Verzenio

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 )] . 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 a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The 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 a single agent at 200 mg twice daily in 132 patients in MONARCH 1 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 1 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 a high risk of recurrence The safety of VERZENIO was evaluated in monarchE, a 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 3 or 4 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 8 and laboratory abnormalities are shown in Table 9 . Table 8: Adverse Reactions (≥10%) of Patients Receiving VERZENIO Plus Tamoxifen or an Aromatase Inhibitor [with a Difference between Arms of ≥2%] in monarchE a 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 Plus Tamoxifen or an Aromatase Inhibitor N=2791 Tamoxifen or an Aromatase Inhibitor N=2800 All Grades a % Grade 3 % Grade 4 % All Grades b % Grade 3 % Grade 4 % Gastrointestinal Disorders Diarrhea 84 8 0 9 0.2 0 Nausea 30 0.5 0 9 <0.1 0 Vomiting 18 0.5 0 4.6 0.1 0 Stomatitis c 14 0.1 0 5 0 0 Infections and Infestations Infections d 51 4.9 0.6 39 2.7 0.1 General Disorders and Administration Site Conditions Fatigue e 41 2.9 0 18 0.1 0 Nervous System Disorders Headache 20 0.3 0 15 0.2 0 Dizziness 11 0.1 0 7 <0.1 0 Metabolism and Nutrition Disorders Decreased appetite 12 0.6 0 2.4 <0.1 0 Skin and Subcutaneous Tissue Disorders Rash f 11 0.4 0 4.5 0 0 Alopecia 11 0 0 2.7 0 0 Clinically 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 a Difference between Arms of ≥2%] in monarchE VERZENIO Plus Tamoxifen or an Aromatase Inhibitor N=2791 Tamoxifen or an Aromatase Inhibitor N=2800 All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Creatinine increased 99 0.5 0 91 <0.1 0 White blood cell decreased 89 19 <0.1 28 1.1 0 Neutrophil count decreased 84 18 0.7 23 1.6 0.3 Anemia 68 1.0 0 17 0.1 0 Lymphocyte count decreased 59 13 0.2 24 2.4 0.1 Platelet count decreased 37 0.7 0.2 10 0.1 0.1 Alanine aminotransferase increased 37 2.5 <0.1 24 1.2 0 Aspartate aminotransferase increased 31 1.5 <0.1 18 0.9 0 Hypokalemia 11 1.2 0.1 3.8 0.1 0.1 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 setting The safety of VERZENIO was evaluated in MONARCH 3, a 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 physician's 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 3 or 4 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 3 cases (2%) of placebo plus an aromatase inhibitor treated patients. Causes of death for patients receiving VERZENIO plus an aromatase inhibitor included: 3 (0.9%) patient deaths due to underlying disease, 3 (0.9%) due to lung infection, 3 (0.9%) due to VTE, 1 (0.3%) due to pneumonitis, and 1 (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 8 days, and the median durations of diarrhea for Grades 2 and for Grade 3 were 11 days and 8 days, respectively. Most diarrhea events recovered or resolved (88%) with supportive treatment and/or dose reductions [see Dosage and Administration ( 2.2 ) and Patient Counseling Information ( 17 )] . Nineteen percent of patients with diarrhea required a dose omission and 13% required a 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 a Difference between Arms of ≥2%] in MONARCH 3 a 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 plus Anastrozole or Letrozole N=327 Placebo plus Anastrozole or Letrozole N=161 All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Gastrointestinal Disorders Diarrhea 81 9 0 30 1.2 0 Nausea 39 0.9 0 20 1.2 0 Abdominal pain 29 1.2 0 12 1.2 0 Vomiting 28 1.2 0 12 1.9 0 Constipation 16 0.6 0 12 0 0 Infections and Infestations Infections a 39 4.0 0.9 29 2.5 0.6 General Disorders and Administration Site Conditions Fatigue 40 1.8 0 32 0 0 Influenza like illness 10 0 0 8 0 0 Skin and Subcutaneous Tissue Disorders Alopecia 27 0 0 11 0 0 Rash 14 0.9 0 5 0 0 Pruritus 13 0 0 9 0 0 Metabolism and Nutrition Disorders Decreased appetite 24 1.2 0 9 0.6 0 Investigations Weight decreased 10 0.6 0 3.1 0.6 0 Respiratory, Thoracic, and Mediastinal Disorders Cough 13 0 0 9 0 0 Dyspnea 12 0.6 0.3 6 0.6 0 Nervous System Disorders Dizziness 11 0.3 0 9 0 0 Additional adverse reactions in MONARCH 3 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 a Difference Between Arms of ≥2%] in MONARCH 