Ribociclib

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.

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 )

None. None. ( 4 )

Interstitial Lung Disease (ILD)/Pneumonitis: Severe, life threatening, or fatal ILD/pneumonitis can occur with KISQALI treatment. Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Interrupt and evaluate patients with new or worsening respiratory symptoms suspected to be due to ILD/pneumonitis. Permanently discontinue KISQALI in patients with recurrent symptomatic or severe ILD/pneumonitis. ( 2.2 , 5.1 ) Severe Cutaneous Adverse Reactions (SCARs): SCARs including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug-reaction with eosinophilia and systemic symptoms (DRESS) can occur with KISQALI treatment. Permanently discontinue KISQALI in patients with SCARs or other life-threatening cutaneous reactions. ( 2.2 , 5.2 ) QT Interval Prolongation: KISQALI has been shown to prolong the QT interval in a concentration-dependent manner. Monitor electrocardiograms (ECGs) and electrolytes prior to initiation of treatment with KISQALI. Repeat ECGs at approximately Day 14 of the first cycle, and as clinically indicated. Monitor electrolytes at the beginning of each cycle for 6 cycles, and as clinically indicated. Avoid using KISQALI with drugs known to prolong QT interval and/or strong CYP3A inhibitors. ( 2.2 , 5.3 , 7.1 , 7.4 ) Increased QT Prolongation with Concomitant Use of Tamoxifen: KISQALI is not indicated for concomitant use with tamoxifen. ( 5.4 ) Hepatotoxicity: Increases in serum transaminase and bilirubin levels have been observed. Perform liver function tests (LFTs) before initiating treatment with KISQALI. Monitor LFTs every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated. ( 2.2 , 5.5 ) Neutropenia: Perform complete blood count (CBC) before initiating therapy with KISQALI. Monitor CBC every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated. ( 2.2 , 5.6 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception during therapy. ( 5.7 , 8.1 , 8.3 )

5.1 Interstitial Lung Disease/Pneumonitis Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with KISQALI and other CDK 4/6 inhibitors. In patients with early breast cancer (NATALEE) who received 400 mg KISQALI plus a non-steroidal aromatase inhibitor (NSAI), 1.5% of patients had ILD/pneumonitis (Grade 1-2). In patients with advanced or metastatic breast cancer (MONALEESA-2, MONALEESA-3, MONALEESA-7), 1.6% of patients had ILD/pneumonitis (any Grade, 0.4% had Grade 3-4, and 0.1% had a fatal outcome). Additional cases of ILD/pneumonitis have occurred in the postmarketing setting, some resulting in death [see Adverse Reactions (6.2)] . Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis which may include hypoxia, cough, and dyspnea. In patients who have new or worsening respiratory symptoms suspected to be due to ILD or pneumonitis, interrupt KISQALI immediately and evaluate the patient. Permanently discontinue KISQALI in patients with severe ILD/pneumonitis or any recurrent symptomatic ILD/pneumonitis [see Dosage and Administration (2.2)] .

