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A - Drug Name

abemaciclib

COMMON TRADE NAME(S):   Verzenio™

 
B - Mechanism of Action and Pharmacokinetics

Abemaciclib inhibits cyclin-dependent kinases 4 and 6 (CDK4 and CDK6). It blocks retinoblastoma tumor suppressor protein phosphorylation and prevents progression through the cell cycle, resulting in arrest at the G1 phase, leading to suppression of tumour growth. Senescence and apoptosis were produced with continuous in vitro exposure to abemaciclib, and tumor size was reduced in xenograft models when administered daily alone or in combination with antiestrogens.



Absorption
Bioavailability

45% (following a single 200 mg oral dose)

Effects with food

Cmax increased by 26%; AUC increased by 9%

Time to reach steady state

5 days (following repeated twice daily dosing)

Peak plasma levels

8 hours


Distribution
PPB

96-98%

Cross blood brain barrier?

Yes

Metabolism
Active metabolites

Yes

Inactive metabolites

Yes

Elimination
Feces

81% as metabolites

Urine

3%

Half-life

24.8 hours

 
C - Indications and Status
Health Canada Approvals:

For the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer:

  • in combination with an aromatase inhibitor in postmenopausal women as initial endocrine-based therapy.*

  • in combination with fulvestrant in women with disease progression following endocrine therapy.**

  • monotherapy in women with disease progression following endocrine therapy and at least 2 prior chemotherapy regimens.***
     

*Clinical effectiveness based on the benefit observed in patients treated with abemaciclib in combination with letrozole or anastrozole.

**Pre- or perimenopausal women must also be treated with a gonadotropin-releasing hormone (GnRH) agonist.

***At least one chemotherapy regimen should have been administered in the metastatic setting, and at least one should have contained a taxane.



 
D - Adverse Effects

Emetogenic Potential:  

Minimal – No routine prophylaxis; PRN recommended

The following table contains adverse effects that occurred in ≥ 2% more of patients receiving abemaciclib in combination with anastrozole or letrozole compared to placebo in combination with anastrozole or letrozole, in a phase III trial (Monarch 3). Severe adverse events from other studies or post-marketing may also be included.

ORGAN SITE SIDE EFFECT* (%) ONSET**
Cardiovascular Cardiotoxicity (rare) E
Hypotension (rare) E
Venous thromboembolism (6%) E
Dermatological Alopecia (28%) (≤ Grade 2) E
Dry skin (10%) E
Nail disorder (5%) D
Palmar-plantar erythrodysesthesia syndrome (PPES) (rare) E
Rash, pruritus (15%) E
Gastrointestinal Anorexia, weight loss (26%) E
Constipation (17%) E
Diarrhea (82%) E
Dry mouth (5%) E
Dyspepsia (8%) E
Mucositis (13%) (≤ Grade 2) E
Nausea, vomiting (41%) (Generally mild) E
General Edema - limbs (10%) E
Fall (6%) E
Fatigue (41%) E
Flu-like symptoms (12%) E
Hematological Myelosuppression ± infection (44%) (including febrile neutropenia; 2% severe) E  D
Hepatobiliary ↑ LFTs (17%) E  D
Hypersensitivity Hypersensitivity (rare) E
Metabolic / Endocrine Abnormal electrolyte(s) (9%) (↓ PO4, ↓ K, ↓ Ca ) E
Musculoskeletal Muscle weakness (5%) E
Osteonecrosis of jaw (rare) D
Nervous System Cognitive disturbance (rare) E
Dizziness (14%) E
Dysgeusia (10%) E
Headache (20%) E
Ophthalmic Dry eye (5%) E
Watering eyes (7%) E
Renal Creatinine increased (21%) E
Nephrotoxicity (rare) I  E
Respiratory Cough, dyspnea (15%) E
Pneumonitis (5%) E


* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

The most common side effects for abemaciclib include diarrhea, myelosuppression ± infection, fatigue, nausea, vomiting, alopecia, anorexia, weight loss, creatinine increased, headache, ↑ LFTs and constipation.

Diarrhea is the most common adverse reaction across clinical studies with a higher incidence during the initial month of treatment. Grade 3 diarrhea has occurred. Diarrhea had been associated with dehydration and infection. The median time to onset of the first diarrhea event was 6 to 8 days and the median duration of grade 2 and 3 diarrhea was 9 to 11 days and 6 to 8 days, respectively.

