Special Warning : אזהרת שימוש

5 WARNINGS AND PRECAUTIONS
5.1 Bone Marrow Suppression
Cabazitaxel S.K. is contraindicated in patients with neutrophils ≤1,500/mm3 [see Contraindications (4)]. Closely monitor patients with hemoglobin <10 g/dL.
Bone marrow suppression manifested as neutropenia, anemia, thrombocytopenia and/or pancytopenia may occur. Neutropenic deaths have been reported.
In a randomized trial (TROPIC) in previously treated patients with metastatic castration-resistant prostate cancer, five patients (1.3%) died from infection (sepsis or septic shock). All had grade 4 neutropenia and one had febrile neutropenia. One additional patient’s death was attributed to neutropenia without a documented infection. Twenty-two (6%) patients discontinued cabazitaxel treatment due to neutropenia, febrile neutropenia, infection, or sepsis. The most common adverse reaction leading to treatment discontinuation in the cabazitaxel group was neutropenia (2%). Grade 3-4 neutropenia has been observed in 82% of patients treated with cabazitaxel in the randomized trial. In a randomized trial (PROSELICA) comparing two doses of cabazitaxel in previously treated metastatic castration-resistant prostate cancer, 8 patients (1%) on the 20 mg/m2 arm and 15 patients (3%) on the 25 mg/m2 arm died from infection; of these, 4 deaths on the 20 mg/m2 arm and 8 deaths on the 25 mg/m2 arm occurred within the first 30 days of treatment.
Fewer patients receiving cabazitaxel 20 mg/m2 were reported to have infectious adverse reactions. Grade 1-4 infections were experienced by 160 patients (28%) on the 20 mg/m2 arm and 227 patients (38%) on the 25 mg/m2 arm. Grade 3-4 infections were experienced by 57 patients (10%) on the 20 mg/m2 arm and 120 patients (20%) on the 25 mg/m2 arm.
Noninferiority for overall survival was demonstrated between these two arms [see Adverse Reactions (6.1)].


