Verzenio (Abemaciclib)

VERZENIO^® is a kinase inhibitor indicated:

• in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive, early breast cancer at high risk of recurrence. (
  1.1 Early Breast Cancer

  VERZENIO^®(abemaciclib) is indicated:

  • in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive, early breast cancer at high risk of recurrence
    [see Clinical Studies ].
  ,
  14.1 Early Breast Cancer

  VERZENIO in Combination with Standard Endocrine Therapy (monarchE)

  Patients with HR-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence

  monarchE (NCT03155997) was a randomized (1:1), open-label, two cohort, multicenter study in adult women and men with HR-positive, HER2-negative, node-positive, resected, early breast cancer with clinical and pathological features consistent with a high risk of disease recurrence. To be enrolled, patients had to have HR-positive HER2-negative early breast cancer with tumor involvement in at least 1 axillary lymph node (pALN) and to be enrolled in cohort 1 had to have either:

  • ≥4 pALN or
  • 1-3 pALN and at least one of:
    • –tumor grade 3 or
    • –tumor size ≥50 mm

  Patients enrolled in cohort 2 could not have met the eligibility criteria for cohort 1. To be enrolled in cohort 2, patients had to have 1-3 pALN and Ki-67 score ≥20%. Breast tumor samples were tested at central sites using the Ki-67 IHC MIB-1 pharmDx (Dako Omnis) assay to establish if the Ki-67 score was ≥20%.

  Patients were randomized to receive 2 years of VERZENIO plus physician's choice of standard endocrine therapy or standard endocrine therapy alone. Randomization to treatment was stratified by prior treatment (neoadjuvant chemotherapy versus adjuvant chemotherapy versus no chemotherapy); menopausal status (premenopausal versus postmenopausal); and region (North America/Europe versus Asia versus other). Men were stratified as postmenopausal. After the end of the study treatment period, standard adjuvant endocrine therapy was continued for a duration of at least 5 years if deemed medically appropriate.

  The major efficacy outcome measure was invasive disease–free survival (IDFS). IDFS was defined as the time from randomization to the first occurrence of: ipsilateral invasive breast tumor recurrence, regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, second primary non-breast invasive cancer, or death attributable to any cause. Overall survival (OS) was an additional outcome measure.

  A statistically significant difference in IDFS was observed in the intent-to-treat (ITT) population which was primarily attributed to the patients treated in cohort 1. While the OS data in cohort 2 remains immature, more deaths were observed among those receiving VERZENIO plus standard endocrine therapy compared to those receiving standard endocrine therapy alone (10/253 vs. 5/264).

  Of 5637 patients randomized, 5120 (91%) were randomized in cohort 1. Patient median age was 51 years (range, 22-89 years), 99% were women, 70% were White, 24% were Asian, 1.7% were Black or African American, 2.1% were American Indian or Alaska Native, and 0.1% were Native Hawaiian or Other Pacific Islander. Forty-three percent of patients were premenopausal. Most patients received prior chemotherapy (37% neoadjuvant, 59% adjuvant) and prior radiotherapy (96%). Sixty-five percent of the patients had 4 or more positive lymph nodes with 22% having ≥10 positive lymph nodes, 41% had Grade 3 tumor, and 24% had pathological tumor size ≥50 mm. The majority of patients (99%) had estrogen receptor positive disease and 87% had progesterone receptor positive disease. Initial endocrine therapy received by patients included letrozole (39%), tamoxifen (31%), anastrozole (22%), or exemestane (8%).

  Efficacy results for cohort 1 are summarized in Table 16and Figure 1. At the time of OS interim analysis 2, OS was immature and a total of 315 (6%) of patients had died in cohort 1.

  Table 16: Efficacy Results in monarchE in Cohort 1

  Abbreviation: CI = confidence interval.
  	VERZENIO Plus Tamoxifen or an Aromatase Inhibitor N=2555	Tamoxifen or an Aromatase Inhibitor N=2565
  Invasive Disease–Free Survival (IDFS)
  Number of patients with an event, n (%)	317 (12)	474 (18)
  Hazard ratio (95% CI)	0.65 (0.57, 0.75)
  IDFS at 48 months, % (95% CI)	85.5 (83.8, 87.0)	78.6 (76.7, 80.4)

  Figure 1: Kaplan-Meier Curves of Invasive Disease–Free Survival VERZENIO plus Tamoxifen or an Aromatase Inhibitor versus Tamoxifen or an Aromatase Inhibitor in Cohort 1 (monarchE)

  

  

  )
• in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. (
  1.2 Advanced or Metastatic Breast Cancer

  VERZENIO (abemaciclib) is indicated:

  • in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.
  • in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.
  • as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.
  )
• in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. (
  1.2 Advanced or Metastatic Breast Cancer

  VERZENIO (abemaciclib) is indicated:

  • in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.
  • in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.
  • as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.
  )
• as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. (
  1.2 Advanced or Metastatic Breast Cancer

  VERZENIO (abemaciclib) is indicated:

  • in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.
  • in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.
  • as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.
  )

VERZENIO tablets are taken orally with or without food. (

• Recommended starting dose in combination with fulvestrant, tamoxifen, or an aromatase inhibitor: 150 mg twice daily. (
  2.1 Recommended Dose and Schedule

  • When used in combination with fulvestrant, tamoxifen, or an aromatase inhibitor, the recommended dose of VERZENIO is 150 mg taken orally twice daily. Refer to the Full Prescribing Information for the recommended dose of the fulvestrant, tamoxifen, or aromatase inhibitor being used.
  • Pre/perimenopausal women and men treated with the combination of VERZENIO plus an aromatase inhibitor should be treated with a gonadotropin-releasing hormone agonist (GnRH) according to current clinical practice standards.
  • Pre/perimenopausal women treated with the combination of VERZENIO plus fulvestrant should be treated with a GnRH according to current clinical practice standards
  • When used as monotherapy, the recommended dose of VERZENIO is 200 mg taken orally twice daily.
  • For early breast cancer, continue VERZENIO until completion of 2 years of treatment or until disease recurrence, or unacceptable toxicity.
  • For advanced or metastatic breast cancer, continue treatment until disease progression or unacceptable toxicity.

