Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The most common adverse reactions at the recommended doses were nasopharyngitis
(14.3%), upper respiratory tract infection (14.2%), cough (8.2%), headache (3.7%) and
muscle spasms (3.5%). These were in the vast majority mild or moderate and became less
frequent if treatment was continued.
At the recommended doses, the adverse reaction profile of Onbrez Breezhaler in patients with
COPD shows clinically insignificant systemic effects of beta2-adrenergic stimulation. Mean
heart rate changes were less than one beat per minute, and tachycardia was infrequent and
reported at a similar rate as under placebo treatment. Relevant prolongations of QTcF were not
detectable in comparison to placebo. The frequency of notable QTcF intervals [i.e., >450 ms
(males) and >470 ms (females)] and reports of hypokalaemia were similar to placebo. The
mean of the maximum changes in blood glucose were similar between Onbrez Breezhaler and
on placebo.

Tabulated summary of adverse reactions
The Onbrez Breezhaler Phase III clinical development programme involved patients with a
clinical diagnosis of moderate to severe COPD. 4,764 patients were exposed to indacaterol up
to one year at doses up to twice the maximum recommended dose. Of these patients, 2,611
were on treatment with 150 microgram once-daily and 1,157 on treatment with 300
microgram once-daily. Approximately 41% of patients had severe COPD. The mean age of
patients was 64 years, with 48% of patients aged 65 years or older, and the majority (80%)
was Caucasian.
Adverse reactions in Table1 are listed according to MedDRA system organ class in the COPD
safety database. Within each system organ class, adverse reactions are ranked by frequency in
descending order according to the following convention: 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
(<1/10,000), not known (cannot be estimated from the available data).

Table 1       Adverse reactions
 Adverse Reactions                              Frequency category       Frequency category
                                                Onbrez Breezhaler        Onbrez Breezhaler
                                                     150 mcg               300 mcg
 Infections and infestations
 - Upper respiratory tract infection                   Common                Very common
 - Nasopharyngitis                                     Common                Very common
 - Sinusitis                                           Common                  Common
 Immune System Disorders
 - Hypersensitivity1                                  Uncommon                Uncommon
 Metabolism and nutrition disorders
 - Diabetes mellitus and hyperglycemia                Uncommon                 Common
 Nervous system disorders
 - Headache                                            Common                  Common
 - Dizziness                                           Common                  Common
ONB API JUN21 V1.1                                                   Ref EMA SmPC 15Dec2020
    - Paraesthesia                                       Uncommon                Uncommon
    Cardiac disorders
    - Ischaemic heart disease                            Uncommon                 Common
    - Atrial fibrillation                                Uncommon                Uncommon
    - Palpitations                                       Uncommon                 Common
    - Tachycardia                                        Uncommon                Uncommon
    Respiratory, thoracic and
    mediastinal disorders
    - Cough                                               Common                   Common
    - Oropharyngeal pain including throat                 Common                   Common
    irritation
    - Rhinorrhoea                                         Common                  Common
    - Paradoxical bronchospasm                           Uncommon                Uncommon
    Skin and subcutaneous tissue
    disorders
    Pruritus/rash                                        Uncommon                  Common
    Musculoskeletal and connective
    tissue disorders
    - Muscle spasm                                        Common                  Common
    - Myalgia                                            Uncommon                Uncommon
    - Musculoskeletal pain                               Uncommon                 Common



    General disorders and
    administration site conditions
    - Chest pain                                          Common                   Common
    - Peripheral oedema                                   Common                   Common


1
  Reports of hypersensitivity have been received from post-approval marketing experience in
association with the use of Onbrez Breezhaler. These were reported voluntarily from a
population of uncertain size,and it is therefore not always possible to reliably estimate the
frequency or establish a causal relationship to exposure to the medicinal product. Therefore
the frequency was calculated from clinical trial experience.

At 600 microgram once-daily, the safety profile of Onbrez Breezhaler was overall similar to
that of recommended doses. An additional adverse reaction was tremor (common).

Description of selected adverse reactions
In Phase III clinical studies, healthcare providers observed during clinic visits that on average
17-20% of patients experienced a sporadic cough that occurred usually within 15 seconds
following inhalation and typically lasted for 5 seconds (about 10 seconds in current smokers).
It was observed with a higher frequency in female than in male patients and in current
smokers than in ex-smokers. This cough experienced post inhalation did not lead to any

ONB API JUN21 V1.1                                                    Ref EMA SmPC 15Dec2020
patient discontinuing from the studies at the recommended doses (cough is a symptom in
COPD and only 8.2% of patients reported cough as an adverse event). There is no evidence
that cough experienced post inhalation is associated with bronchospasm, exacerbations,
deteriorations of disease or loss of efficacy.

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://sideeffects.health.gov.il/.