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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
Brands: Verzenio

Medically reviewed on Oct 8, 2018

Introduction

See also: Kisqali

Antineoplastic agent; a selective inhibitor of cyclin-dependent kinases 4 (CDK4) and 6 (CDK6).1 2 3

Uses for Abemaciclib

Breast Cancer

In combination with an aromatase inhibitor (e.g., anastrozole, letrozole) for initial treatment of hormone receptor-positive, human epidermal growth factor receptor type 2 (HER2)-negative advanced or metastatic breast cancer in postmenopausal women.1 14

In combination with fulvestrant for treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer in women with disease progression following endocrine therapy.1 2

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.1 3

Abemaciclib Dosage and Administration

General

  • Obtain CBC and liver function tests at baseline, every 2 weeks for the initial 2 months of therapy, monthly for the next 2 months, and then as clinically indicated.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

  • Consult respective manufacturers' labelings for information on dosage and administration (including dosage adjustments), adverse effects, and contraindications of other antineoplastic agents used in combination regimens.1

Administration

Oral Administration

Administer orally twice daily without regard to food at approximately the same time each day.1

Swallow tablets whole; do not break, chew, crush, or split.1

If a dose is missed or vomited, take the next dose at the regularly scheduled time.1 Do not double the dose or take extra doses.1

Dosage

Adults

Breast Cancer
Initial Therapy for Advanced Breast Cancer
Oral

150 mg twice daily in combination with an aromatase inhibitor (e.g., anastrozole, letrozole).1 Continue therapy until disease progression or unacceptable toxicity occurs.1

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.1 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.1

Previously Treated Advanced Breast Cancer: Monotherapy
Oral

200 mg twice daily.1

Continue therapy until disease progression or unacceptable toxicity occurs.1

Dosage Modification for Toxicity
Oral

Adverse effects may require temporary interruption and/or dosage reduction or discontinuance.1

Dosages <50 mg twice daily not recommended; discontinue drug if 50-mg twice daily dosage is not tolerated.1

Recommended dosage modifications for abemaciclib during monotherapy or combination therapy with fulvestrant or an aromatase inhibitor in Table 1.1

Table 1: Dosage Modifications for Abemaciclib Toxicity

Toxicity Occurrence

Dosage Modification after Recovery from Toxicity

Single-agent Abemaciclib

(Starting Dosage = 200 mg twice daily)

Abemaciclib in Combination with Fulvestrant 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.1 When toxicity improves to grade 2 or less, resume therapy at reduced dosage.1

For first occurrence of grade 3 hematologic toxicity, temporarily interrupt abemaciclib therapy.1 When toxicity improves to grade 2 or less, resume therapy at same dosage.1 If grade 3 hematologic toxicity recurs, temporarily interrupt abemaciclib therapy; upon improvement to grade 2 or less, resume therapy at reduced dosage.1

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

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.1

Diarrhea
Oral

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

For persistent grade 2 diarrhea lasting ≥24 hours, temporarily interrupt abemaciclib therapy.1 When diarrhea resolves, resume therapy at same dosage.1 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.1

If grade 1 diarrhea occurs, no dosage modification required.1

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.1

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.1 When toxicity improves to grade 1 or less, resume therapy at reduced dosage.1

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.1 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.1

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.1

Other Toxicity
Oral

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

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

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

Dosage Modification with Concomitant Drugs or Foods Affecting Hepatic Microsomal Enzymes
Oral

Avoid concomitant use with ketoconazole.1

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.1 (See Drugs and Foods Affecting Hepatic Microsomal Enzymes under Interactions.)

Prescribing Limits

Adults

Breast Cancer
Oral

Dosages <50 mg twice daily not recommended.1

Special Populations

Hepatic Impairment

Severe preexisting hepatic impairment (Child-Pugh class C): Reduce dosage frequency to once daily.1 (See Hepatic Impairment under Cautions.)

Mild or moderate preexisting hepatic impairment (Child-Pugh class A or B): No dosage adjustment required.1

Renal Impairment

Mild or moderate renal impairment (Clcr 30–89 mL/minute): No dosage adjustment required.1 (See Renal Impairment under Cautions.)

