Abemaciclib (Monograph)

Brand name: Verzenio
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Aug 24, 2023. Written by ASHP.

Introduction

Antineoplastic agent; a selective inhibitor of cyclin-dependent kinases 4 (CDK4) and 6 (CDK6).

Uses for Abemaciclib

Breast Cancer

In combination with an aromatase inhibitor or tamoxifen for the adjuvant treatment of hormone receptor-positive, human epidermal growth factor receptor type 2 (HER2)-negative, node-positive, early-stage breast cancer in adults who are at high risk for recurrence.

In combination with an aromatase inhibitor (e.g., anastrozole, letrozole) for initial treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer in men and postmenopausal women.

In combination with fulvestrant for treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer in adults with disease progression following endocrine therapy.

Monotherapy for treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer in adults with disease progression following endocrine therapy and prior chemotherapy for metastatic disease.

Abemaciclib Dosage and Administration

General

Pretreatment Screening

• Obtain baseline complete blood cell (CBC) counts and liver function tests.

• Verify pregnancy status in females of reproductive potential prior to initiation of therapy.

Patient Monitoring

• Monitor CBC counts and liver function tests every 2 weeks for the initial 2 months of therapy, monthly for the next 2 months, and then as clinically indicated.

• Monitor for signs or symptoms of interstitial lung disease or pneumonitis.

• Monitor for signs or symptoms of venous thromboembolism (e.g., deep-vein thrombosis, pulmonary embolism).

Dispensing and Administration Precautions

• Based on the Institute for Safe Medication Practices (ISMP), abemaciclib is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.

Other General Considerations

• Premenopausal or perimenopausal women receiving abemaciclib in combination with fulvestrant or an aromatase inhibitor should be treated with a gonadotropin-releasing hormone (GnRH, luteinizing hormone-releasing hormone) agonist (e.g., goserelin) according to current standards of care.

• Men receiving combination therapy with abemaciclib and an aromatase inhibitor should be treated with a GnRH agonist according to current standards of care.

• Consult the respective manufacturers' labelings on the dosage, method of administration, and administration sequence of other antineoplastic agents used in combination regimens.

Administration

Oral Administration

Administer orally twice daily without regard to food at approximately the same time each day.

Swallow tablets whole; do not break, chew, crush, or split.

If a dose is missed or vomited, take the next dose at the regularly scheduled time. Do not double the dose or take extra doses.

Dosage

Adults

Breast Cancer

Adjuvant Therapy for Early-stage Breast Cancer

Oral

150 mg twice daily in combination with an aromatase inhibitor (e.g., anastrozole, letrozole) or tamoxifen. Continue therapy for 2 years or until disease progression or unacceptable toxicity occurs.

Treat premenopausal or perimenopausal women receiving combination therapy with abemaciclib and an aromatase inhibitor or fulvestrant with a gonadotropin-releasing hormone (GnRH, luteinizing hormone-releasing hormone) agonist (e.g., goserelin) according to current standards of care.

Treat men receiving combination therapy with abemaciclib and an aromatase inhibitor with a GnRH agonist according to current standards of care.

Initial Therapy for Advanced Breast Cancer

Oral

150 mg twice daily in combination with an aromatase inhibitor (e.g., anastrozole, letrozole). Continue therapy until disease progression or unacceptable toxicity occurs.

Treat premenopausal or perimenopausal women receiving combination therapy with abemaciclib and aromatase inhibitor with a gonadotropin-releasing hormone (GnRH, luteinizing hormone-releasing hormone) agonist (e.g., goserelin) according to current standards of care.

Treat men receiving combination therapy with abemaciclib and an aromatase inhibitor with a GnRH agonist according to current standards of care.

Previously Treated Advanced Breast Cancer: Combination Therapy

Oral

150 mg twice daily given continuously; administer in combination with fulvestrant 500 mg IM on days 1, 15, and 29 of cycle 1 followed by once monthly thereafter.

Treat premenopausal or perimenopausal women receiving combination therapy with abemaciclib and fulvestrant with a gonadotropin-releasing hormone (GnRH, luteinizing hormone-releasing hormone) agonist (e.g., goserelin) according to current standards of care.

