KISQALI

KISQALI (ribociclib) is a kinase inhibitor. The chemical name of ribociclib succinate is: Butanedioic acid—7-cyclopentyl- N , N -dimethyl-2-{[5-(piperazin-1-yl) pyridin-2-yl]amino}-7 H -pyrrolo[2,3- d ]pyrimidine-6-carboxamide (1/1). Ribociclib succinate is a light yellow to yellowish brown crystalline powder. The molecular formula for ribociclib succinate is C 23 H 30 N 8 O·C 4 H 6 O 4 and the molecular weight is 552.64 g/mol (Free base: 434.55 g/mol). The chemical structure of ribociclib is shown below: KISQALI film-coated tablets are supplied for oral use and contain 200 mg of ribociclib free base (equivalent to 254.40 mg ribociclib succinate). The tablets also contain colloidal silicon dioxide, crospovidone, hydroxypropylcellulose, magnesium stearate and microcrystalline cellulose. The film-coating contains iron oxide black, iron oxide red, lecithin (soya), polyvinyl alcohol (partially hydrolysed), talc, titanium dioxide, and xanthan gum as inactive ingredients. The Following chemical structure of KISQALI film-coated tablets are supplied for oral administration and contain 200 mg of ribociclib free base (equivalent to 254.40 mg ribociclib succinate). The tablets also contain colloidal silicon dioxide, crospovidone, hydroxypropylcellulose, magnesium stearate and microcrystalline cellulose. The film-coating contains iron oxide black, iron oxide red, lecithin (soya), polyvinyl alcohol (partially hydrolysed), talc, titanium dioxide, and xanthan gum as inactive ingredients.

KISQALI is a kinase inhibitor indicated: in combination with an aromatase inhibitor for the adjuvant treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative stage II and III early breast cancer at high risk of recurrence. ( 1 ) for the treatment of adults with HR-positive, HER2-negative advanced or metastatic breast cancer in combination with: an aromatase inhibitor as initial endocrine-based therapy; or fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy. ( 1 ) 1.1 Early Breast Cancer KISQALI is indicated in combination with an aromatase inhibitor for the adjuvant treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative stage II and III early breast cancer at high risk of recurrence. 1.2 Advanced or Metastatic Breast Cancer KISQALI is indicated for the treatment of adults with HR-positive, HER2-negative advanced or metastatic breast cancer in combination with: an aromatase inhibitor as initial endocrine-based therapy; or fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy.

KISQALI tablets are taken orally with or without food in combination with an aromatase inhibitor or fulvestrant. ( 2 ) Early Breast Cancer Recommended starting dose: 400 mg orally (two 200 mg tablets) taken once daily with or without food for 21 consecutive days followed by 7 days off treatment. ( 2.1 ) Advanced or Metastatic Breast Cancer Recommended starting dose: 600 mg orally (three 200 mg tablets) taken once daily with or without food for 21 consecutive days followed by 7 days off treatment. ( 2.1 ) Dose interruption, reduction, and/or discontinuation may be required based on individual safety and tolerability. ( 2.2 ) 2.1 Recommended Dosage Important Administration Instructions KISQALI can be taken with or without food [see Clinical Pharmacology (12.3)] . Pre/perimenopausal women, or men, treated with the combination KISQALI plus an aromatase inhibitor or fulvestrant, should be treated with a luteinizing hormone-releasing hormone (LHRH) agonist according to current clinical practice standards. Patients should take their dose of KISQALI at approximately the same time each day, preferably in the morning. If the patient vomits after taking the dose, or misses a dose, no additional dose should be taken that day. The next prescribed dose should be taken at the usual time. KISQALI tablets should be swallowed whole (tablets should not be chewed, crushed or split prior to swallowing). No tablet should be ingested if it is broken, cracked, or otherwise not intact. Early Breast Cancer The recommended dosage of KISQALI is 400 mg (two 200 mg film-coated tablets) taken orally, once daily for 21 consecutive days followed by 7 days off in 28-day treatment cycles. KISQALI should be given in combination with an aromatase inhibitor. Refer to the Full Prescribing Information for the recommended dosage of the aromatase inhibitor. In patients with early breast cancer, treatment with KISQALI should continue for 3 years or until disease recurrence or unacceptable toxicity occurs. Advanced or Metastatic Breast Cancer The recommended dosage of KISQALI is 600 mg (three 200 mg film-coated tablets) taken orally, once daily for 21 consecutive days followed by 7 days off in 28-day treatment cycles. KISQALI should be given in combination with endocrine therapy (fulvestrant or an aromatase inhibitor). Refer to the Full Prescribing Information for the recommended dose of endocrine therapy. 