KISQALI

5 WARNINGS AND PRECAUTIONS Interstitial Lung Disease (ILD)/Pneumonitis: Severe, life threatening, or fatal ILD/pneumonitis can occur with KISQALI treatment. Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Interrupt and evaluate patients with new or worsening respiratory symptoms suspected to be due to ILD/pneumonitis. Permanently discontinue KISQALI in patients with recurrent symptomatic or severe ILD/pneumonitis. ( 2.2 , 5.1 ) Severe Cutaneous Adverse Reactions (SCARs): SCARs including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug-reaction with eosinophilia and systemic symptoms (DRESS) can occur with KISQALI treatment. Permanently discontinue KISQALI in patients with SCARs or other life-threatening cutaneous reactions. ( 2.2 , 5.2 ) QT Interval Prolongation: KISQALI has been shown to prolong the QT interval in a concentration-dependent manner. Monitor electrocardiograms (ECGs) and electrolytes prior to initiation of treatment with KISQALI. Repeat ECGs at approximately Day 14 of the first cycle, and as clinically indicated. Monitor electrolytes at the beginning of each cycle for 6 cycles, and as clinically indicated. Avoid using KISQALI with drugs known to prolong QT interval and/or strong CYP3A inhibitors. ( 2.2 , 5.3 , 7.1 , 7.4 ) Increased QT Prolongation with Concomitant Use of Tamoxifen: KISQALI is not indicated for concomitant use with tamoxifen. ( 5.4 ) Hepatotoxicity: Increases in serum transaminase and bilirubin levels have been observed. Perform liver function tests (LFTs) before initiating treatment with KISQALI. Monitor LFTs every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated. ( 2.2 , 5.5 ) Neutropenia: Perform complete blood count (CBC) before initiating therapy with KISQALI. Monitor CBC every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated. ( 2.2 , 5.6 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception during therapy. ( 5.7 , 8.1 , 8.3 ) 5.1 Interstitial Lung Disease/Pneumonitis Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with KISQALI and other CDK 4/6 inhibitors. In patients with early breast cancer (NATALEE) who received 400 mg KISQALI plus a non-steroidal aromatase inhibitor (NSAI), 1.5% of patients had ILD/pneumonitis (Grade 1-2). In patients with advanced or metastatic breast cancer (MONALEESA-2, MONALEESA-3, MONALEESA-7), 1.6% of patients had ILD/pneumonitis (any Grade, 0.4% had Grade 3-4, and 0.1% had a fatal outcome). Additional cases of ILD/pneumonitis have occurred in the postmarketing setting, some resulting in death [see Adverse Reactions (6.2)] . Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis which may include hypoxia, cough, and dyspnea. In patients who have new or worsening respiratory symptoms suspected to be due to ILD or pneumonitis, interrupt KISQALI immediately and evaluate the patient. Permanently discontinue KISQALI in patients with severe ILD/pneumonitis or any recurrent symptomatic ILD/pneumonitis [see Dosage and Administration (2.2)] . 5.2 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) can occur in patients treated with KISQALI [see Adverse Reactions (6.2)] . If signs or symptoms of severe cutaneous reactions occur, interrupt KISQALI until the etiology of the reaction has been determined [see Dosage and Administration (2.2)] . Early consultation with a dermatologist is recommended to ensure greater diagnostic accuracy and appropriate management. If SJS, TEN, or DiHS/DRESS is confirmed, permanently discontinue KISQALI. Do not reintroduce KISQALI in patients who have experienced SCARs or other life-threatening cutaneous reactions during KISQALI treatment. 5.3 QT Interval Prolongation KISQALI has been shown to prolong the QT interval in a concentration-dependent manner [see Clinical Pharmacology (12.2)] . Avoid KISQALI in patients who are at significant risk of developing Torsades de Pointes (TdP), including those with: congenital long QT syndrome; uncontrolled or significant cardiac disease, recent myocardial infarction, heart failure, unstable angina, bradyarrhythmias, uncontrolled hypertension, high degree atrioventricular block, severe aortic stenosis, or uncontrolled hypothyroidism; electrolyte abnormalities; taking drugs known to prolong QT interval and/or strong CYP3A inhibitors as this may lead to prolongation of the QTcF interval. Based on the observed QT prolongation during treatment, KISQALI may require dose interruption, reduction or discontinuation as described in Table 4 [see Dosage and Administration (2.2), Drug Interactions (7.4)] . In patients with early breast cancer (NATALEE) who received 400 mg KISQALI plus NSAI, 8 out of 2494 patients (0.3%) had > 500 ms post-baseline QTcF interval value and 50 out of 2494 patients (2%) had > 60 ms QTcF increase from baseline. QTcF prolongation was reversible with dose interruption. The majority of QTcF prolongation occurred within the first four weeks of KISQALI. There were no reported cases of Torsades de Pointes. In patients with advanced or metastatic breast cancer (MONALEESA-2, MONALEESA-3, and MONALEESA-7) who received 600 mg KISQALI plus NSAI or fulvestrant, 15 out of 1054 patients (1.4%) had a > 500 ms post-baseline QTcF value and 61 out of 1054 patients (6%) had a > 60 ms QTcF increase from baseline. QTcF prolongation was reversible with dose interruption. The majority of QTcF prolongation occurred within the first four weeks of KISQALI. There were no reported cases of Torsades de Pointes. In MONALEESA-2, in the KISQALI plus letrozole treatment arm, there was one (0.3%) sudden death in a patient with Grade 3 hypokalemia and Grade 2 QT prolongation. No cases of sudden death were reported in MONALEESA-7 or MONALEESA-3 [see Adverse Reactions (6)] . Perform ECG in all patients prior to starting KISQALI. Initiate treatment with KISQALI only in patients with QTcF values less than 450 ms. Repeat ECG at approximately Day 14 of the first cycle, and as clinically indicated. Monitor serum electrolytes (including potassium, calcium, phosphorous and magnesium) prior to the initiation of KISQALI at the beginning of the first 6 cycles, and as clinically indicated. Correct any abnormality before starting KISQALI [see Dosage and Administration (2.2)] . 