Special Warning : אזהרת שימוש

5     WARNINGS AND PRECAUTIONS

5.1   Hepatotoxicity
Serious hepatic adverse reactions occurred in 3% of patients treated with RETEVMO. Increased AST occurred in 59% of patients, including Grade 3 or 4 events in 11% and increased ALT occurred in 55% of patients, including Grade 3 or 4 events in 12% [see Adverse Reactions (6.1)]. The median time to first onset for increased AST was 6 weeks (range: 1 day to 3.4 years) and increased ALT was 5.8 weeks (range: 1 day to 2.5 years).
Monitor ALT and AST prior to initiating RETEVMO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce the dose or permanently discontinue RETEVMO based on the severity [see Dosage and Administration (2.5)].

5.2    Interstitial Lung Disease/ Pneumonitis

Severe, life-threatening, and fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with RETEVMO. ILD/pneumonitis occurred in 1.8% of patients who received RETEVMO, including 0.3% with Grade 3 or 4 events, and 0.3% with fatal reactions.

Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Withhold RETEVMO 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 the dose or permanently discontinue RETEVMO based on severity of confirmed ILD [see Dosage and Administration (2.5)].

5.3   Hypertension
Hypertension occurred in 41% of patients, including Grade 3 hypertension in 20% and Grade 4 in one (0.1%) patient [see Adverse Reactions (6.1)]. Overall, 6.3% had their dose interrupted and 1.3% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti- hypertension medications.
Do not initiate RETEVMO in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating RETEVMO. Monitor blood pressure after 1 week, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce the dose, or permanently discontinue RETEVMO based on the severity [see Dosage and Administration (2.5)].


5.4   QT Interval Prolongation
RETEVMO can cause concentration-dependent QT interval prolongation [see Clinical Pharmacology (12.2)].
An increase in QTcF interval to >500 ms was measured in 7% of patients and an increase in the QTcF interval of at least 60 ms over baseline was measured in 20% of patients [see Adverse Reactions (6.1)]. RETEVMO has not been studied in patients with clinically significant active cardiovascular disease or recent myocardial infarction.
Monitor patients who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, and severe or uncontrolled heart failure. Assess QT interval, electrolytes and TSH at baseline and periodically during treatment, adjusting frequency based upon risk factors including diarrhea. Correct hypokalemia, hypomagnesemia and hypocalcemia prior to initiating RETEVMO and during treatment.
Monitor the QT interval more frequently when RETEVMO is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and reduce the dose or permanently discontinue RETEVMO based on the severity [see Dosage and Administration (2.5)].

5.5   Hemorrhagic Events
Serious including fatal hemorrhagic events can occur with RETEVMO. Grade ≥3 hemorrhagic events occurred in 3.1% of patients treated with RETEVMO, including 4 (0.5%) patients with fatal hemorrhagic events, including cerebral hemorrhage (n = 2), tracheostomy site hemorrhage (n = 1), and hemoptysis (n=1).
Permanently discontinue RETEVMO in patients with severe or life-threatening hemorrhage [see Dosage and Administration (2.5)].

5.6   Hypersensitivity
Hypersensitivity occurred in 6% of patients receiving RETEVMO, including Grade 3 hypersensitivity in 1.9%.
The median time to onset was 1.9 weeks (range: 5 days to 2 years). Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or transaminitis.
If hypersensitivity occurs, withhold RETEVMO and begin corticosteroids at a dose of 1 mg/kg prednisone (or equivalent). Upon resolution of the event, resume RETEVMO at a reduced dose and increase the dose of RETEVMO by 1 dose level each week as tolerated until reaching the dose taken prior to onset of hypersensitivity [see Dosage and Administration (2.5)]. Continue steroids until patient reaches target dose and then taper. Permanently discontinue RETEVMO for recurrent hypersensitivity.

5.7   Tumor Lysis Syndrome
Tumor lysis syndrome (TLS) occurred in 0.6% of patients with medullary thyroid carcinoma receiving RETEVMO [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.

5.8   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, RETEVMO has the potential to adversely affect wound healing.
Withhold RETEVMO for at least 7 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 RETEVMO after resolution of wound healing complications has not been established.



