Abemaciclib, a selective inhibitor of cyclin-dependent kinases 4 (CDK4) and 6 (CDK6), is an antineoplastic agent.1, 2, 3
Adjuvant Therapy for Early-stage Breast Cancer
Abemaciclib is used 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.1, 20, 21 Guidelines generally recommend abemaciclib as a treatment option (in combination with endocrine therapy) for hormone receptor-positive, HER2-negative, early-stage breast cancer in patients with a Ki-67 score of ≥20%, ≥4 positive axillary lymph nodes, or 1-3 positive axillary lymph nodes with additional high-risk features (e.g., grade 3 histology, tumor size ≥5 cm).71
This indication for abemaciclib is based principally on the results of a randomized, open-label, two cohort, multicenter, phase 3 study (monarchE) in a cohort of female (any menopausal status) and male patients with hormone receptor-positive, HER2-negative, node-positive, resected early-stage breast cancer with clinical and pathological features consistent with a high risk of recurrence.1, 20, 21 In cohort 1, patients were required to have ≥4 positive axillary lymph nodes or 1-3 positive axillary lymph nodes and at least one of the following: grade 3 histology or tumor size ≥5 cm.1, 20 Patients enrolled in cohort 2 could not meet the eligibility requirements for cohort 1 and were required to have 1-3 positive axillary lymph nodes and a Ki-67 score ≥20%.1 Patients with available untreated breast tumor samples were tested retrospectively at central sites using the Ki-67 immunohistochemistry (IHC) MIB-1 pharmDx assay to establish if the Ki-67 score was ≥20%.1 Eligible patients were randomized within 16 months of surgical resection to receive abemaciclib 150 mg twice daily in combination with the investigator's choice of standard endocrine therapy for 2 years.1, 20, 21 The primary measure of efficacy was invasive disease-free survival as defined by the Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials (STEEP) criteria; an additional outcome was overall survival.1, 20, 21 In cohort 1, the median age of patients was 51 years (range: 22-89); 99% were women, 70% were white, 24% were Asian, 43% were premenopausal, 37% received prior neoadjuvant chemotherapy, 59% received prior adjuvant chemotherapy, and 96% received prior radiotherapy.1 Initial endocrine therapy included letrozole (39%), tamoxifen (31%), anastrozole (22%), or exemestane (8%).1
At the time of the final analysis, patients in cohort 1 who received abemaciclib in combination with endocrine therapy had fewer invasive disease events compared with those receiving standard endocrine therapy alone (12.4 versus 18.5%; hazard ratio: 0.653).1, 21 At the time of data analysis, a significant difference was noted for invasive disease-free survival in the intent to treat population, which was primarily attributed to patients treated in cohort 1.1 Invasive disease-free survival at 48 months was 85.5% in patients receiving abemaciclib in combination with endocrine therapy and 78.6% in those receiving standard endocrine therapy in cohort 1.1 The overall survival (OS) analysis for cohort 2 remains immature, but more deaths were observed in patients receiving abemaciclib in combination with endocrine therapy (10/253) compared to those receiving standard endocrine therapy alone (5/264).1
Initial Therapy for Advanced Breast Cancer
Abemaciclib is used in combination with an aromatase inhibitor for the initial treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer in adults.1, 14, 18 Guidelines generally recommend CDK 4/6 inhibitors, including abemaciclib, in combination with an aromatase inhibitor for the first-line treatment of hormone receptor-positive metastatic breast cancer in men and postmenopausal women.70
This indication for abemaciclib is based principally on the results of a randomized, double-blind, placebo-controlled phase 3 study (MONARCH-3) in postmenopausal women with previously untreated hormone receptor-positive, HER2-negative advanced or metastatic breast cancer.1, 14 In this study, 493 patients were randomized (stratified by site of metastases and prior neoadjuvant or adjuvant endocrine therapy) in a 2:1 ratio to receive either abemaciclib (150 mg orally twice daily) in combination with an aromatase inhibitor (letrozole 2.5 mg or anastrozole 1 mg orally once daily) or placebo in combination with an aromatase inhibitor.1, 14 Treatment was continued until disease progression, death, or unacceptable toxicity occurred or treatment was discontinued for other reasons.14 Cross over to the opposite treatment arm was not permitted.14 The primary measure of efficacy was progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST).14 In this study, the median age of patients was 63 years; 58% were white, 30% were Asian, 40% had de novo metastatic disease, 53% had visceral involvement, 22% had bone-only disease, 51% had received prior systemic therapy, and 39% had received prior chemotherapy.1, 14 All patients enrolled in the study had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.14 Patients who had received prior therapy with a cyclin-dependent kinase (CDK) 4/6 inhibitor or everolimus were excluded from the study.14
