POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of VERZENIO. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Respiratory disorders: Interstitial lung disease (ILD)/pneumonitis [see Warnings and Precautions (5.3)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. 50 mg tablets: oval beige tablet with Lilly debossed on one side and 50 on the other side.100 mg tablets: oval white to practically white tablet with Lilly debossed on one side and 100 on the other side.150 mg tablets: oval yellow tablet with Lilly debossed on one side and 150 on the other side.200 mg tablets: oval beige tablet with Lilly debossed on one side and 200 on the other side.. Tablets: 50 mg, 100 mg, 150 mg, and 200 mg. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. CYP3A Inhibitors: Avoid concomitant use of ketoconazole. Reduce the VERZENIO dose with concomitant use of other strong and moderate CYP3A inhibitors. (2.3, 7.1) CYP3A Inducers: Avoid concomitant use of strong and moderate CYP3A inducers. (7.1). CYP3A Inhibitors: Avoid concomitant use of ketoconazole. Reduce the VERZENIO dose with concomitant use of other strong and moderate CYP3A inhibitors. (2.3, 7.1). CYP3A Inducers: Avoid concomitant use of strong and moderate CYP3A inducers. (7.1). 7.1 Effect of Other Drugs on VERZENIO. CYP3A InhibitorsStrong and moderate CYP3A4 inhibitors increased the exposure of abemaciclib plus its active metabolites to clinically meaningful extent and may lead to increased toxicity.. KetoconazoleAvoid concomitant use of ketoconazole. Ketoconazole is predicted to increase the AUC of abemaciclib by up to 16-fold [see Clinical Pharmacology (12.3)].. Other Strong CYP3A InhibitorsIn patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the VERZENIO dose to 100 mg twice daily with concomitant use of strong CYP3A inhibitors other than ketoconazole. In patients who have had dose reduction to 100 mg twice daily due to adverse reactions, further reduce the VERZENIO dose to 50 mg twice daily with concomitant use of strong CYP3A inhibitors. If patient taking VERZENIO discontinues strong CYP3A inhibitor, increase the VERZENIO dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the inhibitor. Patients should avoid grapefruit products [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].. Moderate CYP3A InhibitorsWith concomitant use of moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the VERZENIO dose in 50 mg decrements as demonstrated in Table 1, if necessary.. Strong and Moderate CYP3A InducersCoadministration of strong or moderate CYP3A inducers decreased the plasma concentrations of abemaciclib plus its active metabolites and may lead to reduced activity. Avoid concomitant use of strong or moderate CYP3A inducers and consider alternative agents [see Clinical Pharmacology (12.3)].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in greater detail in other sections of the labeling:Diarrhea [see Warnings and Precautions (5.1)].Neutropenia [see Warnings and Precautions (5.2)].Interstitial Lung Disease (ILD) or Pneumonitis [see Warnings and Precautions (5.3)].Hepatotoxicity [see Warnings and Precautions (5.4)].Venous Thromboembolism [see Warnings and Precautions (5.5)].. Diarrhea [see Warnings and Precautions (5.1)].. Neutropenia [see Warnings and Precautions (5.2)].. Interstitial Lung Disease (ILD) or Pneumonitis [see Warnings and Precautions (5.3)].. Hepatotoxicity [see Warnings and Precautions (5.4)].. Venous Thromboembolism [see Warnings and Precautions (5.5)].. Most common adverse reactions (incidence >=20%) were diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, and thrombocytopenia. (6)To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Studies Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety population described in the Warnings and Precautions reflect exposure to VERZENIO in 3691 patients from four clinical trials: monarchE, MONARCH 1, MONARCH 2, and MONARCH 3. The safety population includes exposure to VERZENIO as single agent at 200 mg twice daily in 132 patients in MONARCH and to VERZENIO at 150 mg twice daily in 3559 patients administered in combination with fulvestrant, tamoxifen, or an aromatase inhibitor in monarchE, MONARCH 2, and MONARCH 3. The median duration of exposure ranged from 4.5 months in MONARCH to 24 months in monarchE. The most common adverse reactions (incidence >=20%) across clinical trials were: diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, and thrombocytopenia.. Early Breast Cancer. monarchE: VERZENIO in Combination with Tamoxifen or an Aromatase Inhibitor as Adjuvant Treatment. Adult patients with HR-positive, HER2-negative, node-positive early breast cancer at high risk of recurrenceThe safety of VERZENIO was evaluated in monarchE, study of 5591 adult patients receiving VERZENIO plus endocrine therapy (tamoxifen or an aromatase inhibitor) or endocrine therapy (tamoxifen or an aromatase inhibitor) alone [see Clinical Studies (14.1)]. Patients were randomly assigned to receive 150 mg of VERZENIO orally, twice daily, plus tamoxifen or an aromatase inhibitor, or tamoxifen or an aromatase inhibitor, for two years or until discontinuation criteria were met. The median duration of VERZENIO treatment was 24 months.The most frequently reported (>=5%) Grade or adverse reactions were neutropenia, leukopenia, diarrhea, and lymphopenia.Fatal adverse reactions occurred in 0.8% of patients who received VERZENIO plus endocrine therapy (tamoxifen or an aromatase inhibitor), including: cardiac failure (0.1%), cardiac arrest, myocardial infarction, ventricular fibrillation, cerebral hemorrhage, cerebrovascular accident, pneumonitis, hypoxia, diarrhea and mesenteric artery thrombosis (0.03% each).Permanent VERZENIO treatment discontinuation due to an adverse reaction was reported in 19% of patients receiving VERZENIO, plus tamoxifen or an aromatase inhibitor. Of the patients receiving tamoxifen or an aromatase inhibitor, 1% permanently discontinued due to an adverse reaction. The most common adverse reactions leading to VERZENIO discontinuations were diarrhea (5%), fatigue (2%), and neutropenia (0.9%).Dose interruption of VERZENIO due to an adverse reaction occurred in 62% of patients receiving VERZENIO plus tamoxifen or aromatase inhibitors. Adverse reactions leading to VERZENIO dose interruptions in >=5% of patients were diarrhea (20%), neutropenia (16%), leukopenia (7%), and fatigue (5%).Dose reductions of VERZENIO due to an adverse reaction occurred in 44% of patients receiving VERZENIO plus endocrine therapy (tamoxifen or an aromatase inhibitor). Adverse reactions leading to VERZENIO dose reductions in >=5% were diarrhea (17%), neutropenia (8%), and fatigue (5%).The most common adverse reactions reported (>=20%) in the VERZENIO, plus tamoxifen or an aromatase inhibitor, arm and >=2% higher than the tamoxifen or an aromatase inhibitor arm were: diarrhea, infections, neutropenia, fatigue, leukopenia, nausea, anemia, and headache. Adverse reactions are shown in Table and laboratory abnormalities are shown in Table 9.Table 8: Adverse Reactions (>=10%) of Patients Receiving VERZENIO Plus Tamoxifen or an Aromatase Inhibitor [with Difference between Arms of >=2%] in monarchEa Includes the following fatal adverse reactions: diarrhea (n=1), and infections (n=4)b Includes the following fatal adverse reactions: infections (n=5)c Includes mouth ulceration, mucosal inflammation, oropharyngeal pain, stomatitis.d Includes all reported preferred terms that are part of the Infections and Infestations system organ class. Most common infections (>5%) include upper respiratory tract infection, urinary tract infection, and nasopharyngitis.e Includes asthenia, fatigue.f Includes exfoliative rash, mucocutaneous rash, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash maculovesicular, rash morbilliform, rash papular, rash papulosquamous, rash pruritic, rash vesicular, vulvovaginal rash.VERZENIO PlusTamoxifen or an Aromatase InhibitorN=2791Tamoxifen or an Aromatase InhibitorN=2800All Gradesa%Grade 3%Grade 4%All Gradesb%Grade 3%Grade 4%Gastrointestinal Disorders Diarrhea848090.20 Nausea300.509<0.10 Vomiting180.504.60.10 Stomatitisc 140.10500Infections and Infestations Infectionsd 514.90.6392.70.1General Disorders and Administration Site Conditions Fatiguee 412.90180.10Nervous System Disorders Headache200.30150.20 Dizziness110.107<0.10Metabolism and Nutrition Disorders Decreased appetite120.602.4<0.10Skin and Subcutaneous Tissue Disorders Rashf 110.404.500 Alopecia11002.700Clinically relevant adverse reactions in <10% of patients who received VERZENIO in combination with tamoxifen or an aromatase inhibitor in monarchE include:Pruritus-9%Dyspepsia-8%Nail disorder-6% (includes nail bed disorder, nail bed inflammation, nail discoloration, nail disorder, nail dystrophy, nail pigmentation, nail ridging, nail toxicity, onychalgia, onychoclasis, onycholysis, onychomadesis)Lacrimation increased-6%Dysgeusia-5%Interstitial lung disease (ILD)/pneumonitis-3% (includes pneumonitis, radiation pneumonitis, interstitial lung disease, pulmonary fibrosis, organizing pneumonia, radiation fibrosis lung, lung opacity, sarcoidosis)Venous thromboembolic events (VTEs)-3% (includes catheter site thrombosis, cerebral venous thrombosis, deep vein thrombosis, device related thrombosis, embolism, hepatic vein thrombosis, jugular vein occlusion, jugular vein thrombosis, ovarian vein thrombosis, portal vein thrombosis, pulmonary embolism, subclavian vein thrombosis, venous thrombosis limb)Table 9: Laboratory Abnormalities (>=10%) in Patients Receiving VERZENIO Plus Tamoxifen or an Aromatase Inhibitor [with Difference between Arms of >=2%] in monarchEVERZENIOPlus Tamoxifen or an Aromatase InhibitorN=2791Tamoxifen or an Aromatase InhibitorN=2800All Grades%Grade 3%Grade 4%All Grades%Grade 3%Grade 4%Creatinine increased990.5091<0.10White blood cell decreased8919<0.1281.10Neutrophil count decreased84180.7231.60.3Anemia681.00170.10Lymphocyte count decreased59130.2242.40.1Platelet count decreased370.70.2100.10.1Alanine aminotransferase increased372.5<0.1241.20Aspartate aminotransferase increased311.5<0.1180.90Hypokalemia111.20.13.80.10.1. Pruritus-9%. Dyspepsia-8%. Nail disorder-6% (includes nail bed disorder, nail bed inflammation, nail discoloration, nail disorder, nail dystrophy, nail pigmentation, nail ridging, nail toxicity, onychalgia, onychoclasis, onycholysis, onychomadesis). Lacrimation increased-6%. Dysgeusia-5%. Interstitial lung disease (ILD)/pneumonitis-3% (includes pneumonitis, radiation pneumonitis, interstitial lung disease, pulmonary fibrosis, organizing pneumonia, radiation fibrosis lung, lung opacity, sarcoidosis). Venous thromboembolic events (VTEs)-3% (includes catheter site thrombosis, cerebral venous thrombosis, deep vein thrombosis, device related thrombosis, embolism, hepatic vein thrombosis, jugular vein occlusion, jugular vein thrombosis, ovarian vein thrombosis, portal vein thrombosis, pulmonary embolism, subclavian vein thrombosis, venous thrombosis limb). Advanced or Metastatic Breast Cancer. MONARCH 3: VERZENIO in Combination with an Aromatase Inhibitor (Anastrozole or Letrozole) as Initial Endocrine-Based Therapy. Postmenopausal Women with HR-positive, HER2-negative locoregionally recurrent or metastatic breast cancer with no prior systemic therapy in this disease settingThe safety of VERZENIO was evaluated in MONARCH 3, study of 488 women receiving VERZENIO plus an aromatase inhibitor or placebo plus an aromatase inhibitor [see Clinical Studies (14.2)]. Patients were randomly assigned to receive 150 mg of VERZENIO or placebo orally twice daily, plus physicians choice of anastrozole or letrozole once daily. Median duration of treatment was 15.1 months for the VERZENIO arm and 13.9 months for the placebo arm.The most frequently reported (>=5%) Grade or adverse reactions were neutropenia, diarrhea, leukopenia, increased ALT, and anemia.Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 11 cases (3%) of VERZENIO plus an aromatase inhibitor treated patients versus cases (2%) of placebo plus an aromatase inhibitor treated patients. Causes of death for patients receiving VERZENIO plus an aromatase inhibitor included: (0.9%) patient deaths due to underlying disease, (0.9%) due to lung infection, (0.9%) due to VTE, (0.3%) due to pneumonitis, and (0.3%) due to cerebral infarction.Permanent treatment discontinuation due to an adverse reaction was reported in 13% of patients receiving VERZENIO plus an aromatase inhibitor and in 3% of patients receiving placebo plus an aromatase inhibitor. Adverse reactions leading to permanent discontinuation for patients receiving VERZENIO plus an aromatase inhibitor were diarrhea (2%), ALT increased (2%), infection (1%), venous thromboembolic events (VTE) (1%), neutropenia (0.9%), renal impairment (0.9%), AST increased (0.6%), dyspnea (0.6%), pulmonary fibrosis (0.6%) and anemia, rash, weight decreased and thrombocytopenia (each 0.3%).Dose interruption of VERZENIO due to an adverse reaction occurred in 56% of patients receiving VERZENIO plus anastrazole or letrozole. Adverse reactions leading to VERZENIO dose interruptions in >=5% of patients were neutropenia (16%) and diarrhea (15%).Dose reductions due to an adverse reaction occurred in 43% of patients receiving VERZENIO plus anastrozole or letrozole. Adverse reactions leading to dose reductions in >=5% of patients were diarrhea and neutropenia. VERZENIO dose reductions due to diarrhea of any grade occurred in 13% of patients receiving VERZENIO plus an aromatase inhibitor compared to 2% of patients receiving placebo plus an aromatase inhibitor. VERZENIO dose reductions due to neutropenia of any grade occurred in 11% of patients receiving VERZENIO plus an aromatase inhibitor compared to 0.6% of patients receiving placebo plus an aromatase inhibitor.The most common adverse reactions reported (>=20%) in the VERZENIO arm and >=2% than the placebo arm were: diarrhea, neutropenia, fatigue, infections, nausea, abdominal pain, anemia, vomiting, alopecia, decreased appetite, and leukopenia. Adverse reactions are shown in Table 10 and laboratory abnormalities in Table 11. Diarrhea incidence was greatest during the first month of VERZENIO dosing. The median time to onset of the first diarrhea event was days, and the median durations of diarrhea for Grades and for Grade were 11 days and days, respectively. Most diarrhea events recovered or resolved (88%) with supportive treatment and/or dose reductions [see Dosage and Administration (2.3) and Patient Counseling Information (17)]. Nineteen percent of patients with diarrhea required dose omission and 13% required dose reduction. The median time to the first dose reduction due to diarrhea was 38 days.Table 10: Adverse Reactions (>=10%) in Patients Receiving VERZENIO Plus Anastrozole or Letrozole [with Difference between Arms of >=2%] in MONARCH 3a Includes all reported preferred terms that are part of the Infections and Infestations system organ class. Most common infections (>1%) include upper respiratory tract infection, lung infection, and pharyngitis.VERZENIO plusAnastrozole or LetrozoleN=327Placebo plusAnastrozole