3 VERZENIO plus Anastrozole or Letrozole N=327 Placebo plus Anastrozole or Letrozole N=161 Laboratory Abnormality All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Creatinine increased 98 2.2 0 84 0 0 White blood cell decreased 82 13 0 27 0.6 0 Anemia 82 1.6 0 28 0 0 Neutrophil count decreased 80 19 2.9 21 2.6 0 Lymphocyte count decreased 53 7 0.6 26 1.9 0 Platelet count decreased 36 1.3 0.6 12 0.6 0 Alanine aminotransferase increased 48 6 0.6 25 1.9 0 Aspartate aminotransferase increased 37 3.8 0 23 0.6 0 Creatinine Increased Abemaciclib 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 therapy The safety of VERZENIO (150 mg twice daily) plus fulvestrant (500 mg) versus placebo plus fulvestrant was evaluated in MONARCH 2 [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 8 months for patients receiving placebo plus fulvestrant. The most frequently reported (≥5%) Grade 3 or 4 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: 7 (2%) patient deaths due to underlying disease, 4 (0.9%) due to sepsis, 2 (0.5%) due to pneumonitis, 2 (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 a Difference Between Arms of ≥2%] in MONARCH 2 a 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 Fulvestrant N=441 Placebo plus Fulvestrant N=223 All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Gastrointestinal Disorders Diarrhea 86 13 0 25 0.4 0 Nausea 45 2.7 0 23 0.9 0 Abdominal pain a 35 2.5 0 16 0.9 0 Vomiting 26 0.9 0 10 1.8 0 Stomatitis 15 0.5 0 10 0 0 Infections and Infestations Infections b 43 5 0.7 25 3.1 0.4 General Disorders and Administration Site Conditions Fatigue c 46 2.7 0 32 0.4 0 Edema peripheral 12 0 0 7 0 0 Pyrexia 11 0.5 0.2 6 0.4 0 Metabolism and Nutrition Disorders Decreased appetite 27 1.1 0 12 0.4 0 Respiratory, Thoracic and Mediastinal Disorders Cough 13 0 0 11 0 0 Skin and Subcutaneous Tissue Disorders Alopecia 16 0 0 1.8 0 0 Pruritus 13 0 0 6 0 0 Rash 11 1.1 0 4.5 0 0 Nervous System Disorders Headache 20 0.7 0 15 0.4 0 Dysgeusia 18 0 0 2.7 0 0 Dizziness 12 0.7 0 6 0 0 Investigations Weight decreased 10 0.2 0 2.2 0.4 0 Additional adverse reactions in MONARCH 2 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 a Difference Between Arms of ≥2%]in MONARCH 2 VERZENIO plus Fulvestrant N=441 Placebo plus Fulvestrant N=223 All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Creatinine increased 98 1.2 0 74 0 0 White blood cell decreased 90 23 0.7 33 0.9 0 Neutrophil count decreased 87 29 3.5 30 3.7 0.5 Anemia 84 2.6 0 34 0.5 0 Lymphocyte count decreased 63 12 0.2 32 1.8 0 Platelet count decreased 53 0.9 1.2 15 0 0 Alanine aminotransferase increased 41 3.9 0.7 32 1.4 0 Aspartate aminotransferase increased 37 3.9 0 25 3.7 0.5 Creatinine Increased Abemaciclib 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 a 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 setting The safety of VERZENIO was evaluated in MONARCH 1, a 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 3 or 4 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 1 a Includes asthenia, fatigue. VERZENIO N=132 All Grades % Grade 3 % Grade 4 % Gastrointestinal Disorders Diarrhea 90 20 0 Nausea 64 4.5 0 Abdominal pain 39 2.3 0 Vomiting 35 1.5 0 Constipation 17 0.8 0 Dry mouth 14 0 0 Stomatitis 14 0 0 Infections and Infestations Infections 31 4.5 0 General Disorders and Administration Site Conditions Fatigue a 65 13 0 Pyrexia 11 0 0 Metabolism and Nutrition Disorders Decreased appetite 45 3.0 0 Dehydration 10 2.3 0 Respiratory, Thoracic and Mediastinal Disorders Cough 19 0 0 Musculoskeletal and Connective Tissue Disorders Arthralgia 15 0 0 Nervous System Disorders Headache 20 0 0 Dysgeusia 12 0 0 Dizziness 11 0 0 Skin and Subcutaneous Tissue Disorders Alopecia 12 0 0 Investigations Weight decreased 14 0 0 Table 15: Laboratory Abnormalities for Patients Receiving VERZENIO in MONARCH 1 VERZENIO N=132 All Grades % Grade 3 % Grade 4 % Creatinine increased 99 0.8 0 White blood cell decreased 91 28 0 Neutrophil count decreased 88 22 4.6 Anemia 69 0 0 Lymphocyte count decreased 42 13 0.8 Platelet count decreased 41 2.3 0 ALT increased 31 3.1 0 AST increased 30 3.8 0 Creatinine Increased Abemaciclib 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 a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Respiratory disorders : Interstitial lung disease (ILD)/pneumonitis [see Warnings and Precautions ( 5.3 )] .