At the time of the interim analysis, patients receiving abemaciclib in combination with an aromatase inhibitor had a longer median progression-free survival than those receiving placebo in combination with an aromatase inhibitor (28.2 versus 14.8 months; hazard ratio: 0.54).1 Final analyses for progression-free survival at a median follow-up of 26.7 months showed that progression-free survival benefit was maintained in patients receiving abemaciclib in combination with an aromatase inhibitor compared with those receiving placebo in combination with an aromatase inhibitor (28.2 versus 14.8 months, respectively; hazard ratio: 0.54).18 The results of the final progression-free survival analysis based on an independent, blinded, central radiologic assessment were consistent with the investigator assessment.18 Among patients with measurable disease, patients receiving abemaciclib in combination with an aromatase inhibitor also had higher overall response rates compared with those receiving placebo in combination with an aromatase inhibitor (55.4 versus 40.2%).1 Overall response rate for abemaciclib- and placebo-treated patients at the time of the final analysis remained similar to the interim results.1, 18 A subset analysis of progression-free survival based on site of metastases and prior endocrine therapy consistently showed progression-free survival benefit in patients receiving abemaciclib in combination with an aromatase inhibitor compared with those receiving placebo in combination with an aromatase inhibitor.18 Median overall survival had not been reached at the time of the interim analysis.1
Previously Treated Advanced Breast Cancer
Abemaciclib is used alone or in combination with fulvestrant for the treatment of adults with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer with disease progression following previous therapy.1, 2, 3, 19, 22 Guidelines state that abemaciclib must be used in combination with either an aromatase inhibitor or fulvestrant in men and postmenopausal women with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer depending on previous exposure to endocrine therapy.70
Abemaciclib is used in combination with fulvestrant for the treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer in adults with disease progression following endocrine therapy.1, 2 A statistically significant progression-free survival benefit has been observed in women with previously treated, hormone receptor-positive, HER2-negative advanced or metastatic breast cancer receiving combined therapy with abemaciclib and fulvestrant compared with patients receiving placebo in combination with fulvestrant.1, 2, 19, 22
This indication for abemaciclib is based principally on the results of a randomized, double-blind, placebo-controlled phase 3 study (MONARCH-2) in women with hormone receptor-positive, HER2-negative metastatic breast cancer.1, 2 Patients enrolled in this study had disease progression following prior endocrine therapy.1 In this study, 669 patients were randomized (stratified according to sensitivity to endocrine therapy and site of metastases) in a 2:1 ratio to receive either abemaciclib in combination with fulvestrant or placebo in combination with fulvestrant.1, 2 Patients randomized to abemaciclib received 200 mg orally twice daily upon initiation of the study, but the protocol was amended to reduce the abemaciclib dosage to 150 mg twice daily following review of safety data and dosage reduction rates.2 All patients enrolled in the study received fulvestrant 500 mg IM on days 1 and 15 during cycle 1 followed by day 1 of each 28-day cycle thereafter.1, 2 Patients were treated until disease progression, unacceptable toxicity, or death occurred.1, 2 Premenopausal or perimenopausal patients received goserelin acetate for at least 4 weeks prior to and during the study.1 The primary measure of efficacy was progression-free survival as assessed by the investigator according to RECIST.2 In this study, the median age of patients was 60 years; 56% were Caucasian, 20% had de novo metastatic disease, 56% had visceral disease, 27% had bone-only disease, 25% had primary resistance to endocrine therapy (defined as disease that relapsed during the initial 2 years of adjuvant endocrine therapy or disease progression within the initial 6 months of first-line endocrine therapy for metastatic disease), and 17% were premenopausal or perimenopausal.1 The majority of patients (99%) had an ECOG performance status of 0 or 1.1 Patients who had received chemotherapy for metastatic disease or prior therapy with a CDK4/6 inhibitor, fulvestrant, or everolimus were excluded from the study.1, 2