or LetrozoleN=161All Grades%Grade 3%Grade 4%All Grades%Grade 3%Grade 4%Gastrointestinal Disorders Diarrhea8190301.20 Nausea390.90201.20 Abdominal pain291.20121.20 Vomiting281.20121.90 Constipation160.601200Infections and Infestations Infectionsa 394.00.9292.50.6General Disorders and Administration Site Conditions Fatigue401.803200 Influenza like illness1000800Skin and Subcutaneous Tissue Disorders Alopecia27001100 Rash140.90500 Pruritus1300900Metabolism and Nutrition Disorders Decreased appetite241.2090.60Investigations Weight decreased100.603.10.60Respiratory, Thoracic, and Mediastinal Disorders Cough1300900 Dyspnea120.60.360.60Nervous System Disorders Dizziness110.30900Additional adverse reactions in MONARCH include venous thromboembolic events (deep vein thrombosis, pulmonary embolism, and pelvic venous thrombosis), which were reported in 5% of patients treated with VERZENIO plus anastrozole or letrozole as compared to 0.6% of patients treated with anastrozole or letrozole plus placebo.Table 11: Laboratory Abnormalities (>=10%) in Patients Receiving VERZENIO Plus Anastrozole or Letrozole [with Difference Between Arms of >=2%] in MONARCH 3VERZENIO plusAnastrozole or LetrozoleN=327Placebo plusAnastrozole or LetrozoleN=161Laboratory AbnormalityAll Grades%Grade 3%Grade 4%All Grades%Grade 3%Grade 4%Creatinine increased982.208400White blood cell decreased82130270.60Anemia821.602800Neutrophil count decreased80192.9212.60Lymphocyte count decreased5370.6261.90Platelet count decreased361.30.6120.60Alanine aminotransferase increased4860.6251.90Aspartate aminotransferase increased373.80230.60. Creatinine IncreasedAbemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function [see Clinical Pharmacology (12.3)]. Across the clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of VERZENIO dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated GFR, which are not based on creatinine, may be considered to determine whether renal function is impaired.. MONARCH 2: VERZENIO in Combination with Fulvestrant. Women with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression on or after prior adjuvant or metastatic endocrine therapyThe safety of VERZENIO (150 mg twice daily) plus fulvestrant (500 mg) versus placebo plus fulvestrant was evaluated in MONARCH [see Clinical Studies (14.2)]. The data described below reflect exposure to VERZENIO in 441 patients with HR-positive, HER2-negative advanced breast cancer who received at least one dose of VERZENIO plus fulvestrant in MONARCH 2.Median duration of treatment was 12 months for patients receiving VERZENIO plus fulvestrant and months for patients receiving placebo plus fulvestrant.The most frequently reported (>=5%) Grade or adverse reactions were neutropenia, diarrhea, leukopenia, anemia, and infections.Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 18 cases (4%) of VERZENIO plus fulvestrant treated patients versus 10 cases (5%) of placebo plus fulvestrant treated patients. Causes of death for patients receiving VERZENIO plus fulvestrant included: (2%) patient deaths due to underlying disease, (0.9%) due to sepsis, (0.5%) due to pneumonitis, (0.5%) due to hepatotoxicity, and one (0.2%) due to cerebral infarction.Permanent study treatment discontinuation due to an adverse reaction were reported in 9% of patients receiving VERZENIO plus fulvestrant and in 3% of patients receiving placebo plus fulvestrant. Adverse reactions leading to permanent discontinuation for patients receiving VERZENIO plus fulvestrant were infection (2%), diarrhea (1%), hepatotoxicity (1%), fatigue (0.7%), nausea (0.2%), abdominal pain (0.2%), acute kidney injury (0.2%), and cerebral infarction (0.2%).Dose interruption of VERZENIO due to an adverse reaction occurred in 52% of patients receiving VERZENIO plus fulvestrant. Adverse reactions leading to VERZENIO dose interruptions in >=5% of patients were diarrhea (19%) and neutropenia (16%).Dose reductions due to an adverse reaction occurred in 43% of patients receiving VERZENIO plus fulvestrant. Adverse reactions leading to reductions in >=5% of patients were diarrhea and neutropenia. VERZENIO dose reductions due to diarrhea of any grade occurred in 19% of patients receiving VERZENIO plus fulvestrant compared to 0.4% of patients receiving placebo and fulvestrant. VERZENIO dose reductions due to neutropenia of any grade occurred in 10% of patients receiving VERZENIO plus fulvestrant compared to no patients receiving placebo plus fulvestrant.The most common adverse reactions reported (>=20%) in the VERZENIO arm were: diarrhea, fatigue, neutropenia, nausea, infections, abdominal pain, anemia, leukopenia, decreased appetite, vomiting, and headache. Adverse reactions are shown in Table 12 and laboratory abnormalities in Table 13.Table 12: Adverse Reactions (>=10%) in Patients Receiving VERZENIO Plus Fulvestrant [with Difference Between Arms of >=2%] in MONARCH 2a Includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, abdominal tenderness.b Includes upper respiratory tract infection, urinary tract infection, lung infection, pharyngitis, conjunctivitis, sinusitis, vaginal infection, sepsis.c Includes asthenia, fatigue.VERZENIO plus FulvestrantN=441Placebo plus FulvestrantN=223All Grades%Grade 3%Grade 4%All Grades%Grade 3%Grade 4%Gastrointestinal Disorders Diarrhea86130250.40 Nausea452.70230.90 Abdominal paina 352.50160.90 Vomiting260.90101.80 Stomatitis150.501000Infections and Infestations Infectionsb 4350.7253.10.4General Disorders and Administration Site Conditions Fatiguec 462.70320.40 Edema peripheral1200700 Pyrexia110.50.260.40Metabolism and Nutrition Disorders Decreased appetite271.10120.40Respiratory, Thoracic and Mediastinal Disorders Cough13001100Skin and Subcutaneous Tissue Disorders Alopecia16001.800 Pruritus1300600 Rash111.104.500Nervous System Disorders Headache200.70150.40 Dysgeusia18002.700 Dizziness120.70600Investigations Weight decreased100.202.20.40Additional adverse reactions in MONARCH include venous thromboembolic events (deep vein thrombosis, pulmonary embolism, cerebral venous sinus thrombosis, subclavian vein thrombosis, axillary vein thrombosis, and DVT inferior vena cava), which were reported in 5% of patients treated with VERZENIO plus fulvestrant as compared to 0.9% of patients treated with fulvestrant plus placebo.Table 13: Laboratory Abnormalities (>=10%) in Patients Receiving VERZENIO Plus Fulvestrant [with Difference Between Arms of >=2%]in MONARCH 2VERZENIO plus FulvestrantN=441Placebo plus FulvestrantN=223All Grades%Grade 3%Grade 4%All Grades%Grade 3%Grade 4%Creatinine increased981.207400White blood cell decreased90230.7330.90Neutrophil count decreased87293.5303.70.5Anemia842.60340.50Lymphocyte count decreased63120.2321.80Platelet count decreased530.91.21500Alanine aminotransferase increased413.90.7321.40Aspartate aminotransferase increased373.90253.70.5. Creatinine IncreasedAbemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function [see Clinical Pharmacology (12.3)]. In clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of VERZENIO dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated glomerular filtration rate (GFR), which are not based on creatinine, may be considered to determine whether renal function is impaired.. MONARCH 1: VERZENIO Administered as Monotherapy in Metastatic Breast Cancer. Patients with HR-positive, HER2-negative breast cancer who received prior endocrine therapy and 1-2 chemotherapy regimens in the metastatic settingThe safety of VERZENIO was evaluated in MONARCH 1, single-arm, open-label, multicenter study in 132 women with measurable HR-positive, HER2-negative metastatic breast cancer [see Clinical Studies (14.2)].. Patients received 200 mg VERZENIO orally twice daily until development of progressive disease or unmanageable toxicity. Median duration of treatment was 4.5 months.The most frequently reported (>=5%) Grade or adverse reactions were diarrhea, neutropenia, fatigue, and leukopenia.Deaths due to adverse reactions during treatment or during the 30-day follow up were reported in 2% of patients. Cause of death in these patients was due to infection (2 patients) or pneumonitis (1 patient).Ten patients (8%) discontinued study treatment from adverse reactions due to (1 patient each), abdominal pain, arterial thrombosis, aspartate aminotransferase (AST) increased, blood creatinine increased, chronic kidney disease, diarrhea, ECG QT prolonged, fatigue, hip fracture, and lymphopenia.Dose interruption of VERZENIO due to an adverse reaction occurred in 58% of patients. The most frequent (>=5%) adverse reactions leading to dose interruptions were diarrhea (24%), neutropenia (16%), fatigue (10%), vomiting (6%), and nausea (5%).Forty-nine percent of patients had dose reductions due to an adverse reaction. The most frequent adverse reactions that led to dose reductions were diarrhea (20%), neutropenia (11%), and fatigue (9%).The most common reported adverse reactions (>=20%) were: diarrhea, fatigue, nausea, decreased appetite, abdominal pain, neutropenia, vomiting, infections, anemia, headache, and thrombocytopenia. Adverse reactions are shown in Table 14 and laboratory abnormalities in Table 15.Table 14: Adverse Reactions (>=10%) of Patients in MONARCH 1a Includes asthenia, fatigue.VERZENION=132All Grades%Grade 3%Grade 4%Gastrointestinal Disorders Diarrhea90200 Nausea644.50 Abdominal pain392.30 Vomiting351.50 Constipation170.80 Dry mouth1400 Stomatitis1400Infections and Infestations Infections314.50General Disorders and Administration Site Conditions Fatiguea 65130 Pyrexia1100Metabolism and Nutrition Disorders Decreased appetite453.00 Dehydration102.30Respiratory, Thoracic and Mediastinal Disorders Cough1900Musculoskeletal and Connective Tissue Disorders Arthralgia1500Nervous System Disorders Headache2000 Dysgeusia1200 Dizziness1100Skin and Subcutaneous Tissue Disorders Alopecia1200Investigations Weight decreased1400Table 15: Laboratory Abnormalities for Patients Receiving VERZENIO in MONARCH 1VERZENION=132All Grades%Grade 3%Grade 4%Creatinine increased990.80White blood cell decreased91280Neutrophil count decreased88224.6Anemia6900Lymphocyte count decreased42130.8Platelet count decreased412.30ALT increased313.10AST increased303.80. Creatinine IncreasedAbemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function [see Clinical Pharmacology (12.3)]. In clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of VERZENIO dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated GFR, which are not based on creatinine, may be considered to determine whether renal function is impaired.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of VERZENIO. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Respiratory disorders: Interstitial lung disease (ILD)/pneumonitis [see Warnings and Precautions (5.3)].

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. In repeat-dose toxicity studies up to 6-months duration, oral administration of abemaciclib resulted in retinal atrophy of the eyes in mice at dose of 150 mg/kg/day (approximately 10 times the exposure at the maximum recommended human dose based on AUC) and in rats at dose of 30 mg/kg/day (approximately times the exposure at the maximum recommended human dose based on AUC). In 2-year rat carcinogenicity study, oral administration of abemaciclib resulted in retinal atrophy in the eyes at doses >=0.3 mg/kg/day (approximately 0.05 times the exposure at the maximum recommended human dose based on AUC).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Abemaciclib was assessed for carcinogenicity in 2-year rat study. Abemaciclib was not carcinogenic in male and female rats at oral doses up to mg/kg/day (approximately time the exposure at the maximum recommended human dose based on AUC).Abemaciclib and its active human metabolites M2 and M20 were not mutagenic in bacterial reverse mutation (Ames) assay or clastogenic in an in vitro chromosomal aberration assay in Chinese hamster ovary cells or human peripheral blood lymphocytes. Abemaciclib, M2, and M20 were not clastogenic in an in vivo rat bone marrow micronucleus assay.Abemaciclib may impair fertility in males of reproductive potential. In repeat-dose toxicity studies up to 3-months duration, abemaciclib-related findings in the testis, epididymis, prostate, and seminal vesicle at doses >=10 mg/kg/day in rats and >=0.3 mg/kg/day in dogs included decreased organ weights, intratubular cellular debris, hypospermia, tubular dilatation, atrophy, and degeneration/necrosis. These doses in rats and dogs resulted in approximately and 0.02 times, respectively, the exposure (AUC) in humans at the maximum recommended human dose. In rat male fertility study, abemaciclib had no effects on mating and fertility at oral doses up to 10 mg/kg/day (approximately times the exposure at the maximum recommended human dose based on AUC).In rat female fertility and early embryonic development study, abemaciclib did not affect mating and fertility at doses up to 20 mg/kg/day (approximately times the exposure at the maximum recommended human dose based on AUC).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Abemaciclib is an inhibitor of cyclin-dependent kinases and (CDK4 and CDK6). These kinases are activated upon binding to D-cyclins. In estrogen receptor-positive (ER+) breast cancer cell lines, cyclin D1 and CDK4/6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression, and cell proliferation. In vitro, continuous exposure to abemaciclib inhibited Rb phosphorylation and blocked progression from G1 into phase of the cell cycle, resulting in senescence and apoptosis. In breast cancer xenograft models, abemaciclib dosed daily without interruption as single agent or in combination with antiestrogens resulted in reduction of tumor size.. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyBased on evaluation of the QTc interval in patients and in healthy volunteer study, abemaciclib did not cause large mean increases (i.e., 20 ms) in the QTc interval.. 