Adverse reactions : תופעות לוואי

8. ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling: •   Myelosuppression [see Warnings and Precautions (7.1)]
•   Hepatotoxicity [see Warnings and Precautions (7.2)]
•   Extravasation Resulting in Tissue Necrosis [see Warnings and Precautions (7.3)] •   Rhabdomyolysis [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 practice.
The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to ZEPZELCA as a single agent at a dose of 3.2 mg/m2 intravenously every 21 days in 554 patients with advanced solid tumors. Among 554 patients who received ZEPZELCA, including 105 patients with small cell lung cancer (SCLC) in PM1183-B-005-14 (Study B-005), 24% were exposed for 6 months or longer and 5% were exposed for greater than one year.
Small Cell Lung Cancer (SCLC)
The safety of ZEPZELCA was evaluated in a cohort of 105 patients with previously treated SCLC in Study B-005 [see Clinical Studies (14)]. Patients received ZEPZELCA 3.2 mg/m2 intravenously every 21 days. All patients in this study received a pre-specified anti-emetic regimen consisting of a corticosteroid and serotonin antagonist. Patients could receive G-CSF for secondary prophylaxis (i.e., after patients had an initial decrease in WBC), but not primary prophylaxis. Among patients who received ZEPZELCA, 29% were exposed for 6 months or longer and 6% were exposed for greater than one year.
Serious adverse reactions occurred in 34% of patients who received ZEPZELCA. Serious adverse reactions in ≥ 3% of patients included pneumonia, febrile neutropenia, neutropenia, respiratory tract infection, anemia, dyspnea, and thrombocytopenia.
Permanent discontinuation due to an adverse reaction occurred in two patients (1.9%) who received ZEPZELCA. Adverse reactions resulting in permanent discontinuation in ≥ 1% of patients who received ZEPZELCA, which included peripheral neuropathy and myelosuppression.
Dosage interruptions due to an adverse reaction occurred in 30.5% of patients who received ZEPZELCA. Adverse reactions requiring dosage interruption in ≥ 3% of patients who received ZEPZELCA included neutropenia, and hypoalbuminemia.
Dose reductions due to an adverse reaction occurred in 25% of patients who received ZEPZELCA. Adverse reactions requiring dosage reductions in ≥ 3% of patients who received ZEPZELCA included neutropenia, febrile neutropenia and fatigue.
The most common adverse reactions, including laboratory abnormalities, (≥ 20%) were leukopenia, lymphopenia, fatigue, anemia, neutropenia, increased creatinine, increased alanine aminotransferase, increased glucose, thrombocytopenia, nausea, decreased appetite, musculoskeletal pain, decreased albumin, constipation, dyspnea, decreased sodium, increased aspartate aminotransferase, vomiting, cough, decreased magnesium and diarrhea.
Table 3 summarizes the adverse reactions in the SCLC cohort of Study B-005.

Table 3: Adverse Reactions (≥ 10%) in Patients with SCLC Who Received ZEPZELCA in Study B-005 ZEPZELCA
(n=105)
Adverse Reaction                                                       All Gradesa,b (%)           Grades 3-4 (%) General disorders
Fatigue                                                                        77                         12 Pyrexia                                                                        13                         0 Chest pain                                                                     10                         0 Gastrointestinal disorders
Nausea                                                                               37                            0 Constipation                                                                         31                            0 Vomiting                                                                             22                            0 Diarrhea                                                                             20                            4 Abdominal   painc                                                                    11                            1 Musculoskeletal and connective tissue disorders
Musculoskeletal paind                                                                33                            4 Metabolism and nutrition disorders
Decreased appetite                                                                   33                            1 Respiratory, thoracic and mediastinal disorders
Dyspnea                                                                              31                            6 Coughe                                                                               20                            0 Infections and infestations
Respiratory tract infectionf                                                         18                            5 Pneumoniag                                                                           10                            7 Nervous system disorders
Peripheral neuropathyh                                                               11                            1 Headache                                                                             10                            1 a
Graded per NCI CTCAE 4.0.
b
No grade 5 adverse reactions were reported.
c
Includes abdominal pain, abdominal pain upper and abdominal discomfort.
d
Includes musculoskeletal pain, back pain, arthralgia, pain in extremity, musculoskeletal chest pain, neck pain, bone pain and myalgia.
e
Includes cough and productive cough.
f
Includes upper respiratory tract infection, viral upper respiratory tract infection, respiratory tract infection and bronchitis.
g
Includes pneumonia and lung infection.
h
Includes neuropathy peripheral, neuralgia, paresthesia, peripheral sensory neuropathy, hypoesthesia, and hyperesthesia.

Clinically relevant adverse reactions in < 10% of patients who received ZEPZELCA include dysgeusia, febrile neutropenia and pneumonitis.
Table 4 summarizes the laboratory abnormalities in Study B-005.

Table 4: Select Laboratory Abnormalities (≥ 20%) Worsening from Baseline in Patients with SCLC Who Received ZEPZELCA in Study B-005
ZEPZELCAa
(n=105)

Laboratory Abnormality                                                       All Gradesb (%)               Grades 3-4 (%) 
Hematology
Decreased leukocytes                                                                 79                           29 Decreased lymphocytes                                                                79                           43 Decreased hemoglobin                                                                 74                           10 Decreased neutrophils                                                                71                           46 Decreased platelets                                                                  37                            7 Chemistry
Increased creatinine                                                                 69                            0 Increased alanine aminotransferase                                                   66                            4 Increased glucose                                                                    52                            5 Decreased albumin                                                                  32                            1 Decreased sodium                                                                   31                            7 Increased aspartate aminotransferase                                               26                            2 Decreased magnesium                                                                22                            0 a
The denominator used to calculate the rate varied from 95 to 105 based on the number of patients with a baseline value and at least one post- treatment value.
b
Graded per NCI CTCAE 4.0.

8.2            Postmarketing Experience
The following adverse reactions have been identified during post-approval use of ZEPZELCA. 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.
General disorders and administration site conditions: Extravasation including tissue necrosis requiring debridement.
Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis.
Metabolism and nutrition disorders: Tumor lysis syndrome.


Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization 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