Severe renal impairment (Clcr <30 mL/minute), end-stage renal disease, or patients receiving dialysis: No specific dosage recommendations at this time.1

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Cautions for Abemaciclib

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Diarrhea

Diarrhea occurs frequently.1 May result in dehydration or infection.1 Median time to onset: 6–8 days in patients receiving abemaciclib combination therapy.1 Median duration of grade 2 or 3 diarrhea: 6–11 days in patients receiving abemaciclib combination therapy.1 Median times to onset and resolution of diarrhea similar in principal efficacy studies.1

Monitor for development of diarrhea and immediately treat as necessary with appropriate therapy (e.g., antidiarrheal agents, fluid replacement).1 If diarrhea occurs, temporary interruption, dosage reduction, or discontinuance of abemaciclib may be necessary.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Neutropenia

Neutropenia, including febrile neutropenia and neutropenic sepsis, reported.1 Median time to onset of grade 3 or greater neutropenia: 29–33 days.1 Median duration of grade 3 or greater neutropenia: 11–15 days.1

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.1 If neutropenia occurs, temporary interruption, dosage reduction, or discontinuance of abemaciclib may be necessary.1 (See Dosage Modification for Toxicity under Dosage and Administration.) 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.1

Hepatic Toxicity

Hepatotoxicity reported.1 Median time to onset of grade 3 or greater elevations in ALT or AST concentrations: 57–61 or 71–185 days, respectively, in patients receiving abemaciclib combination therapy; these elevations in aminotransferases improved to less than grade 3 or resolved in 13–15 days.1

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.1 If hepatotoxicity occurs, temporary interruption, dosage reduction, or discontinuance of abemaciclib may be necessary.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

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.1

Monitor for manifestations of venous thromboembolic events, including pulmonary embolism.1 If a venous thromboembolic event occurs, initiate appropriate medical intervention.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryofetal toxicity and teratogenicity demonstrated in animals.1

Avoid pregnancy during therapy.1 Women of childbearing potential should use effective contraceptive methods while receiving abemaciclib and for ≥3 weeks after the drug is discontinued.1 If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.1

Impairment of Fertility

Animal studies suggest abemaciclib may impair male fertility.1

Specific Populations

Pregnancy

May cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions and also see Advice to Patients.)

In women of childbearing potential, manufacturer recommends a pregnancy test prior to initiating abemaciclib therapy.1

Lactation

Not known whether abemaciclib distributes into human milk or if drug has any effect on milk production or nursing infant.1 Discontinue nursing during therapy and for ≥3 weeks after drug is discontinued.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

No overall differences in safety and efficacy relative to younger adults.1 Most common grade 3 or 4 toxicities included neutropenia, diarrhea, fatigue, nausea, dehydration, leukopenia, anemia, infection, and elevated serum ALT concentrations.1

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.1

Severe hepatic impairment prolonged mean elimination half-life and increased potency-adjusted total exposure to unbound drug and active metabolites; dosage adjustment recommended.1 (See Hepatic Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics: Absorption.)

Renal Impairment

Mild or moderate renal impairment did not substantially affect systemic exposure of abemaciclib; dosage adjustment not necessary.1

Not studied in patients with severe renal impairment.1

Abemaciclib increases Scr by inhibiting tubular secretion of creatinine;1 does not cause clinically important change in GFR.1

Common Adverse Effects

In combination with an aromatase inhibitor (i.e., anastrozole or letrozole) for initial treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer: Diarrhea,1 14 neutropenia,1 14 fatigue,1 14 infection (most commonly upper respiratory tract infection, lung infection, and pharyngitis),1 14 nausea,1 14 abdominal pain,1 14 anemia,1 14 vomiting,1 14 alopecia,1 14 decreased appetite,1 14 leukopenia,1 14 constipation,1 14 rash,1 cough,1 pruritus,1 dyspnea,1 dizziness,1 decreased weight,1 influenza-like illness,1 thrombocytopenia,1 elevated Scr concentrations (see Renal Impairment under Cautions),1 decreased lymphocyte count,1 elevated AST and/or ALT concentrations,1 14 decreased platelet count.1