  VERZENIO may be taken with or without food

  [see Clinical Pharmacology ]

  .

  Instruct patients to take their doses of VERZENIO at approximately the same times every day.

  If the patient vomits or misses a dose of VERZENIO, instruct the patient to take the next dose at its scheduled time. Instruct patients to swallow VERZENIO tablets whole and not to chew, crush, or split tablets before swallowing. Instruct patients not to ingest VERZENIO tablets if broken, cracked, or otherwise not intact.
  )
• Recommended starting dose as monotherapy: 200 mg twice daily. (
  2.1 Recommended Dose and Schedule

  • When used in combination with fulvestrant, tamoxifen, or an aromatase inhibitor, the recommended dose of VERZENIO is 150 mg taken orally twice daily. Refer to the Full Prescribing Information for the recommended dose of the fulvestrant, tamoxifen, or aromatase inhibitor being used.
  • Pre/perimenopausal women and men treated with the combination of VERZENIO plus an aromatase inhibitor should be treated with a gonadotropin-releasing hormone agonist (GnRH) according to current clinical practice standards.
  • Pre/perimenopausal women treated with the combination of VERZENIO plus fulvestrant should be treated with a GnRH according to current clinical practice standards
  • When used as monotherapy, the recommended dose of VERZENIO is 200 mg taken orally twice daily.
  • For early breast cancer, continue VERZENIO until completion of 2 years of treatment or until disease recurrence, or unacceptable toxicity.
  • For advanced or metastatic breast cancer, continue treatment until disease progression or unacceptable toxicity.

  VERZENIO may be taken with or without food

  [see Clinical Pharmacology ]

  .

  Instruct patients to take their doses of VERZENIO at approximately the same times every day.

  If the patient vomits or misses a dose of VERZENIO, instruct the patient to take the next dose at its scheduled time. Instruct patients to swallow VERZENIO tablets whole and not to chew, crush, or split tablets before swallowing. Instruct patients not to ingest VERZENIO tablets if broken, cracked, or otherwise not intact.
  )
• Dosing interruption and/or dose reductions may be required based on individual safety and tolerability. (
  2.2 Dose Modification

  Dose Modifications for Adverse Reactions

  The recommended VERZENIO dose modifications for adverse reactions are provided in Tables 1- 7. Discontinue VERZENIO for patients unable to tolerate 50 mg twice daily.

  Table 1: VERZENIO Dose Modification — Adverse Reactions

  Dose Level	VERZENIO Dose Combination with Fulvestrant, Tamoxifen, or an Aromatase Inhibitor	VERZENIO Dose for Monotherapy
  Recommended starting dose	150 mg twice daily	200 mg twice daily
  First dose reduction	100 mg twice daily	150 mg twice daily
  Second dose reduction	50 mg twice daily	100 mg twice daily
  Third dose reduction	not applicable	50 mg twice daily

  Table 2: VERZENIO Dose Modification and Management — Hematologic Toxicities^a

  Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events.
  aIf blood cell growth factors are required, suspend VERZENIO dose for at least 48 hours after the last dose of blood cell growth factor and until toxicity resolves to ≤Grade 2. Resume at next lower dose unless already performed for the toxicity that led to the use of the growth factor. Growth factor use as per current treatment guidelines.
  Monitor complete blood counts prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated.
  CTCAE Grade	VERZENIO Dose Modifications
  Grade 1 or 2	No dose modification is required.
  Grade 3	Suspend dose until toxicity resolves to ≤Grade 2. Dose reduction is not required.
  Grade 3 recurrent, or Grade 4	Suspend dose until toxicity resolves to ≤Grade 2. Resume at next lower dose .

  Table 3: VERZENIO Dose Modification and Management — Diarrhea

  At the first sign of loose stools, start treatment with antidiarrheal agents and increase intake of oral fluids.
  CTCAE Grade	VERZENIO Dose Modifications
  Grade 1	No dose modification is required.
  Grade 2	If toxicity does not resolve within 24 hours to ≤Grade 1, suspend dose until resolution. No dose reduction is required.
  Grade 2 that persists or recurs after resuming the same dose despite maximal supportive measures	Suspend dose until toxicity resolves to ≤Grade 1. Resume at next lower dose .
  Grade 3 or 4 or requires hospitalization	Suspend dose until toxicity resolves to ≤Grade 1. Resume at next lower dose .

  Table 4: VERZENIO Dose Modification and Management — Hepatotoxicity

  Abbreviations: ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit of normal.
  Monitor ALT, AST, and serum bilirubin prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated.
  CTCAE Grade for ALT and AST	VERZENIO Dose Modifications
  Grade 1 (>ULN-3.0 x ULN) Grade 2 (>3.0-5.0 x ULN), WITHOUT increase in total bilirubin above 2 x ULN	No dose modification is required.
  Persistent or Recurrent Grade 2, or Grade 3 (>5.0-20.0 x ULN), WITHOUT increase in total bilirubin above 2 x ULN	Suspend dose until toxicity resolves to baseline or Grade 1. Resume at next lower dose.
  Elevation in AST and/or ALT >3 x ULN WITH total bilirubin >2 x ULN, in the absence of cholestasis	Discontinue VERZENIO.
  Grade 4 (>20.0 x ULN)	Discontinue VERZENIO.

  Table 5: VERZENIO Dose Modification and Management — Interstitial Lung Disease/Pneumonitis

  CTCAE Grade	VERZENIO Dose Modifications
  Grade 1 or 2	No dose modification is required.
  Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1	Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose .
  Grade 3 or 4	Discontinue VERZENIO.

