Abemaciclib

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# Overview
Abemaciclib is an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) that is FDA approved 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.   Common adverse reactions include diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, and thrombocytopenia..

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- In combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women 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 women 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.
- 150 mg taken orally twice daily.
- 500 mg of fulverstrant is administered on Days 1, 15, and 29; and once monthly thereafter.
- 200 mg taken orally twice daily.
- Continue treatment until disease progression or unacceptable toxicity. Abemaciclib may be taken with or without food.
- Instruct patients to take their doses of abemaciclib at approximately the same times every day.
- If the patient vomits or misses a dose of abemaciclib, instruct the patient to take the next dose at its scheduled time. Instruct patients to swallow abemaciclib tablets whole and not to chew, crush, or split tablets before swallowing. Instruct patients not to ingest abemaciclib tablets if broken, cracked, or otherwise not intact.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding abemaciclib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding abemaciclib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Abemaciclib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding abemaciclib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding abemaciclib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

# Contraindications
- None

# Warnings
- Diarrhea occurred in 81% of patients receiving abemaciclib plus an aromatase inhibitor in MONARCH 3, 86% of patients receiving abemaciclib plus fulvestrant in MONARCH 2, and 90% of patients receiving abemaciclib alone in MONARCH 1. Grade 3 diarrhea occurred in 9% of patients receiving abemaciclib plus an aromatase inhibitor in MONARCH 3, 13% of patients receiving abemaciclib plus fulvestrant in MONARCH 2, and in 20% of patients receiving abemaciclib alone in MONARCH 1. Episodes of diarrhea have been associated with dehydration and infection.
- Instruct patients that at the first sign of loose stools, they should start antidiarrheal therapy such as loperamide, increase oral fluids, and notify their healthcare provider for further instructions and appropriate follow up. For Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization, discontinue abemaciclib until toxicity resolves to Grade 1, and then resume abemaciclib at the next lower dose.
- Neutropenia occurred in 41% of patients receiving abemaciclib plus an aromatase inhibitor in MONARCH 3, 46% of patients receiving abemaciclib plus fulvestrant in MONARCH 2, and 37% of patients receiving abemaciclib alone in MONARCH 1. A Grade 3 decrease in neutrophil count (based on laboratory findings) occurred in 22% of patients receiving abemaciclib plus an aromatase inhibitor in MONARCH 3, 32% of patients receiving abemaciclib plus fulvestrant in MONARCH 2, and in 27% of patients receiving abemaciclib in MONARCH 1. In MONARCH 3, the median time to first episode of Grade 3 neutropenia was 33 days, and in MONARCH 2 and MONARCH 1 was 29 days. In MONARCH 3, median duration of Grade 3 neutropenia was 11 days, and for MONARCH 2 and MONARCH 1 was 15 days.
- Monitor complete blood counts prior to the start of abemaciclib therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.
- Febrile neutropenia has been reported in <1% of patients exposed to abemaciclib in the MONARCH studies. Two deaths due to neutropenic sepsis were observed in MONARCH 2. Inform patients to promptly report any episodes of fever to their healthcare provider.
- In MONARCH 3, Grade 3 increases in ALT (6% versus 2%) and AST (3% versus 1%) were reported in the abemaciclib and placebo arms, respectively. In MONARCH 2, Grade 3 increases in ALT (4% versus 2%) and AST (2% versus 3%) were reported in the abemaciclib and placebo arms, respectively.
- In MONARCH 3, for patients receiving abemaciclib plus an aromatase inhibitor with Grade 3 ALT increased, median time to onset was 61 days, and median time to resolution to Grade <3 was 14 days. In MONARCH 2, for patients receiving abemaciclib plus fulvestrant with Grade 3 ALT increased, median time to onset was 57 days, and median time to resolution to Grade <3 was 14 days. In MONARCH 3, for patients receiving abemaciclib plus an aromatase inhibitor with Grade 3 AST increased, median time to onset was 71 days, and median time to resolution was 15 days. In MONARCH 2, for patients receiving abemaciclib plus fulvestrant with Grade 3 AST increased, median time to onset was 185 days, and median time to resolution was 13 days.
- Monitor liver function tests (LFTs) prior to the start of abemaciclib therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, dose discontinuation, or delay in starting treatment cycles is recommended for patients who develop persistent or recurrent Grade 2, or Grade 3 or 4, hepatic transaminase elevation.
- In MONARCH 3, venous thromboembolic events were reported in 5% of patients treated with abemaciclib plus an aromatase inhibitor as compared to 0.6% of patients treated with an aromatase inhibitor plus placebo. In MONARCH 2, venous thromboembolic events were reported in 5% of patients treated with abemaciclib plus fulvestrant as compared to 0.9% of patients treated with fulvestrant plus placebo. Venous thromboembolic events included deep vein thrombosis, pulmonary embolism, pelvic venous thrombosis, cerebral venous sinus thrombosis, subclavian and axillary vein thrombosis, and inferior vena cava thrombosis. Across the clinical development program, deaths due to venous thromboembolism have been reported.
- Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate.
- Based on findings from animal studies and the mechanism of action, abemaciclib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of abemaciclib to pregnant rats during the period of organogenesis caused teratogenicity and decreased fetal weight at maternal exposures that were similar to the human clinical exposure based on area under the curve (AUC) at the maximum recommended human dose.
- Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with abemaciclib and for at least 3 weeks after the last dose.

