KISQALI

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)] Hepatobiliary Toxicity [see Warnings and Precautions (5.5)] Neutropenia [see Warnings and Precautions (5.6)] 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 pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to KISQALI in 1065 patients in MONALEESA-2, MONALEESA-7, and MONALEESA-3. Among these patients who received KISQALI, 76% were exposed for 6 months or longer and 62% were exposed for greater than one year. In this pooled safety population, 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%). 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 study 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%). Permanent discontinuation of both KISQALI and letrozole due to an adverse reaction occurred in 7% of patients. Permanent discontinuation of KISQALI alone occurred in of 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 8 summarizes the adverse reactions in MONALEESA-2. Table 8: 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 Edema peripheral 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 9 summarizes the laboratory abnormalities in MONALEESA-2. Table 9: 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 an 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 study 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 on 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 of 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 10 summarizes the adverse reactions in MONALEESA-7. Table 10: 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 11: 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 study 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. Permanent discontinuation of both KISQALI and fulvestrant due to an adverse reaction occurred in 8% of patients. Permanent discontinuation of KISQALI alone occurred in of 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 12 summarizes the adverse reactions in MONALEESA-3. Table 12: 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 a 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 Edema peripheral 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 13: 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 study 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)

4 CONTRAINDICATIONS None. None. ( 4 )

11 DESCRIPTION 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.

2 DOSAGE AND ADMINISTRATION KISQALI tablets are taken orally with or without food in combination with an aromatase inhibitor or fulvestrant. ( 2 ) 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 Dosing and Administration The recommended dose of KISQALI is 600 mg (three 200 mg film-coated tablets) taken orally, once daily for 21 consecutive days followed by 7 days off treatment resulting in a complete cycle of 28 days. KISQALI can be taken with or without food [see Clinical Pharmacology (12.3)] . When given with KISQALI, refer to the Full Prescribing Information for the recommended dose of the aromatase inhibitor being used. When given with KISQALI, the recommended dose of fulvestrant is 500 mg administered on Days 1, 15, 29, and once monthly thereafter. Please refer to the Full Prescribing Information of fulvestrant. Pre/perimenopausal women, or men, treated with the combination KISQALI plus an aromatase inhibitor should be treated with a luteinizing hormone-releasing hormone (LHRH) agonist according to current clinical practice standards. Men treated with the combination of KISQALI plus 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. 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 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 further dose reduction below 200 mg/day is required, discontinue the treatment. 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 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 ECGs with QTcF* > 480 ms [see Warnings and Precautions (5.3)] Interrupt KISQALI treatment If QTcF prolongation resolves to < 481 ms, resume treatment at the next lower dose level; If QTcF ≥ 481 ms recurs, interrupt dose until QTcF resolves to < 481 ms; then resume KISQALI at next lower dose level. ECGs with QTcF > 500 ms [see Warnings and Precautions (5.3)] Interrupt KISQALI treatment if QTcF greater than 500 ms If QTcF prolongation resolves to < 481 ms, resume treatment at the next lower dose level. Permanently discontinue KISQALI if QTcF interval prolongation is either greater than 500 ms or greater than 60 ms change from baseline AND associated with any of the following: Torsades de Pointes, polymorphic ventricular tachycardia, unexplained syncope, or signs/symptoms of serious arrhythmia. Electrocardiograms (ECGs) should be assessed prior to initiation of treatment. Repeat ECGs at approximately Day 14 of the first cycle and at the beginning of the second cycle, and as clinically indicated. In case of (QTcF) prolongation at any given time during treatment, more frequent ECG monitoring is recommended. *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, more frequent monitoring is recommended. 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) above 38°C 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 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 No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A). The recommended starting dose is 400 mg KISQALI once daily for patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)] . Review the Full Prescribing Information for the coadministered aromatase inhibitor or fulvestrant for dose modifications related to hepatic impairment. Dose Modification for Renal Impairment No dose adjustment is necessary in patients with mild or moderate 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)] .

1 INDICATIONS AND USAGE KISQALI is indicated for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (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 in postmenopausal women or in men. KISQALI is a kinase inhibitor indicated for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (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 in postmenopausal women or in men. ( 1 )

10 OVERDOSAGE There is limited experience with reported cases of overdose with KISQALI in humans. General symptomatic and supportive measures should be initiated in all cases of overdose where necessary.

7 DRUG INTERACTIONS CYP3A4 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 sensitive CYP3A substrates with narrow therapeutic indices 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 a strong CYP3A4 inhibitor (ritonavir) increased ribociclib exposure in healthy subjects by 3.2-fold [see Clinical Pharmacology (12.3)] . Avoid concomitant use of strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, and voriconazole) and consider alternative concomitant medications with less potential for CYP3A inhibition. 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)] . Instruct patients to avoid grapefruit or grapefruit juice, which are known to inhibit cytochrome CYP3A enzymes and may increase the exposure to ribociclib [see Patient Counseling Information (17)] . 7.2 Drugs That May Decrease Ribociclib Plasma Concentrations CYP3A4 Inducers Coadministration of a strong CYP3A4 inducer (rifampin) decreased the plasma exposure of ribociclib in healthy subjects by 89% [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 (e.g., phenytoin, rifampin, carbamazepine, and St. John’s wort (Hypericum perforatum). 7.3 Effect of KISQALI on Other Drugs CYP3A Substrates with Narrow Therapeutic Index Coadministration of midazolam (a sensitive CYP3A4 substrate) with multiple doses of KISQALI (400 mg) increased the midazolam exposure by 3.8-fold in healthy subjects, compared with administration of midazolam alone [see Clinical Pharmacology (12.3)] . KISQALI given at the clinically relevant dose of 600 mg is predicted to increase the midazolam AUC by 5.2-fold. Therefore, caution is recommended when KISQALI is administered with CYP3A substrates with a narrow therapeutic index. The dose of a sensitive CYP3A substrate with a narrow therapeutic index, including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus, may need to be reduced as ribociclib can increase their exposure. 7.4 Drugs That Prolong the QT Interval Avoid coadministration of KISQALI with medicinal products with a known potential to prolong QT, such as antiarrhythmic medicines (including, but not limited to amiodarone, disopyramide, procainamide, quinidine, and sotalol), and other drugs that are known to prolong the QT interval (including, but not limited to, chloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil, pimozide, and ondansetron) [see Warnings and Precautions (5.3), Clinical Pharmacology (12.2)] .

