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Neutropenia [see Neutropenia under Precautions].
Interstitial Lung Disease (ILD)/Pneumonitis [see Interstitial Lung Disease (ILD)/Pneumonitis under Precautions].
Hepatotoxicity [see Hepatotoxicity under Precautions].
Venous Thromboembolism [see Venous Thromboembolism under Precautions].
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.
MONARCH 3: YULAREB 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: MONARCH 3 was a study of 488 women receiving YULAREB plus an aromatase inhibitor or placebo plus an aromatase inhibitor. Patients were randomly assigned to receive 150 mg of YULAREB 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 YULAREB arm and 13.9 months for the placebo arm. Median dose compliance was 98% for the YULAREB arm and 99% for the placebo arm.
Dose reductions due to an adverse reaction occurred in 43% of patients receiving YULAREB plus anastrozole or letrozole. Adverse reactions leading to dose reductions in ≥5% of patients were diarrhea and neutropenia. YULAREB dose reductions due to diarrhea of any grade occurred in 13% of patients receiving YULAREB plus an aromatase inhibitor compared to 2% of patients receiving placebo plus an aromatase inhibitor. YULAREB dose reductions due to neutropenia of any grade occurred in 11% of patients receiving YULAREB plus an aromatase inhibitor compared to 0.6% of patients receiving placebo plus an aromatase inhibitor.
Permanent treatment discontinuation due to an adverse event was reported in 13% of patients receiving YULAREB plus an aromatase inhibitor and in 3% of patients receiving placebo plus an aromatase inhibitor. Adverse reactions leading to permanent discontinuation for patients receiving YULAREB 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%).
Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 11 cases (3%) of YULAREB plus an aromatase inhibitor treated patients versus 3 cases (2%) of placebo plus an aromatase inhibitor treated patients. Causes of death for patients receiving YULAREB 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 event, 1 (0.3%) due to pneumonitis, and 1 (0.3%) due to cerebral infarction. The most common adverse reactions reported (≥20%) in the YULAREB arm and ≥2% than the placebo arm were diarrhea, neutropenia, fatigue, infections, nausea, abdominal pain, anemia, vomiting, alopecia, decreased appetite, and leukopenia (Table 9). The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, diarrhea, leukopenia, increased ALT, and anemia. Diarrhea incidence was greatest during the first month of YULAREB 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 Dose Modification under Dosage & Administration and Patient Counselling Information].
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. (See Table 9.)
Click on icon to see table/diagram/imageAdditional 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 YULAREB plus anastrozole or letrozole as compared to 0.6% of patients treated with anastrozole or letrozole plus placebo. (See Table 10.)
Click on icon to see table/diagram/imageCreatinine Increased: Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function [see Pharmacology: Pharmacokinetics under Actions]. Across the clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of YULAREB 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: YULAREB 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 YULAREB (150 mg twice daily) plus fulvestrant (500 mg) versus placebo plus fulvestrant was evaluated in MONARCH 2. The data described as follows reflect exposure to YULAREB in 441 patients with HR-positive, HER2-negative advanced breast cancer who received at least one dose of YULAREB plus fulvestrant in MONARCH 2.
Median duration of treatment was 12 months for patients receiving YULAREB plus fulvestrant and 8 months for patients receiving placebo plus fulvestrant.
Dose reductions due to an adverse reaction occurred in 43% of patients receiving YULAREB plus fulvestrant. Adverse reactions leading to dose reductions in ≥5% of patients were diarrhea and neutropenia. YULAREB dose reductions due to diarrhea of any grade occurred in 19% of patients receiving YULAREB plus fulvestrant compared to 0.4% of patients receiving placebo and fulvestrant. YULAREB dose reductions due to neutropenia of any grade occurred in 10% of patients receiving YULAREB plus fulvestrant compared to no patients receiving placebo plus fulvestrant.
Permanent study treatment discontinuation due to an adverse event were reported in 9% of patients receiving YULAREB plus fulvestrant and in 3% of patients receiving placebo plus fulvestrant. Adverse reactions leading to permanent discontinuation for patients receiving YULAREB 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%).
Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 18 cases (4%) of YULAREB plus fulvestrant treated patients versus 10 cases (5%) of placebo plus fulvestrant treated patients. Causes of death for patients receiving YULAREB 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.
The most common adverse reactions reported (≥20%) in the YULAREB arm were diarrhea, fatigue, neutropenia, nausea, infections, abdominal pain, anemia, leukopenia, decreased appetite, vomiting, and headache (Table 11). The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, diarrhea, leukopenia, anemia, and infections. (See Table 11.)
Click on icon to see table/diagram/imageAdditional 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 YULAREB plus fulvestrant as compared to 0.9% of patients treated with fulvestrant plus placebo. (See Table 12.)
Click on icon to see table/diagram/imageCreatinine Increased: Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function [see Pharmacology: Pharmacokinetics under Actions]. In clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of YULAREB 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.
Postmarketing experience: The following adverse reactions have been identified during post-approval use of YULAREB. 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 Interstitial Lung Disease (ILD)/Pneumonitis under Precautions].
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