Special Warning : אזהרת שימוש

5      WARNINGS AND PRECAUTIONS
5.1    Palmar-Plantar Erythrodysesthesia Syndrome
In INVICTUS, Grade 1-2 palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 21% of the 85 patients who received QINLOCK [see Adverse Reactions (6.1)]. PPES led to dose discontinuation in 1.2% of patients, dose interruption in 2.4% of patients, and dose reduction in 1.2% of patients.
Based on severity, withhold QINLOCK and then resume at same or reduced dose [see Dosage and Administration (2.2)].
5.2    New Primary Cutaneous Malignancies
In INVICTUS, cutaneous squamous cell carcinoma (cuSCC) occurred in 4.7% of the 85 patients who received QINLOCK, with a median time to event of 4.6 months (range: 3.8 to 6 months). In the pooled safety population, cuSCC and keratoacanthoma occurred in 7% and 1.9% of patients, respectively.
In INVICTUS, melanoma occurred in 2.4% of the 85 of patients who received QINLOCK. In the pooled safety population, melanoma occurred in 0.9% of patients.
Perform dermatologic evaluations when initiating QINLOCK and routinely during treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Continue QINLOCK at the same dose.
5.3    Hypertension
In INVICTUS, Grade 1-3 hypertension occurred in 14% of the 85 patients who received QINLOCK, including Grade 3 hypertension in 7% [see Adverse Reactions (6.1)].
Do not initiate QINLOCK in patients with uncontrolled hypertension. Adequately control blood pressure prior to initiating QINLOCK. Monitor blood pressure as clinically indicated during treatment with QINLOCK, and initiate or adjust antihypertensive therapy as appropriate. Based on severity, withhold QINLOCK and then resume at same or reduced dose or permanently discontinue [see Dosage and Administration (2.2)].
5.4    Cardiac Dysfunction
In INVICTUS, cardiac failure occurred in 1.2% of the 85 patients who received QINLOCK. In the pooled safety population, cardiac dysfunction (including cardiac failure, acute left ventricular failure, diastolic dysfunction, and ventricular hypertrophy) occurred in 1.7% of 351 patients, including Grade 3 adverse reactions in 1.1%.
In INVICTUS, Grade 3 decreased ejection fraction occurred in 2.6% of the 77 patients who received QINLOCK and who had a baseline and at least one post-baseline echocardiogram. In the pooled safety population, Grade 3 decreased ejection fraction occurred in 3.4% of the 263 patients who received QINLOCK and who had a baseline and at least one post-baseline echocardiogram.
In INVICTUS, cardiac dysfunction led to dose discontinuation in 1.2% of the 85 patients who received QINLOCK. The safety of QINLOCK has not been assessed in patients with a baseline ejection fraction below 50%.
Assess ejection fraction by echocardiogram or MUGA scan prior to initiating QINLOCK and during treatment, as clinically indicated. Permanently discontinue QINLOCK for Grade 3 or 4 left ventricular systolic dysfunction [see Dosage and Administration (2.2)].
5.5    Risk of Impaired Wound Healing
Impaired wound healing complications can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, QINLOCK has the potential to adversely affect wound healing.
Withhold QINLOCK for at least 1 week 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 QINLOCK after resolution of wound healing complications has not been established.

5.6       Photosensitivity

QINLOCK may cause photosensitivity reactions. In all patients treated with QINLOCK in clinical trials (n=621), photosensitivity reactions occurred in 0.6% of patients.
Advise patients to limit direct ultraviolet exposure during treatment with QINLOCK and for at least one week after discontinuation of treatment.
5.7       Embryo-Fetal Toxicity
Based on findings from animal studies and its mechanism of action, QINLOCK can cause fetal harm when administered to a pregnant woman. Oral administration of ripretinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations primarily associated with the cardiovascular and skeletal systems, anatomic variations, decreased fetal body weight, and increased post-implantation loss at exposures approximately one half of the recommended dose of 150 mg once daily based on area under the curve (AUC).
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with QINLOCK and for at least 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with QINLOCK and for at least 1 week after the last dose [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].
A barrier method contraception should be added if systemic contraceptive steroids are used.

5.8       Effects on ability to drive and use machines

QINLOCK has no influence on the ability to drive and use machines. In some patients, fatigue has been reported following administration of QINLOCK. If a patient experiences fatigue, this may influence their ability to drive or use machines.
6     ADVERSE REACTIONS
The following clinically significant adverse reactions are discussed elsewhere in the labeling: •   Palmar-Plantar Erythrodysesthesia Syndrome [see Warnings and Precautions (5.1)] •   New Primary Cutaneous Malignancies [see Warnings and Precautions (5.2)] •   Hypertension [see Warnings and Precautions (5.3)]
•   Cardiac Dysfunction [see Warnings and Precautions (5.4)]
•   Photosensitivity [see Warnings and Precautions (5.6)]