Previously Treated Advanced Breast Cancer: Monotherapy

Oral

200 mg twice daily.

Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Oral

Adverse effects may require temporary interruption and/or dosage reduction or discontinuance.

Dosages <50 mg twice daily not recommended; discontinue drug if 50-mg twice daily dosage is not tolerated.

Recommended dosage modifications for abemaciclib during monotherapy or combination therapy with fulvestrant or an aromatase inhibitor in Table 1.

Hematologic Toxicity

Oral

If grade 4 hematologic toxicity occurs, temporarily interrupt abemaciclib therapy. When toxicity improves to grade 2 or less, resume therapy at reduced dosage.

For first occurrence of grade 3 hematologic toxicity, temporarily interrupt abemaciclib therapy. When toxicity improves to grade 2 or less, resume therapy at same dosage. If grade 3 hematologic toxicity recurs, temporarily interrupt abemaciclib therapy; upon improvement to grade 2 or less, resume therapy at reduced dosage.

If grade 1 or 2 hematologic toxicity occurs, no dosage modification required.

May administer hematopoietic growth factors (e.g., granulocyte colony-stimulating factor [G-CSF]) if clinically indicated; however, withhold abemaciclib for ≥48 hours after the last dose of a hematopoietic growth factor and until the toxicity improves to grade 2 or less.

Diarrhea

Oral

If grade 3 or 4 diarrhea or diarrhea requiring hospitalization occurs, temporarily interrupt abemaciclib therapy. When diarrhea improves to grade 1 or less, resume therapy at reduced dosage.

For persistent grade 2 diarrhea lasting ≥24 hours, temporarily interrupt abemaciclib therapy. When diarrhea resolves, resume therapy at same dosage. If grade 2 diarrhea persists or recurs despite optimal supportive measures, temporarily interrupt abemaciclib therapy; upon improvement to grade 1 or less, resume therapy at reduced dosage.

If grade 1 diarrhea occurs, no dosage modification required.

Hepatic Toxicity

Oral

If grade 4 serum ALT and/or AST elevations (i.e., >20 times the ULN) or serum ALT and/or AST elevations >3 times the ULN with total bilirubin concentrations >2 times the ULN in the absence of cholestasis occur, discontinue abemaciclib therapy.

If grade 3 serum ALT and/or AST elevations (i.e., >5 times the ULN, but ≤20 times the ULN) with total bilirubin concentrations ≤2 times the ULN occur, temporarily interrupt abemaciclib therapy. When toxicity improves to grade 1 or less, resume therapy at reduced dosage.

If grade 2 serum ALT and/or AST elevations (i.e., >3 times the ULN, but ≤5 times the ULN) with total bilirubin concentrations ≤2 times the ULN occur, no dosage modification required. For persistent or recurrent grade 2 serum ALT and/or AST elevations with total bilirubin concentrations ≤2 times the ULN, temporarily interrupt abemaciclib therapy; upon improvement to grade 1 or baseline, resume therapy at reduced dosage.

If grade 1 serum ALT and/or AST elevations (i.e., exceeding the ULN, but ≤3 times the ULN) with total bilirubin concentrations ≤2 times the ULN occur, no dosage modification required.

Interstitial Lung Disease (ILD)/Pneumonitis

Oral

If grade 3 or 4 ILD/pneumonitis occurs, permanently discontinue abemaciclib therapy.

If grade 2 ILD/pneumonitis occurs, no dosage modification required. If grade 2 ILD/pneumonitis persists or recurs despite optimal supportive measures for up to 7 days, temporarily interrupt abemaciclib therapy; upon improvement to grade 1 or baseline, resume therapy at reduced dosage.

If grade 1 ILD/pneumonitis occurs, no dosage modification required.

Venous Thromboembolic Event

Oral

For venous thromboembolic events of any grade in patients with early-stage breast cancer, interrupt abemaciclib therapy and treat as clinically indicated. When the patient is clinically stable, resume abemaciclib therapy.

For grade 1 or 2 venous thromboembolic events in patients with advanced or metastatic breast cancer, no dosage adjustment is necessary.

