, Influenza like illness, Hernia 

pain, Malaise, Chest pain 

Investigations Uncommon Blood alkaline phosphatase increased, Bacteria or 

fungus sputum test positive 
Adverse reactions that occurred only with the initiation dose assessment (MTT) are dehydration, forced 

expiratory volume decreased, hypoxia, diarrhoea, abdominal pain upper, aphthous stomatitis, odynophagia, chest 

pain and blood alkaline phosphatase increased. 

 

Description of selected adverse reactions 

Twenty seven (7.1%) out of 378 patients who undertook the mannitol tolerance test (MTT)  in study 

301, 18 (5.3%) out of 341 patientsin study 302 and 25 (5.1%) out of 486 patients in Study 303  had  a 

positive  (MTT). In study 301, overall the most frequently reported adverse reactions during the MTT 

were cough in 20 (5.3%) subjects, wheezing/bronchospasm in seven (1.9%) subjects and chest 

discomfort in six (1.6%) subjects. In study 302 the most frequent adverse reaction reported during the 

MTT was cough in seven patients (2.1%),and in study 303 the most frequently reported adverse 

reaction from the MTT was also cough in eight patients (1.6%). 

 

Paediatric population (6 to 17 years of age) 

Frequency, type and severity of adverse reactions in children are similar to those observed in adults. 

 



 

8 

Initiation dose (6 to 17 years of age) 

The most commonly observed adverse reaction associated with the use of Bronchitol during the 

initiation dose assessment with the paediatric population is cough (4.8% of patients). 

 

The most important adverse reaction associated with the use of Bronchitol during the initiation dose 

assessment with the paediatric population is bronchospasm. 

 

Therapeutic dose regimen(6 to 17 years of age) 

The most commonly observed adverse reaction associated with the use of Bronchitol is cough. This 

was observed in 7.8% of patients compared to 3.8% of patients in the control arm. The most important 

adverse reaction associated with the use of Bronchitol is haemoptysis.  

 

 

 

Table 2: Frequency of adverse reactions with Bronchitol in the phase 3 studies (initiation dose 

assessment and/or treatment phase) – paediatric population (6 to 17 years of age) 

System organ class Frequency Adverse Reaction 

Psychiatric disorders Uncommon Initial insomnia 

Nervous system Common Headache 

 Uncommon Dizziness 

Ear and labyrinth disorders Uncommon Ear Pain 

Respiratory, thoracic and 

mediastinal disorders 

Common Cough, Condition aggravated, Haemoptysis,   

Oropharyngeal pain, Chest discomfort, Wheezing, 

Asthma, Productive cough 

 Uncommon Bronchitis, Bronchopneumonia, Dysphonia, 

Hyperventilation, Sputum Discoloured, Throat 

irritation, Pharyngitis, Upper respiratory tract 

infection, Bronchospasm, Dyspnoea, Chest pain 

Gastrointestinal disorders Common Vomiting, Post-tussive vomiting 

 Uncommon Nausea, Odynophagia, Retching 

Skin and subcutaneous tissue 

disorders 

Uncommon Pruritus, Pruritic rash 

Musculoskeletal and 

connective tissue disorders 

Uncommon Musculoskeletal chest pain 

Renal and urinary disorders Uncommon Urinary incontinence 

General disorders and 

administration site 

conditions 

Uncommon Pyrexia 

Investigations Common Bacteria sputum identified 
Adverse reactions that occurred only with initiation dose assessment (MTT) are bronchospasm, chest pain, 

odynophagia and retching  

 

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 

 

Susceptible persons may suffer bronchoconstriction in the event of an inhaled overdose. If excessive 

coughing and bronchoconstriction occurs, a beta2 agonist should be given, and oxygen if necessary. 

 

 

5. PHARMACOLOGICAL PROPERTIES 

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


 

9 

 

5.1 Pharmacodynamic properties 

 

Pharmacotherapeutic group: Cough and cold preparations, Mucolytic. ATC code: R05CB16 

 

Mechanism of action 

Bronchitol is an inhaled hyperosmotic medicinal product. While the exact mechanism of action is 

unknown, inhaled mannitol may change the viscoelastic properties of mucus, increase the hydration of 

the periciliary fluid layer and contribute to increased mucus clearance of the retained secretions 

through mucociliary activity. Productive cough can contribute to sputum clearance.  

   

Pharmacodynamic effects 

In the ITT population of an open label dose response study, DPM-CF-202, the mean (SD) percent 

change in FEV1 for the 400 mg dose was 8.75 (SD: 12.4) and -1.569 (SD: 9.0) for 40 mg dose (p < 

0.0001).  