In combination with fulvestrant for treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer in patients with disease progression following endocrine therapy: Diarrhea,1 2 fatigue,1 2 neutropenia,1 2 nausea,1 2 infection (includes urinary tract and upper respiratory tract infection, lung infection, pharyngitis, conjunctivitis, sinusitis, vaginal infection, sepsis),1 2 abdominal pain,1 2 anemia,1 2 leukopenia,1 2 decreased appetite,1 2 vomiting,1 2 headache,1 2 dysgeusia,1 2 alopecia,1 2 thrombocytopenia,1 2 stomatitis,1 2 cough,1 2 pruritus,1 2 constipation,2 dizziness,1 2 peripheral edema,1 2 pyrexia,1 2 rash,1 2 decreased weight,1 2 myasthenia,2 elevated Scr concentrations (see Renal Impairment under Cautions),1 2 decreased lymphocyte count,1 decreased platelet count,1 elevated AST and/or ALT concentrations.1 2

Monotherapy in patients with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy for metastatic disease: Diarrhea,1 3 fatigue,1 3 nausea,1 3 decreased appetite,1 3 abdominal pain,1 3 neutropenia,1 vomiting,1 3 infection,1 anemia,1 headache,1 3 thrombocytopenia,1 cough,1 constipation,1 leukopenia,1 arthralgia,1 decreased weight,1 dry mouth,1 stomatitis,1 alopecia,1 dysgeusia,1 dizziness,1 pyrexia,1 dehydration,1 elevated Scr concentrations (see Renal Impairment under Cautions),1 3 decreased leukocyte count,1 decreased neutrophil count,1 decreased lymphocyte count,1 elevated AST and/or ALT concentrations,1 3 hypokalemia,3 hyponatremia.3

Interactions for Abemaciclib

Metabolized mainly by CYP3A4 to active metabolites (M-2, M-18, and M-20).1

In vitro studies indicate that abemaciclib, M-2, and M-20 do not induce CYP isoenzymes 1A2, 2B6, and 3A.1 Down-regulation of messenger RNA (mRNA) for CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2D6, and 3A4 by abemaciclib, M-2, and M-20 observed; however, mechanism and clinical relevance of this effect unknown.1 Autoinhibition of abemaciclib metabolism via CYP3A4 not observed.1

In vitro studies indicate inhibition of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) by abemaciclib.1 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 OAT3.1 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 OATP1B3.1

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible increased systemic exposure to abemaciclib and its active metabolites and increased risk of adverse effects.1 Avoid concomitant use with ketoconazole.1 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.1 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.1 (See Specific Drugs and Foods under Interactions.)

Potent CYP3A inducers: Possible decreased systemic exposure to abemaciclib and its active metabolites and reduced efficacy of abemaciclib.1 Avoid concomitant use with potent CYP3A inducers; consider choosing alternative agent with no or minimal CYP3A induction potential.1 (See Specific Drugs and Foods under Interactions.)

Specific Drugs and Foods

Drug

Interaction

Comments

Anastrozole

No effect on pharmacokinetics of anastrozole or abemaciclib1

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

Possible increased systemic exposure to abemaciclib, M-2, and M-20 and increased adverse effects1

Itraconazole: Simulations suggest increased potency-adjusted total AUC of unbound abemaciclib, M-2, and M-20 by 2.2-fold1 4

Ketoconazole: Simulations suggest increased AUC of abemaciclib by up to 16-fold1 4

Ketoconazole: Avoid concomitant use1

Potent CYP3A inhibitors (e.g., itraconazole, posaconazole, voriconazole):4 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 to 50 mg twice daily1

If potent CYP3A inhibitor discontinued, resume abemaciclib (after 3–5 terminal half-lives of the CYP3A inhibitor) at dosage used prior to initiation of potent CYP3A inhibitor1

Cobicistat

Possible increased systemic exposure to abemaciclib, M-2, and M-20 and increased adverse effects1

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 to 50 mg twice daily1

If cobicistat discontinued, resume abemaciclib (after 3–5 terminal half-lives of the CYP3A inhibitor) at dosage used prior to initiation of potent CYP3A inhibitor1

Conivaptan

Possible increased systemic exposure to abemaciclib, M-2, and M-20 and increased adverse effects1

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 to 50 mg twice daily1

If conivaptan discontinued, resume abemaciclib (after 3–5 terminal half-lives of the CYP3A inhibitor) at dosage used prior to initiation of potent CYP3A inhibitor1

