Special Warning : אזהרת שימוש

5          WARNINGS AND PRECAUTIONS

5.1        Interstitial Lung Disease/Pneumonitis
Severe, life-threatening, and fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with GAVRETO. Pneumonitis occurred in 12% of patients who received GAVRETO, including 3.3% with Grade 3-4, and 0.2% with fatal reactions.
Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Withhold GAVRETO and promptly investigate for ILD in any patient who presents with acute or worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever). Withhold, reduce dose or permanently discontinue GAVRETO based on severity of confirmed ILD [see Dosage and Administration (2.3)].

5.2        Hypertension
Hypertension occurred in 35% of patients, including Grade 3 hypertension in 18% of patients [see Adverse Reactions (6.1)]. Overall, 8% had their dose interrupted and 4.8% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications.
Do not initiate GAVRETO in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating GAVRETO. Monitor blood pressure after 1 week, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue GAVRETO based on the severity [see Dosage and Administration (2.3)].

5.3        Hepatotoxicity
Serious hepatic adverse reactions occurred in 1.5% of patients treated with GAVRETO.
Increased AST occurred in 49% of patients, including Grade 3 or 4 in 7% and increased ALT occurred in 37% of patients, including Grade 3 or 4 in 4.8% [see Adverse Reactions (6.1)]. The median time to first onset for increased AST was 15 days (range: 5 days to 2.5 years) and for increased ALT was 24 days (range: 7 days to 3.7 years).
Monitor AST and ALT prior to initiating GAVRETO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose or permanently discontinue GAVRETO based on severity [see Dosage and Administration (2.3)].

5.4        Hemorrhagic Events
Serious, including fatal, hemorrhagic events can occur with GAVRETO. Grade ≥ 3 hemorrhagic events occurred in 4.1% of patients treated with GAVRETO including one patient with a fatal hemorrhagic event.
Permanently discontinue GAVRETO in patients with severe or life-threatening hemorrhage [see Dosage and Administration (2.3)].

5.5         Tumor Lysis Syndrome
Cases of tumor lysis syndrome (TLS) have been reported in patients with medullary thyroid carcinoma receiving GAVRETO [see Adverse Reactions (6.1)]. Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration.
Closely monitor patients at risk, consider appropriate prophylaxis including hydration, and treat as clinically indicated.

5.6         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, GAVRETO has the potential to adversely affect wound healing.
Withhold GAVRETO for at least 5 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
GAVRETO after resolution of wound healing complications has not been established.

5.7         Embryo-Fetal Toxicity
Based on findings from animal studies and its mechanism of action, GAVRETO can cause fetal harm when administered to a pregnant woman. Oral administration of pralsetinib to pregnant rats during the period of organogenesis resulted in malformations and embryolethality at maternal exposures below the human exposure at the clinical dose of 400 mg once daily.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with GAVRETO and for 2 weeks after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with GAVRETO and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3)].


Effects on ability to drive and use machines:

Gavreto has minor influence on the ability to drive and use machines. Caution should be exercised when driving or operating machines as patients may experience fatigue while taking Gavreto.


6           ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling: •   Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1)] •   Hypertension [see Warnings and Precautions (5.2)]
•   Hepatotoxicity [see Warnings and Precautions (5.3)]
•   Hemorrhagic Events [see Warnings and Precautions (5.4)]

•    Tumor Lysis Syndrome [see Warnings and Precautions (5.5)]
•    Risk of Impaired Wound Healing [see Warnings and Precautions (5.6)] •    Embryo-Fetal Toxicity [see Warnings and Precautions (5.7)]

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 in the WARNINGS AND PRECAUTIONS reflect exposure to GAVRETO as a single agent at 400 mg orally once daily in 540 patients in ARROW [see Clinical Studies (14)]. Among 540 patients who received GAVRETO, 71% were exposed for 6 months or longer and 57% were exposed for greater than one year. The most common adverse reactions (≥ 25%) were musculoskeletal pain, constipation, hypertension, diarrhea, fatigue, edema, pyrexia, and cough. The most common Grade 3-4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased phosphate, decreased leukocytes, decreased sodium, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased calcium (corrected), decreased platelets, increased alkaline phosphatase, increased potassium, decreased potassium and increased bilirubin.