  

Clinical efficacy and safety 

Three Phase 3, 26-week double blind, randomised, parallel arm, controlled, intervention studies 

(DPM-CF-301,DPM-CF-302 and DPM-CF-303) have been performed in which 324 (DPM-CF-301) 

and 318 (DPM-CF-302) patients aged 6 years and above were randomised in a 3:2 ratio to inhaled 

mannitol 400 mg twice daily or to control (inhaled mannitol 50 mg twice daily). In the third study 

(DPM-CF-303) 423 adult patients were randomised in a 1:1 ratio to inhaled mannitol 400 mg twice 

daily or to control. Twenty seven (7.1%) out of 378 patients who undertook the mannitol tolerance 

test (MTT) in study 301, 18 (5.3) out of 341 patients in study 302 and 25 out of 486 patients (5.1%) in 

study 303 had  a positive  MTT defined as either 1) a fall in FEV1 >20% from baseline at midpoint 

(step 4) or 2) fall from baseline > 20 % at end of test that did not recover to < 20% within 15 minutes 

or 3) who had a fall in FEV1 > 50% from baseline at end of test (step 6) or 4) who had a fall in Sp02 

to < 89% during the procedure. An additional 2.8% (n=34) of patients from the three studies had 

incomplete MTTs and were not randomised. 

 

Mean (SD) baseline FEV1 percent predicted in study DPM-CF-301 (safety population, N= 295) was 

62.4 (SD:16.45) and 61.4 (SD:16.13) in the mannitol and control groups, respectively. These figures 

for study DPM-CF-302 (N=305) are as follows: 65.24 (SD:13.90) and 64.35 (SD:15.29). In study 

DPM-CF-303 (N=423) the baseline FEV1 percent predicted was 63.17 (SD: 15.15) and 62.98 (SD: 

13.65).In study DPM-CF-301 64.4 % of the patient population were adults while in study DPM-CF-

302 this figure was 49.5%. Study DPM-CF-303 was all adult patients. Fifty five % of patients were 

receiving rhDNase in study DPM-CF-301 while in study DPM-CF-302 this number was 75% and for 

DPM-CF-303 this was 67.6%. The percentage of patients receiving inhaled antibiotics was 55% in 

study DPM-CF-301, 56% in study DPM-CF-302 and 52% in Study DPM-CF-303. Concomitant 

administration with hypertonic saline was not permitted in these trials.  

 

The primary pre-specified endpoint i.e. the change from baseline in FEV1 (ml) in the modified ITT 

(mITT) population (n=269, 297 and 423 in studies DPM-CF-301,DPM-CF-302 and DPM-CF-303, 

respectively) compared to control over the 26 weeks period is provided in Table 3 alongside FEV1 

presented as absolute and relative change % predicted. 

 

Table 3 – Change in FEV1 from baseline over 26 weeks in the mITT and adult populations 

 

 Effect size estimate 

 DPM-CF-301 DPM-CF-302 DPM-CF-303 

 
FEV1  

(95% CI) 
p value  

FEV1  

(95% CI) 
p value 

FEV1  

(95% CI) 
p value 

 Overall Population  



 

10 

 N=269 N=297 N=423 

Absolute mL  
94.5 

(46.2, 142.7)  
<0.001  

54.1 

(-1.97, 110.3)  
0.059 

54  

(8, 100) 

0.020 

Absolute % 

predicted  

2.4 

(0.9, 3.9)  
0.001  

1.9 

(-0.02, 3.8)  
0.052 

1.2  

(0.07, 2.4) 

0.037 

Relative % 

predicted 

3.5 

(1.0, 6.1)  
0.007  

3.6 

(0.3, 6.9)  
0.033  

2.3  

(0.3, 4.2) 

0.024 

 Adult Population  

 N=171 N=144 N=423 

Absolute mL  
108.5 

(47.6, 169.4)  
<0.001  

85.9 

(4.6, 167.3)  
0.038 

54  

(8, 100) 

0.020 

Absolute % 

predicted  

2.7 

(0.9, 4.5)  
0.004  

2.3 

(-0.4, 5.1)  
0.095 

1.2  

(0.07, 2.4) 

0.037 

Relative % 

predicted 

4.3  

(1.1, 7.5)  
0.008  

5.0  

(0.2, 9.8)  
0.040  

2.3 

(0.3, 4.2) 

0.024 

Note: There were some differences in analysis methods across the 3 studies.  In DPM-CF-303 imputation of 

missing data was performed using a baseline observation carried forward (BOCF) approach whereas no 

imputation was performed in DPM-CF-301 or DPM-CF-302. 

 

The treatment effect of Bronchitol on FEV1 was less evident in the subgroup of patients who were 

receiving concomitant rhDNase.In rhDNase users in study 301 the relative change in FEV1 % 

predicted from baseline across 26 weeks of treatment was  2.83 (95% CI -0.62, 6.27). For non-users 

the relative change was 4.30 (95% CI 0.53, 8.07). In study 302 the relative change (95% CI) for 

rhDNase users and non-users was 3.21 (-0.61, 7.03) and 4.73 (-1.93, 11.40), respectively. In study 303 

the relative change (95% CI) for rhDNase users and non-users was 1.30 (-0.91, 3.51) and 4.45 (0.52, 

8.38), respectively. 

