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Abemaciclib

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); ~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:

In combination with fulvestrant for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in women 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 labeling.

Dosing: Adult

Breast cancer (advanced or metastatic): Oral:

Monotherapy: 200 mg twice daily; continue until disease progression or unacceptable toxicity (Dickler 2017)

Combination 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.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

ESRD: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

Hepatic impairment at treatment initiation:

Mild or moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): Reduce the abemaciclib frequency to once daily.

Hepatotoxicity during treatment:

Grade 1 (ALT, AST >ULN to 3 times ULN): No abemaciclib dosage adjustment necessary.

Grade 2 (ALT, AST >3 to 5 times ULN) without increase in total bilirubin >2 times ULN: No abemaciclib dosage adjustment necessary.

Persistent or recurrent grade 2 or grade 3 (ALT, AST >5 to 20 times ULN) without increase in total bilirubin >2 times ULN: Withhold abemaciclib until toxicity resolves to baseline or grade 1, then resume at the next lower dose.

AST and/or ALT >3 times ULN with total bilirubin >2 times ULN (in the absence of cholestasis): Discontinue abemaciclib treatment.

Grade 4 (ALT, AST >20 times ULN): Discontinue abemaciclib treatment.

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 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 dose of the growth factor and until toxicity resolves to grade 2 or lower; 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 or lower (no abemaciclib dosage reduction is necessary).

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

Non-hematologic 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 or lower 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 or lower and then resume abemaciclib at the next lower dose.

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

Other toxicities (excluding diarrhea, hematologic toxicity or hepatotoxicity):

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 or lower and then resume abemaciclib at the next lower dose.

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

Administration

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

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

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

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

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

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

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. Avoid combination

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

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

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

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

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

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

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

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification

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

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. 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 occurred in nearly half of patients treated with abemaciclib in combination with fulvestrant and in over one-third of patients treated with abemaciclib as a single-agent. Grade 3 or higher neutropenia has been observed in nearly one-third of patients (either as monotherapy or in combination with fulvestrant). The median time to first episode of neutropenia (>grade 3) was 29 days and the median duration of grade 3 or higher neutropenia was 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 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 days and the median duration of grade 2 and 3 diarrhea was 9 days and 6 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 or higher ALT elevation was 57 days and the median time to resolution (to below grade 3) was 14 days; the median time to onset of grade 3 or higher AST elevation was 185 days and the median time to resolution was 13 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.

• Thromboembolism: VTE events have been reported in patients treated with abemaciclib in combination with fulvestrant. VTEs reported included deep vein thrombosis, pulmonary embolism, 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 and venous thrombosis and pulmonary embolism.

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. Abemaciclib may impair fertility in males of reproductive potential (based on findings in animal studies).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, lack of appetite, abdominal pain, headache, constipation, dry mouth, mouth irritation, mouth sores, joint pain, change in taste, dizziness, hair loss, or weight loss. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of fluid and electrolyte problems (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 or persistent diarrhea, severe loss of strength and energy, bruising, bleeding, fast breathing, tachycardia, or signs of blood clots (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; angina; shortness of breath; tachycardia; or coughing up blood) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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