Adverse reactions : תופעות לוואי

6       ADVERSE REACTIONS

The following clinically significant adverse reactions are discussed elsewhere in the labeling [see Warnings and Precautions (5)]:


•   Hypertension and hypertensive crisis [see Warnings and Precautions (5.1)] •   Arterial thromboembolic events [see Warnings and Precautions (5.2)] •   Venous thromboembolic events [see Warnings and Precautions (5.3)] •   Hemorrhage [see Warnings and Precautions (5.4)]
•   Cardiac failure [see Warnings and Precautions (5.5)]
•   Gastrointestinal perforation and fistula formation [see Warnings and Precautions (5.6)] •   Thyroid dysfunction [see Warnings and Precautions (5.7)]
•   Reversible posterior leukoencephalopathy syndrome [see Warnings and Precautions (5.9)]
•   Proteinuria [see Warnings and Precautions (5.10)]
•   Hepatotoxicity [see Warnings and Precautions (5.11)]
•   Hepatic impairment [see Warnings and Precautions (5.12)]

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 clinical practice.

The safety of INLYTA has been evaluated in 715 patients in monotherapy studies, which included 537 patients with advanced RCC. The data described [see Adverse Reactions (6.1)] reflect exposure to INLYTA in 359 patients with advanced RCC who participated in a randomized clinical study versus sorafenib [see Clinical Studies (14)].
The median duration of treatment was 6.4 months (range 0.03 to 22.0) for patients who received INLYTA and 5.0 months (range 0.03 to 20.1) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse reaction occurred in 199/359 patients (55%) receiving INLYTA and 220/355 patients (62%) receiving sorafenib. Permanent discontinuation due to an adverse reaction occurred in 34/359 patients (9%) receiving INLYTA and 46/355 patients (13%) receiving sorafenib.
The most common (≥20%) adverse reactions observed following treatment with INLYTA were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation.
Table 1 presents adverse reactions reported in ≥10% patients who received INLYTA or sorafenib.

Table 1. Adverse Reactions Occurring in ≥10% of Patients Who Received INLYTA or Sorafenib
INLYTA                      Sorafenib
(N=359)                     (N=355)
Adverse Reactiona                    All Gradesb    Grade 3/4    All Gradesb   Grade 3/4 %            %              %            %
Diarrhea                                                  55           11             53            7 Hypertension                                              40           16             29           11 Fatigue                                                   39           11             32            5 Decreased appetite                                        34            5             29            4 Nausea                                                    32            3             22            1 
                                                               INLYTA                     Sorafenib
(N=359)                    (N=355)
Adverse Reactiona                     All Gradesb    Grade 3/4 All Gradesb     Grade 3/4 %            %            %             %
Dysphonia                                                 31            0           14             0 Palmar-plantar erythrodysesthesia syndrome                27            5           51            16 Weight decreased                                          25            2           21             1 Vomiting                                                  24            3           17             1 Asthenia                                                  21            5           14             3 Constipation                                              20            1           20             1 Hypothyroidism                                            19           <1            8             0 Cough                                                     15            1           17             1 Mucosal inflammation                                      15            1           12             1 Arthralgia                                                15            2           11             1 Stomatitis                                                15            1           12            <1 Dyspnea                                                   15            3           12             3 Abdominal pain                                            14            2           11             1 Headache                                                  14            1           11             0 Pain in extremity                                         13            1           14             1 Rash                                                      13           <1           32             4 Proteinuria                                               11            3            7             2 Dysgeusia                                                 11            0            8             0 Dry skin                                                  10            0           11             0 Dyspepsia                                                 10            0            2             0 Pruritus                                                   7            0           12             0 Alopecia                                                   4            0           32             0 Erythema                                                   2            0           10            <1 a
Percentages are treatment-emergent, all-causality events b
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 
Selected adverse reactions (all grades) that were reported in <10% of patients treated with INLYTA included dizziness (9%), upper abdominal pain (8%), myalgia (7%), dehydration (6%), epistaxis (6%), anemia (4%), hemorrhoids (4%), hematuria (3%), tinnitus (3%), lipase increased (3%), glossodynia (3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal-vein occlusion/thrombosis (1%), polycythemia (1%), and transient ischemic attack (1%).

Table 2 presents the most common laboratory abnormalities reported in ≥10% patients who received INLYTA or sorafenib.



Table 2. Laboratory Abnormalities Occurring in ≥10% of Patients Who Received INLYTA or Sorafenib
INLYTA                         Sorafenib
Laboratory                          All Gradesa Grade 3/4          All Gradesa Grade 3/4 Abnormality                     N                            N
%        %                     %            %
Hematology
Hemoglobin decreased                320         35             <1        316         52             4 Lymphocytes (absolute) decreased    317         33              3        309         36             4 Platelets decreased                 312         15             <1        310         14             0 White blood cells decreased         320         11              0        315         16            <1 Chemistry
Creatinine increased                336         55              0        318         41            <1 Bicarbonate decreased               314         44             <1        291         43             0 Hypocalcemia                        336         39              1        319         59             2 ALP increased                       336         30              1        319         34             1 Hyperglycemia                       336         28              2        319         23             2 Lipase increased                    338         27              5        319         46            15 Amylase increased                   338         25              2        319         33             2 ALT increased                       331         22             <1        313         22             2 AST increased                       331         20             <1        311         25             1 Hypernatremia                       338         17              1        319         13             1 Hypoalbuminemia                     337         15             <1        319         18             1 Hyperkalemia                        333         15              3        314         10             3 Hypoglycemia                        336         11             <1        319          8            <1 Hyponatremia                        338         13              4        319         11             2 Hypophosphatemia                    336         13              2        318         49            16 a
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase 
Selected laboratory abnormalities (all grades) that were reported in <10% of patients treated with INLYTA included hemoglobin increased (above the upper limit of normal) (9% for INLYTA versus 1% for sorafenib) and hypercalcemia (6% for INLYTA versus 2% for sorafenib).

6.2     Postmarketing Experience

The following adverse reactions have been identified during postapproval use of INLYTA.
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.

Vascular disorders: arterial (including aortic), aneurysms, dissections, and rupture.

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