Adverse reactions : תופעות לוואי

8     ADVERSE REACTIONS
The following serious adverse reactions are also described elsewhere in the labeling: 


•      Ocular Disorders [see Warning and Precautions (7.1)].

•      Hyperphosphatemia [see Warning and Precautions (7.2)].
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 BALVERSA was evaluated in the BLC2001 study that included 87 patients with locally advanced or metastatic urothelial carcinoma which had susceptible FGFR3 or FGFR2 genetic alterations, and which progressed during or following at least one line of prior chemotherapy including within 12 months of neoadjuvant or adjuvant chemotherapy [see Clinical Studies (14.1)]. Patients were treated with BALVERSA at 8 mg orally once daily; with a dose increase to 9 mg in patients with phosphate levels <5.5 mg/dL on Day 14 of Cycle 1. Median duration of treatment was 5.3 months (range: 0 to 17 months).
The most common adverse reactions (ARs) including laboratory abnormalities (≥20%) were phosphate increased, stomatitis, fatigue, creatinine increased, diarrhea, dry mouth, nail disorder, alanine aminotransferase increased, alkaline phosphatase increased, sodium decreased, decreased appetite, albumin decreased, dysgeusia, hemoglobin decreased, dry skin, aspartate aminotransferase increased, magnesium decreased, dry eye, alopecia, palmar-plantar erythrodysesthesia syndrome, constipation, phosphate decreased, abdominal pain, calcium increased, nausea, and musculoskeletal pain. The most common Grade 3 or greater ARs (>1%) were stomatitis, nail dystrophy, hyponatremia, palmar- plantar erythrodysesthesia syndrome, paronychia, nail disorder, keratitis, and hyperphosphatemia.
An adverse reaction with a fatal outcome in 1% of patients was acute myocardial infarction.
Serious adverse reactions occurred in 41% of patients including eye disorders (10%).
Permanent discontinuation due to an adverse reaction occurred in 13% of patients. The most frequent reasons for permanent discontinuation included eye disorders (6%).
Dosage interruptions occurred in 68% of patients. The most frequent adverse reactions requiring dosage interruption included hyperphosphatemia (24%), stomatitis (17%), eye disorders (17%), and palmar-plantar erythro-dysesthesia syndrome (8%).
Dose reductions occurred in 53% of patients. The most frequent adverse reactions for dose reductions included eye disorders (23%), stomatitis (15%), hyperphosphatemia (7%), palmar-plantar erythro-dysesthesia syndrome (7%), paronychia (7%), and nail dystrophy (6%).
Table 3 presents ARs reported in ≥10% of patients treated with BALVERSA at 8 mg once daily.



Table 3:        Adverse Reactions Reported in ≥ 10% (Any Grade) or ≥5% (Grade 3-4) of Patients
BALVERSA 8 mg daily (N=87)
Adverse Reaction                          All Grades (%)          Grade 3-4 (%) Any                                             100                     67 Gastrointestinal disorders                       92                     24 Stomatitis                                    56                       9 Diarrhea                                       47                      2 Dry mouth                                      45                      0 Constipation                                   28                      1 Abdominal paina                                23                      2 Nausea                                         21                      1 Vomiting                                       13                      2 Metabolism and nutrition disorders               90                     16 Decreased appetite                             38                      0 Hyponatremia                                  11                      10 General disorders and admin. site                69                     13 conditions
Fatigueb                                      54                         10 Pyrexia                                       14                         1 Skin and subcutaneous disorders                 75                         16 Nail disorderc                                45                         10 Dry skind                                     34                         0 Palmar-plantar erythrodysesthesia             26                         6 Alopecia                                      26                         0 Nail discoloration                            11                         0 Eye disorders                                   62                         11 Dry eyee                                      28                         6 Vision blurred                                17                         0 Lacrimation increased                         10                         0 Nervous system disorders                        57                         5 Dysgeusia                                     37                         1 Infections and infestations                     56                         20 Paronychia                                    17                         3 Urinary tract infection                       17                         6 Conjunctivitis                                11                         0 Respiratory, thoracic and mediastinal           40                         7 disorders
Oropharyngeal pain                            11                         1 Dyspneaf                                      10                         2 Renal and urinary tract disorders               38                         10 Hematuria                                     11                         2 Musculoskeletal and connective tissue           31                         0 disorders
Musculoskeletal paing                         20                         0 Arthralgia                                    11                         0 Investigations                                  44                         5 Weight decreasedh                             16                         0 Blood creatinine increased                   11                         0 


 a
Includes abdominal pain, abdominal discomfort, abdominal pain upper, and abdominal pain lower b
Includes asthenia, fatigue, lethargy, and malaise c
Includes onycholysis, onychoclasis, nail disorder, nail dystrophy, nail ridging, and onychomadesis d
Includes dry skin and xerostomia e
Includes dry eye, xerophthalmia, keratitis, foreign body sensation, and corneal erosion f
Includes dyspnea and dyspnea exertional g
Includes back pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal chest pain, neck pain, pain in extremity h
Includes weight decreased and cachexia


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 http://sideeffects.health.gov.il


Table 4:               Laboratory Abnormalities Reported in ≥ 10% (All Grade) or ≥ 5% (Grade 3-4) of Patients
BALVERSA 8 mg daily (N=86a)
Laboratory Abnormality                                      All Grades (%)         Grade 3-4 (%) Hematology
Hemoglobin decreased                                               35                                     3 Platelets decreased                                                19                                     1 Leukocytes decreased                                               17                                     0 Neutrophils decreased                                              10                                     2 Chemistry
Phosphate increased                                                76                                    1 Creatinine increased                                               52                                    5 Sodium decreased                                                   40                                    16 Alanine aminotransferase increased                                 41                                    1 Alkaline phosphatase increased                                     41                                    1 Albumin decreased                                                  37                                    0 Aspartate aminotransferase increased                               30                                    0 Magnesium decreased                                                30                                    1 Phosphate decreased                                                24                                    9 Calcium increased                                                  22                                    3 Potassium increased                                                16                                    0 Fasting glucose decreased                                          10                                    0 a
One of the 87 patients had no laboratory tests.