Diltiazem

Simulations suggest increased potency-adjusted total AUC of unbound abemaciclib, M-2, and M-20 by 1.7-fold1 4

Elvitegravir

Ritonavir-boosted elvitegravir: Possible increased systemic exposure to abemaciclib, M-2, and M-20 and increased adverse effects1

Ritonavir-boosted elvitegravir: 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 to 50 mg twice daily1

If ritonavir-boosted elvitegravir discontinued, resume abemaciclib (after 3–5 terminal half-lives of the CYP3A inhibitor) at dosage used prior to initiation of potent CYP3A inhibitor1

Exemestane

No effect on pharmacokinetics of exemestane or abemaciclib1

Fulvestrant

No effect on pharmacokinetics of fulvestrant or abemaciclib1

Grapefruit or grapefruit juice

Possible increased systemic exposure to abemaciclib1

Avoid concomitant use1

HCV antivirals (fixed combination of ombitasvir/paritaprevir/ritonavir with or without dasabuvir)

Ombitasvir/paritaprevir/ritonavir with or without dasabuvir: Possible increased systemic exposure to abemaciclib, M-2, and M-20 and increased adverse effects1

Ombitasvir/paritaprevir/ritonavir with or without dasabuvir: 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 to 50 mg twice daily1

If ombitasvir/paritaprevir/ritonavir with or without dasabuvir discontinued, resume abemaciclib (after 3–5 terminal half-lives of the CYP3A inhibitor) at dosage used prior to initiation of potent CYP3A inhibitor1

HIV protease inhibitors (e.g., ritonavir-boosted indinavir, ritonavir/lopinavir, nelfinavir, ritonavir, ritonavir-boosted saquinavir, ritonavir-boosted tipranavir)

Possible increased systemic exposure to abemaciclib, M-2, and M-20 and increased adverse effects1

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 to 50 mg twice daily1

If potent CYP3A inhibitor discontinued, resume abemaciclib (after 3–5 terminal half-lives of the CYP3A inhibitor) at dosage used prior to initiation of potent CYP3A inhibitor1

Idelalisib

Possible increased systemic exposure to abemaciclib, M-2, and M-20 and increased adverse effects1

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 to 50 mg twice daily1

If idelalisib discontinued, resume abemaciclib (after 3–5 terminal half-lives of the CYP3A inhibitor) at dosage used prior to initiation of potent CYP3A inhibitor1

Letrozole

No effect on pharmacokinetics of letrozole or abemaciclib1

Loperamide

No effect on pharmacokinetics of loperamide or abemaciclib, M-2, or M-201

Macrolides (e.g., clarithromycin)

Possible increased systemic exposure to abemaciclib, M-2, and M-20 and increased adverse effects1

Clarithromycin: Increased potency-adjusted total AUC of unbound abemaciclib, M-2, and M-20 by 1.7-fold1

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 to 50 mg twice daily1

If potent CYP3A inhibitor discontinued, resume abemaciclib (after 3–5 terminal half-lives of the CYP3A inhibitor) at dosage used prior to initiation of potent CYP3A inhibitor1

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%, respectively1

Nefazodone

Possible increased systemic exposure to abemaciclib, M-2, and M-20 and increased adverse effects1

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 to 50 mg twice daily1

If nefazodone discontinued, resume abemaciclib (after 3–5 terminal half-lives of the CYP3A inhibitor) at dosage used prior to initiation of potent CYP3A inhibitor1

Rifampin

Decreased potency-adjusted total AUC of unbound abemaciclib, M-2, and M-20 by 67%1

Avoid concomitant use1

Select alternative agent with less CYP3A induction potential1

Verapamil

Simulations suggest increased potency-adjusted total AUC of unbound abemaciclib, M-2, and M-20 by 1.3-fold1 4

Abemaciclib Pharmacokinetics

Absorption

Bioavailability

Following oral administration, median time to peak plasma concentrations is 8 hours.1

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.1

Steady-state concentrations achieved in 5 days.1

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.1

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.1

Mild or moderate renal impairment (Clcr 30–89 mL/minute) does not substantially affect systemic exposure.1 Data lacking for severe renal impairment (Clcr <30 mL/minute).1