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ribociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. These kinases are activated upon binding to D-cyclins and play a crucial role in signaling pathways which lead to cell cycle progression and cellular proliferation. The cyclin D-CDK4/6 complex regulates cell cycle progression through phosphorylation of the retinoblastoma protein (pRb). In vitro , ribociclib decreased pRb phosphorylation leading to arrest in the G1 phase of the cell cycle and reduced cell proliferation in breast cancer cell lines. In vivo , treatment with single agent ribociclib in a rat xenograft model with human tumor cells led to decreased tumor volumes, which correlated with inhibition of pRb phosphorylation. In studies using patient-derived estrogen receptor positive breast cancer xenograft models, combination of ribociclib and antiestrogen (e.g., letrozole) resulted in increased tumor growth inhibition compared to each drug alone. Additionally, the combination of ribociclib and fulvestrant resulted in tumor growth inhibition in an estrogen receptor positive breast cancer xenograft model. 12.2 Pharmacodynamics Cardiac Electrophysiology Serial, triplicate ECGs were collected following a single dose and at steady-state to evaluate the effect of ribociclib on the QTcF interval in patients with advanced cancer. A pharmacokinetic-pharmacodynamic analysis included a total of 997 patients treated with ribociclib at doses ranging from 50 to 1200 mg. The analysis suggested that ribociclib causes concentration-dependent increases in the QTcF interval. The estimated mean change from baseline in QTcF for KISQALI 600 mg in combination with aromatase inhibitors or fulvestrant was 22.0 ms (90% CI: 20.6, 23.4) and 23.7 ms (90% CI: 22.3, 25.1), respectively, and was 34.7 ms (90% CI: 31.6, 37.8) in combination with tamoxifen at the geometric mean C max at steady-state [see Warnings and Precautions (5.3, 5.4)] . 12.3 Pharmacokinetics Ribociclib exhibited over-proportional increases in exposure (peak plasma concentrations (C max ) and area under the time concentration curve (AUC)) across the dose range of 50 mg to 1200 mg following both single dose and repeated doses. Following repeated 600 mg once daily administration, steady-state was generally achieved after 8 days and ribociclib accumulated with a geometric mean accumulation ratio of 2.51 (range, 0.972 to 6.40). Absorption The time to reach C max (T max ) following ribociclib administration was between 1 and 4 hours. Food Effect: Compared to the fasted state, oral administration of a single 600 mg dose of KISQALI film-coated tablet with a high-fat, high-calorie meal (approximately 800 to 1000 calories with ~50% calories from fat, ~35% calories from carbohydrates, and ~15% calories from protein) had no effect on the rate and extent of absorption of ribociclib (C max GMR: 1.00; 90% CI: 0.898, 1.11; AUC inf GMR: 1.06; 90% CI: 1.01, 1.12). Distribution Binding of ribociclib to human plasma proteins in vitro was approximately 70% and independent of concentration (10 to 10,000 ng/mL). Ribociclib was equally distributed between red blood cells and plasma with a mean in vivo blood-to-plasma ratio of 1.04. The apparent volume of distribution at steady-state (Vss/F) was 1090 L based on population PK analysis. Metabolism In vitro and in vivo studies indicated ribociclib undergoes extensive hepatic metabolism mainly via CYP3A4 in humans. Following oral administration of a single 600 mg dose of radio-labeled ribociclib to humans, the primary metabolic pathways for ribociclib involved oxidation (dealkylation, C and/or N-oxygenation, oxidation (-2H)) and combinations thereof. Phase II conjugates of ribociclib Phase I metabolites involved N-acetylation, sulfation, cysteine conjugation, glycosylation and glucuronidation. Ribociclib was the major circulating drug-derived entity in plasma (44%). The major circulating metabolites included metabolite M13 (CCI284, N-hydroxylation), M4 (LEQ803, N-demethylation), and M1 (secondary glucuronide), each representing an estimated 9%, 9%, and 8% of total radioactivity, and 22%, 20%, and 18% of ribociclib exposure. Clinical activity (pharmacological and safety) of ribociclib was due primarily to parent drug, with negligible contribution from circulating metabolites. Ribociclib was extensively metabolized with unchanged drug accounting for 17% and 12% in feces and urine, respectively. Metabolite LEQ803 was a significant metabolite in excreta and represented approximately 14% and 4% of the administered dose in feces and urine, respectively. Numerous other metabolites were detected in both feces and urine in minor amounts (≤ 3% of the administered dose). Elimination The geometric mean plasma effective half-life (based on accumulation ratio) was 32.0 hours (63% CV) and the geometric mean apparent oral clearance (CL/F) was 25.5 L/hr (66% CV) at steady-state at 600 mg in patients with advanced cancer. The geometric mean apparent plasma terminal half-life (t ½) of ribociclib ranged from 29.7 to 54.7 hours and geometric mean CL/F of ribociclib ranged from 39.9 to 77.5 L/hr at 600 mg across studies in healthy subjects. Ribociclib is eliminated mainly via feces, with a small contribution of the renal route. In 6 healthy male subjects, following a single oral dose of radio-labeled ribociclib, 92% of the total administered radioactive dose was recovered within 22 days; feces was the major route of excretion (69%), with 23% of the dose recovered in urine. Specific Populations Patients with Hepatic Impairment Based on a pharmacokinetic trial in patients with hepatic impairment, mild (Child-Pugh class A) hepatic impairment had no effect on the exposure of ribociclib. The mean exposure for ribociclib was increased less than 2-fold in patients with moderate (Child-Pugh class B; geometric mean ratio [GMR]: 1.44 for C max ; 1.28 for AUC inf ) or severe (Child-Pugh class C; GMR: 1.32 for C max ; 1.29 for AUC inf ) hepatic impairment. Based on a population pharmacokinetic analysis that included 160 patients with normal hepatic function and 47 patients with mild hepatic impairment, mild hepatic impairment had no effect on the exposure of ribociclib, further supporting the findings from the dedicated hepatic impairment study. Patients with Renal Impairment The effect of renal impairment on the pharmacokinetics of ribociclib was assessed in a renal impairment study in non-cancer subjects with normal renal function (eGFR ≥ 90 mL/min/1.73 m 2 , n = 9), severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m 2 , n = 6), and End Stage Renal Disease (ESRD; eGFR < 15 mL/min/1.73 m 2 , n = 4) at a single ribociclib dose of 400 mg/day. In subjects with severe renal impairment and ESRD, AUC inf increased 2.37-fold and 3.81-fold, and C max increased 2.10-fold and 2.68-fold relative to the exposure in non-cancer study participants with normal renal function. Mild (60 mL/min/1.73 m 2 ≤ eGFR < 90 mL/min/1.73 m 2 ) or moderate renal impairment (30 mL/min/1.73 m 2 ≤ eGFR < 60 mL/min/1.73 m 2 ) had no effect on the exposure of ribociclib based on a population PK analysis that included 438 cancer patients with normal renal function, 488 patients with mild renal impairment, and 113 patients with moderate renal impairment. In addition, in a sub-group analysis of data from studies following oral administration of ribociclib 600 mg as a single dose or repeat doses in cancer patients with mild or moderate renal impairment, AUC and C max were comparable to patients with normal renal function, suggesting no clinically meaningful effect of mild or moderate renal impairment on ribociclib exposure. Effect of Age, Weight, Gender, and Race Population PK analysis showed that there are no clinically relevant effects of age, body weight, gender, or race on the systemic exposure of ribociclib. Drug Interaction Studies Drugs That Affect Ribociclib Plasma Concentrations CYP3A Inhibitors: A drug interaction trial in healthy subjects was conducted with ritonavir (a strong CYP3A inhibitor). Compared to ribociclib alone, ritonavir (100 mg twice a day for 14 days) increased ribociclib C max and AUC inf by 1.7-fold and 3.2-fold, respectively, following a single 400 mg ribociclib dose. C max and AUC for LEQ803 (a prominent metabolite of LEE011, accounting for less than 10% of parent exposure) decreased by 96% and 98%, respectively. A moderate CYP3A4 inhibitor (erythromycin) is predicted to increase ribociclib C max and AUC by 1.3-fold and 1.9-fold, respectively. CYP3A Inducers: A drug interaction trial in healthy subjects was conducted with rifampicin (a strong CYP3A4 inducer). Compared to ribociclib alone, rifampicin (600 mg daily for 14 days) decreased ribociclib C max and AUC inf by 81% and 89%, respectively, following a single 600 mg ribociclib dose. LEQ803 C max increased 1.7-fold and AUC inf decreased by 27%, respectively. A moderate CYP3A inducer (efavirenz) is predicted to decrease ribociclib C max and AUC by 37% and 60%, respectively. Drugs That are Affected by KISQALI CYP3A4 and CYP1A2 Substrates: A drug interaction trial in healthy subjects was conducted as a cocktail study with midazolam (sensitive CYP3A4 substrate) and caffeine (sensitive CYP1A2 substrate). Compared to midazolam and caffeine alone, multiple doses of ribociclib (400 mg once daily for 8 days) increased midazolam C max and AUC inf by 2.1-fold and 3.8-fold, respectively. Administration of ribociclib at 600 mg once daily is predicted to increase midazolam C max and AUC by 2.4-fold and 5.2-fold, respectively. The effect of multiple doses of 400 mg ribociclib on caffeine was minimal, with C max decreased by 10% and AUC inf increased slightly by 20%. Only weak inhibitory effects on CYP1A2 substrates are predicted at 600 mg ribociclib once daily dose. Gastric pH-Elevating Agents: Coadministration of ribociclib with drugs that elevate the gastric pH was not evaluated in a clinical trial; however, altered ribociclib absorption was not identified in a population PK analysis and was not predicted using physiology based PK models. Letrozole: Data from a clinical trial in patients with breast cancer and population PK analysis indicated no drug interaction between ribociclib and letrozole following coadministration of the drugs. Anastrozole: Data from a clinical trial in patients with breast cancer indicated no clinically relevant drug interaction between ribociclib and anastrozole following coadministration of the drugs. Exemestane: Data from a clinical trial in patients with breast cancer indicated no clinically relevant drug interaction between ribociclib and exemestane following coadministration of the drugs. Fulvestrant: Data from a clinical trial in patients with breast cancer indicated no clinically relevant effect of fulvestrant on ribociclib exposure following coadministration of the drugs. Tamoxifen: KISQALI is not indicated for concomitant use with tamoxifen. Data from a clinical trial in patients with breast cancer indicated that tamoxifen C max and AUC increased approximately 2-fold following coadministration of 600 mg ribociclib. In vitro Studies Effect of ribociclib on CYP Enzymes: In vitro , ribociclib was a reversible inhibitor of CYP1A2, CYP2E1 and CYP3A4/5 and a time-dependent inhibitor of CYP3A4/5, at clinically relevant concentrations. In vitro evaluations indicated that KISQALI has no potential to inhibit the activities of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 at clinically relevant concentrations. It has no potential for time-dependent inhibition of CYP1A2, CYP2C9, and CYP2D6, and no induction of CYP1A2, CYP2B6, CYP2C9, and CYP3A4 at clinically relevant concentrations. Effect of ribociclib on Transporters: In vitro evaluations indicated that KISQALI has a low potential to inhibit the activities of drug transporters P-gp, OATP1B1/B3, OCT1, MATEK2 at clinically relevant concentrations. KISQALI may inhibit BCRP, OCT2, MATE1, and human BSEP at clinically relevant concentrations. Effect of Transporters on ribociclib: Based on in vitro data, P-gp and BCRP mediated transport are unlikely to affect the extent of oral absorption of ribociclib at therapeutic doses. Ribociclib is not a substrate for hepatic uptake transporters OATP1B1/1B3 or OCT1 in vitro .