At a median follow-up of 19.5 months, patients receiving abemaciclib in combination with fulvestrant had a longer median progression-free survival compared with patients receiving placebo in combination with fulvestrant (16.4 versus 9.3 months; hazard ratio: 0.55).1, 2 The results of the progression-free survival analysis based on an independent, blinded, central radiologic assessment were consistent with the investigator assessment.1, 2 Among patients with measurable disease, patients receiving abemaciclib in combination with fulvestrant also had higher overall response rates compared with those receiving placebo in combination with fulvestrant (48.1 versus 21.3%).1, 2 At a median follow-up of 47.7 months, patients receiving abemaciclib in combination with fulvestrant had a longer median overall survival compared with patients receiving placebo in combination with fulvestrant (46.7 versus 37.3 months; hazard ratio: 0.76).1, 19 A subset analysis of progression-free survival and overall survival based on site of metastases and sensitivity to endocrine therapy consistently showed treatment benefit with abemaciclib and fulvestrant combination therapy compared with placebo and fulvestrant therapy.1, 19 An additional analysis suggests that the clinical outcomes in a subgroup of 114 premenopausal women were consistent with the overall study population.22
Abemaciclib monotherapy is used for the 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
This indication for abemaciclib is based principally on the results of an open-label, noncomparative phase 2 study (MONARCH-1) in women with hormone receptor-positive, HER2-negative metastatic breast cancer.1, 3 Patients enrolled in this study had received a taxane in any setting and 1-2 prior chemotherapy regimens for metastatic disease and had disease progression during or following prior endocrine therapy.1, 3 In this study, 132 patients received abemaciclib 200 mg orally twice daily until disease progression or unacceptable toxicity occurred.1, 3 The primary measure of efficacy was overall response rate as assessed by the investigator according to RECIST.3 The median age of patients was 58 years and 85% of patients were Caucasian.1 All patients enrolled in the study had an ECOG performance status of 0 or 1.1 The median duration of metastatic disease was 27.6 months; 90% had visceral disease and 51% had at least 3 sites of metastases.1 Approximately one-half (51%) of patients received one prior line of chemotherapy in the metastatic setting; 69% of patients received a taxane-based regimen and 55% received capecitabine.1 Patients who had received prior therapy with a CDK4/6 inhibitor were excluded from the study.3
In this study, the investigator-assessed overall response rate was 19.7%; none of the patients achieved a complete response.1, 3 At the time of data analysis, the median duration of response was 8.6 months.1 Effects of abemaciclib on overall response rate as assessed by an independent review facility and investigator-assessed overall response rate were comparable.1, 3 At the time of the final analysis at a follow-up of 18 months, the median overall survival was 22.3 months.3
Dispensing and Administration Precautions
Abemaciclib is administered orally without regard to food at approximately the same time each day.1 The tablets should be swallowed intact and should not be broken, chewed, crushed, or split.1
If a dose of abemaciclib is missed or vomited, patients should not take an extra dose.1 The next dose should be taken at the regularly scheduled time.1
Store abemaciclib at 20-25ºC (excursions permitted to 15-30ºC).1
Adjuvant Therapy for Early-stage Breast Cancer
For the adjuvant treatment of patients with hormone receptor-positive, human epidermal growth factor receptor type 2 (HER2)-negative, node-positive, early-stage breast cancer with high risk of recurrence, the recommended adult dosage of abemaciclib is 150 mg twice daily in combination with an aromatase inhibitor (e.g., anastrozole, letrozole) or tamoxifen.1 Therapy should be continued for 2 years or until disease progression or unacceptable toxicity occurs.1
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.1
Men receiving combination therapy with abemaciclib and an aromatase inhibitor should be treated with a GnRH agonist according to current standards of care.1
Initial Therapy for Advanced Breast Cancer
For the initial treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer in men or postmenopausal women, the recommended adult dosage of abemaciclib is 150 mg twice daily in combination with an aromatase inhibitor (e.g., anastrozole, letrozole).1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Premenopausal or perimenopausal patients receiving combination therapy with abemaciclib and aromatase inhibitor should be treated with a GnRH agonist (e.g., goserelin) according to current standards of care.1
Men receiving combination therapy with abemaciclib and an aromatase inhibitor should be treated with a GnRH agonist according to current standards of care.1
Previously Treated Advanced Breast Cancer
For use in combination with fulvestrant in the treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer in patients with disease progression following endocrine therapy, the recommended adult dosage of abemaciclib is 150 mg twice daily.1 Fulvestrant 500 mg is administered IM on days 1, 15, and 29, and then once monthly thereafter.1 Premenopausal or perimenopausal patients receiving combination therapy with abemaciclib and fulvestrant should be treated with a GnRH agonist (e.g., goserelin) according to current standards of care.1