5.2 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) can occur in patients treated with KISQALI [see Adverse Reactions (6.2)] . If signs or symptoms of severe cutaneous reactions occur, interrupt KISQALI until the etiology of the reaction has been determined [see Dosage and Administration (2.2)] . Early consultation with a dermatologist is recommended to ensure greater diagnostic accuracy and appropriate management. If SJS, TEN, or DiHS/DRESS is confirmed, permanently discontinue KISQALI. Do not reintroduce KISQALI in patients who have experienced SCARs or other life-threatening cutaneous reactions during KISQALI treatment. 5.3 QT Interval Prolongation KISQALI has been shown to prolong the QT interval in a concentration-dependent manner [see Clinical Pharmacology (12.2)] . Avoid KISQALI in patients who are at significant risk of developing Torsades de Pointes (TdP), including those with: congenital long QT syndrome; uncontrolled or significant cardiac disease, recent myocardial infarction, heart failure, unstable angina, bradyarrhythmias, uncontrolled hypertension, high degree atrioventricular block, severe aortic stenosis, or uncontrolled hypothyroidism; electrolyte abnormalities; taking drugs known to prolong QT interval and/or strong CYP3A inhibitors as this may lead to prolongation of the QTcF interval. Based on the observed QT prolongation during treatment, KISQALI may require dose interruption, reduction or discontinuation as described in Table 4 [see Dosage and Administration (2.2), Drug Interactions (7.4)] . In patients with early breast cancer (NATALEE) who received 400 mg KISQALI plus NSAI, 8 out of 2494 patients (0.3%) had > 500 ms post-baseline QTcF interval value and 50 out of 2494 patients (2%) had > 60 ms QTcF increase from baseline. QTcF prolongation was reversible with dose interruption. The majority of QTcF prolongation occurred within the first four weeks of KISQALI. There were no reported cases of Torsades de Pointes. In patients with advanced or metastatic breast cancer (MONALEESA-2, MONALEESA-3, and MONALEESA-7) who received 600 mg KISQALI plus NSAI or fulvestrant, 15 out of 1054 patients (1.4%) had a > 500 ms post-baseline QTcF value and 61 out of 1054 patients (6%) had a > 60 ms QTcF increase from baseline. QTcF prolongation was reversible with dose interruption. The majority of QTcF prolongation occurred within the first four weeks of KISQALI. There were no reported cases of Torsades de Pointes. In MONALEESA-2, in the KISQALI plus letrozole treatment arm, there was one (0.3%) sudden death in a patient with Grade 3 hypokalemia and Grade 2 QT prolongation. No cases of sudden death were reported in MONALEESA-7 or MONALEESA-3 [see Adverse Reactions (6)] . Perform ECG in all patients prior to starting KISQALI. Initiate treatment with KISQALI only in patients with QTcF values less than 450 ms. Repeat ECG at approximately Day 14 of the first cycle, and as clinically indicated. Monitor serum electrolytes (including potassium, calcium, phosphorous and magnesium) prior to the initiation of KISQALI at the beginning of the first 6 cycles, and as clinically indicated. Correct any abnormality before starting KISQALI [see Dosage and Administration (2.2)] .

5.4 Increased QT Prolongation with Concomitant Use of Tamoxifen Avoid use of tamoxifen with KISQALI. In MONALEESA-7, the observed mean QTcF increase from baseline was > 10 ms higher in the tamoxifen plus placebo subgroup compared with the non-steroidal aromatase inhibitors (NSAIs) plus placebo subgroup. In the placebo arm, an increase of > 60 ms from baseline occurred in 6/90 (7%) of patients receiving tamoxifen, and in no patients receiving an NSAI. An increase of > 60 ms from baseline in the QTcF interval was observed in 14/87 (16%) of patients in the KISQALI and tamoxifen combination and in 18/245 (7%) of patients receiving KISQALI plus an NSAI [see Clinical Pharmacology (12.2)] .

5.5 Hepatotoxicity In patients with early and advanced or metastatic breast cancer, drug-induced liver injury and increases in transaminases occurred with KISQALI. In patients with early breast cancer (NATALEE) treated with KISQALI, drug-induced liver injury was reported in 9 patients (0.4%), of which 5 were Grade ≥ 3, and 8 had resolved as of the data cutoff. There were 8 (0.3%) clinically confirmed Hy’s Law cases (including 4 out of 9 drug-induced liver injury mentioned above), 6 of which had resolved within 303 days and 2 of which were improving, all after discontinuation of KISQALI. […]