4 CONTRAINDICATIONS None. None. ( 4 )

11 DESCRIPTION Abemaciclib is a kinase inhibitor for oral administration. It is a white to yellow powder with the empirical formula C 27 H 32 F 2 N 8 and a 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)-1 H -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

2 DOSAGE AND ADMINISTRATION VERZENIO tablets are taken orally with or without food. ( 2.1 ) Recommended starting dose in combination with fulvestrant, tamoxifen, or an aromatase inhibitor: 150 mg twice daily. ( 2.1 ) Recommended starting dose as monotherapy: 200 mg twice daily. ( 2.1 ) Dosing interruption and/or dose reductions may be required based on individual safety and tolerability. ( 2.2 ) 2.1 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 a 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 a 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 2 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 a 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. 2.2 Dose Modification Dose Modifications for Adverse Reactions The 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 Reactions Dose Level VERZENIO Dose Combination with Fulvestrant, Tamoxifen, or an Aromatase Inhibitor VERZENIO Dose for Monotherapy Recommended starting dose 150 mg twice daily 200 mg twice daily First dose reduction 100 mg twice daily 150 mg twice daily Second dose reduction 50 mg twice daily 100 mg twice daily Third dose reduction not applicable 50 mg twice daily Table 2: VERZENIO Dose Modification and Management — Hematologic Toxicities a 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 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. CTCAE Grade VERZENIO Dose Modifications Grade 1 or 2 No dose modification is required. Grade 3 Suspend dose until toxicity resolves to ≤Grade 2. Dose reduction is not required. Grade 3 recurrent, or Grade 4 Suspend dose until toxicity resolves to ≤Grade 2. Resume at next lower dose . Table 3: VERZENIO Dose Modification and Management — Diarrhea At the first sign of loose stools, start treatment with antidiarrheal agents and increase intake of oral fluids. CTCAE Grade VERZENIO Dose Modifications Grade 1 No dose modification is required. Grade 2 If toxicity does not resolve within 24 hours to ≤Grade 1, suspend dose until resolution. No dose reduction is required. Grade 2 that persists or recurs after resuming the same dose despite maximal supportive measures Suspend dose until toxicity resolves to ≤Grade 1. Resume at next lower dose . Grade 3 or 4 or requires hospitalization Suspend dose until toxicity resolves to ≤Grade 1. Resume at next lower dose . Table 4: VERZENIO Dose Modification and Management — Hepatotoxicity Abbreviations: 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 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. CTCAE Grade for ALT and AST VERZENIO Dose Modifications Grade 1 (>ULN-3.0 x ULN) Grade 2 (>3.0-5.0 x ULN), WITHOUT increase in total bilirubin above 2 x ULN No dose modification is required. Persistent or Recurrent Grade 2, or Grade 3 (>5.0-20.0 x ULN), WITHOUT increase in total bilirubin above 2 x ULN Suspend dose until toxicity resolves to baseline or Grade 1. Resume at next lower dose. Elevation in AST and/or ALT >3 x ULN WITH total bilirubin >2 x ULN, in the absence of cholestasis Discontinue VERZENIO. Grade 4 (>20.0 x ULN) Discontinue VERZENIO. Table 5: VERZENIO Dose Modification and Management — Interstitial Lung Disease/Pneumonitis CTCAE Grade VERZENIO Dose Modifications Grade 1 or 2 No dose modification is required. Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1 Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose . Grade 3 or 4 Discontinue VERZENIO. Table 6: VERZENIO Dose Modification and Management — Venous Thromboembolic Events (VTEs) CTCAE Grade VERZENIO Dose Modifications Early Breast Cancer Any Grade Suspend dose and treat as clinically indicated. Resume VERZENIO when the patient is clinically stable. Advanced or Metastatic Breast Cancer Grade 1 or 2 No dose modification is required. Grade 3 or 4 Suspend dose and treat as clinically indicated. Resume VERZENIO when the patient is clinically stable. Table 7: VERZENIO Dose Modification and Management — Other Toxicities a a Excluding diarrhea, hematologic toxicity, hepatotoxicity, ILD/pneumonitis, and VTEs. CTCAE Grade VERZENIO Dose Modifications Grade 1 or 2 No dose modification is required. Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1 Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose . Grade 3 or 4 Suspend 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 Inhibitors Avoid 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 a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the VERZENIO dose to 50 mg twice daily. If a patient taking VERZENIO discontinues a 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 Impairment For 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.