For use as a single-agent in the treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer in patients with disease progression following endocrine therapy and chemotherapy in the metastatic setting, the recommended adult dosage of abemaciclib is 200 mg twice daily.1
Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity
Dosage interruption and/or reduction or discontinuance of abemaciclib therapy may be necessary based on severity of adverse reactions.1 The following table on Dosage Modifications for Abemaciclib Toxicity indicates the recommended dosage modifications for abemaciclib during monotherapy or combination therapy with fulvestrant or an aromatase inhibitor.1
Toxicity Occurrence | Dosage Modification after Recovery from Toxicity |
|
|---|---|---|
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 |
|
For grade 4 hematologic toxicity, abemaciclib therapy should be interrupted until the toxicity improves to grade 2 or less.1 Upon resumption of therapy, the dosage of abemaciclib should be reduced.1 Hematopoietic growth factors (e.g., granulocyte colony-stimulating factor [G-CSF]) may be administered if clinically indicated; however, abemaciclib therapy should be withheld for at least 48 hours after the last dose of a hematopoietic growth factor and until the toxicity improves to grade 2 or less.1
For the first occurrence of grade 3 hematologic toxicity, abemaciclib therapy should be interrupted; therapy may be resumed at the same dosage when the toxicity improves to grade 2 or less.1 If grade 3 hematologic toxicity recurs, abemaciclib therapy should be withheld again; therapy may then be resumed at a reduced dosage when the toxicity improves to grade 2 or less.1
For grade 1 or 2 hematologic toxicity, no dosage adjustment is necessary.1
For grade 3 or 4 diarrhea or diarrhea requiring hospitalization, abemaciclib therapy should be interrupted until the toxicity improves to grade 1 or less.1 Upon resumption of therapy, the dosage of abemaciclib should be reduced.1
For persistent grade 2 diarrhea lasting 24 hours or longer, abemaciclib therapy should be interrupted; therapy may be resumed at the same dosage when the toxicity resolves.1 If grade 2 diarrhea persists or recurs despite optimal supportive measures, abemaciclib therapy should be withheld again; therapy may then be resumed at a reduced dosage when the toxicity improves to grade 1 or less.1
For grade 1 diarrhea, no dosage adjustment is necessary.1
For grade 4 serum aminotransferase (ALT and/or AST) elevations (i.e., exceeding 20 times the upper limit of normal [ULN]) or serum ALT and/or AST elevations exceeding 3 times the ULN with total bilirubin concentrations exceeding 2 times the ULN in the absence of cholestasis, abemaciclib therapy should be discontinued.1
For grade 3 serum ALT and/or AST elevations (i.e., exceeding 5 times the ULN, but no more than 20 times the ULN) with total bilirubin concentrations no more than 2 times the ULN, abemaciclib therapy should be interrupted until the toxicity improves to grade 1 or baseline.1 Upon resumption of therapy, the dosage of abemaciclib should be reduced.1
For grade 2 serum ALT and/or AST elevations (i.e., exceeding 3 times the ULN, but no more than 5 times the ULN) with total bilirubin concentrations no more than 2 times the ULN, no dosage adjustment is necessary.1 If grade 2 serum ALT and/or AST elevations with total bilirubin concentrations no more than 2 times the ULN persist or recur, abemaciclib therapy should be interrupted until the toxicity improves to grade 1 or baseline.1 Upon resumption of therapy, the dosage of abemaciclib should be reduced.1
For grade 1 serum ALT and/or AST elevations (i.e., exceeding the ULN, but no more than 3 times the ULN) with total bilirubin concentrations no more than 2 times the ULN, no dosage adjustment is necessary.1
Interstitial Lung Disease/Pneumonitis
For grade 3 or 4 interstitial lung disease (ILD)/pneumonitis, abemaciclib therapy should be permanently discontinued.1, 17
For grade 2 ILD/pneumonitis, abemaciclib therapy may be continued at the same dosage.1 If grade 2 ILD/pneumonitis persists or recurs despite optimal supportive measures for up to 7 days, abemaciclib therapy should be interrupted until the toxicity improves to grade 1 or baseline.1 Upon resumption of therapy, the dosage of abemaciclib should be reduced.1
For grade 1 ILD/pneumonitis, no dosage adjustment is necessary.1
For venous thromboembolic events of any grade in patients with early-stage breast cancer, interrupt abemaciclib therapy and treat as clinically indicated.1 When the patient is clinically stable, resume abemaciclib therapy.1
For grade 1 or 2 venous thromboembolic events in patients with advanced or metastatic breast cancer, no dosage adjustment is necessary.1
For grade 3 or 4 venous thromboembolic events in patients with advanced or metastatic breast cancer, interrupt abemaciclib therapy and treat as clinically indicated.1 When the patient is clinically stable, resume abemaciclib therapy.1
For grade 3 or 4 adverse reactions, abemaciclib therapy should be interrupted until the toxicity improves to grade 1 or baseline.1 Upon resumption of therapy, the dosage of abemaciclib should be reduced.1