5.4 Increased QT Prolongation with Concomitant Use of Tamoxifen Avoid use of tamoxifen with KISQALI. In MONALEESA-7, the observed mean QTcF increase from baseline was > 10 ms higher in the tamoxifen plus placebo subgroup compared with the non-steroidal aromatase inhibitors (NSAIs) plus placebo subgroup. In the placebo arm, an increase of > 60 ms from baseline occurred in 6/90 (7%) of patients receiving tamoxifen, and in no patients receiving an NSAI. An increase of > 60 ms from baseline in the QTcF interval was observed in 14/87 (16%) of patients in the KISQALI and tamoxifen combination and in 18/245 (7%) of patients receiving KISQALI plus an NSAI [see Clinical Pharmacology (12.2)] . 5.5 Hepatotoxicity In patients with early and advanced or metastatic breast cancer, drug-induced liver injury and increases in transaminases occurred with KISQALI. In patients with early breast cancer (NATALEE) treated with KISQALI, drug-induced liver injury was reported in 9 patients (0.4%), of which 5 were Grade ≥ 3, and 8 had resolved as of the data cutoff. There were 8 (0.3%) clinically confirmed Hy’s Law cases (including 4 out of 9 drug-induced liver injury mentioned above), 6 of which had resolved within 303 days and 2 of which were improving, all after discontinuation of KISQALI. Grade 3 or 4 increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) occurred in 8% and 4.7% respectively; including Grade 4 increases in ALT (1.5%) and AST (0.8%). In patients with advanced or metastatic breast cancer (MONALEESA-2, MONALEESA-7 and MONALEESA-3) treated with KISQALI Grade 3 or 4 increases in ALT and AST occurred in 11% and 8%, respectively. Among the patients who had Grade ≥ 3 ALT/AST elevation, the median time-to-onset was 92 days for the KISQALI plus aromatase inhibitor or fulvestrant treatment arms. The median time to resolution to Grade ≤ 2 was 21 days in the KISQALI plus aromatase inhibitor or fulvestrant treatment arms. In MONALEESA-2 and MONALEESA-3, concurrent elevations in ALT or AST greater than three times the ULN and total bilirubin greater than two times the ULN, with normal alkaline phosphatase, in the absence of cholestasis (Hy’s Law) occurred in 6 (1%) patients and all patients recovered after discontinuation of KISQALI. Perform liver function tests (LFTs) in all patients before initiating KISQALI. Monitor LFTs every 2 weeks for first 2 cycles, at the beginning of each of the subsequent 4 cycles, and as clinically indicated [see Dosage and Administration (2.2)] . Based on the severity of the transaminase elevations, KISQALI may require dose interruption, reduction, or discontinuation as described in Table 5 (Dose Modification and Management for Hepatobiliary Toxicity) [see Dosage and Administration (2.2)] . 5.6 Neutropenia KISQALI causes concentration-dependent neutropenia. In patients with early breast cancer (NATALEE) who received KISQALI plus NSAI, 94%, including 45% of Grade 3 or 4, had a decrease in neutrophil counts (based on laboratory findings), 63% had an adverse reaction of neutropenia, and 0.3% had febrile neutropenia. The median time to Grade ≥ 2 neutropenia was 18 days. The median time to resolution of Grade ≥ 3 neutropenia to Grade < 3 was 10 days. Treatment discontinuation due to neutropenia was required in 1.1% of patients. In patients with advanced or metastatic breast cancer (MONALEESA-2, MONALEESA-7, and MONALEESA-3) who received KISQALI plus NSAI or fulvestrant, 75% had neutropenia, 62% had Grade 3 or 4 decrease in neutrophil count (based on laboratory findings), and 1.7% had febrile neutropenia. The median time to Grade ≥ 2 neutropenia was 17 days. The median time to resolution of Grade ≥ 3 neutropenia to Grade < 3 was 12 days. Treatment discontinuation due to neutropenia was required in 1% of patients. Perform a complete blood count (CBC) in all patients before initiating KISQALI. Monitor CBC every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated. Based on the severity of the neutropenia, KISQALI may require dose interruption, reduction, or discontinuation as described in Table 6 [see Dosage and Administration (2.2)] . 5.7 Embryo-Fetal Toxicity Based on findings from animal studies and the mechanism of action, KISQALI can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of ribociclib to pregnant rats and rabbits during organogenesis caused embryo-fetal toxicities at maternal exposures that were 0.6 and 1.5 times the human clinical exposure, respectively, based on area under the curve (AUC). Advise pregnant women of the potential risk to a fetus. Advise women of reproductive potential to use effective contraception during therapy with KISQALI and for at least 3 weeks after the last dose [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)] .