12.3 Pharmacokinetics. The pharmacokinetics of abemaciclib were characterized in patients with solid tumors, including breast cancer, and in healthy subjects.Following single and repeated twice daily dosing of 50 mg (0.3 times the approved recommended 150 mg dosage) to 200 mg of abemaciclib, the increase in plasma exposure (AUC) and Cmax was approximately dose proportional. Steady state was achieved within days following repeated twice daily dosing, and the estimated geometric mean accumulation ratio was 2.3 (50% CV) and 3.2 (59% CV) based on Cmax and AUC, respectively.. AbsorptionThe absolute bioavailability of abemaciclib after single oral dose of 200 mg is 45% (19% CV). The median Tmax of abemaciclib is 8.0 hours (range: 4.1-24.0 hours).. Effect of FoodA high-fat, high-calorie meal (approximately 800 to 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) administered to healthy subjects increased the AUC of abemaciclib plus its active metabolites by 9% and increased Cmax by 26%.. DistributionIn vitro, abemaciclib was bound to human plasma proteins, serum albumin, and alpha-1-acid glycoprotein in concentration independent manner from 152 ng/mL to 5066 ng/mL. In clinical study, the mean (standard deviation, SD) bound fraction was 96.3% (1.1) for abemaciclib, 93.4% (1.3) for M2, 96.8% (0.8) for M18, and 97.8% (0.6) for M20. The geometric mean systemic volume of distribution is approximately 690.3 (49% CV).In patients with advanced cancer, including breast cancer, concentrations of abemaciclib and its active metabolites M2 and M20 in cerebrospinal fluid are comparable to unbound plasma concentrations.. EliminationThe geometric mean hepatic clearance (CL) of abemaciclib in patients was 26.0 L/h (51% CV), and the mean plasma elimination half-life for abemaciclib in patients was 18.3 hours (72% CV).. MetabolismHepatic metabolism is the main route of clearance for abemaciclib. Abemaciclib is metabolized to several metabolites primarily by cytochrome P450 (CYP) 3A4, with formation of N-desethylabemaciclib (M2) representing the major metabolism pathway. Additional metabolites include hydroxyabemaciclib (M20), hydroxy-N-desethylabemaciclib (M18), and an oxidative metabolite (M1). M2, M18, and M20 are equipotent to abemaciclib and their AUCs accounted for 25%, 13%, and 26% of the total circulating analytes in plasma, respectively.. ExcretionAfter single 150 mg oral dose of radiolabeled abemaciclib, approximately 81% of the dose was recovered in feces and approximately 3% recovered in urine. The majority of the dose eliminated in feces was metabolites.. Specific Populations. Age, Gender, and Body WeightBased on population pharmacokinetic analysis in patients with cancer, age (range 24-91 years), gender (134 males and 856 females), and body weight (range 36-175 kg) had no effect on the exposure of abemaciclib.. Patients with Renal ImpairmentIn population pharmacokinetic analysis of 990 individuals, in which 381 individuals had mild renal impairment (60 mL/min <= CLcr <90 mL/min) and 126 individuals had moderate renal impairment (30 mL/min <= CLcr <60 mL/min), mild and moderate renal impairment had no effect on the exposure of abemaciclib [see Use in Specific Populations (8.6)]. The effect of severe renal impairment (CLcr <30 mL/min) on pharmacokinetics of abemaciclib is unknown.. Patients with Hepatic ImpairmentFollowing single 200 mg oral dose of abemaciclib, the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2, M18, M20) in plasma increased 1.2-fold in subjects with mild hepatic impairment (Child-Pugh A, n=9), 1.1-fold in subjects with moderate hepatic impairment (Child-Pugh B, n=10), and 2.4-fold in subjects with severe hepatic impairment (Child-Pugh C, n=6) relative to subjects with normal hepatic function (n=10) [see Use in Specific Populations (8.7)]. In subjects with severe hepatic impairment, the mean plasma elimination half-life of abemaciclib increased to 55 hours compared to 24 hours in subjects with normal hepatic function.. Drug Interaction Studies. Effects of Other Drugs on Abemaciclib. Strong CYP3A Inhibitors: Ketoconazole (a strong CYP3A inhibitor) is predicted to increase the AUC of abemaciclib by up to 16-fold.Coadministration of 500 mg twice daily doses of clarithromycin (a strong CYP3A inhibitor) with single 50 mg dose of VERZENIO (0.3 times the approved recommended 150 mg dosage) increased the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2, M18, and M20) by 2.5-fold relative to abemaciclib alone in cancer patients.. Moderate CYP3A Inhibitors: Verapamil and diltiazem (moderate CYP3A inhibitors) are predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 1.6-fold and 2.4-fold, respectively.. Strong CYP3A Inducers: Coadministration of 600 mg daily doses of rifampin (a strong CYP3A inducer) with single 200 mg dose of VERZENIO decreased the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 70% in healthy subjects.. Moderate CYP3A Inducers: Efavirenz, bosentan, and modafinil (moderate CYP3A inducers) are predicted to decrease the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 53%, 41%, and 29%, respectively.. Loperamide: Co-administration of single mg dose of loperamide with single 400 mg dose of abemaciclib in healthy subjects increased the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2 and M20) by 12%, which is not considered clinically relevant.. Endocrine Therapies: In clinical studies in patients with breast cancer, there was no clinically relevant effect of fulvestrant, anastrozole, letrozole, exemestane, or tamoxifen on abemaciclib pharmacokinetics.. Effects of Abemaciclib on Other Drugs. Loperamide: In clinical drug interaction study in healthy subjects, coadministration of single mg dose of loperamide with single 400 mg abemaciclib (2.7 times the approved recommended 150 mg dosage) increased loperamide AUC0-INF by 9% and Cmax by 35% relative to loperamide alone. These increases in loperamide exposure are not considered clinically relevant.. Metformin: In clinical drug interaction study in healthy subjects, coadministration of single 1000 mg dose of metformin, clinically relevant substrate of renal OCT2, MATE1, and MATE2-K transporters, with single 400 mg dose of abemaciclib (2.7 times the approved recommended 150 mg dosage) increased metformin AUC0-INF by 37% and Cmax by 22% relative to metformin alone. Abemaciclib reduced the renal clearance and renal secretion of metformin by 45% and 62%, respectively, relative to metformin alone, without any effect on glomerular filtration rate (GFR) as measured by iohexol clearance and serum cystatin C.. Endocrine Therapies: In clinical studies in patients with breast cancer, there was no clinically relevant effect of abemaciclib on the pharmacokinetics of fulvestrant, anastrozole, letrozole, exemestane, or tamoxifen.. CYP Metabolic Pathways: In clinical drug interaction study in patients with cancer, multiple doses of abemaciclib (200 mg twice daily for days) did not result in clinically meaningful changes in the pharmacokinetics of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 substrates. Abemaciclib is substrate of CYP3A4, and time-dependent changes in pharmacokinetics of abemaciclib as result of autoinhibition of its metabolism were not observed.. In Vitro Studies. Transporter Systems: Abemaciclib and its major active metabolites inhibit the renal transporters OCT2, MATE1, and MATE2-K at concentrations achievable at the approved recommended dosage. The observed serum creatinine increase in clinical studies with abemaciclib is likely due to inhibition of tubular secretion of creatinine via OCT2, MATE1, and MATE2-K [see Adverse Effects (6.1)]. Abemaciclib and its major metabolites at clinically relevant concentrations do not inhibit the hepatic uptake transporters OCT1, OATP1B1, and OATP1B3 or the renal uptake transporters OAT1 and OAT3.Abemaciclib is substrate of P-gp and BCRP. Abemaciclib and its major active metabolites, M2 and M20, are not substrates of hepatic uptake transporters OCT1, organic anion transporting polypeptide 1B1 (OATP1B1), or OATP1B3.Abemaciclib inhibits P-gp and BCRP. The clinical consequences of this finding on sensitive P-gp and BCRP substrates are unknown.. P-gp and BCRP Inhibitors: In vitro, abemaciclib is substrate of P-gp and BCRP. The effect of P-gp or BCRP inhibitors on the pharmacokinetics of abemaciclib has not been studied.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Early Breast Cancer. VERZENIO in Combination with Standard Endocrine Therapy (monarchE). Patients with HR-positive, HER2-negative, node-positive early breast cancer at high risk of recurrencemonarchE (NCT03155997) was randomized (1:1), open-label, two cohort, multicenter study in adult women and men with HR-positive, HER2-negative, node-positive, resected, early breast cancer with clinical and pathological features consistent with high risk of disease recurrence. To be enrolled in cohort 1, patients had to have HR positive, HER2-negative early breast cancer with tumor involvement in at least axillary lymph node (pALN) and either:>=4 pALN or1-3 pALN and at least one of:-tumor grade 3-tumor size >= 50 mm. Patients with available untreated breast tumor samples were tested retrospectively at central sites using the Ki-67 IHC MIB-1 pharmDx (Dako Omnis) assay to establish if the Ki-67 score was >=20%, specified in the protocol as Ki-67 high.Patients were randomized to receive years of VERZENIO plus physicians choice of standard endocrine therapy or standard endocrine therapy alone. Randomization to treatment was stratified by prior treatment (neoadjuvant chemotherapy versus adjuvant chemotherapy versus no chemotherapy); menopausal status (premenopausal versus postmenopausal); and region (North America/Europe versus Asia versus other). Men were stratified as postmenopausal. After the end of the study treatment period, standard adjuvant endocrine therapy was continued for duration of at least years if deemed medically appropriate.Among the 2003 patients with Ki-67 score >=20% in cohort 1, patient median age was 51 years (range, 24-88 years), 99% were women, 68% were White, 25% were Asian, 2.1% were Black or African American, 1.5% were American Indian or Alaska Native, and 0.2% were Native Hawaiian or Other Pacific Islander. Forty-six percent of patients were premenopausal. Most patients received prior chemotherapy (37% neoadjuvant, 60% adjuvant) and prior radiotherapy (95%). Fifty-seven percent of the patients had or more positive lymph nodes with 20% having >=10 positive lymph nodes, 58% had Grade tumor, and 19% had pathological tumor size >=50 mm. The majority of patients (99%) were estrogen receptor positive and 84% were progesterone receptor positive. Initial endocrine therapy received by patients included letrozole (39%), tamoxifen (33%), anastrozole (19%), or exemestane (8%).The major efficacy outcome measure was invasive disease-free survival (IDFS). IDFS was defined as the time from randomization to the first occurrence of: ipsilateral invasive breast tumor recurrence, regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, second primary non-breast invasive cancer, or death attributable to any cause. Overall survival was an additional outcome measure.Efficacy results are summarized in Table 16 and Figure 1. At the time of IDFS analysis, overall survival was immature. total of 95 (4.7%) of patients had died.Table 16: Efficacy Results in monarchE in Cohort Patients with Ki-67 Score >=20%Abbreviation: CI confidence interval.a This p-value is from the pre-specified final IDFS analysis for cohort patients with Ki-67 score >=20%.VERZENIO PlusTamoxifen or an Aromatase InhibitorN=1017Tamoxifen or an Aromatase InhibitorN=986Invasive Disease-Free Survival (IDFS) Number of patients with an event (n, %)104 (10.2)158 (16.0) Hazard ratio (95% CI)0.626 (0.488, 0.803) p-value0.0042a IDFS at 36 months (%, 95% CI)86.1 (82.8, 88.8)79.0 (75.3, 82.3)Figure 1: Kaplan-Meier Curves of Invasive Disease-Free Survival VERZENIO plus Tamoxifen or an Aromatase Inhibitor versus Tamoxifen or an Aromatase Inhibitor in Cohort Patients with Ki-67 Score >=20% (monarchE). >=4 pALN or. 1-3 pALN and at least one of:-tumor grade 3-tumor size >= 50 mm. -tumor grade 3. -tumor size >= 50 mm.. Figure 1. 14.2 Advanced or Metastatic Breast Cancer. VERZENIO in Combination with an Aromatase Inhibitor (Anastrozole or Letrozole) (MONARCH 3). Postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer with no prior systemic therapy in this disease settingMONARCH (NCT02246621) was randomized (2:1), double-blinded, placebo-controlled, multicenter study in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer in combination with nonsteroidal aromatase inhibitor as initial endocrine-based therapy, including patients not previously treated with systemic therapy for breast cancer.Randomization was stratified by disease site (visceral, bone only, or other) and by prior (neo)adjuvant endocrine therapy (aromatase inhibitor versus other versus no prior endocrine therapy). total of 493 patients were randomized to receive 150 mg VERZENIO or placebo orally twice daily, plus physicians choice of letrozole (80% of patients) or anastrozole (20% of patients). Patient median age was 63 years (range, 32-88 years) and the majority were White (58%) or Asian (30%). total of 51% had received prior systemic therapy and 39% of patients had received chemotherapy, 53% had visceral disease, and 22% had bone-only disease.Efficacy results are summarized in Table 17 and Figure 2. PFS was evaluated according to RECIST version 1.1 and PFS assessment based on blinded independent radiologic review was consistent with the investigator assessment. Consistent results were observed across patient stratification subgroups of disease site and prior (neo)adjuvant endocrine therapy. At the time of the PFS analysis, 19% of patients had died, and overall survival data were immature.Table 17: Efficacy Results in MONARCH (Investigator Assessment, Intent-to-Treat Population)Abbreviations: CI confidence interval, NR not reached.a Complete response partial response.b Based upon confirmed responses.VERZENIO plusAnastrozole or LetrozolePlacebo plusAnastrozole or LetrozoleProgression-Free SurvivalN=328N=165 Number of patients with an event (n, %)138 (42.1)108 (65.5) Median (months, 95% CI)28.2 (23.5, NR)14.8 (11.2, 19.2) Hazard ratio (95% CI)0.540 (0.418, 0.698) p-value<0.0001Objective Response for Patients with Measurable DiseaseN=267N=132 Objective response ratea,b (n, %)148 (55.4)53 (40.2) 95% CI49.5, 61.431.8, 48.5Figure 2: Kaplan-Meier Curves of Progression-Free Survival: VERZENIO plus Anastrozole or Letrozole versus Placebo plus Anastrozole or Letrozole (MONARCH 3). Figure 2. VERZENIO in Combination with Fulvestrant (MONARCH 2). Patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression on or after prior adjuvant or metastatic endocrine therapyMONARCH (NCT02107703) was randomized, placebo-controlled, multicenter study in women with HR-positive, HER2-negative metastatic breast cancer in combination with fulvestrant in patients with disease progression following endocrine therapy who had not received chemotherapy in the metastatic setting. Randomization was stratified by disease site (visceral, bone only, or other) and by sensitivity to prior endocrine therapy (primary or secondary resistance). Primary endocrine therapy resistance was defined as relapse while on the first years of adjuvant endocrine therapy or progressive disease within the first months of first line endocrine therapy for metastatic breast cancer. total of 669 patients were randomized to receive VERZENIO or placebo orally twice daily plus intramuscular injection of 500 mg fulvestrant on days and 15 of cycle and then on day of cycle and beyond (28-day cycles). Pre/perimenopausal women were enrolled in the study and received the gonadotropin-releasing hormone agonist goserelin for at least weeks prior to and for the duration of MONARCH 2. Patients remained on continuous treatment until development of progressive disease or unmanageable toxicity.Patient median age was 60 years (range, 32-91 years), and 37% of patients were older than 65. The majority were White (56%), and 99% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of or 1. Twenty percent (20%) of patients had de novo metastatic disease, 27% had bone-only