KISQALI FEMARA CO-PACK consists of ribociclib 200 mg film-coated tablets co-packaged with letrozole 2.5 mg tablets. Ribociclib KISQALI (ribociclib) is a kinase inhibitor. Ribociclib succinate is a light yellow to yellowish brown crystalline powder. 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). 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 hydrolyzed), talc, titanium dioxide, and xanthan gum as inactive ingredients. Letrozole FEMARA (letrozole) is a nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis). Letrozole is a white to yellowish crystalline powder, practically odorless, freely soluble in dichloromethane, slightly soluble in ethanol, and practically insoluble in water. It has a molecular weight of 285.31 g/mol, empirical formula C 17 H 11 N 5 , and a melting range of 184°C to 185°C. The chemical name of letrozole is 4,4'-(1H-1,2,4-Triazol-1ylmethylene) dibenzonitrile, and its structural formula is FEMARA is available as 2.5 mg tablets for oral administration. Inactive Ingredients: colloidal silicon dioxide, ferric oxide, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, maize starch, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, talc, and titanium dioxide. ribociclib structure letrozole structure

KISQALI FEMARA CO-PACK, a co-packaged product containing ribociclib, a kinase inhibitor, and letrozole, an aromatase inhibitor, is indicated: 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. as initial endocrine-based therapy for the treatment of adults with HR-positive, HER2-negative advanced or metastatic breast cancer therapy

Early Breast Cancer KISQALI ® FEMARA ® CO-PACK is indicated 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

Advanced or Metastatic Breast Cancer KISQALI ® FEMARA ® CO-PACK indicated as initial endocrine-based therapy for the treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.

KISQALI FEMARA CO-PACK is KISQALI (ribociclib) tablets co-packaged with FEMARA (letrozole) tablets. 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. Tablet: 2.5 mg letrozole. Dark yellow, film-coated, round, slightly biconvex, with beveled edges (imprinted with the letters “FV” on one side and “CG” on the other side). Tablets: KISQALI: 200 mg FEMARA: 2.5 mg

KISQALI FEMARA CO-PACK tablets are taken in combination orally with or without food. Early Breast Cancer KISQALI recommended starting dose: 400 mg orally (two 200 mg tablets) taken once daily for 21 consecutive days followed by 7 days off KISQALI treatment. Advanced or Metastatic Breast Cancer KISQALI recommended starting dose: 600 mg orally (three 200 mg tablets) taken once daily for 21 consecutive days followed by 7 days off KISQALI treatment. KISQALI dose interruption, reduction, and/or discontinuation may be required based on individual safety and tolerability. FEMARA: 2.5 mg (one tablet) continuously for a 28-day cycle

Recommended Dosage Important Administration Instructions The KISQALI FEMARA CO-PACK is comprised of ribociclib tablets co-packaged with letrozole tablets, to provide a 28-day treatment regimen. KISQALI FEMARA CO-PACK can be taken with or without food [ see Clinical Pharmacology ]. Pre/perimenopausal women, or men, treated with KISQALI FEMARA CO-PACK should be treated with a luteinizing hormone-releasing hormone (LHRH) agonist according to current clinical practice standards. Patients should take their doses of KISQALI FEMARA CO-PACK 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. Tablets should be swallowed whole (tablets should not be chewed, crushed or split prior to swallowing). No tablet should be ingested if it is broken, cracked, or otherwise not intact. Early Breast Cancer KISQALI: The recommended dosage of KISQALI is 400 mg (two 200 mg film-coated tablets) taken orally, once daily for 21 consecutive days followed by 7 days off in 28-day treatment cycles. FEMARA: 2.5 mg (one tablet) taken once daily throughout the 28-day cycle. In patients with early breast cancer, treatment with KISQALI should continue for 3 years or until disease recurrence or unacceptable toxicity occurs. Advanced or Metastatic Breast Cancer KISQALI: The recommended dosage for KISQALI is 600 mg (three 200 mg film-coated tablets) taken orally, once daily for 21 consecutive days followed by 7 days off in 28-day treatment cycles. FEMARA: 2.5 mg (one tablet) taken once daily throughout the 28-day cycle. Refer to the Full Prescribing Information for the recommended dosage for each product