12.1 Mechanism of Action Ribociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. These kinases are activated upon binding to D-cyclins and play a crucial role in signaling pathways which lead to cell cycle progression and cellular proliferation. The cyclin D-CDK4/6 complex regulates cell cycle progression through phosphorylation of the retinoblastoma protein (pRb). In vitro , ribociclib decreased pRb phosphorylation leading to arrest in the G1 phase of the cell cycle and reduced cell proliferation in breast cancer cell lines. In vivo , treatment with single agent ribociclib in a rat xenograft model with human tumor cells led to decreased tumor volumes, which correlated with inhibition of pRb phosphorylation. In studies using patient-derived estrogen receptor positive breast cancer xenograft models, combination of ribociclib and antiestrogen (e.g., letrozole) resulted in increased tumor growth inhibition compared to each drug alone. Additionally, the combination of ribociclib and fulvestrant resulted in tumor growth inhibition in an estrogen receptor positive breast cancer xenograft model.

12.2 Pharmacodynamics Cardiac Electrophysiology Serial, triplicate ECGs were collected following a single dose and at steady-state to evaluate the effect of ribociclib on the QTcF interval in patients with advanced cancer. A pharmacokinetic-pharmacodynamic analysis included a total of 997 patients treated with ribociclib at doses ranging from 50 to 1200 mg. The analysis suggested that ribociclib causes concentration-dependent increases in the QTcF interval. The estimated mean change from baseline in QTcF for KISQALI 600 mg in combination with aromatase inhibitors or fulvestrant was 22.0 ms (90% CI: 20.6, 23.4) and 23.7 ms (90% CI: 22.3, 25.1), respectively, and was 34.7 ms (90% CI: 31.6, 37.8) in combination with tamoxifen at the geometric mean C max at steady-state [see Warnings and Precautions (5.3, 5.4)] .