For grade 3 or 4 venous thromboembolic events in patients with advanced or metastatic breast cancer, interrupt abemaciclib therapy and treat as clinically indicated. When the patient is clinically stable, resume abemaciclib therapy.

Other Toxicity

Oral

If grade 3 or 4 adverse reactions occur, temporarily interrupt abemaciclib therapy. When toxicity improves to grade 1 or baseline, resume therapy at reduced dosage.

If grade 2 adverse reactions occur, no dosage modification required. If grade 2 adverse reactions persist or recur despite optimal supportive measures for up to 7 days, temporarily interrupt abemaciclib therapy; upon improvement to grade 1 or baseline, resume therapy at reduced dosage.

If grade 1 adverse reactions occur, no dosage modification required.

Dosage Modification with Concomitant Drugs or Foods Affecting Hepatic Microsomal Enzymes

Oral

Avoid concomitant use with ketoconazole.

If used concomitantly with other potent CYP3A inhibitors, reduce initial abemaciclib dosage (200 or 150 mg twice daily depending on indication) to 100 mg twice daily or, in those already receiving a reduced dosage of abemaciclib (100 mg twice daily), reduce dosage of abemaciclib to 50 mg twice daily.

If used concomitantly with moderate CYP3A inhibitors, monitor for signs of abemaciclib toxicity and consider dosage modification for adverse reactions (see Table 1).

Prescribing Limits

Adults

Breast Cancer

Oral

Dosages <50 mg twice daily not recommended.

Special Populations

Hepatic Impairment

Severe preexisting hepatic impairment (Child-Pugh class C): Reduce dosage frequency to once daily.

Mild or moderate preexisting hepatic impairment (Child-Pugh class A or B): No dosage adjustment required.

Renal Impairment

Mild or moderate renal impairment (Cl_cr 30–89 mL/minute): No dosage adjustment required.

Severe renal impairment (Cl_cr <30 mL/minute), end-stage renal disease, or patients receiving dialysis: No specific dosage recommendations at this time.

Geriatric Patients

No specific dosage recommendations at this time.

Related/similar drugs

Kisqali, Ibrance, Arimidex, Femara, Xeloda, Herceptin, Verzenio

Cautions for Abemaciclib

Contraindications

• Manufacturer states none known.

Warnings/Precautions

Diarrhea

Diarrhea occurs frequently. May result in dehydration or infection. Median time to onset: 6–8 days. Median duration of grade 2 or 3 diarrhea: 6–11 or 5–8 days, respectively, in clinical trials.

Monitor for development of diarrhea and immediately treat as necessary with appropriate therapy (e.g., antidiarrheal agents, fluid replacement) at first sign of loose stools. If diarrhea occurs, temporary interruption, dosage reduction, or discontinuance of abemaciclib may be necessary.

Neutropenia

Neutropenia, including febrile neutropenia and neutropenic sepsis, reported. Median time to onset of grade 3 or greater neutropenia: 29–33 days. Median duration of grade 3 or greater neutropenia: 11–16 days.

Monitor CBC at baseline, every 2 weeks during the initial 2 months of therapy, monthly during the next 2 months, and then as clinically indicated. If neutropenia occurs, temporary interruption, dosage reduction, or discontinuance of abemaciclib may be necessary. May administer hematopoietic growth factors (e.g., G-CSF) if clinically indicated; however, withhold abemaciclib for ≥48 hours after the last dose of hematopoietic growth factor and until the toxicity improves to grade 2 or less.

ILD/Pneumonitis

Severe, life-threatening, or fatal ILD/pneumonitis reported with CDK4 and CDK6 inhibitors, including abemaciclib.

Monitor patients clinically and by radiographic imaging for manifestations of ILD or pneumonitis.

If manifestations of ILD or pneumonitis occur and other etiologies (e.g., infection, neoplastic) have been excluded, temporary interruption, dosage reduction, or discontinuance of abemaciclib may be necessary.

Hepatic Toxicity

Hepatotoxicity reported. Median time to onset of grade 3 or greater elevations in AST concentrations: 71–185 days; these elevations resolved in 11–15 days.