disease, and 56% had visceral disease. Twenty-five percent (25%) of patients had primary endocrine therapy resistance. Seventeen percent (17%) of patients were pre- or perimenopausal.The efficacy results from the MONARCH study are summarized in Table 18, Figure 3, and Figure 4. PFS assessment based on blinded independent radiologic review was consistent with the investigator assessment. Consistent results were observed across patient stratification subgroups of disease site and endocrine therapy resistance for PFS and OS.Table 18: Efficacy Results in MONARCH (Intent-to-Treat Population)Abbreviation: CI confidence interval, OS overall survival.a Stratified by disease site (visceral metastases vs. bone-only metastases vs. other) and endocrine therapy resistance (primary resistance vs. secondary resistance)b Data from pre-specified interim analysis (77% of the number of events needed for the planned final analysis) with the p-value compared with the allocated alpha of 0.021.c Complete response partial response.VERZENIO plus FulvestrantPlacebo plus FulvestrantProgression-Free Survival(Investigator Assessment)N=446N=223 Number of patients with an event (n, %)222 (49.8)157 (70.4) Median (months, 95% CI)16.4 (14.4, 19.3)9.3 (7.4, 12.7) Hazard ratio (95% CI)a 0.553 (0.449, 0.681) p-valuea p<.0001Overall Survivalb Number of deaths (n, %)211 (47.3)127 (57.0) Median OS in months (95% CI)46.7 (39.2, 52.2)37.3 (34.4, 43.2) Hazard ratio (95% CI)a 0.757 (0.606, 0.945) p-valuea p=.0137Objective Response for Patients with Measurable DiseaseN=318N=164 Objective response ratec (n, %)153 (48.1)35 (21.3) 95% CI42.6, 53.615.1, 27.6Figure 3: Kaplan-Meier Curves of Progression-Free Survival: VERZENIO plus Fulvestrant versus Placebo plus Fulvestrant (MONARCH 2)Figure 4: Kaplan-Meier Curves of Overall Survival: VERZENIO plus Fulvestrant versus Placebo plus Fulvestrant (MONARCH 2). Figure 3. Figure 4. VERZENIO Administered as Monotherapy in Metastatic Breast Cancer (MONARCH 1). Patients with HR-positive, HER2-negative breast cancer who received prior endocrine therapy and 1-2 chemotherapy regimens in the metastatic settingMONARCH (NCT02102490) was single-arm, open-label, multicenter study in women with measurable HR-positive, HER2-negative metastatic breast cancer whose disease progressed during or after endocrine therapy, had received taxane in any setting, and who received or prior chemotherapy regimens in the metastatic setting. total of 132 patients received 200 mg VERZENIO orally twice daily on continuous schedule until development of progressive disease or unmanageable toxicity.Patient median age was 58 years (range, 36-89 years), and the majority of patients were White (85%). Patients had an Eastern Cooperative Oncology Group performance status of (55% of patients) or (45%). The median duration of metastatic disease was 27.6 months. Ninety percent (90%) of patients had visceral metastases, and 51% of patients had or more sites of metastatic disease. Fifty-one percent (51%) of patients had had one line of chemotherapy in the metastatic setting. Sixty-nine percent (69%) of patients had received taxane-based regimen in the metastatic setting and 55% had received capecitabine in the metastatic setting. Table 19 provides the efficacy results from MONARCH 1.Table 19: Efficacy Results in MONARCH (Intent-to-Treat Population)Abbreviations: CI confidence interval, NR not reached.a All responses were partial responses.b Based upon confirmed responses.VERZENIO 200 mgN=132Investigator AssessedIndependent ReviewObjective Response Ratea,b, (%)26 (19.7)23 (17.4)95% CI (%)13.3, 27.511.4, 25.0Median Duration of Response8.6 months7.2 months95% CI (%)5.8, 10.25.6, NR.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Studies Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety population described in the Warnings and Precautions reflect exposure to VERZENIO in 3691 patients from four clinical trials: monarchE, MONARCH 1, MONARCH 2, and MONARCH 3. The safety population includes exposure to VERZENIO as single agent at 200 mg twice daily in 132 patients in MONARCH and to VERZENIO at 150 mg twice daily in 3559 patients administered in combination with fulvestrant, tamoxifen, or an aromatase inhibitor in monarchE, MONARCH 2, and MONARCH 3. The median duration of exposure ranged from 4.5 months in MONARCH to 24 months in monarchE. The most common adverse reactions (incidence >=20%) across clinical trials were: diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, and thrombocytopenia.. Early Breast Cancer. monarchE: VERZENIO in Combination with Tamoxifen or an Aromatase Inhibitor as Adjuvant Treatment. Adult patients with HR-positive, HER2-negative, node-positive early breast cancer at high risk of recurrenceThe safety of VERZENIO was evaluated in monarchE, study of 5591 adult patients receiving VERZENIO plus endocrine therapy (tamoxifen or an aromatase inhibitor) or endocrine therapy (tamoxifen or an aromatase inhibitor) alone [see Clinical Studies (14.1)]. Patients were randomly assigned to receive 150 mg of VERZENIO orally, twice daily, plus tamoxifen or an aromatase inhibitor, or tamoxifen or an aromatase inhibitor, for two years or until discontinuation criteria were met. The median duration of VERZENIO treatment was 24 months.The most frequently reported (>=5%) Grade or adverse reactions were neutropenia, leukopenia, diarrhea, and lymphopenia.Fatal adverse reactions occurred in 0.8% of patients who received VERZENIO plus endocrine therapy (tamoxifen or an aromatase inhibitor), including: cardiac failure (0.1%), cardiac arrest, myocardial infarction, ventricular fibrillation, cerebral hemorrhage, cerebrovascular accident, pneumonitis, hypoxia, diarrhea and mesenteric artery thrombosis (0.03% each).Permanent VERZENIO treatment discontinuation due to an adverse reaction was reported in 19% of patients receiving VERZENIO, plus tamoxifen or an aromatase inhibitor. Of the patients receiving tamoxifen or an aromatase inhibitor, 1% permanently discontinued due to an adverse reaction. The most common adverse reactions leading to VERZENIO discontinuations were diarrhea (5%), fatigue (2%), and neutropenia (0.9%).Dose interruption of VERZENIO due to an adverse reaction occurred in 62% of patients receiving VERZENIO plus tamoxifen or aromatase inhibitors. Adverse reactions leading to VERZENIO dose interruptions in >=5% of patients were diarrhea (20%), neutropenia (16%), leukopenia (7%), and fatigue (5%).Dose reductions of VERZENIO due to an adverse reaction occurred in 44% of patients receiving VERZENIO plus endocrine therapy (tamoxifen or an aromatase inhibitor). Adverse reactions leading to VERZENIO dose reductions in >=5% were diarrhea (17%), neutropenia (8%), and fatigue (5%).The most common adverse reactions reported (>=20%) in the VERZENIO, plus tamoxifen or an aromatase inhibitor, arm and >=2% higher than the tamoxifen or an aromatase inhibitor arm were: diarrhea, infections, neutropenia, fatigue, leukopenia, nausea, anemia, and headache. Adverse reactions are shown in Table and laboratory abnormalities are shown in Table 9.Table 8: Adverse Reactions (>=10%) of Patients Receiving VERZENIO Plus Tamoxifen or an Aromatase Inhibitor [with Difference between Arms of >=2%] in monarchEa Includes the following fatal adverse reactions: diarrhea (n=1), and infections (n=4)b Includes the following fatal adverse reactions: infections (n=5)c Includes mouth ulceration, mucosal inflammation, oropharyngeal pain, stomatitis.d Includes all reported preferred terms that are part of the Infections and Infestations system organ class. Most common infections (>5%) include upper respiratory tract infection, urinary tract infection, and nasopharyngitis.e Includes asthenia, fatigue.f Includes exfoliative rash, mucocutaneous rash, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash maculovesicular, rash morbilliform, rash papular, rash papulosquamous, rash pruritic, rash vesicular, vulvovaginal rash.VERZENIO PlusTamoxifen or an Aromatase InhibitorN=2791Tamoxifen or an Aromatase InhibitorN=2800All Gradesa%Grade 3%Grade 4%All Gradesb%Grade 3%Grade 4%Gastrointestinal Disorders Diarrhea848090.20 Nausea300.509<0.10 Vomiting180.504.60.10 Stomatitisc 140.10500Infections and Infestations Infectionsd 514.90.6392.70.1General Disorders and Administration Site Conditions Fatiguee 412.90180.10Nervous System Disorders Headache200.30150.20 Dizziness110.107<0.10Metabolism and Nutrition Disorders Decreased appetite120.602.4<0.10Skin and Subcutaneous Tissue Disorders Rashf 110.404.500 Alopecia11002.700Clinically relevant adverse reactions in <10% of patients who received VERZENIO in combination with tamoxifen or an aromatase inhibitor in monarchE include:Pruritus-9%Dyspepsia-8%Nail disorder-6% (includes nail bed disorder, nail bed inflammation, nail discoloration, nail disorder, nail dystrophy, nail pigmentation, nail ridging, nail toxicity, onychalgia, onychoclasis, onycholysis, onychomadesis)Lacrimation increased-6%Dysgeusia-5%Interstitial lung disease (ILD)/pneumonitis-3% (includes pneumonitis, radiation pneumonitis, interstitial lung disease, pulmonary fibrosis, organizing pneumonia, radiation fibrosis lung, lung opacity, sarcoidosis)Venous thromboembolic events (VTEs)-3% (includes catheter site thrombosis, cerebral venous thrombosis, deep vein thrombosis, device related thrombosis, embolism, hepatic vein thrombosis, jugular vein occlusion, jugular vein thrombosis, ovarian vein thrombosis, portal vein thrombosis, pulmonary embolism, subclavian vein thrombosis, venous thrombosis limb)Table 9: Laboratory Abnormalities (>=10%) in Patients Receiving VERZENIO Plus Tamoxifen or an Aromatase Inhibitor [with Difference between Arms of >=2%] in monarchEVERZENIOPlus Tamoxifen or an Aromatase InhibitorN=2791Tamoxifen or an Aromatase InhibitorN=2800All Grades%Grade 3%Grade 4%All Grades%Grade 3%Grade 4%Creatinine increased990.5091<0.10White blood cell decreased8919<0.1281.10Neutrophil count decreased84180.7231.60.3Anemia681.00170.10Lymphocyte count decreased59130.2242.40.1Platelet count decreased370.70.2100.10.1Alanine aminotransferase increased372.5<0.1241.20Aspartate aminotransferase increased311.5<0.1180.90Hypokalemia111.20.13.80.10.1. Pruritus-9%. Dyspepsia-8%. Nail disorder-6% (includes nail bed disorder, nail bed inflammation, nail discoloration, nail disorder, nail dystrophy, nail pigmentation, nail ridging, nail toxicity, onychalgia, onychoclasis, onycholysis, onychomadesis). Lacrimation increased-6%. Dysgeusia-5%. Interstitial lung disease (ILD)/pneumonitis-3% (includes pneumonitis, radiation pneumonitis, interstitial lung disease, pulmonary fibrosis, organizing pneumonia, radiation fibrosis lung, lung opacity, sarcoidosis). Venous thromboembolic events (VTEs)-3% (includes catheter site thrombosis, cerebral venous thrombosis, deep vein thrombosis, device related thrombosis, embolism, hepatic vein thrombosis, jugular vein occlusion, jugular vein thrombosis, ovarian vein thrombosis, portal vein thrombosis, pulmonary embolism, subclavian vein thrombosis, venous thrombosis limb). Advanced or Metastatic Breast Cancer. MONARCH 3: VERZENIO in Combination with an Aromatase Inhibitor (Anastrozole or Letrozole) as Initial Endocrine-Based Therapy. Postmenopausal Women with HR-positive, HER2-negative locoregionally recurrent or metastatic breast cancer with no prior systemic therapy in this disease settingThe safety of VERZENIO was evaluated in MONARCH 3, study of 488 women receiving VERZENIO plus an aromatase inhibitor or placebo plus an aromatase inhibitor [see Clinical Studies (14.2)]. Patients were randomly assigned to receive 150 mg of VERZENIO or placebo orally twice daily, plus physicians choice of anastrozole or letrozole once daily. Median duration of treatment was 15.1 months for the VERZENIO arm and 13.9 months for the placebo arm.The most frequently reported (>=5%) Grade or adverse reactions were neutropenia, diarrhea, leukopenia, increased ALT, and anemia.Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 11 cases (3%) of VERZENIO plus an aromatase inhibitor treated patients versus cases (2%) of placebo plus an aromatase inhibitor treated patients. Causes of death for patients receiving VERZENIO plus an aromatase inhibitor included: (0.9%) patient deaths due to underlying disease, (0.9%) due to lung infection, (0.9%) due to VTE, (0.3%) due to pneumonitis, and (0.3%) due to cerebral infarction.Permanent treatment discontinuation due to an adverse reaction was reported in 13% of patients receiving VERZENIO plus an aromatase inhibitor and in 3% of patients receiving placebo plus an aromatase inhibitor. Adverse reactions leading to permanent discontinuation for patients receiving VERZENIO plus an aromatase inhibitor were diarrhea (2%), ALT increased (2%), infection (1%), venous thromboembolic events (VTE) (1%), neutropenia (0.9%), renal impairment (0.9%), AST increased (0.6%), dyspnea (0.6%), pulmonary fibrosis (0.6%) and anemia, rash, weight decreased and thrombocytopenia (each 0.3%).Dose interruption of VERZENIO due to an adverse reaction occurred in 56% of patients receiving VERZENIO plus anastrazole or letrozole. Adverse reactions leading to VERZENIO dose interruptions in >=5% of patients were neutropenia (16%) and diarrhea (15%).Dose reductions due to an adverse reaction occurred in 43% of patients receiving VERZENIO plus anastrozole or letrozole. Adverse reactions leading to dose reductions in >=5% of patients were diarrhea and neutropenia. VERZENIO dose reductions due to diarrhea of any grade occurred in 13% of patients receiving VERZENIO plus an aromatase inhibitor compared to 2% of patients receiving placebo plus an aromatase inhibitor. VERZENIO dose reductions due to neutropenia of any grade occurred in 11% of patients receiving VERZENIO plus an aromatase inhibitor compared to 0.6% of patients receiving placebo plus an aromatase inhibitor.The most common adverse reactions reported (>=20%) in the VERZENIO arm and >=2% than the placebo arm were: diarrhea, neutropenia, fatigue, infections, nausea, abdominal pain, anemia, vomiting, alopecia, decreased appetite, and leukopenia. Adverse reactions are shown in Table 10 and laboratory abnormalities in Table 11. Diarrhea incidence was greatest during the first month of VERZENIO dosing. The median time to onset of the first diarrhea event was days, and the median durations of diarrhea for Grades and for Grade were 11 days and days, respectively. Most diarrhea events recovered or resolved (88%) with supportive treatment and/or dose reductions [see Dosage and Administration (2.3) and Patient Counseling Information (17)]. Nineteen percent of patients with diarrhea required dose omission and 13% required dose reduction. The median time to the first dose reduction due to diarrhea was 38 days.Table 10: Adverse Reactions (>=10%) in Patients Receiving VERZENIO Plus Anastrozole or Letrozole [with Difference between Arms of >=2%] in MONARCH 3a Includes all reported preferred terms that are part of the Infections and Infestations system organ class. Most common infections (>1%) include upper respiratory tract infection, lung infection, and pharyngitis.VERZENIO