1 INDICATIONS AND USAGE VERZENIO ® is a 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 2 (HER2)-negative, node-positive, early breast cancer at high risk of recurrence. ( 1.1 , 14.1 ) in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (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 2 (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 ® (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 2 (HER2)-negative, node-positive, early breast cancer at high risk of recurrence [see 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 adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (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 2 (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.

7 DRUG INTERACTIONS CYP3A Inhibitors: Avoid concomitant use of ketoconazole. Reduce the VERZENIO dose with concomitant use of other strong and moderate CYP3A inhibitors. ( 2.2 , 7.1 ) CYP3A Inducers: Avoid concomitant use of strong and moderate CYP3A inducers. ( 7.1 ) 7.1 Effect of Other Drugs on VERZENIO CYP3A Inhibitors Strong and moderate CYP3A4 inhibitors increased the exposure of abemaciclib plus its active metabolites to a clinically meaningful extent and may lead to increased toxicity. Ketoconazole Avoid 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 Inhibitors 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 with concomitant use of strong CYP3A inhibitors other than ketoconazole. In patients who have had a 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 a patient taking VERZENIO discontinues a 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 ( 2.2 ) and Clinical Pharmacology ( 12.3 )] . Moderate CYP3A Inhibitors 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. Strong and Moderate CYP3A Inducers Coadministration 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 )] .