 

Study 303 did not show a superior treatment effect of Bronchitol on FEV1 for female patients, in 

whom the underlying cystic fibrosis disease course may be worse than males for reasons that are not 

fully understood. In female patients, the adjusted mean change in FEV1 was 27ml for Bronchitol and 

44ml for the control arm, suggesting potentially inferior benefit on lung function with Bronchitol 

compared to the control, although the difference was not statistically significant (p=0.480). 

 

The number of subjects with at least one protocol defined pulmonary exacerbation (PDPE, defined by 

the presence of at least 4 symptoms and signs plus the use of intravenous antibiotics) was 18.1% in 

the mannitol arm and 28% in the control arm in study 301 (ITT population).  In study 302 15.2% 

subjects in the mannitol arm and 19% in the control had a PDPE. In study 303 13.4% subjects in the 

mannitol arm and 13.6% in the control had a PDPE.  

 

The estimated effect of treatment (mean change and 95% CI from baseline over 26 weeks, mITT 

population) on FVC was 108.78 ml (95% CI: 49.21, 168.35) in study 301 and 71.4 ml (95% CI: 10.57, 

132.13) in study 302 and 40 ml (95% CI: -12, 92) in study 303. 

 

Paediatric population 

The safety and efficacy of Bronchitol in children and adolescents aged less than 18 years has not been 

established (see section 4.2). 

 



 

11 

In studies DPM-CF-301 and 302 relative % predicted FEV1 compared to control in children (6-11 

years) was improved by 0.44% (95% CI -5.90, 6.77, N=43) and 6.1% (95% CI -1.28, 13.54, N=59) 

over 26 weeks (p=0.892 and 0.104) respectively.  

 

In adolescents (12-17 years) relative change in % predicted FEV1 compared to control improved by 

3.31% (95% CI -2.29, 8.90, N=55) and 0.42% (95% CI -5.45, 6.29, N=94) over 26 weeks (p=0.245 

and 0.888) respectively.  

 

5.2 Pharmacokinetic properties 

 

Absorption 

In a study of 18 healthy male adult volunteers, the absolute bioavailability of mannitol powder for 

inhalation by comparison to mannitol administered intravenously was 0.59% ± 0.15. 

The rate and extent of absorption of mannitol after inhaled administration was very similar to that 

observed after oral administration. The Tmax after inhaled administration was 1.5 ± 0.5 hours. 

 

In a study of 9 cystic fibrosis patients (6 adults, 3 adolescents), using 400 mg inhaled mannitol as a 

single dose (Day 1) then twice a day for 7 days (Days 2 - 7), pharmacokinetic parameters were similar 

for adults and adolescents, except for a longer average apparent terminal half life for adolescents 

(Day 1 = 7.29 hours, Day 7 = 6.52 hours) compared with adults (Day 1 = 6.10 hours, 

Day 7 = 5.42 hours). Overall, the comparison of AUCs between Day 1 and Day 7 showed a time 

independence of pharmacokinetics, indicating linearity at the dose level administered in this study. 

 

Biotransformation 

A small percentage of systemically absorbed mannitol undergoes hepatic metabolism to glycogen and 

carbon dioxide. Studies in rats, mice and humans have demonstrated that mannitol has no toxic 

metabolites. The metabolic pathway of inhaled mannitol was not examined in pharmacokinetic 

studies. 

 

Distribution 

Lung deposition studies have demonstrated a 24.7% deposition of inhaled mannitol confirming its 

distribution to the target organ. Nonclinical toxicology studies indicate that mannitol inhaled into the 

lungs is absorbed into the bloodstream, with the maximum serum concentration being achieved 

occurring at 1 hour. There is no evidence that mannitol is accumulated in the body, therefore 

distribution of inhaled mannitol was not examined in PK studies. 

 

Elimination 

The cumulative amount of mannitol filtered into the urine over the 24 hour collection period was 

similar for inhaled (55%) and oral (54%) mannitol. When administered intravenously, mannitol is 

eliminated largely unchanged by glomerular filtration and 87% of the dose is excreted in the urine 

within 24 hours. The mean terminal half-life in adults was approximately 4 to 5 hours from serum and 

approximately 3.66 hours from urine. 

 

Paediatric population 

The safety and efficacy of Bronchitol in children and adolescents aged 6 to 18 years has not yet been 

established. 

 

The limited data available in adolescents aged 12 to 17 years indicate the pharmacokinetic parameters 

of inhaled mannitol are similar to the adult population.  

 

There are no data available for children under 12 years of age. 

 

5.3 Preclinical safety data 

 

In male rats after 13 weeks of inhaled mannitol dosing, elevated circulating lymphocyte numbers and 

mandibular lymph node plasmacytosis was observed at doses greater than 9.3 fold the maximal dose. 



 

12 

The elevated lymphocyte count was within historical control values, did not progress and was 

essentially resolved by the end of the in life phase of the study and following withdrawal of treatment. 

