Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The most common adverse reactions in Phase 3 clinical studies were dyspnoea (14.0% versus 7.8% on placebo), diarrhoea (11.0% versus 8.4% on placebo), and nausea (10.2% versus 7.6% on placebo).

Serious adverse reactions included hepatobiliary events, e.g., transaminase elevations, cholestatic hepatitis and hepatic encephalopathy.

Tabulated list of adverse reactions

Adverse reactions identified from the 24-week, placebo-controlled, Phase 3 studies (trials 809-103 and 809-104) in patients aged 12 years and older and from a 24-week, placebo-controlled study in patients aged 6 to 11 years (trial 809-109), who are homozygous for the F508del mutation in the CFTR gene are presented in Table 4 and are listed by system organ class and frequency. Adverse reactions observed with ivacaftor alone are also provided in Table 4. Adverse reactions are ranked under the MedDRA frequency classification: 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); and not known (frequency cannot be estimated using the available data).


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Table 4: Adverse reactions in lumacaftor/ivacaftor-treated patients and in patients treated with ivacaftor alone
System organ class           Frequency                        Adverse reactions Infections and infestations    very common        Nasopharyngitis* common             Upper respiratory tract infection, rhinitis
Psychiatric disorders          not known          Depression
Vascular disorders             uncommon           Hypertension
Nervous system disorders       very common        Headache, dizziness* uncommon           Hepatic encephalopathy†
Ear and labyrinth disorders    common             Ear pain*, ear discomfort*, tinnitus*, tympanic membrane hyperaemia*, vestibular disorder* uncommon           Ear congestion*
Respiratory, thoracic and      very common        Nasal congestion, dyspnoea, productive cough, mediastinal disorders                             sputum increased common             Respiration abnormal, oropharyngeal pain, sinus congestion*, rhinorrhoea, pharyngeal erythema*, bronchospasm
Gastrointestinal disorders     very common        Abdominal pain*, abdominal pain upper, diarrhoea, nausea common             Flatulence, vomiting
Hepatobiliary disorders        common             Transaminase elevations uncommon           Cholestatic hepatitis‡
Skin and subcutaneous tissue   common             Rash disorders
Reproductive system and        common             Menstruation irregular, dysmenorrhoea, breast disorders                                  metrorrhagia, breast mass* uncommon           Menorrhagia, amenorrhoea, polymenorrhoea,
breast inflammation*, gynaecomastia*, nipple disorder*, nipple pain*, oligomenorrhoea
Investigations                 very common        Bacteria in sputum* common             Blood creatine phosphokinase increased uncommon           Blood pressure increased
* Adverse reactions and frequencies observed in patients in clinical studies with ivacaftor monotherapy †
1 patient out of 738
‡
2 patients out of 738

The safety data from 1,029 patients aged 12 years and older who were homozygous for the F508del mutation in the CFTR gene treated with lumacaftor/ivacaftor for up to an additional 96 weeks in the long-term safety and efficacy rollover study (trial 809-105) were similar to the 24-week, placebo-controlled studies (see section 5.1).


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Description of selected adverse reactions
Hepatobiliary adverse reactions
During trials 809-103 and 809-104, the incidence of maximum transaminase (ALT or AST) levels > 8, > 5, and > 3 x ULN was 0.8%, 2.0%, and 5.2%; and 0.5%, 1.9%, and 5.1% in lumacaftor/ivacaftor- and placebo-treated patients, respectively. The incidence of transaminase-related adverse reactions was 5.1% and 4.6% in lumacaftor/ivacaftor-treated patients and those who received placebo, respectively. Seven patients who received lumacaftor/ivacaftor had liver-related serious adverse reactions with elevated transaminases, including 3 with concurrent elevation in total bilirubin. Following discontinuation of lumacaftor/ivacaftor, liver function tests returned to baseline or improved substantially in all patients (see section 4.4).

Among 7 patients with pre-existing cirrhosis and/or portal hypertension who received lumacaftor/ivacaftor in the placebo-controlled, Phase 3 studies, worsening liver function with increased ALT, AST, bilirubin, and hepatic encephalopathy was observed in one patient. The event occurred within 5 days of the start of dosing and resolved following discontinuation of lumacaftor/ivacaftor (see section 4.4).

Post–marketing cases of liver function decompensation including liver failure leading to death have been reported in CF patients with pre-existing cirrhosis with portal hypertension who were treated with lumacaftor/ivacaftor (see section 4.4).

Respiratory adverse reactions
During trials 809-103 and 809-104, the incidence of respiratory adverse reactions (e.g., chest discomfort, dyspnoea, bronchospasm, and respiration abnormal) was 26.3% in lumacaftor/ivacaftor-treated patients compared to 17.0% in patients who received placebo. The incidence of these adverse reactions was more common in patients with lower pre-treatment FEV1. Approximately three-quarters of the events began during the first week of treatment, and in most patients the events resolved without dosing interruption.
The majority of adverse reactions were mild or moderate in severity, non-serious and did not result in treatment discontinuation (see section 4.4).