Age (24–91 years), gender, and body weight (36–175 kg) do not substantially affect pharmacokinetics.1 15

Distribution

Extent

Not known whether distributed into human milk.1

CSF concentrations of abemaciclib and its active metabolites similar to unbound plasma concentrations in patients with advanced cancer.1

Plasma Protein Binding

>93% (mainly plasma proteins, albumin, α1-acid glycoprotein).1

Elimination

Metabolism

Principally metabolized by CYP3A4.1

Elimination Route

Eliminated in feces (81% of recovered dose [mainly as metabolites]) and urine (approximately 3%).1

Half-life

18.3 hours.1

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

Actions

  • Selective inhibitor of CDK4 and 6.1 2 3

  • 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.1

  • Inhibits the G1 into S phase of the cell cycle and reduces cellular proliferation of breast cancer cells.1

  • Combination of abemaciclib and an antiestrogen or as a single-agent reduced tumor volume in breast tumor xenografts.1 16

Advice to Patients

  • Importance of advising patients to swallow abemaciclib tablets whole and not to break, chew, crush, or split the tablets.1

  • 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.1

  • Risk of diarrhea.1 Importance of informing patients that early identification and intervention is critical for the optimal management of diarrhea.1 Importance of informing patients how to manage diarrhea (e.g., oral hydration, antidiarrheal agents) at the first sign of loose stools.1 Importance of informing clinician if diarrhea occurs.1

  • Risk of neutropenia.1 Importance of promptly informing clinician if signs or symptoms of neutropenia or infection (e.g., fever) occur.1

  • Risk of hepatotoxicity.1 Importance of promptly informing clinician if symptoms of hepatotoxicity (e.g., fatigue, anorexia, right upper quadrant pain, bleeding diathesis) occur.1

  • Risk of venous thromboembolic events.1 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).1

  • Risk of fetal harm.1 Necessity of advising women of childbearing potential to use an effective method of contraception during treatment and for ≥3 weeks after discontinuance of therapy.1 Importance of women informing clinicians if they are or plan to become pregnant.1 Apprise patient of potential fetal hazard if used during pregnancy.1

  • Importance of advising women to discontinue nursing during therapy and for >3 weeks after discontinuance of the drug.1

  • 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.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

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

Tablets

50 mg

Verzenio

Lilly

100 mg

Verzenio

Lilly

150 mg

Verzenio

Lilly

200 mg

Verzenio

Lilly

AHFS DI Essentials™. © Copyright 2018, Selected Revisions October 8, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Eli Lilly and Company. Verzenio (Abemaciclib) tablets prescribing information. Indianapolis, IN; 2017 Sept.

2. Sledge GW, Toi M, Neven P et al. MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. J Clin Oncol. 2017; 35:2875-2884. http://www.ncbi.nlm.nih.gov/pubmed/28580882?dopt=AbstractPlus

3. Dickler MN, Tolaney SM, Rugo HS et al. MONARCH 1, A Phase II Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, as a Single Agent, in Patients with Refractory HR/HER2Metastatic Breast Cancer. Clin Cancer Res. 2017; 23:5218-5224. http://www.ncbi.nlm.nih.gov/pubmed/28533223?dopt=AbstractPlus

4. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 208716Orig1s000: Multi-discipline review. From FDA website. Accessed 2018 Mar 8. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208716Orig1s000MultidisciplineR.pdf

5. Morikawa A, Henry NL. Palbociclib for the Treatment of Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer. Clin Cancer Res. 2015; 21:3591-6. http://www.ncbi.nlm.nih.gov/pubmed/26100274?dopt=AbstractPlus

6. Rocca A, Farolfi A, Bravaccini S et al. Palbociclib (PD 0332991) : targeting the cell cycle machinery in breast cancer. Expert Opin Pharmacother. 2014; 15:407-20. http://www.ncbi.nlm.nih.gov/pubmed/24369047?dopt=AbstractPlus

7. Murphy CG, Dickler MN. The Role of CDK4/6 Inhibition in Breast Cancer. Oncologist. 2015; 20:483-90. http://www.ncbi.nlm.nih.gov/pubmed/25876993?dopt=AbstractPlus

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