This effect was not noted in any other species and did not result in clinical signs. 

 

In dogs an increased occurrence of coughing was observed both during and immediately post dose for 

low and high dose inhaled mannitol administration. No treatment-related adverse effect occurred 

greater than 13 fold the maximal therapeutic dose. 

 

No mutagenic or genotoxic effect has been revealed when mannitol was assayed in a standard battery 

of genotoxicity tests. 

 

Mannitol was shown not to be an irritant in an isolated bovine eye assay or when introduced into 

rabbit eyes. 

 

No evidence of carcinogenicity was observed when dietary mannitol (≤5%) was administered to mice 

and rats for 2 years. Carcinogenicity studies have not been carried out with inhaled mannitol. 

 

Reproduction and developmental toxicity studies have not been carried out with inhaled mannitol. 

However, studies conducted with mannitol administered via other routes indicated no effect on foetal 

survival in mice, rats and hamsters and on embryo and foetal development in rats and rabbits. 

 

Animal reproduction studies have not been carried out with inhaled mannitol. However, studies 

conducted with orally administered mannitol indicated no teratogenic effects in mice or rats, at doses 

of up to 1.6 g/kg, or in hamsters at 1.2 g/kg. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

None. 

 

6.2 Incompatibilities 

 

Not applicable. 

 

6.3 Shelf life 

 

3 years 

 

Discard the inhaler and its cap 1 week after first use. 

 

6.4 Special precautions for storage 

 

Store below 30°C. 

 

Store in the original blister in order to protect from moisture. The capsules must only be removed 

immediately before use. 

 

6.5 Nature and contents of container 

 

Aluminium/polyamide/PVC/aluminium blisters. Cartons containing 10 or 280 capsules for initial dose 

and treatment use respectively. 

 

The initiation dose carton contains 1 blister (of 10 capsules) and one inhaler device. 

 



 

13 

The 2-week carton contains 28 blisters (of 10 capsules each) and two inhaler devices. 

 

6.6 Special precautions for disposal 

 

No special requirements. 

 

Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Pharmaxis Europe Limited 

108 Q House, 

Furze Road, 

Sandyford, 

Dublin 18, 

D18AY29 

Ireland 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/12/760/001-002 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 13 April 2012 

Date of latest renewal: 11 January 2017 

 

 

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/. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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


 

14 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER 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 

 



 

15 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturers responsible for batch release 

 

Mawdsleys Clinical Services, 

Unit 22, Quest Park,  

Wheatley Hall Road, 

Doncaster, DN2 4LT,  

United Kingdom 

 

or 

 

Arvato distribution GmbH 

Gottlieb-Daimler Straβe 1 

33428 Harsewinkel 

North Rhine-Westphalia 

Germany 

 

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 restricted medical prescription (see Annex I: Summary of Product 

Characteristics, section 4.2). 

  

 

C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  

 

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 profile or as the result of 

an important (pharmacovigilance or risk minimisation) milestone being reached. 

 

 Additional risk minimisation measures  
 

Prior to launch of the medicinal product in each Member State, the Marketing Authorisation Holder 

shall agree the content and format of the educational material with the national competent authority. 

 



 

16 

The Marketing Authorisation Holder (MAH) should ensure that, at launch, all Healthcare 

Professionals who are expected to use and/or prescribe Bronchitol are provided with an educational 

pack.  

 

The educational pack should contain the following: 

 Summary of Product Characteristics and Patient Information Leaflet  

 Educational material for Healthcare Professionals 

 

The educational material for Healthcare Professionals should be a leaflet that includes information on 

the following key elements: 

 

 The risk of bronchospasm during treatment  

o The need to perform the Bronchitol initiation dose assessment to identify patients who 

have bronchial hyperresponsiveness in response to inhaled mannitol by measuring the 

degree of bronchoconstriction that occurs following sequential administrations of 

mannitol. 

o How to perform the Bronchitol initiation dose assessment safely and how long to 

monitor the patient for.  

o How to interpret the results of the Bronchitol initiation dose assessment as Pass, Fail 

or Incomplete. 

o That therapeutic doses of Bronchitol should only be prescribed if the patient has 

passed the initiation dose assessment. 

o The need of pre-medication by a bronchodilator 5-15 minutes before the Bronchitol 

initiation dose assessment and before each therapeutic administration of Bronchitol. 

o The need to check that the patient knows how to correctly use the bronchodilator. 

o The need to review the patient after approximately six weeks to assess for signs and 

symptoms of bronchospasm. 

o The risk of bronchospasm during long term treatment even if the Bronchitol initiation 

dose assessment was initially passed and the need to reiterate it in case of doubt. 

 

 The risk of haemoptysis during treatment 

o That Bronchitol has not been studied in patients with a history of significant 

haemoptysis (>60 ml) in the previous three months.  

o The need for monitoring and when to withhold treatment. 

 

 The potential risk of cough related sequelae during treatment 

o The need to train the patient to minimise cough during administration in using 

the correct inhalation technique. 
 

