Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile

Initiation dose assessment
The most commonly observed adverse reaction associated with the use of Bronchitol during the initiation dose assessment is cough (3.6% of patients), (see section 4.4).

The most important adverse reaction associated with
4 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 10.2% of patients compared to 5.0% of patients in the control arm.
Cough which led to cessation of treatment was also commonly experienced and was observed in 4.7% 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% and 2.9% in the Bronchitol arms for studies 301 and 302, respectively vs. 3.4% and 0% in the control arms. Total haemoptysis incidence including during exacerbation was 15.8% in the mannitol arm and 14.6% in the control arm (see section 4.4).

Tabulated list of adverse reactions
Frequencies provided in Table 1 and 2 are based on the observations on the day of screening and during two pivotal comparative clinical studies investigating the effect of Bronchitol (safety population, 361 patients on Bronchitol).

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.

Table1:Frequency of adverse reactions with Bronchitol during the treatment phase and on the day of screening
Uncommon                 Common           Very common System organ class Bacterial disease carrier                                           Infections and infestations Oral candidiasis
Staphylococcal infection
Decreased appetite                                                  Metabolism and nutrition CF related diabetes                                                 disorders Dehydration1
Initial insomnia                                                    Psychiatric Disorders Morbid thoughts
Dizziness2                Headache                                  Nervous system disorders Ear Pain                                                            Ear and labyrinth disorders Wheezing1                 Haemoptysis            Cough              Respiratory, thoracic and Bacteria sputum           Condition aggravated2                     mediastinal disorders identified                Pharyngolaryngeal pain
Asthma                    Cough1
Rhinorrhoea               Chest discomfort2
2
Bronchospasm              Wheezing



5
Fungus sputum test        Productive cough positive                  Throat irritation
Dysphonia
Dyspnoea
Hyperventilation
Obstructive airways disorder
Respiratory tract congestion
Sputum discoloured
Bronchitis
Bronchopneumonia
Lung infection
Pharyngitis
Upper respiratory tract infection
Hypoxia1
Productive cough1
Forced expiratory volume decreased1
Chest pain1
Throat irritation1
Nausea2                   Post-tussive vomiting       Gastrointestinal disorders Vomiting1                 Vomiting
Diarrhoea1
Eructation
Flatulence
Gastrooesophageal reflux disease
Glossodynia
Retching2
Stomatitis
Abdominal pain upper1
Apthous Stomatitis1
Odynophagia1
Post-tussive vomiting1
Acne                                                  Skin and subcutaneous tissue Cold sweat                                            disorders
Pruritus
Rash
Rash pruritic
Musculoskeletal chest                                 Musculoskeletal and connective pain                                                  tissue disorders Arthralgia
Back pain
Joint stiffness
Musculoskeletal pain
Urinary incontinence                                  Renal and urinary disorders Influenza like illness                                General disorders and Fatigue2                                              administration site conditions Hernia pain
Malaise
Pyrexia
Blood alkaline                                        Investigations phosphatase increased1


6
1
Adverse reaction occurred on the day of screening
2
Adverse reaction occurred both during the treatment phase and on the day of screening 
Twenty seven (7%) out of 389 patients enrolled in study 301 and 14 (4.1%) out of 342 enrolled in study 302 were not randomised due to a positive mannitol tolerance test (MTT). In study 301, overall the most frequently reported events during the MTT were cough in 18 (4.8%) subjects, wheezing/bronchospasm in eight (2.1%) subjects and chest discomfort in six (1.6%) subjects. In study 302 the most frequent clinical sign or symptom reported during the MTT was cough (7.9%).

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
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
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.

Table2: Frequency of adverse reactions with Bronchitol during the treatment phase and on the day of screening-paediatric population
Uncommon                 Common           Very common System organ class Initial insomnia                                                    Psychiatric disorders Dizziness2               Headache                                   Nervous system disorders Ear Pain                                                            Ear and labyrinth disorders Bronchitis               Cough2                                     Respiratory, thoracic and Bronchopneumonia         Condition aggravated                       mediastinal disorders Dysphonia                Haemoptysis
Hyperventilation         Pharyngolaryngeal pain
Sputum Discoloured       Bacteria sputum
Throat irritation        identified
Pharyngitis              Chest discomfort
Upper respiratory tract Wheezing infection                Asthma
Bronchospasm1            Productive cough
Dyspnoea
Chest discomfort1
Chest pain1
Nausea2                  Vomiting                                   Gastrointestinal disorders 1
Vomiting                 Post-tussive vomiting
Odynophagia1
Post-tussive vomiting1
Retching1
Pruritus                                                            Skin and subcutaneous tissue Pruritic rash                                                       disorders Musculoskeletal chest                                               Musculoskeletal and connective pain                                                                tissue disorders Urinary incontinence                                                Renal and urinary disorders Pyrexia                                                             General disorders and 
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administration site conditions
1
Adverse reaction occurred on the day of screening
2
Adverse reaction occurred both during the treatment phase and on the day of screening 
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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.
gov.il and emailed to the Registration Holder’s Patient Safety Unit at: drugsafety@neopharmgroup.com