plusAnastrozole or LetrozoleN=327Placebo plusAnastrozole or LetrozoleN=161All Grades%Grade 3%Grade 4%All Grades%Grade 3%Grade 4%Gastrointestinal Disorders Diarrhea8190301.20 Nausea390.90201.20 Abdominal pain291.20121.20 Vomiting281.20121.90 Constipation160.601200Infections and Infestations Infectionsa 394.00.9292.50.6General Disorders and Administration Site Conditions Fatigue401.803200 Influenza like illness1000800Skin and Subcutaneous Tissue Disorders Alopecia27001100 Rash140.90500 Pruritus1300900Metabolism and Nutrition Disorders Decreased appetite241.2090.60Investigations Weight decreased100.603.10.60Respiratory, Thoracic, and Mediastinal Disorders Cough1300900 Dyspnea120.60.360.60Nervous System Disorders Dizziness110.30900Additional adverse reactions in MONARCH include venous thromboembolic events (deep vein thrombosis, pulmonary embolism, and pelvic venous thrombosis), which were reported in 5% of patients treated with VERZENIO plus anastrozole or letrozole as compared to 0.6% of patients treated with anastrozole or letrozole plus placebo.Table 11: Laboratory Abnormalities (>=10%) in Patients Receiving VERZENIO Plus Anastrozole or Letrozole [with Difference Between Arms of >=2%] in MONARCH 3VERZENIO plusAnastrozole or LetrozoleN=327Placebo plusAnastrozole or LetrozoleN=161Laboratory AbnormalityAll Grades%Grade 3%Grade 4%All Grades%Grade 3%Grade 4%Creatinine increased982.208400White blood cell decreased82130270.60Anemia821.602800Neutrophil count decreased80192.9212.60Lymphocyte count decreased5370.6261.90Platelet count decreased361.30.6120.60Alanine aminotransferase increased4860.6251.90Aspartate aminotransferase increased373.80230.60. Creatinine IncreasedAbemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function [see Clinical Pharmacology (12.3)]. Across the clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of VERZENIO dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated GFR, which are not based on creatinine, may be considered to determine whether renal function is impaired.. MONARCH 2: VERZENIO in Combination with Fulvestrant. Women with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression on or after prior adjuvant or metastatic endocrine therapyThe safety of VERZENIO (150 mg twice daily) plus fulvestrant (500 mg) versus placebo plus fulvestrant was evaluated in MONARCH [see Clinical Studies (14.2)]. The data described below reflect exposure to VERZENIO in 441 patients with HR-positive, HER2-negative advanced breast cancer who received at least one dose of VERZENIO plus fulvestrant in MONARCH 2.Median duration of treatment was 12 months for patients receiving VERZENIO plus fulvestrant and months for patients receiving placebo plus fulvestrant.The most frequently reported (>=5%) Grade or adverse reactions were neutropenia, diarrhea, leukopenia, anemia, and infections.Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 18 cases (4%) of VERZENIO plus fulvestrant treated patients versus 10 cases (5%) of placebo plus fulvestrant treated patients. Causes of death for patients receiving VERZENIO plus fulvestrant included: (2%) patient deaths due to underlying disease, (0.9%) due to sepsis, (0.5%) due to pneumonitis, (0.5%) due to hepatotoxicity, and one (0.2%) due to cerebral infarction.Permanent study treatment discontinuation due to an adverse reaction were reported in 9% of patients receiving VERZENIO plus fulvestrant and in 3% of patients receiving placebo plus fulvestrant. Adverse reactions leading to permanent discontinuation for patients receiving VERZENIO plus fulvestrant were infection (2%), diarrhea (1%), hepatotoxicity (1%), fatigue (0.7%), nausea (0.2%), abdominal pain (0.2%), acute kidney injury (0.2%), and cerebral infarction (0.2%).Dose interruption of VERZENIO due to an adverse reaction occurred in 52% of patients receiving VERZENIO plus fulvestrant. Adverse reactions leading to VERZENIO dose interruptions in >=5% of patients were diarrhea (19%) and neutropenia (16%).Dose reductions due to an adverse reaction occurred in 43% of patients receiving VERZENIO plus fulvestrant. Adverse reactions leading to reductions in >=5% of patients were diarrhea and neutropenia. VERZENIO dose reductions due to diarrhea of any grade occurred in 19% of patients receiving VERZENIO plus fulvestrant compared to 0.4% of patients receiving placebo and fulvestrant. VERZENIO dose reductions due to neutropenia of any grade occurred in 10% of patients receiving VERZENIO plus fulvestrant compared to no patients receiving placebo plus fulvestrant.The most common adverse reactions reported (>=20%) in the VERZENIO arm were: diarrhea, fatigue, neutropenia, nausea, infections, abdominal pain, anemia, leukopenia, decreased appetite, vomiting, and headache. Adverse reactions are shown in Table 12 and laboratory abnormalities in Table 13.Table 12: Adverse Reactions (>=10%) in Patients Receiving VERZENIO Plus Fulvestrant [with Difference Between Arms of >=2%] in MONARCH 2a Includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, abdominal tenderness.b Includes upper respiratory tract infection, urinary tract infection, lung infection, pharyngitis, conjunctivitis, sinusitis, vaginal infection, sepsis.c Includes asthenia, fatigue.VERZENIO plus FulvestrantN=441Placebo plus FulvestrantN=223All Grades%Grade 3%Grade 4%All Grades%Grade 3%Grade 4%Gastrointestinal Disorders Diarrhea86130250.40 Nausea452.70230.90 Abdominal paina 352.50160.90 Vomiting260.90101.80 Stomatitis150.501000Infections and Infestations Infectionsb 4350.7253.10.4General Disorders and Administration Site Conditions Fatiguec 462.70320.40 Edema peripheral1200700 Pyrexia110.50.260.40Metabolism and Nutrition Disorders Decreased appetite271.10120.40Respiratory, Thoracic and Mediastinal Disorders Cough13001100Skin and Subcutaneous Tissue Disorders Alopecia16001.800 Pruritus1300600 Rash111.104.500Nervous System Disorders Headache200.70150.40 Dysgeusia18002.700 Dizziness120.70600Investigations Weight decreased100.202.20.40Additional adverse reactions in MONARCH include venous thromboembolic events (deep vein thrombosis, pulmonary embolism, cerebral venous sinus thrombosis, subclavian vein thrombosis, axillary vein thrombosis, and DVT inferior vena cava), which were reported in 5% of patients treated with VERZENIO plus fulvestrant as compared to 0.9% of patients treated with fulvestrant plus placebo.Table 13: Laboratory Abnormalities (>=10%) in Patients Receiving VERZENIO Plus Fulvestrant [with Difference Between Arms of >=2%]in MONARCH 2VERZENIO plus FulvestrantN=441Placebo plus FulvestrantN=223All Grades%Grade 3%Grade 4%All Grades%Grade 3%Grade 4%Creatinine increased981.207400White blood cell decreased90230.7330.90Neutrophil count decreased87293.5303.70.5Anemia842.60340.50Lymphocyte count decreased63120.2321.80Platelet count decreased530.91.21500Alanine aminotransferase increased413.90.7321.40Aspartate aminotransferase increased373.90253.70.5. Creatinine IncreasedAbemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function [see Clinical Pharmacology (12.3)]. In clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of VERZENIO dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated glomerular filtration rate (GFR), which are not based on creatinine, may be considered to determine whether renal function is impaired.. MONARCH 1: VERZENIO Administered as Monotherapy in Metastatic Breast Cancer. Patients with HR-positive, HER2-negative breast cancer who received prior endocrine therapy and 1-2 chemotherapy regimens in the metastatic settingThe safety of VERZENIO was evaluated in MONARCH 1, single-arm, open-label, multicenter study in 132 women with measurable HR-positive, HER2-negative metastatic breast cancer [see Clinical Studies (14.2)].. Patients received 200 mg VERZENIO orally twice daily until development of progressive disease or unmanageable toxicity. Median duration of treatment was 4.5 months.The most frequently reported (>=5%) Grade or adverse reactions were diarrhea, neutropenia, fatigue, and leukopenia.Deaths due to adverse reactions during treatment or during the 30-day follow up were reported in 2% of patients. Cause of death in these patients was due to infection (2 patients) or pneumonitis (1 patient).Ten patients (8%) discontinued study treatment from adverse reactions due to (1 patient each), abdominal pain, arterial thrombosis, aspartate aminotransferase (AST) increased, blood creatinine increased, chronic kidney disease, diarrhea, ECG QT prolonged, fatigue, hip fracture, and lymphopenia.Dose interruption of VERZENIO due to an adverse reaction occurred in 58% of patients. The most frequent (>=5%) adverse reactions leading to dose interruptions were diarrhea (24%), neutropenia (16%), fatigue (10%), vomiting (6%), and nausea (5%).Forty-nine percent of patients had dose reductions due to an adverse reaction. The most frequent adverse reactions that led to dose reductions were diarrhea (20%), neutropenia (11%), and fatigue (9%).The most common reported adverse reactions (>=20%) were: diarrhea, fatigue, nausea, decreased appetite, abdominal pain, neutropenia, vomiting, infections, anemia, headache, and thrombocytopenia. Adverse reactions are shown in Table 14 and laboratory abnormalities in Table 15.Table 14: Adverse Reactions (>=10%) of Patients in MONARCH 1a Includes asthenia, fatigue.VERZENION=132All Grades%Grade 3%Grade 4%Gastrointestinal Disorders Diarrhea90200 Nausea644.50 Abdominal pain392.30 Vomiting351.50 Constipation170.80 Dry mouth1400 Stomatitis1400Infections and Infestations Infections314.50General Disorders and Administration Site Conditions Fatiguea 65130 Pyrexia1100Metabolism and Nutrition Disorders Decreased appetite453.00 Dehydration102.30Respiratory, Thoracic and Mediastinal Disorders Cough1900Musculoskeletal and Connective Tissue Disorders Arthralgia1500Nervous System Disorders Headache2000 Dysgeusia1200 Dizziness1100Skin and Subcutaneous Tissue Disorders Alopecia1200Investigations Weight decreased1400Table 15: Laboratory Abnormalities for Patients Receiving VERZENIO in MONARCH 1VERZENION=132All Grades%Grade 3%Grade 4%Creatinine increased990.80White blood cell decreased91280Neutrophil count decreased88224.6Anemia6900Lymphocyte count decreased42130.8Platelet count decreased412.30ALT increased313.10AST increased303.80. Creatinine IncreasedAbemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function [see Clinical Pharmacology (12.3)]. In clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of VERZENIO dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated GFR, which are not based on creatinine, may be considered to determine whether renal function is impaired.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Abemaciclib is kinase inhibitor for oral administration. It is white to yellow powder with the empirical formula C27H32F2N8 and molecular weight 506.59.The chemical name for abemaciclib is 2-Pyrimidinamine, N-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl]-. Abemaciclib has the following structure:VERZENIO (abemaciclib) tablets are provided as immediate-release oval white, beige, or yellow tablets. Inactive ingredients are as follows: Excipients--microcrystalline cellulose 102, microcrystalline cellulose 101, lactose monohydrate, croscarmellose sodium, sodium stearyl fumarate, silicon dioxide. Color mixture ingredients--polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide yellow, and iron oxide red.. Abemaciclib Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. VERZENIO tablets are taken orally with or without food. (2.2)Recommended starting dose in combination with fulvestrant, tamoxifen, or an aromatase inhibitor: 150 mg twice daily. (2.2)Recommended starting dose as monotherapy: 200 mg twice daily. (2.2)Dosing interruption and/or dose reductions may be required based on individual safety and tolerability. (2.3). Recommended starting dose in combination with fulvestrant, tamoxifen, or an aromatase inhibitor: 150 mg twice daily. (2.2). Recommended starting dose as monotherapy: 200 mg twice daily. (2.2). Dosing interruption and/or dose reductions may be required based on individual safety and tolerability. (2.3). 2.1 Patient Selection. Patient Selection for Early Breast CancerSelect patients for treatment of early breast cancer with VERZENIO in combination with endocrine therapy based on Ki-67 score >=20% in tumor specimens [see Clinical Studies (14.1)]. Information on FDA-approved tests for the measurement of Ki-67 score is available at http://www.fda.gov/CompanionDiagnostics.. 2.2 Recommended Dose and Schedule. When used in combination with fulvestrant, tamoxifen, or an aromatase inhibitor, the recommended dose of VERZENIO is 150 mg taken orally twice daily. Refer to the Full Prescribing Information for the recommended dose of the fulvestrant, tamoxifen, or aromatase inhibitor being used.Pre/perimenopausal women and men treated with the combination of VERZENIO plus an aromatase inhibitor should be treated with gonadotropin-releasing hormone agonist (GnRH) according to current clinical practice standards.Pre/perimenopausal women treated with the combination of VERZENIO plus fulvestrant should be treated with GnRH according to current clinical practice standardsWhen used as monotherapy, the recommended dose of VERZENIO is 200 mg taken orally twice daily.For early breast cancer, continue VERZENIO until completion of years of treatment or until disease recurrence, or unacceptable toxicity.For advanced or metastatic breast cancer, continue treatment until disease progression or unacceptable toxicity.VERZENIO may be taken with or without food [see Clinical Pharmacology (12.3)].Instruct patients to take their doses of VERZENIO at approximately the same times every day.If the patient vomits or misses dose of VERZENIO, instruct the patient to take the next dose at its scheduled time. Instruct patients to swallow VERZENIO tablets whole and not to chew, crush, or split tablets before swallowing. Instruct patients not to ingest VERZENIO tablets if broken, cracked, or otherwise not intact.. When used in combination with fulvestrant, tamoxifen, or an aromatase inhibitor, the recommended dose of VERZENIO is 150 mg taken orally twice daily. Refer to the Full Prescribing Information for the recommended dose of the fulvestrant, tamoxifen, or aromatase inhibitor being used.. Pre/perimenopausal women and men treated with the combination of VERZENIO plus an aromatase inhibitor should be treated with gonadotropin-releasing hormone agonist (GnRH) according to current clinical practice standards.. Pre/perimenopausal women treated with the combination of VERZENIO plus fulvestrant should be treated with GnRH according to current clinical practice standards. When used as monotherapy, the recommended dose of VERZENIO is 200 mg taken orally twice daily.. For early breast cancer, continue VERZENIO until completion of years of treatment or until disease recurrence, or unacceptable toxicity.. For advanced or metastatic breast cancer, continue treatment until disease progression or unacceptable toxicity.. 