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Verzenio

Generic Name: Abemaciclib
Class: Antineoplastic Agents
Chemical Name: N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-amine
Molecular Formula: C27H32F2N8
CAS Number: 1231929-97-7

Introduction

Abemaciclib is an antineoplastic agent.

Uses for Verzenio

Abemaciclib has the following uses:

Abemaciclib is a kinase inhibitor indicated 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.1

Abemaciclib is a kinase inhibitor indicated as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.1

Verzenio Dosage and Administration

General

Abemaciclib is available in the following dosage form(s) and strength(s):

Tablets: 50 mg, 100 mg, 150 mg, and 200 mg.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Abemaciclib tablets are taken orally with or without food.1

  • Recommended starting dose in combination with fulvestrant: 150 mg twice daily.1

  • Recommended starting dose as monotherapy: 200 mg twice daily.1

  • Dosing interruption and/or dose reductions may be required based on individual safety and tolerability.1

Cautions for Verzenio

Contraindications

None.1

Warnings/Precautions

Diarrhea

Diarrhea occurred in 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 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.1

In MONARCH 2, diarrhea incidence was greatest during the first month of abemaciclib dosing. The median time to onset of the first diarrhea event was 6 days, and the median duration of diarrhea for Grades 2 and 3 were 9 days and 6 days, respectively. Twenty-two percent of patients with diarrhea required a dose omission and 22% required a dose reduction. In the MONARCH 1 study, the time to onset and resolution for diarrhea were similar to those in MONARCH 2.1

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.1

Neutropenia

Neutropenia occurred in 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 32% of patients receiving abemaciclib plus fulvestrant in MONARCH 2 and in 27% of patients receiving abemaciclib in MONARCH 1. In MONARCH 2 and MONARCH 1, the median time to first episode of Grade >3 neutropenia was 29 days, and the median duration of Grade ≥3 neutropenia was 15 days.1

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.1

Febrile neutropenia has been reported in 1% of patients exposed to abemaciclib in MONARCH 2 and MONARCH 1. Two deaths due to neutropenic sepsis were observed in MONARCH 2. Inform patients to promptly report any episodes of fever to their healthcare provider.1

Hepatotoxicity

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.1

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. For patients with Grade ≥3 AST increased, median time to onset was 185 days, and median time to resolution was 13 days.1

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.1

Venous Thromboembolism

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, 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.1

Embryo-fetal Toxicity

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.1

Specific Populations

Pregnancy

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.1

In an embryo-fetal development study, pregnant rats received oral doses of abemaciclib up to 15 mg/kg/day during the period of organogenesis. Doses ≥4 mg/kg/day caused decreased fetal body weights and increased incidence of cardiovascular and skeletal malformations and variations. These findings included absent innominate artery and aortic arch, malpositioned subclavian artery, unossified sternebra, bipartite ossification of thoracic centrum, and rudimentary or nodulated ribs. At 4 mg/kg/day in rats, the maternal systemic exposures were approximately equal to the human exposure (AUC) at the recommended dose.1

Lactation

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.1

Females and Males of Reproductive Potential

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.1

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.1

Based on findings in animals, abemaciclib may impair fertility in males of reproductive potential.1

Pediatric Use

The safety and effectiveness of abemaciclib have not been established in pediatric patients.1

Geriatric Use

Of the 441 patients who received abemaciclib in MONARCH 2, 35% were 65 years of age or older and 9% were 75 years of age or older. Of the 132 patients who received abemaciclib in MONARCH 1, 32% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or effectiveness of abemaciclib were observed between these patients and younger patients.1

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. 1

Hepatic Impairment

No dosage adjustments are necessary in patients with mild or moderate hepatic impairment (Child-Pugh A or B).1

Reduce the dosing frequency when administering abemaciclib to patients with severe hepatic impairment (Child-Pugh C).1

Common Adverse Effects

Most common adverse reactions (incidence ≥20%) were diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, and thrombocytopenia.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • CYP3A Inhibitors: Avoid concomitant use of ketoconazole. Reduce the abemaciclib dose with concomitant use of other strong CYP3A inhibitors.1

  • CYP3A Inducers: Avoid concomitant use of strong CYP3A inducers.1

Actions

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.1

Advice to Patients

Advise patients to read the FDA-approved Patient Information.1

Diarrhea

Abemaciclib may cause diarrhea, which may be severe in some cases.1

Early identification and intervention is critical for the optimal management of diarrhea. Instruct patients that at the first sign of loose stools, they should start antidiarrheal therapy (for example, loperamide) and notify their healthcare provider for further instructions and appropriate follow up.1

Encourage patients to increase oral fluids.1

If diarrhea does not resolve with antidiarrheal therapy within 24 hours to ≤Grade 1, suspend abemaciclib dosing.1

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.1

Hepatotoxicity

Inform patients of the signs and symptoms of hepatotoxicity. Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatotoxicity.1

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.1

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.1

Lactation

Advise lactating women not to breastfeed during abemaciclib treatment and for at least 3 weeks after the last dose. 1

Drug Interactions

Inform patients to avoid concomitant use of ketoconazole. Dose reduction may be required for other strong CYP3A inhibitors.1

Grapefruit may interact with abemaciclib. Advise patients not to consume grapefruit products while on treatment with abemaciclib.1

Advise patients to avoid concomitant use of CYP3A inducers and to consider alternative agents.1

Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products.1

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).1

If patient vomits or misses a dose, advise the patient to take the next prescribed dose at the usual time.1

Advise the patient that abemaciclib may be taken with or without food.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Abemaciclib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet

50 mg

Verzenio

Eli Lilly and Company

100 mg

Verzenio

Eli Lilly and Company

150 mg

Verzenio

Eli Lilly and Company

200 mg

Verzenio

Eli Lilly and Company

AHFS Drug Information. © Copyright 2017, Selected Revisions October 16, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Eli Lilly and Company. Verzenio (abemaciclib) ORAL prescribing information. 2017 Sep.

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