5.9       Hypothyroidism

RETEVMO can cause hypothyroidism. Hypothyroidism occurred in 13% of patients treated with RETEVMO; all reactions were Grade 1 or 2. Hypothyroidism occurred in 13% of patients (50/373) with thyroid cancer and 13% of patients (53/423) with other solid tumors including NSCLC [see Adverse Reactions (6.1)].

Monitor thyroid function before treatment with RETEVMO and periodically during treatment. Treat with thyroid hormone replacement as clinically indicated. Withhold RETEVMO until clinically stable or permanently discontinue RETEVMO based on severity [see Dosage and Administration (2.5)].

5.10 Embryo-Fetal Toxicity
Based on data from animal reproduction studies and its mechanism of action, RETEVMO can cause fetal harm when administered to a pregnant woman. Administration of selpercatinib to pregnant rats during organogenesis at maternal exposures that were approximately equal to those observed at the recommended human dose of 160 mg twice daily resulted in embryolethality and malformations.
Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3)].

5.11 Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis in Pediatric Patients Slipped capital femoral epiphysis/slipped upper femoral epiphysis (SCFE/SUFE) occurred in 1 adolescent (3.7% of 27 patients) receiving RETEVMO in LIBRETTO-121 and 1 adolescent (0.5% of 193 patients) receiving RETEVMO in LIBRETTO-531 [see Adverse Reactions (6.1)]. Monitor patients for symptoms indicative of SCFE/SUFE and treat as medically and surgically appropriate [see Adverse Reactions (6.1)].

5.12 Effects on ability to drive and use machines
RETEVMO may have minor influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or using machines in case they experience fatigue or dizziness during treatment with RETEVMO.

6         ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling: •   Hepatotoxicity [see Warnings and Precautions (5.1)]
•   Interstitial Lung Disease / Pneumonitis [see Warnings and Precautions (5.2)] •   Hypertension [see Warnings and Precautions (5.3)]
•   QT Interval Prolongation [see Warnings and Precautions (5.4)]
•   Hemorrhagic Events [see Warnings and Precautions (5.5)]
•   Hypersensitivity [see Warnings and Precautions (5.6)]
•   Tumor Lysis Syndrome [see Warnings and Precautions (5.7)]
•   Risk of Impaired Wound Healing [see Warnings and Precautions (5.8)] •   Hypothyroidism [see Warnings and Precautions (5.9)]
•   Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis in Adolescent Patients [see Warnings and Precautions (5.11)].



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 safety population described in the WARNINGS and PRECAUTIONS and below reflects exposure to RETEVMO as a single agent administered at 160 mg orally twice daily evaluated in 796 patients with advanced solid tumors in LIBRETTO-001 [see Clinical Studies (14)].
RET Gene Fusion or Gene Mutation Positive Solid Tumors
LIBRETTO-001
Among the 796 patients who received RETEVMO, 84% were exposed for 6 months or longer and 73% were exposed for greater than one year. Among these patients, 96% received at least one dose of RETEVMO at the recommended dosage of 160 mg orally twice daily.
The median age was 59 years (range: 15 to 92 years); 0.3% were pediatric patients 12 to 16 years of age; 51% were male; and 69% were White, 23% were Asian, and 3% were Black or African American; and 5% were Hispanic/Latino. The most common tumors were NSCLC (45%), MTC (40%), and non-medullary thyroid carcinoma (7%).
Serious adverse reactions occurred in 44% of patients who received RETEVMO. The most frequent serious adverse reactions (≥2% of patients) were pneumonia, pleural effusion, abdominal pain, hemorrhage, hypersensitivity, dyspnea, and hyponatremia. Fatal adverse reactions occurred in 3% of patients; fatal adverse reactions included sepsis (n = 6), respiratory failure (n = 5), hemorrhage (n = 4), pneumonia (n = 3), pneumonitis (n = 2), cardiac arrest (n=2), sudden death (n = 1), and cardiac failure (n = 1).
Permanent discontinuation due to an adverse reaction occurred in 8% of patients who received RETEVMO.
Adverse reactions resulting in permanent discontinuation in ≥0.5% of patients included increased ALT (0.6%), fatigue (0.6%), sepsis (0.5%), and increased AST (0.5%).
Dosage interruptions due to an adverse reaction occurred in 64% of patients who received RETEVMO.
Adverse reactions requiring dosage interruption in ≥5% of patients included increased ALT, increased AST, diarrhea, and hypertension.
Dose reductions due to an adverse reaction occurred in 41% of patients who received RETEVMO. Adverse reactions requiring dosage reductions in ≥2% of patients included increased ALT, increased AST, QT prolongation, fatigue, diarrhea, drug hypersensitivity, and edema.
The most common adverse reactions (≥25%) were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache.
The most common Grade 3 or 4 laboratory abnormalities (≥5%) were decreased lymphocytes, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), decreased sodium, and decreased calcium.
Table 5 summarizes the adverse reactions in LIBRETTO-001.