Myelosuppression was reported in patients receiving abemaciclib. Grade 3 or higher neutropenia has been observed with both monotherapy and combination therapy. The median time to first episode of neutropenia (≥ grade 3) was 29 to 37 days and the median duration of ≥ grade 3 neutropenia was 12 to 15 days. Febrile neutropenia has occurred rarely, and deaths due to neutropenic sepsis have been observed.

Venous thromboembolism (VTE), including deep vein thrombosis (DVT), pulmonary embolism, pelvic venous thrombosis, cerebral venous thrombosis, subclavian and axillary vein thrombosis, and inferior vena cava thrombosis have been reported in up to 6% of patients. Deaths due to VTE have occurred.

Hepatotoxicity and increases in ALT have been reported including Grade 3 or higher events. The median time to onset of ≥ grade 3 ALT elevation was 57 to 64 days and the median time to resolution (to < grade 3) was 14 days.

Severe, life threatening and fatal interstitial lung disease (ILD)/pneumonitis has been reported with abemaciclib. Across clinical trials, 3.2% of patients had ILD/pneumonitis of any grade with 0.4% of patients experiencing ≥ grade 3 ILD. The median time to onset was 8.2 months.

 
E - Dosing

Refer to protocol by which patient is being treated. 



Adults:

Monotherapy:


Oral: 200 mg BID

In combination with endocrine therapy*:


Oral: 150 mg BID

*Pre/perimenopausal women treated with abemaciclib plus fulvestrant should be treated with a gonadotropin releasing hormone (GnRH) agonist according to local clinical practice.


Dosage with Toxicity:

Dose Level Abemaciclib Dose (mg BID)
Combination with
Endocrine Therapy
Single Agent
0 150 200
-1 100 150
-2 50 100
-3 Discontinue 50
-4 Not applicable Discontinue

 

Toxicity

Grade

Action

Hematologic* Grade 3 Hold until ≤ grade 2; resume at same dose.
Grade 4 or recurrent grade 3 Hold until ≤ grade 2; resume at 1 dose level ↓.
Diarrhea** Grade 2

If no resolution to ≤ grade 1 within 24 hours, hold until resolution; resume at same dose.

Grade 2 that persists/recurs after resumption at the same dose (despite maximal supportive measures) Hold until ≤ grade 1; resume at 1 dose level ↓.
≥ Grade 3 or requires hospitalization Hold until ≤ grade 1; resume at 1 dose level ↓.
Interstitial lung disease (ILD)/ Pneumonitis Persistent or recurrent grade 2 toxicity that does not resolve to baseline or grade 1 within 7 days (despite maximal supportive measures) Hold until recovery to baseline or ≤ grade 1; resume at 1 dose level ↓.
Grade 3 or 4 Discontinue
Hepatotoxicity Persistent or recurrent grade 2 or grade 3 (ALT, AST >5 to 20 times ULN) without increase in total bilirubin >2 times ULN Hold until recovery to baseline or grade 1; resume at 1 dose level ↓.
AST and/or ALT >3 times ULN with total bilirubin >2 times ULN (in the absence of cholestasis) Discontinue
Grade 4 (ALT, AST >20 times ULN) Discontinue
All other non-hematologic toxicities Persistent or recurrent grade 2 toxicity that does not resolve to baseline or grade 1 within 7 days (despite maximal supportive measures) Hold until recovery to baseline or ≤ grade 1; resume at 1 dose level ↓.
≥ Grade 3 Hold until recovery to baseline or ≤ grade 1; resume at 1 dose level ↓.

*If blood cell growth factors are required, hold abemaciclib for at least 48 hours after the last growth factor dose and until toxicity resolves to ≤ grade 2; resume at the next lower dose (unless already reduced due to the toxicity that required the growth factor). Growth factor use is as per current local guidelines.

**At the first sign of loose stools, begin management with antidiarrheal agents (i.e. loperamide) and increase oral fluid intake.



Dosage with Hepatic Impairment:

Hepatic Impairment Abemaciclib Dose
Mild or moderate impairment (Child-Pugh class A or B) No dosage adjustment necessary.
Severe impairment (Child-Pugh class C) Reduce abemaciclib frequency to once daily.