# Adverse Reactions

## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

### MONARCH 3: Abemaciclib 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 abemaciclib plus an aromatase inhibitor or placebo plus an aromatase inhibitor. Patients were randomly assigned to receive 150 mg of abemaciclib 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 abemaciclib arm and 13.9 months for the placebo arm. Median dose compliance was 98% for the abemaciclib arm and 99% for the placebo arm.
- Dose reductions due to an adverse reaction occurred in 43% of patients receiving abemaciclib plus anastrozole or letrozole. Adverse reactions leading to dose reductions in 5% of patients were diarrhea and neutropenia. Abemaciclib dose reductions due to diarrhea of any grade occurred in 13% of patients receiving abemaciclib plus an aromatase inhibitor compared to 2% of patients receiving placebo plus an aromatase inhibitor. Abemaciclib dose reductions due to neutropenia of any grade occurred in 11% of patients receiving abemaciclib 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 abemaciclib plus an aromatase inhibitor and in 3% placebo plus an aromatase inhibitor. Adverse reactions leading to permanent discontinuation for patients receiving abemaciclib 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 abemaciclib plus an aromatase inhibitor treated patients versus 3 cases (2%) of placebo plus an aromatase inhibitor treated patients. Causes of death for patients receiving abemaciclib 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 abemaciclib arm and 2% than the placebo arm were diarrhea, neutropenia, fatigue, infections, nausea, abdominal pain, anemia, vomiting, alopecia, decreased appetite, and leukopenia. 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 abemaciclib 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. 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.
- 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 abemaciclib plus anastrozole or letrozole as compared to 0.6% of patients treated with anastrozole or letrozole plus placebo.
- Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function. Across the clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of abemaciclib 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.
- 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 abemaciclib (150 mg twice daily) plus fulvestrant (500 mg) versus placebo plus fulvestrant was evaluated in MONARCH 2. The data described below reflect exposure to abemaciclib in 441 patients with HR-positive, HER2-negative advanced breast cancer who received at least one dose of abemaciclib plus fulvestrant in MONARCH 2.
- Median duration of treatment was 12 months for patients receiving abemaciclib plus fulvestrant and 8 months for patients receiving placebo plus fulvestrant.
- Dose reductions due to an adverse reaction occurred in 43% of patients receiving abemaciclib plus fulvestrant. Adverse reactions leading to dose reductions in 5% of patients were diarrhea and neutropenia. Abemaciclib dose reductions due to diarrhea of any grade occurred in 19% of patients receiving abemaciclib plus fulvestrant compared to 0.4% of patients receiving placebo and fulvestrant. Abemaciclib dose reductions due to neutropenia of any grade occurred in 10% of patients receiving abemaciclib 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 abemaciclib plus fulvestrant and in 3% of patients receiving placebo plus fulvestrant. Adverse reactions leading to permanent discontinuation for patients receiving abemaciclib 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 abemaciclib plus fulvestrant treated patients versus 10 cases (5%) of placebo plus fulvestrant treated patients. Causes of death for patients receiving abemaciclib 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 abemaciclib arm were diarrhea, fatigue, neutropenia, nausea, infections, abdominal pain, anemia, leukopenia, decreased appetite, vomiting, and headache. The most frequently reported (5%) Grade 3 or 4 adverse reactions were neutropenia, diarrhea, leukopenia, anemia, and infections.
- 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 abemaciclib plus fulvestrant as compared to 0.9% of patients treated with fulvestrant plus placebo.
- Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function. In clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of abemaciclib 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.
- Patients with HR-positive, HER2-negative breast cancer who received prior endocrine therapy and 1-2 chemotherapy regimens in the metastatic setting
- Safety data below are based on MONARCH 1, a single-arm, open-label, multicenter study in 132 women with measurable HR-positive, HER2-negative metastatic breast cancer. Patients received 200 mg abemaciclib orally twice daily until development of progressive disease or unmanageable toxicity. Median duration of treatment was 4.5 months.
- 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. 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%).
- Deaths 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.
- The most common reported adverse reactions (20%) were diarrhea, fatigue, nausea, decreased appetite, abdominal pain, neutropenia, vomiting, infections, anemia, headache, and thrombocytopenia. Severe (Grade 3 and 4) neutropenia was observed in patients receiving abemaciclib.
- Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function. In clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of abemaciclib 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.