For grade 2 adverse reactions, abemaciclib therapy may be continued at the same dosage.1 If grade 2 adverse reactions persist or recur despite optimal supportive measures for up to 7 days, abemaciclib therapy should be interrupted until the toxicity improves to grade 1 or baseline.1 Upon resumption of therapy, the dosage of abemaciclib should be reduced.1
For grade 1 adverse reactions, no dosage adjustment is necessary.1
Dosage Modification with Concomitant Drugs or Foods Affecting Hepatic Microsomal Enzymes
Concomitant use of abemaciclib with ketoconazole, a potent inhibitor of cytochrome P-450 (CYP) isoenzyme 3A (CYP3A), must be avoided; however, when abemaciclib is used concomitantly with other potent CYP3A inhibitors, the manufacturer recommends reducing the initial dosage of abemaciclib (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), further reducing the dosage of abemaciclib to 50 mg twice daily.1 When concomitant use of the potent CYP3A inhibitor is discontinued, the abemaciclib dosage should be returned (after at least 3-5 elimination half-lives of the CYP3A inhibitor) to the dosage used prior to initiation of the potent CYP3A inhibitor.1
Patients receiving abemaciclib concomitantly with moderate CYP3A inhibitors should be monitored for signs of abemaciclib toxicity and dosage modifications for adverse reactions (see Table 1) should be considered.1
For patients with severe preexisting hepatic impairment (Child-Pugh class C), the manufacturer recommends reducing the dosage frequency from twice daily to once daily.1 No dosage adjustment is necessary in patients with mild or moderate preexisting hepatic impairment (Child-Pugh class A or B).1
Dosage adjustment is not necessary in patients with mild or moderate renal impairment (creatinine clearance 30-89 mL/minute).1 The effects of severe renal impairment (creatinine clearance less than 30 mL/minute), end-stage renal disease, or dialysis on the pharmacokinetics of abemaciclib have not been established, and the manufacturer makes no specific dosage recommendations for such patients.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
The manufacturer states there are no known contraindications to the use of abemaciclib.1
Severe diarrhea, sometimes resulting in dehydration or infection, has occurred in patients receiving abemaciclib, generally during the initial month of therapy.1 Across 4 clinical studies, diarrhea was reported in 81-90% of abemaciclib-treated patients; grade 3 diarrhea occurred in 8-20% of patients.1 The median time to first occurrence of diarrhea was 6-8 days in patients receiving abemaciclib and the median duration of grade 2 or 3 diarrhea was 6-11 or 5-8 days, respectively.1 Temporary interruption or dosage reduction of abemaciclib was necessary in 19-26 or 13-23% of patients, respectively.1
Patients receiving abemaciclib should be monitored for development of diarrhea and immediately treated as necessary with appropriate therapy (e.g., antidiarrheal agents, fluid replacement) at the first sign of loose stools.1 Temporary interruption, dosage reduction, or discontinuance of abemaciclib may be necessary depending on the severity of the diarrhea.1
Neutropenia, including febrile neutropenia and fatal neutropenic sepsis, has occurred in patients receiving abemaciclib.1 Across 4 clinical studies, neutropenia was reported in 37-46% of abemaciclib-treated patients; grade 3 or greater neutropenia occurred in 19-32% of patients.1 The median time to first occurrence of grade 3 or greater neutropenia was 29-33 days and the median duration was 11-16 days.1 Febrile neutropenia was reported in less than 1% of abemaciclib-treated patients.1 In the MONARCH-2 study, fatal neutropenic sepsis occurred in 2 patients receiving abemaciclib in combination with fulvestrant.1
Complete blood cell (CBC) counts should be monitored at baseline, every 2 weeks during the initial 2 months of therapy, monthly during the next 2 months, and then as clinically indicated.1 Temporary interruption, dosage reduction, or discontinuance of abemaciclib may be necessary if neutropenia occurs during therapy with the drug.1
Interstitial Lung Disease/Pneumonitis
Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis has occurred in patients receiving cyclin-dependent kinases 4 (CDK4) and 6 (CDK6) inhibitors, including abemaciclib.1 In the monarchE trial evaluating abemaciclib in patients with early-stage breast cancer, ILD or pneumonitis occurred in 3% of patients receiving abemaciclib in combination with an aromatase inhibitor, grade 3 or 4 ILD or pneumonitis occurred in 0.4% of patients and 1 patient died.1 In the MONARCH-1, MONARCH-2, and MONARCH-3 studies evaluating abemaciclib in patients with advanced or metastatic breast cancer, ILD or pneumonitis occurred in 3.3% of abemaciclib-treated patients, and grade 3 or 4 ILD or pneumonitis occurred in 0.6% of abemaciclib-treated patients.1 ILD or pneumonitis resulting in death occurred in 0.4% of abemaciclib-treated patients.1 Cases of ILD or pneumonitis, including fatal cases, also have been reported during postmarketing experience in patients receiving abemaciclib.1