Based on guidelines for the use of G-CSF and the adverse reactions profile of Cabazitaxel S.K., primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features (older patients, poor performance status, previous episodes of febrile neutropenia, extensive prior radiation ports, poor nutritional status, or other serious comorbidities) that predispose them to increased complications from prolonged neutropenia.
The effectiveness of primary prophylaxis with G-CSF in patients receiving cabazitaxel has not been studied. Therapeutic use of G-CSF and secondary prophylaxis should be considered in all patients at increased risk for neutropenia complications.
Monitoring of complete blood counts is essential on a weekly basis during cycle 1 and before each treatment cycle thereafter so that the dose can be adjusted, if needed [see Dosage and Administration (2.2)].
5.2 Increased Toxicities in Elderly Patients
In a randomized trial (TROPIC), 2% of patients (3/131) <65 years of age and 6% (15/240) ≥65 years of age died of causes other than disease progression within 30 days of the last cabazitaxel dose. Patients ≥65 years of age are more likely to experience certain adverse reactions, including neutropenia and febrile neutropenia. The incidence of the following grade 3-4 adverse reactions were higher in patients ≥65 years of age compared to younger patients; neutropenia (87% vs 74%), and febrile neutropenia (8% vs 6%).
In a randomized clinical trial (PROSELICA) comparing two doses of cabazitaxel , deaths due to infection within 30 days of starting cabazitaxel occurred in 0.7% (4/580) patients on the 20 mg/m2 arm and 1.3% (8/595) patients on the 25 mg/m2 arm; all of these patients were >60 years of age.
In PROSELICA, on the 20 mg/m2 arm, 3% (5/178) of patients <65 years of age and 2% (9/402) ≥65 years of age died of causes other than disease progression within 30 days of the last 
cabazitaxel dose. On the 25 mg/m2 arm, 2% (3/175) patients <65 years of age and 5% (20/420) ≥65 years of age died of causes other than disease progression within 30 days of the last cabazitaxel dose [see Adverse Reactions (6) and Use in Specific Populations (8.5)].
5.3 Hypersensitivity Reactions
Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of cabazitaxel , thus facilities and equipment for the treatment of hypotension and bronchospasm should be available. Severe hypersensitivity reactions can occur and may include generalized rash/erythema, hypotension and bronchospasm.
Premedicate all patients prior to the initiation of the infusion of cabazitaxel [see Dosage and Administration (2.1)]. Observe patients closely for hypersensitivity reactions, especially during the first and second infusions.
Severe hypersensitivity reactions require immediate discontinuation of the cabazitaxel infusion and appropriate therapy. cabazitaxel is contraindicated in patients with a history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80 [see Contraindications (4)].
5.4 Gastrointestinal Adverse Reactions
Nausea, vomiting and severe diarrhea, at times, may occur. Deaths related to diarrhea and electrolyte imbalance occurred in the randomized clinical trials. Intensive measures may be required for severe diarrhea and electrolyte imbalance. Antiemetic prophylaxis is recommended.
Treat patients with rehydration, antidiarrheal or antiemetic medications as needed. Treatment delay or dosage reduction may be necessary if patients experience Grade ≥ 3 diarrhea [see Dosage and Administration (2.2)].
Gastrointestinal (GI) hemorrhage and perforation, ileus, enterocolitis, neutropenic enterocolitis, including fatal outcome, have been reported in patients treated with cabazitaxel [see Adverse Reactions (6.2)]. Risk may be increased with neutropenia, age, steroid use, concomitant use of NSAIDs, antiplatelet therapy or anticoagulants, and patients with a prior history of pelvic radiotherapy, adhesions, ulceration and GI bleeding.
Abdominal pain and tenderness, fever, persistent constipation, diarrhea, with or without neutropenia, may be early manifestations of serious gastrointestinal toxicity and should be evaluated and treated promptly. cabazitaxel treatment delay or discontinuation may be necessary.
The incidence of gastrointestinal adverse reactions is greater in the patients who have received prior radiation. In PROSELICA, diarrhea was reported in 41% (297/732) of patients who had received prior radiation and in 27% (118/443) of patients without prior radiation. Of the patients who had previously received radiation, more patients on the 25 mg/m2 arm reported diarrhea, compared to patients on the 20 mg/m2 arm.
5.5 Renal Failure
In the randomized clinical trial (TROPIC), renal failure of any grade occurred in 4% of the patients being treated with cabazitaxel , including four cases with fatal outcome. Most cases occurred in association with sepsis, dehydration, or obstructive uropathy [see Adverse Reactions (6.1)]. Some deaths due to renal failure did not have a clear etiology. Appropriate measures should be taken to identify causes of renal failure and treat aggressively.


5.6 Urinary Disorders Including Cystitis
Cystitis, radiation cystitis, and hematuria, including that requiring hospitalization, has been reported with cabazitaxel in patients who previously received pelvic radiation [see Adverse Reactions (6.2)]. In PROSELICA, cystitis and radiation cystitis were reported in 1.2% and 1.5% of patients who received prior radiation, respectively. Hematuria was reported in 19.4% of patients who received prior radiation and in 14.4% of patients who did not receive prior radiation. Cystitis from radiation recall may occur late in treatment with cabazitaxel . Monitor patients who previously received pelvic radiation for signs and symptoms of cystitis while on cabazitaxel . Interrupt or discontinue cabazitaxel in patients experiencing severe hemorrhagic cystitis. Medical and/or surgical supportive treatment may be required to treat severe hemorrhagic cystitis.
5.7 Respiratory Disorders
Interstitial pneumonia/pneumonitis, interstitial lung disease and acute respiratory distress syndrome have been reported and may be associated with fatal outcome [see Adverse Reactions (6.2)]. Patients with underlying lung disease may be at higher risk for these events. Acute respiratory distress syndrome may occur in the setting of infection.
Interrupt cabazitaxel if new or worsening pulmonary symptoms develop. Closely monitor, promptly investigate, and appropriately treat patients receiving cabazitaxel . Consider discontinuation. The benefit of resuming cabazitaxel treatment must be carefully evaluated.
5.8 Use in Patients with Hepatic Impairment
Cabazitaxel is extensively metabolized in the liver.
cabazitaxel is contraindicated in patients with severe hepatic impairment (total bilirubin >3 × ULN) [see Contraindications (4)]. Dose should be reduced for patients with mild (total bilirubin >1 to ≤1.5 × ULN or AST >1.5 × ULN) and moderate (total bilirubin >1.5 to ≤3.0 × ULN and any AST) hepatic impairment, based on tolerability data in these patients [see Dosage and Administration (2.3) and Use in Specific Populations (8.7)]. Administration of cabazitaxel to patients with mild and moderate hepatic impairment should be undertaken with caution and close monitoring of safety.
5.9 Embryo-Fetal Toxicity
Based on findings in animal reproduction studies and its mechanism of action, cabazitaxel can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)].
There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, intravenous administration of cabazitaxel in pregnant rats during organogenesis caused embryonic and fetal death at doses lower than the maximum recommended human dose (approximately 0.06 times the Cmax in patients at the recommended human dose).
Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of Cabazitaxel S.K. [see Use in Specific Populations (8.1, 8.3)].
6   ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in another section of the label:


