Adverse reactions : תופעות לוואי

6.         ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling: •   Diarrhea [see Warnings and Precautions (5.1)]
•   Hepatotoxicity [see Warnings and Precautions (5.2)]

6.1        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.
Extended Adjuvant Treatment of Early Stage Breast Cancer
ExteNET
The data described below reflect the safety data of NERLYNX as a single agent in ExteNET , a multicenter, randomized, double-blind, placebo-controlled study of NERLYNX within 2 years after completion of adjuvant treatment with trastuzumab-based therapy in women with HER2-positive early-stage breast cancer. Patients who received NERLYNX in this trial were not required to receive any prophylaxis with antidiarrheal agents to prevent the NERLYNX-related diarrhea. Patients were treated with 240 mg of NERLYNX given orally once daily with food, continuously until disease recurrence or for up to one year. The median duration of treatment was 11.6 months in the NERLYNX arm and 11.8 months in the placebo arm. The median age was 52 years (60% were ≥50 years old, 12% were ≥65 years old); 81% were Caucasian, 3% Black or African American, 14% Asian, and 3% other. A total of 1408 patients were treated with NERLYNX.
NERLYNX dose reduction due to an adverse reaction of any grade occurred in 31% of patients receiving NERLYNX compared to 2.6% of patients receiving placebo. Permanent discontinuation due to any adverse reaction was reported in 28% of NERLYNX-treated patients. The most common adverse reaction leading to discontinuation was diarrhea, accounting for 17% of NERLYNX-treated patients.
The most common adverse reactions (≥5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increased, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased and urinary tract infection. The most frequently reported Grade 3 or 4 adverse reactions were diarrhea, vomiting, nausea, and abdominal pain.
Serious adverse reactions in the NERLYNX arm included diarrhea (1.6%), vomiting (0.9%), dehydration (0.6%), cellulitis (0.4%), renal failure (0.4%), erysipelas (0.4%), ALT (0.3%), AST increased (0.3%), nausea (0.3%), fatigue (0.2%), and abdominal pain (0.2%).
Table 8 summarizes the adverse reactions in ExteNET.
Table 8:           Adverse Reactions Reported in ≥2% of NERLYNX-Treated Patients in ExteNET System Organ Class                               NERLYNX                                                Placebo (Preferred Term)                                 n=1408                                                n=1408 All Grades        Grade 3            Grade 4         All Grades         Grade 3         Grade 4 (%)            (%)                (%)                (%)              (%)            (%) Gastrointestinal Disorders
Diarrhea                        95              40                         0.1               35                 2              0 Nausea                          43               2                          0                22                0.1             0 Abdominal pain*                 36               2                          0                15                0.4             0 Vomiting                        26               3                          0                 8                0.4             0 †
Stomatitis                      14              0.6                         0                 6                0.1             0 Dyspepsia                       10              0.4                         0                 4                 0              0 Abdominal distension             5              0.3                         0                 3                 0              0 Dry mouth                        3              0.1                         0                 2                 0              0 General Disorders and Administration Site Conditions
Fatigue                         27               2                          0                20                0.4             0 Hepatobiliary Disorders
Alanine aminotransferase         9               1                         0.2                3                0.2             0 increased
Aspartate aminotransferase       7              0.5                        0.2                3                0.3             0 increased
Infections and Infestations
Urinary tract infection          5              0.1                         0                 2                 0              0 Investigations
Weight decreased                 5              0.1                         0                0.5                0              0 Metabolism and Nutrition Disorders
Decreased appetite              12              0.2                         0                 3                 0              0 Dehydration                      4              0.9                        0.1               0.4               0.1             0 Musculoskeletal and Connective Tissue Disorders
Muscle spasms                   11              0.1                         0                 3                0.1             0 Respiratory, Thoracic and Mediastinal Disorders
Epistaxis                        5               0                          0                 1                0.1             0 Skin and Subcutaneous Tissue Disorders
Rash‡                           18              0.6                         0                 9                 0              0 Dry skin                         6               0                          0                 2                 0              0 Nail Disorder§                   8              0.3                         0                 2                 0              0 Skin fissures                    2              0.1                         0                0.1                0              0 *     Includes abdominal pain, abdominal pain upper, and abdominal pain lower †     Includes stomatitis, aphthous stomatitis, mouth ulceration, oral mucosal blistering, mucosal inflammation, oropharyngeal pain, oral pain, glossodynia, glossitis, and cheilitis
‡     Includes rash, rash erythematous, rash follicular, rash generalized, rash pruritic, rash pustular, rash maculo-papular, rash papular, dermatitis, dermatitis acneiform, and toxic skin eruption
§     Includes nail disorder, paronychia, onychoclasis, nail discoloration, nail toxicity, nail growth abnormal, and nail dystrophy 

