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

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.

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 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).

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.

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.

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 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

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.