Table 5: Adverse Reactions (≥20%) in Patients Who Received RETEVMO in LIBRETTO-001 RETEVMO
Adverse Reaction                                                  (n = 796) Grades 1-4#                                 Grades 3-4
(%)                                         (%)
General Disorders and Administration Site Conditions
Edema1                                  49                                         0.8* 

Fatigue2                                      46                                                3.1* Arthralgia                                    21                                                0.3* Gastrointestinal Disorders
Diarrhea3                                     47                                                 5* Dry Mouth                                     43                                                  0 Abdominal pain4                               34                                                2.5* Constipation                                  33                                                0.8* Nausea                                        31                                                1.1* Vomiting                                      22                                                1.8* Vascular Disorders
Hypertension                                  41                                                 20 Skin and Subcutaneous Tissue Disorders
Rash5                                         33                                                0.6* Nervous System Disorders
Headache6                                     28                                                1.4* Respiratory, Thoracic and Mediastinal Disorders
Cough7                                        24                                                  0 Dyspnea8                                      22                                                 3.1 Blood and Lymphatic System Disorders
Hemorrhage9                                   22                                                 2.6 Investigations
Prolonged QT interval                         21                                                4.8* 1    Edema includes edema peripheral, face edema, periorbital edema, eye edema, eyelid edema, orbital edema, localized edema, lymphedema, scrotal edema, peripheral swelling, scrotal swelling, swelling, swelling face, eye swelling, generalized edema, genital edema.
2    Fatigue includes asthenia and malaise.
3    Diarrhea includes defecation urgency, frequent bowel movements, gastrointestinal hypermotility, anal incontinence.
4    Abdominal pain includes abdominal pain upper, abdominal pain lower, abdominal discomfort, abdominal tenderness, epigastric discomfort, gastrointestinal pain.
5    Rash includes rash erythematous, rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, butterfly rash, exfoliative rash, rash follicular, rash generalized, rash vesicular.
6    Headache includes sinus headache, tension headache.
7    Cough includes productive cough, upper airway cough syndrome.
8    Dyspnea includes dyspnea exertional, dyspnea at rest.
9    Hemorrhage includes epistaxis, hematuria, hemoptysis, contusion, rectal hemorrhage, vaginal hemorrhage, ecchymosis, hematochezia, petechiae, traumatic hematoma, anal hemorrhage, blood blister, blood urine present, cerebral hemorrhage, gastric hemorrhage, hemorrhage intracranial, hemorrhage subcutaneous, spontaneous hematoma, abdominal wall hematoma, angina bullosa hemorrhagica, conjunctival hemorrhage, disseminated intravascular coagulation, diverticulum intestinal hemorrhagic, eye hemorrhage, gastrointestinal hemorrhage, gingival bleeding, hematemesis, hemorrhagic stroke, hemorrhoidal hemorrhage, hepatic hemorrhage, hepatic hematoma, intraabdominal hemorrhage, laryngeal hemorrhage, lower gastrointestinal hemorrhage, melena, mouth hemorrhage, occult blood positive, post procedural hemorrhage, postmenopausal hemorrhage, pelvic hematoma, periorbital hematoma, periorbital hemorrhage, pharyngeal hemorrhage, pulmonary contusion, purpura, retinal hemorrhage, retroperitoneal hematoma, scleral hemorrhage, skin hemorrhage, subarachnoid hemorrhage, subdural hemorrhage, upper gastrointestinal hemorrhage, uterine hemorrhage, vessel puncture site hematoma.
*    Only includes a grade 3 adverse reaction.
#    Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 

Clinically relevant adverse reactions in ≤15% of patients who received RETEVMO include hypothyroidism (13%); pneumonia (11%), hypersensitivity (6%); interstitial lung disease/pneumonitis, chylothorax, chylous ascites or tumor lysis syndrome (all < 2%).
Table 6 summarizes the laboratory abnormalities in LIBRETTO-001.