## Postmarketing Experience
There is limited information regarding Abemaciclib Postmarketing Experience in the drug label.

# Drug Interactions
- Strong CYP3A Inhibitors
- Strong CYP3A Inducers
- Strong 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.
- In patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the abemaciclib dose to 100 mg twice daily with concomitant use of other strong CYP3A inhibitors. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the abemaciclib dose to 50 mg twice daily with concomitant use of other strong CYP3A inhibitors. If a patient taking abemaciclib discontinues a strong CYP3A inhibitor, increase the abemaciclib dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the strong inhibitor. Patients should avoid grapefruit products.
- Coadministration of abemaciclib with rifampin, a strong CYP3A inducer, decreased the plasma concentrations of abemaciclib plus its active metabolites and may lead to reduced activity. Avoid concomitant use of strong CYP3A inducers and consider alternative agents.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
Based on findings in animals and its mechanism of action, abemaciclib can cause fetal harm when administered to a pregnant woman. 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. 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.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Abemaciclib in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Abemaciclib during labor and delivery.

### Nursing Mothers
- 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 abemaciclib, advise lactating women not to breastfeed during abemaciclib treatment and for at least 3 weeks after the last dose.

### Pediatric Use
- The safety and effectiveness of abemaciclib have not been established in pediatric patients.

### Geriatic Use
- Of the 900 patients who received abemaciclib 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 abemaciclib were observed between these patients and younger patients.

### Gender
There is no FDA guidance on the use of Abemaciclib with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Abemaciclib with respect to specific racial populations.

### Renal Impairment
- No dosage adjustment is required for patients with mild or moderate renal impairment (CLcr 30-89 mL/min, estimated by Cockcroft-Gault ). 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.

### 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 abemaciclib to patients with severe hepatic impairment (Child-Pugh C).

### Females of Reproductive Potential and Males
Pregnancy Testing
- Based on animal studies, abemaciclib can cause fetal harm when administered to a pregnant woman. Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with abemaciclib.
Contraception
- Abemaciclib can cause fetal harm when administered to a pregnant woman . Advise females of reproductive potential to use effective contraception during abemaciclib treatment and for at least 3 weeks after the last dose.
Infertility
- Based on findings in animals, abemaciclib may impair fertility in males of reproductive potential.