The following adverse reactions are discussed in greater detail in other sections of the labeling: Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1)] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)] QT Interval Prolongation [see Warnings and Precautions (5.3, 5.4)] Hepatotoxicity [see Warnings and Precautions (5.5)] Neutropenia [see Warnings and Precautions (5.6)] In patients with early breast cancer, the most common (incidence ≥ 20%) adverse reactions, including laboratory abnormalities, are lymphocytes decreased, leukocytes decreased, neutrophils decreased, hemoglobin decreased, alanine aminotransferase increased, aspartate aminotransferase increased, infections, creatinine increased, platelets decreased, headache, nausea, and fatigue. ( 6 ) In patients with advanced or metastatic breast cancer, the most common (incidence ≥ 20%) adverse reactions, including laboratory abnormalities, are leukocytes decreased, neutrophils decreased, hemoglobin decreased, lymphocytes decreased, aspartate aminotransferase increased, gamma glutamyl transferase increased, alanine aminotransferase increased, infections, nausea, creatinine increased, fatigue, platelets decreased, diarrhea, vomiting, headache, constipation, alopecia, cough, rash, back pain, and glucose serum decreased. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in WARNINGS AND PRECAUTIONS reflect exposure to KISQALI plus non-steroidal aromatase inhibitor (NSAI) in 2526 patients with early breast cancer (NATALEE), of whom 51% completed 36 months of KISQALI treatment. The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were lymphocytes decreased (97%), leukocytes decreased (95%), neutrophils decreased (94%), hemoglobin decreased (47%), alanine aminotransferase increased (45%), aspartate aminotransferase increased (44%), infections (37%), creatinine increased (33%), platelets decreased (28%), headache (23%), nausea (23%), and fatigue (22%). In addition, the pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to KISQALI in 1065 patients with advanced or metastatic breast cancer (MONALEESA-2, MONALEESA-3, MONALEESA-7), of whom 76% were exposed for 6 months or longer, and 62% were exposed for greater than one year. The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were leukocytes decreased (95%), neutrophils decreased (93%), hemoglobin decreased (68%), lymphocytes decreased (66%), aspartate aminotransferase increased (55%), gamma-glutamyl transferase increased (53%), alanine aminotransferase increased (52%), infections (47%), nausea (47%), creatinine increased (42%), fatigue (35%), platelets decreased (34%), diarrhea (33%), vomiting (29%), headache (27%), constipation (25%), alopecia (25%), cough (24%), rash (24%), back pain (24%), and glucose serum decreased (20%). NATALEE: KISQALI in Combination with a Non-steroidal Aromatase Inhibitor as Adjuvant Treatment Adults with HR-positive, HER2-negative Stage II and III Early Breast Cancer at High Risk of Recurrence The safety of KISQALI was evaluated in NATALEE, a clinical trial of 5101 patients who received KISQALI plus NSAI or NSAI alone, with or without goserelin [see Clinical Studies (14)] . The median duration of exposure to KISQALI was 33 months. Serious adverse reactions occurred in 14% of patients who received KISQALI. Serious adverse reactions in > 0.5% of patients who received KISQALI included COVID-19 (1.1%), pneumonia (0.8%), and pulmonary embolism (0.6%). Fatal adverse reactions occurred in 0.6% of patients who received KISQALI. Fatal adverse reactions in ≥ 0.1% of patients receiving KISQALI included COVID-19 or COVID-19 pneumonia (0.2%) and pulmonary embolism (0.1%). Permanent discontinuation of KISQALI due to an adverse reaction occurred in 20% of patients. Adverse reactions which resulted in permanent discontinuation of KISQALI in ≥ 2% of patients were alanine aminotransferase or aspartate aminotransferase increased (8%). Dosage interruptions of both KISQALI plus NSAI due to an adverse reaction occurred in 73% of patients. Adverse reactions which required dosage interruption in ≥ 5% of patients included neutropenia or neutrophil count decreased (43%), alanine aminotransferase or aspartate aminotransferase increased (11%), COVID-19 (10%), and hypomagnesemia (5%). Dose reductions of KISQALI due to an adverse reaction occurred in 23% of patients. Adverse reactions which required dose reductions in ≥ 2% of patients included neutropenia or neutrophil count decreased (14%) and liver function abnormal (2.3%). The most common (≥ 20% on KISQALI plus NSAI and ≥ 2% higher than placebo) adverse reactions, including laboratory abnormalities, were neutropenia, infections, nausea, headache, fatigue, leukopenia, and abnormal liver function tests. Table 10 summarizes the adverse reactions in NATALEE. Table 10: Adverse Reactions (≥ 10% and ≥ 2% Higher Than NSAI Alone Arm) in NATALEE Abbreviation: NSAI, non-steroidal aromatase inhibitor. Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 1 Infections: urinary tract infections; respiratory tract infections. 2 Only includes a Grade 3 adverse reaction. Adverse reaction KISQALI + NSAI (n = 2526) NSAI (n = 2441) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Infections and infestations Infections 1 37 2.0 27