During a 24-week, open-label, Phase 3b clinical study (trial 809-011 [Part B]) in 46 patients aged 12 years and older with advanced lung disease (ppFEV1 < 40) [mean ppFEV1 29.1 at baseline (range: 18.3 to 42.0)], the incidence of respiratory adverse reactions was 65.2%. In the subgroup of 28 patients who were initiated at the full dose of lumacaftor/ivacaftor (2 tablets every 12 hours), the incidence was 71.4%, and in the 18 patients who were initiated at a reduced dose of lumacaftor/ivacaftor (1 tablet every 12 hours for up to 2 weeks, and subsequently increased to the full dose), the incidence was 55.6%. Of the patients who were initiated lumacaftor/ivacaftor at the full dose, one patient had a serious respiratory event, three patients subsequently had their dose reduced, and three patients discontinued treatment. No serious respiratory adverse reactions, dose reductions or discontinuations were seen in patients who were initiated at the half dose (see section 4.4).

Menstrual abnormalities
During trials 809-103 and 809-104, the incidence of combined menstrual abnormalities (amenorrhoea, dysmenorrhoea, menorrhagia, menstruation irregular, metrorrhagia, oligomenorrhoea, and polymenorrhoea) was 9.9 % in lumacaftor/ivacaftor-treated female patients and 1.7% in placebo-treated females. These menstrual events occurred more frequently in the subset of female patients who were taking hormonal contraceptives (25.0%) versus patients who were not taking hormonal contraceptives 
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(3.5%) (see section 4.5). Most of these reactions were mild or moderate in severity and non-serious. In lumacaftor/ivacaftor-treated patients, approximately two-thirds of these reactions resolved, and the median duration was 10 days.

Increased blood pressure
During trials 809-103 and 809-104, adverse reactions related to increased blood pressure (e.g., hypertension, blood pressure increased) were reported in 0.9% (7/738) of patients treated with lumacaftor/ivacaftor and in no patients who received placebo.

In patients treated with lumacaftor/ivacaftor (mean baseline 114 mmHg systolic and 69 mmHg diastolic), the maximum increase from baseline in mean systolic and diastolic blood pressure was 3.1 mmHg and 1.8 mmHg, respectively. In patients who received placebo (mean baseline 114 mmHg systolic and 69 mmHg diastolic), the maximum increase from baseline in mean systolic and diastolic blood pressure was 0.9 mmHg and 0.9 mmHg, respectively.

The proportion of patients who experienced a systolic blood pressure value > 140 mmHg or a diastolic blood pressure > 90 mmHg on at least two occasions was 3.4% and 1.5% in patients treated with lumacaftor/ivacaftor, respectively, compared with 1.6% and 0.5% in patients who received placebo (see section 4.4).

Paediatric population

Safety data were evaluated in 161 paediatric patients aged 6 to 11 years (trials 809-011and 809-109) and in 194 patients aged 12 to 17 years with CF who are homozygous for the F508del mutation and who received lumacaftor/ivacaftor in clinical studies. Patients aged 12 to 17 years were included in trials 809- 103 and 809-104. The safety profile in these paediatric patients is generally consistent with that in adult patients.

Long-term safety data from a 96-week rollover extension study in 239 patients aged 6 years and older who were homozygous for the F508del mutation in the CFTR gene (trial 809-110) were generally consistent with the 24-week parent studies in patients aged 6 to 11 years (trial 809-011 and trial 809-109).

Description of selected adverse reactions for patients aged 6 to 11 years Hepatobiliary adverse reactions
During the 24-week, open-label Phase 3 clinical study in 58 patients aged 6 to 11 years (trial 809-011), the incidence of maximum transaminase (ALT or AST) levels > 8, > 5, and > 3 x ULN was 5.3%, 8.8%, and 19.3%. No patients had total bilirubin levels > 2 x ULN. Lumacaftor/ivacaftor dosing was maintained or successfully resumed after interruption in all patients with transaminase elevations, except 1 patient who discontinued treatment permanently.

During the 24-week, placebo-controlled Phase 3 clinical study in 204 patients aged 6 to 11 years (trial 809-109), the incidence of maximum transaminase (ALT or AST) levels > 8, > 5, and > 3 x ULN was 1.0%, 4.9%, and 12.6% in the lumacaftor/ivacaftor patients, and 2.0%, 3.0%, and 7.9% in the placebo-treated patients. No patients had total bilirubin levels > 2 x ULN. Two patients in the lumacaftor/ivacaftor group and two patients in the placebo group discontinued treatment permanently due to transaminase elevations.

Respiratory adverse reactions
During the 24-week, open-label Phase 3 clinical study (trial 809-011) in 58 patients aged 6 to 11 years (mean baseline ppFEV1 was 91.4), the incidence of respiratory adverse reactions was 6.9% (4/58).
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During the 24-week, placebo-controlled Phase 3 clinical study (trial 809-109) in patients aged 6 to 11 years (mean baseline ppFEV1 was 89.8), the incidence of respiratory adverse reactions was 18.4% in lumacaftor/ivacaftor patients and 12.9% in placebo patients. A decline in ppFEV1 at initiation of therapy was observed during serial post dose spirometry assessments. The absolute change from pre-dose at 4- 6 hours post-dose was -7.7 on day 1 and -1.3 on day 15 in lumacaftor/ivacaftor patients. The post-dose decline was resolved by week 16.

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