Advanced or Metastatic Breast Cancer
NALA
The data described below reflect the safety data of NERLYNX plus capecitabine in NALA, a randomized, multicenter, multinational, open-label, active-controlled study of HER2+ metastatic breast cancer in patients, with or without brain metastases, who have received two or more prior anti HER2-based regimens in the metastatic setting.
Patients were treated with NERLNX 240 mg orally once daily Days 1-21 of a 21-day cycle in combination with capecitabine (750 mg/m2 given orally twice daily) Days 1-14 of a 21-day cycle or lapatinib 1250 mg orally once daily Days 1-21 of a 21-day cycle in combination with capecitabine (1000 mg/m2 given orally twice daily) Days 1-14 of a 21-day cycle until disease progression. The median duration of treatment was 5.7 months in the NERLYNX plus capecitabine arm and 4.4 months in the lapatinib plus capecitabine arm.
NERLYNX dose reduction due to an adverse reaction of any grade occurred in 10% of patients receiving NERLYNX plus capecitabine. Permanent discontinuation due to any adverse reaction was reported in 14% of NERLYNX plus capecitabine treated patients. The most common adverse reactions leading to discontinuation were vomiting (3.6%), diarrhea (2.6%), nausea (2.6%), and palmar-plantar erythrodysaesthesia syndrome (2.3%) of NERLYNX plus capecitabine -treated patients.
The most common adverse reactions of any grade (≥5%) in the NERLYNX plus capecitabine arm were diarrhea, nausea, vomiting, decreased appetite, constipation, fatigue/asthenia, weight decreased, dizziness, back pain, arthralgia, urinary tract infection, upper respiratory tract infection, abdominal distention, renal impairment, and muscle spasms. The most frequently reported Grade 3 or 4 adverse reactions were diarrhea, nausea, vomiting, fatigue, and decreased appetite.
Serious adverse reactions ≥2% in the NERLYNX plus capecitabine arm included diarrhea (7%), vomiting (3%), nausea (2.3%), and acute kidney injury (2.3%).
Table 9 summarizes the adverse reactions in NALA.
Table 9:       Adverse Reactions Reported in ≥2% of NERLYNX-Treated Patients in Combination with Capecitabine in NALA
System Organ Class               NERLYNX plus capecitabine                    Lapatinib plus capecitabine (Preferred Term)                       n=303                                           n=311 All Grades   Grade 3       Grade 4           All Grades      Grade 3      Grade 4 (%)        (%)           (%)                 (%)           (%)          (%) Gastrointestinal Disorders
Diarrhea                        83              25                0             66            13            0 Nausea                          53             4.3                0             42            2.9           0 Vomiting                        46               4                0             31            1.9           0 Constipation                    31               1                0             13             0            0 Abdominal distension             8             0.3                0             3.2           0.6           0 General Disorders and Administration Site Conditions
Fatigue/asthenia                45               6                0             40            4.5           0 Malaise                         4.3              0                0             2.3           0.3           0 Influenza like illness           4               0                0             1.3            0            0 Infections and Infestations
Urinary tract infection          9             0.7                0             4.2           0.6           0 Upper respiratory tract
8             0.3                0             4.5           0.3           0 infection


Metabolism and Nutrition Disorders
Decreased appetite               35             2.6               0             22            2.3           0 Musculoskeletal and Connective Tissue Disorders
Back Pain                        10             0.3               0              8            0.3           0 Arthralgia                       10              0                0              6             1            0 Muscle spasms                     5              0                0             1.9            0            0 System Organ Class                   NERLYNX plus capecitabine                          Lapatinib plus capecitabine (Preferred Term)                           n=303                                                 n=311 All Grades   Grade 3       Grade 4                 All Grades      Grade 3      Grade 4 (%)        (%)           (%)                       (%)           (%)          (%) Nervous System Disorder
Dizziness                                14               0.3               0               10               0.6      0 Renal and urinary disorders
Renal impairment*                         7                2               0.3               1                0      0.3 Dysuria                                  4.6               0                0               1.9               0       0 Investigations
Weight decreased                         20               0.3               0               13               0.6      0 * Renal impairment includes acute kidney injury, blood creatinine increased, renal failure, and renal impairment CONTROL
The CONTROL (NCT02400476) study was a multicenter, open-label, multi-cohort trial evaluating patients with early stage HER2-positive breast cancer treated with neratinib 240 mg daily for up to one year receiving loperamide prophylaxis with and without an additional anti-diarrheal treatment. All patients received loperamide 4 mg loading dose, followed by 4 mg three times a day from Days 1-14, followed by 4 mg twice a day on Days 15-56, followed by loperamide as needed through 1 year of treatment with neratinib [see Dosage and Administration (3.1)]. One cohort of patients received budesonide 9 mg once daily on cycle 1 Days 1-28, in addition to loperamide. At the interim analysis, the incidence of all grade diarrhea for patients receiving loperamide alone (n=109) was 78% compared to 86% of patients who received budesonide and loperamide (n=64). The incidence of Grade 2 diarrhea was 25% compared to 33%, respectively. The incidence of Grade 3 diarrhea was 32% compared to 28%, respectively. Diarrhea leading to treatment discontinuation occurred in 18% of patients treated with loperamide alone compared to 11% of the patients who received loperamide and budesonide.
Reporting suspected adverse reaction 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/