•   Bone Marrow Suppression [see Warnings and Precautions (5.1)].
•   Increased Toxicities in Elderly Patients [see Warnings and Precautions (5.2)].
•   Hypersensitivity Reactions [see Warnings and Precautions (5.3)].
•   Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.4)].
•   Renal Failure [see Warnings and Precautions (5.5)].
•   Urinary Disorders Including Cystitis [see Warnings and Precautions (5.6)].
•   Respiratory Disorders [see Warnings and Precautions (5.7)].
•   Use in Patients with Hepatic Impairment [see Warnings and Precautions (5.8)].
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.
TROPIC Trial (cabazitaxel + prednisone compared to mitoxantrone)
The safety of cabazitaxel in combination with prednisone was evaluated in 371 patients with metastatic castration-resistant prostate cancer treated in the randomized TROPIC trial, compared to mitoxantrone plus prednisone.
Deaths due to causes other than disease progression within 30 days of last study drug dose were reported in 18 (5%) cabazitaxel -treated patients and 3 (< 1%) mitoxantrone-treated patients.
The most common fatal adverse reactions in cabazitaxel -treated patients were infections (n=5) and renal failure (n=4). The majority (4 of 5 patients) of fatal infection-related adverse reactions occurred after a single dose of cabazitaxel . Other fatal adverse reactions in cabazitaxel - treated patients included ventricular fibrillation, cerebral hemorrhage, and dyspnea.
The most common (≥10%) grade 1-4 adverse reactions were anemia, leukopenia, neutropenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea, dysgeusia, cough, arthralgia, and alopecia.
The most common (≥5%) grade 3-4 adverse reactions in patients who received cabazitaxel were neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, fatigue, and asthenia.
Treatment discontinuations due to adverse drug reactions occurred in 18% of patients who received cabazitaxel and 8% of patients who received mitoxantrone. The most common adverse reactions leading to treatment discontinuation in the cabazitaxel group were neutropenia and renal failure. Dose reductions were reported in 12% of cabazitaxel -treated patients and 4% of mitoxantrone-treated patients. Dose delays were reported in 28% of cabazitaxel -treated patients and 15% of mitoxantrone-treated patients.


Table 2: Incidence of Adverse Reactions* and Hematologic Abnormalities in ≥ 5% of Patients Receiving cabazitaxel in Combination with Prednisone or Mitoxantrone in Combination with Prednisone in TROPIC cabazitaxel 25 mg/m2 every 3        Mitoxantrone 12 mg/m2 every 3 weeks with prednisone 10 mg daily    weeks with prednisone 10 mg daily n=371                                n=371
Grade 1-4           Grade 3-4       Grade 1-4          Grade 3-4