 Obligation to conduct post-authorisation measures 
 

The MAH shall complete, within the stated timeframe, the below measures: 

 

Description Due date 

The applicant is requested to submit periodic analysis of the CF study every 6 

months for 3 years and annually for 2 years. The final report is expected in Q3 

2018. 

Q3 2018 

 

 

 

 

 

 

 

 

 



 

17 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

 

 

 

 

 

 

 

 

 

 

 



 

18 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



 

19 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON – INITIATION DOSE PACK 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Bronchitol 40 mg inhalation powder, hard capsules 

mannitol 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each hard capsule contains 40 mg mannitol. 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Inhalation powder, hard capsule. 

 

10 hard capsules and 1 inhaler 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Initiation dose must be used under medical supervision and include monitoring of lung function. 

 

Use as directed by your doctor. 

 

Refer to package leaflet for inhaler device instructions. 

 

Capsules contain powder for oral inhalation using the inhaler device enclosed. 

 

Do not remove capsules from blister until immediately before use. 

 

Read the package leaflet before use. 

 

Inhalation use 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 

 

The capsules are not to be swallowed. 

 

 



 

20 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Store below 30°C  

Store in the original blister in order to protect from moisture. 

 

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 

 

Pharmaxis Europe Limited 

108 Q House, 

Furze Road, 

Sandyford, 

Dublin 18, 

D18AY29 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/12/760/001 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

Bronchitol 40 mg 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included.  

 
 



 

21 

18.  UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN:  

 



 

22 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON – 2-WEEK TREATMENT PACK 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Bronchitol 40 mg, inhalation powder, hard capsules 

mannitol 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each hard capsule contains 40 mg mannitol. 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Inhalation powder, hard capsule. 

2-week treatment pack of 280 hard capsules and 2 inhalers 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Use as directed by your doctor. 

 

Refer to enclosed leaflet for inhaler device instructions. 

 

Capsules contain powder for oral inhalation using the inhaler device enclosed. 

 

Do not remove capsules from blister until immediately before use. 

 

Read the package leaflet before use. 

 

Inhalation use 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 

 

The capsules are not to be swallowed. 

 

 

8. EXPIRY DATE 

 

EXP 



 

23 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Store below 30°C  

Store in the original blister in order to protect from moisture. 

 

 

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 

 

Pharmaxis Europe Limited 

108 Q House, 

Furze Road, 

Sandyford, 

Dublin 18, 

D18AY29, 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/12/760/002 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Bronchitol 40 mg 

 

 

17.  UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

18.  UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN 



 

24 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTERS 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Bronchitol 40 mg, inhalation powder, hard capsules 

Mannitol 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Pharmaxis 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

 

 

 

 

 

 



 

25 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



 

26 

Package Leaflet: Information for the user 

 

Bronchitol 40 mg inhalation powder, hard capsules 

Mannitol 

 

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 Bronchitol is and what it is used for 

2. What you need to know before you use Bronchitol 

3. How to use Bronchitol 

4. Possible side effects 

5. How to store Bronchitol 

6. Contents of the pack and other information 

 

  

1. What Bronchitol is and what it is used for 

 

What Bronchitol is 

Bronchitol contains a medicine called mannitol which is a mucolytic agent. 

 

What Bronchitol is used for 

Bronchitol is for use in adults 18 years of age and over. As well as using Bronchitol you will normally 

keep using the other medicines you take for cystic fibrosis.  

 

How Bronchitol works 

Bronchitol is inhaled into the lungs to help with cystic fibrosis, an inherited disease that affects the 

glands in the lungs, gut and pancreas that secrete fluids such as mucus and digestive juices. 

 

Bronchitol helps by increasing the amount of water on the surface of your airways and in your mucus. 

This helps your lungs to clear mucus more easily. It also helps improve the condition of your lungs 

and your breathing. As a result you may get a ‘productive cough’, which also helps to remove mucus 

from your lungs. 

 

 

2. What you need to know before you use Bronchitol 

 

Do not use Bronchitol 

- if you are allergic to mannitol  

- if you are sensitive to mannitol. Before you are started on Bronchitol, your doctor will check 

whether your airways are too sensitive to mannitol. If you are too sensitive to mannitol, your 

airways will become narrower, and you may find it harder to breathe. 

If either of the above apply to you (or you are not sure), talk to your doctor or pharmacist before using 

this medicine. 

 

Warnings and precautions 

Talk to your doctor or pharmacist before using this medicine: 

- if you have asthma; 



 

27 

- if you have ever coughed up blood or had blood in your sputum; 

- if you have severe cystic fibrosis, in particular if your lung function measured by the Forced 

Expiratory Volume in first second of expiration (FEV1) is usually less than 30%. 

 

Inhaling medicines can cause chest tightness and wheezing and this can happen immediately after 

taking this medicine. Your doctor will help you take your first dose of Bronchitol and check your lung 

function before, during and after dosing. Your doctor may ask you to use other medicines such as a 

bronchodilator before taking Bronchitol. 