12.3 Pharmacokinetics Ribociclib exhibited over-proportional increases in exposure (peak plasma concentrations (C max ) and area under the time concentration curve (AUC)) across the dose range of 50 mg to 1200 mg following both single dose and repeated doses. Following repeated 600 mg once daily administration, steady-state was generally achieved after 8 days and ribociclib accumulated with a geometric mean accumulation ratio of 2.51 (range, 0.972 to 6.40). Absorption The time to reach C max (T max ) following ribociclib administration was between 1 and 4 hours. Food Effect: Compared to the fasted state, oral administration of a single 600 mg dose of KISQALI film-coated tablet with a high-fat, high-calorie meal (approximately 800 to 1000 calories with ~50% calories from fat, ~35% calories from carbohydrates, and ~15% calories from protein) had no effect on the rate and extent of absorption of ribociclib (C max GMR: 1.00; 90% CI: 0.898, 1.11; AUC inf GMR: 1.06; 90% CI: 1.01, 1.12). Distribution Binding of ribociclib to human plasma proteins in vitro was approximately 70% and independent of concentration (10 to 10,000 ng/mL). Ribociclib was equally distributed between red blood cells and plasma with a mean in vivo blood-to-plasma ratio of 1.04. The apparent volume of distribution at steady-state (Vss/F) was 1090 L based on population PK analysis. Metabolism In vitro and in vivo studies indicated ribociclib undergoes extensive hepatic metabolism mainly via CYP3A4 in humans. Following oral administration of a single 600 mg dose of radio-labeled ribociclib to humans, the primary metabolic pathways for ribociclib involved oxidation (dealkylation, C and/or N-oxygenation, oxidation (-2H)) and combinations thereof. Phase II conjugates of ribociclib Phase I metabolites involved N-acetylation, sulfation, cysteine conjugation, glycosylation and glucuronidation. Ribociclib was the major circulating drug-derived entity in plasma (44%). The major circulating metabolites included metabolite M13 (CCI284, N-hydroxylation), M4 (LEQ803, N-demethylation), and M1 (secondary glucuronide), each representing an estimated 9%, 9%, and 8% of total radioactivity, and 22%, 20%, and 18% of ribociclib exposure. Clinical activity (pharmacological and safety) of ribociclib was due primarily to parent drug, with negligible contribution from circulating metabolites. Ribociclib was extensively metabolized with unchanged drug accounting for 17% and 12% in feces and urine, respectively. Metabolite LEQ803 was a significant metabolite in excreta and represented approximately 14% and 4% of the administered dose in feces and urine, respectively. Numerous other metabolites were detected in both feces and urine in minor amounts (≤ 3% of the administered dose). Elimination The geometric mean plasma effective half-life (based on accumulation ratio) was 32.0 hours (63% CV) and the geometric mean apparent oral clearance (CL/F) was 25.5 L/hr (66% CV) at steady-state at 600 mg in patients with advanced cancer. The geometric mean apparent plasma terminal half-life (t ½) of ribociclib ranged from 29.7 to 54.7 hours and geometric mean CL/F of ribociclib ranged from 39.9 to 77.5 L/hr at 600 mg across studies in healthy subjects. Ribociclib is eliminated mainly via feces, with a small contribution of the renal route. In 6 healthy male subjects, following a single oral dose of radio-labeled ribociclib, 92% of the total administered radioactive dose was recovered within 22 days; feces was the major route of excretion (69%), with 23% of the dose recovered in urine. Specific Populations Patients with Hepatic Impairment Based on a pharmacokinetic trial in patients with hepatic impairment, mild (Child-Pugh class A) hepatic impairment had no effect on the exposure of ribociclib. The mean exposure for ribociclib was increased less than 2-fold in patients with moderate (Child-Pugh class B; geometric mean ratio [GMR]: 1.44 for C max ; 1.28 for AUC inf ) or severe (Child-Pugh class C; GMR: 1.32 for C max ; 1.29 for AUC inf ) hepatic impairment. Based on a population pharmacokinetic analysis that included 160 patients with normal hepatic function and 47 patients with mild hepatic impairment, mild hepatic impairment had no effect on the exposure of ribociclib, further supporting the findings from the dedicated hepatic impairment study. Patients with Renal Impairment The effect of renal impairment on the pharmacokinetics of ribociclib was assessed in a renal impairment study in non-cancer subjects with normal renal function (eGFR ≥ 90 mL/min/1.73 m 2 , n = 9), severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m 2 , n = 6), and End Stage Renal Disease (ESRD; eGFR < 15 mL/min/1.73 m 2 , n = 4) at a single ribociclib dose of 400 mg/day. In subjects with severe renal impairment and ESRD, AUC inf increased 2.37-fold and 3.81-fold, and C max increased 2.10-fold and 2.68-fold relative to the exposure in non-cancer study participants with normal renal function. Mild (60 mL/min/1.73 m 2 ≤ eGFR < 90 mL/min/1.73 m 2 ) or moderate renal impairment (30 mL/min/1.73 m 2 ≤ eGFR < 60 mL/min/1.73 m 2 ) had no effect on the exposure of ribociclib based on a population PK analysis that included 438 cancer patients with normal renal function, 488 patients with mild renal impairment, and 113 patients with moderate renal impairment. In addition, in a sub-group analysis of data from studies following oral administration of ribociclib 600 mg as a single dose or repeat doses in cancer patients with mild or moderate renal impairment, AUC and C max were comparable to patients with normal renal function, suggesting no clinically meaningful effect of mild or moderate renal impairment on ribociclib exposure. Effect of Age, Weight, Gender, and Race Population PK analysis showed that there are no clinically relevant effects of age, body weight, gender, or race on the systemic exposure of ribociclib. Drug Interaction Studies Drugs That Affect Ribociclib Plasma Concentrations CYP3A Inhibitors: A drug interaction trial in healthy subjects was conducted with ritonavir (a strong CYP3A inhibitor). Compared to ribociclib alone, ritonavir (100 mg twice a day for 14 days) increased ribociclib C max and AUC inf by 1.7-fold and 3.2-fold, respectively, following a single 400 mg ribociclib dose. C max and AUC for LEQ803 (a prominent metabolite of LEE011, accounting for less than 10% of parent exposure) decreased by 96% and 98%, respectively. A moderate CYP3A4 inhibitor (erythromycin) is predicted to increase ribociclib C max and AUC by 1.3-fold and 1.9-fold, respectively. CYP3A Inducers: A drug interaction trial in healthy subjects was conducted with rifampicin (a strong CYP3A4 inducer). Compared to ribociclib alone, rifampicin (600 mg daily for 14 days) decreased ribociclib C max and AUC inf by 81% and 89%, respectively, following a single 600 mg ribociclib dose. LEQ803 C max increased 1.7-fold and AUC inf decreased by 27%, respectively. A moderate CYP3A inducer (efavirenz) is predicted to decrease ribociclib C max and AUC by 37% and 60%, respectively. Drugs That are Affected by KISQALI CYP3A4 and CYP1A2 Substrates: A drug interaction trial in healthy subjects was conducted as a cocktail study with midazolam (sensitive CYP3A4 substrate) and caffeine (sensitive CYP1A2 substrate). Compared to midazolam and caffeine alone, multiple doses of ribociclib (400 mg once daily for 8 days) increased midazolam C max and AUC inf by 2.1-fold and 3.8-fold, respectively. Administration of ribociclib at 600 mg once daily is predicted to increase midazolam C max and AUC by 2.4-fold and 5.2-fold, respectively. The effect of multiple doses of 400 mg ribociclib on caffeine was minimal, with C max decreased by 10% and AUC inf increased slightly by 20%. Only weak inhibitory effects on CYP1A2 substrates are predicted at 600 mg ribociclib once daily dose. Gastric pH-Elevating Agents: Coadministration of ribociclib with drugs that elevate the gastric pH was not evaluated in a clinical trial; however, altered ribociclib absorption was not identified in a population PK analysis and was not predicted using physiology based PK models. Letrozole: Data from a clinical trial in patients with breast cancer and population PK analysis indicated no drug interaction between ribociclib and letrozole following coadministration of the drugs. Anastrozole: Data from a clinical trial in patients with breast cancer indicated no clinically relevant drug interaction between ribociclib and anastrozole following coadministration of the drugs. Exemestane: Data from a clinical trial in patients with breast cancer indicated no clinically relevant drug interaction between ribociclib and exemestane following coadministration of the drugs. Fulvestrant: Data from a clinical trial in patients with breast cancer indicated no clinically relevant effect of fulvestrant on ribociclib exposure following coadministration of the drugs. Tamoxifen: KISQALI is not indicated for concomitant use with tamoxifen. Data from a clinical trial in patients with breast cancer indicated that tamoxifen C max and AUC increased approximately 2-fold following coadministration of 600 mg ribociclib. In vitro Studies Effect of ribociclib on CYP Enzymes: In vitro , ribociclib was a reversible inhibitor of CYP1A2, CYP2E1 and CYP3A4/5 and a time-dependent inhibitor of CYP3A4/5, at clinically relevant concentrations. In vitro evaluations indicated that KISQALI has no potential to inhibit the activities of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 at clinically relevant concentrations. It has no potential for time-dependent inhibition of CYP1A2, CYP2C9, and CYP2D6, and no induction of CYP1A2, CYP2B6, CYP2C9, and CYP3A4 at clinically relevant concentrations. Effect of ribociclib on Transporters: In vitro evaluations indicated that KISQALI has a low potential to inhibit the activities of drug transporters P-gp, OATP1B1/B3, OCT1, MATEK2 at clinically relevant concentrations. KISQALI may inhibit BCRP, OCT2, MATE1, and human BSEP at clinically relevant concentrations. Effect of Transporters on ribociclib: Based on in vitro data, P-gp and BCRP mediated transport are unlikely to affect the extent of oral absorption of ribociclib at therapeutic doses. Ribociclib is not a substrate for hepatic uptake transporters OATP1B1/1B3 or OCT1 in vitro .

