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Abemaciclib

Medically reviewed by Drugs.com. Last updated on Aug 1, 2019.

Pronunciation

(a bem a SYE klib)

Index Terms

  • LY2835219
  • Verzenio

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Verzenio: 50 mg, 100 mg, 150 mg, 200 mg

Brand Names: U.S.

  • Verzenio

Pharmacologic Category

  • Antineoplastic Agent, Cyclin-Dependent Kinase Inhibitor

Pharmacology

Abemaciclib is a potent small molecule cyclin-dependent kinase (CDK) inhibitor which is selective for CDK 4 and 6; it blocks retinoblastoma tumor suppressor protein phosphorylation and prevents progression through the cell cycle, resulting in arrest at the G1 phase (Sledge 2017). Abemaciclib either alone or in combination with endocrine therapy has resulted in decreased tumor size.

Distribution

~690.3 L; concentrations of abemaciclib and active metabolites M2 and M20 in CSF are comparable to unbound plasma concentrations

Metabolism

Primarily hepatic, via CYP3A4; forms primary metabolite N-desethylabemaciclib (M2; active), as well as additional metabolites including hydroxyabemaciclib (M20; active), hydroxy-N-desethylabemaciclib (M18; active), and an oxidative metabolite (M1).

Excretion

Feces (~81%; primarily as metabolites); Urine (~3%)

Time to Peak

8 hours (range: 4.1 to 24 hours)

Half-Life Elimination

18.3 hours

Protein Binding

Bound to plasma proteins, serum albumin, and alpha-1 acid glycoprotein: ~96% (abemaciclib); ~93% (M2 metabolite); ~97% (M18 metabolite); ~98% (M20 metabolite)

Special Populations: Hepatic Function Impairment

Following a single 200 mg oral dose, the relative potency of abemaciclib (and active metabolites) in plasma increased 1.2-fold in subjects with mild impairment (Child-Pugh class A), 1.1-fold in subjects with moderate impairment (Child-Pugh class B), and 2.4-fold in subjects with severe impairment (Child-Pugh class C) compared to subjects with normal hepatic function. In subjects with severe impairment, the mean elimination half-life of abemaciclib increased to 55 hours compared to 24 hours in subjects with normal hepatic function.

Use: Labeled Indications

Breast cancer, advanced or metastatic:

As initial endocrine-based therapy (in combination with an aromatase inhibitor) for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in postmenopausal females.

In combination with fulvestrant for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer in females with disease progression following endocrine therapy

As monotherapy for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer in patients with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to abemaciclib or any component of the formulation.

Dosing: Adult

Breast cancer, HR-positive, HER2-negative (advanced or metastatic): Oral:

Initial endocrine-based therapy in postmenopausal females: 150 mg twice daily (in combination with an aromatase inhibitor); continue until disease progression or unacceptable toxicity (Goetz 2017)

Progressive disease following endocrine therapy and prior chemotherapy: 200 mg twice daily (as a single-agent); continue until disease progression or unacceptable toxicity (Dickler 2017)

Progressive disease on prior endocrine therapy: 150 mg twice daily (in combination with fulvestrant [and a gonadotropin releasing hormone agonist if pre- or perimenopausal]); continue until disease progression or unacceptable toxicity (Sledge 2017)

Missed/vomited doses: If a dose is missed or vomited, take the next dose at the scheduled time.

Dosage adjustment for concomitant strong CYP3A inhibitor therapy: Avoid concomitant use with the strong CYP3A inhibitor ketoconazole. With concurrent use of other strong CYP3A inhibitors, reduce the abemaciclib dose to 100 mg twice daily (if starting dose was 200 mg or 150 mg twice daily). For patients who have received a dose reduction to 100 mg twice daily due to toxicities, reduce the abemaciclib dose to 50 mg twice daily. If the strong CYP3A inhibitor is discontinued, allow 3 to 5 inhibitor half-lives to elapse and then increase abemaciclib dose to the dose used prior to initiating the strong CYP3A inhibitor.

Dosage adjustment for concomitant moderate CYP3A inhibitor therapy: Monitor for adverse reactions and consider dose reduction in 50 mg decrements if clinically necessary.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Recommended abemaciclib dosage adjustments for adverse reactions:

Starting dose 200 mg twice a day (monotherapy):

First dose reduction: Reduce abemaciclib dose to 150 mg twice daily.

Second dose reduction: Reduce abemaciclib dose to 100 mg twice daily.

Third dose reduction: Reduce abemaciclib dose to 50 mg twice daily.

Starting dose 150 mg twice a day (in combination with an aromatase inhibitor or fulvestrant):

First dose reduction: Reduce abemaciclib dose to 100 mg twice daily.