### Immunocompromised Patients
There is no FDA guidance one the use of Abemaciclib in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- When used in combination with fulvestrant or an aromatase inhibitor, the recommended dose of abemaciclib is 150 mg taken orally twice daily.
- When given with abemaciclib, refer to the Full Prescribing Information for the recommended dose of the aromatase inhibitor being used.
- When given with abemaciclib, the recommended dose of fulvestrant is 500 mg administered on Days 1, 15, and 29; and once monthly thereafter. Refer to the Full Prescribing Information for fulvestrant. Pre/perimenopausal women treated with the combination of abemaciclib plus fulvestrant should be treated with a gonadotropin-releasing hormone agonist according to current clinical practice standards.
- When used as monotherapy, the recommended dose of abemaciclib is 200 mg taken orally twice daily.
- Continue treatment until disease progression or unacceptable toxicity. Abemaciclib may be taken with or without food.
- Instruct patients to take their doses of abemaciclib at approximately the same times every day.
- If the patient vomits or misses a dose of abemaciclib, instruct the patient to take the next dose at its scheduled time. Instruct patients to swallow abemaciclib tablets whole and not to chew, crush, or split tablets before swallowing. Instruct patients not to ingest abemaciclib tablets if broken, cracked, or otherwise not intact.

### Monitoring
- Avoid concomitant use of the strong CYP3A inhibitor ketoconazole.
- With concomitant use of other strong CYP3A inhibitors, in patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the abemaciclib 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 abemaciclib dose to 50 mg twice daily. If a patient taking abemaciclib discontinues a strong CYP3A inhibitor, increase the abemaciclib dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the strong inhibitor.
- For patients with severe hepatic impairment (Child Pugh-C), reduce the abemaciclib dosing frequency to once daily.

# IV Compatibility
There is limited information regarding the compatibility of Abemaciclib and IV administrations.

# Overdosage
- There is no known antidote for abemaciclib. The treatment of overdose of abemaciclib should consist of general supportive measures.

# Pharmacology

## 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.

## Structure
- Abemaciclib is a kinase inhibitor for oral administration. It is a white to yellow powder with the empirical formula C27H32F2N8 and a molecular weight 506.59.
- The chemical name for abemaciclib is 2-Pyrimidinamine, N--2-pyridinyl]-5-fluoro-4--. Abemaciclib has the following structure:

## Pharmacodynamics
- 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.

## Pharmacokinetics
- The pharmacokinetics of abemaciclib were characterized in patients with solid tumors, including metastatic breast cancer, and in healthy subjects.
- Following single and repeated twice daily dosing of 50 mg (0.3 times the approved recommended 150 mg dosage) to 200 mg of abemaciclib, the increase in plasma exposure (AUC) and Cmax was approximately dose proportional. Steady state was achieved within 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 Cmax and AUC, respectively.
- The absolute bioavailability of abemaciclib after a single oral dose of 200 mg is 45% (19% CV). The median Tmax of abemaciclib is 8.0 hours (range: 4.1-24.0 hours).
Effect of 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 Cmax by 26%.
- 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.
- 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).
- 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.
- 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.
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. 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 AUC0-INF of abemaciclib plus its active metabolites (M2, M18, M20) in plasma increased 1.2-fold in subjects with mild hepatic impairment (Child-Pugh A, n=9), 1.1-fold in subjects with moderate hepatic impairment (Child-Pugh B, n=10), and 2.4-fold in subjects with severe hepatic impairment (Child-Pugh C, n=6) relative to subjects with normal hepatic function (n=10). 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.
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.
- Itraconazole (a strong CYP3A inhibitor) is predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18 and M20) by 2.2-fold. Coadministration of 500 mg twice daily doses of clarithromycin (a strong CYP3A inhibitor) with a single 50 mg dose of abemaciclib (0.3 times the approved recommended 150 mg dosage) increased the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2, M18, and M20) by 1.7-fold relative to abemaciclib alone in cancer patients.
- Moderate CYP3A Inhibitors: Diltiazem and verapamil (moderate CYP3A inhibitors) are predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 1.7-fold and 1.3-fold, respectively.
- Strong CYP3A Inducers: Coadministration of 600 mg daily doses of rifampin (a strong CYP3A inducer) with a single 200 mg dose of abemaciclib decreased the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2, M18, and M20) by 67% in healthy subjects.
- Moderate CYP3A Inducers: The effect of moderate CYP3A inducers on the pharmacokinetics of abemaciclib is unknown.
- 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 AUC0-INF of abemaciclib plus its active metabolites (M2 and M20) by 12%, which is not considered clinically relevant.
- Endocrine Therapies: In clinical studies in patients with breast cancer, there was no clinically relevant effect of fulvestrant, anastrozole, letrozole, or exemestane 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 AUC0-INF by 9% and Cmax 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 AUC0-INF by 37% and Cmax by 22% relative to metformin alone. Abemaciclib reduced the renal clearance and renal secretion of metformin by 45% and 62%, respectively, relative to metformin alone, without any effect on glomerular filtration rate (GFR) as measured by iohexol clearance and serum cystatin C.
- Endocrine Therapies: In clinical studies in patients with breast cancer, there was no clinically relevant effect of abemaciclib on the pharmacokinetics of fulvestrant, anastrozole, letrozole, or exemestane.
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. 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.
- CYP Metabolic Pathways: abemaciclib and its major active metabolites, M2 and M20, do not induce CYP1A2, CYP2B6, or CYP3A at clinically relevant concentrations. Abemaciclib and its major active metabolites, M2 and M20, down regulate mRNA of CYPs, including CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6 and CYP3A4. The mechanism of this down regulation and its clinical relevance are not understood. However, abemaciclib is a substrate of CYP3A4, and time-dependent changes in pharmacokinetics of abemaciclib as a result of autoinhibition of its metabolism was not observed.
- 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.