2.2 Dose Modifications Dose Modifications for Adverse Reactions The recommended dose modifications for adverse reactions are listed in Table 1. Table 1: Recommended Dose Modification for Adverse Reactions Level KISQALI Dose Number of tablets Early breast cancer Starting dose 400 mg/day two 200 mg tablets Dose reduction 200 mg/day * one 200 mg tablet Advanced or metastatic breast cancer Starting dose 600 mg/day three 200 mg tablets First dose reduction 400 mg/day two 200 mg tablets Second dose reduction 200 mg/day * one 200 mg tablet *If dose reduction below 200 mg/day is required, discontinue KISQALI. Tables 2, 3, 4, 5, 6, and 7 summarize recommendations for dose interruption, reduction, or discontinuation of KISQALI in the management of specific adverse reactions. Dose modification of KISQALI is recommended based on individual patient safety and tolerability. Table 2: Dose Modification and Management for Interstitial Lung Disease/Pneumonitis Grade 1 (asymptomatic) Grade 2 (symptomatic) Grade 3 (severe symptomatic) or 4 (life-threatening) ILD/Pneumonitis [see Warnings and Precautions (5.1)] No dose interruption or adjustment is required. Initiate appropriate medical therapy and monitor as clinically indicated. Dose interruption until recovery to Grade ≤ 1 then consider resuming KISQALI at the next lower dose level*. If Grade 2 recurs, discontinue KISQALI. Discontinue KISQALI. Abbreviation: ILD, interstitial lung disease. Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. *An individualized benefit-risk assessment should be performed when considering resuming KISQALI. Table 3: Dose Modification and Management for Cutaneous Adverse Reactions, Including SCARs Grade 1 (< 10% body surface area (BSA) with active skin toxicity, no signs of systemic involvement) Grade 2 (10%-30% BSA with active skin toxicity, no signs of systemic involvement) Grade 3 (severe rash not responsive to medical management; > 30% BSA with active skin toxicity, signs of systemic involvement present; SJS*) Grade 4 (any % BSA associated with extensive superinfection, with IV antibiotics indicated; life threatening consequences; TEN**) Cutaneous adverse reactions, including SCARs [see Warnings and Precautions (5.2)] No dose adjustment is required. Initiate appropriate medical therapy and monitor as clinically indicated. Interrupt KISQALI until the etiology of the reaction has been determined. If the etiology is a SCAR, permanently discontinue KISQALI. If the etiology is not a SCAR, interrupt dose until recovery to Grade ≤ 1, then resume KISQALI at same dose level. If the cutaneous adverse reaction still recurs at Grade 3, resume KISQALI at the next lower dose level. Permanently discontinue KISQALI. Abbreviations: BSA, body surface area; SCARs, severe cutaneous adverse reactions; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis. *SJS (Grade 3 and 4) is defined as skin sloughing covering < 10% BSA and 10%-30% BSA, respectively, with associated signs (e.g., erythema, purpura, epidermal detachment, and mucous membrane detachment). **TEN (Grade 4) is defined as skin sloughing covering ≥ 30% BSA with associated symptoms (e.g., erythema, purpura, epidermal detachment, and mucous membrane detachment). Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Table 4: Dose Modification and Management for QT Prolongation QTcF* prolongation Early breast cancer Advanced or metastatic breast cancer > 480 ms and ≤ 500 ms Interrupt KISQALI treatment and wait until QTcF resolves to ≤ 480 ms Resume at the same dose Reduce to the next lower dose level If QTcF > 480 ms recurs, interrupt KISQALI treatment and wait until QTcF resolves to ≤ 480 ms, then resume at next lower dose level. > 500 ms Interrupt KISQALI treatment and wait until QTcF resolves to ≤ 480 ms, then resume at next lower dose level. If QTcF > 500 ms recurs, discontinue KISQALI. Permanently discontinue KISQALI if QTcF interval prolongation is either > 500 ms or > 60 ms change from baseline AND associated with any of the following: Torsades de Pointes, polymorphic ventricular tachycardia, syncope, or signs/symptoms of serious arrhythmia. Note: If dose reduction below 200 mg/day is required, discontinue KISQALI. Electrocardiograms (ECGs) should be assessed prior to initiation of treatment in all patients. Repeat ECGs at approximately Day 14 of the first cycle, and as clinically indicated. In case of QTcF prolongation at any given time during treatment, monitor ECG more frequently, and as clinically indicated * QTcF = QT interval corrected by Fridericia’s formula. Table 5: Dose Modification and Management for Hepatobiliary Toxicity Grade 1 (> ULN – 3 x ULN) Grade 2 (> 3 to 5 x ULN) Grade 3 (> 5 to 20 x ULN) Grade 4 (> 20 x ULN) AST and/or ALT elevations from baseline*, WITHOUT increase in total bilirubin above 2 x ULN [see Warnings and Precautions (5.5)] No dose adjustment is required. Baseline* at < Grade 2: Dose interruption until recovery to ≤ baseline grade, then resume KISQALI at same dose level. If Grade 2 recurs, resume KISQALI at next lower dose level. ----------------------------- Baseline* at Grade 2: No dose interruption. Dose interruption until recovery to ≤ baseline* grade, then resume at next lower dose level. If Grade 3 recurs, discontinue KISQALI. Discontinue KISQALI. Combined elevations in AST and/or ALT WITH total bilirubin increase, in the absence of cholestasis [see Warnings and Precautions (5.5)] If patients develop ALT and/or AST > 3 x ULN along with total bilirubin > 2 x ULN irrespective of baseline grade, discontinue KISQALI. 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. If Grade ≥ 2 abnormalities are noted, monitor more frequently, and as clinically indicated. Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; ULN, upper limit of normal. *Baseline = prior to treatment initiation. Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Table 6: Dose Modification and Management for Neutropenia Grade 1 or 2 (ANC 1000/mm 3 – < LLN) Grade 3 (ANC 500 - < 1000/mm 3 ) Grade 3 febrile* neutropenia Grade 4 (ANC < 500/mm 3 ) Neutropenia [see Warnings and Precautions (5.6)] No dose adjustment is required. Dose interruption until recovery to Grade ≤ 2. Resume KISQALI at the same dose level. If toxicity recurs at Grade 3, dose interruption until recovery, then resume KISQALI at the next lower dose level. Dose interruption until recovery of neutropenia to Grade ≤ 2. Resume KISQALI at the next lower dose level. Dose interruption until recovery to Grade ≤ 2. Resume KISQALI at the next lower dose level. Perform complete blood counts (CBCs) before initiating treatment with KISQALI. Monitor CBC every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated. Abbreviations: ANC, absolute neutrophil count; LLN, lower limit of normal. *Grade 3 neutropenia with single episode of fever > 38.3°C (or) 38°C or above for more than one hour and/or concurrent infection. Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Table 7: Dose Modification and Management for Other Toxicities* Grade 1 or 2 Grade 3 Grade 4 Other Toxicities No dose adjustment is required. Initiate appropriate medical therapy and monitor as clinically indicated. Dose interruption until recovery to Grade ≤ 1 then resume KISQALI at same dose level. If Grade 3 recurs, resume KISQALI at the next lower dose level. Discontinue KISQALI. *Excluding interstitial lung disease (ILD)/pneumonitis, cutaneous adverse reactions, including severe cutaneous adverse reactions (SCARs), QT interval prolongation, hepatobiliary toxicity, and neutropenia. Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Refer to the Full Prescribing Information for the coadministered aromatase inhibitor or fulvestrant for dose modification guidelines in the event of toxicity and other relevant safety information. Dose Modification for Use with Strong CYP3A Inhibitors Avoid concomitant use of KISQALI with strong CYP3A inhibitors and consider an alternative concomitant medication with less potential for CYP3A inhibition [see Drug Interactions (7.1)] . If a strong CYP3A inhibitor must be coadministered, reduce the KISQALI dose as shown in Table 8. Table 8: Dose Modification for Use with Strong CYP3A Inhibitors Indication Co-administration with Strong CYP3A Inhibitors Early breast cancer Reduce the KISQALI dose to 200 mg once daily. Advanced or metastatic breast cancer Reduce the KISQALI dose to 400 mg once daily. If the strong inhibitor is discontinued, change the KISQALI dose (after at least 5 half-lives of the strong CYP3A inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)] . Dose Modification for Hepatic Impairment The recommended dose modifications for patients with hepatic impairment are shown in Table 9 [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)] . Table 9: Dose Modification for Hepatic Impairment Indication Mild hepatic impairment (Child-Pugh class A) Moderate and severe hepatic impairment (Child-Pugh class B or C) Early breast cancer No dose adjustment is necessary No dose adjustment is necessary Advanced or metastatic breast cancer No dose adjustment is necessary KISQALI 400 mg once daily Review the Full Prescribing Information for the co-administered aromatase inhibitor or fulvestrant for dose modifications related to hepatic impairment. Dose Modification for Severe Renal Impairment The recommended starting dose is 200 mg KISQALI once daily for patients with severe renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)] .

None. None. ( 4 )

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 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%), pruritis (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 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 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)

CYP3A Inhibitors: Avoid concomitant use of KISQALI with strong CYP3A inhibitors. If strong inhibitors cannot be avoided, reduce KISQALI dose. ( 2.2 , 7.1 ) CYP3A4 Inducers: Avoid concomitant use of KISQALI with strong CYP3A inducers. ( 7.2 ) CYP3A Substrates: The dose of CYP3A substrates may need to be reduced when given concurrently with KISQALI. ( 7.3 ) Drugs Known to Prolong QT Interval: Avoid concomitant use of drugs known to prolong QT interval, such as anti-arrhythmic medicines. ( 7.4 ) 7.1 Drugs That May Increase Ribociclib Plasma Concentrations CYP3A4 Inhibitors Coadministration of strong CYP3A inhibitors increases ribociclib exposure [see Clinical Pharmacology (12.3)] . Increased ribociclib concentrations may increase the incidence and severity of adverse reactions, including QTcF prolongation [see Warnings and Precautions (5.3)] . Avoid concomitant use of strong CYP3A inhibitors with KISQALI and consider alternative concomitant medications with less potential for CYP3A inhibition. In patients with early breast cancer, if coadministration of KISQALI with a strong CYP3A inhibitor cannot be avoided, reduce the dose of KISQALI to 200 mg once daily. In patients with advanced or metastatic breast cancer, if coadministration of KISQALI with a strong CYP3A inhibitor cannot be avoided, reduce the dose of KISQALI to 400 mg once daily [see Dosage and Administration (2.2)] . 7.2 Drugs That May Decrease Ribociclib Plasma Concentrations CYP3A Inducers Coadministration of strong CYP3A inducers decreases the plasma exposure of ribociclib [see Clinical Pharmacology (12.3)] . Avoid concomitant use of strong CYP3A inducers and consider an alternate concomitant medication with no or minimal potential to induce CYP3A. 7.3 Effect of KISQALI on Other Drugs CYP3A Substrates Coadministration of sensitive CYP3A4 substrates with multiple doses of KISQALI increases the substrate exposure [see Clinical Pharmacology (12.3)] . For CYP3A substrates where minimal increases in the concentration may increase CYP3A substrate adverse reactions, monitor for increased adverse reactions of the CYP3A substrate during treatment with KISQALI. The dose of the sensitive CYP3A substrate may need to be reduced as KISQALI can increase its exposure. 7.4 Drugs That Prolong the QT Interval Avoid coadministration of KISQALI with products with a known potential to prolong QT interval, such as antiarrhythmic drugs and other drugs that are known to prolong the QT interval. If concomitant use cannot be avoided, monitor ECG when initiating, during concomitant use, and as clinically indicated [see Warnings and Precautions (5.3), Clinical Pharmacology (12.2)] .