Abemaciclib
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
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
- 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
(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:
Pharmacodynamics
(Description)
Pharmacokinetics
(Description)
Nonclinical Toxicology
(Description)
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.