 

Inhaling medicines can also cause cough and this can happen with Bronchitol. Talk to your doctor if 

the cough won’t go away or worries you. 

 

Children and adolescents 

Bronchitol should not be used by children and adolescents under the age of 18. This is because there 

is limited information in this group of people. 

 

Other medicines and Bronchitol 

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 

medicines. 

 

You can carry on using your medicines for cystic fibrosis when you are using Bronchitol, this 

includes inhaled antibiotics such as tobramycin and colistimethate sodium. If you are not sure, talk to 

your doctor or pharmacist before using Bronchitol. 

 

Pregnancy and breast-feeding  

- If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor 

for advice before using this medicine. You should avoid using this medicine if you are 

pregnant. 

- If you are breast-feeding or plan to breast-feed ask your doctor for advice before using this 

medicine. It is not known if this medicine passes into the breast milk. 

 

Driving and using machines 

Bronchitol is not likely to affect your ability to drive or use any tools or machines. 

 

 

3. How to use Bronchitol 

 

Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if 

you are not sure. 

 

Always take your bronchodilator before using Bronchitol.  

 

How much to use 

 

Adults 18 years of age and over 

 

Initiation dose 

Before you are prescribed Bronchitol your doctor will help you take your first dose of Bronchitol and 

test your lung function at each step to make sure you aren’t sensitive to mannitol. The first dose is 

taken in 4 steps:-  

 

Step 1 – 1 capsule (40 mg) 

Step 2 – 2 capsules (80 mg) 

Step 3 – 3 capsules (120 mg) 

Step 4 – 4 capsules (160 mg) 

 



 

28 

At the end of the initiation dose you will have taken 10 capsules (400 mg) which is the same as the 

usual dose. 

 

Treatment dose (2-week packs) 

- You must use Bronchitol every day. 

- The usual dose is 10 capsules (400 mg) inhaled in the morning, and 10 capsules inhaled in the 

evening. 

- Have the evening dose at least 2 to 3 hours before you go to bed. 

- For the best results, inhale each capsule one after another, so there is as little delay as possible 

between capsules. 

 

Order of using this medicine 

Use Bronchitol as part of your normal daily treatment routine. The suggested order is as follows, 

unless otherwise advised by your doctor: 

1. Use your bronchodilator; 

2. Wait 5 to 15 minutes; 

3. Use your Bronchitol before physiotherapy if this is part of your treatment routine. 

4. Dornase alfa (Pulmozyme) if this is part of your treatment routine 

5. Inhaled antibiotics if this is part of your treatment routine 

 

How to use your medicine 

- Bronchitol is breathed in (inhaled) as a powder from the capsule using the inhaler supplied in 

the pack. It is for inhalation use only and must not be administered by any other route. The 

capsules must not be swallowed.  

- The powder in the capsules must only be inhaled using the inhaler included in the pack. 

- Use a new inhaler each week. 

- Each of the ten capsules is put into the inhaler one at a time. 

- Inhale the contents of the capsule using the inhaler, with one or two breaths in. 

 

For instructions on how to use the inhaler, see the end of the leaflet. 

 

If you use more Bronchitol than you should 

If you think you have used too much medicine, tell your doctor or pharmacist straight away. You may: 

- feel that you cannot breathe; 

- become wheezy; 

- cough a lot. 

The doctor may give you oxygen and medicines to help you breathe. 

 

If you forget to use Bronchitol 

- If you forget a dose, use it as soon as you remember it and carry on as usual. However, if it is 

nearly time for the next dose, skip the missed dose. 

- Do not use a double dose to make up for a forgotten dose. 

 

If you stop using Bronchitol 

If you stop using Bronchitol your symptoms may get worse. Do not stop using your Bronchitol 

without talking to your doctor first, even if you feel better. Your doctor will tell you how long to use 

this medicine for. 

 

If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 

 

 

4. Possible side effects 

 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 



 

29 

Stop using Bronchitol and see a doctor straight away if you notice the following serious side 

effects: 

- Difficulty breathing, which may be due to narrowing of the airways, worsening of asthma 

symptoms or wheezing. This happens commonly, which may affect up to 1 in 10 people. 

- Coughing up blood or blood in your sputum. This happens commonly. 

 

Tell your doctor straight away if you notice any of the following side effects: 

- Severe cough. This happens commonly. 

- Worsening of symptoms. This happens commonly. 