Second dose reduction: Reduce abemaciclib dose to 50 mg twice daily.

If unable to tolerate 50 mg twice daily: Discontinue abemaciclib treatment.

Hematologic toxicities:

Note: If blood cell growth factors are required, withhold abemaciclib dose for at least 48 hours after the last growth factor dose and until toxicity resolves to ≤ grade 2; resume abemaciclib at the next lower dose (unless already reduced due to the toxicity that required the growth factor).

Grade 1 or 2: No abemaciclib dosage adjustment necessary.

Grade 3: Withhold abemaciclib until toxicity resolves to ≤ grade 2 (no abemaciclib dosage reduction is necessary)

Grade 4 or recurrent grade 3: Withhold abemaciclib until toxicity resolves to ≤ grade 2 and then resume abemaciclib at the next lower dose.

Nonhematologic toxicities:

Diarrhea: At the first sign of loose stools, begin management with antidiarrheal agents and increase oral fluid intake.

Grade 1: No abemaciclib dosage adjustment necessary.

Grade 2: If toxicity does not resolve to ≤ grade 1 within 24 hours, withhold abemaciclib until resolution (no abemaciclib dosage reduction is necessary).

Grade 2 that persists or recurs after resumption at the same dose (despite maximal supportive measures): Withhold abemaciclib until toxicity resolves to ≤ grade 1 and then resume abemaciclib at the next lower dose.

Grade 3 or 4 or requires hospitalization: Withhold abemaciclib until toxicity resolves to ≤ grade 1 and then resume abemaciclib at the next lower dose.

Interstitial lung disease/pneumonitis:

Grade 1 or 2: No abemaciclib dosage adjustment necessary.

Persistent or recurrent grade 2 toxicity that does not resolve to baseline or grade 1 within 7 days (despite maximal supportive measures): Withhold abemaciclib until toxicity resolves to baseline or to ≤ grade 1 and then resume abemaciclib at the next lower dose.

Grade 3 or 4: Discontinue abemaciclib.

Other toxicities (excluding diarrhea, hematologic, hepatotoxicity, and interstitial lung disease/pneumonitis):

Grade 1 or 2: No abemaciclib dosage adjustment necessary.

Persistent or recurrent grade 2 toxicity that does not resolve to baseline or grade 1 within 7 days (despite maximal supportive measures): Withhold abemaciclib until toxicity resolves to baseline or to ≤ grade 1 and then resume abemaciclib at the next lower dose.

Grade 3 or 4: Withhold abemaciclib until toxicity resolves to baseline or to ≤ grade 1 and then resume abemaciclib at the next lower dose.

Administration

Oral: Administer at approximately the same times each day. May be administered with or without food. Swallow whole, do not crush, chew, or split tablets (do not ingest if tablets are broken, cracked, or not fully intact).

Dietary Considerations

Avoid grapefruit and grapefruit products. A high-fat, high-calorie meal (800 to 1,000 calories with 500 to 600 calories from fat) increases exposure.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Abemaciclib. Avoid combination

CYP3A4 Inducers (Strong): May decrease the serum concentration of Abemaciclib. Avoid combination

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Abemaciclib. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Abemaciclib. Management: In patients taking abemaciclib at a dose of 200 mg or 150 mg twice daily, reduce the dose to 100 mg twice daily when combined with strong CYP3A4 inhibitors. In patients taking abemaciclib 100 mg twice daily, decrease the dose to 50 mg twice daily. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Grapefruit Juice: May increase the serum concentration of Abemaciclib. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Ketoconazole (Systemic): May increase the serum concentration of Abemaciclib. Avoid combination

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

MetFORMIN: Abemaciclib may increase the serum concentration of MetFORMIN. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

>10%:

Central nervous system: Fatigue (65%), headache (20%), dizziness (11%)

Dermatologic: Alopecia (12%)

Endocrine & metabolic: Weight loss (14%)

Gastrointestinal: Diarrhea (90%), nausea (64%), decreased appetite (45%), abdominal pain (39%), vomiting (35%), constipation (17%), stomatitis (14%), xerostomia (14%), dysgeusia (12%)

Hematologic & oncologic: Anemia (25% to 68%; grade 3: 5%), decreased absolute lymphocyte count (42%; grade 3: 13%; grade 4: <1%), neutropenia (37%; grade 3: 19%; grade 4: 5%), thrombocytopenia (20%; grade 3: 4%), leukopenia (17%, grade 3: 5%; grade 4: <1%)

Hepatic: Increased serum ALT (31%), increased serum AST (30%)

Infection: Infection (31%)

Neuromuscular & skeletal: Arthralgia (15%)

Renal: Increased serum creatinine (13% to 98%)

