Abemaciclib

Abemaciclib
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];

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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)

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.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

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

Non–Guideline-Supported Use

There is limited information regarding Abemaciclib Off-Label Non-Guideline-Supported Use and Dosage (Adults) 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 (Pediatrics) in the drug label.

Non–Guideline-Supported Use

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

Contraindications

• None

Warnings

Diarrhea

• Diarrhea occurred in 81% of patients receiving VERZENIO plus an aromatase inhibitor in MONARCH 3, 86% of patients receiving VERZENIO plus fulvestrant in MONARCH 2, and 90% of patients receiving VERZENIO alone in MONARCH 1. Grade 3 diarrhea occurred in 9% of patients receiving VERZENIO plus an aromatase inhibitor in MONARCH 3, 13% of patients receiving VERZENIO plus fulvestrant in MONARCH 2, and in 20% of patients receiving VERZENIO 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 VERZENIO until toxicity resolves to ≤Grade 1, and then resume VERZENIO at the next lower dose.

Neutropenia

• Neutropenia occurred in 41% of patients receiving VERZENIO plus an aromatase inhibitor in MONARCH 3, 46% of patients receiving VERZENIO plus fulvestrant in MONARCH 2, and 37% of patients receiving VERZENIO alone in MONARCH 1. A Grade ≥3 decrease in neutrophil count (based on laboratory findings) occurred in 22% of patients receiving VERZENIO plus an aromatase inhibitor in MONARCH 3, 32% of patients receiving VERZENIO plus fulvestrant in MONARCH 2, and in 27% of patients receiving VERZENIO 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 VERZENIO 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 VERZENIO 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.

Hepatotoxicity

• In MONARCH 3, Grade ≥3 increases in ALT (6% versus 2%) and AST (3% versus 1%) were reported in the VERZENIO and placebo arms, respectively. In MONARCH 2, Grade ≥3 increases in ALT (4% versus 2%) and AST (2% versus 3%) were reported in the VERZENIO and placebo arms, respectively.

• In MONARCH 3, for patients receiving VERZENIO 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 VERZENIO 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 VERZENIO 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 VERZENIO 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 VERZENIO 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.

Venous Thromboembolism

• In MONARCH 3, venous thromboembolic events were reported in 5% of patients treated with VERZENIO 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 VERZENIO 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.

Embryo-Fetal Toxicity

• Based on findings from animal studies and the mechanism of action, VERZENIO 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 VERZENIO and for at least 3 weeks after the last dose.

Adverse Reactions

Clinical Trials Experience

MONARCH 3: VERZENIO in Combination with an Aromatase Inhibitor (Anastrozole or Letrozole) as Initial Endocrine-Based Therapy

Central Nervous System

• Dizziness

Cardiovascular

• Neutropenia
• Anemia
• Leukopenia
• Thrombocytopenia

Respiratory

• Cough
• Dyspnea

Gastrointestinal

• Diarrhea
• Nausea
• Abdominal pain
• Vomiting
• Constipation

Hypersensitive Reactions

• There is limited information regarding hypersensitive reactions from Abemaciclib

Miscellaneous

• Infections
• Fatigue
• Influenza like illness
• Alopecia
• Rash
• Pruritus
• Decreased appetite
• Blood creatinine increased
• Alanine aminotransferase increased
• Aspartate aminotransferase increased
• Weight decreased

MONARCH 2: VERZENIO in Combination with Fulvestrant

Central Nervous System

• Heachache
• Dysgeusia
• Dizziness

Cardiovascular

• Neutropenia
• Anemia
• Leukopenia
• Thrombocytopenia

Respiratory

• Cough

Gastrointestinal

• Diarrhea
• Nausea
• Abdominal pain
• Vomiting
• Stomatitis

Hypersensitive Reactions

• There is limited information regarding hypersensitive reactions from Abemaciclib

Miscellaneous

• Infections
• Fatigue
• Edemaperipheral
• Pyrexia
• Decreased appetite
• Alopecia
• Pruritus
• Rash
• Alanine aminotransferase increased
• Aspartate aminotransferase increased
• Creatine increased
• Weight decreased