 

Other side effects include: 

 

Common (May affect up to 1 in 10 people) 

- Cough 

- Chest discomfort 

- Headache 

- Pain in the back of your mouth and throat and discomfort when swallowing 

- Vomiting, vomiting after coughing 

 

Uncommon (may affect up to 1 in 100 people) 

- Burning or painful sensation on the tongue 

- CF related diabetes 

- Chest and abdominal pain 

- Change in voice 

- Cold sweat 

- Congestion 

- Dehydration 

- Decreased appetite 

- Diarrhoea 

- Ear pain 

- Feeling tired 

- Feeling dizzy 

- Feeling sick (nausea) 

- Feeling unwell 

- Flu and fever 

- Wind  

- Heartburn 

- Hernia pain 

- Hyperventilation 

- Itching, rash, acne 

- Joint stiffness and pain 

- Morbid thoughts 

- Mouth ulcers 

- Respiratory tract infection 

- Runny nose 

- Sputum infection 

- Throat irritation 

- Trouble sleeping 

- Yeast infection of the mouth (thrush) 

- Unintentional loss of urine  

 

 

 

 

Reporting of side effects 



 

30 

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 Bronchitol 

 

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 carton and blister after EXP. The 

expiry date refers to the last day of that month. 

 

Store below 30°C. 

 

Store in the original package in order to protect from moisture. 

 

Once removed from the blister a capsule should be used immediately. 

 

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 Bronchitol contains: 

The active substance is mannitol. Each capsule contains 40 milligrams mannitol. Average inhaled 

dose per capsule is 32.2 milligrams mannitol. 

 

What Bronchitol looks like and contents of the pack: 

 

Bronchitol is a powder for inhalation that is filled into hard capsules. Bronchitol 40 mg inhalation 

powder, hard capsules contain a white or almost white powder filled into clear, colourless, hard, 

capsules with “PXS 40 mg” imprinted on them. The powder is inhaled into the lungs using the inhaler 

provided in the pack. 

 

One initiation dose pack of Bronchitol contains 1 blister with 10 capsules and 1 inhaler. The initiation 

dose pack is used during the initiation dose assessment with your doctor. 

 

One 2-week treatment pack of Bronchitol contains 28 blisters with 10 capsules each (280 capsules in 

total) and 2 inhalers. The 2-week treatment pack is for treatment use. 

 

Marketing Authorisation Holder 

 

Pharmaxis Europe Limited, 108 Q House, Furze Road, Sandyford, Dublin 18, D18AY29, Ireland. 

 

Manufacturer 

 

Mawdsleys Clinical Services, Unit 22, Quest Park, Wheatley Hall Road, Doncaster, DN2 4LT, United 

Kingdom. 

 

 

Arvato distribution GmbH, Gottlieb-Daimler Straβe 1, 33428 Harsewinkel, North Rhine-Westphalia 

Germany 

 

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


 

31 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien Lietuva 

Pharmaxis Europe Limited  

Tél/Tel: + 353 (0) 1431 9816 

 

AB "PharmaSwiss 

Tel: + 370 5 279 07 62 

 

България 

Pharmaxis Europe Limited 

Teл.: + 353 (0) 1431 9816 

 

Luxembourg/Luxemburg 

Pharmaxis Europe Limited  

Tél/Tel: + 353 (0) 1431 9816 

 

 

Česká republika 

4 Life Pharma CZ, s.r.o. 

Tel: +420 244 403 003 

 

Magyarország 

Pharmaxis Europe Limited  

Tel.: + 353 (0) 1431 9816 

Danmark 

Chiesi Pharma AB 

Tlf: + 46 8 753 35 20 

 

Malta 

Pharmaxis Europe Limited  

Tel: + 353 (0) 1431 9816 

Deutschland 

Chiesi GmbH 

Tel: +49 (0) 40 897 240 

 

Nederland 

Pharmaxis Europe Limited  

Tel: + 353 (0) 1431 9816 

 

Eesti 

PharmaSwiss Eesti OÜ 

Tel: + 372 6827400 

 

Norge 

Chiesi Pharma AB 

Tlf: + 46 8 753 35 20 

Ελλάδα 

Chiesi Hellas A.E.B.E. 

Τηλ: +  30.210.617.97.63 

 

Österreich 

Pharmaxis Europe Limited  

Tel: + 353 (0) 1431 9816 

 

España 

Medicare Pharma S.L.C 

Tel: +34 91 848 9534  

Polska 

IMED Poland Sp. z o. o.  

Tel: +48 22 663 43 10 

 

France 

Pharmaxis Europe Limited  

Tél: + 353 (0) 1431 9816 

 

Portugal 

Pharmaxis Europe Limited  

Tel: + 353 (0) 1431 9816 

 

Hrvatska 

PharmaSwiss d.o.o 

Tel: + 385(1)6311-833 

 

Ireland 

Chiesi Limited 

Tel: + 44 (0)161 488 5555 

 

România 

Pharmaxis Europe Limited  

Tel: + 353 (0) 1431 9816 

 

Slovenija 

PharmaSwiss d.o.o 

Tel: + 386 (0) 1 2364 700 

 

Ísland 

Pharmaxis Europe Limited  

Sími: + 353 (0) 1431 9816                             

Slovenská republika 

4 Life Pharma SK, s.r.o. 

Tel: + 420 244 403 003 



 

32 

 

Italia 

Chiesi Farmaceutici S.p.A 

Tel: +39 0521 2791 

 

                                                                                             

 

Suomi/Finland 

   Chiesi Pharma AB 

   Puh/Tel: + 46 8 753 35 20 

 

Κύπρος 

Chiesi Hellas A.E.B.E. 