Patients receiving abemaciclib should be monitored clinically and by radiographic imaging for manifestations of ILD or pneumonitis.1, 17 If manifestations suggestive of ILD or pneumonitis (e.g., hypoxia, cough, dyspnea, interstitial infiltrates) occur, the possibility of other etiologies (e.g., infection, neoplastic) should be excluded.1, 17 Temporary interruption, dosage reduction, or discontinuance of abemaciclib may be necessary if ILD or pneumonitis occurs during therapy with the drug.1, 17
Hepatotoxicity has occurred in patients receiving abemaciclib.1 In the monarchE, MONARCH-2, and MONARCH-3 studies, grade 3 or greater elevations in serum ALT or AST concentrations were reported in 2-6 or 2-3%, respectively, of abemaciclib-treated patients.1 The median time to onset of grade 3 or greater elevations in AST concentrations was 71-185 days in abemaciclib-treated patients and the median time to resolution to less than grade 3 severity was 11-15 days.1
Liver function tests (i.e., serum ALT, AST, and bilirubin concentrations) should be monitored at baseline, every 2 weeks during the initial 2 months of therapy, monthly during the next 2 months, and then as clinically indicated.1 Temporary interruption, dosage reduction, or discontinuance of abemaciclib may be necessary if hepatotoxicity occurs during therapy with the drug.1
Venous thromboembolic events (i.e., deep-vein thrombosis, pulmonary embolism, pelvic venous thrombosis, cerebral venous sinus thrombosis, subclavian and axillary vein thrombosis, inferior vena cava thrombosis) have occurred in patients receiving abemaciclib.1 Venous thromboembolic events occurred in 2-5% of abemaciclib-treated patients across 3 clinical trials (monarchE, MONARCH-2, MONARCH-3).1 Fatal venous thromboembolic events have occurred in clinical trials.1 Abemaciclib has not been studied in patients with early-stage breast cancer with a history of venous thromboembolism.1
Patients should be monitored for signs or symptoms of venous thromboembolic events, including pulmonary embolism.1 If a venous thromboembolic event occurs, patients should receive appropriate medical intervention.1 Interrupt treatment with abemaciclib 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.1
Fetal/Neonatal Morbidity and Mortality
There are no adequate and well-controlled studies of abemaciclib in pregnant females; however, based on its mechanism of action and animal findings, abemaciclib may cause fetal harm.1 Embryofetal toxicity (e.g., decreased fetal weight) and teratogenicity (e.g., cardiovascular and skeletal abnormalities) have been demonstrated in rats receiving abemaciclib at exposure levels similar to the human exposure at the maximum recommended dosage.1
Pregnancy should be avoided during abemaciclib therapy.1 The manufacturer recommends confirmation of pregnancy status prior to initiation of abemaciclib, and females of reproductive potential should be advised to use effective contraceptive methods during and for at least 3 weeks after discontinuance of the drug.1 Patients should be apprised of the potential hazard to the fetus if abemaciclib is used during pregnancy.1
Abemaciclib may cause fetal harm if administered to pregnant females based on its mechanism of action and animal findings.1
Verify pregnancy status prior to initiation of abemaciclib therapy.1
It is not known whether abemaciclib is distributed into human milk.1 Because of the potential for serious adverse reactions to abemaciclib in nursing infants, women should be advised to discontinue nursing during and for at least 3 weeks after discontinuance of abemaciclib therapy.1 The effects of the drug on nursing infants or on milk production are unknown.1
Females and Males of Reproductive Potential
Results of animal studies suggest that abemaciclib may impair male fertility.1
In a general toxicology study, degeneration of reproductive tissues, decreased reproductive organ weights, intratubular cellular debris, hypospermia, and tubular dilation were observed in male animals receiving abemaciclib at exposure levels as low as 0.02 times the human exposure at the maximum recommended dosage for up to 3 months.1 Additional animal studies did not find any adverse effects on mating or fertility among male animals receiving abemaciclib at exposure levels 2-3 times the human exposure at the maximum recommended dosage.1
Safety and efficacy of abemaciclib have not been established in pediatric patients.1
In the monarchE study, 15% of patients were 65 years of age or older and 2.7% were 75 years of age or older.1
In the MONARCH-1, MONARCH-2, and MONARCH-3 studies, 38% of patients were 65 years of age or older and 10% were 75 years of age or older.1 No overall differences in safety and efficacy were observed between geriatric patients and younger adults.1 Grade 3 or 4 adverse reactions occurring in at least 5% of geriatric patients in MONARCH-1, MONARCH-2, and MONARCH-3 were neutropenia, diarrhea, fatigue, nausea, dehydration, leukopenia, anemia, infection, and elevated serum ALT concentrations.1
Among patients 24-91 years of age, age did not appear to substantially affect systemic exposure to abemaciclib.1