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Abemaciclib is an inhibitor of cyclin-dependent kinases 4 and 6 (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 S phase of the cell cycle, resulting in senescence and apoptosis. In breast cancer xenograft models, abemaciclib dosed daily without interruption as a single agent or in combination with antiestrogens resulted in reduction of tumor size. 12.2 Pharmacodynamics Cardiac Electrophysiology Based on evaluation of the QTc interval in patients and in a 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 C max was approximately dose proportional. Steady state was achieved within 5 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 C max and AUC, respectively. Absorption The absolute bioavailability of abemaciclib after a single oral dose of 200 mg is 45% (19% CV). The median T max of abemaciclib is 8.0 hours (range: 4.1-24.0 hours). Effect of Food A 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 C max by 26%. Distribution In vitro, abemaciclib was bound to human plasma proteins, serum albumin, and alpha-1-acid glycoprotein in a concentration independent manner from 152 ng/mL to 5066 ng/mL. In a 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 L (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. Elimination The 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). Metabolism Hepatic 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. Excretion After a 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 Weight Based on a 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 Impairment In a 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 Impairment Following a single 200 mg oral dose of abemaciclib, the relative potency adjusted unbound AUC 0-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 a single 50 mg dose of VERZENIO (0.3 times the approved recommended 150 mg dosage) increased the relative potency adjusted unbound AUC 0-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 a single 200 mg dose of VERZENIO decreased the relative potency adjusted unbound AUC 0-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 a single 8 mg dose of loperamide with a single 400 mg dose of abemaciclib in healthy subjects increased the relative potency adjusted unbound AUC 0-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 a clinical drug interaction study in healthy subjects, coadministration of a single 8 mg dose of loperamide with a single 400 mg abemaciclib (2.7 times the approved recommended 150 mg dosage) increased loperamide AUC 0-INF by 9% and C max by 35% relative to loperamide alone. These increases in loperamide exposure are not considered clinically relevant. Metformin: In a clinical drug interaction study in healthy subjects, coadministration of a single 1000 mg dose of metformin, a clinically relevant substrate of renal OCT2, MATE1, and MATE2-K transporters, with a single 400 mg dose of abemaciclib (2.7 times the approved recommended 150 mg dosage) increased metformin AUC 0-INF by 37% and C max 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 a clinical drug interaction study in patients with cancer, multiple doses of abemaciclib (200 mg twice daily for 7 days) did not result in clinically meaningful changes in the pharmacokinetics of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 substrates. Abemaciclib is a substrate of CYP3A4, and time-dependent changes in pharmacokinetics of abemaciclib as a 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 a 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 a substrate of P-gp and BCRP. The effect of P-gp or BCRP inhibitors on the pharmacokinetics of abemaciclib has not been studied.

12.1 Mechanism of Action Abemaciclib is an inhibitor of cyclin-dependent kinases 4 and 6 (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 S phase of the cell cycle, resulting in senescence and apoptosis. In breast cancer xenograft models, abemaciclib dosed daily without interruption as a single agent or in combination with antiestrogens resulted in reduction of tumor size.

12.2 Pharmacodynamics Cardiac Electrophysiology Based on evaluation of the QTc interval in patients and in a 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 C max was approximately dose proportional. Steady state was achieved within 5 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 C max and AUC, respectively. Absorption The absolute bioavailability of abemaciclib after a single oral dose of 200 mg is 45% (19% CV). The median T max of abemaciclib is 8.0 hours (range: 4.1-24.0 hours). Effect of Food A 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 C max by 26%. Distribution In vitro, abemaciclib was bound to human plasma proteins, serum albumin, and alpha-1-acid glycoprotein in a concentration independent manner from 152 ng/mL to 5066 ng/mL. In a 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 L (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. Elimination The 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). Metabolism Hepatic 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. Excretion After a 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 Weight Based on a 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 Impairment In a 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 Impairment Following a single 200 mg oral dose of abemaciclib, the relative potency adjusted unbound AUC 0-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 a single 50 mg dose of VERZENIO (0.3 times the approved recommended 150 mg dosage) increased the relative potency adjusted unbound AUC 0-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 a single 200 mg dose of VERZENIO decreased the relative potency adjusted unbound AUC 0-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 a single 8 mg dose of loperamide with a single 400 mg dose of abemaciclib in healthy subjects increased the relative potency adjusted unbound AUC 0-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 a clinical drug interaction study in healthy subjects, coadministration of a single 8 mg dose of loperamide with a single 400 mg abemaciclib (2.7 times the approved recommended 150 mg dosage) increased loperamide AUC 0-INF by 9% and C max by 35% relative to loperamide alone. These increases in loperamide exposure are not considered clinically relevant. Metformin: In a clinical drug interaction study in healthy subjects, coadministration of a single 1000 mg dose of metformin, a clinically relevant substrate of renal OCT2, MATE1, and MATE2-K transporters, with a single 400 mg dose of abemaciclib (2.7 times the approved recommended 150 mg dosage) increased metformin AUC 0-INF by 37% and C max 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 a clinical drug interaction study in patients with cancer, multiple doses of abemaciclib (200 mg twice daily for 7 days) did not result in clinically meaningful changes in the pharmacokinetics of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 substrates. Abemaciclib is a substrate of CYP3A4, and time-dependent changes in pharmacokinetics of abemaciclib as a 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 a 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 a substrate of P-gp and BCRP. The effect of P-gp or BCRP inhibitors on the pharmacokinetics of abemaciclib has not been studied.