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1)] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)] QT Interval Prolongation [see Warnings and Precautions (5.3, 5.4)] Hepatotoxicity [see Warnings and Precautions (5.5)] Neutropenia [see Warnings and Precautions (5.6)] In patients with early breast cancer, the most common (incidence ≥ 20%) adverse reactions, including laboratory abnormalities, are lymphocytes decreased, leukocytes decreased, neutrophils decreased, hemoglobin decreased, alanine aminotransferase increased, aspartate aminotransferase increased, infections, creatinine increased, platelets decreased, headache, nausea, and fatigue. ( 6 ) In patients with advanced or metastatic breast cancer, the most common (incidence ≥ 20%) adverse reactions, including laboratory abnormalities, are leukocytes decreased, neutrophils decreased, hemoglobin decreased, lymphocytes decreased, aspartate aminotransferase increased, gamma glutamyl transferase increased, alanine aminotransferase increased, infections, nausea, creatinine increased, fatigue, platelets decreased, diarrhea, vomiting, headache, constipation, alopecia, cough, rash, back pain, and glucose serum decreased. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 data described in WARNINGS AND PRECAUTIONS reflect exposure to KISQALI plus non-steroidal aromatase inhibitor (NSAI) in 2526 patients with early breast cancer (NATALEE), of whom 51% completed 36 months of KISQALI treatment. The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were lymphocytes decreased (97%), leukocytes decreased (95%), neutrophils decreased (94%), hemoglobin decreased (47%), alanine aminotransferase increased (45%), aspartate aminotransferase increased (44%), infections (37%), creatinine increased (33%), platelets decreased (28%), headache (23%), nausea (23%), and fatigue (22%). In addition, the pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to KISQALI in 1065 patients with advanced or metastatic breast cancer (MONALEESA-2, MONALEESA-3, MONALEESA-7), of whom 76% were exposed for 6 months or longer, and 62% were exposed for greater than one year. The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were leukocytes decreased (95%), neutrophils decreased (93%), hemoglobin decreased (68%), lymphocytes decreased (66%), aspartate aminotransferase increased (55%), gamma-glutamyl transferase increased (53%), alanine aminotransferase increased (52%), infections (47%), nausea (47%), creatinine increased (42%), fatigue (35%), platelets decreased (34%), diarrhea (33%), vomiting (29%), headache (27%), constipation (25%), alopecia (25%), cough (24%), rash (24%), back pain (24%), and glucose serum decreased (20%). NATALEE: KISQALI in Combination with a Non-steroidal Aromatase Inhibitor as Adjuvant Treatment Adults with HR-positive, HER2-negative Stage II and III Early Breast Cancer at High Risk of Recurrence The safety of KISQALI was evaluated in NATALEE, a clinical trial of 5101 patients who received KISQALI plus NSAI or NSAI alone, with or without goserelin [see Clinical Studies (14)] . The median duration of exposure to KISQALI was 33 months. Serious adverse reactions occurred in 14% of patients who received KISQALI. Serious adverse reactions in > 0.5% of patients who received KISQALI included COVID-19 (1.1%), pneumonia (0.8%), and pulmonary embolism (0.6%). Fatal adverse reactions occurred in 0.6% of patients who received KISQALI. Fatal adverse reactions in ≥ 0.1% of patients receiving KISQALI included COVID-19 or COVID-19 pneumonia (0.2%) and pulmonary embolism (0.1%). Permanent discontinuation of KISQALI due to an adverse reaction occurred in 20% of patients. Adverse reactions which resulted in permanent discontinuation of KISQALI in ≥ 2% of patients were alanine aminotransferase or aspartate aminotransferase increased (8%). Dosage interruptions of both KISQALI plus NSAI due to an adverse reaction occurred in 73% of patients. Adverse reactions which required dosage interruption in ≥ 5% of patients included neutropenia or neutrophil count decreased (43%), alanine aminotransferase or aspartate aminotransferase increased (11%), COVID-19 (10%), and hypomagnesemia (5%). Dose reductions of KISQALI due to an adverse reaction occurred in 23% of patients. Adverse reactions which required dose reductions in ≥ 2% of patients included neutropenia or neutrophil count decreased (14%) and liver function abnormal (2.3%). The most common (≥ 20% on KISQALI plus NSAI and ≥ 2% higher than placebo) adverse reactions, including laboratory abnormalities, were neutropenia, infections, nausea, headache, fatigue, leukopenia, and abnormal liver function tests. Table 10 summarizes the adverse reactions in NATALEE. Table 10: Adverse Reactions (≥ 10% and ≥ 2% Higher Than NSAI Alone Arm) in NATALEE Abbreviation: NSAI, non-steroidal aromatase inhibitor. Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 1 Infections: urinary tract infections; respiratory tract infections. 