Table 6: Select Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients Who Received RETEVMO in LIBRETTO-001
RETEVMO1
Grades 1-4#                                    Grades 3-4
Laboratory Abnormality                              (%)                                            (%) Chemistry
Increased AST                                          59                                             11 Decreased calcium                                      59                                            5.7 Increased ALT                                          56                                             12 Decreased albumin                                      56                                            2.3 Increased glucose                                      53                                            2.8 Increased creatinine                                   47                                            2.4 Decreased sodium                                       42                                             11 Increased alkaline                                     40                                            3.4 phosphatase
Increased total cholesterol                            35                                            1.7 Increased potassium                                    34                                            2.7 Decreased glucose                                      34                                            1.0 Decreased magnesium                                    33                                            0.6 Increased bilirubin                                    30                                            2.8 Hematology
Decreased lymphocytes                                  52                                             20 Decreased platelets                                    37                                            3.2 Decreased hemoglobin                                   28                                            3.5 Decreased neutrophils                                  25                                            3.2 1    Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available, which ranged from 765 to 791 patients.
#    Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 

LIBRETTO-121
The safety population described below reflects exposure to RETEVMO as a single agent at 92 mg/m2 orally twice daily evaluated in 27 patients with advanced solid tumors harboring an activating RET alteration in LIBRETTO-121 [see Clinical Studies (14)]. Among the 27 pediatric and adolescent patients who received RETEVMO, 81% were exposed for 6 months or longer and 59% were exposed for greater than one year.
The median age was 13 years (range: 2 to 20 years); 22% were pediatric patients 2 to 12 years of age; 59% were male; and 52% were White, 26% were Asian, and 11% were Black or African American; and 19% were Hispanic/Latino. The most common cancers were MTC (52%), and papillary thyroid cancer (37%).


Serious adverse reactions occurred in 22% of patients who received RETEVMO. The serious adverse reactions (in 1 patient each) were abdominal infection, abdominal pain, aspiration, constipation, diarrhea, epiphysiolysis, nausea, pneumonia, pneumatosis intestinalis, rhinovirus infection, sepsis, vomiting.
Dosage interruptions due to an adverse reaction occurred in 22% of patients who received RETEVMO.
Adverse reactions requiring dosage interruption in ≥5% of patients included decreased neutrophils.
Dose reductions due to an adverse reaction occurred in 15% of patients who received RETEVMO. Adverse reactions requiring dosage reductions in ≥2% of patients included decreased neutrophils, increased ALT, and increased weight.
The most common adverse reactions (≥25%) were musculoskeletal pain, diarrhea, headache, nausea, vomiting, coronavirus infection, abdominal pain, fatigue, pyrexia, and hemorrhage.
The most common Grade 3 or 4 laboratory abnormalities (≥5%) were decreased calcium, decreased hemoglobin, and decreased neutrophils.
Table 7 summarizes the adverse reactions in LIBRETTO-121.
Table 7: Adverse Reactions (≥15%) in Patients Who Received RETEVMO in LIBRETTO-121 Adverse Reactions                                                 RETEVMO N= 27
Grades 1-4#                                 Grades 3-4
%                                           %
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain1                            56                                         0 Gastrointestinal disorders
Diarrhea2                                         41                                         0 Nausea                                            30                                       3.7* Vomiting                                          30                                        7* Abdominal pain3                                   26                                         0 Constipation                                      19                                        7* Stomatitis4                                       15                                         0 Nervous System Disorders
Headache                                          33                                         0 Infections and Infestations
Coronavirus infection                             30                                         0 Upper respiratory tract                           22                                         0 infection
General Disorders and Administration Site Conditions
Fatigue
5
26                                         0
Pyrexia                                           26                                         0 Edema
6
19                                         0
Increased weight                                  19                                         7* 
Blood and Lymphatic System Disorders
Hemorrhage7                                        26                                           3.7* Respiratory, Thoracic and Mediastinal Disorders
Oropharyngeal pain                                 22                                               0 Cough                                              22                                               0 Endocrine Disorders
Hypothyroidism8                                    19                                               0 Skin and Subcutaneous Tissue Disorders
Rash 9                                             19                                               0 Renal and Urinary Disorders
Proteinuria                                        15                                               0 1
Musculoskeletal pain includes arthralgia, back pain, bone pain, musculoskeletal chest pain, noncardiac chest pain, neck pain, pain in extremity
2
Diarrhea includes anal incontinence
3
Abdominal pain includes abdominal pain upper
4
Stomatitis includes angular cheilitis
5
Fatigue includes asthenia and malaise
6
Edema includes edema peripheral, face edema, localized edema, generalized edema, swelling 7
Hemorrhage includes mouth hemorrhage, epistaxis
8
Hypothyroidism includes blood thyroid stimulating hormone increased, thyroglobulin increased 9
Rash includes rash maculopapular
*
No Grade 4 events were reported.
#
Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.


