Special Warning : אזהרת שימוש

5          WARNINGS AND PRECAUTIONS

5.1     Interstitial Lung Disease (ILD)/Pneumonitis
ILD/pneumonitis, which can be fatal, occurred in patients treated with TABRECTA [see Adverse Reactions (6.1)].
ILD/pneumonitis occurred in 4.8% of patients treated with TABRECTA in GEOMETRY mono-1, with 1.9% of patients experiencing Grade 3 ILD/pneumonitis and one patient experiencing death (0.3%). Nine patients (2.4%) discontinued TABRECTA due to ILD/pneumonitis. The median time-to-onset of Grade 3 or higher ILD/pneumonitis was 1.8 months (range: 0.2 months to 1.7 years).

Monitor for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever).
Immediately withhold TABRECTA in patients with suspected ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis are identified [see Dosage and Administration (2.3)].
5.2     Hepatotoxicity
Hepatotoxicity occurred in patients treated with TABRECTA [see Adverse Reactions (6.1)]. Increased alanine aminotransferase (ALT)/aspartate aminotransferase (AST) occurred in 15% of patients treated with TABRECTA in GEOMETRY mono-1. Grade 3 or 4 increased ALT/AST occurred in 7% of patients. Three patients (0.8%) discontinued TABRECTA due to increased ALT/AST. The median time-to-onset of Grade 3 or higher increased ALT/AST was 1.8 months (range: 0.5 to 46.4 months).

Monitor liver function tests (including ALT, AST, and total bilirubin) prior to the start of TABRECTA, every 2 weeks during the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop increased transaminases or bilirubin. Based on the severity of the adverse reaction, withhold, dose reduce, or permanently discontinue TABRECTA [see Dosage and Administration (2.3)].

5.3 Pancreatic Toxicity
Elevations in amylase and lipase levels occurred in patients treated with TABRECTA [see Adverse Reactions (6.1)]. Increased amylase/lipase occurred in 14% of patients treated with TABRECTA in GEOMETRY mono-1. Grade 3 and 4 increased amylase/lipase occurred in 7% and 1.9% of patients, respectively. Three patients (0.8%) discontinued TABRECTA due to increased amylase/lipase. The median time-to-onset of Grade 3 or higher increased amylase/lipase was 2 months (range: 0.03 to 31.1 months). Pancreatitis (Grade 3) occurred in one patient (0.3%); TABRECTA was permanently discontinued for this event.
Monitor amylase and lipase at baseline and regularly during treatment with TABRECTA. Based on the severity of the adverse reaction, temporarily withhold, dose reduce, or permanently discontinue TABRECTA [see Dosage and Administration (2.3)].
5.4        Hypersensitivity Reactions
Serious hypersensitivity reactions occurred in patients treated with TABRECTA in clinical trials other than GEOMETRY mono-1 [see Adverse Reactions (6.1)]. Signs and symptoms of hypersensitivity included pyrexia, chills, pruritus, rash, decreased blood pressure, nausea and vomiting.
5.5       Risk of Photosensitivity
Based on findings from animal studies, there is a potential risk of photosensitivity reactions with TABRECTA [see Nonclinical Toxicology (13.2)]. In GEOMETRY mono-1, it was recommended that patients use precautionary measures against ultraviolet exposure such as use of sunscreen or protective clothing during treatment with TABRECTA. Advise 
TAB API AUG24 V5                                                                                USPI 03.24 patients to limit direct ultraviolet exposure during treatment with TABRECTA.
5.6     Embryo-Fetal Toxicity
Based on findings from animal studies and its mechanism of action, TABRECTA can cause fetal harm when administered to a pregnant woman. Oral administration of capmatinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations at exposures less than the human exposure based on area under the curve (AUC) at the 400 mg twice daily clinical dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TABRECTA and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with TABRECTA and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3)].

6         ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
•     ILD/Pneumonitis [see Warnings and Precautions (5.1)]
•     Hepatotoxicity [see Warnings and Precautions (5.2)]
•     Pancreatic Toxicity [see Warnings and Precautions (5.3)]
•     Hypersensitivity reactions [see Warnings and Precautions (5.4)] 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.
Metastatic Non-Small Cell Lung Cancer
The safety of TABRECTA was evaluated in GEOMETRY mono-1 [see Clinical Studies (14)]. Patients received TABRECTA 400 mg orally twice daily until disease progression or unacceptable toxicity (N = 373). Among patients who received
TABRECTA, 37% were exposed for at least 6 months and 22% were exposed for at least one year.
Serious adverse reactions occurred in 53% of patients who received TABRECTA. Serious adverse reactions in ≥ 2% of patients included dyspnea (7%), pneumonia (7%), pleural effusion (4.3%), musculoskeletal pain (3.8%), general physical health deterioration (2.9%), ILD/pneumonitis (2.7%), edema (2.4%), and vomiting (2.4%). Fatal adverse reactions occurred in 0.5% of patients who received TABRECTA, including pneumonitis (0.3%) and death, not otherwise specified (0.3%).
Permanent discontinuation of TABRECTA due to an adverse reaction occurred in 17% of patients. The most frequent adverse reactions (≥ 1%) leading to permanent discontinuation of TABRECTA were ILD/pneumonitis (2.4%), edema (2.4%), fatigue (1.3%), and pneumonia (1.1%).
Dose interruptions due to an adverse reaction occurred in 57% of patients who received TABRECTA. Adverse reactions requiring dosage interruption in > 2% of patients who received TABRECTA included edema, increased blood creatinine, nausea, increased lipase, vomiting, increased ALT, dyspnea, pneumonia, fatigue, increased amylase, increased AST, musculoskeletal pain, abdominal pain, and increased blood bilirubin.
Dose reductions due to an adverse reaction occurred in 26% of patients who received TABRECTA. Adverse reactions requiring dosage reductions in > 2% of patients who received TABRECTA included edema, increased ALT and increased blood creatinine.
The most common adverse reactions (≥ 20%) in patients who received TABRECTA were edema, nausea, musculoskeletal pain, fatigue, vomiting, dyspnea, cough, and decreased appetite.