2.3 Dose Modification. Dose Modifications for Adverse ReactionsThe recommended VERZENIO dose modifications for adverse reactions are provided in Tables 1-7. Discontinue VERZENIO for patients unable to tolerate 50 mg twice daily.Table 1: VERZENIO Dose Modification -- Adverse ReactionsDose LevelVERZENIO DoseCombination with Fulvestrant, Tamoxifen, or an Aromatase InhibitorVERZENIO Dosefor MonotherapyRecommended starting dose150 mg twice daily200 mg twice dailyFirst dose reduction100 mg twice daily150 mg twice dailySecond dose reduction50 mg twice daily100 mg twice dailyThird dose reductionnot applicable50 mg twice dailyTable 2: VERZENIO Dose Modification and Management -- Hematologic Toxicitiesa Abbreviation: CTCAE Common Terminology Criteria for Adverse Events.a If blood cell growth factors are required, suspend VERZENIO dose for at least 48 hours after the last dose of blood cell growth factor and until toxicity resolves to <=Grade 2. Resume at next lower dose unless already performed for the toxicity that led to the use of the growth factor. Growth factor use as per current treatment guidelines.Monitor complete blood counts prior to the start of VERZENIO therapy, every weeks for the first months, monthly for the next months, and as clinically indicated.CTCAE GradeVERZENIO Dose ModificationsGrade or 2No dose modification is required.Grade 3Suspend dose until toxicity resolves to <=Grade 2.Dose reduction is not required.Grade recurrent, or Grade 4Suspend dose until toxicity resolves to <=Grade 2.Resume at next lower dose.Table 3: VERZENIO Dose Modification and Management -- DiarrheaAt the first sign of loose stools, start treatment with antidiarrheal agents and increase intake of oral fluids.CTCAE GradeVERZENIO Dose ModificationsGrade 1No dose modification is required.Grade 2If toxicity does not resolve within 24 hours to <=Grade 1, suspend dose until resolution. No dose reduction is required.Grade that persists or recurs after resuming the same dose despite maximal supportive measuresSuspend dose until toxicity resolves to <=Grade 1.Resume at next lower dose.Grade or or requires hospitalizationSuspend dose until toxicity resolves to <=Grade 1.Resume at next lower dose.Table 4: VERZENIO Dose Modification and Management -- HepatotoxicityAbbreviations: ALT alanine aminotransferase, AST aspartate aminotransferase, ULN upper limit of normal.Monitor ALT, AST, and serum bilirubin prior to the start of VERZENIO therapy, every weeks for the first months, monthly for the next months, and as clinically indicated.CTCAE Grade for ALT and ASTVERZENIO Dose ModificationsGrade (>ULN-3.0 ULN)Grade (>3.0-5.0 ULN),WITHOUT increase in total bilirubin above x ULNNo dose modification is required.Persistent or Recurrent Grade 2, or Grade (>5.0-20.0 ULN), WITHOUT increase in total bilirubin above x ULNSuspend dose until toxicity resolves to baseline or Grade 1.Resume at next lower dose.Elevation in AST and/or ALT >3 ULN WITH total bilirubin >2 ULN, in the absence of cholestasisDiscontinue VERZENIO.Grade (>20.0 ULN)Discontinue VERZENIO.Table 5: VERZENIO Dose Modification and Management -- Interstitial Lung Disease/PneumonitisCTCAE GradeVERZENIO Dose ModificationsGrade or 2No dose modification is required.Persistent or recurrent Grade toxicity that does not resolve with maximal supportive measures within days to baseline or Grade 1Suspend dose until toxicity resolves to baseline or <=Grade 1.Resume at next lower dose.Grade or 4Discontinue VERZENIO.Table 6: VERZENIO Dose Modification and Management -- Venous Thromboembolic Events (VTEs)CTCAE GradeVERZENIO Dose ModificationsEarly Breast CancerAny GradeSuspend dose and treat as clinically indicated. Resume VERZENIO when the patient is clinically stable.Advanced or Metastatic Breast CancerGrade or 2No dose modification is required.Grade or 4Suspend dose and treat as clinically indicated. Resume VERZENIO when the patient is clinically stable.Table 7: VERZENIO Dose Modification and Management -- Other Toxicitiesa Excluding diarrhea, hematologic toxicity, hepatotoxicity, ILD/pneumonitis, and VTEs.CTCAE GradeVERZENIO Dose ModificationsGrade or 2No dose modification is required.Persistent or recurrent Grade toxicity that does not resolve with maximal supportive measures within days to baseline or Grade 1Suspend dose until toxicity resolves to baseline or <=Grade 1.Resume at next lower dose.Grade or 4Suspend dose until toxicity resolves to baseline or <=Grade 1.Resume at next lower dose.Refer to the Full Prescribing Information for coadministered fulvestrant, tamoxifen, or an aromatase inhibitor for dose modifications and other relevant safety information.. Dose Modification for Use with Strong and Moderate CYP3A InhibitorsAvoid concomitant use of the strong CYP3A inhibitor ketoconazole.With concomitant use of strong CYP3A inhibitors other than ketoconazole, in patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the VERZENIO dose to 100 mg twice daily. In patients who have had dose reduction to 100 mg twice daily due to adverse reactions, further reduce the VERZENIO dose to 50 mg twice daily. If patient taking VERZENIO discontinues CYP3A inhibitor, increase the VERZENIO dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the strong inhibitor [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. With concomitant use of moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the VERZENIO dose in 50 mg decrements as demonstrated in Table 1, if necessary.. Dose Modification for Patients with Severe Hepatic ImpairmentFor patients with severe hepatic impairment (Child Pugh-C), reduce the VERZENIO dosing frequency to once daily [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. Refer to the Full Prescribing Information for the coadministered fulvestrant, tamoxifen, or aromatase inhibitor for dose modification requirements for severe hepatic impairment.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of abemaciclib were characterized in patients with solid tumors, including breast cancer, and in healthy subjects.Following single and repeated twice daily dosing of 50 mg (0.3 times the approved recommended 150 mg dosage) to 200 mg of abemaciclib, the increase in plasma exposure (AUC) and Cmax was approximately dose proportional. Steady state was achieved within days following repeated twice daily dosing, and the estimated geometric mean accumulation ratio was 2.3 (50% CV) and 3.2 (59% CV) based on Cmax and AUC, respectively.. AbsorptionThe absolute bioavailability of abemaciclib after single oral dose of 200 mg is 45% (19% CV). The median Tmax of abemaciclib is 8.0 hours (range: 4.1-24.0 hours).. Effect of FoodA high-fat, high-calorie meal (approximately 800 to 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) administered to healthy subjects increased the AUC of abemaciclib plus its active metabolites by 9% and increased Cmax by 26%.. DistributionIn vitro, abemaciclib was bound to human plasma proteins, serum albumin, and alpha-1-acid glycoprotein in concentration independent manner from 152 ng/mL to 5066 ng/mL. In clinical study, the mean (standard deviation, SD) bound fraction was 96.3% (1.1) for abemaciclib, 93.4% (1.3) for M2, 96.8% (0.8) for M18, and 97.8% (0.6) for M20. The geometric mean systemic volume of distribution is approximately 690.3 (49% CV).In patients with advanced cancer, including breast cancer, concentrations of abemaciclib and its active metabolites M2 and M20 in cerebrospinal fluid are comparable to unbound plasma concentrations.. EliminationThe geometric mean hepatic clearance (CL) of abemaciclib in patients was 26.0 L/h (51% CV), and the mean plasma elimination half-life for abemaciclib in patients was 18.3 hours (72% CV).. MetabolismHepatic metabolism is the main route of clearance for abemaciclib. Abemaciclib is metabolized to several metabolites primarily by cytochrome P450 (CYP) 3A4, with formation of N-desethylabemaciclib (M2) representing the major metabolism pathway. Additional metabolites include hydroxyabemaciclib (M20), hydroxy-N-desethylabemaciclib (M18), and an oxidative metabolite (M1). M2, M18, and M20 are equipotent to abemaciclib and their AUCs accounted for 25%, 13%, and 26% of the total circulating analytes in plasma, respectively.. ExcretionAfter single 150 mg oral dose of radiolabeled abemaciclib, approximately 81% of the dose was recovered in feces and approximately 3% recovered in urine. The majority of the dose eliminated in feces was metabolites.. Specific Populations. Age, Gender, and Body WeightBased on population pharmacokinetic analysis in patients with cancer, age (range 24-91 years), gender (134 males and 856 females), and body weight (range 36-175 kg) had no effect on the exposure of abemaciclib.. Patients with Renal ImpairmentIn population pharmacokinetic analysis of 990 individuals, in which 381 individuals had mild renal impairment (60 mL/min <= CLcr <90 mL/min) and 126 individuals had moderate renal impairment (30 mL/min <= CLcr <60 mL/min), mild and moderate renal impairment had no effect on the exposure of abemaciclib [see Use in Specific Populations (8.6)]. The effect of severe renal impairment (CLcr <30 mL/min) on pharmacokinetics of abemaciclib is unknown.. Patients with Hepatic ImpairmentFollowing single 200 mg oral dose of abemaciclib, the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2, M18, M20) in plasma increased 1.2-fold in subjects with mild hepatic impairment (Child-Pugh A, n=9), 1.1-fold in subjects with moderate hepatic impairment (Child-Pugh B, n=10), and 2.4-fold in subjects with severe hepatic impairment (Child-Pugh C, n=6) relative to subjects with normal hepatic function (n=10) [see Use in Specific Populations (8.7)]. In subjects with severe hepatic impairment, the mean plasma elimination half-life of abemaciclib increased to 55 hours compared to 24 hours in subjects with normal hepatic function.. Drug Interaction Studies. Effects of Other Drugs on Abemaciclib. Strong CYP3A Inhibitors: Ketoconazole (a strong CYP3A inhibitor) is predicted to increase the AUC of abemaciclib by up to 16-fold.Coadministration of 500 mg twice daily doses of clarithromycin (a strong CYP3A inhibitor) with single 50 mg dose of VERZENIO (0.3 times the approved recommended 150 mg dosage) increased the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2, M18, and M20) by 2.5-fold relative to abemaciclib alone in cancer patients.. Moderate CYP3A Inhibitors: Verapamil and diltiazem (moderate CYP3A inhibitors) are predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 1.6-fold and 2.4-fold, respectively.. Strong CYP3A Inducers: Coadministration of 600 mg daily doses of rifampin (a strong CYP3A inducer) with single 200 mg dose of VERZENIO decreased the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 70% in healthy subjects.. Moderate CYP3A Inducers: Efavirenz, bosentan, and modafinil (moderate CYP3A inducers) are predicted to decrease the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 53%, 41%, and 29%, respectively.. Loperamide: Co-administration of single mg dose of loperamide with single 400 mg dose of abemaciclib in healthy subjects increased the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2 and M20) by 12%, which is not considered clinically relevant.. Endocrine Therapies: In clinical studies in patients with breast cancer, there was no clinically relevant effect of fulvestrant, anastrozole, letrozole, exemestane, or tamoxifen on abemaciclib pharmacokinetics.. Effects of Abemaciclib on Other Drugs. Loperamide: In clinical drug interaction study in healthy subjects, coadministration of single mg dose of loperamide with single 400 mg abemaciclib (2.7 times the approved recommended 150 mg dosage) increased loperamide AUC0-INF by 9% and Cmax by 35% relative to loperamide alone. These increases in loperamide exposure are not considered clinically relevant.. Metformin: In clinical drug interaction study in healthy subjects, coadministration of single 1000 mg dose of metformin, clinically relevant substrate of renal OCT2, MATE1, and MATE2-K transporters, with single 400 mg dose of abemaciclib (2.7 times the approved recommended 150 mg dosage) increased metformin AUC0-INF by 37% and Cmax by 22% relative to metformin alone. Abemaciclib reduced the renal clearance and renal secretion of metformin by 45% and 62%, respectively, relative to metformin alone, without any effect on glomerular filtration rate (GFR) as measured by iohexol clearance and serum cystatin C.. Endocrine Therapies: In clinical studies in patients with breast cancer, there was no clinically relevant effect of abemaciclib on the pharmacokinetics of fulvestrant, anastrozole, letrozole, exemestane, or tamoxifen.. CYP Metabolic Pathways: In clinical drug interaction study in patients with cancer, multiple doses of abemaciclib (200 mg twice daily for days) did not result in clinically meaningful changes in the pharmacokinetics of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 substrates. Abemaciclib is substrate of CYP3A4, and time-dependent changes in pharmacokinetics of abemaciclib as result of autoinhibition of its metabolism were not observed.. In Vitro Studies. Transporter Systems: Abemaciclib and its major active metabolites inhibit the renal transporters OCT2, MATE1, and MATE2-K at concentrations achievable at the approved recommended dosage. The observed serum creatinine increase in clinical studies with abemaciclib is likely due to inhibition of tubular secretion of creatinine via OCT2, MATE1, and MATE2-K [see Adverse Effects (6.1)]. Abemaciclib and its major metabolites at clinically relevant concentrations do not inhibit the hepatic uptake transporters OCT1, OATP1B1, and OATP1B3 or the renal uptake transporters OAT1 and OAT3.Abemaciclib is substrate of P-gp and BCRP. Abemaciclib and its major active metabolites, M2 and M20, are not substrates of hepatic uptake transporters OCT1, organic anion transporting polypeptide 1B1 (OATP1B1), or OATP1B3.Abemaciclib inhibits P-gp and BCRP. The clinical consequences of this finding on sensitive P-gp and BCRP substrates are unknown.. P-gp and BCRP Inhibitors: In vitro, abemaciclib is substrate of P-gp and BCRP. The effect of P-gp or BCRP inhibitors on the pharmacokinetics of abemaciclib has not been studied.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Based on animal studies, VERZENIO can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating treatment with VERZENIO.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during VERZENIO treatment and for weeks after the last dose.. Infertility. MalesBased on findings in animals, VERZENIO may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 2791 VERZENIO-treated patients in monarchE, 15% were 65 years of age or older and 2.7% were 75 years of age or older.Of the 900 patients who received VERZENIO in MONARCH 1, MONARCH 2, and MONARCH 3, 38% were 65 years of age or older and 10% were 75 years of age or older. The most common adverse reactions (>=5%) Grade or in patients >=65 years of age across MONARCH 1, 2, and were: neutropenia, diarrhea, fatigue, nausea, dehydration, leukopenia, anemia, infections, and ALT increased.No overall differences in safety or effectiveness of VERZENIO were observed between these patients and younger patients.

HEPATIC IMPAIRMENT SUBSECTION.