Clinically relevant adverse reactions in <15% of patients who received RETEVMO include dizziness (11%), urinary tract infection (11%), decreased appetite (7%), electrocardiogram QT prolonged (7%), hypersensitivity (7%), hypertension (7%), and pneumonia (3.7%).


Table 8 summarizes the laboratory abnormalities in LIBRETTO-121.
Table 8: Select Laboratory Abnormalities (≥15%) Worsening from Baseline in Patients Who Received RETEVMO in LIBRETTO-121

RETEVMO1
Grades 1-4#                            Grades 3-4
Laboratory Abnormality                               (%)                                    (%) Chemistry
Decreased calcium                                       59                                      7 Increased ALT                                           56                                    3.7* Increased alkaline phosphatase                          52                                      0 Increased AST                                           48                                    3.7* 
Decreased albumin                                             44                                         0 Increased bilirubin                                           30                                         0 Increased creatinine                                          22                                         0 Decreased potassium                                           22                                        3.7 Decreased magnesium                                           15                                        3.7 Hematology
Decreased neutrophils                                         44                                        7* Decreased lymphocytes                                         24                                        4.8 Decreased platelets                                           22                                         0 Decreased hemoglobin                                          19                                        7* 1 Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available, which ranged from 21 to 27 patients.
* No Grade 4 abnormalities were reported.
# Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.



Treatment-naïve RET Fusion-Positive Non-small Cell Lung Cancer
LIBRETTO-431
The safety population described below reflects exposure to RETEVMO as a single agent administered at 160 mg orally twice daily evaluated in 158 patients with unresectable locally advanced or metastatic RET fusion-positive NSCLC in LIBRETTO-431 [see Clinical Studies (14)]. Among the 158 patients who received RETEVMO, the median duration of exposure was 16.7 months (range: 5 days to 37.9 months); 87% were exposed for 6 months or longer and 70% were exposed for one year or longer.
The median age was 61 years (range: 31 to 87 years); 46% were male; and 36% were White, 58% were Asian, 1.3% were Black or African American, 1.3% were American Indian or Alaska Native, and 3.2% were missing.
Serious adverse reactions occurred in 35% of patients who received RETEVMO. The most frequent serious adverse reactions (≥2% of patients) were pleural effusion, and abnormal hepatic function. Fatal adverse reactions occurred in 4.4% of patients who received RETEVMO; fatal adverse reactions included myocardial infarction (n = 2), respiratory failure (n = 2), cardiac arrest, malnutrition, and sudden death (n = 1, each).
Permanent discontinuation due to an adverse reaction occurred in 10% of patients who received RETEVMO.
Adverse reactions resulting in permanent discontinuation in ≥1% of patients included increased ALT (1.3%), and myocardial infarction (1.3%).
Dosage interruptions due to an adverse reaction occurred in 72% of patients who received RETEVMO.
Adverse reactions requiring dosage interruption in ≥5% of patients included increased ALT, hypertension, increased AST, QT prolongation, diarrhea, and COVID-19 infection.
Dose reductions due to an adverse reaction occurred in 51% of patients who received RETEVMO. Adverse reactions requiring dose reductions in ≥5% of patients included increased ALT, increased AST, QT prolongation.
The most common adverse reactions (≥25%) in patients who received RETEVMO were hypertension, diarrhea, edema, dry mouth, rash, fatigue, abdominal pain, and musculoskeletal pain.
The most common Grade 3 or 4 laboratory abnormalities (≥5%) in patients who received RETEVMO were increased ALT, increased AST, and decreased lymphocytes.
Table 9 summarizes the adverse reactions in LIBRETTO-431.


