Adverse reactions : תופעות לוואי

8     adverse reactions
The following clinically significant adverse reactions are described elsewhere in the labeling: • Dyslipidemia [see Warnings and Precautions (7.1)]
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 practice.
The safety of ORSERDU was evaluated in 467 patients with ER+/HER2- advanced breast cancer following CDK4/6 inhibitor therapy in EMERALD, a randomized, open-label, multicenter study [see Clinical Studies (15)]. Patients received ORSERDU 345 mg orally once daily (n=237) or standard of care (SOC) consisting of fulvestrant or an aromatase inhibitor (n=230). Among patients who received ORSERDU, 22% were exposed for 6 months or longer and 9% were exposed for greater than one year.
Serious adverse reactions occurred in 12% of patients who received ORSERDU. Serious adverse reactions in >1% of patients who received ORSERDU were musculoskeletal pain (1.7%) and nausea (1.3%). Fatal adverse reactions occurred in 1.7% of patients who received ORSERDU, including cardiac arrest, septic shock, diverticulitis, and unknown cause (one patient each).
Permanent discontinuation of ORSERDU due to an adverse reaction occurred in 6% of patients. Adverse reactions which resulted in permanent discontinuation of ORSERDU in >1% of patients were musculoskeletal pain (1.7%) and nausea (1.3%).



Dosage interruptions of ORSERDU due to an adverse reaction occurred in 15% of patients. Adverse reactions which resulted in dosage interruption of ORSERDU in >1% of patients were nausea (3.4%), musculoskeletal pain (1.7%), and increased ALT (1.3%).
Dosage reductions of ORSERDU due to an adverse reaction occurred in 3% of patients. Adverse reactions which required dosage reductions of ORSERDU in >1% of patients were nausea (1.7%).
The most common (>10%) adverse reactions, including laboratory abnormalities, of ORSERDU were musculoskeletal pain, nausea, increased cholesterol, increased AST, increased triglycerides, fatigue, decreased hemoglobin, vomiting, increased ALT, decreased sodium, increased creatinine, decreased appetite, diarrhea, headache, constipation, abdominal pain, hot flush, and dyspepsia.
Table 3 summarizes the adverse reactions in EMERALD.
Table 3: Adverse Reactions (>10%) in Patients with ER-positive, HER2-negative, Advanced or Metastatic Breast Cancer Who Received ORSERDU in EMERALDa
ORSERDU                 Fulvestrant or an Aromatase
(n=237)                          Inhibitor
Adverse Reaction                                                            (n=230) All Grades       Grade 3 or 4 c   All Grades     Grade 3 or 4 c
(%)              (%)             (%)             (%)
Musculoskeletal and connective tissue disorders
Musculoskeletal painb             41                7               39              1 Gastrointestinal disorders
Nausea                            35               2.5              19             0.9 Vomitingb                         19               0.8              9               0 Diarrhea                          13                0               10              1 Constipation                      12                0               6               0 Abdominal painb                   11                1               10             0.9 Dyspepsia                         10                0              2.6              0 General disorders
Fatigueb                           26                2               27              1 Metabolism and nutrition disorders
Decreased appetite                 15               0.8              10             0.4 Nervous system
Headache                           12                2               12              0 Vascular disorders
Hot flush                          11                0               8               0 a Adverse  reactions were graded using NCI CTCAE version 5.0.
b Includes other related terms c
Only includes Grade 3 adverse reactions.

Clinically relevant adverse reactions in < 10% of patients who received ORSERDU included rash, insomnia, dyspnea, cough, dizziness, stomatitis and gastroesophageal reflux disease.
Table 4 summarizes the laboratory abnormalities in EMERALD.
Table 4: Select Laboratory Abnormalities (>10%) That Worsened from Baseline in Patients with ER-positive, HER2-negative, Advanced or Metastatic Breast Cancer Who Received ORSERDU in EMERALDa
Laboratory Abnormality                      ORSERDUa                 Fulvestrant or an Aromatase Inhibitora
All Grades       Grade 3 or 4     All Grades        Grade 3 or 4
(%)              (%)              (%)                (%)
Chemistry
Cholesterol increased                  30               1                17                 0 


Laboratory Abnormality                              ORSERDUa                        Fulvestrant or an Aromatase Inhibitora
All Grades          Grade 3 or 4          All Grades       Grade 3 or 4 (%)                 (%)                   (%)              (%)
Aspartate aminotransferase                   29                  0                     34               1 increased
Triglycerides increased                     27                    2                   15                    1 Alanine aminotransferase                    17                    0                   24                    1 increased
Sodium decreased                            16                    1                   15                    0 Creatinine increased                        16                    0                   6                     0 Hematology
Hemoglobin decreased                        26                    1                   20                    2 a
The denominator used to calculate the rate varied from 29 to 236 for ORSERDU and from 37 to 225 for fulvestrant or an aromatase inhibitor based on the number of patients with a baseline value and at least one post-treatment value.

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