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3 DOSAGE FORMS AND STRENGTHS Tablet: 200 mg ribociclib (equivalent to 254.40 mg ribociclib succinate). Film coated, light greyish violet, round, curved with beveled edges, debossed with “RIC” on one side and “NVR” on the other side. Tablets: 200 mg ( 3 )

KISQALI ribociclib RIBOCICLIB SUCCINATE RIBOCICLIB SILICON DIOXIDE CROSPOVIDONE HYDROXYPROPYL CELLULOSE, UNSPECIFIED MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE FERROSOFERRIC OXIDE FERRIC OXIDE RED LECITHIN, SOYBEAN POLYVINYL ALCOHOL, UNSPECIFIED TALC TITANIUM DIOXIDE XANTHAN GUM light greyish violet RIC;NVR KISQALI ribociclib RIBOCICLIB SUCCINATE RIBOCICLIB SILICON DIOXIDE CROSPOVIDONE HYDROXYPROPYL CELLULOSE, UNSPECIFIED MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE FERROSOFERRIC OXIDE FERRIC OXIDE RED LECITHIN, SOYBEAN POLYVINYL ALCOHOL, UNSPECIFIED TALC TITANIUM DIOXIDE XANTHAN GUM light greyish violet RIC;NVR KISQALI ribociclib RIBOCICLIB SUCCINATE RIBOCICLIB SILICON DIOXIDE CROSPOVIDONE HYDROXYPROPYL CELLULOSE, UNSPECIFIED MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE FERROSOFERRIC OXIDE FERRIC OXIDE RED LECITHIN, SOYBEAN POLYVINYL ALCOHOL, UNSPECIFIED TALC TITANIUM DIOXIDE XANTHAN GUM light greyish violet RIC;NVR

13.2 Animal Toxicology and/or Pharmacology In vivo cardiac safety studies in dogs demonstrated dose and concentration related QTc interval prolongation at an exposure similar to patients receiving the recommended dose of 600 mg. There is a potential to induce incidences of premature ventricular contractions (PVCs) at elevated exposures (approximately 5-fold the anticipated clinical C max ).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study with oral administration of ribociclib daily in cycles of 3 weeks on/1 week off, ribociclib was not carcinogenic at doses up to 50 mg/kg in male rats and 600 mg/kg in female rats. Systemic exposure in male and female rats were 1.3 and 1.8 times, respectively, the human exposure at the highest recommended dose of 600 mg/day based on AUC. Ribociclib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vitro human lymphocyte chromosomal aberration assay or an in vivo rat bone marrow micronucleus assay. In a fertility and early embryonic development study, female rats received oral doses of ribociclib for 14 days prior to mating through the first week of pregnancy. Ribociclib did not affect reproductive function, fertility or early embryonic development at doses up to 300 mg/kg/day (approximately 0.6 times the clinical exposure in patients at the highest recommended dose of 600 mg/day based on AUC). A fertility study in male rats has not been performed with ribociclib. In repeat-dose toxicity studies with oral administration of ribociclib daily for 3 weeks on /1 week off in rats up to 26 weeks duration and dogs up to 39 weeks duration, atrophic changes in testes were reported. Findings included degeneration of seminiferous tubular epithelia in the testes and hypospermia and luminal cellular debris in the epididymides of rats and dogs and vacuolation of epithelia in the epididymides of rats. These findings were observed at doses ≥ 75 mg/kg in rats and ≥ 1 mg/kg in dogs which resulted in systemic exposures that were 1.4 and 0.03 times the human exposure at the highest recommended daily dose of 600 mg/day based on AUC, respectively. These effects can be linked to a direct anti-proliferative effect on the testicular germ cells resulting in atrophy of the seminiferous tubules and showed a trend towards reversibility in rats and dogs after a four-week non-dosing period.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study with oral administration of ribociclib daily in cycles of 3 weeks on/1 week off, ribociclib was not carcinogenic at doses up to 50 mg/kg in male rats and 600 mg/kg in female rats. Systemic exposure in male and female rats were 1.3 and 1.8 times, respectively, the human exposure at the highest recommended dose of 600 mg/day based on AUC. Ribociclib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vitro human lymphocyte chromosomal aberration assay or an in vivo rat bone marrow micronucleus assay. In a fertility and early embryonic development study, female rats received oral doses of ribociclib for 14 days prior to mating through the first week of pregnancy. Ribociclib did not affect reproductive function, fertility or early embryonic development at doses up to 300 mg/kg/day (approximately 0.6 times the clinical exposure in patients at the highest recommended dose of 600 mg/day based on AUC). A fertility study in male rats has not been performed with ribociclib. In repeat-dose toxicity studies with oral administration of ribociclib daily for 3 weeks on /1 week off in rats up to 26 weeks duration and dogs up to 39 weeks duration, atrophic changes in testes were reported. Findings included degeneration of seminiferous tubular epithelia in the testes and hypospermia and luminal cellular debris in the epididymides of rats and dogs and vacuolation of epithelia in the epididymides of rats. These findings were observed at doses ≥ 75 mg/kg in rats and ≥ 1 mg/kg in dogs which resulted in systemic exposures that were 1.4 and 0.03 times the human exposure at the highest recommended daily dose of 600 mg/day based on AUC, respectively. These effects can be linked to a direct anti-proliferative effect on the testicular germ cells resulting in atrophy of the seminiferous tubules and showed a trend towards reversibility in rats and dogs after a four-week non-dosing period. 13.2 Animal Toxicology and/or Pharmacology In vivo cardiac safety studies in dogs demonstrated dose and concentration related QTc interval prolongation at an exposure similar to patients receiving the recommended dose of 600 mg. There is a potential to induce incidences of premature ventricular contractions (PVCs) at elevated exposures (approximately 5-fold the anticipated clinical C max ).