2 Only includes a Grade 3 adverse reaction. Adverse reaction KISQALI + NSAI (n = 2526) NSAI (n = 2441) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Infections and infestations Infections 1 37 2.0 27 0.9 Nervous system disorders Headache 2 23 0.4 17 0.2 Gastrointestinal disorders Nausea 2 23 0.2 8 0.1 Diarrhea 2 15 0.6 6 0.1 Constipation 2 13 0.2 5 0 Abdominal pain 2 11 0.5 7 0.4 General disorders and administration-site conditions Fatigue 2 22 0.8 13 0.2 Asthenia 2 17 0.6 12 0.1 Pyrexia 2 11 0.2 6 0.1 Skin and subcutaneous tissue disorders Alopecia 15 0 4.6 0 Respiratory, thoracic, and mediastinal disorders Cough 2 13 0.1 8 0.1 Clinically relevant adverse reactions reported in < 10% of patients who received KISQALI plus NSAI included rash (9%), dizziness (9%), vomiting (8%), peripheral edema (7%), pruritus (7%), dyspnea (7%), stomatitis (6%), oropharyngeal pain (6%), hypocalcemia (5%), hypokalemia (4.8%), decreased appetite (4.8%). Table 11 summarizes the laboratory abnormalities in NATALEE. Table 11: Select Laboratory Abnormalities (≥ 10%) in Patients in NATALEE Who Received KISQALI Plus NSAI Abbreviation: NSAI, non-steroidal aromatase inhibitor. Laboratory abnormality KISQALI + NSAI (n = 2526) NSAI (n = 2441) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology Lymphocytes decreased 97 19 88 6 Leukocytes decreased 95 27 45 0.6 Neutrophils decreased 94 45 35 1.7 Hemoglobin decreased 47 0.6 26 0.3 Platelets decreased 28 0.4 13 0.3 Chemistry Alanine aminotransferase increased 45 8 35 1 Aspartate aminotransferase increased 44 5 33 1 Creatinine increased 33 0.3 11 0 MONALEESA-2: KISQALI in Combination with Letrozole Postmenopausal Women with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy The safety of KISQALI was evaluated in MONALEESA-2, a clinical trial of 668 postmenopausal women receiving KISQALI plus letrozole or placebo plus letrozole [see Clinical Studies (14)] . The median duration of exposure to KISQALI plus letrozole was 13 months with 58% of patients exposed for ≥ 12 months. Serious adverse reactions occurred in 21% of patients who received KISQALI plus letrozole. Serious adverse reactions in ≥ 1% of patients receiving KISQALI plus letrozole included abdominal pain (1.5%), vomiting (1.5%), constipation (1.2%), nausea (1.2%), anemia (1.2%), febrile neutropenia (1.2%), dyspnea (1.2%), and alanine aminotransferase increased (1.2%). Fatal adverse reactions occurred in 1.8% of patients who received KISQALI. Fatal adverse reactions in ≥ 0.1% of patients receiving KISQALI included acute respiratory failure (0.6%), acute myocardial infarction, sudden death (with Grade 3 hypokalemia and Grade 2 QT prolongation), unknown cause, and pneumonia (0.3% each). Permanent discontinuation of both KISQALI and letrozole due to an adverse reaction occurred in 7% of patients. Permanent discontinuation of KISQALI alone occurred in 7% of patients. Adverse reactions which resulted in permanent discontinuation of both KISQALI and letrozole in ≥ 2% of patients were alanine aminotransferase increased (5%), aspartate aminotransferase increased (3%), and vomiting (2%). Dosage interruptions of both KISQALI and letrozole due to an adverse reaction occurred in 71% of patients. Adverse reactions which required dosage interruption in ≥ 5% of patients included neutropenia (39%), neutrophils decreased (12%), vomiting (6%), nausea (5%), alanine aminotransferase increased (5%), and leukocytes decreased (5%). Dose reductions of KISQALI due to an adverse reaction occurred in 45% of patients receiving KISQALI plus letrozole. Adverse reactions which required dose reductions in ≥ 2% of patients included neutropenia (24%), neutrophils decreased (8%), and alanine aminotransferase increased (3%). Antiemetics and antidiarrheal medications were used to manage symptoms as clinically indicated. The most common (≥ 20% on the KISQALI arm and ≥ 2% higher than placebo) adverse reactions, including laboratory abnormalities, were neutrophils decreased, leukocytes decreased, hemoglobin decreased, nausea, lymphocytes decreased, alanine aminotransferase increased, aspartate aminotransferase increased, fatigue, diarrhea, alopecia, vomiting, platelets decreased, constipation, headache, and back pain. Table 12 summarizes the adverse reactions in MONALEESA-2. Table 12: Adverse Reactions (≥ 10% and ≥ 2% Higher Than Placebo Arm) in MONALEESA-2 Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 1 Only includes a Grade 3 adverse reaction. Adverse reaction KISQALI + Letrozole (n = 334) Placebo + Letrozole (n = 330) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Gastrointestinal disorders Nausea 1 52 2.4 29 0.6 Diarrhea 1 35 1.2 22 0.9 Vomiting 1 29 3.6 16 0.9 Constipation 1 25 1.2 19 0 Stomatitis 1 12 0.3 7 0 Abdominal pain 1 11 1.2 8 0 General disorders and administration-site conditions Fatigue 37 2.4 30 0.9 Pyrexia 1 13 0.3 6 0 Peripheral edema 1 12 0 10 0 Skin and subcutaneous tissue disorders Alopecia 1 33 0 16 0 Rash 1 17 0.6 8 0 Pruritus 1 14 0.6 6 0 Nervous system disorders Headache 1 22 0.3 19 0.3 Insomnia 1 12 0.3 9 0 Musculoskeletal and connective tissue disorders Back pain 1 20 2.1 18 0.3 Metabolism and nutrition disorders Decreased appetite 1 19 1.5 15 0.3 Respiratory, thoracic and mediastinal disorders Dyspnea 1 12 1.2 9 0.6 Infections and infestations Urinary tract infections 1 11 0.6 8 0 Clinically relevant adverse reactions in < 10% of patients in MONALEESA-2 receiving KISQALI plus letrozole included interstitial lung disease (0.3%), lung infiltration (0.3%), pneumonitis (0.3%), and pulmonary fibrosis (0.6%). Table 13 summarizes the laboratory abnormalities in MONALEESA-2. Table 13: Select Laboratory Abnormalities (≥ 10%) in Patients in MONALEESA-2 Who Received KISQALI Plus Letrozole Laboratory abnormality KISQALI + Letrozole (n = 334) Placebo + Letrozole (n = 330) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology Leukocytes decreased 93 34 29 1.5 Neutrophils decreased 93 60 24 1.2 Hemoglobin decreased 57 1.8 26 1.2 Lymphocytes decreased 51 14 22 3.9 Platelets decreased 29 0.9 6 0.3 Chemistry Alanine aminotransferase increased 46 10 36 1.2 Aspartate aminotransferase increased 44 7 32 1.5 Creatinine increased 20 0.6 6 0 Phosphorous decreased 13 5 4 0.6 Potassium decreased 11 1.2 7 1.2 MONALEESA-7: KISQALI in Combination with a Non-Steroidal Aromatase Inhibitor Pre/perimenopausal Patients with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy The safety of KISQALI was evaluated in MONALEESA-7, a clinical trial of 672 pre/perimenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer receiving either KISQALI plus a NSAI or tamoxifen plus goserelin or placebo plus NSAI or tamoxifen plus goserelin [see Clinical Studies (14)] . The median duration of exposure in the KISQALI plus a NSAI arm was 15.2 months with 66% of patients exposed for ≥ 12 months. The safety data reported below are based on 495 pre/perimenopausal patients receiving KISQALI plus NSAI plus goserelin or placebo plus NSAI plus goserelin. Serious adverse reactions occurred in 17% of patients who received KISQALI plus NSAI plus goserelin. Serious adverse reactions in ≥ 1% of patients receiving KISQALI plus NSAI plus goserelin included drug-induced liver injury (1.6%), abdominal pain (1.2%), dyspnea (1.2%), febrile neutropenia (1.2%), and back pain (1.2%). Permanent discontinuation of both KISQALI and NSAI due to an adverse reaction occurred in 3% of patients. Permanent discontinuation of KISQALI alone occurred in 3% of patients. Adverse reactions which resulted in permanent discontinuation of both KISQALI and NSAI in ≥ 2% of patients were alanine aminotransferase increased (2%), and aspartate aminotransferase increased (2%). Dosage interruptions of KISQALI plus NSAI plus goserelin due to an adverse reaction occurred in 73% of patients. Adverse reactions which required dosage interruption in ≥ 5% of patients included neutropenia (41%), neutrophils decreased (26%), and leukocytes decreased (6%). Dose reductions of KISQALI due to an adverse reaction occurred in 33% of patients receiving KISQALI plus NSAI plus goserelin. Adverse reactions which required dose reductions in ≥ 2% of patients included neutropenia (17%), neutrophils decreased (5%), and alanine aminotransferase increased (2%). The most common (≥ 20% on the KISQALI arm and ≥ 2% higher than placebo) adverse reactions, including laboratory abnormalities, were leukocytes decreased, neutrophils decreased, hemoglobin decreased, lymphocytes decreased, gamma-glutamyl transferase increased, aspartate aminotransferase increased, infections, arthralgia, alanine aminotransferase increased, nausea, platelets decreased, and alopecia. Table 14 summarizes the adverse reactions in MONALEESA-7. Table 14: Adverse Reactions Occurring in ≥ 10% and ≥ 2% Higher Than Placebo Arm in MONALEESA-7 (NSAI) (All Grades) Abbreviation: NSAI, non-steroidal aromatase inhibitor. Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 1 Infections: urinary tract infections; respiratory tract infections, gastroenteritis, sepsis (< 1%). 2 Only includes a Grade 3 adverse reactions. Adverse reaction KISQALI + NSAI + Goserelin (n = 248) Placebo + NSAI + Goserelin (n = 247) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Infections and infestations Infections 1;2 36 1.6 24 0.4 Musculoskeletal and connective tissue disorders Arthralgia 2 34 0.8 29 1.2 Gastrointestinal disorders Nausea 2 32 0 20 0 Constipation 2 16 0 12 0 Stomatitis 2 10 0 8 0.4 Skin and subcutaneous tissue disorders Alopecia 2 21 0 13 0 Rash 2 17 0.4 9 0 Pruritus 2 11 0 4 0 General disorders and administration-site conditions Pyrexia 2 17 0.8 7 0 Pain in extremity 2 10 0 8 1.2 Respiratory, thoracic and mediastinal disorders Cough 2 15 0 10 0 Clinically relevant adverse reactions in < 10% of patients in MONALEESA-7 receiving KISQALI plus NSAI included thrombocytopenia (9%), dry skin (9%), oropharyngeal pain (7%), dyspepsia (5%), lacrimation increased (4%), dry eye (4%), vitiligo (3%), hypocalcemia (2%), blood bilirubin increased (1%), syncope (0.4%), and pneumonitis (0.4%). Table 15: Select Laboratory Abnormalities (≥ 10%) in Patients in MONALEESA-7 Who Received KISQALI Plus NSAI Plus Goserelin Abbreviation: NSAI, non-steroidal aromatase inhibitor. Laboratory abnormality KISQALI + NSAI + Goserelin (n = 248) Placebo + NSAI + Goserelin (n = 247) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology Leukocytes decreased 93 36 30 0.8 Neutrophils decreased 92 63 27 2.4 Hemoglobin decreased 84 2.4 51 0.4 Lymphocytes decreased 55 14 18 2.8 Platelets decreased 26 0.4 9 0.4 Chemistry Gamma-glutamyl transferase increased 42 7 42 9 Aspartate aminotransferase increased 37 4.8 35 1.6 Alanine aminotransferase increased 33 6 31 1.6 Phosphorous decreased 14 1.6 11 0.8 Potassium decreased 