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

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 Abemaciclib

Miscellaneous

(list/description of adverse reactions)

Condition 2

Central Nervous System

(list/description of adverse reactions)

Cardiovascular

(list/description of adverse reactions)

Respiratory

(list/description of adverse reactions)

Gastrointestinal

(list/description of adverse reactions)

Hypersensitive Reactions

(list/description of adverse reactions)

Miscellaneous

(list/description of adverse reactions)

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

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Pediatric Use

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Geriatic Use

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Gender

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Race

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Renal Impairment

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Hepatic Impairment

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Females of Reproductive Potential and Males

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Immunocompromised Patients

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Others

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Administration and Monitoring

Administration

(Oral/Intravenous/etc)

Monitoring

Condition 1

(Description regarding monitoring, from Warnings section)

Condition 2

(Description regarding monitoring, from Warnings section)

Condition 3

(Description regarding monitoring, from Warnings section)

IV Compatibility

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

Overdosage

Acute Overdose

Signs and Symptoms

(Description)

Management

(Description)

Chronic Overdose

Signs and Symptoms

(Description)

Management

(Description)

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

(Description)

Pharmacokinetics

(Description)

Nonclinical Toxicology

(Description)

Clinical Studies

Condition 1

(Description)

Condition 2

(Description)

Condition 3

(Description)

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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Patient Counseling Information

(Patient Counseling 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.