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.
Unless otherwise specified, the pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to QINLOCK as a single agent in 351 patients with advanced solid tumors enrolled in either an 
open-label dose finding with cohort expansion trial or INVICTUS. Among the patients who received QINLOCK in these trials, 52% were exposed for 6 months or longer and 21% were exposed for greater than one year.
Gastrointestinal Stromal Tumor
Patients Who Received Prior Treatment with Imatinib, Sunitinib and Regorafenib The safety of QINLOCK was evaluated in INVICTUS [see Clinical Studies (14)]. Patients received QINLOCK 150 mg taken orally once daily (n=85) or placebo (n=43). Among the patients who received QINLOCK, 46% were exposed for 6 months or longer and 3.5% were exposed for greater than one year.
Serious adverse reactions occurred in 31% of patients who received QINLOCK. Serious adverse reactions that occurred in >2% of patients were abdominal pain (4.7%), anemia (3.5%), nausea (2.4%), and vomiting (2.4%).
Permanent discontinuation due to an adverse reaction occurred in 8% of patients who received QINLOCK.
Adverse reactions resulting in permanent discontinuation in ≥1% of patients included general physical health deterioration (2.4%), anemia (1.2%), cardiac failure (1.2%), PPES (1.2%), and vomiting (1.2%).
Dosage interruptions due to an adverse reaction occurred in 24% of patients who received QINLOCK. Adverse reactions requiring dosage interruption in >2% of patients included nausea (3.5%), increased blood bilirubin (2.4%), and PPES (2.4%).
Dose reductions due to an adverse reaction occurred in 7% of patients who received QINLOCK. Adverse reactions resulting in a dose reduction in ≥1.2% of patients were abdominal pain, agitation, alopecia, arthritis, dermatosis, gastrointestinal disorder, hyperesthesia, myalgia, PPES, and decreased weight.

The most common adverse reactions (≥20%), were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, PPES, and vomiting. The most common Grade 3 or 4 laboratory abnormalities (≥4%) were increased lipase and decreased phosphate.

Table 2 summarizes the adverse reactions in INVICTUS.
Table 2:         Adverse Reactions (≥10%) in Patients with Gastrointestinal Stromal Tumor Who Received QINLOCK in INVICTUS
Adverse Reaction                                         QINLOCK                                Placebo (N=85)                               (N=43)
Grades 1-4        Grades 3-4       Grades 1-4             Grades 3-4
Skin and subcutaneous tissue
Alopecia                                            52                0                4.7                    0 Palmar-plantar erythrodysesthesia syndrome          21                0                 0                     0 Dry skin                                            13                0                 7                     0 Pruritus                                            11                0                4.7                    0 General
Fatigue                                             42               3.5               23                    2.3 Peripheral edema                                    17               1.2               7                      0 Asthenia                                            13               1.2               14                    4.7 Gastrointestinal
Nausea                                              39               3.5               12                     0 Abdominal pain                                      36                7                30                    4.7 Constipation                                        34               1.2               19                     0 Diarrhea                                            28               1.2               14                    2.3 Vomiting                                            21               3.5               7                      0 Stomatitis                                          11                0                0                      0 
Musculoskeletal and connective tissue
Myalgia                                                   32                  1.2                12                   0 Arthralgia                                                18                   0                 4.7                  0 Muscle spasms                                             15                   0                 4.7                  0 Metabolism and nutrition
Decreased appetite                                        27                  1.2                 21                 2.3 Investigations
Decreased weight                                          19                   0                  12                  0 Nervous system
Headache                                                  19                   0                 4.7                  0 Vascular
Hypertension                                              14                   7                 4.7                  0 Respiratory, thoracic and mediastinal
Dyspnea                                                   13                   0                  0                   0 
Table 3 summarizes the laboratory abnormalities in INVICTUS.

Table 3:          Select Laboratory Abnormalities (≥10%) Worsening from Baseline in Patients with Gastrointestinal Stromal Tumor Who Received QINLOCK with a Difference Between Arms of >5% Compared to Placebo in INVICTUS
Laboratory Abnormality                                           QINLOCKa                               Placeboa (N=85)                               (N=43)
Grades 1-4     Grades 3-4b           Grades 1-4       Grades 3-4
Hematology
Increased activated partial thromboplastin time                35                    0              9                  0 Increased INR                                                  21                   3.8            15                  0 Decreased neutrophil count                                     10                    0             2.5                 0 Chemistry
Increased lipase                                               32                    7             13                  8 Decreased phosphate                                            26                   4.9            2.5                 0 Increased triglycerides                                        26                   2.4            23                  0 Decreased calcium                                              23                    0              8                  0 Increased blood bilirubin                                      22                    0              5                 2.5 Increased CPK                                                  21                   1.2            10                  0 Decreased sodium                                               17                   2.4            10                 2.5 Increased creatinine                                           16                    0             18                  0 Increased serum amylase                                        13                   1.2             5                  0 Increased ALT                                                  12                   1.2             5                  0 CPK=creatine phosphokinase; INR=international normalized ratio; AST=aspartate aminotransferase; ALT=alanine aminotransferase a.
The denominator used to calculate the rate varied from 82 to 83 for QINLOCK and 34 to 40 for placebo based on the number of patients with a baseline value and at least one post-treatment value.
b.
Only includes Grade 3 laboratory abnormalities.

Other Adverse Reactions
Clinically relevant adverse reactions that occurred in <10% of QINLOCK-treated patients in INVICTUS included peripheral sensory neuropathy, dermatitis acneiform, and rash.


Clinically relevant adverse reactions that occurred in <10% of patients in the pooled safety population included cardiac ischemic events (including acute coronary syndrome and fatal cardiac arrest or myocardial infarction).
Photosensitivity occurred in 0.6% [see Warnings and Precautions (5.6)].
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.

Effects on Driving