Adverse reactions : תופעות לוואי

6 ADVERSE REACTIONS
The following serious adverse reactions are described elsewhere in the labeling: •   Skin Reactions [see Boxed Warning, Warnings and Precautions (5.1)] •   Hyperglycemia [see Warnings and Precautions (5.2)]
•   Pneumonitis [see Warnings and Precautions (5.3)]
•   Peripheral Neuropathy [see Warnings and Precautions (5.4)]
•   Ocular Disorders [see Warnings and Precautions (5.5)]
•   Infusion Site Extravasation [see Warnings and Precautions (5.6)] 


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.
The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to PADCEV as a single agent at 1.25 mg/kg in 680 patients in EV-301, EV-201, EV-101 (NCT02091999), and EV-102 (NCT03070990). Ocular disorders reflect 384 patients in EV-201, EV-101, and EV-102. Among 680 patients receiving PADCEV, 36% were exposed for > 6 months and 9% were exposed for ≥ 12 months. In this pooled population, the most common (> 20%) adverse reactions, including laboratory abnormalities, were rash, aspartate aminotransferase increased, glucose increased, creatinine increased, fatigue, peripheral neuropathy, lymphocytes decreased, alopecia, decreased appetite, hemoglobin decreased, diarrhea, sodium decreased, nausea, pruritus, phosphate decreased, dysgeusia, alanine aminotransferase increased, anemia, albumin decreased, neutrophils decreased, urate increased, lipase increased, platelets decreased, weight decreased and dry skin.
The data described in the following sections reflect exposure to PADCEV from an open-label, randomized, study (EV-301); and Cohort 1 and Cohort 2 of an open-label, single arm, two cohort study (EV-201). Patients received PADCEV 1.25 mg/kg on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity.
Previously Treated Locally Advanced or Metastatic Urothelial Cancer
EV-301
The safety of PADCEV was evaluated in EV-301 in patients with locally advanced or metastatic urothelial cancer (n=296) who received at least one dose of PADCEV 1.25 mg/kg and who were previously treated with a PD-1 or PD-L1 inhibitor and a platinum-based chemotherapy [see Clinical Studies (12)]. Routine ophthalmologic exams were not conducted in EV-301. The median duration of exposure to PADCEV was 5 months (range: 0.5 to 19.4 months).
Serious adverse reactions occurred in 47% of patients treated with PADCEV. The most common serious adverse reactions (≥ 2%) were urinary tract infection, acute kidney injury (7% each) and pneumonia (5%). Fatal adverse reactions occurred in 3% of patients, including multiorgan dysfunction (1.0%), hepatic dysfunction, septic shock, hyperglycemia, pneumonitis and pelvic abscess (0.3% each).
Adverse reactions leading to discontinuation occurred in 17% of patients; the most common adverse reactions (≥ 2%) leading to discontinuation were peripheral neuropathy (5%) and rash (4%).
Adverse reactions leading to dose interruption occurred in 61% of patients; the most common adverse reactions (≥ 4%) leading to dose interruption were peripheral neuropathy (23%), rash (11%) and fatigue (9%).
Adverse reactions leading to dose reduction occurred in 34% of patients; the most common adverse reactions (≥ 2%) leading to dose reduction were peripheral neuropathy (10%), rash (8%), decreased appetite (3%) and fatigue (3%).



Table 3 summarizes the most common (≥ 15%) adverse reactions in EV-301.