  Table 6: VERZENIO Dose Modification and Management — Venous Thromboembolic Events (VTEs)

  CTCAE Grade	VERZENIO Dose Modifications
  Early Breast Cancer
  Any Grade	Suspend dose and treat as clinically indicated. Resume VERZENIO when the patient is clinically stable.
  Advanced or Metastatic Breast Cancer
  Grade 1 or 2	No dose modification is required.
  Grade 3 or 4	Suspend dose and treat as clinically indicated. Resume VERZENIO when the patient is clinically stable.

  Table 7: VERZENIO Dose Modification and Management — Other Toxicities^a

  aExcluding diarrhea, hematologic toxicity, hepatotoxicity, ILD/pneumonitis, and VTEs.
  CTCAE Grade	VERZENIO Dose Modifications
  Grade 1 or 2	No dose modification is required.
  Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1	Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose .
  Grade 3 or 4	Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose .

  Refer to the Full Prescribing Information for coadministered fulvestrant, tamoxifen, or an aromatase inhibitor for dose modifications and other relevant safety information.

  Dose Modification for Use with Strong and Moderate CYP3A Inhibitors

  Avoid concomitant use of the strong CYP3A inhibitor ketoconazole.

  With concomitant use of strong CYP3A inhibitors other than ketoconazole, in patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the VERZENIO dose to 100 mg twice daily. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the VERZENIO dose to 50 mg twice daily. If a patient taking VERZENIO discontinues a CYP3A inhibitor, increase the VERZENIO dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the strong inhibitor

  [see Drug Interactions and Clinical Pharmacology ].

  With concomitant use of moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the VERZENIO dose in 50 mg decrements as demonstrated in Table 1, if necessary.

  Dose Modification for Patients with Severe Hepatic Impairment

  For patients with severe hepatic impairment (Child Pugh-C), reduce the VERZENIO dosing frequency to once daily

  [see Use in Specific Populations and Clinical Pharmacology ].

  Refer to the Full Prescribing Information for the coadministered fulvestrant, tamoxifen, or aromatase inhibitor for dose modification requirements for severe hepatic impairment.
  )

50 mg tablets: oval beige tablet with “Lilly” debossed on one side and “50” on the other side.

100 mg tablets: oval white to practically white tablet with “Lilly” debossed on one side and “100” on the other side.

150 mg tablets: oval yellow tablet with “Lilly” debossed on one side and “150” on the other side.

200 mg tablets: oval beige tablet with “Lilly” debossed on one side and “200” on the other side.

Lactation: Advise not to breastfeed. (

• Diarrhea: VERZENIO can cause severe cases of diarrhea, associated with dehydration and infection. Instruct patients at the first sign of loose stools to initiate antidiarrheal therapy, increase oral fluids, and notify their healthcare provider. (
  2.2 Dose Modification

  Dose Modifications for Adverse Reactions

  The recommended VERZENIO dose modifications for adverse reactions are provided in Tables 1- 7. Discontinue VERZENIO for patients unable to tolerate 50 mg twice daily.

  Table 1: VERZENIO Dose Modification — Adverse Reactions

  Dose Level	VERZENIO Dose Combination with Fulvestrant, Tamoxifen, or an Aromatase Inhibitor	VERZENIO Dose for Monotherapy
  Recommended starting dose	150 mg twice daily	200 mg twice daily
  First dose reduction	100 mg twice daily	150 mg twice daily
  Second dose reduction	50 mg twice daily	100 mg twice daily
  Third dose reduction	not applicable	50 mg twice daily

  Table 2: VERZENIO Dose Modification and Management — Hematologic Toxicities^a

  Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events.
  aIf blood cell growth factors are required, suspend VERZENIO dose for at least 48 hours after the last dose of blood cell growth factor and until toxicity resolves to ≤Grade 2. Resume at next lower dose unless already performed for the toxicity that led to the use of the growth factor. Growth factor use as per current treatment guidelines.
  Monitor complete blood counts prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated.
  CTCAE Grade	VERZENIO Dose Modifications
  Grade 1 or 2	No dose modification is required.
  Grade 3	Suspend dose until toxicity resolves to ≤Grade 2. Dose reduction is not required.
  Grade 3 recurrent, or Grade 4	Suspend dose until toxicity resolves to ≤Grade 2. Resume at next lower dose .

  Table 3: VERZENIO Dose Modification and Management — Diarrhea

  At the first sign of loose stools, start treatment with antidiarrheal agents and increase intake of oral fluids.
  CTCAE Grade	VERZENIO Dose Modifications
  Grade 1	No dose modification is required.
  Grade 2	If toxicity does not resolve within 24 hours to ≤Grade 1, suspend dose until resolution. No dose reduction is required.
  Grade 2 that persists or recurs after resuming the same dose despite maximal supportive measures	Suspend dose until toxicity resolves to ≤Grade 1. Resume at next lower dose .
  Grade 3 or 4 or requires hospitalization	Suspend dose until toxicity resolves to ≤Grade 1. Resume at next lower dose .

  Table 4: VERZENIO Dose Modification and Management — Hepatotoxicity

  Abbreviations: ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit of normal.
  Monitor ALT, AST, and serum bilirubin prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated.
  CTCAE Grade for ALT and AST	VERZENIO Dose Modifications
  Grade 1 (>ULN-3.0 x ULN) Grade 2 (>3.0-5.0 x ULN), WITHOUT increase in total bilirubin above 2 x ULN	No dose modification is required.
  Persistent or Recurrent Grade 2, or Grade 3 (>5.0-20.0 x ULN), WITHOUT increase in total bilirubin above 2 x ULN	Suspend dose until toxicity resolves to baseline or Grade 1. Resume at next lower dose.
  Elevation in AST and/or ALT >3 x ULN WITH total bilirubin >2 x ULN, in the absence of cholestasis	Discontinue VERZENIO.
  Grade 4 (>20.0 x ULN)	Discontinue VERZENIO.