Dose Modifications Dose Modifications for Adverse Reactions The recommended dose modifications of KISQALI for adverse reactions are listed in Table 1. Dose modifications are not recommended for FEMARA when administered with KISQALI for the adverse reactions of KISQALI, including neutropenia, hepatobiliary toxicity, or QT prolongation . Table 1: Recommended Dose Modification of KISQALI FEMARA CO-PACK for Adverse Reactions Level KISQALI FEMARA Dose Number of tablets Dose Number of tablets Early breast cancer Starting dose 400 mg/day two 200 mg tablets 2.5 mg/day one 2.5 mg tablet Dose reduction 200 mg/day * one 200 mg tablet 2.5 mg/day one 2.5 mg tablet Advanced or metastatic breast cancer Starting dose 600 mg/day three 200 mg tablets 2.5 mg/day one 2.5 mg tablet First dose reduction 400 mg/day two 200 mg tablets 2.5 mg/day one 2.5 mg tablet Second dose reduction 200 mg/day* one 200 mg tablet 2.5 mg/day one 2.5 mg tablet *If dose reduction below 200 mg/day is required, discontinue KISQALI. Tables 2, 3, 4, 5, 6, and 7 summarize recommendations for dose interruption, reduction, or discontinuation of KISQALI in the management of specific adverse reactions. Dose modification of KISQALI FEMARA CO-PACK is recommended based on individual patient safety and tolerability. Table 2: Dose Modification and Management for Interstitial Lung Disease/Pneumonitis Grade 1 (asymptomatic) Grade 2 (symptomatic) Grade 3 (severe symptomatic) or 4 (life-threatening) ILD/Pneumonitis 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 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 of KISQALI for QT Prolongation QTcF* prolongation Early breast cancer Advanced or metastatic breast cancer > 480 ms and ≤ 500 ms Interrupt KISQALI treatment and wait until QTcF resolves to ≤ 480 ms Resume at the same dose Reduce to the next lower dose level If QTcF > 480 ms recurs, interrupt KISQALI treatment and wait until QTcF resolves to ≤ 480 ms, then resume at next lower dose level. > 500 ms Interrupt KISQALI treatment and wait until QTcF resolves to ≤ 480 ms, then resume at next lower dose level. If QTcF > 500 ms recurs, discontinue KISQALI. Permanently discontinue KISQALI if QTcF interval prolongation is either > 500 ms or > 60 ms change from baseline AND associated with any of the following: Torsades de Pointes, polymorphic ventricular tachycardia, syncope, or signs/symptoms of serious arrhythmia. Note: If dose reduction below 200 mg/day is required, discontinue KISQALI. Electrocardiograms (ECGs) should be assessed prior to initiation of treatment in all patients. Repeat ECGs at approximately Day 14 of the first cycle, and as clinically indicated. In case of QTcF prolongation at any given time during treatment, monitor ECG more frequently, and as clinically indicated. * QTcF = QT interval corrected by Fridericia’s formula. Table 5: Dose Modification and Management of KISQALI 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 No dose adjustment is required. Baseline* at < Grade 2: Dose interruption until recovery to ≤ baseline grade, and 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, and 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 If patients develop ALT and/or AST > 3 x ULN along with total bilirubin > 2 x ULN irrespective of baseline grade, discontinue KISQALI. Perform Liver Function Tests (LFTs) before initiating treatment with KISQALI. Monitor LFTs every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated. If Grade ≥ 2 abnormalities are noted, monitor more frequently, and as clinically indicated. Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; ULN, upper limit of normal. *Baseline = prior to treatment initiation. Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Table 6: Dose Modification and Management of KISQALI 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 No dose adjustment is required. Dose interruption until recovery to Grade ≤ 2. Resume KISQALI at the same dose level. If toxicity recurs at Grade 3, dose interruption until recovery, then resume KISQALI at the next lower dose level. Dose interruption until recovery of neutropenia to Grade ≤ 2. Resume KISQALI at the next lower dose level. Dose interruption until recovery to Grade ≤ 2. Resume KISQALI at the next lower dose level. Perform complete blood counts (CBCs) before initiating treatment with KISQALI. Monitor CBC every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated. Abbreviations: ANC, absolute neutrophil count; LLN, lower limit of normal. *Grade 3 neutropenia with single episode of fever > 38.3°C (or) 38°C or above for more than one hour and/or concurrent infection. Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Table 7: Dose Modification and Management of KISQALI 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 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 FEMARA CO-PACK with strong CYP3A inhibitors and consider an alternative concomitant medication with less potential for CYP3A inhibition . If a strong CYP3A inhibitor must be coadministered, reduce the KISQALI dose as shown in Table 8 Table 8: Dose Modification for Use with Strong CYP3A Inhibitors Indication Co-administration with Strong CYP3A Inhibitors Early breast cancer Reduce the KISQALI dose to 200 mg once daily. Advanced or metastatic breast cancer Reduce the KISQALI dose to 400 mg once daily. If the strong inhibitor is discontinued, change the KISQALI dose (after at least 5 half-lives of the strong CYP3A inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor . Dose Modification for Hepatic Impairment The recommended dose modifications for patients with hepatic impairment are shown in Table 9 . Table 9: Dose Modification for Hepatic Impairment Indication Mild hepatic impairment (Child-Pugh class A) Moderate and severe hepatic impairment (Child-Pugh class B or C) Early breast cancer No dose adjustment is necessary No dose adjustment is necessary Advanced or metastatic breast cancer No dose adjustment is necessary KISQALI 400 mg once daily The dose of FEMARA in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50% . The recommended dose of FEMARA for such patients is 2.5 mg administered every other day. The effect of hepatic impairment on FEMARA exposure in noncirrhotic cancer patients with elevated bilirubin levels has not been determined . Review the Full Prescribing Information for the coadministered aromatase inhibitor or fulvestrant for dose modifications related to hepatic impairment. Dose Modification for Renal Impairment The recommended starting dose is 200 mg KISQALI once daily for patients with severe renal impairment . No dosage adjustment of FEMARA is required for patients with renal impairment if creatinine clearance is greater than or equal to 10 mL/min .