8.7 Hepatic Impairment. No dosage adjustments are necessary in patients with mild or moderate hepatic impairment (Child-Pugh or B).Reduce the dosing frequency when administering VERZENIO to patients with severe hepatic impairment (Child-Pugh C) [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedVERZENIO 50 mg tablets are oval beige tablet with Lilly debossed on one side and 50 on the other side.VERZENIO 100 mg tablet are oval white to practically white tablet with Lilly debossed on one side and 100 on the other side.VERZENIO 150 mg tablets are oval yellow tablet with Lilly debossed on one side and 150 on the other side.VERZENIO 200 mg tablets are oval beige tablet with Lilly debossed on one side and 200 on the other side.VERZENIO tablets are supplied in 7-day dose pack configurations as follows:200 mg dose pack (14 tablets) each blister pack contains 14 tablets (200 mg per tablet) (200 mg twice daily)NDC 0002-6216-54150 mg dose pack (14 tablets) each blister pack contains 14 tablets (150 mg per tablet) (150 mg twice daily)NDC 0002-5337-54100 mg dose pack (14 tablets) each blister pack contains 14 tablets (100 mg per tablet) (100 mg twice daily)NDC 0002-4815-5450 mg dose pack (14 tablets) each blister pack contains 14 tablets (50 mg per tablet) (50 mg twice daily)NDC 0002-4483-54. 200 mg dose pack (14 tablets) each blister pack contains 14 tablets (200 mg per tablet) (200 mg twice daily). 150 mg dose pack (14 tablets) each blister pack contains 14 tablets (150 mg per tablet) (150 mg twice daily). 100 mg dose pack (14 tablets) each blister pack contains 14 tablets (100 mg per tablet) (100 mg twice daily). 50 mg dose pack (14 tablets) each blister pack contains 14 tablets (50 mg per tablet) (50 mg twice daily). Storage and HandlingStore at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. VERZENIO(R) is kinase inhibitor indicated:in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor (HER2)-negative, node-positive, early breast cancer at high risk of recurrence and Ki-67 score >=20% as determined by an FDA approved test. (1.1, 2.1, 14.1)in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor (HER2)-negative advanced or metastatic breast cancer. (1.2)in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. (1.2)as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. (1.2). in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor (HER2)-negative, node-positive, early breast cancer at high risk of recurrence and Ki-67 score >=20% as determined by an FDA approved test. (1.1, 2.1, 14.1). in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor (HER2)-negative advanced or metastatic breast cancer. (1.2). in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. (1.2). as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. (1.2). 1.1 Early Breast Cancer. VERZENIO(R) (abemaciclib) is indicated:in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor (HER2)-negative, node-positive, early breast cancer at high risk of recurrence and Ki-67 score >=20% as determined by an FDA approved test [see Dosage and Administration (2.1) and Clinical Studies (14.1)]. in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor (HER2)-negative, node-positive, early breast cancer at high risk of recurrence and Ki-67 score >=20% as determined by an FDA approved test [see Dosage and Administration (2.1) and Clinical Studies (14.1)]. 1.2 Advanced or Metastatic Breast Cancer. VERZENIO (abemaciclib) is indicated:in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor (HER2)-negative advanced or metastatic breast cancer.in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.. in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor (HER2)-negative advanced or metastatic breast cancer.. in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.. as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise patients to read the FDA-approved Patient Information.DiarrheaVERZENIO may cause diarrhea, which may be severe in some cases [see Warnings and Precautions (5.1)].Early identification and intervention is critical for the optimal management of diarrhea. Instruct patients that at the first sign of loose stools, they should start antidiarrheal therapy (for example, loperamide) and notify their healthcare provider for further instructions and appropriate follow up.Encourage patients to increase oral fluids.If diarrhea does not resolve with antidiarrheal therapy within 24 hours to <=Grade 1, suspend VERZENIO dosing [see Dosage and Administration (2.3)].NeutropeniaAdvise patients of the possibility of developing neutropenia and to immediately contact their healthcare provider should they develop fever, particularly in association with any signs of infection [see Warnings and Precautions (5.2)].Interstitial Lung Disease/PneumonitisAdvise patients to immediately report new or worsening respiratory symptoms [see Warnings and Precautions (5.3)].HepatotoxicityInform patients of the signs and symptoms of hepatotoxicity. Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatotoxicity [see Warnings and Precautions (5.4)].Venous ThromboembolismAdvise patients to immediately report any signs or symptoms of thromboembolism such as pain or swelling in an extremity, shortness of breath, chest pain, tachypnea, and tachycardia [see Warnings and Precautions (5.5)].Embryo-Fetal ToxicityAdvise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)].Advise females of reproductive potential to use effective contraception during VERZENIO treatment and for weeks after the last dose [see Use in Specific Populations (8.1, 8.3)].LactationAdvise lactating women not to breastfeed during VERZENIO treatment and for at least weeks after the last dose [see Use in Specific Populations (8.2)].InfertilityInform males of reproductive potential that VERZENIO may impair fertility [see Use in Specific Populations (8.3)].Drug InteractionsInform patients to avoid concomitant use of ketoconazole. Dose reduction may be required for other strong CYP3A inhibitors or for moderate CYP3A inhibitors [see Dosage and Administration (2.3) and Drug Interactions (7)].Grapefruit may interact with VERZENIO. Advise patients not to consume grapefruit products while on treatment with VERZENIO.Advise patients to avoid concomitant use of strong and moderate CYP3A inducers and to consider alternative agents [see Dosage and Administration (2.3) and Drug Interactions (7)].Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Dosage and Administration (2.3) and Drug Interactions (7)].DosingInstruct patients to take the doses of VERZENIO at approximately the same times every day and to swallow whole (do not chew, crush, or split them prior to swallowing) [see Dosage and Administration (2.2)].If patient vomits or misses dose, advise the patient to take the next prescribed dose at the usual time [see Dosage and Administration (2.2)].Advise the patient that VERZENIO may be taken with or without food [see Dosage and Administration 2.2)].Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USACopyright (C) 2017, 2021, Eli Lilly and Company. All rights reserved.VER-0007-USPI-20211012. Early identification and intervention is critical for the optimal management of diarrhea. Instruct patients that at the first sign of loose stools, they should start antidiarrheal therapy (for example, loperamide) and notify their healthcare provider for further instructions and appropriate follow up.. Encourage patients to increase oral fluids.. If diarrhea does not resolve with antidiarrheal therapy within 24 hours to <=Grade 1, suspend VERZENIO dosing [see Dosage and Administration (2.3)].. Advise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)].. Advise females of reproductive potential to use effective contraception during VERZENIO treatment and for weeks after the last dose [see Use in Specific Populations (8.1, 8.3)].. Inform patients to avoid concomitant use of ketoconazole. Dose reduction may be required for other strong CYP3A inhibitors or for moderate CYP3A inhibitors [see Dosage and Administration (2.3) and Drug Interactions (7)].. Grapefruit may interact with VERZENIO. Advise patients not to consume grapefruit products while on treatment with VERZENIO.. Advise patients to avoid concomitant use of strong and moderate CYP3A inducers and to consider alternative agents [see Dosage and Administration (2.3) and Drug Interactions (7)].. Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Dosage and Administration (2.3) and Drug Interactions (7)].. Instruct patients to take the doses of VERZENIO at approximately the same times every day and to swallow whole (do not chew, crush, or split them prior to swallowing) [see Dosage and Administration (2.2)].. If patient vomits or misses dose, advise the patient to take the next prescribed dose at the usual time [see Dosage and Administration (2.2)].. Advise the patient that VERZENIO may be taken with or without food [see Dosage and Administration 2.2)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are no data on the presence of abemaciclib in human milk, or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed infants from VERZENIO, advise lactating women not to breastfeed during VERZENIO treatment and for weeks after the last dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Abemaciclib is an inhibitor of cyclin-dependent kinases and (CDK4 and CDK6). These kinases are activated upon binding to D-cyclins. In estrogen receptor-positive (ER+) breast cancer cell lines, cyclin D1 and CDK4/6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression, and cell proliferation. In vitro, continuous exposure to abemaciclib inhibited Rb phosphorylation and blocked progression from G1 into phase of the cell cycle, resulting in senescence and apoptosis. In breast cancer xenograft models, abemaciclib dosed daily without interruption as single agent or in combination with antiestrogens resulted in reduction of tumor size.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Abemaciclib was assessed for carcinogenicity in 2-year rat study. Abemaciclib was not carcinogenic in male and female rats at oral doses up to mg/kg/day (approximately time the exposure at the maximum recommended human dose based on AUC).Abemaciclib and its active human metabolites M2 and M20 were not mutagenic in bacterial reverse mutation (Ames) assay or clastogenic in an in vitro chromosomal aberration assay in Chinese hamster ovary cells or human peripheral blood lymphocytes. Abemaciclib, M2, and M20 were not clastogenic in an in vivo rat bone marrow micronucleus assay.Abemaciclib may impair fertility in males of reproductive potential. In repeat-dose toxicity studies up to 3-months duration, abemaciclib-related findings in the testis, epididymis, prostate, and seminal vesicle at doses >=10 mg/kg/day in rats and >=0.3 mg/kg/day in dogs included decreased organ weights, intratubular cellular debris, hypospermia, tubular dilatation, atrophy, and degeneration/necrosis. These doses in rats and dogs resulted in approximately and 0.02 times, respectively, the exposure (AUC) in humans at the maximum recommended human dose. In rat male fertility study, abemaciclib had no effects on mating and fertility at oral doses up to 10 mg/kg/day (approximately times the exposure at the maximum recommended human dose based on AUC).In rat female fertility and early embryonic development study, abemaciclib did not affect mating and fertility at doses up to 20 mg/kg/day (approximately times the exposure at the maximum recommended human dose based on AUC).. 13.2 Animal Toxicology and/or Pharmacology. In repeat-dose toxicity studies up to 6-months duration, oral administration of abemaciclib resulted in retinal atrophy of the eyes in mice at dose of 150 mg/kg/day (approximately 10 times the exposure at the maximum recommended human dose based on AUC) and in rats at dose of 30 mg/kg/day (approximately times the exposure at the maximum recommended human dose based on AUC). In 2-year rat carcinogenicity study, oral administration of abemaciclib resulted in retinal atrophy in the eyes at doses >=0.3 mg/kg/day (approximately 0.05 times the exposure at the maximum recommended human dose based on AUC).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE CARTON VERZENIO 50 mg 14ct14 tabletsNDC 0002-4483-54Rx onlyVerzenio(R) (abemaciclib) tablets50 mg dose7-Day SupplyThis 50 mg Dose Pack contains fourteen 50 mg tablets.www.verzenio.comLIFT TO OPENLilly. PACKAGE CARTON VERZENIO 50 mg 14ct.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of VERZENIO have not been established in pediatric patients.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Cardiac ElectrophysiologyBased on evaluation of the QTc interval in patients and in healthy volunteer study, abemaciclib did not cause large mean increases (i.e., 20 ms) in the QTc interval.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on findings in animals and its mechanism of action, VERZENIO can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to fetus. In animal reproduction studies, administration of abemaciclib during organogenesis was teratogenic and caused decreased fetal weight at maternal exposures that were similar to human clinical exposure based on AUC at the maximum recommended human dose (see Data). Advise pregnant women of the potential risk to fetus.The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.. Data. Animal DataIn an embryo-fetal development study, pregnant rats received oral doses of abemaciclib up to 15 mg/kg/day during the period of organogenesis. Doses >=4 mg/kg/day caused decreased fetal body weights and increased incidence of cardiovascular and skeletal malformations and variations. These findings included absent innominate artery and aortic arch, malpositioned subclavian artery, unossified sternebra, bipartite ossification of thoracic centrum, and rudimentary or nodulated ribs. At mg/kg/day in rats, the maternal systemic exposures were approximately equal to the human exposure (AUC) at the recommended dose.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1.1, 1.2)10/2021Dosage and Administration (2.1, 2.2, 2.3)10/2021Warnings and Precautions (5.5)10/2021.

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment. No dosage adjustment is required for patients with mild or moderate renal impairment (CLcr >=30-89 mL/min, estimated by Cockcroft-Gault [C-G]). The pharmacokinetics of abemaciclib in patients with severe renal impairment (CLcr <30 mL/min, C-G), end stage renal disease, or in patients on dialysis is unknown [see Clinical Pharmacology (12.3)].

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: October 2021PATIENT INFORMATIONVERZENIO(R)(ver-ZEN-ee-oh)(abemaciclib)tabletsWhat is the most important information should know about VERZENIOVERZENIO may cause serious side effects including:Diarrhea. Diarrhea is common with VERZENIO treatment and may sometimes be severe. Diarrhea may cause you to develop dehydration or an infection. The most common time to develop diarrhea is during the first month of VERZENIO treatment. If you develop diarrhea during treatment with VERZENIO, your healthcare provider may tell you to temporarily stop taking VERZENIO, stop your treatment, or decrease your dose.-If you have any loose stools, start taking an antidiarrheal medicine (such as loperamide), drink more fluids, and tell your healthcare provider right away.Low white blood cell counts (neutropenia). Low white blood cell counts are common during treatment with VERZENIO and may cause serious infections that can lead to death. Your healthcare provider should check your white blood cell counts before and during treatment. If you develop low white blood cell counts during treatment with VERZENIO, your healthcare provider may tell you to temporarily stop taking VERZENIO, decrease your dose, or wait before starting your next month of treatment. Tell your healthcare provider right away if you have signs and symptoms of low white blood cell counts or infections, such as fever and chills. Lung problems. VERZENIO may cause severe or life-threatening inflammation of the lungs during treatment that can lead to death. If you develop lung problems during treatment with VERZENIO, your healthcare provider may tell you to temporarily stop taking VERZENIO, decrease your dose, or stop your treatment. Tell your healthcare provider right away if you have any new or worsening symptoms, including:-trouble breathing or shortness of breath-cough with or without mucus-chest pain Liver problems. VERZENIO can cause serious liver problems. Your healthcare provider should do blood tests to check your liver before and during treatment with VERZENIO. If you develop liver problems during treatment with VERZENIO, your healthcare provider may reduce your dose or stop your treatment. Tell your healthcare provider right away if you have any of the following signs and symptoms of liver problems:-feeling very tired-pain on the upper right side of your stomach area (abdomen)-loss of appetite-bleeding or bruising more easily than normalBlood clots in your veins, or in the arteries of your lungs. VERZENIO may cause serious blood clots that have led to death. If you develop blood clots during treatment with VERZENIO, your healthcare provider may tell you to temporarily stop taking VERZENIO. Tell your healthcare provider right away if you get any of the following signs and symptoms of blood clot:-pain or swelling in your arms or legs-shortness of breath-chest pain-rapid breathing-rapid heart rateSee What are the possible side effects of VERZENIO for more information about side effects.What is VERZENIOVERZENIO is prescription medicine used:in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) to treat adults with hormone receptor (HR)-positive, human epidermal growth factor receptor (HER2)-negative, node-positive, early breast cancer with high risk of coming back as determined by your healthcare provider.in combination with an aromatase inhibitor as the first endocrine-based therapy to treat women who have gone through menopause (postmenopausal), and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor (HER2)-negative breast cancer that has worsened or that has spread to other parts of the body (metastatic).in combination with fulvestrant to treat adults with hormone receptor (HR)-positive, human epidermal growth factor receptor (HER2)-negative breast cancer that has worsened or spread to other parts of the body (metastatic) and whose disease has progressed after endocrine therapy.alone to treat adults with HR-positive, HER2-negative breast cancer that has worsened or that has spread to other parts of the body (metastatic) and whose disease has progressed after endocrine therapy and prior chemotherapy.When VERZENIO is used in combination with fulvestrant, tamoxifen, or an aromatase inhibitor, also read the Patient Information for the prescribed product. Ask your healthcare provider if you are not sure.It is not known if VERZENIO is safe and effective in children.Before taking VERZENIO, tell your healthcare provider about all of your medical conditions, including if you:have fever, chills, or any other signs of an infection.have history of blood clots in your veins.have lung or breathing problems.have liver or kidney problems.are pregnant or plan to become pregnant. VERZENIO can harm your unborn baby. Females who are able to become pregnant: -Your healthcare provider will do pregnancy test before you start treatment with VERZENIO.-You should use effective birth control (contraception) during treatment with VERZENIO and for weeks after the last dose of VERZENIO.-Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with VERZENIO. are breastfeeding or plan to breastfeed. It is not known if VERZENIO passes into your breast milk. Do not breastfeed during treatment with VERZENIO and for at least weeks after the last dose of VERZENIO.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VERZENIO may affect the way other medicines work, and other medicines may affect how VERZENIO works, causing serious side effects.Especially tell your healthcare provider if you take medicine that contains ketoconazole.Know the medicines you take. Keep list of them to show your healthcare provider or pharmacist when you get new medicine.How should take VERZENIOTake VERZENIO exactly as your healthcare provider tells you.Your healthcare provider may change your dose if needed. Do not stop taking VERZENIO or change the dose without talking to your healthcare provider.VERZENIO may be taken with or without food.Swallow VERZENIO tablets whole. Do not chew, crush, or split the tablets before swallowing. Do not take VERZENIO tablets if they are broken, cracked, or damaged.Take your doses of VERZENIO at about the same time every day.If you vomit or miss dose of VERZENIO, take your next dose at your regular time. Do not take doses of VERZENIO at the same time to make up for the missed dose.What should avoid during treatment with VERZENIOAvoid taking ketoconazole during treatment with VERZENIO. Tell your healthcare provider if you take medicine that contains ketoconazole.Avoid grapefruit and products that contain grapefruit during treatment with VERZENIO. Grapefruit may increase the amount of VERZENIO in your blood.What are the possible side effects of VERZENIOVERZENIO may cause serious side effects, including:See What is the most important information should know about VERZENIO The most common side effects of VERZENIO include:nauseainfectionslow red blood cell counts (anemia)decreased appetiteheadachehair thinning or hair loss (alopecia)abdominal paintirednesslow white blood cell counts (leukopenia)vomitinglow platelet count (thrombocytopenia)VERZENIO may cause fertility problems in males. This may affect your ability to father child. Talk to your healthcare provider if this is concern for you.These are not all the possible side effects of VERZENIO. For more information, ask your healthcare provider or pharmacist.Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store VERZENIOStore VERZENIO at room temperature between 68F to 77F (20C to 25C).Keep VERZENIO and all medicines out of the reach of children.General information about the safe and effective use of VERZENIO.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use VERZENIO for condition for which it was not prescribed. Do not give VERZENIO to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for more information about VERZENIO that is written for health professionals.What are the ingredients in VERZENIOActive ingredient: abemaciclib Inactive ingredients: microcrystalline cellulose 102, microcrystalline cellulose 101, lactose monohydrate, croscarmellose sodium, sodium stearyl fumarate, silicon dioxide. Color mixture ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide yellow, iron oxide red. Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright (C) 2017, 2021, Eli Lilly and Company. All rights reserved.VER-0004-PPI-20211012For more information, go to www.verzenio.com or call 1-800-545-5979.. Diarrhea. Diarrhea is common with VERZENIO treatment and may sometimes be severe. Diarrhea may cause you to develop dehydration or an infection. The most common time to develop diarrhea is during the first month of VERZENIO treatment. If you develop diarrhea during treatment with VERZENIO, your healthcare provider may tell you to temporarily stop taking VERZENIO, stop your treatment, or decrease your dose.-If you have any loose stools, start taking an antidiarrheal medicine (such as loperamide), drink more fluids, and tell your healthcare provider right away.. -If you have any loose stools, start taking an antidiarrheal medicine (such as loperamide), drink more fluids, and tell your healthcare provider right away.. Low white blood cell counts (neutropenia). Low white blood cell counts are common during treatment with VERZENIO and may cause serious infections that can lead to death. Your healthcare provider should check your white blood cell counts before and during treatment. If you develop low white blood cell counts during treatment with VERZENIO, your healthcare provider may tell you to temporarily stop taking VERZENIO, decrease your dose, or wait before starting your next month of treatment. Tell your healthcare provider right away if you have signs and symptoms of low white blood cell counts or infections, such as fever and chills. Lung problems. VERZENIO may cause severe or life-threatening inflammation of the lungs during treatment that can lead to death. If you develop lung problems during treatment with VERZENIO, your healthcare provider may tell you to temporarily stop taking VERZENIO, decrease your dose, or stop your treatment. Tell your healthcare provider right away if you have any new or worsening symptoms, including:-trouble breathing or shortness of breath-cough with or without mucus-chest pain -trouble breathing or shortness of breath. -cough with or without mucus. -chest pain. Liver problems. VERZENIO can cause serious liver problems. Your healthcare provider should do blood tests to check your liver before and during treatment with VERZENIO. If you develop liver problems during treatment with VERZENIO, your healthcare provider may reduce your dose or stop your treatment. Tell your healthcare provider right away if you have any of the following signs and symptoms of liver problems:. -feeling very tired. -pain on the upper right side of your stomach area (abdomen). -loss of appetite. -bleeding or bruising more easily than normal. Blood clots in your veins, or in the arteries of your lungs. VERZENIO may cause serious blood clots that have led to death. If you develop blood clots during treatment with VERZENIO, your healthcare provider may tell you to temporarily stop taking VERZENIO. Tell your healthcare provider right away if you get any of the following signs and symptoms of blood clot:. -pain or swelling in your arms or legs. -shortness of breath. -chest pain. -rapid breathing. -rapid heart rate. in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) to treat adults with hormone receptor (HR)-positive, human epidermal growth factor receptor (HER2)-negative, node-positive, early breast cancer with high risk of coming back as determined by your healthcare provider.. in combination with an aromatase inhibitor as the first endocrine-based therapy to treat women who have gone through menopause (postmenopausal), and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor (HER2)-negative breast cancer that has worsened or that has spread to other parts of the body (metastatic).. in combination with fulvestrant to treat adults with hormone receptor (HR)-positive, human epidermal growth factor receptor (HER2)-negative breast cancer that has worsened or spread to other parts of the body (metastatic) and whose disease has progressed after endocrine therapy.. alone to treat adults with HR-positive, HER2-negative breast cancer that has worsened or that has spread to other parts of the body (metastatic) and whose disease has progressed after endocrine therapy and prior chemotherapy.. have fever, chills, or any other signs of an infection.. have history of blood clots in your veins.. have lung or breathing problems.. have liver or kidney problems.. are pregnant or plan to become pregnant. VERZENIO can harm your unborn baby. Females who are able to become pregnant: -Your healthcare provider will do pregnancy test before you start treatment with VERZENIO.-You should use effective birth control (contraception) during treatment with VERZENIO and for weeks after the last dose of VERZENIO.-Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with VERZENIO. -Your healthcare provider will do pregnancy test before you start treatment with VERZENIO.. -You should use effective birth control (contraception) during treatment with VERZENIO and for weeks after the last dose of VERZENIO.. -Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with VERZENIO.. are breastfeeding or plan to breastfeed. It is not known if VERZENIO passes into your breast milk. Do not breastfeed during treatment with VERZENIO and for at least weeks after the last dose of VERZENIO.. Take VERZENIO exactly as your healthcare provider tells you.. Your healthcare provider may change your dose if needed. Do not stop taking VERZENIO or change the dose without talking to your healthcare provider.. VERZENIO may be taken with or without food.. Swallow VERZENIO tablets whole. Do not chew, crush, or split the tablets before swallowing. Do not take VERZENIO tablets if they are broken, cracked, or damaged.. Take your doses of VERZENIO at about the same time every day.. If you vomit or miss dose of VERZENIO, take your next dose at your regular time. Do not take doses of VERZENIO at the same time to make up for the missed dose.. Avoid taking ketoconazole during treatment with VERZENIO. Tell your healthcare provider if you take medicine that contains ketoconazole.. Avoid grapefruit and products that contain grapefruit during treatment with VERZENIO. Grapefruit may increase the amount of VERZENIO in your blood.. See What is the most important information should know about VERZENIO nausea. infections. low red blood cell counts (anemia). decreased appetite. headache. hair thinning or hair loss (alopecia). abdominal pain. tiredness. low white blood cell counts (leukopenia). vomiting. low platelet count (thrombocytopenia). Store VERZENIO at room temperature between 68F to 77F (20C to 25C).