Τηλ: +  30.210.617.97.63 

                                                                                            

Sverige 

Chiesi Pharma AB 

Tel: + 46 8 753 35 20 

 

Latvija 

UAB PharmaSwiss 

Tel: + 371 67502185 

 

United Kingdom 

Chiesi Limited 

Tel: + 44 (0)161 488 5555 

 

 

This leaflet was last revised in MM/YYYY. 

 

Other sources of information 

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. 

 

------------------------------------------------------------------------------------------------------------------------- 

How to use the inhaler 

 

Below is a diagram that shows what the inhaler looks like. Bronchitol capsules can only be used with 

the inhaler provided in the pack. 

 

Inhaler device  

The following steps explain how to use the inhaler. For more advice on how to look after your inhaler, 

please see the end of the instructions. 

 

 

 

1. Take off the cap 

- Using both hands, hold the inhaler upright 

and take off the cap. 

 

 

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


 

33 

 

 

 

 

 

2. Open the inhaler 

- Hold the bottom of the inhaler firmly with 

one hand. 

- You should hold the inhaler along the 

bottom to make sure you don’t press the 

piercing buttons. 

- Then open it by turning the mouth-piece in 

the direction of the arrow on the inhaler. 

 

 

 

 

3. Put in the capsule 

- First make sure your hands are dry. 

- Then take out a capsule from the blister 

(only remove the capsule just before use). 

- Put the capsule into the capsule-shaped 

space in the bottom of the inhaler. 

 

 

 

 

 

4. Close the inhaler 

- Keep the inhaler in an upright position. 

- Then twist the mouth-piece into the closed 

position - when it is closed you will hear a 

‘click’. 

 

 

 

 

 

5. Make a hole in the capsule  

- This lets the powder in the capsule be 

released when you breathe in. In this leaflet 

we call making the hole ‘piercing’. 

- Hold the inhaler upright and fully press in 

both ‘Piercing’ buttons on the sides of the 

inhaler at the same time, then release them. 

Only do this once. This is because piercing 

the capsule more than once may make it split 

or break-up. 

 

 

6. Prepare for inhalation 

- Tilt the inhaler so that the mouth-piece faces 

slightly downward. 



 

34 

- This allows the capsule to drop forward into the spinning chamber. 

- Keep the inhaler tilted in this way and breathe out completely (away from the inhaler). 

 

 

 

 

7. Inhale 

- Tilt your head back slightly. 

- Keeping the inhaler tilted downward, put the 

inhaler to your mouth and make sure you 

close your lips tightly around the 

mouth-piece. 

- Take a steady deep breath in, to fill your 

lungs - then hold your breath for 5 seconds. 

When you breathe in you should hear a 

‘rattling’ sound as the capsule spins in the 

inhaler. If this does not happen, the capsule 

may be stuck. 

- If you do not hear the rattling, hold the inhaler with the mouth-piece facing downwards, and tap 

the bottom firmly. Do not try to loosen the capsule by pressing the piercing buttons again. 

Repeat the inhalation to get your dose. 

 

8. Breathe out 

- Take the inhaler away from your mouth. 

- Breathe out, and then breathe normally 

again. 

 

 

 

 

 

 

 

 

 

9. Check the capsule 

- Look to see if the capsule is empty - the 

capsule must spin in the inhaler in order to 

empty. If the capsule has not emptied you 

may need to repeat steps 6 to 8. 

 

 

 

 

 

 

10. Take out the used capsule  

- Turn the inhaler upside down, tap the bottom and throw the empty capsule away. 

11. Repeat steps 3 to 10 for each capsule  

- Perform these steps for each of the ten capsules.  

- To get the best results from Bronchitol, inhale each capsule one after another. 

 

Extra information on how to look after your inhaler 

- Keep your inhaler dry and always make sure your hands are dry before using it. 

- Never breathe or cough into your inhaler. 

- Never take your inhaler apart. 



 

35 

- Never place a capsule directly into the mouth-piece of your inhaler. 

- Never leave a used capsule in your inhaler chamber. 

- Use a new inhaler each week. 

- If your inhaler breaks, use your second inhaler and talk to your doctor. 

 

Cleaning the inhaler - Usually your inhaler will give you the correct dose of medicine for 7 days 

without needing cleaning. However, if your inhaler does need cleaning, the steps to follow are: 

1. Ensure your inhaler is empty. 

2. Wash your inhaler in warm water with the mouth-piece open.  

3. Shake it until there are no large water droplets left in the inhaler.  

4. Leave it to dry in the air - lay it on its side with the mouth-piece open. 

5. You must let it fully dry, this can take up to 24 hours. While it is drying, use your other inhaler. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


	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