NDA209092

KISQALI

ribociclib

0078-0860

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL NDC 0078-0860-01 Rx only Kisqali ® (ribociclib) tablets 200 mg daily dose (one 200 mg tablet) 21 Film-coated tablets Contents: 1 individual monthly blister pack. Blister pack contains 21 tablets (200 mg per tablet). NOVARTIS PRINCIPAL DISPLAY PANEL NDC 0078-0860-01 Rx only Kisqali® (ribociclib) tablets 200 mg daily dose (one 200 mg tablet) 21 Film-coated tablets Contents: 1 individual monthly blister pack. Blister pack contains 21 tablets (200 mg per tablet). NOVARTIS

Indications and Usage ( 1 ) 12/2021 Dosage and Administration, Dosing and Administration ( 2.1 ) 12/2021 Warnings and Precautions ( 5 ) 10/2022

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Interstitial Lung Disease/Pneumonitis Advise patients to immediately report new or worsening respiratory symptoms [see Warnings and Precautions (5.1)] . Severe Cutaneous Adverse Reactions Inform patients of the signs and symptoms of severe cutaneous adverse reactions (e.g., skin pain/burning, rapidly-spreading skin rash, and/or mucosal lesions accompanied by fever or flu-like symptoms). Advise patients to contact their healthcare provider immediately if they develop signs and symptoms of severe cutaneous adverse reactions [see Warnings and Precautions (5.2)] . QT Prolongation Inform patients of the signs and symptoms of QT prolongation. Advise patients to contact their healthcare provider immediately for signs or symptoms of QT prolongation [see Warnings and Precautions (5.3, 5.4)] . Hepatobiliary Toxicity Inform patients of the signs and symptoms of hepatobiliary toxicity. Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatobiliary toxicity [see Warnings and Precautions (5.5)] . Neutropenia Advise patients of the possibility of developing neutropenia and to immediately contact their healthcare provider should they develop a fever, particularly in association with any suggestion of infection [see Warnings and Precautions (5.6)] . Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.7), Use in Specific Populations (8.1)] . Advise females of reproductive potential to use effective contraception during KISQALI therapy and for at least 3 weeks after the last dose [Use in Specific Populations (8.3)] . Lactation Advise lactating women not to breastfeed during treatment with KISQALI and for at least 3 weeks after the last dose [see Use in Specific Populations (8.2)] . Drug Interactions Inform patients to avoid grapefruit or grapefruit juice while taking KISQALI [see Drug Interactions (7.1)] . Inform patients to avoid strong CYP3A inhibitors, strong CYP3A inducers, and drugs known to prolong the QT interval [see Drug Interactions (7.1, 7.2, 7.4)] . Dosing Instruct patients to take the doses of KISQALI at approximately the same time every day and to swallow whole (do not chew, crush, or split them prior to swallowing) [see Dosage and Administration (2.1)] . If patient vomits or misses a dose, advise the patient to take the next prescribed dose at the usual time [see Dosage and Administration (2.1)] . Advise the patient that KISQALI may be taken with or without food [see Dosage and Administration (2.1)] . Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2022-58