  Table 5: VERZENIO Dose Modification and Management — Interstitial Lung Disease/Pneumonitis

  CTCAE Grade	VERZENIO Dose Modifications
  Grade 1 or 2	No dose modification is required.
  Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1	Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose .
  Grade 3 or 4	Discontinue VERZENIO.

  Table 6: VERZENIO Dose Modification and Management — Venous Thromboembolic Events (VTEs)

  CTCAE Grade	VERZENIO Dose Modifications
  Early Breast Cancer
  Any Grade	Suspend dose and treat as clinically indicated. Resume VERZENIO when the patient is clinically stable.
  Advanced or Metastatic Breast Cancer
  Grade 1 or 2	No dose modification is required.
  Grade 3 or 4	Suspend dose and treat as clinically indicated. Resume VERZENIO when the patient is clinically stable.

  Table 7: VERZENIO Dose Modification and Management — Other Toxicities^a

  aExcluding diarrhea, hematologic toxicity, hepatotoxicity, ILD/pneumonitis, and VTEs.
  CTCAE Grade	VERZENIO Dose Modifications
  Grade 1 or 2	No dose modification is required.
  Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1	Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose .
  Grade 3 or 4	Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose .

  Refer to the Full Prescribing Information for coadministered fulvestrant, tamoxifen, or an aromatase inhibitor for dose modifications and other relevant safety information.

  Dose Modification for Use with Strong and Moderate CYP3A Inhibitors

  Avoid concomitant use of the strong CYP3A inhibitor ketoconazole.

  With concomitant use of strong CYP3A inhibitors other than ketoconazole, in patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the VERZENIO dose to 100 mg twice daily. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the VERZENIO dose to 50 mg twice daily. If a patient taking VERZENIO discontinues a CYP3A inhibitor, increase the VERZENIO dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the strong inhibitor

  [see Drug Interactions and Clinical Pharmacology ].

  With concomitant use of moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the VERZENIO dose in 50 mg decrements as demonstrated in Table 1, if necessary.

  Dose Modification for Patients with Severe Hepatic Impairment

  For patients with severe hepatic impairment (Child Pugh-C), reduce the VERZENIO dosing frequency to once daily

  [see Use in Specific Populations and Clinical Pharmacology ].

  Refer to the Full Prescribing Information for the coadministered fulvestrant, tamoxifen, or aromatase inhibitor for dose modification requirements for severe hepatic impairment.
  ,
  5.1 Diarrhea

  Severe diarrhea associated with dehydration and infection occurred in patients treated with VERZENIO.

  Across four clinical trials in 3691 patients, diarrhea occurred in 81% to 90% of patients who received VERZENIO. Grade 3 diarrhea occurred in 8% to 20% of patients receiving VERZENIO

  [see Adverse Reactions ].

  Most patients experienced diarrhea during the first month of VERZENIO treatment. The median time to onset of the first diarrhea event ranged from 6 to 8 days; and the median duration of Grade 2 and Grade 3 diarrhea ranged from 6 to 11 days and 5 to 8 days, respectively. Across trials, 19% to 26% of patients with diarrhea required a VERZENIO dose interruption and 13% to 23% required a dose reduction.

  Instruct patients to start antidiarrheal therapy such as loperamide at the first sign of loose stools, increase oral fluids, and notify their healthcare provider for further instructions and appropriate follow up

  [see Patient Counseling Information ].

  For Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization, discontinue VERZENIO until toxicity resolves to ≤Grade 1, and then resume VERZENIO at the next lower dose

  [see Dosage and Administration ]

  .
  )
• Neutropenia: Monitor complete blood counts prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. (
  2.2 Dose Modification

  Dose Modifications for Adverse Reactions

  The recommended VERZENIO dose modifications for adverse reactions are provided in Tables 1- 7. Discontinue VERZENIO for patients unable to tolerate 50 mg twice daily.

  Table 1: VERZENIO Dose Modification — Adverse Reactions

  Dose Level	VERZENIO Dose Combination with Fulvestrant, Tamoxifen, or an Aromatase Inhibitor	VERZENIO Dose for Monotherapy
  Recommended starting dose	150 mg twice daily	200 mg twice daily
  First dose reduction	100 mg twice daily	150 mg twice daily
  Second dose reduction	50 mg twice daily	100 mg twice daily
  Third dose reduction	not applicable	50 mg twice daily

  Table 2: VERZENIO Dose Modification and Management — Hematologic Toxicities^a

  Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events.
  aIf blood cell growth factors are required, suspend VERZENIO dose for at least 48 hours after the last dose of blood cell growth factor and until toxicity resolves to ≤Grade 2. Resume at next lower dose unless already performed for the toxicity that led to the use of the growth factor. Growth factor use as per current treatment guidelines.
  Monitor complete blood counts prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated.
  CTCAE Grade	VERZENIO Dose Modifications
  Grade 1 or 2	No dose modification is required.
  Grade 3	Suspend dose until toxicity resolves to ≤Grade 2. Dose reduction is not required.
  Grade 3 recurrent, or Grade 4	Suspend dose until toxicity resolves to ≤Grade 2. Resume at next lower dose .

  Table 3: VERZENIO Dose Modification and Management — Diarrhea

  At the first sign of loose stools, start treatment with antidiarrheal agents and increase intake of oral fluids.
  CTCAE Grade	VERZENIO Dose Modifications
  Grade 1	No dose modification is required.
  Grade 2	If toxicity does not resolve within 24 hours to ≤Grade 1, suspend dose until resolution. No dose reduction is required.
  Grade 2 that persists or recurs after resuming the same dose despite maximal supportive measures	Suspend dose until toxicity resolves to ≤Grade 1. Resume at next lower dose .
  Grade 3 or 4 or requires hospitalization	Suspend dose until toxicity resolves to ≤Grade 1. Resume at next lower dose .

