Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Pharmaxis Europe Limited, 108 Q House, Furze Road, Sandyford, Dublin 18, D18AY29, Ireland
Hypersensitivity to the active substance.
Bronchial hyperresponsiveness to inhaled mannitol (see section 4.4).
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:
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 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.
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 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:
The reinstitution or withholding of Bronchitol following smaller episodes of haemoptysis should be based on clinical judgement.
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.
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.
Efficacy and safety have not been established in non-CF bronchiectasis patients. Therefore, treatment with Bronchitol is not recommended.
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.
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.
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.
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).
Bronchitol has no or negligible influence on the ability to drive and use machines.
The safety profile of Bronchitol has been evaluated in clinical studies involving more than 1200 patients (See Table 1).
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).
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).
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)
Uncommon: Bacterial disease carrier, Bronchitis, Bronchopneumonia, Lung infection, Oral candidiasis, Pharyngitis, Staphylococcal infection, Upper respiratory tract infection
Uncommon: Decreased appetite, CF related diabetes, Dehydration
Uncommon: Initial insomnia, Morbid thoughts
Common: Headache
Uncommon: Dizziness
Uncommon: Ear pain
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
Common: Post-tussive vomiting, Vomiting Uncommon Nausea, Diarrhoea, Eructation, Flatulence, Gastrooesophageal reflux disease, Glossodynia, Retching, Stomatitis, Abdominal pain upper, Aphthous Stomatitis, Odynophagia
Uncommon: Acne, Cold sweat, Pruritus, Rash, Rash pruritic
Uncommon: Musculoskeletal chest pain, Arthralgia, Back pain, Joint stiffness, Musculoskeletal pain
Uncommon: Urinary incontinence
Common: Condition aggravated, Chest discomfort
Uncommon: Pyrexia, Fatigue, Influenza like illness, Hernia pain, Malaise, Chest pain
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.
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%).
Frequency, type and severity of adverse reactions in children are similar to those observed in adults.
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.
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)
Uncommon: Initial insomnia
Common: Headache
Uncommon: Dizziness
Uncommon: Ear Pain
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
Common: Vomiting, Post-tussive vomiting
Uncommon: Nausea, Odynophagia, Retching
Uncommon: Pruritus, Pruritic rash
Uncommon: Musculoskeletal chest pain
Uncommon: Urinary incontinence
Uncommon: Pyrexia
Common: Bacteria sputum identified
Adverse reactions that occurred only with initiation dose assessment (MTT) are bronchospasm, chest pain, odynophagia and retching
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*.
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