11 1.2 14 1.2 Glucose serum decreased 10 0.4 10 0.4 Creatinine increased 8 0 2 0 MONALEESA-3: KISQALI in Combination with Fulvestrant Postmenopausal Patients with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy or After Disease Progression on Endocrine Therapy The safety of KISQALI was evaluated in MONALEESA-3, a clinical trial of 724 postmenopausal women receiving KISQALI plus fulvestrant or placebo plus fulvestrant [see Clinical Studies (14)] . The median duration of exposure to KISQALI plus fulvestrant was 15.8 months with 58% of patients exposed for ≥ 12 months. Serious adverse reactions occurred in 29% of patients who received KISQALI plus fulvestrant. Serious adverse reactions in ≥ 1% of patients receiving KISQALI plus fulvestrant included pneumonia (1.9%), nausea (1.4%), vomiting (1.4%), anemia (1.2%), dyspnea (1.2%), neutropenia (1.2%). One case (0.2%) of fatal adverse reaction (pneumonia) occurred in patients who received KISQALI plus fulvestrant. Fatal adverse reactions occurred in 1.2% of patients who received KISQALI. Fatal adverse reactions in ≥ 0.1% of patients receiving KISQALI included cardiac failure, ventricular arrhythmia, pneumonia, acute respiratory distress, pulmonary embolism, and hemorrhagic shock (0.2% each). Permanent discontinuation of both KISQALI and fulvestrant due to an adverse reaction occurred in 8% of patients. Permanent discontinuation of KISQALI alone occurred in 9% of patients. Adverse reactions which resulted in permanent discontinuation of both KISQALI and fulvestrant in ≥ 2% of patients were alanine aminotransferase increased (5%), and aspartate aminotransferase increased (3%). Dosage interruptions of KISQALI plus fulvestrant due to an adverse reaction occurred in 72% of patients. Adverse reactions which required dosage interruption in ≥ 5% of patients included neutropenia (40%), neutrophils decreased (13%), alanine aminotransferase increased (8%), aspartate aminotransferase increased (8%), and leukocytes decreased (5%). Dose reductions of KISQALI due to an adverse reaction occurred in 32% of patients receiving KISQALI plus fulvestrant. Adverse reactions which required dose reductions in ≥ 2% of patients included neutropenia (15%), and neutrophils decreased (3%). The most common (≥ 20% on the KISQALI arm and ≥ 2% higher than placebo) adverse reactions, including laboratory abnormalities, were leukocytes decreased, neutrophils decreased, lymphocytes decreased, creatinine increased, hemoglobin decreased, gamma-glutamyl transferase increased, aspartate aminotransferase increased, nausea, alanine aminotransferase increased, infections, platelets decreased, diarrhea, vomiting, constipation, glucose serum decreased, cough, rash, and pruritus. Table 16 summarizes the adverse reactions in MONALEESA-3. Table 16: Adverse Reactions (≥ 10% and ≥ 2% Higher Than Placebo Arm) in MONALEESA-3 Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 1 Infections: urinary tract infections; respiratory tract infections; gastroenteritis; sepsis (1%). 2 Only include Grade 3 adverse reactions. 3 Includes the following fatal adverse reactions: pneumonia (n = 1). Adverse reaction KISQALI + Fulvestrant (n = 483) Placebo + Fulvestrant (n = 241) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Gastrointestinal disorders Nausea 2 45 1.4 28 0.8 Diarrhea 2 29 0.6 20 0.8 Vomiting 2 27 1.4 13 0 Constipation 2 25 0.8 12 0 Abdominal pain 2 17 1.4 13 0.8 Infections and infestations Infections 1;2;3 42 4.6 30 1.7 Skin and subcutaneous tissue disorders Rash 2 23 0.8 8 0 Pruritus 2 20 0.2 7 0 Alopecia 2 19 0 5 0 Respiratory, thoracic and mediastinal disorders Cough 2 22 0 15 0 Dyspnea 15 1.4 12 1.7 Metabolism and nutrition disorders Decreased appetite 2 16 0.2 13 0 General disorders and administration-site conditions Peripheral edema 2 15 0 7 0 Pyrexia 2 11 0.2 7 0 Nervous system disorders Dizziness 2 13 0.2 8 0 Clinically relevant adverse reactions in < 10% of patients in MONALEESA-3 receiving KISQALI plus fulvestrant included thrombocytopenia (9%) dry skin (8%), dysgeusia (7%), dry mouth (5%), vertigo (5%), dry eye (5%), lacrimation increased (4%), erythema (4%), hypocalcemia (4%), blood bilirubin increased (1%), syncope (1%), interstitial lung disease (0.4%), pneumonitis (0.4%), hypersensitivity pneumonitis (0.2%), and acute respiratory distress syndrome (0.2%). Table 17: Select Laboratory Abnormalities (≥ 10%) in Patients in MONALEESA-3 Who Received KISQALI Plus Fulvestrant Laboratory abnormality KISQALI + Fulvestrant (n = 483) Placebo + Fulvestrant (n = 241) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology Leukocytes decreased 95 26 26 0.4 Neutrophils decreased 92 53 21 0.8 Lymphocytes decreased 69 16 35 4.1 Hemoglobin decreased 60 4.3 35 2.9 Platelets decreased 33 1.9 11 0 Chemistry Creatinine increased 65 1 33 0.4 Gamma-glutamyl transferase increased 52 8 49 10 Aspartate aminotransferase increased 50 7 43 2.9 Alanine aminotransferase increased 44 11 37 1.7 Glucose serum decreased 23 0 18 0 Phosphorous decreased 18 4.6 8 0.8 Albumin decreased 12 0 8 0 COMPLEEMENT-1: KISQALI in Combination with Letrozole and Goserelin or Leuprolide Men with HR-positive, HER2-negative Advanced Breast Cancer for Initial Endocrine-Based Therapy The safety of KISQALI in combination with letrozole was evaluated in men (n = 39) in an open-label, multicenter clinical trial for the treatment of adult patients with HR-positive, HER2-negative, advanced breast cancer who received no prior hormonal therapy for advanced disease (COMPLEEMENT-1) [see Clinical Studies (14)] . The median duration of exposure to KISQALI was 20.8 months (range, 0.5 to 30.6 months). Other adverse reactions occurring in men treated with KISQALI plus letrozole and goserelin or leuprolide were similar to those occurring in women treated with KISQALI plus endocrine therapy. 