  Table 4: VERZENIO Dose Modification and Management — Hepatotoxicity

  Abbreviations: ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit of normal.
  Monitor ALT, AST, and serum bilirubin prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated.
  CTCAE Grade for ALT and AST	VERZENIO Dose Modifications
  Grade 1 (>ULN-3.0 x ULN) Grade 2 (>3.0-5.0 x ULN), WITHOUT increase in total bilirubin above 2 x ULN	No dose modification is required.
  Persistent or Recurrent Grade 2, or Grade 3 (>5.0-20.0 x ULN), WITHOUT increase in total bilirubin above 2 x ULN	Suspend dose until toxicity resolves to baseline or Grade 1. Resume at next lower dose.
  Elevation in AST and/or ALT >3 x ULN WITH total bilirubin >2 x ULN, in the absence of cholestasis	Discontinue VERZENIO.
  Grade 4 (>20.0 x ULN)	Discontinue VERZENIO.

  Table 5: VERZENIO Dose Modification and Management — Interstitial Lung Disease/Pneumonitis

  CTCAE Grade	VERZENIO Dose Modifications
  Grade 1 or 2	No dose modification is required.
  Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1	Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose .
  Grade 3 or 4	Discontinue VERZENIO.

  Table 6: VERZENIO Dose Modification and Management — Venous Thromboembolic Events (VTEs)

  CTCAE Grade	VERZENIO Dose Modifications
  Early Breast Cancer
  Any Grade	Suspend dose and treat as clinically indicated. Resume VERZENIO when the patient is clinically stable.
  Advanced or Metastatic Breast Cancer
  Grade 1 or 2	No dose modification is required.
  Grade 3 or 4	Suspend dose and treat as clinically indicated. Resume VERZENIO when the patient is clinically stable.

  Table 7: VERZENIO Dose Modification and Management — Other Toxicities^a

  aExcluding diarrhea, hematologic toxicity, hepatotoxicity, ILD/pneumonitis, and VTEs.
  CTCAE Grade	VERZENIO Dose Modifications
  Grade 1 or 2	No dose modification is required.
  Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1	Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose .
  Grade 3 or 4	Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose .

  Refer to the Full Prescribing Information for coadministered fulvestrant, tamoxifen, or an aromatase inhibitor for dose modifications and other relevant safety information.

  Dose Modification for Use with Strong and Moderate CYP3A Inhibitors

  Avoid concomitant use of the strong CYP3A inhibitor ketoconazole.

  With concomitant use of strong CYP3A inhibitors other than ketoconazole, in patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the VERZENIO dose to 100 mg twice daily. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the VERZENIO dose to 50 mg twice daily. If a patient taking VERZENIO discontinues a CYP3A inhibitor, increase the VERZENIO dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the strong inhibitor

  [see Drug Interactions and Clinical Pharmacology ].

  With concomitant use of moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the VERZENIO dose in 50 mg decrements as demonstrated in Table 1, if necessary.

  Dose Modification for Patients with Severe Hepatic Impairment

  For patients with severe hepatic impairment (Child Pugh-C), reduce the VERZENIO dosing frequency to once daily

  [see Use in Specific Populations and Clinical Pharmacology ].

  Refer to the Full Prescribing Information for the coadministered fulvestrant, tamoxifen, or aromatase inhibitor for dose modification requirements for severe hepatic impairment.
  ,
  5.2 Neutropenia

  Neutropenia, including febrile neutropenia and fatal neutropenic sepsis, occurred in patients treated with VERZENIO.

  Across four clinical trials in 3691 patients, neutropenia occurred in a 37% to 46% of patients receiving VERZENIO. A Grade ≥3 decrease in neutrophil count (based on laboratory findings) occurred in 19% to 32% of patients receiving VERZENIO. Across trials, the median time to the first episode of Grade ≥3 neutropenia ranged from 29 days to 33 days, and the median duration of Grade ≥3 neutropenia ranged from 11 days to 16 days

  [see Adverse Reactions ]

  .

  Febrile neutropenia has been reported in <1% of patients exposed to VERZENIO across trials. Two deaths due to neutropenic sepsis were observed in MONARCH 2. Inform patients to promptly report any episodes of fever to their healthcare provider

  [see Patient Counseling Information ]

  .

  Monitor complete blood counts prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia

  [see Dosage and Administration ]

  .
  )
• Interstitial Lung Disease (ILD)/Pneumonitis: Severe and fatal cases of ILD/pneumonitis have been reported. Monitor for clinical symptoms or radiological changes indicative of ILD/pneumonitis. Permanently discontinue VERZENIO in all patients with Grade 3 or 4 ILD or pneumonitis. (
  2.2 Dose Modification

  Dose Modifications for Adverse Reactions

  The recommended VERZENIO dose modifications for adverse reactions are provided in Tables 1- 7. Discontinue VERZENIO for patients unable to tolerate 50 mg twice daily.

  Table 1: VERZENIO Dose Modification — Adverse Reactions

  Dose Level	VERZENIO Dose Combination with Fulvestrant, Tamoxifen, or an Aromatase Inhibitor	VERZENIO Dose for Monotherapy
  Recommended starting dose	150 mg twice daily	200 mg twice daily
  First dose reduction	100 mg twice daily	150 mg twice daily
  Second dose reduction	50 mg twice daily	100 mg twice daily
  Third dose reduction	not applicable	50 mg twice daily

  Table 2: VERZENIO Dose Modification and Management — Hematologic Toxicities^a

  Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events.
  aIf blood cell growth factors are required, suspend VERZENIO dose for at least 48 hours after the last dose of blood cell growth factor and until toxicity resolves to ≤Grade 2. Resume at next lower dose unless already performed for the toxicity that led to the use of the growth factor. Growth factor use as per current treatment guidelines.
  Monitor complete blood counts prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated.
  CTCAE Grade	VERZENIO Dose Modifications
  Grade 1 or 2	No dose modification is required.
  Grade 3	Suspend dose until toxicity resolves to ≤Grade 2. Dose reduction is not required.
  Grade 3 recurrent, or Grade 4	Suspend dose until toxicity resolves to ≤Grade 2. Resume at next lower dose .