RET Fusion-Positive Non-Small Cell Lung Cancer
The safety of GAVRETO was evaluated as a single agent at 400 mg orally once daily in 281 patients with metastatic rearranged during transfection (RET fusion-positive) non-small cell lung cancer (NSCLC) in ARROW [see Clinical Studies (14.1)]. Among the 281 patients who received GAVRETO, 72% were exposed for 6 months or longer and 56% were exposed for ≥1 year.
The median age was 60 years (range: 26 to 87 years); 54% were female, 46% were White, 46% were Asian, and 4% were Hispanic/Latino.
Serious adverse reactions occurred in 65% of patients who received GAVRETO. The most frequent serious adverse reactions (in ≥ 2% of patients) were pneumonia, anemia, pneumonitis, pyrexia, sepsis, urinary tract infection, coronavirus infection, pleural effusion, dyspnea, musculoskeletal pain, pulmonary embolism, and seizure. Fatal adverse reactions occurred in 7% of patients; fatal adverse reactions which occurred in > 1 patient included pneumonia (n = 8), sepsis (n=3) and COVID (n=3).
Permanent discontinuation due to an adverse reaction occurred in 20% of patients who received GAVRETO. Adverse reactions resulting in permanent discontinuation which occurred in ≥ 2% of patients included pneumonitis (3.2%), and pneumonia (2.8%).
Dosage interruptions due to an adverse reaction occurred in 73% of patients who received GAVRETO. Adverse reactions requiring dosage interruption in ≥ 2% of patients included anemia, pneumonia, pneumonitis, neutropenia, hypertension, increased blood creatine  phosphokinase, fatigue, pyrexia. increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), coronavirus infection, diarrhea, hypophosphatemia, musculoskeletal pain, thrombocytopenia, dyspnea, hemorrhage, leukopenia, lymphopenia, edema, sepsis, and vomiting.
Dose reductions due to adverse reactions occurred in 51% of patients who received GAVRETO.
Adverse reactions requiring dosage reductions in ≥ 2% of patients included anemia, neutropenia, pneumonitis, increased blood creatine phosphokinase, leukopenia, hypertension, fatigue, pneumonia, and lymphopenia.
Table 4 summarizes the adverse reactions in patients with NSCLC in ARROW.
Table 4:           Adverse Reactions (≥ 15%) in RET Fusion-Positive NSCLC Patients Who Received GAVRETO in ARROW
Adverse reaction                           GAVRETO
N = 281
Grades 1 - 4               Grades 3 or 4
(%)                        (%)
Gastrointestinal disorders
Constipation                               45                         0.7 Diarrhea                                   30                         2.5 Nausea                                     19                         0 Dry mouth                                  17                         0 General Disorders and Administration Site Conditions
Edema1                                     44                         0 Fatigue   2
42                         2.5
Pyrexia                                    29                         0.7 Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain3                      44                         2.5 Increased Blood Creatine Phosphokinase     19                         9 Vascular
Hypertension4                            38                         18 Respiratory, thoracic and mediastinal disorders
Cough5                                     36                         0.4 Dyspnea                                    21                         2.1 Infection and Infestations
Pneumonia6                                 24                         13 Urinary tract infection                    16                         3.6 Metabolism and Nutrition Disorders

Adverse reaction                                            GAVRETO
N = 281
Grades 1 - 4                      Grades 3 or 4
(%)                               (%)
Decreased appetite                                     18                                1.1 Nervous system disorders
Taste disorder7                                             17                                0 Headache       8
15                                1.1
Skin and subcutaneous tissue disorders
Rash9                                                       17                                0 1
Includes the preferred terms: Edema, Swelling face, Peripheral swelling, Ge neralized oedema, Edema peripheral, Face edema, Periorbital edema, Eyelid edema, Swelling, Localized edema
2
Includes the preferred terms: Fatigue, Asthenia

Includes the preferred terms: Myalgia, Arthralgia, Pain in extremity, Neck pain, Musculoskele tal pain, Back pain, 3.