Monitor liver function tests (i.e., serum ALT, AST, and bilirubin concentrations) at baseline, every 2 weeks during the initial 2 months of therapy, monthly during the next 2 months, and then as clinically indicated. If hepatotoxicity occurs, temporary interruption, dosage reduction, or discontinuance of abemaciclib may be necessary.

Thromboembolic Events

Venous thromboembolic events (i.e., DVT, pulmonary embolism, pelvic venous thrombosis, cerebral venous sinus thrombosis, subclavian and axillary vein thrombosis, inferior vena cava thrombosis), sometimes fatal, reported.

Monitor for manifestations of venous thromboembolic events, including pulmonary embolism. Interrupt abemaciclib therapy in patients with early-stage breast cancer who develop a venous thromboembolic event of any grade and in patients with advanced or metastatic breast cancer who develop a grade 3 or 4 venous thromboembolic event. Initiate appropriate medical intervention.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryofetal toxicity and teratogenicity demonstrated in animals.

Avoid pregnancy during therapy. Females of reproductive potential should use effective contraceptive methods while receiving abemaciclib and for ≥3 weeks after the drug is discontinued. If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm.

In females of reproductive potential, manufacturer recommends a pregnancy test prior to initiating abemaciclib therapy.

Lactation

Not known whether abemaciclib distributes into human milk or if drug has any effect on milk production or nursing infant. Discontinue nursing during therapy and for ≥3 weeks after drug is discontinued.

Females and Males of Reproductive Potential

Animal studies suggest abemaciclib may impair male fertility.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in safety and efficacy relative to younger adults. Most common grade 3 or 4 toxicities included neutropenia, diarrhea, fatigue, nausea, dehydration, leukopenia, anemia, infection, and elevated serum ALT concentrations.

Hepatic Impairment

Mild or moderate hepatic impairment did not substantially affect potency-adjusted total exposure to unbound drug and active metabolites; dosage adjustment not necessary.

Severe hepatic impairment prolonged mean elimination half-life and increased potency-adjusted total exposure to unbound drug and active metabolites; dosage adjustment recommended.

Renal Impairment

Mild or moderate renal impairment did not substantially affect systemic exposure of abemaciclib; dosage adjustment not necessary.

Not studied in patients with severe renal impairment.

Abemaciclib increases S_cr by inhibiting tubular secretion of creatinine; does not cause clinically important change in GFR.

Common Adverse Effects

Adverse effects reported in ≥20% of patients: Diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, thrombocytopenia.

Drug Interactions

Metabolized mainly by CYP3A4 to active metabolites (M-2, M-18, and M-20).

Autoinhibition of abemaciclib metabolism via CYP3A4 not observed.

In vitro studies indicate inhibition of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) by abemaciclib. Abemaciclib, M-2, and M-20 inhibit organic cation transporter (OCT) 2, multidrug and toxic compound extrusion protein (MATE) 1, and MATE2K, but do not inhibit OCT1, organic anion transport protein (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, and OAT3. In vitro, the drug is a substrate for P-gp and BCRP, but abemaciclib, M-2, and M-20 are not substrates for OCT1, OATP1B1, or OATP1B3.

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent or moderate CYP3A inhibitors: Possible increased systemic exposure to abemaciclib and its active metabolites and increased risk of adverse effects. Avoid concomitant use with ketoconazole. If concomitant use with other potent CYP3A inhibitors cannot be avoided, reduce initial abemaciclib dosage (200 or 150 mg twice daily depending on indication) to 100 mg twice daily or, in those already receiving a reduced dosage of abemaciclib (100 mg twice daily), reduce dosage of abemaciclib to 50 mg twice daily. If potent CYP3A inhibitor is discontinued, resume abemaciclib (after 3–5 terminal half-lives of the CYP3A inhibitor) at dosage used prior to initiation of potent CYP3A inhibitor. If used concomitantly with moderate CYP3A inhibitors, monitor for signs of abemaciclib toxicity and consider dosage modification for adverse reactions.

Potent or moderate CYP3A inducers: Possible decreased systemic exposure to abemaciclib and its active metabolites and reduced efficacy of abemaciclib. Avoid concomitant use with potent or moderate CYP3A inducers; consider choosing alternative agent with no or minimal CYP3A induction potential.