20230303

19

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 )

Verzenio abemaciclib abemaciclib abemaciclib Microcrystalline Cellulose Lactose Monohydrate Croscarmellose Sodium Silicon Dioxide Sodium Stearyl Fumarate Water Polyvinyl Alcohol, Unspecified Polyethylene Glycol, Unspecified Titanium Dioxide Talc Ferric Oxide Yellow Ferric Oxide Red beige modified oval Lilly;50 Verzenio abemaciclib abemaciclib abemaciclib Microcrystalline Cellulose Lactose Monohydrate Croscarmellose Sodium Silicon Dioxide Sodium Stearyl Fumarate Water Polyvinyl Alcohol, Unspecified Polyethylene Glycol, Unspecified Titanium Dioxide Talc white modified oval Lilly;100 Verzenio abemaciclib abemaciclib abemaciclib Microcrystalline Cellulose Lactose Monohydrate Croscarmellose Sodium Silicon Dioxide Sodium Stearyl Fumarate Water Polyvinyl Alcohol, Unspecified Polyethylene Glycol, Unspecified Titanium Dioxide Talc Ferric Oxide Yellow yellow modified oval Lilly;150 Verzenio abemaciclib abemaciclib abemaciclib Microcrystalline Cellulose Lactose Monohydrate Croscarmellose Sodium Silicon Dioxide Sodium Stearyl Fumarate Water Polyvinyl Alcohol, Unspecified Polyethylene Glycol, Unspecified Titanium Dioxide Talc Ferric Oxide Yellow Ferric Oxide Red beige modified oval Lilly;200

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 a dose of 150 mg/kg/day (approximately 10 times the exposure at the maximum recommended human dose based on AUC) and in rats at a dose of 30 mg/kg/day (approximately 5 times the exposure at the maximum recommended human dose based on AUC). In a 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).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Abemaciclib was assessed for carcinogenicity in a 2-year rat study. Abemaciclib was not carcinogenic in male and female rats at oral doses up to 3 mg/kg/day (approximately 1 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 a 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 2 and 0.02 times, respectively, the exposure (AUC) in humans at the maximum recommended human dose. In a rat male fertility study, abemaciclib had no effects on mating and fertility at oral doses up to 10 mg/kg/day (approximately 2 times the exposure at the maximum recommended human dose based on AUC). In a rat female fertility and early embryonic development study, abemaciclib did not affect mating and fertility at doses up to 20 mg/kg/day (approximately 3 times the exposure at the maximum recommended human dose based on AUC).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Abemaciclib was assessed for carcinogenicity in a 2-year rat study. Abemaciclib was not carcinogenic in male and female rats at oral doses up to 3 mg/kg/day (approximately 1 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 a 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 2 and 0.02 times, respectively, the exposure (AUC) in humans at the maximum recommended human dose. In a rat male fertility study, abemaciclib had no effects on mating and fertility at oral doses up to 10 mg/kg/day (approximately 2 times the exposure at the maximum recommended human dose based on AUC). In a rat female fertility and early embryonic development study, abemaciclib did not affect mating and fertility at doses up to 20 mg/kg/day (approximately 3 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 a dose of 150 mg/kg/day (approximately 10 times the exposure at the maximum recommended human dose based on AUC) and in rats at a dose of 30 mg/kg/day (approximately 5 times the exposure at the maximum recommended human dose based on AUC). In a 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).

NDA208716

Verzenio

abemaciclib

0002-5337

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE CARTON – VERZENIO 50 mg 14ct 14 tablets NDC 0002-4483-54 Rx only Verzenio ® (abemaciclib) tablets 50 mg dose 7-Day Supply This 50 mg Dose Pack contains fourteen 50 mg tablets. www.verzenio.com LIFT TO OPEN Lilly PACKAGE CARTON – VERZENIO 50 mg 14ct

Indications and Usage ( 1.1 , 1.2 ) 03/2023 Dosage and Administration, Patient Selection Removed ( 2 ) 03/2023