Table 3. Adverse Reactions (≥ 15%) in Patients Treated with PADCEV in EV-301 PADCEV                           Chemotherapy n=296                              n=291
All Grades        Grade 3-4        All Grades       Grade 3-4
Adverse Reaction                           %                %                %               % Skin and subcutaneous tissue disorders
Rash1                                      54               14               20              0.3 Alopecia                                   47                0               38               0 Pruritus                                   34                2                7               0 Dry skin                                   17                0                4               0 General disorders and administration site conditions
Fatigue2                                   50                9               40               7 3
Pyrexia                                    22                2               14               0 Nervous system disorders
Peripheral neuropathy4                     50                5               34               3 5
Dysgeusia                                  26                0                8               0 Metabolism and nutrition disorders
Decreased appetite                         41                5               27               2 Gastrointestinal disorders
Diarrhea6                                  35                4               23               2 Nausea                                     30                1               25               2 Constipation                               28                1               25               2 7
Abdominal Pain                             20                1               14               3 Musculoskeletal and connective tissue disorders
Musculoskeletal Pain8                      25                2               35               5 Eye Disorders
Dry eye9                                   24              0.7                6              0.3 Blood and lymphatic system disorders
Anemia                                     20                6               30              12 Infections and infestations
Urinary Tract Infection10                  17                6               13               3 Vascular disorders
Hemorrhage11                               17                3               13               2 Investigations
Weight decreased                           16              0.3                7               0 1
Includes: blister, blood blister, conjunctivitis, dermatitis, dermatitis bullous, drug eruption, eczema, erythema, erythema multiforme, exfoliative rash, intertrigo, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash vesicular, skin irritation, skin exfoliation, stomatitis 2
Includes: fatigue, asthenia
3
Includes: pyrexia, hyperthermia, hyperpyrexia, body temperature increased 4
Includes: burning sensation, demyelinating polyneuropathy, dysesthesia, hypoesthesia, muscular weakness, neuralgia, neuropathy peripheral, neurotoxicity, paresthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peroneal nerve palsy, peripheral sensory neuropathy, gait disturbance, polyneuropathy, sensory loss 5
Includes: dysgeusia, ageusia, hypogeusia
6
Includes: diarrhea, colitis, enterocolitis
7
Includes: abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, hepatic pain, abdominal tenderness, gastrointestinal pain
8
Includes: myalgia, arthralgia, back pain, bone pain, pain in extremity, musculoskeletal pain, arthritis, neck pain, non- cardiac chest pain, musculoskeletal chest pain, spinal pain, musculoskeletal stiffness, musculoskeletal discomfort 9
Includes: blepharitis, conjunctivitis, dry eye, eye irritation, keratitis, keratopathy, lacrimation increased, Meibomian gland dysfunction, ocular discomfort, punctate keratitis
10
Includes: urinary tract infection, urinary tract infection bacterial, urinary tract infection enterococcal, streptococcal urinary tract infection, escherichia urinary tract infection, pyelonephritis acute, escherichia pyelonephritis, urinary tract infection fungal, cystitis, urinary tract infection staphylococcal, urinary tract infection pseudomonal 11
Includes: hematuria, rectal hemorrhage, gastrointestinal hemorrhage, epistaxis, upper gastrointestinal hemorrhage, tumor hemorrhage, hemoptysis, vaginal hemorrhage, anal hemorrhage, hemorrhagic stroke, urethral hemorrhage, infusion site hemorrhage, conjunctival hemorrhage, hemorrhagic ascites, hemorrhoidal hemorrhage 

Clinically relevant adverse reactions (< 15%) include vomiting (14%), aspartate aminotransferase increased (12%), hyperglycemia (10%), alanine aminotransferase increased (9%), pneumonitis (3%) and infusion site extravasation (0.7%).

Table 4. Selected Laboratory Abnormalities Reported in ≥ 15% (Grades 2-4) or ≥ 5% (Grade 3-4) of Patients Treated with PADCEV in EV-301
PADCEV1                         Chemotherapy1
Grades 2-4            Grade 3-4             Grades 2-4              Grade 3-4 Laboratory Abnormality                                  %                     %                     %                       % Hematology
Lymphocytes decreased                                     41                    14                     34                     18 Hemoglobin decreased                                      28                     4                     42                     14 Neutrophils decreased                                     27                    12                     25                     17 Chemistry
Phosphate decreased                                       39                     8                     24                      6 Glucose increased (non-fasting)                           33                     9                     27                      6 Creatinine increased                                      18                     2                     13                      0 Potassium decreased                                       16                     2                      7                      3 Lipase increased                                          13                     8                      7                      4 Sodium decreased                                           8                     8                      5                      5 1
The denominator used to calculate the rate varied from 262 to 287 based on the number of patients with a baseline value and at least one post-treatment value


EV-201, Cohort 1
The safety of PADCEV was evaluated in EV-201, Cohort 1 in patients (n=125) with locally advanced or metastatic urothelial cancer who had received prior treatment with a PD-1 or PD-L1 inhibitor and platinum- based chemotherapy [see Clinical Studies (12)]. Patients received PADCEV 1.25 mg/kg on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity. The median duration of exposure to PADCEV was 4.6 months (range: 0.5-15.6).
Serious adverse reactions occurred in 46% of patients treated with PADCEV. The most common serious adverse reactions (≥ 3%) were urinary tract infection (6%), cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea (3%), and rash (3%). Fatal adverse reactions occurred in 