Musculoskeletal chest pain, Bone pain, Musculoskeletal stiffness
4
Includes the preferred terms: hypertension, blood pressure increased
5
Includes the preferred terms: Cough, Productive Cough, upper-airway cough syndrome 6
Includes the preferred terms: Pneumonia, Pneumocystis jirovecii pneumonia, Pneumonia cytomegaloviral, Atypical pneumonia, Lung infection, Pneumonia bacterial, Pneumonia haemophilus, Pneumonia influenzal, Pneumonia streptococcal, Pneumonia viral, Pneumonia pseudomonal
7
Includes the preferred terms: Dysgeusia, Ageusia
8
Includes the preferred terms: Headache, Tension Headache
9
Includes the preferred terms: Rash, Rash maculo -papular, Dermatitis acneiform, Erythema, Rash generalized, Rash papular, Rash macular, Rash erythematous


Clinically relevant adverse reactions occurring in < 15% of patients included pneumonitis (14%), vomiting (14%), abdominal pain (14%), and stomatitis (6%).

Table 5 summarizes the laboratory abnormalities in ARROW.
Table 5:           Select Laboratory Abnormalities (≥ 20%) Worsening from Baseline in RET Fusion-Positive NSCLC Patients Who Received GAVRETO in ARROW
GAVRETO
N=281
Laboratory Abnormality
Grades 1-4                Grades 3-4
(%)                       (%)
Chemistry
Increased AST                                          80                        3.2 Increased ALT                                          58                        3.9 Decreased albumin                                      52                         0 Decreased calcium (corrected)                          50                        1.8 Decreased phosphate                                    50                        17 Increased creatinine                                   45                        1.4 Increased alkaline phosphatase                         43                        2.5 Decreased sodium                                       42                        10 Decreased Potassium                                    27                        4.6 Increased Potassium                                    27                        1.8 Decreased Magnesium                                    25                         0 Increased Bilirubin                                    20                        1.8 Hematology
Decreased leukocytes                                   79                        11 Decreased hemoglobin                                   78                        18 Decreased lymphocytes                                  73                        32 Decreased neutrophils                                  70                        21 Decreased platelets                                    33                         5 

Clinically relevant laboratory abnormalities occurring in < 20% of patients who received GAVRETO included increased magnesium (14%).