  Table 3: VERZENIO Dose Modification and Management — Diarrhea

  At the first sign of loose stools, start treatment with antidiarrheal agents and increase intake of oral fluids.
  CTCAE Grade	VERZENIO Dose Modifications
  Grade 1	No dose modification is required.
  Grade 2	If toxicity does not resolve within 24 hours to ≤Grade 1, suspend dose until resolution. No dose reduction is required.
  Grade 2 that persists or recurs after resuming the same dose despite maximal supportive measures	Suspend dose until toxicity resolves to ≤Grade 1. Resume at next lower dose .
  Grade 3 or 4 or requires hospitalization	Suspend dose until toxicity resolves to ≤Grade 1. Resume at next lower dose .

  Table 4: VERZENIO Dose Modification and Management — Hepatotoxicity

  Abbreviations: ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit of normal.
  Monitor ALT, AST, and serum bilirubin prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated.
  CTCAE Grade for ALT and AST	VERZENIO Dose Modifications
  Grade 1 (>ULN-3.0 x ULN) Grade 2 (>3.0-5.0 x ULN), WITHOUT increase in total bilirubin above 2 x ULN	No dose modification is required.
  Persistent or Recurrent Grade 2, or Grade 3 (>5.0-20.0 x ULN), WITHOUT increase in total bilirubin above 2 x ULN	Suspend dose until toxicity resolves to baseline or Grade 1. Resume at next lower dose.
  Elevation in AST and/or ALT >3 x ULN WITH total bilirubin >2 x ULN, in the absence of cholestasis	Discontinue VERZENIO.
  Grade 4 (>20.0 x ULN)	Discontinue VERZENIO.

  Table 5: VERZENIO Dose Modification and Management — Interstitial Lung Disease/Pneumonitis

  CTCAE Grade	VERZENIO Dose Modifications
  Grade 1 or 2	No dose modification is required.
  Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1	Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose .
  Grade 3 or 4	Discontinue VERZENIO.

  Table 6: VERZENIO Dose Modification and Management — Venous Thromboembolic Events (VTEs)

  CTCAE Grade	VERZENIO Dose Modifications
  Early Breast Cancer
  Any Grade	Suspend dose and treat as clinically indicated. Resume VERZENIO when the patient is clinically stable.
  Advanced or Metastatic Breast Cancer
  Grade 1 or 2	No dose modification is required.
  Grade 3 or 4	Suspend dose and treat as clinically indicated. Resume VERZENIO when the patient is clinically stable.

  Table 7: VERZENIO Dose Modification and Management — Other Toxicities^a

  aExcluding diarrhea, hematologic toxicity, hepatotoxicity, ILD/pneumonitis, and VTEs.
  CTCAE Grade	VERZENIO Dose Modifications
  Grade 1 or 2	No dose modification is required.
  Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1	Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose .
  Grade 3 or 4	Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose .

  Refer to the Full Prescribing Information for coadministered fulvestrant, tamoxifen, or an aromatase inhibitor for dose modifications and other relevant safety information.

  Dose Modification for Use with Strong and Moderate CYP3A Inhibitors

  Avoid concomitant use of the strong CYP3A inhibitor ketoconazole.

  With concomitant use of strong CYP3A inhibitors other than ketoconazole, in patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the VERZENIO dose to 100 mg twice daily. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the VERZENIO dose to 50 mg twice daily. If a patient taking VERZENIO discontinues a CYP3A inhibitor, increase the VERZENIO dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the strong inhibitor

  [see Drug Interactions and Clinical Pharmacology ].

  With concomitant use of moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the VERZENIO dose in 50 mg decrements as demonstrated in Table 1, if necessary.

  Dose Modification for Patients with Severe Hepatic Impairment

  For patients with severe hepatic impairment (Child Pugh-C), reduce the VERZENIO dosing frequency to once daily

  [see Use in Specific Populations and Clinical Pharmacology ].

  Refer to the Full Prescribing Information for the coadministered fulvestrant, tamoxifen, or aromatase inhibitor for dose modification requirements for severe hepatic impairment.
  ,
  5.3 Interstitial Lung Disease (ILD) or Pneumonitis

  Severe, life-threatening, or fatal interstitial lung disease (ILD) or pneumonitis can occur in patients treated with VERZENIO and other CDK4/6 inhibitors. In VERZENIO-treated patients in early breast cancer (monarchE, N=2791), 3% of patients experienced ILD or pneumonitis of any grade: 0.4% were Grade 3 or 4 and there was one fatality (0.1%). In VERZENIO-treated patients in advanced or metastatic breast cancer (N=900) (MONARCH 1, MONARCH 2, MONARCH 3), 3.3% of VERZENIO-treated patients had ILD or pneumonitis of any grade: 0.6% had Grade 3 or 4, and 0.4% had fatal outcomes. Additional cases of ILD or pneumonitis have been observed in the postmarketing setting, with fatalities reported

  [see Adverse Reactions ]

  .

  Monitor patients for pulmonary symptoms indicative of ILD or pneumonitis. Symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded by means of appropriate investigations.

  Dose interruption or dose reduction is recommended for patients who develop persistent or recurrent Grade 2 ILD or pneumonitis. Permanently discontinue VERZENIO in all patients with Grade 3 or 4 ILD or pneumonitis

  [see Dosage and Administration ]

  .
  )
• Hepatotoxicity: Increases in serum transaminase levels have been observed. Perform liver function tests (LFTs) before initiating treatment with VERZENIO. Monitor LFTs every two weeks for the first two months, monthly for the next 2 months, and as clinically indicated. (
  2.2 Dose Modification

  Dose Modifications for Adverse Reactions

  The recommended VERZENIO dose modifications for adverse reactions are provided in Tables 1- 7. Discontinue VERZENIO for patients unable to tolerate 50 mg twice daily.