14 CLINICAL STUDIES MONALEESA-2: KISQALI in Combination with Letrozole Postmenopausal Women with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy MONALEESA-2 was a randomized, double-blind, placebo-controlled, multicenter clinical study of KISQALI plus letrozole vs. placebo plus letrozole conducted in postmenopausal women with HR-positive, HER2-negative, advanced breast cancer who received no prior therapy for advanced disease. A total of 668 patients were randomized to receive either KISQALI plus letrozole (n = 334) or placebo plus letrozole (n = 334), stratified according to the presence of liver and/or lung metastases. Letrozole 2.5 mg was given orally once daily for 28 days, with either KISQALI 600 mg or placebo orally once daily for 21 consecutive days followed by 7 days off until disease progression or unacceptable toxicity. The major efficacy outcome measure for the study was investigator-assessed progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Patients enrolled in MONALEESA-2 had a median age of 62 years (range, 23 to 91) and 45% of patients were older than 65. The majority of patients were White (82%), and all patients had an ECOG performance status of 0 or 1. A total of 47% of patients had received chemotherapy and 51% had received antihormonal therapy in the neoadjuvant or adjuvant setting. Thirty-four percent (34%) of patients had de novo metastatic disease, 21% had bone only disease, and 59% had visceral disease. The efficacy results are summarized in Table 14, Figure 1 and Figure 2. The PFS assessment based on a blinded independent central radiological review was consistent with investigator assessment. Consistent results were observed across patient subgroups of prior adjuvant or neoadjuvant chemotherapy or hormonal therapies, liver and/or lung involvement, and bone-only metastatic disease. Table 14: Efficacy Results – MONALEESA-2 (Investigator Assessment, Intent-to-Treat Population) Abbreviations: CI, confidence interval; NR, not reached. a p-value estimated from one-sided log-rank test. KISQALI + Letrozole Placebo + Letrozole Progression-free Survival N = 334 N = 334 Events (%) 93 (27.8) 150 (44.9) Median (months, 95% CI) NR (19.3 – NR) 14.7 (13.0 – 16.5) Hazard Ratio (95% CI) 0.556 (0.429, 0.720) p-value < 0.0001 a Overall Survival N = 334 N = 334 Events (n, %) 181 (54.2%) 219 (65.6%) Median (months, 95% CI) 63.9 (52.4, 71.0) 51.4 (47.2, 59.7) Hazard Ratio (95% CI) 0.765 (0.528, 0.932) p-value 0.004 a Overall Response Rate N = 256 N = 245 Patients with measurable disease (95% CI) 52.7 (46.6, 58.9) 37.1 (31.1, 43.2) Figure 1 Kaplan-Meier Progression-Free Survival Curves – MONALEESA-2 (Intent-to-Treat Population) Figure 2 Kaplan-Meier Overall Survival Curves – MONALEESA-2 (Intent-to-Treat Population) MONALEESA-7: KISQALI in Combination with an Aromatase Inhibitor Pre/perimenopausal Patients with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy MONALEESA-7 was a randomized, double-blind, placebo-controlled study of KISQALI plus either a NSAI or tamoxifen and goserelin vs. placebo plus either a NSAI or tamoxifen and goserelin conducted in pre/perimenopausal women with HR-positive, HER2-negative, advanced breast cancer who received no prior endocrine therapy for advanced disease. A total of 672 patients were randomized to receive KISQALI plus NSAI or tamoxifen plus goserelin (n = 335) or placebo plus NSAI or tamoxifen plus goserelin (n = 337), stratified according to the presence of liver and/or lung metastases, prior chemotherapy for advanced disease and endocrine combination partner (tamoxifen and goserelin vs. NSAI and goserelin). NSAI (letrozole 2.5 mg or anastrozole 1 mg) or tamoxifen 20 mg were given orally once daily on a continuous daily schedule, goserelin was administered as a sub-cutaneous injection on Day 1 of each 28-day cycle, with either KISQALI 600 mg or placebo orally once daily for 21 consecutive days followed by 7 days off until disease progression or unacceptable toxicity. The major efficacy outcome measure for the study was investigator-assessed progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Patients enrolled in MONALEESA-7 had a median age of 44 years (range, 25 to 58) and were primarily White (58%), Asian (29%), or Black (3%). Nearly all patients (99%) had an ECOG performance status of 0 or 1. Of the 672 patients, 33% had received chemotherapy in the adjuvant vs. 18% in the neoadjuvant setting and 40% had received endocrine therapy in the adjuvant vs. 0.7% in the neoadjuvant setting prior to study entry. Forty percent (40%) of patients had de novo metastatic disease, 24% had bone only disease, and 57% had visceral disease. Demographics and baseline disease characteristics were balanced and comparable between study arms, and endocrine combination partner. The efficacy results from a pre-specified subgroup analysis of 495 patients who had received KISQALI or placebo with NSAI plus goserelin are summarized in Table 15, Figure 3, and Figure 4. Consistent results were observed in stratification factor subgroups of disease site and prior chemotherapy for advanced disease. Table 15: Efficacy Results – MONALEESA-7 (NSAI) Abbreviations: CI, confidence interval; NR, not reached; NSAI, non-steroidal aromatase inhibitors. *Based on confirmed responses. 1 Investigator Assessment. KISQALI + NSAI + Goserelin Placebo + NSAI + Goserelin Progression-Free Survival 1 N = 248 N = 247 Events (n, %) 92 (37.1%) 132 (53.4%) Median (months, 95% CI) 27.5 (19.1, NR) 13.8 (12.6, 17.4) Hazard Ratio (95% CI) 0.569 (0.436, 0.743) Overall Survival N = 248 N = 247 Events (n, %) 61 (24.6%) 80 (32.4%) Median (months, 95% CI) NR (NR, NR) 40.7 (37.4, NR) Hazard Ratio (95% CI) 0.699 (0.501, 0.976) Overall Response Rate* 1 N = 192 N = 199 Patients with measurable disease (95% CI) 50.5 (43.4, 57.6) 36.2 (29.5, 42.9) Figure 3 Kaplan-Meier Progression-Free Survival Curves – MONALEESA-7 (NSAI, Investigator Assessment) Figure 4 Kaplan-Meier Overall Survival Curves- MONALEESA-7 (NSAI) MONALEESA-3: KISQALI in Combination with Fulvestrant Postmenopausal Women with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy or After Disease Progression on Endocrine Therapy MONALEESA-3 was a randomized double-blind, placebo-controlled study of ribociclib in combination with fulvestrant for the treatment of postmenopausal women with hormone receptor positive, HER2-negative, advanced breast cancer who have received no or only one line of prior endocrine treatment. A total of 726 patients were randomized in a 2:1 ratio to receive KISQALI 600 mg and fulvestrant (n = 484) or placebo and fulvestrant (n = 242), stratified according to the presence of liver and/or lung metastases and prior endocrine therapy for advanced or metastatic disease. Fulvestrant 500 mg was administered intramuscularly on Days 1, 15, 29, and once monthly thereafter, with either KISQALI 600 mg or placebo given orally once daily for 21 consecutive days followed by 7 days off until disease progression or unacceptable toxicity. The major efficacy outcome measure for the study was investigator-assessed progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Patients enrolled in this study had a median age of 63 years (range, 31 to 89). Of the patients enrolled, 47% were 65 years and older, including 14% age 75 years and older. The patients enrolled were primarily White (85%), Asian (9%), and Black (0.7%). Nearly all patients (99.7%) had an ECOG performance status of 0 or 1. First and second line patients were enrolled in this study (of which 19% had de novo metastatic disease). Forty-three percent (43%) of patients had received chemotherapy in the adjuvant vs. 13% in the neoadjuvant setting and 59% had received endocrine therapy in the adjuvant vs. 1% in the neoadjuvant setting prior to study entry. Twenty-one percent (21%) of patients had bone only disease and 61% had visceral disease. Demographics and baseline disease characteristics were balanced and comparable between study arms. The efficacy results from MONALEESA-3 are summarized in Table 16, Figure 5, and Figure 6. Consistent results were observed in stratification factor subgroups of disease site and prior endocrine treatment for advanced disease. Table 16: Efficacy Results – MONALEESA-3 (Investigator Assessment, Intent-to-Treat Population) Abbreviations: CI, confidence interval; NR, not reached. a p-value is obtained from the one-sided log-rank. *Based on confirmed responses. 1 Investigator Assessment. KISQALI + Fulvestrant Placebo + Fulvestrant Progression-Free Survival a,1 N = 484 N = 242 Events (n, %) 210 (43.4%) 151 (62.4%) Median (months, 95% CI) 20.5 (18.5, 23.5) 12.8 (10.9, 16.3) Hazard Ratio (95% CI) 0.593 (0.480 to 0.732) p-value a < 0.0001 Overall Survival N = 484 N = 242 Events (n, %) 167 (34.5%) 108 (44.6%) Median (months, 95% CI) NR (42.5, NR) 40.0 (37.0, NR) Hazard Ratio (95% CI) 0.724 (0.568, 0.924) p-value a 0.00455 Overall Response Rate *,1 N = 379 N = 181 Patients with measurable disease (95% CI) 40.9 (35.9, 45.8) 28.7 (22.1, 35.3) Figure 5 Kaplan-Meier Progression-Free Survival Curves – MONALEESA-3 (Investigator Assessment) Figure 6 Kaplan-Meier plot of Overall Survival- MONALEESA-3 (Intent-to-Treat Population) COMPLEEMENT-1: KISQALI in combination with Letrozole and Goserelin or Leuprolide Men with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy COMPLEEMENT-1 (NCT 02941926) was an open-label, multicenter clinical study of ribociclib in combination with letrozole and goserelin or leuprolide for the treatment of adults with HR-positive, HER2-negative, advanced breast cancer who received no prior hormonal therapy for advanced disease. The study included 39 male patients who received KISQALI 600 mg orally once daily for 21 consecutive days followed by 7 days off; and letrozole 2.5 mg orally once daily for 28 days; and goserelin 3.6 mg as injectable subcutaneous implant or leuprolide 7.5 mg as intramuscular injection administered on Day 1 of each 28-day cycle. Patients were treated until disease progression or unacceptable toxicity occurred. Male patients enrolled in this study had a median age of 62 years (range, 33 to 80). Of these patients, 39% were 65 years and older, including 10% aged 75 years and older. The male patients enrolled were White (72%), Asian (8%), and Black (3%), with 17% unknown. Nearly all male patients (97%) had an ECOG performance status of 0 or 1. The majority of male patients (97%) had 4 or less metastatic sites, which were primarily bone and visceral (69% each). Table 17 summarizes the efficacy results in male patients from COMPLEEMENT-1. Table 17: Efficacy Results in Male Patients 1 – COMPLEEMENT-1 (Investigator Assessment, Intent-to-Treat Population) Abbreviations: CI, confidence interval, NR, not reached. *Based on confirmed responses. 1 Patients with measurable disease. 2 Investigator Assessment. 3 Proportion of patients with complete response or partial response. KISQALI + Letrozole + Goserelin or Leuprolide Overall Response Rate *,2 N = 32 (95% CI) 46.9 (29.1, 65.3) Duration of Response (DoR) 3 N = 15 Median (months, 95% CI) NR (21.3, NR) Patients with DoR ≥ 12 months, n (%) 12 (80.0%) Figure 1 Kaplan-Meier Progression-Free Survival Curves – MONALEESA-2 (Intent-to-Treat Population) Figure 2 Kaplan-Meier Overall Survival Curves – MONALEESA-2 (Intent-to-Treat Population) Figure 3 Kaplan-Meier Progression-Free Survival Curves – MONALEESA-7 (NSAI, Investigator Assessment) Figure 4 Kaplan-Meier Overall Survival Curves- MONALEESA-7 (NSAI) Figure 5 Kaplan-Meier Progression-Free Survival Curves – MONALEESA-3 (Investigator Assessment) Figure 2 Kaplan-Meier Overall Survival Curves – MONALEESA-2 (Intent-to-Treat Population)

8.5 Geriatric Use Of 334 patients who received KISQALI in MONALEESA-2, 150 patients (45%) were ≥ 65 years of age and 35 patients (11%) were ≥ 75 years of age. Of 484 patients who received KISQALI in MONALEESA-3, 226 patients (47%) were ≥ 65 years of age and 65 patients (14%) were ≥ 75 years of age. Of 248 patients who received KISQALI in MONALEESA-7, no patients were ≥ 65 years of age. No overall differences in safety or effectiveness of KISQALI were observed between these patients and younger patients.