n (%)              n (%)       n (%)       n (%)
Any Adverse Reaction
Blood and Lymphatic System Disorders
Neutropenia†                   347 (94%)             303 (82%)   325 (87%)   215 (58%) Febrile Neutropenia             27 (7%)               27 (7%)     5 (1%)      5 (1%) Anemia†                        361 (98%)             39 (11%)    302 (82%)    18 (5%) Leukopenia†                    355 (96%)             253 (69%)   343 (93%)   157 (42%) Thrombocytopenia†              176 (48%)              15 (4%)    160 (43%)    6 (2%) Cardiac Disorders
Arrhythmia‡                     18 (5%)               4 (1%)      6 (2%)      1 (<1%) Gastrointestinal Disorders
Diarrhea                       173 (47%)              23 (6%)    39 (11%)     1 (<1%) Nausea                         127 (34%)              7 (2%)     85 (23%)     1 (<1%) Vomiting                       83 (22%)               6 (2%)     38 (10%)       0 Constipation                   76 (20%)               4 (1%)     57 (15%)     2 (<1%) Abdominal Pain§                64 (17%)               7 (2%)      23 (6%)       0 Dyspepsia¶                     36 (10%)                 0         9 (2%)        0 General Disorders and Administration Site Conditions
Fatigue                        136 (37%)              18 (5%)    102 (27%)    11 (3%) Asthenia                       76 (20%)               17 (5%)    46 (12%)     9 (2%) Pyrexia                        45 (12%)               4 (1%)      23 (6%)     1 (<1%) Peripheral Edema                34 (9%)               2 (<1%)     34 (9%)     2 (<1%) Mucosal Inflammation            22 (6%)               1 (<1%)     10 (3%)     1 (<1%) Pain                            20 (5%)               4 (1%)      18 (5%)     7 (2%) Infections and Infestations
Urinary Tract Infection#        29 (8%)               6 (2%)      12 (3%)     4 (1%) Investigations
Weight Decreased                32 (9%)                 0         28 (8%)     1 (<1%) Metabolism and Nutrition Disorders
Anorexia                       59 (16%)               3 (<1%)    39 (11%)     3 (<1%) Dehydration                     18 (5%)               8 (2%)      10 (3%)     3 (<1%) Musculoskeletal and Connective Tissue Disorders
Back Pain                      60 (16%)               14 (4%)    45 (12%)     11 (3%) Arthralgia                     39 (11%)               4 (1%)      31 (8%)     4 (1%) Muscle Spasms                   27 (7%)                 0         10 (3%)       0 Nervous System Disorders


Peripheral NeuropathyÞ           50 (13%)                   3 (<1%)       12 (3%)               3 (<1%) Dysgeusia                        41 (11%)                     0           15 (4%)                 0 Dizziness                         30 (8%)                     0           21 (6%)               2 (<1%) Headache                          28 (8%)                     0           19 (5%)                 0 Renal and Urinary Tract Disorders
Hematuria                        62 (17%)                   7 (2%)        13 (4%)               1 (<1%) Dysuria                           25 (7%)                     0            5 (1%)                 0 Respiratory, Thoracic and Mediastinal Disorders
Dyspnea                          43 (12%)                   4 (1%)        16 (4%)               2 (<1%) Cough                            40 (11%)                     0           22 (6%)                 0 Skin and Subcutaneous Tissue Disorders
Alopecia                         37 (10%)                     0           18 (5%)                 0 Vascular Disorders
Hypotension                       20 (5%)               2 (<1 %)           9 (2%)               1 (<1%) Median Duration of                              6 cycles                                 4 cycles Treatment

*Graded using NCI      CTCAE version 3
†
Based on laboratory values, cabazitaxel : n =369, mitoxantrone: n = 370.
‡
Includes atrial fibrillation, atrial flutter, atrial tachycardia, atrioventricular block complete, bradycardia, palpitations, supraventricular tachycardia, tachyarrhythmia, and tachycardia.
§
Includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and GI pain.
¶
Includes gastroesophageal reflux disease and reflux gastritis.
#
Includes urinary tract infection enterococcal and urinary tract infection fungal.
Þ
Includes peripheral motor neuropathy and peripheral sensory neuropathy.