  Table 1: VERZENIO Dose Modification — Adverse Reactions

  Dose Level	VERZENIO Dose Combination with Fulvestrant, Tamoxifen, or an Aromatase Inhibitor	VERZENIO Dose for Monotherapy
  Recommended starting dose	150 mg twice daily	200 mg twice daily
  First dose reduction	100 mg twice daily	150 mg twice daily
  Second dose reduction	50 mg twice daily	100 mg twice daily
  Third dose reduction	not applicable	50 mg twice daily

  Table 2: VERZENIO Dose Modification and Management — Hematologic Toxicities^a

  Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events.
  aIf blood cell growth factors are required, suspend VERZENIO dose for at least 48 hours after the last dose of blood cell growth factor and until toxicity resolves to ≤Grade 2. Resume at next lower dose unless already performed for the toxicity that led to the use of the growth factor. Growth factor use as per current treatment guidelines.
  Monitor complete blood counts prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated.
  CTCAE Grade	VERZENIO Dose Modifications
  Grade 1 or 2	No dose modification is required.
  Grade 3	Suspend dose until toxicity resolves to ≤Grade 2. Dose reduction is not required.
  Grade 3 recurrent, or Grade 4	Suspend dose until toxicity resolves to ≤Grade 2. Resume at next lower dose .

  Table 3: VERZENIO Dose Modification and Management — Diarrhea

  At the first sign of loose stools, start treatment with antidiarrheal agents and increase intake of oral fluids.
  CTCAE Grade	VERZENIO Dose Modifications
  Grade 1	No dose modification is required.
  Grade 2	If toxicity does not resolve within 24 hours to ≤Grade 1, suspend dose until resolution. No dose reduction is required.
  Grade 2 that persists or recurs after resuming the same dose despite maximal supportive measures	Suspend dose until toxicity resolves to ≤Grade 1. Resume at next lower dose .
  Grade 3 or 4 or requires hospitalization	Suspend dose until toxicity resolves to ≤Grade 1. Resume at next lower dose .

  Table 4: VERZENIO Dose Modification and Management — Hepatotoxicity

  Abbreviations: ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit of normal.
  Monitor ALT, AST, and serum bilirubin prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated.
  CTCAE Grade for ALT and AST	VERZENIO Dose Modifications
  Grade 1 (>ULN-3.0 x ULN) Grade 2 (>3.0-5.0 x ULN), WITHOUT increase in total bilirubin above 2 x ULN	No dose modification is required.
  Persistent or Recurrent Grade 2, or Grade 3 (>5.0-20.0 x ULN), WITHOUT increase in total bilirubin above 2 x ULN	Suspend dose until toxicity resolves to baseline or Grade 1. Resume at next lower dose.
  Elevation in AST and/or ALT >3 x ULN WITH total bilirubin >2 x ULN, in the absence of cholestasis	Discontinue VERZENIO.
  Grade 4 (>20.0 x ULN)	Discontinue VERZENIO.

  Table 5: VERZENIO Dose Modification and Management — Interstitial Lung Disease/Pneumonitis

  CTCAE Grade	VERZENIO Dose Modifications
  Grade 1 or 2	No dose modification is required.
  Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1	Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose .
  Grade 3 or 4	Discontinue VERZENIO.

  Table 6: VERZENIO Dose Modification and Management — Venous Thromboembolic Events (VTEs)

  CTCAE Grade	VERZENIO Dose Modifications
  Early Breast Cancer
  Any Grade	Suspend dose and treat as clinically indicated. Resume VERZENIO when the patient is clinically stable.
  Advanced or Metastatic Breast Cancer
  Grade 1 or 2	No dose modification is required.
  Grade 3 or 4	Suspend dose and treat as clinically indicated. Resume VERZENIO when the patient is clinically stable.

  Table 7: VERZENIO Dose Modification and Management — Other Toxicities^a

  aExcluding diarrhea, hematologic toxicity, hepatotoxicity, ILD/pneumonitis, and VTEs.
  CTCAE Grade	VERZENIO Dose Modifications
  Grade 1 or 2	No dose modification is required.
  Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1	Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose .
  Grade 3 or 4	Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose .

  Refer to the Full Prescribing Information for coadministered fulvestrant, tamoxifen, or an aromatase inhibitor for dose modifications and other relevant safety information.

  Dose Modification for Use with Strong and Moderate CYP3A Inhibitors

  Avoid concomitant use of the strong CYP3A inhibitor ketoconazole.

  With concomitant use of strong CYP3A inhibitors other than ketoconazole, in patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the VERZENIO dose to 100 mg twice daily. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the VERZENIO dose to 50 mg twice daily. If a patient taking VERZENIO discontinues a CYP3A inhibitor, increase the VERZENIO dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the strong inhibitor

  [see Drug Interactions and Clinical Pharmacology ].

  With concomitant use of moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the VERZENIO dose in 50 mg decrements as demonstrated in Table 1, if necessary.

  Dose Modification for Patients with Severe Hepatic Impairment

  For patients with severe hepatic impairment (Child Pugh-C), reduce the VERZENIO dosing frequency to once daily

  [see Use in Specific Populations and Clinical Pharmacology ].

  Refer to the Full Prescribing Information for the coadministered fulvestrant, tamoxifen, or aromatase inhibitor for dose modification requirements for severe hepatic impairment.
  ,
  5.4 Hepatotoxicity

  Grade ≥3 ALT (2% to 6%) and AST (2% to 3%) were reported in patients receiving VERZENIO.