Following administration of a single 200-mg dose of abemaciclib, potency-adjusted total exposure to unbound drug and active metabolites in individuals with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C) increased by 1.2-, 1.1-, or 2.4-fold, respectively, compared with individuals with normal hepatic function;1 however, the mean elimination half-life of abemaciclib was prolonged by more than twofold in patients with severe hepatic impairment (55 hours) compared with individuals with normal hepatic function (24 hours).1 Dosage adjustment is required in patients with severe hepatic impairment.1
Population pharmacokinetic analysis indicated that mild or moderate renal impairment (creatinine clearance 30 to less than 90 mL/minute) did not appear to substantially affect systemic exposure to abemaciclib.1
Pharmacokinetics of abemaciclib have not been established in patients with severe renal impairment (creatinine clearance less than 30 mL/minute).1
Abemaciclib has been shown to increase serum creatinine concentrations; however, it does not cause a clinically important change in glomerular filtration rate (GFR).1 Abemaciclib inhibits tubular secretion of creatinine by inhibiting renal organic cation transporter (OCT) 2, multidrug and toxin extrusion transporter (MATE) 1, and MATE2K.1 In clinical studies, the mean increase in serum creatinine concentrations was 0.2-0.3 mg/dL.1 Elevated concentrations of serum creatinine generally occurred during the initial month of therapy and were reversible after discontinuance of abemaciclib.1 The manufacturer states that parameters not based on serum creatinine concentrations (e.g., BUN or cystatin C concentrations, estimated GFR) may be considered to evaluate renal function.1
Adverse effects reported in 20% or more of patients treated with abemaciclib include diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, and thrombocytopenia.1
Metabolism of abemaciclib to the active N -desethyl (M-2), hydroxy- N -desethyl (M-18), and hydroxy (M-20) metabolites is mediated principally by cytochrome P-450 (CYP) isoenzyme 3A4.1
Autoinhibition of abemaciclib metabolism via CYP3A4 has not been observed.1
In vitro studies indicate that abemaciclib inhibits P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).1 Abemaciclib and its major active metabolites also 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 at clinically relevant concentrations.1 In vitro, the drug is a substrate for P-gp and BCRP, but the drug and its major active metabolites are not substrates for OCT1, OATP1B1, or OATP1B3.1
Drugs and Foods Affecting Hepatic Microsomal Enzymes
Concomitant use of abemaciclib with potent or moderate inhibitors of CYP3A may result in increased systemic exposure (area under the concentration-time curve [AUC]) of abemaciclib and its active metabolites and an increased incidence of adverse effects.1 When the potent CYP3A inhibitor clarithromycin (500 mg twice daily) was administered concomitantly with abemaciclib (single 50-mg dose) in healthy individuals, the potency-adjusted total AUC of unbound abemaciclib and its active metabolites was increased 2.5-fold compared with cancer patients receiving the drug alone.1 Simulations using physiologically based pharmacokinetic models suggest that the potent CYP3A inhibitor itraconazole may increase the potency-adjusted total AUC of unbound abemaciclib and its active metabolites by 2.2-fold; however, ketoconazole may increase the AUC of abemaciclib by up to 16-fold.4 Simulations using physiologically based pharmacokinetic models suggest that the moderate CYP3A inhibitors diltiazem and verapamil may increase the potency-adjusted total AUC of unbound abemaciclib and its active metabolites approximately 2.4- and 1.6-fold, respectively.1, 4
Concomitant use of abemaciclib with the potent CYP3A inhibitor ketoconazole must be avoided; however, when abemaciclib is used concomitantly with other potent CYP3A inhibitors (e.g., clarithromycin, itraconazole),4 the manufacturer of abemaciclib recommends reducing the initial dosage of abemaciclib (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), further reducing the dosage of abemaciclib to 50 mg twice daily.1 When concomitant use of the potent CYP3A inhibitor is discontinued, the abemaciclib dosage should be returned (after at least 3-5 elimination half-lives of the CYP3A inhibitor) to the dosage used prior to initiation of the potent CYP3A inhibitor.1
If abemaciclib is used concomitantly with moderate CYP3A inhibitors, patients should be monitored for signs of abemaciclib toxicity and dosage modifications for adverse reactions should be considered.1
Grapefruit products are CYP3A inhibitors and should be avoided because of the potential for increased systemic exposure of abemaciclib during concurrent use.1
Concomitant use of abemaciclib with potent or moderate inducers of CYP3A may result in decreased peak plasma concentrations and AUC of abemaciclib and its active metabolites and reduced abemaciclib efficacy.1 When the potent CYP3A inducer rifampin (600 mg daily) was administered concomitantly with abemaciclib (single 200-mg dose) in healthy individuals, the potency-adjusted total AUC of unbound abemaciclib and its active metabolites was decreased by approximately 70%.1 Moderate CYP3A inducers efavirenz, bosentan, and modafinil are predicted to decrease the potency-adjusted total AUC of unbound abemaciclib and its active metabolites by 53, 41, and 29%, respectively.1