PROSELICA Trial (comparison of two doses of cabazitaxel )
In a noninferiority, multicenter, randomized, open-label study (PROSELICA), 1175 patients with metastatic castration-resistant prostate cancer, previously treated with a docetaxel-containing regimen, were treated with either cabazitaxel 25 mg/m2 (n=595) or the 20 mg/m2 (n=580) dose.
Deaths within 30 days of last study drug dose were reported in 22 (3.8%) patients in the 20 mg/m2 and 32 (5.4%) patients in the 25 mg/m2 arm. The most common fatal adverse reactions in cabazitaxel -treated patients were related to infections, and these occurred more commonly on the 25 mg/m2 arm (n=15) than on the 20 mg/m2 arm (n=8). Other fatal adverse reactions in cabazitaxel -treated patients included cerebral hemorrhage, respiratory failure, paralytic ileus, diarrhea, acute pulmonary edema, disseminated intravascular coagulation, renal failure, sudden death, cardiac arrest, ischemic stroke, diverticular perforation, and cardiorenal syndrome.
Grade 1-4 adverse reactions occurring ≥5% more commonly in patients on the 25 mg/m2 versus 20 mg/m2 arms were leukopenia, neutropenia, thrombocytopenia, febrile neutropenia, decreased appetite, nausea, diarrhea, asthenia, and hematuria.
Grade 3-4 adverse reactions occurring ≥5% more commonly in patients on the 25 mg/m2 versus 20 mg/m2 arms were leukopenia, neutropenia, and febrile neutropenia.
Treatment discontinuations due to adverse drug reactions occurred in 17% of patients in the 20 mg/m2 group and 20% of patients in the 25 mg/m2 group. The most common adverse reactions leading to treatment discontinuation were fatigue and hematuria. The patients in the 20 mg/m2 group received a median of 6 cycles (median duration of 18 weeks), while patients in the 25 mg/m2 group received a median of 7 cycles (median duration of 21 weeks). In the 25 mg/m2 group, 128 patients (22%) had a dose reduced from 25 to 20 mg/m2, 19 patients (3%) had a dose reduced from 20 to 15 mg/m2 and 1 patient (0.2%) had a dose reduced from 15 to 12 mg/m2. In the 20 mg/m2 group, 58 patients (10%) had a dose reduced from 20 to 15 mg/m2, and 9 patients (2%) had a dose reduced from 15 to 12 mg/m2.


Table 3: Incidence of Adverse Reactions* in ≥5% of Patients Receiving cabazitaxel 20 mg/m2 or 25 mg/m2 in Combination with Prednisone in PROSELICA cabazitaxel 20 mg/m2 every 3        cabazitaxel 25 mg/m2 every 3 weeks with prednisone 10 mg daily   weeks with prednisone 10 mg daily n=580                               n=595
Primary System Organ
Grade 1-4          Grade 3-4         Grade 1-4         Grade 3-4
Class n (%)              n (%)             n (%)             n (%)
Preferred Term
Blood and Lymphatic System Disorders
Febrile Neutropenia            12 (2%)               12 (2%)        55 (9%)            55 (9%) †
Neutropenia                    18 (3%)               14 (2%)       65 (11%)           57 (10%) Infections and Infestations
Urinary tract infection‡       43 (7%)               12 (2%)       66 (11%)            14 (2%) Neutropenic infection§         15 (3%)               13 (2%)        42 (7%)            36 (6%) Metabolism and Nutrition Disorders
Decreased appetite             76 (13%)              4 (0.7%)      110 (19%)           7 (1%) Nervous System Disorders
Dysgeusia                      41 (7%)                  0          63 (11%)              0 Peripheral sensory
38 (7%)                  0          63 (11%)           4 (0.7%) neuropathy
Dizziness                      24 (4%)                  0           32 (5%)              0 Headache                       29 (5%)               1 (0.2%)       24 (4%)           1 (0.2%) Respiratory, Thoracic and Mediastinal Disorders
Dyspnea                        30 (5%)               5 (0.9%)       46 (8%)           4 (0.7%) Cough                          34 (6%)                  0           35 (6%)              0 Gastrointestinal Disorders
Diarrhea                      178 (31%)               8 (1%)       237 (40%)           24 (4%) Nausea                        142 (25%)              4 (0.7%)      191 (32%)           7 (1%) Vomiting                       84 (15%)              7 (1.2%)      108 (18 %)          8 (1%) 