Dosage with Renal Impairment:

Renal Impairment Abemaciclib Dose
Mild or Moderate (CrCl ≥ 30 mL/min) No dosage adjustment necessary.
Severe (CrCl < 30 mL/min); ESRD Has not been studied


Dosage in the elderly:

No overall differences in safety or efficacy between patients ≥ 65 years of age and younger.  No dosage adjustment is required.  Patients ≥65 years of age reported more hematologic adverse events, hypokalemia (including grade 3), hypocalcemia, grade ≥3 infections, decreased appetite, and increased blood creatinine compared to younger patients in a subgroup analysis from clinical studies.



Dosage based on ethnicity:

Higher incidences of increased ALT and AST and neutropenia have been reported in East Asian patients compared to Caucasian patients in clinical trials.  No dose adjustment based on race is required.



Children:

Safety and efficacy have not been established. 



 
F - Administration Guidelines
  • Abemaciclib tablets should be swallowed whole (do not chew, crush, or split tablets before swallowing). Tablets should not be ingested if they are not intact.

  • Abemaciclib doses may be taken with or without food and should be administered at approximately the same times every day.

  • Avoid fruit or juice from grapefruit, Seville oranges or starfruit.

  • Abemaciclib tablets contain lactose; carefully consider use in patients with hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption

  • If a dose is missed or vomited, the next dose should be taken at the scheduled time. The patient should not take 2 doses at the same time to make up for the missed dose.

  • Store at room temperature (15°C to 30°C).
 
G - Special Precautions
Contraindications:

  • Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container.

Other Warnings/Precautions:

  • There are no data regarding abemaciclib safety or efficacy in patients with prior exposure to other CDK 4/6 inhibitors.


Other Drug Properties:

  • Carcinogenicity:

    No data

Pregnancy and Lactation:
  • Genotoxicity: Unlikely

    Not observed in animal studies

  • Embryotoxicity: Yes

    Observed in animal studies.

    Abemaciclib is not recommended for use in pregnancy.  Adequate contraception should be used by both sexes during treatment, and for at least 3 weeks after the last dose.

  • Breastfeeding:

    Breastfeeding is not recommended during abemaciclib treatment and for at least 3 weeks after the last dose.

  • Fertility effects: Unknown

    In animal studies, no effects on female reproductive organs were observed. However, cytotoxic effects to the male reproductive tract in rats and dogs indicate that abemaciclib may impair fertility in males

 
H - Interactions

Abemaciclib inhibits the renal transporters organic cation transporter 2 (OCT2), multidrug and extrusion toxin protein (MATE1), and MATE2.

In vitro, abemaciclib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

AGENT EFFECT MECHANISM MANAGEMENT
CYP3A4 inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges or starfruit) ↑ abemaciclib concentration and/or toxicity ↓ metabolism of abemaciclib Avoid co-administration with strong CYP3A4 inhibitors. Use caution when co-administered with moderate or weak CYP3A inhibitors. If co-administration with a CYP3A inhibitor is unavoidable, reduce abemaciclib dose to 50 mg twice daily* (based on a 150 mg or 200 mg twice daily starting dose) when combined with strong or moderate CYP3A4 inhibitors. If a CYP3A inhibitor is discontinued, increase the abemaciclib dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the inhibitor. *When combined with clarithromycin, diltiazem or verapamil, abemaciclib dose should be reduced to 100 mg twice daily
CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc) ↓ abemaciclib concentration and/or efficacy ↑ metabolism of abemaciclib Avoid co-administration with strong CYP3A4 inducers. Use with caution when co-administered with moderate or weak CYP3A4 inducers.
OCT2, MATE1, MATE2 substrates (i.e. metformin) ↑ substrate concentration and/or toxicity ↓ substrate renal clearance and secretion Caution
 
I - Recommended Clinical Monitoring
Recommended Clinical Monitoring

Monitor Type Monitor Frequency

CBC

Baseline, every two weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated.

Liver function tests

Baseline, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated.
Creatinine Baseline and as clinically indicated

Clinical toxicity assessment for signs and symptoms of venous thrombosis, infections, gastrointestinal, respiratory, dermatologic effects and fatigue

At each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version



Suggested Clinical Monitoring

Monitor Type Monitor Frequency

Electrolytes (including calcium)

Baseline and as clinically indicated
 
K - References

Goetz, Matthew P; Toi et al. MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. Journal of Clinical Oncology 11/2017, Volume 35, Issue 32.

Verzenio (abemaciclib) product monograph. Toronto, Ontario: Eli Lilly Canada Inc., September 2019.


April 2020 Reformatted dose levels table

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.