Table 9: Adverse Reactions (≥15%) in Patients on Either Arm in LIBRETTO-431 RETEVMO                                  Chemotherapy
Adverse Reaction                                (n=158)                         with or without pembrolizumab (n=98)
Grades 1-4#             Grades 3-4           Grades              Grades 3-4 (%)                    (%)                1-4#                  (%)
(%)
Vascular disorders
Hypertension                           48                     20*                 7                   3.1* Gastrointestinal disorders
Diarrhea1                              44                     1.3*               24                   2.0* Dry mouth2                             39                      0                  6                     0 Abdominal pain3                        25                     0.6*               19                   2.0* Constipation                           22                      0                 40                   1.0* Stomatitis4                            18                      0                 16                     0 Nausea                                 13                      0                 44                   1.0* Vomiting5                              13                      0                 23                   1.0* General disorders and administration site conditions
Edema6                                 41                     2.5*               28                     0 Fatigue7                               32                     3.2*               50                    5* Pyrexia                                13                     0.6*               23                     0 Skin and subcutaneous tissue disorders
Rash8                                  33                     1.9*               30                   1.0* Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain9                  25                      0                 28                     0 Investigations
Electrocardiogram QT                   20                      9*                1.0                    0 prolonged
Infections and infestations
COVID-19 infection                     19                     0.6*               18                     0 Metabolism and nutrition disorders
Decreased appetite                     17                      0                 34                   2.0* 1
Diarrhea includes diarrhea, anal incontinence.
2
Dry mouth includes dry mouth, mucosal dryness.
3
Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, gastrointestinal pain.
4
Stomatitis includes stomatitis, mouth ulceration, mucosal inflammation.
5
Vomiting includes vomiting, retching, regurgitation.


6
Edema includes edema, edema peripheral, face edema, periorbital edema, swelling face, peripheral swelling, localized edema, eyelid edema, orbital edema, eye edema, scrotal edema, penile edema, orbital swelling, periorbital swelling.
7
Fatigue includes fatigue, asthenia, malaise.
8
Rash includes rash, rash maculopapular, skin exfoliation, rash erythematous, rash macular, dermatitis, urticaria, rash papular, dermatitis allergic, rash pustular, rash vesicular, genital rash.
9
Musculoskeletal pain includes musculoskeletal pain, arthralgia, back pain, bone pain, musculoskeletal chest pain, non- cardiac chest pain, neck pain, pain in extremity.
*    No Grade 4 abnormalities were reported.
#
Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.


Clinically relevant adverse reactions in <15% of patients who received RETEVMO include headache (14%); hemorrhage (13%); urinary tract infections (12%); hypothyroidism (9%); pneumonia (9%); dizziness (8%); interstitial lung disease/pneumonitis (4.4%); hypersensitivity, chylous ascites, and chylothorax (all < 2%).
Table 10 summarizes the laboratory abnormalities in LIBRETTO-431.

