Abemaciclib (Systemic)

Brand names: Verzenio
Drug class: Antineoplastic Agents

Usage of Abemaciclib (Systemic)

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.

Relate drugs

How to use Abemaciclib (Systemic)

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.

    Table 1: Dosage Modifications for Abemaciclib Toxicity

    Dosage Modification after Recovery from Toxicity

    Dosage Modification after Recovery from Toxicity

    Toxicity Occurrence

    Single-agent Abemaciclib (Starting Dosage = 200 mg twice daily)

    Abemaciclib in Combination with Fulvestrant, Tamoxifen, or an Aromatase Inhibitor (Starting Dosage = 150 mg twice daily)

    First

    Restart at 150 mg twice daily

    Restart at 100 mg twice daily

    Second

    Restart at 100 mg twice daily

    Restart at 50 mg twice daily

    Third

    Restart at 50 mg twice daily

    Discontinue abemaciclib

    Fourth

    Discontinue abemaciclib

    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 (Clcr 30–89 mL/minute): No dosage adjustment required.

    Severe renal impairment (Clcr <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.

    Warnings

    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 Scr 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.

    What other drugs will affect Abemaciclib (Systemic)

    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

    Drug

    Interaction

    Comments

    Anastrozole

    No effect on pharmacokinetics of anastrozole or abemaciclib

    Antifungals, azoles (e.g., itraconazole, ketoconazole)

    Possible increased systemic exposure to abemaciclib, M-2, M-18, and M-20 and increased adverse effects

    Itraconazole: Simulations suggest 2.2-fold increase in potency-adjusted total AUC of unbound abemaciclib, M-2, M-18, and M-20

    Ketoconazole: Simulations suggest increased AUC of abemaciclib by up to 16-fold

    Ketoconazole: Avoid concomitant use

    Other potent CYP3A inhibitors (e.g., itraconazole, posaconazole, voriconazole): Reduce initial abemaciclib dosage (200 or 150 mg twice daily depending on indication) to 100 mg twice daily; in those already receiving a reduced abemaciclib dosage (100 mg twice daily), reduce dosage to 50 mg twice daily

    If potent CYP3A inhibitor discontinued, resume abemaciclib (after 3–5 terminal half-lives of the CYP3A inhibitor) at dosage used prior to initiation of the CYP3A inhibitor

    Bosentan

    Simulations suggest 41% decrease in potency-adjusted total AUC of unbound abemaciclib, M-2, M-18, and M-20

    Avoid concomitant use

    Select alternative agent with less CYP3A induction potential

    Diltiazem

    Simulations suggest approximate 2.4-fold increase in potency-adjusted total AUC of unbound abemaciclib, M-2, M-18, and M-20

    Moderate CYP3A inhibitors (e.g., diltiazem): Monitor for abemaciclib toxicity and consider dosage modification

    Efavirenz

    Simulations suggest 53% decrease in potency-adjusted total AUC of unbound abemaciclib, M-2, M-18, and M-20

    Avoid concomitant use

    Select alternative agent with less CYP3A induction potential

    Exemestane

    No effect on pharmacokinetics of exemestane or abemaciclib

    Fulvestrant

    No effect on pharmacokinetics of fulvestrant or abemaciclib

    Grapefruit or grapefruit juice

    Possible increased systemic exposure to abemaciclib

    Avoid concomitant use

    Letrozole

    No effect on pharmacokinetics of letrozole or abemaciclib

    Loperamide

    No effect on pharmacokinetics of loperamide or abemaciclib, M-2, or M-20

    Macrolides (e.g., clarithromycin)

    Possible increased systemic exposure to abemaciclib, M-2, M-18, and M-20 and increased adverse effects

    Clarithromycin: Increased potency-adjusted total AUC of unbound abemaciclib, M-2, and M-20 by 2.5-fold

    Reduce initial abemaciclib dosage (200 or 150 mg twice daily depending on indication) to 100 mg twice daily; in those already receiving reduced abemaciclib dosage (100 mg twice daily), reduce dosage to 50 mg twice daily

    If potent CYP3A inhibitor discontinued, resume abemaciclib (after 3–5 terminal half-lives of the CYP3A inhibitor) at dosage used prior to initiation of the CYP3A inhibitor

    Metformin

    Increased peak plasma concentrations and AUC of metformin by 22 and 37%, respectively; reduced renal clearance and renal secretion of metformin by 45 and 62%, respectively

    Modafinil

    Simulations suggest 29% decrease in potency-adjusted total AUC of unbound abemaciclib, M-2, M-18, and M-20

    Avoid concomitant use

    Select alternative agent with less CYP3A induction potential

    Rifampin

    Decreased potency-adjusted total AUC of unbound abemaciclib, M-2, M-18, and M-20 by approximately 70%

    Avoid concomitant use

    Select alternative agent with less CYP3A induction potential

    Tamoxifen

    No effect on pharmacokinetics of tamoxifen or abemaciclib

    Verapamil

    Simulations suggest approximate 1.6-fold increase in potency-adjusted total AUC of unbound abemaciclib, M-2, M-18, and M-20

    Moderate CYP3A inhibitors (e.g., verapamil): Monitor for abemaciclib toxicity and consider dosage modification

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