SPL UNCLASSIFIED SECTION.

1.1 Early Breast Cancer. VERZENIO(R) (abemaciclib) is indicated:in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor (HER2)-negative, node-positive, early breast cancer at high risk of recurrence and Ki-67 score >=20% as determined by an FDA approved test [see Dosage and Administration (2.1) and Clinical Studies (14.1)]. in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor (HER2)-negative, node-positive, early breast cancer at high risk of recurrence and Ki-67 score >=20% as determined by an FDA approved test [see Dosage and Administration (2.1) and Clinical Studies (14.1)].

STORAGE AND HANDLING SECTION.

Storage and HandlingStore at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on findings in animals and its mechanism of action, VERZENIO can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to fetus. In animal reproduction studies, administration of abemaciclib during organogenesis was teratogenic and caused decreased fetal weight at maternal exposures that were similar to human clinical exposure based on AUC at the maximum recommended human dose (see Data). Advise pregnant women of the potential risk to fetus.The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.. Data. Animal DataIn an embryo-fetal development study, pregnant rats received oral doses of abemaciclib up to 15 mg/kg/day during the period of organogenesis. Doses >=4 mg/kg/day caused decreased fetal body weights and increased incidence of cardiovascular and skeletal malformations and variations. These findings included absent innominate artery and aortic arch, malpositioned subclavian artery, unossified sternebra, bipartite ossification of thoracic centrum, and rudimentary or nodulated ribs. At mg/kg/day in rats, the maternal systemic exposures were approximately equal to the human exposure (AUC) at the recommended dose.. 8.2 Lactation. Risk SummaryThere are no data on the presence of abemaciclib in human milk, or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed infants from VERZENIO, advise lactating women not to breastfeed during VERZENIO treatment and for weeks after the last dose.. 8.3 Females and Males of Reproductive Potential. Based on animal studies, VERZENIO can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating treatment with VERZENIO.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during VERZENIO treatment and for weeks after the last dose.. Infertility. MalesBased on findings in animals, VERZENIO may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use. The safety and effectiveness of VERZENIO have not been established in pediatric patients.. 8.5 Geriatric Use. Of the 2791 VERZENIO-treated patients in monarchE, 15% were 65 years of age or older and 2.7% were 75 years of age or older.Of the 900 patients who received VERZENIO in MONARCH 1, MONARCH 2, and MONARCH 3, 38% were 65 years of age or older and 10% were 75 years of age or older. The most common adverse reactions (>=5%) Grade or in patients >=65 years of age across MONARCH 1, 2, and were: neutropenia, diarrhea, fatigue, nausea, dehydration, leukopenia, anemia, infections, and ALT increased.No overall differences in safety or effectiveness of VERZENIO were observed between these patients and younger patients.. 8.6 Renal Impairment. No dosage adjustment is required for patients with mild or moderate renal impairment (CLcr >=30-89 mL/min, estimated by Cockcroft-Gault [C-G]). The pharmacokinetics of abemaciclib in patients with severe renal impairment (CLcr <30 mL/min, C-G), end stage renal disease, or in patients on dialysis is unknown [see Clinical Pharmacology (12.3)].. 8.7 Hepatic Impairment. No dosage adjustments are necessary in patients with mild or moderate hepatic impairment (Child-Pugh or B).Reduce the dosing frequency when administering VERZENIO to patients with severe hepatic impairment (Child-Pugh C) [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Diarrhea: VERZENIO can cause severe cases of diarrhea, associated with dehydration and infection. Instruct patients at the first sign of loose stools to initiate antidiarrheal therapy, increase oral fluids, and notify their healthcare provider. (2.3, 5.1)Neutropenia: Monitor complete blood counts prior to the start of VERZENIO therapy, every weeks for the first months, monthly for the next months, and as clinically indicated. (2.3, 5.2)Interstitial Lung Disease (ILD)/Pneumonitis: Severe and fatal cases of ILD/pneumonitis have been reported. Monitor for clinical symptoms or radiological changes indicative of ILD/pneumonitis. Permanently discontinue VERZENIO in all patients with Grade or ILD or pneumonitis. (2.3, 5.3)Hepatotoxicity: Increases in serum transaminase levels have been observed. Perform liver function tests (LFTs) before initiating treatment with VERZENIO. Monitor LFTs every two weeks for the first two months, monthly for the next months, and as clinically indicated. (2.3, 5.4)Venous Thromboembolism: Monitor patients for signs and symptoms of thrombosis and pulmonary embolism and treat as medically appropriate. (2.3, 5.5)Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of potential risk to fetus and to use effective contraception. (5.6, 8.1, 8.3). Diarrhea: VERZENIO can cause severe cases of diarrhea, associated with dehydration and infection. Instruct patients at the first sign of loose stools to initiate antidiarrheal therapy, increase oral fluids, and notify their healthcare provider. (2.3, 5.1). Neutropenia: Monitor complete blood counts prior to the start of VERZENIO therapy, every weeks for the first months, monthly for the next months, and as clinically indicated. (2.3, 5.2). Interstitial Lung Disease (ILD)/Pneumonitis: Severe and fatal cases of ILD/pneumonitis have been reported. Monitor for clinical symptoms or radiological changes indicative of ILD/pneumonitis. Permanently discontinue VERZENIO in all patients with Grade or ILD or pneumonitis. (2.3, 5.3). Hepatotoxicity: Increases in serum transaminase levels have been observed. Perform liver function tests (LFTs) before initiating treatment with VERZENIO. Monitor LFTs every two weeks for the first two months, monthly for the next months, and as clinically indicated. (2.3, 5.4). Venous Thromboembolism: Monitor patients for signs and symptoms of thrombosis and pulmonary embolism and treat as medically appropriate. (2.3, 5.5). Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of potential risk to fetus and to use effective contraception. (5.6, 8.1, 8.3). 5.1 Diarrhea. Severe diarrhea associated with dehydration and infection occurred in patients treated with VERZENIO.Across four clinical trials in 3691 patients, diarrhea occurred in 81% to 90% of patients who received VERZENIO. Grade diarrhea occurred in 8% to 20% of patients receiving VERZENIO [see Adverse Reactions (6.1)]. Most patients experienced diarrhea during the first month of VERZENIO treatment. The median time to onset of the first diarrhea event ranged from to days; and the median duration of Grade and Grade diarrhea ranged from to 11 days and to days, respectively. Across trials, 19% to 26% of patients with diarrhea required VERZENIO dose interruption and 13% to 23% required dose reduction.Instruct patients to start antidiarrheal therapy such as loperamide at the first sign of loose stools, increase oral fluids, and notify their healthcare provider for further instructions and appropriate follow up [see Patient Counseling Information (17)]. For Grade or diarrhea, or diarrhea that requires hospitalization, discontinue VERZENIO until toxicity resolves to <=Grade 1, and then resume VERZENIO at the next lower dose [see Dosage and Administration (2.3)].. 5.2 Neutropenia. Neutropenia, including febrile neutropenia and fatal neutropenic sepsis, occurred in patients treated with VERZENIO.Across four clinical trials in 3691 patients, neutropenia occurred in 37% to 46% of patients receiving VERZENIO. Grade >=3 decrease in neutrophil count (based on laboratory findings) occurred in 19% to 32% of patients receiving VERZENIO. Across trials, the median time to the first episode of Grade >=3 neutropenia ranged from 29 days to 33 days, and the median duration of Grade >=3 neutropenia ranged from 11 days to 16 days [see Adverse Reactions (6.1)].Febrile neutropenia has been reported in <1% of patients exposed to VERZENIO across trials. Two deaths due to neutropenic sepsis were observed in MONARCH 2. Inform patients to promptly report any episodes of fever to their healthcare provider [see Patient Counseling Information (17)].Monitor complete blood counts prior to the start of VERZENIO therapy, every weeks for the first months, monthly for the next months, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade or neutropenia [see Dosage and Administration (2.3)].. 5.3 Interstitial Lung Disease (ILD) or Pneumonitis. Severe, life-threatening, or fatal interstitial lung disease (ILD) or pneumonitis can occur in patients treated with VERZENIO and other CDK4/6 inhibitors. In VERZENIO-treated patients in early breast cancer (monarchE, N=2791), 3% of patients experienced ILD or pneumonitis of any grade: 0.4% were Grade or and there was one fatality (0.1%). In VERZENIO-treated patients in advanced or metastatic breast cancer (N=900) (MONARCH 1, MONARCH 2, MONARCH 3), 3.3% of VERZENIO-treated patients had ILD or pneumonitis of any grade: 0.6% had Grade or 4, and 0.4% had fatal outcomes. Additional cases of ILD or pneumonitis have been observed in the postmarketing setting, with fatalities reported [see Adverse Reactions (6.2)].Monitor patients for pulmonary symptoms indicative of ILD or pneumonitis. Symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded by means of appropriate investigations.Dose interruption or dose reduction is recommended for patients who develop persistent or recurrent Grade ILD or pneumonitis. Permanently discontinue VERZENIO in all patients with Grade or ILD or pneumonitis [see Dosage and Administration (2.3)].. 5.4 Hepatotoxicity. Grade >=3 ALT (2% to 6%) and AST (2% to 3%) were reported in patients receiving VERZENIO.Across three clinical trials in 3559 patients (monarchE, MONARCH 2, MONARCH 3), the median time to onset of Grade >=3 ALT increases ranged from 57 to 87 days and the median time to resolution to Grade <3 was 13 to 14 days. The median time to onset of Grade >=3 AST increases ranged from 71 to 185 days and the median time to resolution to Grade <3 ranged from 11 to 15 days.Monitor liver function tests (LFTs) prior to the start of VERZENIO therapy, every weeks for the first months, monthly for the next months, and as clinically indicated. Dose interruption, dose reduction, dose discontinuation, or delay in starting treatment cycles is recommended for patients who develop persistent or recurrent Grade 2, or any Grade or Grade hepatic transaminase elevation [see Dosage and Administration (2.3)].. 5.5 Venous Thromboembolism. Across three clinical trials in 3559 patients (monarchE, MONARCH 2, MONARCH 3), venous thromboembolic events were reported in 2% to 5% of patients treated with VERZENIO. Venous thromboembolic events included deep vein thrombosis, pulmonary embolism, pelvic venous thrombosis, cerebral venous sinus thrombosis, subclavian and axillary vein thrombosis, and inferior vena cava thrombosis. In clinical trials, deaths due to venous thromboembolism have been reported in patients treated with VERZENIO.VERZENIO has not been studied in patients with early breast cancer who had history of venous thromboembolism. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate. Dose interruption is recommended for early breast cancer patients with any grade venous thromboembolic event and for advanced or metastatic breast cancer patients with Grade or venous thromboembolic event [see Dosage and Administration (2.3)].. 5.6 Embryo-Fetal Toxicity. Based on findings from animal studies and the mechanism of action, VERZENIO can cause fetal harm when administered to pregnant woman. In animal reproduction studies, administration of abemaciclib to pregnant rats during the period of organogenesis caused teratogenicity and decreased fetal weight at maternal exposures that were similar to the human clinical exposure based on area under the curve (AUC) at the maximum recommended human dose.Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with VERZENIO and for weeks after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].