## Nonclinical Toxicology

### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenicity studies have not been conducted with abemaciclib.
- 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 was not clastogenic in an in vivo rat bone marrow micronucleus assay.
- Studies to assess the effects of abemaciclib on fertility have not been performed. 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.

# Clinical Studies
- Postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer with no prior systemic therapy in this disease setting.
- MONARCH 3 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 abemaciclib 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.
- 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 abemaciclib 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.
- 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 abemaciclib 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.

# How Supplied
- 50 mg dose pack (14 tablets)  each blister pack contains 14 tablets (50 mg per tablet) (50 mg twice daily)
- 100 mg dose pack (14 tablets)  each blister pack contains 14 tablets (100 mg per tablet) (100 mg twice daily)
- 150 mg dose pack (14 tablets)  each blister pack contains 14 tablets (150 mg per tablet) (150 mg twice daily)
- 200 mg dose pack (14 tablets)  each blister pack contains 14 tablets (200 mg per tablet) (200 mg twice daily)

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

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information

### Diarrhea
- Abemaciclib may cause diarrhea, which may be severe in some cases.
- 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 abemaciclib dosing.

### 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.

### Hepatotoxicity
- Inform patients of the signs and symptoms of hepatotoxicity. Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatotoxicity.

### 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.

### Embryo-Fetal Toxicity
- Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during abemaciclib therapy and for at least 3 weeks after the last dose. Advise patients to inform their healthcare provider of a known or suspected pregnancy.

### Lactation
- Advise lactating women not to breastfeed during abemaciclib treatment and for at least 3 weeks after the last dose.

### Drug Interactions
- Inform patients to avoid concomitant use of ketoconazole. Dose reduction may be required for other strong CYP3A inhibitors.
- Grapefruit may interact with abemaciclib. Advise patients not to consume grapefruit products while on treatment with abemaciclib.
- Advise patients to avoid concomitant use of CYP3A inducers and to consider alternative agents.
- Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products.

### Dosing
- Instruct patients to take the doses of abemaciclib at approximately the same times every day and to swallow whole (do not chew, crush, or split them prior to swallowing).
- If patient vomits or misses a dose, advise the patient to take the next prescribed dose at the usual time.
- Advise the patient that abemaciclib may be taken with or without food.

# Precautions with Alcohol
Alcohol-Abemaciclib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

# Brand Names
- Verzenio

# Look-Alike Drug Names
There is limited information regarding Abemaciclib Look-Alike Drug Names in the drug label.

# Drug Shortage Status
Drug Shortage

# Price