Adverse reactions : תופעות לוואי

8    ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the label: • Transaminase Elevations [see Warnings and Precautions (7.1)]
• Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (7.2) • Cataracts [see Warnings and Precautions (7.4)]

8.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The overall safety profile of SYMDEKO is based on data from 1001 patients in three double-blind, placebo-controlled, clinical trials: two parallel-group trials of 12 and 24 week duration and one cross-over design trial of 8 weeks duration. Eligible patients were also able to participate in an open-label extension safety study (up to
96 weeks of SYMDEKO). In the three placebo-controlled trials (Trials 1, 2, and 3), a total of 496 patients with CF age 12 years and older received at least one dose of SYMDEKO. The proportion of patients who discontinued study drug prematurely due to adverse reactions was 1.6% for SYMDEKO-treated patients and 2.0% for placebo-treated patients. Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in SYMDEKO-treated patients compared to placebo included distal intestinal obstruction syndrome, 3 (0.6%) SYMDEKO-treated patients vs. 0 placebo. There were no deaths in the placebo- controlled trials, and one death in the open label extension study due to respiratory failure and influenza infection in a patient who had discontinued SYMDEKO seven weeks prior.

The safety profile of SYMDEKO was generally similar across all subgroups of patients, including analysis by age, sex, baseline percent predicted FEV1 (ppFEV1), and geographic regions.

Table 5 shows adverse reactions occurring in ≥3% of SYMDEKO-treated patients that also occurred at a higher rate than in the placebo-treated patients in the 12- and 24-week placebo-controlled, parallel-group trials (Trials 1 and 3).

Table 5: Incidence of Adverse Drug Reactions in ≥3% of SYMDEKO-Treated Patients and Greater than Placebo
Adverse Reactions                  SYMDEKO                  Placebo
(Preferred Term)                    N=334                  N=343 n (%)                  n (%)
Headache                                 49 (15)                44 (13) Nausea                                    29 (9)                 24 (7) Sinus congestion                          13 (4)                  6 (2) Dizziness                                 12 (4)                  8 (2) 
The safety data from the following trials are similar to that observed in Trials 1 and 3:
•    an 8-week randomized, double-blind, placebo-controlled crossover study in 244 patients with CF age 12 years and older who were heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor (Trial 2).
•    a 24-week open-label study in 70 patients with CF age 6 to less than 12 years who were either homozygous for the F508del mutation or heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor (Trial 4).


SYMD-SPC-0923-V1                                                              Page 3 of 15 Laboratory abnormalities
Transaminase elevations
During the placebo-controlled trials in patients age 12 years and older, the incidence of maximum transaminase (ALT or AST) >8, >5, or >3 x the upper limit of normal (ULN) was similar between SYMDEKO-treated patients and placebo-treated patients; 0.2%, 1.0%, and 3.4% in SYMDEKO-treated patients, and 0.4%, 1.0%, and 3.4% in placebo-treated patients. One patient (0.2%) on SYMDEKO and 2 patients (0.4%) on placebo permanently discontinued treatment for elevated transaminases.
No SYMDEKO-treated patients experienced a transaminase elevation >3 x ULN associated with elevated total bilirubin >2 x ULN.

During the 24-week, open-label study in patients age 6 to less than 12 years (Trial 4), the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 x ULN were 1.4%, 4.3%, and 10.0%, respectively. No SYMDEKO-treated patients experienced a transaminase elevation >3 x ULN associated with elevated total bilirubin >2 x ULN or discontinued SYMDEKO treatment due to transaminase elevations.

8.2    Postmarketing Experience
The following adverse reactions have been identified during post approval use of SYMDEKO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders: anaphylaxis
Skin: rash

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