3.2% of patients, including acute respiratory failure, aspiration pneumonia, cardiac disorder, sepsis and pneumonitis (each 0.8%).
Adverse reactions leading to discontinuation occurred in 16% of patients; the most common adverse reaction leading to discontinuation was peripheral neuropathy (6%). Adverse reactions leading to dose interruption occurred in 64% of patients; the most common adverse reactions leading to dose interruption were peripheral neuropathy (18%), rash (9%) and fatigue (6%).
Adverse reactions leading to dose reduction occurred in 34% of patients; the most common adverse reactions leading to dose reduction were peripheral neuropathy (12%), rash (6%), and fatigue (4%).
Table 5 summarizes the All Grades and Grade 3-4 adverse reactions reported in patients in EV-201, Cohort 1.

Table 5. Adverse Reactions Reported in ≥ 15% (All Grades) or ≥ 5% (Grade 3-4) of Patients Treated with PADCEV in EV-201 Cohort 1
PADCEV n=125
All Grades                  Grade 3-4
Adverse Reaction                                           %                          % Any                                                       100                         73 General disorders and administration site conditions
Fatigue1                                                   56                          6 Nervous system disorders
Peripheral neuropathy2                                     56                          4 Dysgeusia                                                  42                          0 Metabolism and nutrition disorders
Decreased appetite                                         52                          2 Skin and subcutaneous tissue disorders
Rash3                                                      52                         13 Alopecia                                                   50                          0 Dry skin                                                   26                          0 Pruritus 4
26                          2
Gastrointestinal disorders
Nausea                                                     45                          3 Diarrhea5                                                  42                          6 Vomiting                                                   18                          2 Eye disorders
Dry eye6                                                   40                          0 1
Includes: asthenia and fatigue
2
Includes: hypoesthesia, gait disturbance, muscular weakness, neuralgia, paresthesia, peripheral motor neuropathy, peripheral sensory neuropathy and peripheral sensorimotor neuropathy
3
Includes: dermatitis acneiform, dermatitis bullous, dermatitis contact, dermatitis exfoliative, drug eruption, erythema, erythema multiforme, exfoliative rash, palmar-plantar erythrodysesthesia syndrome, photosensitivity reaction, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, rash pustular, rash pruritic, rash vesicular, skin exfoliation, stasis dermatitis, and symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) and urticaria
4
Includes: pruritus and pruritus generalized
5
Includes: colitis, diarrhea and enterocolitis
6
Includes: blepharitis, conjunctivitis, dry eye, eye irritation, keratitis, keratopathy, lacrimation increased, limbal stem cell 
deficiency, Meibomian gland dysfunction, ocular discomfort, punctate keratitis, tear break up time decreased 


Clinically relevant adverse reactions (< 15%) include herpes zoster (3%), pneumonitis (2%) and infusion site extravasation (2%).

Table 6. Selected Laboratory Abnormalities Reported in ≥ 15% (Grades 2-4) or ≥ 5% (Grade 3-4) of Patients Treated with PADCEV in EV-201, Cohort 1
PADCEV
Grades 2-4 1               Grade 3-41
Laboratory Abnormality                                     %                         % Hematology
Hemoglobin decreased                                       34                        10 Lymphocytes decreased                                      32                        10 Neutrophils decreased                                      14                         5 Chemistry
Phosphate decreased                                        34                        10 Glucose increased (non-fasting)                            27                         8 Creatinine increased                                       20                         2 2
Potassium decreased                                        19                         1 Lipase increased                                           14                         9 Sodium decreased                                            8                         8 Urate increased                                             7                         7 1
Denominator for each laboratory parameter is based on the number of patients with a baseline and post- treatment laboratory value available for 121 or 122 patients
2
Includes Grade 1 (potassium 3.0-3.5 mmol/L) – Grade 4


EV-201, Cohort 2
The safety of PADCEV was evaluated in EV-201, Cohort 2 in patients with locally advanced or metastatic urothelial cancer (n=89) who received at least one dose of PADCEV 1.25 mg/kg and had prior treatment with a PD-1 or PD-L1 inhibitor and were not eligible for cisplatin-based chemotherapy. The median duration of exposure was 5.98 months (range: 0.3 to 24.6 months).
Serious adverse reactions occurred in 39% of patients treated with PADCEV. The most common serious adverse reactions (≥ 3%) were pneumonia, sepsis and diarrhea (5% each). Fatal adverse reactions occurred in 8% of patients, including acute kidney injury (2.2%), metabolic acidosis, sepsis, multiorgan dysfunction, pneumonia and pneumonitis (1.1% each).
Adverse reactions leading to discontinuation occurred in 20% of patients; the most common adverse reaction (≥ 2%) leading to discontinuation was peripheral neuropathy (7%).
Adverse reactions leading to dose interruption occurred in 60% of patients; the most common adverse reactions (≥ 3%) leading to dose interruption were peripheral neuropathy (19%), rash (9%), fatigue (8%), diarrhea (5%), aspartate aminotransferase increased (3%) and hyperglycemia (3%).