8.4 Pediatric Use The safety and efficacy of KISQALI in pediatric patients has not been established.

8.1 Pregnancy Risk Summary Based on findings from animal studies and the mechanism of action, KISQALI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)] . There are no available human data informing the drug-associated risk. In animal reproduction studies, administration of ribociclib to pregnant animals during organogenesis resulted in increased incidences of post implantation loss and reduced fetal weights in rats and increased incidences of fetal abnormalities in rabbits at exposures 0.6 or 1.5 times the exposure in humans, respectively, at the highest recommended dose of 600 mg/day based on AUC (see Data) . Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies in the U.S. general population. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of ribociclib up to 1000 mg/kg/day and 60 mg/kg/day, respectively, during the period of organogenesis. In rats, 300 mg/kg/day resulted in reduced maternal body weight gain and reduced fetal weights accompanied by skeletal changes related to the lower fetal weights. There were no significant effects on embryo-fetal viability or fetal morphology at 50 or 300 mg/kg/day. In rabbits at doses ≥ 30 mg/kg/day, there were adverse effects on embryo-fetal development, including increased incidences of fetal abnormalities (malformations and external, visceral, and skeletal variants) and fetal growth (lower fetal weights). These findings included reduced/small lung lobes, additional vessel on the descending aorta, additional vessel on the aortic arch, small eyes, diaphragmatic hernia, absent accessory lobe or (partly) fused lung lobes, reduced/small accessory lung lobe, extra/rudimentary 13 th ribs, misshapen hyoid bone, bent hyoid bone alae, and reduced number of phalanges in the pollex. There was no evidence of increased incidence of embryo-fetal mortality. There was no maternal toxicity observed at 30 mg/kg/day. At 300 mg/kg/day in rats and 30 mg/kg/day in rabbits, the maternal systemic exposures (AUC) were approximately 0.6 and 1.5 times, respectively, the exposure in patients at the highest recommended dose of 600 mg/day.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on findings from animal studies and the mechanism of action, KISQALI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)] . There are no available human data informing the drug-associated risk. In animal reproduction studies, administration of ribociclib to pregnant animals during organogenesis resulted in increased incidences of post implantation loss and reduced fetal weights in rats and increased incidences of fetal abnormalities in rabbits at exposures 0.6 or 1.5 times the exposure in humans, respectively, at the highest recommended dose of 600 mg/day based on AUC (see Data) . Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies in the U.S. general population. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of ribociclib up to 1000 mg/kg/day and 60 mg/kg/day, respectively, during the period of organogenesis. In rats, 300 mg/kg/day resulted in reduced maternal body weight gain and reduced fetal weights accompanied by skeletal changes related to the lower fetal weights. There were no significant effects on embryo-fetal viability or fetal morphology at 50 or 300 mg/kg/day. In rabbits at doses ≥ 30 mg/kg/day, there were adverse effects on embryo-fetal development, including increased incidences of fetal abnormalities (malformations and external, visceral, and skeletal variants) and fetal growth (lower fetal weights). These findings included reduced/small lung lobes, additional vessel on the descending aorta, additional vessel on the aortic arch, small eyes, diaphragmatic hernia, absent accessory lobe or (partly) fused lung lobes, reduced/small accessory lung lobe, extra/rudimentary 13 th ribs, misshapen hyoid bone, bent hyoid bone alae, and reduced number of phalanges in the pollex. There was no evidence of increased incidence of embryo-fetal mortality. There was no maternal toxicity observed at 30 mg/kg/day. At 300 mg/kg/day in rats and 30 mg/kg/day in rabbits, the maternal systemic exposures (AUC) were approximately 0.6 and 1.5 times, respectively, the exposure in patients at the highest recommended dose of 600 mg/day. 8.2 Lactation Risk Summary It is not known if ribociclib is present in human milk. There are no data on the effects of ribociclib on the breastfed infant or on milk production. Ribociclib and its metabolites readily passed into the milk of lactating rats. Because of the potential for serious adverse reactions in breastfed infants from KISQALI, advise lactating women not to breastfeed while taking KISQALI and for at least 3 weeks after the last dose. Data In lactating rats administered a single dose of 50 mg/kg, exposure to ribociclib was 3.56-fold higher in milk compared to maternal plasma. 8.3 Females and Males of Reproductive Potential Based on animal studies and mechanism of action, KISQALI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)] . Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to starting treatment with KISQALI. Contraception Females Advise females of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) during treatment with KISQALI and for at least 3 weeks after the last dose. Infertility Males Based on animal studies, KISQALI may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)] . 8.4 Pediatric Use The safety and efficacy of KISQALI in pediatric patients has not been established. 8.5 Geriatric Use Of 334 patients who received KISQALI in MONALEESA-2, 150 patients (45%) were ≥ 65 years of age and 35 patients (11%) were ≥ 75 years of age. Of 484 patients who received KISQALI in MONALEESA-3, 226 patients (47%) were ≥ 65 years of age and 65 patients (14%) were ≥ 75 years of age. Of 248 patients who received KISQALI in MONALEESA-7, no patients were ≥ 65 years of age. No overall differences in safety or effectiveness of KISQALI were observed between these patients and younger patients. 8.6 Hepatic Impairment No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A). A reduced starting dose of 400 mg is recommended in patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) [see Dosage and Administration (2.2)] . Based on a pharmacokinetic trial in patients with hepatic impairment, mild hepatic impairment had no effect on the exposure of ribociclib. The mean exposure for ribociclib was increased less than 2-fold in patients with moderate (geometric mean ratio [GMR]: 1.44 for C max ; 1.28 for AUC inf ) and severe (GMR: 1.32 for C max ; 1.29 for AUC inf ) hepatic impairment [see Clinical Pharmacology (12.3)] . 8.7 Renal Impairment Based on a population pharmacokinetic analysis, no dose adjustment is necessary in patients with mild (60 mL/min/1.73 m 2 ≤ estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m 2 ) or moderate (30 mL/min/1.73 m 2 ≤ eGFR < 60 mL/min/1.73 m 2 ) renal impairment. Based on a renal impairment study in healthy subjects and non-cancer subjects with severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m 2 ), a starting dose of 200 mg is recommended. KISQALI has not been studied in breast cancer patients with severe renal impairment [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)] .

16 HOW SUPPLIED/STORAGE AND HANDLING KISQALI (ribociclib) Tablets Each film-coated tablet contains 200 mg of ribociclib free base. Light greyish violet, round, curved with beveled edge, debossed with “RIC” on one side and “NVR” on the other side; available in: Carton of 3 blister packs (63 tablets total) – each blister pack contains a 7-day supply of 21 tablets (200 mg per tablet) (600 mg daily dose). NDC 0078-0874-63 Carton of 3 blister packs (42 tablets total) – each blister pack contains a 7-day supply of 14 tablets (200 mg per tablet) (400 mg daily dose). NDC 0078-0867-42 Carton of 1 blister pack (21 tablets total) – each blister pack contains a 21-day supply of 21 tablets (200 mg per tablet) (200 mg daily dose). NDC 0078-0860-01 Store at 20°C to 25°C (68°F to 77°F). Store in the original package.