6.2 Postmarketing Experience The following adverse events have been reported during post-approval use of KISQALI. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Respiratory Disorders: Interstitial lung disease/pneumonitis Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia, and systemic symptoms (DRESS)

<table><caption>Table 10: Adverse Reactions (&#x2265; 10% and &#x2265; 2% Higher Than NSAI Alone Arm) in NATALEE</caption><col width="200"/><col width="200"/><col width="200"/><col width="200"/><col width="200"/><tfoot><tr><td colspan="5">Abbreviation: NSAI, non-steroidal aromatase inhibitor. Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. ¹Infections: urinary tract infections; respiratory tract infections. ²Only includes a Grade 3 adverse reaction.</td></tr></tfoot><tbody><tr><td valign="top"><content styleCode="bold">Adverse reaction</content></td><td colspan="2" align="center"><content styleCode="bold">KISQALI + NSAI (n = 2526)</content></td><td colspan="2" align="center"><content styleCode="bold">NSAI (n = 2441)</content></td></tr><tr><td/><td align="center"><content styleCode="bold">All Grades (%)</content></td><td align="center"><content styleCode="bold">Grade 3 or 4 (%)</content></td><td align="center"><content styleCode="bold">All Grades (%)</content></td><td align="center"><content styleCode="bold">Grade 3 or 4 (%)</content></td></tr><tr><td colspan="5"><content styleCode="bold">Infections and infestations</content></td></tr><tr><td>Infections¹</td><td align="center">37</td><td align="center">2.0</td><td align="center">27</td><td align="center">0.9</td></tr><tr><td colspan="5"><content styleCode="bold">Nervous system disorders</content></td></tr><tr><td>Headache²</td><td align="center">23</td><td align="center">0.4</td><td align="center">17</td><td align="center">0.2</td></tr><tr><td colspan="5"><content styleCode="bold">Gastrointestinal disorders</content></td></tr><tr><td>Nausea²</td><td align="center">23</td><td align="center">0.2</td><td align="center">8</td><td align="center">0.1</td></tr><tr><td>Diarrhea²</td><td align="center">15</td><td align="center">0.6</td><td align="center">6</td><td align="center">0.1</td></tr><tr><td>Constipation²</td><td align="center">13</td><td align="center">0.2</td><td align="center">5</td><td align="center">0</td></tr><tr><td>Abdominal pain²</td><td align="center">11</td><td align="center">0.5</td><td align="center">7</td><td align="center">0.4</td></tr><tr><td colspan="5"><content styleCode="bold">General disorders and administration-site conditions</content></td></tr><tr><td>Fatigue²</td><td align="center">22</td><td align="center">0.8</td><td align="center">13</td><td align="center">0.2</td></tr><tr><td>Asthenia²</td><td align="center">17</td><td align="center">0.6</td><td align="center">12</td><td align="center">0.1</td></tr><tr><td>Pyrexia²</td><td align="center">11</td><td align="center">0.2</td><td align="center">6</td><td align="center">0.1</td></tr><tr><td colspan="5"><content styleCode="bold">Skin and subcutaneous tissue disorders</content></td></tr><tr><td>Alopecia </td><td align="center">15</td><td align="center">0</td><td align="center">4.6</td><td align="center">0</td></tr><tr><td colspan="5"><content styleCode="bold">Respiratory, thoracic, and mediastinal disorders</content></td></tr><tr><td>Cough²</td><td align="center">13</td><td align="center">0.1</td><td align="center">8</td><td align="center">0.1</td></tr></tbody></table>

<table><caption>Table 11: Select Laboratory Abnormalities (&#x2265; 10%) in Patients in NATALEE Who Received KISQALI Plus NSAI</caption><col width="200"/><col width="200"/><col width="200"/><col width="200"/><col width="200"/><tfoot><tr><td colspan="5">Abbreviation: NSAI, non-steroidal aromatase inhibitor.</td></tr></tfoot><tbody><tr><td valign="top"><content styleCode="bold">Laboratory abnormality</content></td><td colspan="2" align="center"><content styleCode="bold">KISQALI + NSAI (n = 2526)</content></td><td colspan="2" align="center"><content styleCode="bold">NSAI (n = 2441)</content></td></tr><tr><td/><td align="center"><content styleCode="bold">All Grades (%)</content></td><td align="center"><content styleCode="bold">Grade 3 or 4 (%)</content></td><td align="center"><content styleCode="bold">All Grades (%)</content></td><td align="center"><content styleCode="bold">Grade 3 or 4 (%)</content></td></tr><tr><td styleCode="Toprule" colspan="5"><content styleCode="bold">Hematology</content></td></tr><tr><td>Lymphocytes decreased</td><td align="center">97</td><td align="center">19</td><td align="center">88</td><td align="center">6</td></tr><tr><td>Leukocytes decreased</td><td align="center">95</td><td