0.9 Nervous system disorders Headache 2 23 0.4 17

0.2 Gastrointestinal disorders Nausea 2 23 0.2 8

0.1 Diarrhea 2 15 0.6 6

0.1 Constipation 2 13 0.2 5 0 Abdominal pain 2 11 0.5 7

0.4 General disorders and administration-site conditions Fatigue 2 22 0.8 13

0.2 Asthenia 2 17 0.6 12

0.1 Pyrexia 2 11 0.2 6

0.1 Skin and subcutaneous tissue disorders Alopecia 15 0 4.6 0 Respiratory, thoracic, and mediastinal disorders Cough 2 13 0.1 8

0.1 Clinically relevant adverse reactions reported in < 10% of patients who received KISQALI plus NSAI included rash (9%), dizziness (9%), vomiting (8%), peripheral edema (7%), pruritus (7%), dyspnea (7%), stomatitis (6%), oropharyngeal pain (6%), hypocalcemia (5%), hypokalemia (4.8%), decreased appetite (4.8%). Table 11 summarizes the laboratory abnormalities in NATALEE. Table 11: Select Laboratory Abnormalities (≥ 10%) in Patients in NATALEE Who Received KISQALI Plus NSAI Abbreviation: NSAI, non-steroidal aromatase inhibitor. Laboratory abnormality KISQALI + NSAI (n = 2526) NSAI (n = 2441) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology Lymphocytes decreased 97 19 88 6 Leukocytes decreased 95 27 45

0.6 Neutrophils decreased 94 45 35

1.7 Hemoglobin decreased 47 0.6 26

0.3 Platelets decreased 28 0.4 13

0.3 Chemistry Alanine aminotransferase increased 45 8 35 1 Aspartate aminotransferase increased 44 5 33 1 Creatinine increased 33 0.3 11 0 MONALEESA-2: KISQALI in Combination with Letrozole Postmenopausal Women with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy The safety of KISQALI was evaluated in MONALEESA-2, a clinical trial of 668 postmenopausal women receiving KISQALI plus letrozole or placebo plus letrozole [see Clinical Studies (14)] . The median duration of exposure to KISQALI plus letrozole was 13 months with 58% of patients exposed for ≥ 12 months. Serious adverse reactions occurred in 21% of patients who received KISQALI plus letrozole. […]

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)] .

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 effectiveness of KISQALI in pediatric patients have not been established. The safety and efficacy of KISQALI in combination with chemotherapy was assessed but not established in an open-label, dose-finding multicenter study (Study CLEE011Q12101; NCT05429502) in 12 patients, including 9 pediatric patients aged 4 to <17 years with relapsed or refractory neuroblastoma and other solid tumors. The study was terminated early due to dose-limiting toxicities (DLTs) preventing the identification of a safe dosing regimen for the investigational combination. DLTs included neutropenia, anemia, thrombocytopenia, ventricular tachycardia, respiratory failure, and infection. Ribociclib exposures in pediatric patients aged 1 to < 17 years were within the range of values previously observed in adults based on body surface area.

8.5 Geriatric Use Of the 2549 adults with early breast cancer who received KISQALI in NATALEE, 407 patients (16%) were ≥ 65 years of age and 123 patients (2.4%) were ≥ 75 years of age. No overall differences in safety or effectiveness of KISQALI were observed between older and younger adults with early breast cancer. Of 334 patients with advanced or metastatic breast cancer 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 with advanced or metastatic breast cancer 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 with advanced or metastatic breast cancer 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 older and younger adults with advanced or metastatic breast cancer.

8.6 Hepatic Impairment No dose adjustment is necessary in patients with breast cancer who have mild hepatic impairment (Child-Pugh class A) [see Clinical Pharmacology (12.3)] . A reduced starting dose of 400 mg is recommended in patients with advanced or metastatic breast cancer who have moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) [see Dosage and Administration (2.2)] .

8.7 Renal Impairment No dose adjustment is necessary in patients with breast cancer who have mild to moderate (30 mL/min to 89 mL/min/1.73 m 2 ≤ estimated glomerular filtration rate (eGFR)) renal impairment. A reduced starting dose of 200 mg is recommended in patients with breast cancer who have severe renal impairment [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)] .

Ribociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. These kinases are activated upon binding to D-cyclins and are downstream of 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, resulting in arrest in the G1 phase of the cell cycle and reduced proliferation in breast cancer-derived models. 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) therapies 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.