Respiratory: Cough (19%)

Miscellaneous: Fever (11%)

1% to 10%:

Endocrine & metabolic: Dehydration (10%)

Hematologic & oncologic: Febrile neutropenia (1%)

Frequency not defined:

Cardiovascular: Venous thromboembolism

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Neutropenia commonly occurred in patients treated with abemaciclib, both as a single agent and in combination with an aromatase inhibitor or fulvestrant. 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 33 days and the median duration of ≥ grade 3 neutropenia was 11 to 15 days. Anemia, leukopenia, and thrombocytopenia have also been observed. Monitor complete blood counts prior to treatment initiation, every 2 weeks for the first 2 months, then monthly for the next 2 months, and as clinically indicated. Grade 3 or 4 neutropenia may require treatment interruption, dose reduction, or treatment delay. Febrile neutropenia has occurred rarely, and deaths due to neutropenic sepsis have been observed (case reports).

• Gastrointestinal toxicity: Diarrhea occurred in most patients treated with abemaciclib (either as monotherapy or when used in combination with an aromatase inhibitor or fulvestrant). Grade 3 diarrhea has occurred. Diarrhea had been associated with dehydration and infection. The incidence of diarrhea was higher during the initial month of abemaciclib; 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. Patients should initiate antidiarrheal medications (eg, loperamide) and increase oral fluid intake at the first sign of loose stools. Diarrhea may require treatment interruption and/or dose reduction. Nausea and vomiting (usually mild) may occur; stomatitis has also been reported.

• Hepatotoxicity: Grade 3 or higher increases in ALT and AST have been reported with abemaciclib. The median time to onset of ≥ grade 3 ALT elevation was 57 to 61 days and the median time to resolution (to < grade 3) was 14 days; the median time to onset of ≥ grade 3 AST elevation was 71 to 185 days and the median time to resolution was 13 to 15 days. Monitor liver function tests prior to treatment initiation, every 2 weeks for the first 2 months, then monthly for the next 2 months, and as clinically indicated. Hepatotoxicity may require treatment interruption, dose reduction, treatment delay, and/or discontinuation.

• Pulmonary toxicity: Severe, life-threatening, and/or fatal interstitial lung disease (ILD) and/or pneumonitis may occur with abemaciclib (and other cyclin-dependent kinase inhibitors). Monitor closely for symptoms of ILD/pneumonitis, which may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exam. Exclude infectious, neoplastic, and other causes for pulmonary toxicity. ILD/pneumonitis may require treatment interruption, dose reduction, and/or discontinuation.

• Thromboembolism: VTE events have been reported in patients treated with abemaciclib in combination with an aromatase inhibitor or fulvestrant. VTEs reported included deep vein thrombosis, pulmonary embolism, pelvic venous thrombosis, cerebral venous sinus thrombosis, subclavian and axillary vein thrombosis, and inferior vena cava thrombosis, some VTEs were fatal. Monitor for signs and symptoms of venous thrombosis and pulmonary embolism; manage as medically appropriate.

Disease-related concerns:

Hepatic impairment: Reduced initial doses are recommended for preexisting severe impairment (Child-Pugh class C).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

CBC with differential and platelets (at baseline, every 2 weeks for the first 2 months, monthly for the next 2 months, then as clinically indicated); ALT, AST, and serum bilirubin (at baseline, every 2 weeks for the first 2 months, monthly for the next 2 months, then as clinically indicated); pregnancy testing (prior to treatment in females of reproductive potential). Signs/symptoms of diarrhea/dehydration, interstitial lung disease/pneumonitis, and venous thrombosis and pulmonary embolism. Monitor adherence.

Pregnancy Considerations

Based on the mechanism of action and data from animal reproduction studies, use during pregnancy may cause fetal harm.

Pregnancy testing is recommended prior to treatment in females of reproductive potential. Women of reproductive potential should use effective contraception during therapy and for at least 3 weeks after the last abemaciclib dose.

Patient Education

What is this drug used for?

• It is used to treat breast cancer.

Frequently reported side effects of this drug

• Nausea

• Vomiting

• Lack of appetite

• Abdominal pain

• Fatigue

• Headache

• Constipation

• Diarrhea

• Dry mouth

• Mouth irritation

• Mouth sores

• Joint pain

• Change in taste

• Dizziness

• Hair thinning

• Hair loss

• Weight loss

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice

• Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, tachycardia, increased thirst, seizures, loss of strength and energy, lack of appetite, urinary retention or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting

• Severe loss of strength and energy

• Bruising

• Bleeding

• Swelling of arms or legs

• Fast breathing

• Tachycardia

• Blood clots like numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; tachycardia; or coughing up blood

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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