Adverse reactions leading to dose reduction occurred in 49% of patients; the most common adverse reactions (≥ 3%) leading to dose reduction were peripheral neuropathy (19%), rash (11%) and fatigue (7%).
Table 7 summarizes the All Grades and Grades 3-4 adverse reactions reported in patients in EV-201, Cohort 2.
Table 7. Adverse Reactions ≥ 15% (All Grades) or ≥ 5% (Grades 3-4) in Patients Treated with PADCEV in EV-201, Cohort 2
PADCEV n=89
All Grades                 Grades 3-4
Adverse Reaction                                           (%)                       (%) Skin and subcutaneous tissue disorders
Rash1                                                       66                        17 Alopecia                                                    53                         0 Pruritus                                                    35                         3 Dry skin                                                    19                         1 Nervous system disorders
Peripheral neuropathy2                                      58                         8 Dysgeusia3                                                  29                         0 General disorders and administration site conditions
Fatigue4                                                    48                        11 Metabolism and nutrition disorders
Decreased appetite                                          40                         6 Hyperglycemia                                               16                         9 Blood and lymphatic disorders
Anemia                                                      38                        11 Gastrointestinal disorders
Diarrhea5                                                   36                         8 Nausea                                                      30                         1 Investigations
Weight decreased                                            35                         1 Eye disorders
Dry eye6                                                    30                         0 1
Includes: blister, conjunctivitis, dermatitis bullous, dermatitis exfoliative generalized, eczema, erythema, erythema multiforme, intertrigo, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash vesicular, skin exfoliation, stomatitis 2
Includes: demyelinating polyneuropathy, gait disturbance, hypoesthesia, motor dysfunction, muscle atrophy, muscular weakness, paresthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peroneal nerve palsy, peripheral sensory neuropathy
3
Includes: dysgeusia, ageusia, hypogeusia
4
Includes: fatigue, asthenia
5
Includes: diarrhea, colitis, enterocolitis
6
Includes: blepharitis, conjunctivitis, dry eye, eye irritation, keratitis, keratopathy, lacrimation increased, limbal stem cell deficiency, Meibomian gland dysfunction, ocular discomfort, punctate keratitis, tear break up time decreased 
Clinically relevant adverse reactions (< 15%) include vomiting (13%), aspartate aminotransferase increased (12%), lipase increased (11%), alanine aminotransferase increased (10%), pneumonitis (4%) and infusion site extravasation (1%).


Table 8. Selected Laboratory Abnormalities Reported in ≥ 15% (Grades 2-4) or ≥ 5% (Grades 3-4) of Patients Treated with PADCEV in EV-201, Cohort 2
PADCEV
N=881
1
Grades 2-4               Grade 3-41
Laboratory Abnormality                                     %                        % Hematology
Lymphocytes decreased                                      43                       15 Hemoglobin decreased                                       34                        5 Neutrophils decreased                                      20                        9 Chemistry
Glucose increased (non-fasting)                            36                       13 Phosphate decreased                                        25                        7 Creatinine increased                                       23                        3 Lipase increased                                           18                       11 Urate increased                                             9                        9 Potassium increased                                         8                        6 Sodium decreased                                            7                        7 1
Based on the number of patients with a baseline value and at least one post-treatment value 
6.2 Post Marketing Experience

The following adverse reactions have been identified during post-approval use of PADCEV. 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.
Skin and subcutaneous tissue disorders: Epidermal necrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis [see Warnings and Precautions (5.1)].
6.3 Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the trials described below with the incidence of antibodies in other trials or other enfortumab vedotin products may be misleading.
Following administration of PADCEV 1.25 mg/kg; 16/590 (2.7%) patients tested positive for anti-therapeutic antibody (ATA) against enfortumab vedotin at one or more post-baseline time points. Due to the limited number of patients with ATA against enfortumab vedotin, no conclusions can be drawn concerning a potential effect of immunogenicity on efficacy, safety or pharmacokinetics.

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