17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved Patient Information. Diarrhea VERZENIO 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 ( 2.2 )] . Neutropenia Advise patients of the possibility of developing neutropenia and to immediately contact their healthcare provider should they develop a fever, particularly in association with any signs of infection [see Warnings and Precautions ( 5.2 )] . Interstitial Lung Disease/Pneumonitis Advise patients to immediately report new or worsening respiratory symptoms [see Warnings and Precautions ( 5.3 )] . Hepatotoxicity Inform 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 Thromboembolism Advise 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 Toxicity Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions ( 5.6 ) and Use in Specific Populations ( 8.1 )] . Advise females of reproductive potential to use effective contraception during VERZENIO treatment and for 3 weeks after the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] . Lactation Advise lactating women not to breastfeed during VERZENIO treatment and for at least 3 weeks after the last dose [see Use in Specific Populations ( 8.2 )] . Infertility Inform males of reproductive potential that VERZENIO may impair fertility [see Use in Specific Populations ( 8.3 )] . Drug Interactions 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 ( 2.2 ) 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 ( 2.2 ) 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 ( 2.2 ) and Drug Interactions ( 7 )] . Dosing 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 ( 2.1 )] . If patient vomits or misses a dose, advise the patient to take the next prescribed dose at the usual time [see Dosage and Administration ( 2.1 )] . Advise the patient that VERZENIO may be taken with or without food [see Dosage and Administration 2.1 )] . Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright © 2017, 2023, Eli Lilly and Company. All rights reserved. VER-0008-USPI-20230303

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 recurrence monarchE (NCT03155997) was a 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 a high risk of disease recurrence. To be enrolled, patients had to have HR-positive HER2-negative early breast cancer with tumor involvement in at least 1 axillary lymph node (pALN) and to be enrolled in cohort 1 had to have either: ≥4 pALN or 1-3 pALN and at least one of: – tumor grade 3 or – tumor size ≥50 mm Patients enrolled in cohort 2 could not have met the eligibility criteria for cohort 1. To be enrolled in cohort 2, patients had to have 1-3 pALN and Ki-67 score ≥20%. Breast tumor samples were tested at central sites using the Ki-67 IHC MIB-1 pharmDx (Dako Omnis) assay to establish if the Ki-67 score was ≥20%. Patients were randomized to receive 2 years of VERZENIO plus physician's 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 a duration of at least 5 years if deemed medically appropriate. 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 (OS) was an additional outcome measure. A statistically significant difference in IDFS was observed in the intent-to-treat (ITT) population which was primarily attributed to the patients treated in cohort 1. While the OS data in cohort 2 remains immature, more deaths were observed among those receiving VERZENIO plus standard endocrine therapy compared to those receiving standard endocrine therapy alone (10/253 vs. 5/264). Of 5637 patients randomized, 5120 (91%) were randomized in cohort 1. Patient median age was 51 years (range, 22-89 years), 99% were women, 70% were White, 24% were Asian, 1.7% were Black or African American, 2.1% were American Indian or Alaska Native, and 0.1% were Native Hawaiian or Other Pacific Islander. Forty-three percent of patients were premenopausal. Most patients received prior chemotherapy (37% neoadjuvant, 59% adjuvant) and prior radiotherapy (96%). Sixty-five percent of the patients had 4 or more positive lymph nodes with 22% having ≥10 positive lymph nodes, 41% had Grade 3 tumor, and 24% had pathological tumor size ≥50 mm. The majority of patients (99%) had estrogen receptor positive disease and 87% had progesterone receptor positive disease. Initial endocrine therapy received by patients included letrozole (39%), tamoxifen (31%), anastrozole (22%), or exemestane (8%). Efficacy results for cohort 1 are summarized in Table 16 and Figure 1 . At the time of OS interim analysis 2, OS was immature and a total of 315 (6%) of patients had died in cohort 1. Table 16: Efficacy Results in monarchE in Cohort 1 Abbreviation: CI = confidence interval. VERZENIO Plus Tamoxifen or an Aromatase Inhibitor N=2555 Tamoxifen or an Aromatase Inhibitor N=2565 Invasive Disease–Free Survival (IDFS) Number of patients with an event (n, %) 317 (12.4) 474 (18.5) Hazard ratio (95% CI) 0.653 (0.567, 0.753) p-value 0.0042 a IDFS at 48 months (%, 95% CI) 85.5 (83.8, 87.0) 78.6 (76.7, 80.4) 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 1 (monarchE) 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 setting MONARCH 3 (NCT02246621) was a 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 a 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). A total of 493 patients were randomized to receive 150 mg VERZENIO or placebo orally twice daily, plus physician's 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%). A 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 a 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 OS data were immature. Table 17: Efficacy Results in MONARCH 3 (Investigator Assessment, Intent-to-Treat Population) Abbreviations: CI = confidence interval, NR = not reached. a Complete response + partial response. b Based upon confirmed responses. VERZENIO plus Anastrozole or Letrozole Placebo plus Anastrozole or Letrozole Progression-Free Survival N=328 N=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 <0.0001 Objective Response for Patients with Measurable Disease N=267 N=132 Objective response rate a,b (n, %) 148 (55.4) 53 (40.2) 95% CI 49.5, 61.4 31.8, 48.5 Figure 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 therapy MONARCH 2 (NCT02107703) was a 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 2 years of adjuvant endocrine therapy or progressive disease within the first 6 months of first line endocrine therapy for metastatic breast cancer. A total of 669 patients were randomized to receive VERZENIO or placebo orally twice daily plus intramuscular injection of 500 mg fulvestrant on days 1 and 15 of cycle 1 and then on day 1 of cycle 2 and beyond (28-day cycles). Pre/perimenopausal women were enrolled in the study and received the gonadotropin-releasing hormone agonist goserelin for at least 4 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 0 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 2 study are summarized in Table 18 , Figure 3 , and Figure 4 . PFS assessment based on a 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 2 (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 a 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 Fulvestrant Placebo plus Fulvestrant Progression-Free Survival (Investigator Assessment) N=446 N=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-value a p<.0001 Overall Survival b 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-value a p=.0137 Objective Response for Patients with Measurable Disease N=318 N=164 Objective response rate c (n, %) 153 (48.1) 35 (21.3) 95% CI 42.6, 53.6 15.1, 27.6 Figure 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 a 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 setting MONARCH 1 (NCT02102490) was a 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 a taxane in any setting, and who received 1 or 2 prior chemotherapy regimens in the metastatic setting. A total of 132 patients received 200 mg VERZENIO orally twice daily on a 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 0 (55% of patients) or 1 (45%). The median duration of metastatic disease was 27.6 months. Ninety percent (90%) of patients had visceral metastases, and 51% of patients had 3 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 a 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 1 (Intent-to-Treat Population) Abbreviations: CI = confidence interval, NR = not reached. a All responses were partial responses. b Based upon confirmed responses. VERZENIO 200 mg N=132 Investigator Assessed Independent Review Objective Response Rate a,b , n (%) 26 (19.7) 23 (17.4) 95% CI (%) 13.3, 27.5 11.4, 25.0 Median Duration of Response 8.6 months 7.2 months 95% CI (%) 5.8, 10.2 5.6, NR

