Bronchitol · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-095750 · has-adverse-reaction-information · PDF-Seite 5

Summary of the safety profile The safety profile of Bronchitol has been evaluated in clinical studies involving more than 1200 patients. (See Table 1). 5 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 Metabo

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HOS-095746 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance. Bronchial hyperresponsiveness to inhaled mannitol (see section 4.4).

HOS-095745 · has-indication-information · PDF-Seite 2

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.

HOS-095748 · has-interaction-information · PDF-Seite 5

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.

HOS-095749 · has-pregnancy-information · PDF-Seite 5

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).

HOS-095747 · has-warning-information · PDF-Seite 4

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 wheth

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