Concomitant use of abemaciclib with potent or moderate inducers of CYP3A should be avoided, and selection of an alternative drug with less CYP3A induction potential should be considered.1
Drugs Affected by Hepatic Microsomal Enzymes
A drug interaction study indicated that administration of abemaciclib 200 mg twice daily for 7 days in patients with cancer does not result in clinically significant alterations to the pharmacokinetics of CYP isoenzymes 1A2, 2C9, 2D6, and 3A4 substrates.1
Drugs Affected by Transport Systems
Abemaciclib and its active metabolites inhibit OCT2, MATE1, and MATE2K at clinically relevant concentrations.1 When a single 1-g dose of metformin (a substrate of OCT2, MATE1, and MATE2K) was administered with a single 400-mg dose of abemaciclib, peak plasma concentrations and AUC of metformin increased by 22 and 37%, respectively.1 Abemaciclib reduced the renal clearance and renal secretion of metformin by 45 and 62%, respectively.1
Concomitant administration of abemaciclib and anastrozole did not affect the pharmacokinetics of either drug.1
Concomitant administration of abemaciclib and exemestane did not affect the pharmacokinetics of either drug.1
Concomitant administration of abemaciclib and fulvestrant did not affect the pharmacokinetics of either drug.1
Concomitant administration of abemaciclib and letrozole did not affect the pharmacokinetics of either drug.1
Concomitant administration of loperamide (single 8-mg dose) in healthy individuals receiving abemaciclib (single 400-mg dose) did not have a clinically relevant effect on the pharmacokinetics of abemaciclib and its active metabolites or loperamide.1
Concomitant administration of abemaciclib and tamoxifen did not affect the pharmacokinetics of either drug.1
Abemaciclib, a selective inhibitor of cyclin-dependent kinases 4 (CDK4) and 6 (CDK6), is an antineoplastic agent.1, 2, 3 Several mechanisms contribute to the dysregulation of the cell cycle during the G1 into S phase, including amplification or overexpression of the cyclin D oncogene or the loss of intrinsic CDK inhibitors (i.e., p16, p15, p18, p19, p21, p27, p57)6, 9, 11, 13 in breast cancer.5, 7, 8, 9, 10, 11, 12, 13 Abemaciclib specifically inhibits CDK4 and CDK6 and blocks the interaction of CDK4 and CDK6 with cyclin D, resulting in inhibition of phosphorylation of the tumor suppressor protein retinoblastoma and inhibition of progression of the cell cycle from the G1 into S phase.1, 3, 4 In vitro, abemaciclib has demonstrated decreased phosphorylation of retinoblastoma protein and reduced cellular proliferation of breast cancer cell lines by inhibiting the G1 into S phase of the cell cycle.1 The combination of abemaciclib with an antiestrogen agent or as a single-agent demonstrated reduced tumor volume in xenograft models of breast cancer.1, 16
Area under the serum concentration-time curve (AUC) and peak plasma concentrations of abemaciclib are dose proportional over a dosage range of 50-200 mg.1 Peak plasma concentrations of abemaciclib are achieved in a median of 8 hours following oral administration of the drug.1 Following repeated doses of abemaciclib twice daily, steady-state concentrations of the drug are achieved in 5 days and the mean accumulation ratio for the drug based on AUC or peak plasma concentration is 3.2 or 2.3, respectively.1 Oral administration of abemaciclib with a high-fat, high-calorie meal (approximately 800-1000 calories with fat accounting for over 50% of the caloric content) increases systemic exposure and peak plasma concentrations of abemaciclib and its active metabolites by 9 and 26%, respectively.1 Abemaciclib and its active metabolites are highly bound (more than 93%) to plasma proteins, albumin, and α1-acid glycoprotein.1 Abemaciclib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4.1 The main circulating metabolites, M-2 (an N -desethyl metabolite), M-18 (a hydroxy- N -desethyl metabolite), and M-20 (a hydroxy metabolite) have been shown to be equipotent to abemaciclib, and these metabolites account for 25, 13, and 26%, respectively, of total plasma concentrations of the drug.1 In patients with advanced cancer, including breast cancer, CSF concentrations of abemaciclib and its active metabolites M-2 and M-20 are similar to unbound plasma concentrations.1 Following oral administration of a single radiolabeled dose of abemaciclib, approximately 81% of the radioactivity was recovered in feces (mainly as metabolites) and approximately 3% was recovered in urine.1 The mean plasma elimination half-life of the drug is 18.3 hours.1
Population pharmacokinetic analysis indicated that age (24-91 years), gender, and body weight (36-175 kg) do not have clinically important effects on the exposure of abemaciclib.1, 15
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.
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.23
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions August 24, 2023. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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