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 3 or 4 in patients ≥65 years of age across MONARCH 1, 2, and 3 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.

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

8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action, VERZENIO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a 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 a 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 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. Data Animal Data In 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 4 mg/kg/day in rats, the maternal systemic exposures were approximately equal to the human exposure (AUC) at the recommended dose.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action, VERZENIO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a 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 a 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 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. Data Animal Data In 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 4 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 Summary There 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 3 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 a pregnant woman [see Use in Specific Populations ( 8.1 )] . Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating treatment with VERZENIO. Contraception Females Advise females of reproductive potential to use effective contraception during VERZENIO treatment and for 3 weeks after the last dose. Infertility Males Based 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 3 or 4 in patients ≥65 years of age across MONARCH 1, 2, and 3 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 A or B). Reduce the dosing frequency when administering VERZENIO to patients with severe hepatic impairment (Child-Pugh C) [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied VERZENIO 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 0002-6216-54 150 mg dose pack (14 tablets) – each blister pack contains 14 tablets (150 mg per tablet) (150 mg twice daily) NDC 0002-5337-54 100 mg dose pack (14 tablets) – each blister pack contains 14 tablets (100 mg per tablet) (100 mg twice daily) NDC 0002-4815-54 50 mg dose pack (14 tablets) – each blister pack contains 14 tablets (50 mg per tablet) (50 mg twice daily) NDC 0002-4483-54 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

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