Interstitial Lung Disease (ILD)/Pneumonitis: Patients treated with CDK 4/6 inhibitors should be monitored 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. Severe Cutaneous Adverse Reactions (SCARs): 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. QT Interval Prolongation: 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 ) Hepatobiliary Toxicity: Increases in serum transaminase and bilirubin levels have been observed. Perform liver function tests (LFTs) before initiating treatment with KISQALI FEMARA CO-PACK. Monitor LFTs every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated. ( 2.2, 5.4 ) Neutropenia: Perform complete blood count (CBC) before initiating therapy with KISQALI FEMARA CO-PACK. Monitor CBC every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated. ( 2.2, 5.5 ) Embryo-Fetal Toxicity: Can cause fetal harm when administered to pregnant women. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during therapy. ( 5.6 , 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 CDK4/6 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-7), 1.2% of KISQALI-treated patients had ILD/pneumonitis (any grade, 0.3% had Grade 3-4). Additional cases of ILD/pneumonitis have occurred in the postmarketing setting, some resulting in death . 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 . Refer to the Full Prescribing Information for KISQALI ®

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 . If signs or symptoms of SCARs occur, interrupt KISQALI until the etiology of the reaction has been determined . 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 during KISQALI treatment

QT Interval Prolongation KISQALI has been shown to prolong the QT interval in a concentration-dependent manner . 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 . 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 and MONALEESA-7) who received 600 mg KISQALI plus NSAI, 7 out of 574 patients (1%) had a > 500 ms post-baseline QTcF value, and 29 out of 574 patients (5%) 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 . Perform ECG in all patients prior to starting KISQALI FEMARA CO-PACK. Initiate treatment with KISQALI FEMARA CO-PACK 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 FEMARA CO-PACK, at the beginning of the first 6 cycles, and as clinically indicated. Correct any abnormality before starting KISQALI FEMARA CO-PACK

Hepatobiliary Toxicity In patients with early and advanced or metastatic breast cancer, drug-induced liver injury and increases in transaminases occurred with KISQALI. In patients with early breast cancer (NATALEE) treated with KISQALI, drug-induced liver injury was reported in 9 patients (0.4%), of which 5 were Grade ≥ 3, and 8 had resolved as of the data cutoff. There were 8 (0.3%) clinically confirmed Hy’s Law cases (including 4 out of 9 drug-induced liver injury mentioned above), 6 of which had resolved within 303 days and 2 of which were improving, all after discontinuation of KISQALI. Grade 3 or 4 increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) occurred in 8% and 4.7% respectively; including Grade 4 increases in ALT (1.5%) and AST (0.8%). In patients with advanced or metastatic breast cancer (MONALEESA-2 and MONALEESA-7), treated with KISQALI Grade 3 or 4 increases in ALT and AST occurred in 11% and 8%, respectively. Among the patients who had Grade ≥ 3 ALT/AST elevation, the median time-to-onset was 111 days for the KISQALI plus aromatase inhibitor treatment arm. The median time to resolution to Grade ≤ 2 was 22 days in the KISQALI plus aromatase inhibitor treatment arm. In MONALEESA-2, concurrent elevations in ALT or AST greater than three times the ULN and total bilirubin greater than two times the ULN, with normal alkaline phosphatase, in the absence of cholestasis (Hy’s Law) occurred in 4 (1%) patients and all patients recovered after discontinuation of KISQALI. Perform liver function tests (LFTs) in all patients before initiating KISQALI FEMARA CO-PACK. Monitor LFTs every 2 weeks for first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated . Based on the severity of the transaminase elevations, KISQALI may require dose interruption, reduction, or discontinuation as described in Table 5 (Dose Modification and Management for Hepatobiliary Toxicity)