cabazitaxel 20 mg/m2 every 3                 cabazitaxel 25 mg/m2 every 3 weeks with prednisone 10 mg daily            weeks with prednisone 10 mg daily n=580                                        n=595
Primary System Organ
Grade 1-4             Grade 3-4              Grade 1-4             Grade 3-4 Class n (%)                 n (%)                  n (%)                 n (%) Preferred Term
Constipation                       102 (18%)                2 (0.3%)            107 (18%)              4 (0.7%) Abdominal pain                      34 (6%)                 3 (0.5%)              52 (9%)               7 (1%) Stomatitis                          27 (5%)                    0                  30 (5%)              2 (0.3%) Skin and Subcutaneous Tissue Disorders
Alopecia                            15 (3%)                    0                 36 (6.1%)                 0 Musculoskeletal and Connective Tissue Disorders
Back pain                           64 (11%)                5 (0.9%)             83 (14%)               7 (1%) Bone pain                           46 (8%)                 10 (2%)               50 (8%)              13 (2 %) Arthralgia                          49 (8%)                 3 (0.5%)              41 (7%)              5 (0.8%) Pain in extremity                   30 (5%)                 1 (0.2%)              41 (7%)              3 (0.5%) Renal and Urinary Disorders
Hematuria                           82 (14%)                11 (2%)             124 (21%)               25 (4%) Dysuria                             31 (5%)                 2 (0.3%)              24 (4%)                  0 General Disorders and Administration Site Conditions
Fatigue                            143 (25%)                15 (3%)             161 (27%)               22 (4%) Asthenia                            89 (15%)                11 (2%)             117 (20%)               12 (2%) Edema peripheral                    39 (7%)                 1 (0.2%)              53 (9%)              1 (0.2%) Pyrexia                             27 (5%)                 1 (0.2%)             38 (6 %)              1 (0.2%) Investigations
Weight decreased                    24 (4%)                 1 (0.2%)              44 (7%)                  0 Injury, Poisoning and Procedural Complications
Wrong technique in drug
2 (0.3%)                   0                  32 (5%)                  0 usage process
* Grade from NCI CTCAE version 4.03.
†
Based on adverse event reporting.
‡
Includes urinary tract infection staphylococcal, urinary tract infection bacterial, urinary tract infection fungal, and urosepsis.
§
Includes neutropenic sepsis.



Table 4: Incidence of Hematologic Laboratory Abnormalities in Patients Receiving cabazitaxel 20 mg/m2 or 25 mg/m2 in Combination with Prednisone in Study PROSELICA cabazitaxel 20 mg/m2 every 3         cabazitaxel 25 mg/m2 every 3 weeks with prednisone 10 mg daily   weeks with prednisone 10 mg daily n=577                               n=590
Laboratory                Grade 1-4           Grade 3-4       Grade 1-4           Grade 3-4 Abnormality                n (%)               n (%)           n (%)               n (%) Neutropenia                384 (67%)          241 (42%)        522 (89%)          432 (73%) Anemia                    576 (99.8%)          57 (10%)       588 (99.7%)         81 (14%) Leukopenia                 461 (80%)          167 (29%)        560 (95%)          351 (60%) Thrombocytopenia           202 (35%)           15 (3%)         251 (43%)           25 (4%) 

Hematuria:
In study TROPIC, adverse reactions of hematuria, including those requiring medical intervention, were more common in cabazitaxel -treated patients. The incidence of grade ≥2 hematuria was 6% in cabazitaxel -treated patients and 2% in mitoxantrone-treated patients.
Other factors associated with hematuria were well balanced between arms and do not account for the increased rate of hematuria on the cabazitaxel arm.
In study PROSELICA, hematuria of all grades was observed in 18% of patients overall.
Hepatic Laboratory Abnormalities:
The incidences of grade 3-4 increased AST, increased ALT, and increased bilirubin were each ≤1%.
6.2 Postmarketing Experience
The following adverse reactions have been identified from clinical trials and/or postmarketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made.
Gastrointestinal: Gastritis, intestinal obstruction.
Respiratory: Interstitial pneumonia/pneumonitis, interstitial lung disease and acute respiratory distress syndrome.
Renal and urinary disorders: Radiation recall hemorrhagic cystitis.
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/

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