Table 3 summarizes the adverse reactions in GEOMETRY mono-1.



TAB API AUG24 V5                                                                                  USPI 03.24 Table 3: Adverse Reactions (≥ 10%) in Patients Who Received TABRECTA in GEOMETRY mono-1 Adverse reactions                                                           TABRECTA (N = 373)
Grades 1 to 4           Grades 3 to 4
(%)                     (%)
General disorders and administration-site conditions
Edemaa                                                     59                      13 Musculoskeletal painb                                      40                      4.3 Fatiguec                                                   34                       8 Pyrexiad                                                   14                      0.8 Weight decreased                                           11                      0.5 Gastrointestinal disorders
Nausea                                                     46                      2.4 Vomiting                                                   28                      2.4 Constipation                                               19                      0.8 Diarrhea                                                   19                      0.5 Respiratory, thoracic, and mediastinal disorders
Dyspnea                                                    25                       7 Coughe                                                     21                      0.5 Pneumoniaf                                                 13                       6 Metabolism and nutrition disorders
Decreased appetite                                         21                      1.1 Skin and subcutaneous tissue disorders
Rashg                                                      13                      0.5 Nervous system disorders
Dizzinessh                                                 13                      0.5 a
Edema includes edema peripheral, generalized edema, face edema, edema, localized edema, edema genital, eyelid edema, peripheral swelling, scrotal edema, and penile edema.
b
Musculoskeletal pain includes arthralgia, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non- cardiac chest pain, pain in extremity, pain in jaw, spinal pain.
c
Fatigue includes fatigue and asthenia.
d
Pyrexia includes pyrexia and body temperature increased.
e
Cough includes cough, upper airway cough syndrome, and productive cough.
f
Pneumonia includes pneumonia aspiration, pneumonia, pneumonia influenzal, pneumonia bacterial, lower respiratory tract infection, and lung abscess.
g
Rash includes rash, dermatitis acneiform, rash maculo-papular, eczema, erythema multiforme, rash macular, dermatitis, rash erythematous, rash pustular, dermatitis bullous, and rash vesicular.
h
Dizziness includes dizziness, vertigo, and vertigo positional.

Clinically relevant adverse reactions occurring in < 10% of patients treated with TABRECTA included pruritus (including allergic pruritus), ILD/pneumonitis, cellulitis, acute kidney injury (including renal failure), urticaria, and acute pancreatitis.

Table 4 summarizes the laboratory abnormalities in GEOMETRY mono-1.
Table 4: Select Laboratory Abnormalities (≥ 20%) Worsening From Baseline in Patients Who Received TABRECTA in GEOMETRY mono-1
TABRECTAa
Laboratory abnormalities                                    Grades 1 to 4               Grades 3 to 4 (%)                         (%)
Chemistry
Decreased albumin                                         72                          1.9 Increased creatinine                                      65                          0.5 Increased alanine aminotransferase                        39                           9 Increased amylase                                         34                          4.7 TAB API AUG24 V5                                                                                        USPI 03.24 TABRECTAa
Laboratory abnormalities                                               Grades 1 to 4                     Grades 3 to 4 (%)                               (%)
Increased alkaline phosphatase                                        32                                0.6 Increased gamma-glutamyltransferase                                   30                                 6 Increased lipase                                                      29                                 9 Increased aspartate aminotransferase                                  28                                 6 Decreased phosphate                                                   26                                4.4 Increased potassium                                                   25                                4.1 Decreased sodium                                                      24                                 6 Decreased glucose                                                     23                                0.3 Hematology
Decreased lymphocytes                                                   45                               14 Decreased leukocytes                                                    25                               1.7 Decreased hemoglobin                                                    24                               2.8 a
The denominator used to calculate the rate varied from 359 to 364 based on the number of patients with a baseline value and at least one post-treatment value.
Other Clinical Trials Experience
The following adverse reactions have been reported following administration of TABRECTA: hypersensitivity and thrombocytopenia.


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/ and to Novartis using the following email address: Safetydesk.israel@novartis.com.

Effects on Driving