Adverse reactions : תופעות לוואי

8    ADVERSE REACTIONS
The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: • Elevated Transaminases and Hepatic Injury [see Warnings and Precautions (7.1)] • Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (7.2)] • Cataracts [see Warnings and Precautions (7.5)]

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 safety profile of Trikafta is based on data from 510 CF patients aged 12 years and older in two double-blind, controlled trials of 24 weeks and 4 weeks treatment duration (Trials 1 and 2). Eligible patients were also able to participate in an open-label extension safety study (up to 96 weeks of Trikafta). In the two controlled trials, a total of 257 patients aged 12 years and older received at least one dose of Trikafta.
TRIK-SPC-0324-V1                                               Page 3 of 16 In addition, the following clinical trial has also been conducted [see Use in Specific Populations (10.3) and Clinical Pharmacology (13.3)]: 
•    a 24-week open-label trial in 66 patients with CF aged 6 to less than 12 years who were either homozygous for the F508del mutation or heterozygous for the F508del mutation and a mutation on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor and tezacaftor/ivacaftor (Trial 3).
In Trial 1, the proportion of patients who discontinued study drug prematurely due to adverse events was 1% for Trikafta-treated patients and 0% for placebo-treated patients.

In Trial 1, serious adverse reactions that occurred more frequently in Trikafta-treated patients compared to placebo were rash (1% vs <1%) and influenza (1% vs 0%).
There were no deaths in Trials 1, 2 and 3.

Table 4 shows adverse reactions occurring in ≥5% of Trikafta-treated patients and higher than placebo by ≥1% in the 24-week placebo-controlled, parallel-group trial (Trial 1).

Table 4: Adverse Drug Reactions in ≥5% of Trikafta-Treated Patients and Higher than Placebo by ≥1% in Trial 1 Adverse Drug Reactions                                        Trikafta                                                     Placebo (Preferred Term)                                            N=202                                                       N=201 n (%)                                                       n (%)
Headache                                                                 35 (17)                                                     30 (15) Upper respiratory tract infectiona                                       32 (16)                                                     25 (12) Abdominal painb                                                          29 (14)                                                      18 (9) Diarrhea                                                                 26 (13)                                                      14 (7) Rashc                                                                    21 (10)                                                      10 (5) Alanine aminotransferase increased                                       20 (10)                                                      7 (3) Nasal congestion                                                          19 (9)                                                      15 (7) Blood creatine phosphokinase increased                                    19 (9)                                                      9 (4) Aspartate aminotransferase increased                                      19 (9)                                                      4 (2) Rhinorrhea                                                                17 (8)                                                      6 (3) Rhinitis                                                                  15 (7)                                                      11 (5) Influenza                                                                 14 (7)                                                      3 (1) Sinusitis                                                                 11 (5)                                                      8 (4) Blood bilirubin increased                                                 10 (5)                                                      2 (1) a Includes upper respiratory tract infection and viral upper respiratory tract infection b Includes abdominal pain, abdominal pain upper, abdominal pain lower c Includes: rash, rash generalized, rash erythematous, rash macular, rash pruritic 
Additional adverse reactions that occurred in Trikafta-treated patients at a frequency of 2 to <5% and higher than placebo by ≥1% include the following: Flatulence, abdominal distension, conjunctivitis, pharyngitis, respiratory tract infection, tonsillitis, urinary tract infection, c-reactive protein increased, hypoglycemia, dizziness, dysmenorrhea, acne, eczema and pruritus.

The safety profiles for the CF patients enrolled in Trials 2 and 3 were similar to that observed in Trial 1.

Rash Events
In Trial 1, the overall incidence of rash events was 10% in Trikafta-treated and 5% in placebo-treated patients (see Table 3). The incidence of rash events was higher in female Trikafta-treated patients (16%) than in male Trikafta-treated patients (5%).

Hormonal contraceptives may play a role in the occurrence of rash. For patients taking hormonal contraceptives who develop rash, consider interrupting Trikafta and hormonal contraceptives. Following the resolution of rash, consider resuming Trikafta without the hormonal contraceptives. If rash does not recur, resumption of hormonal contraceptives can be considered.

Laboratory and Vital Sign Abnormalities
Liver Function Test Elevations
In Trial 1, the incidence of maximum transaminase (ALT or AST) >8, >5, or >3 x ULN was 1%, 2%, and 8% in Trikafta-treated patients and 1%, 1%, and 5% in placebo-treated patients. The incidence of adverse reactions of transaminase elevations (AST and/or ALT) was 11% in Trikafta-treated patients and 4% in placebo- treated patients.

In Trial 1, the incidence of maximum total bilirubin elevation >2 x ULN was 4% in Trikafta-treated patients and <1% in placebo-treated patients. Maximum indirect and direct bilirubin elevations >1.5 x ULN occurred in 11% and 3% of Trikafta-treated patients, respectively. No Trikafta-treated patients developed maximum direct bilirubin elevation >2 x ULN.

During Trial 3, in patients aged 6 to less than 12 years, the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 x ULN were 0%, 1.5%, and 10.6%, respectively. No TRIKAFTA-treated patients had transaminase elevation >3 x ULN associated with elevated total bilirubin >2 x ULN or discontinued treatment due to transaminase elevations.


TRIK-SPC-0324-V1                                               Page 4 of 16 Increased Creatine Phosphokinase
In Trial 1, the incidence of maximum creatine phosphokinase elevation >5 x ULN was 10% in Trikafta-treated and 5% in placebo-treated patients. Among the Trikafta-treated patients with creatine phosphokinase elevation >5 x ULN, 14% (3/21) required treatment interruption and none discontinued treatment.

Increased Blood Pressure
In Trial 1, the maximum increase from baseline in mean systolic and diastolic blood pressure was 3.5 mmHg and 1.9 mmHg, respectively for Trikafta-treated patients (baseline: 113 mmHg systolic and 69 mmHg diastolic) and 0.9 mmHg and 0.5 mmHg, respectively for placebo-treated patients (baseline: 114 mmHg systolic and 70 mmHg diastolic).

The proportion of patients who had systolic blood pressure >140 mmHg and 10 mmHg increase from baseline on at least two occasions was 4% in Trikafta-treated patients and 1% in placebo-treated patients. The proportion of patients who had diastolic blood pressure >90 mmHg and 5 mmHg increase from baseline on at least two occasions was 1% in Trikafta-treated patients and 2% in placebo-treated patients.

With the exception of sex differences in rash, the safety profile of Trikafta was generally similar across all subgroups of patients, including analysis by age, sex, baseline percent predicted FEV1 (ppFEV1) and geographic regions.

8.2 Post-marketing Experience
The following adverse reactions have been identified during post approval use of Trikafta. 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.

Hepatobiliary: Liver failure leading to transplantation in a patient with pre-existing cirrhosis and portal hypertension. Liver injury characterized by concomitant transaminase (ALT and AST) and total bilirubin elevations [see Warnings and Precautions (7.1)].

Immune System Disorders: anaphylaxis, angioedema

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