Special Warning : אזהרת שימוש

5         WARNINGS AND PRECAUTIONS

5.1       Hypertension and Hypertensive Crisis

In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypertension was reported in 145/359 patients (40%) receiving INLYTA and 103/355 patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving INLYTA and 39/355 patients (11%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. The median onset time for hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of INLYTA treatment and blood pressure increases have been observed as early as 4 days after starting INLYTA.
Hypertension was managed with standard anti-hypertensive therapy. Discontinuation of INLYTA treatment due to hypertension occurred in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib [see Adverse Reactions (6.1)].

Blood pressure should be well-controlled prior to initiating INLYTA. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensive medications, reduce the INLYTA dose. Discontinue INLYTA if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. If INLYTA is interrupted, patients receiving anti-hypertensive medications should be monitored for hypotension [see Dosage and Administration (2.2)].

5.2     Arterial Thromboembolic Events

In clinical trials, arterial thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib [see Adverse Reactions (6.1)].

In clinical trials with INLYTA, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients (2%), with two deaths secondary to cerebrovascular accident.

Use INLYTA with caution in patients who are at risk for, or who have a history of, these events.
INLYTA has not been studied in patients who had an arterial thromboembolic event within the previous 12 months.

5.3     Venous Thromboembolic Events

In clinical trials, venous thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving INLYTA and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving INLYTA (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib.
Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, venous thromboembolic events were reported in 22/715 patients (3%), with two deaths secondary to pulmonary embolism.


Use INLYTA with caution in patients who are at risk for, or who have a history of, these events.
INLYTA has not been studied in patients who had a venous thromboembolic event within the previous 6 months.

5.4     Hemorrhage

In a controlled clinical study with INLYTA for the treatment of patients with RCC, hemorrhagic events were reported in 58/359 patients (16%) receiving INLYTA and 64/355 patients (18%) receiving sorafenib. Grade 3/4 hemorrhagic events were reported in 5/359 (1%) patients receiving INLYTA (including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena) and 11/355 (3%) patients receiving sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving INLYTA (gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib.

INLYTA has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.

5.5     Cardiac Failure

In a controlled clinical study with INLYTA for the treatment of patients with RCC, cardiac failure was reported in 6/359 patients (2%) receiving INLYTA and 3/355 patients (1%) receiving sorafenib. Grade 3/4 cardiac failure was observed in 2/359 patients (1%) receiving INLYTA and 1/355 patients (<1%) receiving sorafenib. Fatal cardiac failure was reported in 2/359 patients (1%) receiving INLYTA and 1/355 patients (<1%) receiving sorafenib. Monitor for signs or symptoms of cardiac failure throughout treatment with INLYTA. Management of cardiac failure may require permanent discontinuation of INLYTA.

5.6     Gastrointestinal Perforation and Fistula Formation

In a controlled clinical study with INLYTA for the treatment of patients with RCC, gastrointestinal perforation was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, gastrointestinal perforation was reported in 5/715 patients (1%), including one death. In addition to cases of gastrointestinal perforation, fistulas were reported in 4/715 patients (1%).

Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with INLYTA.

5.7     Thyroid Dysfunction

In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypothyroidism was reported in 69/359 patients (19%) receiving INLYTA and 29/355 patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to ≥10 μU/mL occurred in 79/245 
patients (32%) receiving INLYTA and 25/232 patients (11%) receiving sorafenib [see Adverse Reactions (6.1)].

Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state.

5.8      Risk of Impaired Wound Healing

Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, INLYTA has the potential to adversely affect wound healing.

Withhold INLYTA for at least 2 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of INLYTA after resolution of wound healing complications has not been established.

5.9      Reversible Posterior Leukoencephalopathy Syndrome

In a controlled clinical study with INLYTA for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib [see Adverse Reactions (6.1)]. There were two additional reports of RPLS in other clinical trials with INLYTA.

RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. Discontinue INLYTA in patients developing RPLS. The safety of reinitiating INLYTA therapy in patients previously experiencing RPLS is not known.

5.10     Proteinuria

In a controlled clinical study with INLYTA for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11%) receiving INLYTA and 26/355 patients (7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) receiving INLYTA and 6/355 patients (2%) receiving sorafenib [see Adverse Reactions (6.1)].

Monitoring for proteinuria before initiation of, and periodically throughout, treatment with INLYTA is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt INLYTA treatment. INLYTA should be discontinued if the patient develops nephrotic syndrome.

5.11     Hepatotoxicity

In a controlled clinical study with INLYTA for the treatment of patients with RCC, alanine aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with 

Grade 3/4 events in <1% of patients on the INLYTA arm. ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically throughout treatment with INLYTA.

5.12    Use in Patients with Hepatic Impairment

The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child- Pugh class B). INLYTA has not been studied in patients with severe hepatic impairment (Child- Pugh class C) [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

5.13    Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, INLYTA can cause fetal harm when administered to a pregnant woman. There are no available human data to inform the drug-associated risk. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception during treatment with INLYTA and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with INLYTA and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].

5.14    Lactose

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

5.15 Sodium

This medicinal product contains less than 1 mmol (23 mg) sodium per film-coated tablet, that is to say essentially ‘sodium-free’.


5.16 Aneurysms and artery dissections
The use of vascular endothelial growth factor (VEGF) pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating INLYTA, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

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

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