Table 10: Select Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients on Either Arm in LIBRETTO-431
RETEVMO                               Chemotherapy
Laboratory Abnormality1 with or without pembrolizumab
Grades 1-4#        Grades 3-4      Grades 1-4#               Grades 3-4 (%)               (%)              (%)                      (%)
Chemistry
ALT increased                            81                21               63                       4.1 AST increased                            77                10               46                        0 Alkaline phosphatase                     35               1.3               22                        0 Increased
Total bilirubin Increased                52               1.3                9                        0 Blood creatinine Increased               23                0                21                        0 Magnesium decreased                      16               0.6                8                        0 Albumin decreased                        25                0                 5                        0 Calcium decreased                        53               1.9               24                       1.0 Sodium decreased                         31               3.2               41                       2.1 Potassium decreased                      17               1.3               15                       1.0 Hematology
Platelets decreased                      53               3.2               39                        5 Lymphocyte count decreased               53                8                64                        15 Hemoglobin decreased                     21                0                91                        5 Neutrophil count decreased               53               2.0               58                        11 1
Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available: RETEVMO (range: 154 to 157 patients) and chemotherapy with or without pembrolizumab (range: 96 to 97 patients).
# Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.


Increased Creatinine
In healthy subjects administered RETEVMO 160 mg orally twice daily, serum creatinine increased 18% after 10 days. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed [see Clinical Pharmacology (12.3)].


RET-Mutant Medullary Thyroid Cancer
LIBRETTO-531
The safety population described below reflects exposure to RETEVMO as a single agent administered at 160 mg (adults) or at 92 mg/m2 (adolescent, not to exceed 160 mg) orally twice daily, in patients with progressive, advanced, kinase inhibitor naïve, RET-mutant medullary thyroid cancer in LIBRETTO-531 [see Clinical Studies (14.2)]. Among the 193 patients who received RETEVMO, the observed median duration of exposure was 14.5 months (range: 25 days to 36 months); 80% were exposed for 6 months or longer and 59% were exposed for one year or longer.

The median age was 55 years (range: 12 to 84 years); 63% were male; and 69% were White, 28% were Asian, 2.9% were Black or African American and ethnicity was not routinely collected.
Serious adverse reactions occurred in 22% of patients who received RETEVMO. The most frequent serious adverse reactions were pneumonia and pyrexia (n = 3, each) and hypertension and urinary tract infection (n = 2, each). Fatal adverse reactions occurred in 2.1% of patients; fatal adverse reactions included COVID-19,
diabetic ketoacidosis, multiple organ dysfunction syndrome, and sudden death (n=1 each).
Permanent discontinuation due to an adverse reaction occurred in 4.7% of patients who received RETEVMO.
Adverse reactions resulting in permanent discontinuation were edema, multiple organ dysfunction syndrome, sudden death, AST increased, diabetic ketoacidosis, chronic kidney disease, retinopathy, COVID-19, and somatic symptom disorder (n = 1, each).
Dosage interruptions due to an adverse reaction occurred in 49% of patients who received RETEVMO.
Adverse reactions requiring dosage omission in ≥5% of patients included ALT increased (9%) and hypertension (7%).
Dose reductions due to an adverse reaction occurred in 39% of patients who received RETEVMO. One adverse reaction, increased ALT (7%), required a dose reduction in ≥5% of patients.
The most common adverse reactions (≥25%) in patients who received RETEVMO were hypertension, edema, dry mouth, fatigue, and diarrhea.
The most common Grade 3 or 4 laboratory abnormalities (≥5%) in patients who received RETEVMO were decreased lymphocytes, increased ALT, decreased neutrophils, increased ALP, increased blood creatinine, decreased calcium, and increased AST.
Table 11 summarizes the adverse reactions in LIBRETTO-531.

Table 11: Adverse Reactions (≥10%) in Patients Who Received RETEVMO in LIBRETTO-531 

