Adverse reactions : תופעות לוואי

4.8 Undesirable effects
Summary of the safety profile
The most common adverse reactions experienced by patients aged 6 years and older are headache (23.9%), oropharyngeal pain (22.0%), upper respiratory tract infection (22.0%), nasal congestion (20.2%), abdominal pain (15.6%), nasopharyngitis (14.7%), diarrhoea (12.8%), dizziness (9.2%), rash (12.8%) and bacteria in sputum (12.8%). Transaminase elevations occurred in 12.8% of ivacaftor-treated patients versus 11.5% of placebo-treated patients.

In patients aged 2 to less than 6 years the most common adverse reactions were nasal congestion (26.5%), upper respiratory tract infection (23.5%), transaminase elevations (14.7%), rash (11.8%), and bacteria in sputum (11.8%).

Serious adverse reactions in patients who received ivacaftor included abdominal pain and transaminase elevations (see section 4.4).

Tabulated list of adverse reactions
Table 4 reflects the adverse reactions observed with ivacaftor in clinical trials (placebo-controlled and uncontrolled studies) in which the length of exposure to ivacaftor ranged from 16 weeks to 144 weeks.
KALY_50_75_150-SPC-0921-V1                     Page 7 of 19
The frequency of adverse reactions is defined as follows: 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 4: Adverse reactions

System organ class                          Adverse reactions                       Frequency Infections and infestations         Upper respiratory tract infection    very common Nasopharyngitis                      very common
Rhinitis                             common
Nervous system disorders            Headache                             very common Dizziness                            very common
Ear and labyrinth disorders         Ear pain                             common Ear discomfort                       common
Tinnitus                             common
Tympanic membrane hyperaemia         common
Vestibular disorder                  common
Ear congestion                       uncommon
Respiratory, thoracic and           Oropharyngeal pain                   very common mediastinal disorders               Nasal congestion                     very common Sinus congestion                     common
Pharyngeal erythema                  common
Gastrointestinal disorders          Abdominal pain                       very common Diarrhoea                            very common
Hepatobiliary disorders             Transaminase elevations              very common Skin and subcutaneous tissue        Rash                                 very common disorders
Reproductive system and breast      Breast mass                          common disorders                           Breast inflammation                  uncommon Gynaecomastia                        uncommon
Nipple disorder                      uncommon
Nipple pain                          uncommon
Investigations                      Bacteria in sputum                   very common 
Description of selected adverse reactions
Transaminase elevations
During the 48-week placebo-controlled studies 1 and 2 in patients aged 6 years and older, the incidence of maximum transaminase (ALT or AST) >8, >5 or >3 x ULN was 3.7%, 3.7% and 8.3% in ivacaftor-treated patients and 1.0%, 1.9% and 8.7% in placebo-treated patients, respectively. Two patients, one on placebo and one on ivacaftor, permanently discontinued treatment for elevated transaminases, each >8 x ULN. No ivacaftor-treated patients experienced a transaminase elevation >3 x ULN associated with elevated total bilirubin >1.5 x ULN. In ivacaftor-treated patients, most transaminase elevations up to 5 x ULN resolved without treatment interruption. Ivacaftor dosing was interrupted in most patients with transaminase elevations >5 x ULN. In all instances where dosing was interrupted for elevated transaminases and subsequently resumed, ivacaftor dosing was able to be resumed successfully (see section 4.4).

Paediatric population
The safety data of ivacaftor were evaluated in 34 patients between 2 to less than 6 years of age, 61 patients between 6 to less than 12 years of age and 94 patients between 12 to less than 18 years of age.


KALY_50_75_150-SPC-0921-V1                     Page 8 of 19
The safety profile is generally consistent among paediatric patients aged 2 years and older and is also consistent with adult patients.

The incidence of transaminase elevations (ALT or AST) observed in studies 2,5 and 6 (for patients aged 6 to less than 12 years), and study 7 (patients aged 2 to less than 6 years) are described in Table 5. In the placebo-controlled studies, the incidence of transaminase elevations were similar between treatment with ivacaftor (15.0%) and placebo (14.6%). Peak LFT elevations were generally higher in paediatric patients than in older patients. Across all populations, peak LFT elevations returned to baseline levels following interruption, and in almost all instances where dosing was interrupted for elevated transaminases and subsequently resumed, ivacaftor dosing was able to be resumed successfully (see section 4.4). Cases suggestive of positive rechallenge were observed. In study 7, ivacaftor was permanently discontinued in one patient (see section 4.4 for management of elevated transaminases).

Table 5: Transaminase elevations in patients 2 years to < 12 years treated with ivacaftor  n        % of Patients      % of Patients     % of Patients
> 3 x ULN          >5 x ULN          > 8 x ULN

6 to <12 years                  40         15.0% (6)           2.5% (1)          2.5% (1) 
2 to <6 years                   34         14.7% (5)          14.7% (5)          14.7% (5)

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