Specific Drugs and Foods

Abemaciclib Pharmacokinetics

Absorption

Bioavailability

Following oral administration, median time to peak plasma concentrations is 8 hours.

AUC and peak plasma concentrations are dose proportional over dosage range of 50–200 mg; mean accumulation ratio is 3.2 or 2.3 based on AUC or peak plasma concentrations, respectively.

Steady-state concentrations achieved in 5 days.

Food

Administration with high-fat, high-calorie meal (approximately 800–1000 calories with over 50% of calories from fat) increases AUC and peak plasma concentrations of abemaciclib and its active metabolites by 9 and 26%, respectively.

Special Populations

Mild, moderate, or severe (Child-Pugh class A, B, or C) hepatic impairment increases potency-adjusted total exposure to unbound abemaciclib and its active metabolites by 1.2-, 1.1-, or 2.4-fold, respectively; mean elimination half-life of abemaciclib prolonged by >twofold in patients with severe hepatic impairment.

Mild or moderate renal impairment (Cl_cr 30–89 mL/minute) does not substantially affect systemic exposure. Data lacking for severe renal impairment (Cl_cr <30 mL/minute).

Age (24–91 years), gender, and body weight (36–175 kg) do not substantially affect pharmacokinetics.

Distribution

Extent

Not known whether distributed into human milk.

CSF concentrations of abemaciclib and its active metabolites similar to unbound plasma concentrations in patients with advanced cancer.

Plasma Protein Binding

>93% (mainly plasma proteins, albumin, α₁-acid glycoprotein).

Elimination

Metabolism

Principally metabolized by CYP3A4.

Elimination Route

Eliminated in feces (81% of recovered dose [mainly as metabolites]) and urine (approximately 3%).

Half-life

18.3 hours.

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted to 15–30°C).

Actions

• Selective inhibitor of CDK4 and 6.

• CDK4 and CDK6 involved in regulation of progression from the G1 into S phase of the cell cycle through regulation of phosphorylation of the tumor suppressor protein retinoblastoma.

• Inhibits the G1 into S phase of the cell cycle and reduces cellular proliferation of breast cancer cells.

• Combination of abemaciclib and an antiestrogen or as a single-agent reduced tumor volume in breast tumor xenografts.

Advice to Patients

• Advise patients to swallow abemaciclib tablets whole and not to break, chew, crush, or split the tablets.

• If a dose is missed or vomited, importance of administering the next dose at the regularly scheduled time; an additional dose should not be administered to make up for a missed dose.

• Risk of diarrhea. Importance of informing patients that early identification and intervention is critical for the optimal management of diarrhea. Importance of informing patients how to manage diarrhea (e.g., oral hydration, antidiarrheal agents) at the first sign of loose stools. Importance of informing clinician if diarrhea occurs.

• Risk of neutropenia. Importance of promptly informing clinician if signs or symptoms of neutropenia or infection (e.g., fever) occur.

• Risk of severe, life-threatening, or fatal ILD/pneumonitis. Importance of informing clinician immediately if new or worsening cough, chest pain, or shortness of breath occurs.

• Risk of hepatotoxicity. Importance of promptly informing clinician if symptoms of hepatotoxicity (e.g., fatigue, anorexia, right upper quadrant pain, bleeding diathesis) occur.

• Risk of venous thromboembolic events. Importance of promptly informing clinician if any symptoms suggestive of a thromboembolic event occur (e.g., extremity pain or swelling, chest pain, shortness of breath, tachypnea, tachycardia).

• Risk of fetal harm. Necessity of advising females of reproductive potential to use an effective method of contraception during treatment and for ≥3 weeks after discontinuance of therapy. Importance of females informing clinicians if they are or plan to become pregnant. Apprise patient of potential fetal hazard if used during pregnancy.

• Importance of advising females to discontinue nursing during therapy and for >3 weeks after discontinuance of the drug.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., ketoconazole) and dietary (e.g,. ketoconazole, grapefruit products) or herbal supplements, as well as any concomitant illnesses.

• Inform males of reproductive potential that abemaciclib may impair fertility.

• Importance of informing patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

Obtain abemaciclib through designated specialty pharmacies and authorized distributors.

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