RETEVMO                   Cabozantinib or Vandetanib
N = 193                          N = 97
Adverse Reaction                         Grades 1-4 #
Grades 3-4        Grades 1-4#     Grades 3-
(%)                (%)                (%)             4
(%)
Vascular disorders
Hypertension1                                 43                19*                 41             18* 
General disorders and administration-site conditions
Edema2                                     33                                0                       5                  0 Fatigue3                                              28                    4.1*                    47                 9* Pyrexia                                               12                    1.0*                    2.1                 0 Gastrointestinal disorders
Dry mouth4                                            32                    0.5*                    10                1.0* Diarrhea5                                             26                    3.1*                    61                 8* Abdominal pain6                                       18                    0.5*                    21                2.1* Constipation                                          16                     0                      12                  0 Stomatitis7                                           14                    0.5*                    42                13* Pyrexia                                               12                    1.0*                    2.1                 0 Nausea                                                10                    1.0*                    32                 5* Nervous system disorders
Headache8                                             23                    0.5*                    21                  0 Skin and subcutaneous tissue disorders
Rash9                                                 19                    1.6*                    27                4.1* Reproductive system and breast disorders
Erectile dysfunction                                  16                     0                       0                  0 Investigations
Electrocardiogram QT prolonged10                      14                    4.7*                    13                2.1* Metabolism and nutrition disorders
Decreased appetite                                    12                    0.5*                    28                 5* Endocrine disorders
Hypothyroidism11                                      11                     0                      21                  0 1 Hypertension includes hypertension, blood pressure increased.
2 Edema includes edema peripheral, face edema, periorbital edema, swelling face, peripheral swelling, localized edema, eyelid edema, generalized edema, eye swelling, lymphoedema, orbital edema, eye edema, edema, edema genital, swelling, scrotal edema, scrotal swelling, angioedema, skin edema, testicular swelling, vulvovaginal swelling.
3 Fatigue includes fatigue, asthenia, malaise.
4 Dry mouth includes dry mouth, mucosal dryness.
5 Diarrhea includes diarrhea, anal incontinence, defecation urgency, frequent bowel movements, gastrointestinal hypermotility.
6 Abdominal pain included abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, gastrointestinal pain.
7 Stomatitis includes stomatitis, mouth ulceration, mucosal inflammation.
8 Headache includes headache, sinus headache, tension headache.
9 Rash includes rash, rash maculopapular, skin exfoliation, rash erythematous, rash macular, dermatitis, urticaria, rash pruritic, exfoliative rash, rash papular, dermatitis allergic, rash follicular, rash generalized, rash pustular, butterfly rash, rash morbilliform, rash vesicular.
10 Electrocardiogram QT prolongation includes electrocardiogram QT prolonged, electrocardiogram QT interval abnormal.
11 Hypothyroidism includes hypothyroidism, blood thyroid stimulating hormone increased.
* Only includes a Grade 3 adverse reaction
# Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0.

Clinically relevant adverse reactions in ≤10% of patients who received RETEVMO include dizziness (8%); urinary tract infections (8%); vomiting (8%); pneumonia, interstitial lung disease/pneumonitis, chylous ascites and hypersensitivity (all < 2%).
Table 12 summarizes the laboratory abnormalities in LIBRETTO-531.

Table 12: Select Laboratory Abnormalities (≥5%) Worsening from Baseline in Patients Who Received RETEVMO in LIBRETTO-531
RETEVMO1                    Cabozantinib or Vandetanib1
Laboratory Abnormality                  Grades 1-4#        Grades 3-4          Grades 1-4#         Grades 3-4 %                  %                   %                   %
Chemistry
Calcium decreased                            55                  5                  62                  11 ALT increased                                53                  16                 72                   7* AST increased                                47                  5                  68                  3.2* Alkaline phosphatase increased               37                  6                  28                   5 Total bilirubin increased                    32                 1.1                 30                  3.2* Blood creatinine increased                   27                  6                  16                   8 Sodium decreased                             20                 3.2*                16                   0 Albumin decreased                            11                 1.1                  7                   0 Magnesium decreased                           9                 3.3                 26                   9 Potassium decreased                           8                  0                  22                  4.4* Hematology
Lymphocyte count decreased                   41                  18                 36                  13 Neutrophil count decreased                   33                  14                 42                  19 Platelets decreased                          28                 1.1                 34                  1.1* Hemoglobin decreased                         18                 2.1*                23                  2.1* 
1 Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available: RETEVMO (range: 183 to 191 patients) and chemotherapy with or without cabozantinib or vandetanib (range: 91 to 94 patients).
* Only includes a Grade 3 laboratory abnormality
# Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 

Increased Creatinine
In healthy subjects administered RETEVMO 160 mg orally twice daily, serum creatinine increased 18% after 10 days. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed [see Clinical Pharmacology (12.3)].


Reporting of suspected adverse reactions
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

Effects on Driving