VERZENIO Administered as a Monotherapy in Metastatic Breast Cancer (MONARCH 1)

Central Nervous System

• Headache
• Dysgeusia
• Dizziness

Cardiovascular

• Neutropenia
• Anemia
• Thrombocytopenia
• Leukopenia

Respiratory

• Cough

Gastrointestinal

• Diarrhea
• Nausea
• Abdominal pain
• Vomiting
• Constipation
• Dry mouth
• Stomatitis

Hypersensitive Reactions

• There is limited information regarding hypersensitive reactions from Abemaciclib

Miscellaneous

• Infections
• Fatigue
• Pyrexia
• Decreased appetitite
• Dehydration
• Arthralgia
• Alopecia
• Creatinine increased
• Weight decreased

Postmarketing Experience

(Description)

Drug Interactions

• Strong CYP3A Inhibitors
• Strong CYP3A Inducers

Strong CYP3A Inhibitors

• 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.

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 other strong CYP3A inhibitors. 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 other 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 strong inhibitor. Patients should avoid grapefruit products.

Strong CYP3A Inducers

• Coadministration of VERZENIO 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, VERZENIO 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): (Description)

Labor and Delivery

(Description)

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 VERZENIO, advise lactating women not to breastfeed during VERZENIO treatment and for at least 3 weeks after the last dose.

Pediatric Use

• The safety and effectiveness of VERZENIO have not been established in pediatric patients.

Geriatic Use

• 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.

Gender

(Description)

Race

(Description)

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.

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).

Females of Reproductive Potential and Males

Pregnancy Testing

• Based on animal studies, VERZENIO can cause fetal harm when administered to a pregnant woman. Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with VERZENIO.

Contraception

• VERZENIO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during VERZENIO treatment and for at least 3 weeks after the last dose.

Infertility

• Based on findings in animals, VERZENIO may impair fertility in males of reproductive potential.

Immunocompromised Patients

(Description)

Others

(Description)

Administration and Monitoring

Administration

• When used in combination with fulvestrant or an aromatase inhibitor, the recommended dose of VERZENIO is 150 mg taken orally twice daily.

• When given with VERZENIO, refer to the Full Prescribing Information for the recommended dose of the aromatase inhibitor being used.

• When given with VERZENIO, 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 VERZENIO 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 VERZENIO is 200 mg taken orally twice daily.

• Continue treatment until disease progression or unacceptable toxicity. VERZENIO may be taken with or without food.

• 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.

Monitoring

Dose Modification for Use with Strong CYP3A Inhibitors

• 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 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 strong 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.

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.

IV Compatibility

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

Overdosage

Acute Overdose

Signs and Symptoms

(Description)

Management

• There is no known antidote for VERZENIO. The treatment of overdose of VERZENIO should consist of general supportive measures.

Chronic Overdose

Signs and Symptoms

(Description)

Management

• There is no known antidote for VERZENIO. The treatment of overdose of VERZENIO should consist of general supportive measures.

Pharmacology

Abemaciclib
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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-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl]-. Abemaciclib has the following structure:

This image is provided by the National Library of Medicine.

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.

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.

Absorption

• 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%.

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. 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.

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.

• 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 VERZENIO (0.3 times the approved recommended 150 mg dosage) increased the relative potency adjusted unbound AUC0-INF of Abemaciclib plus its active metabolites (M2, M18, and M20) by 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 VERZENIO 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

• 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

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 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.

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.

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.

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

There is limited information regarding Abemaciclib Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

Advise patients to read the FDA-approved Patient Information.

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

There is limited information regarding Abemaciclib Brand Names in the drug label.

Look-Alike Drug Names

• (Paired Confused Name 1a) — (Paired Confused Name 1b)
• (Paired Confused Name 2a) — (Paired Confused Name 2b)
• (Paired Confused Name 3a) — (Paired Confused Name 3b)

Drug Shortage Status

Drug Shortage

Price

References

The contents of this FDA label are provided by the National Library of Medicine.