Neutropenia KISQALI causes concentration-dependent neutropenia. In patients with early breast cancer (NATALEE) who received KISQALI plus NSAI, 94%, including 45% of Grade 3 or 4, had a decrease in neutrophil counts (based on laboratory findings), 63% had an adverse reaction of neutropenia, and 0.3% had febrile neutropenia. The median time to Grade ≥ 2 neutropenia was 18 days. The median time to resolution of Grade ≥ 3 neutropenia to Grade < 3 was 10 days. Treatment discontinuation due to neutropenia was required in 1.1% of patients. In patients with advanced or metastatic breast cancer (MONALEESA-2 and MONALEESA-7), who received KISQALI plus NSAI, 79% had neutropenia, 66% had Grade 3 or 4 decrease in neutrophil count (based on laboratory findings), and 2% had febrile neutropenia. The median time to Grade ≥ 2 neutropenia was 16 days. The median time to resolution of Grade ≥ 3 neutropenia to Grade < 3 was 15 days. Treatment discontinuation due to neutropenia was required in 1% of patients. Perform a complete blood count (CBC) in all patients before initiating KISQALI FEMARA CO-PACK. Monitor CBC every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated. Based on the severity of the neutropenia, KISQALI may require dose interruption, reduction or discontinuation as described in Table 6

Embryo-Fetal Toxicity Based on findings from animal studies and the mechanism of action, KISQALI FEMARA CO-PACK can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of ribociclib to pregnant rats and rabbits during organogenesis caused embryo-fetal toxicities at maternal exposures that were 0.6 and 1.5 times the human clinical exposure, respectively, based on area under the curve (AUC). Letrozole caused embryo-fetal toxicities in rats and rabbits at maternal exposures that were below the maximum recommended human dose (MRHD) on a mg/m 2 basis. Advise pregnant women of the potential risk to a fetus. Advise women of reproductive potential to use effective contraception during therapy with KISQALI FEMARA CO-PACK and for at least 3 weeks after the last dose .

Ribociclib CYP3A4 Inhibitors: Avoid concomitant use of KISQALI FEMARA CO-PACK with strong CYP3A inhibitors. If strong inhibitors cannot be avoided, reduce KISQALI dose. ( 2.2, 7.1 ) CYP3A4 Inducers: Avoid concomitant use of KISQALI FEMARA CO-PACK with strong CYP3A inducers. CYP3A Substrates: The dose of CYP3A substrates with narrow therapeutic indices may need to be reduced when given concurrently with KISQALI FEMARA CO-PACK. Drugs Known to Prolong QT Interval: Avoid concomitant use of drugs known to prolong QT interval, such as anti-arrhythmic medicines

Drugs That May Increase Ribociclib Plasma Concentrations CYP3A4 Inhibitors Coadministration of a strong CYP3A4 inhibitors increases ribociclib exposure . Increased ribociclib concentrations may increase the incidence and severity of adverse reactions, including QTcF prolongation . 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

Drugs That May Decrease Ribociclib Plasma Concentrations CYP3A4 Inducers Coadministration of a strong CYP3A4 inducers decreases the plasma exposure of ribociclib . Avoid concomitant use of strong CYP3A inducers and consider an alternate concomitant medication with no or minimal potential to induce CYP3A

Effect of KISQALI on Other Drugs CYP3A Substrates Coadministration of sensitive CYP3A4 substrates with multiple doses of KISQALI increases the substrate exposure . 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 a sensitive CYP3A substrate may need to be reduced as KISQALI can increase its exposure

Drugs That Prolong the QT Interval Avoid coadministration of KISQALI with products with a known potential to prolong QT interval, such as antiarrhythmic 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 .