align="center">27</td><td align="center">45</td><td align="center">0.6</td></tr><tr><td>Neutrophils decreased</td><td align="center">94</td><td align="center">45</td><td align="center">35</td><td align="center">1.7</td></tr><tr><td>Hemoglobin decreased</td><td align="center">47</td><td align="center">0.6</td><td align="center">26</td><td align="center">0.3</td></tr><tr><td>Platelets decreased</td><td align="center">28</td><td align="center">0.4</td><td align="center">13</td><td align="center">0.3</td></tr><tr><td colspan="5"><content styleCode="bold">Chemistry</content></td></tr><tr><td>Alanine aminotransferase increased</td><td align="center">45</td><td align="center">8</td><td align="center">35</td><td align="center">1</td></tr><tr><td>Aspartate aminotransferase increased</td><td align="center">44</td><td align="center">5</td><td align="center">33</td><td align="center">1</td></tr><tr><td>Creatinine increased</td><td align="center">33</td><td align="center">0.3</td><td align="center">11</td><td align="center">0</td></tr></tbody></table>

<table><caption>Table 12: Adverse Reactions (&#x2265; 10% and &#x2265; 2% Higher Than Placebo Arm) in MONALEESA-2</caption><col width="200"/><col width="200"/><col width="200"/><col width="200"/><col width="200"/><tfoot><tr><td colspan="5">Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. ¹Only includes a Grade 3 adverse reaction.</td></tr></tfoot><tbody><tr><td valign="top"><content styleCode="bold">Adverse reaction</content></td><td colspan="2" align="center"><content styleCode="bold">KISQALI + Letrozole (n = 334)</content></td><td colspan="2" align="center"><content styleCode="bold">Placebo + Letrozole (n = 330)</content></td></tr><tr><td/><td align="center"><content styleCode="bold">All Grades (%)</content></td><td align="center"><content styleCode="bold">Grade 3 or 4 (%)</content></td><td align="center"><content styleCode="bold">All Grades (%)</content></td><td align="center"><content styleCode="bold">Grade 3 or 4 (%)</content></td></tr><tr><td styleCode="Toprule" colspan="5"><content styleCode="bold">Gastrointestinal disorders</content></td></tr><tr><td>Nausea¹</td><td align="center">52</td><td align="center">2.4</td><td align="center">29</td><td align="center">0.6</td></tr><tr><td>Diarrhea¹</td><td align="center">35</td><td align="center">1.2</td><td align="center">22</td><td align="center">0.9</td></tr><tr><td>Vomiting¹</td><td align="center">29</td><td align="center">3.6</td><td align="center">16</td><td align="center">0.9</td></tr><tr><td>Constipation¹</td><td align="center">25</td><td align="center">1.2</td><td align="center">19</td><td align="center">0</td></tr><tr><td>Stomatitis¹</td><td align="center">12</td><td align="center">0.3</td><td align="center">7</td><td align="center">0</td></tr><tr><td>Abdominal pain¹</td><td align="center">11</td><td align="center">1.2</td><td align="center">8</td><td align="center">0</td></tr><tr><td colspan="5"><content styleCode="bold">General disorders and administration-site conditions</content></td></tr><tr><td>Fatigue</td><td align="center">37</td><td align="center">2.4</td><td align="center">30</td><td align="center">0.9</td></tr><tr><td>Pyrexia¹</td><td align="center">13</td><td align="center">0.3</td><td align="center">6</td><td align="center">0</td></tr><tr><td>Peripheral edema¹</td><td align="center">12</td><td align="center">0</td><td align="center">10</td><td align="center">0</td></tr><tr><td colspan="5"><content styleCode="bold">Skin and subcutaneous tissue disorders</content></td></tr><tr><td>Alopecia¹</td><td align="center">33</td><td align="center">0</td><td align="center">16</td><td align="center">0</td></tr><tr><td>Rash¹</td><td align="center">17</td><td align="center">0.6</td><td align="center">8</td><td align="center">0</td></tr><tr><td>Pruritus¹</td><td align="center">14</td><td align="center">0.6</td><td align="center">6</td><td align="center">0</td></tr><tr><td colspan="5"><content styleCode="bold">Nervous system disorders</content></td></tr><tr><td>Headache¹</td><td align="center">22</td><td align="center">0.3</td><td align="center">19</td><td align="center">0.3</td></tr><tr><td>Insomnia¹</td><td align="center">12</td><td align="center">0.3</td><td align="center">9</td><td align="center">0</td></tr><tr><td colspan="5"><content styleCode="bold">Musculoskeletal and connective tissue disorders</content></td></tr><tr><td>Back pain¹</td><td align="center">20</td><td align="center">2.1</td><td align="center">18</td><td align="center">0.3</td></tr><tr><td colspan="5"><content styleCode="bold">Metabolism and nutrition disorders</content></td></tr><tr><td>Decreased appetite¹</td><td align="center">19</td><td align="center">1.5</td><td align="center">15</td><td align="center">0.3</td></tr><tr><td colspan="5"><content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content></td></tr><tr><td>Dyspnea¹</td><td align="center">12</td><td align="center">1.2</td><td align="center">9</td><td align="center">0.6</td></tr><tr><td colspan="5"><content styleCode="bold">Infections and infestations</content></td></tr><tr><td>Urinary tract infections¹</td><td align="center">11</td><td align="center">0.6</td><td align="center">8</td><td align="center">0</td></tr></tbody></table>