RET-altered Thyroid Cancer
The safety of GAVRETO was evaluated as a single agent at 400 mg orally once daily in 138 patients with RET-altered Thyroid Cancer (including 19 patients with RET fusion-positive thyroid cancer) in ARROW [see Clinical Studies (14.2)]. Among the 138 patients who received GAVRETO, 68% were exposed for 6 months or longer, and 40% were exposed for greater than one year.
The median age was 59 years (range: 18 to 83 years); 36% were female, 74% were White, 17% were Asian, and 6% were Hispanic/Latino.
Serious adverse reactions occurred in 39% of patients who received GAVRETO. The most frequent serious adverse reactions (in ≥ 2% of patients) were pneumonia, pneumonitis, urinary tract infection, pyrexia, fatigue, diarrhea, dizziness, anemia, hyponatremia, and ascites. Fatal adverse reaction occurred in 2.2% of patients; fatal adverse reactions that occurred in > 1 patient included pneumonia (n=2).
Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received GAVRETO. Adverse reactions resulting in permanent discontinuation which occurred in > 1 patient included fatigue, pneumonia and anemia.
Dosage interruptions due to an adverse reaction occurred in 67% of patients who received GAVRETO. Adverse reactions requiring dosage interruption in ≥ 2% of patients included neutropenia, hypertension, diarrhea, fatigue, pneumonitis, anemia, increased blood creatine phosphokinase, pneumonia, urinary tract infection, musculoskeletal pain, vomiting, pyrexia, increased AST, dyspnea, hypocalcemia, cough, thrombocytopenia, abdominal pain, increased blood creatinine, dizziness, headache, decreased lymphocyte count, stomatitis, and syncope.
Dose reductions due to adverse reactions occurred in 44% of patients who received GAVRETO.
Adverse reactions requiring dosage reductions in ≥ 2% of patients included neutropenia, anemia, hypertension, increased blood creatine phosphokinase, decreased lymphocyte count, pneumonitis, fatigue and thrombocytopenia.
Table 6 summarizes the adverse reactions occurring in RET-altered Thyroid Cancer Patients in ARROW.
Table 6:           Adverse Reactions (≥ 15%) in RET-altered Thyroid Cancer Patients Who Received GAVRETO in ARROW
GAVRETO
N=138
Adverse Reactions
Grades 1-4                     Grades 3-4
(%)                            (%)
Musculoskeletal
Musculoskeletal Pain1                           42                            0.7* Gastrointestinal
Constipation                                    41                            0.7* 
Diarrhea2                                                     34                                      5* Abdominal Pain    3
17                                     0.7*
Dry mouth                                                     17                                       0 Stomatitis4                                                   17                                     0.7* Nausea                                                        17                                     0.7* Vascular
Hypertension                                                  40                                     21* General
Fatigue5                                                      38                                      6* Edema6                                                        29                                       0 Pyrexia                                                       22                                     2.2* Respiratory
Cough7                                                        27                                     1.4* Dyspnea8                                                      22                                     2.2* Nervous System
Headache9                                                     24                                       0 Peripheral Neuropathy10                                       20                                       0 Dizziness11                                                   19                                     0.7* Dysgeusia12                                                   17                                       0 Skin and Subcutaneous
Rash13                                                        24                                       0 Metabolism and Nutrition
Decreased Appetite                                            15                                       0 1
Musculoskeletal Pain includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, spinal pain 2
Diarrhea includes colitis, diarrhea
3
Abdominal Pain includes abdominal discomfort, abdominal pain, abdominal pain upper, abdominal tenderness, epigastric discomfort
4
Stomatitis includes mucosal inflammation, stomatitis, tongue ulceration 5
Fatigue includes asthenia, fatigue
6
Edema includes eyelid edema, face edema, edema, edema peripheral, periorbital edema 7
Cough includes cough, productive cough, upper-airway cough syndrome
8
Dyspnea includes dyspnea, dyspnea exertional
9
Headache includes headache, migraine
10
Peripheral neuropathy includes dysaesthesia, hyperaesthesia, hypoaesthesia, neuralgia, neuropathy peripheral, paraesthesia, peripheral sensory neuropathy, polyneuropathy
11
Dizziness includes dizziness, dizziness postural, vertigo
12
Dysgeusia includes ageusia, dysgeusia
13
Rash includes dermatitis, dermatitis acneiform, eczema, palmar-plantar, erythrodysaesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular * Only includes a Grade 3 adverse reaction
Clinically relevant adverse reactions in < 15% of patients who received GAVRETO included tumor lysis syndrome and increased creatine phosphokinase.
Table 7 summarizes the laboratory abnormalities occurring in RET-altered Thyroid Cancer Patients in ARROW.
Table 7:             Select Laboratory Abnormalities (≥ 20%) Worsening from Baseline in RET- altered Thyroid Cancer Patients Who Received GAVRETO in ARROW
GAVRETO
N=138
Laboratory Abnormality
Grades 1-4                        Grades 3-4
(%)                               (%)
Chemistry
Decreased calcium (corrected)                                         70                                 9 Increased AST                                                         69                               4.3 Increased ALT                                                         43                               3.6 Increased creatinine                                                  41                                 0 Decreased albumin                                                     41                               1.5 Decreased sodium                                                      28                               2.2 Decreased phosphate                                                   28                                 8 Decreased magnesium                                                   27                               0.7 Increased potassium                                                   26                               1.4 Increased bilirubin                                                   24                               1.4 Increased alkaline phosphatase                                        22                               1.4 Hematology
Decreased lymphocytes                                                 67                                27 Decreased hemoglobin                                                  63                                13 Decreased neutrophils                                                 59                                16 Decreased platelets                                                   31                               2.9 Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available, which ranged from 135 to 138 patients.

Clinically relevant laboratory abnormalities in patients who received GAVRETO included increased phosphate (40%).


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: sideeffects.health.gov.il/ 

Effects on Driving