  Across three clinical trials in 3559 patients (monarchE, MONARCH 2, MONARCH 3), the median time to onset of Grade ≥3 ALT increases ranged from 57 to 87 days and the median time to resolution to Grade <3 was 13 to 14 days. The median time to onset of Grade ≥3 AST increases ranged from 71 to 185 days and the median time to resolution to Grade <3 ranged from 11 to 15 days.

  Monitor liver function tests (LFTs) prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, dose discontinuation, or delay in starting treatment cycles is recommended for patients who develop persistent or recurrent Grade 2, or any Grade 3 or Grade 4 hepatic transaminase elevation

  [see Dosage and Administration ]

  .
  )
• Venous Thromboembolism: Monitor patients for signs and symptoms of thrombosis and pulmonary embolism and treat as medically appropriate. (
  2.2 Dose Modification

  Dose Modifications for Adverse Reactions

  The recommended VERZENIO dose modifications for adverse reactions are provided in Tables 1- 7. Discontinue VERZENIO for patients unable to tolerate 50 mg twice daily.

  Table 1: VERZENIO Dose Modification — Adverse Reactions

  Dose Level	VERZENIO Dose Combination with Fulvestrant, Tamoxifen, or an Aromatase Inhibitor	VERZENIO Dose for Monotherapy
  Recommended starting dose	150 mg twice daily	200 mg twice daily
  First dose reduction	100 mg twice daily	150 mg twice daily
  Second dose reduction	50 mg twice daily	100 mg twice daily
  Third dose reduction	not applicable	50 mg twice daily

  Table 2: VERZENIO Dose Modification and Management — Hematologic Toxicities^a

  Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events.
  aIf blood cell growth factors are required, suspend VERZENIO dose for at least 48 hours after the last dose of blood cell growth factor and until toxicity resolves to ≤Grade 2. Resume at next lower dose unless already performed for the toxicity that led to the use of the growth factor. Growth factor use as per current treatment guidelines.
  Monitor complete blood counts prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated.
  CTCAE Grade	VERZENIO Dose Modifications
  Grade 1 or 2	No dose modification is required.
  Grade 3	Suspend dose until toxicity resolves to ≤Grade 2. Dose reduction is not required.
  Grade 3 recurrent, or Grade 4	Suspend dose until toxicity resolves to ≤Grade 2. Resume at next lower dose .

  Table 3: VERZENIO Dose Modification and Management — Diarrhea

  At the first sign of loose stools, start treatment with antidiarrheal agents and increase intake of oral fluids.
  CTCAE Grade	VERZENIO Dose Modifications
  Grade 1	No dose modification is required.
  Grade 2	If toxicity does not resolve within 24 hours to ≤Grade 1, suspend dose until resolution. No dose reduction is required.
  Grade 2 that persists or recurs after resuming the same dose despite maximal supportive measures	Suspend dose until toxicity resolves to ≤Grade 1. Resume at next lower dose .
  Grade 3 or 4 or requires hospitalization	Suspend dose until toxicity resolves to ≤Grade 1. Resume at next lower dose .

  Table 4: VERZENIO Dose Modification and Management — Hepatotoxicity

  Abbreviations: ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit of normal.
  Monitor ALT, AST, and serum bilirubin prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated.
  CTCAE Grade for ALT and AST	VERZENIO Dose Modifications
  Grade 1 (>ULN-3.0 x ULN) Grade 2 (>3.0-5.0 x ULN), WITHOUT increase in total bilirubin above 2 x ULN	No dose modification is required.
  Persistent or Recurrent Grade 2, or Grade 3 (>5.0-20.0 x ULN), WITHOUT increase in total bilirubin above 2 x ULN	Suspend dose until toxicity resolves to baseline or Grade 1. Resume at next lower dose.
  Elevation in AST and/or ALT >3 x ULN WITH total bilirubin >2 x ULN, in the absence of cholestasis	Discontinue VERZENIO.
  Grade 4 (>20.0 x ULN)	Discontinue VERZENIO.

  Table 5: VERZENIO Dose Modification and Management — Interstitial Lung Disease/Pneumonitis

  CTCAE Grade	VERZENIO Dose Modifications
  Grade 1 or 2	No dose modification is required.
  Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1	Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose .
  Grade 3 or 4	Discontinue VERZENIO.

  Table 6: VERZENIO Dose Modification and Management — Venous Thromboembolic Events (VTEs)

  CTCAE Grade	VERZENIO Dose Modifications
  Early Breast Cancer
  Any Grade	Suspend dose and treat as clinically indicated. Resume VERZENIO when the patient is clinically stable.
  Advanced or Metastatic Breast Cancer
  Grade 1 or 2	No dose modification is required.
  Grade 3 or 4	Suspend dose and treat as clinically indicated. Resume VERZENIO when the patient is clinically stable.

  Table 7: VERZENIO Dose Modification and Management — Other Toxicities^a

  aExcluding diarrhea, hematologic toxicity, hepatotoxicity, ILD/pneumonitis, and VTEs.
  CTCAE Grade	VERZENIO Dose Modifications
  Grade 1 or 2	No dose modification is required.
  Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1	Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose .
  Grade 3 or 4	Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose .

  Refer to the Full Prescribing Information for coadministered fulvestrant, tamoxifen, or an aromatase inhibitor for dose modifications and other relevant safety information.

  Dose Modification for Use with Strong and Moderate CYP3A Inhibitors

  Avoid concomitant use of the strong CYP3A inhibitor ketoconazole.

  With concomitant use of strong CYP3A inhibitors other than ketoconazole, in patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the VERZENIO dose to 100 mg twice daily. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the VERZENIO dose to 50 mg twice daily. If a patient taking VERZENIO discontinues a CYP3A inhibitor, increase the VERZENIO dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the strong inhibitor

  [see Drug Interactions and Clinical Pharmacology ].

  With concomitant use of moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the VERZENIO dose in 50 mg decrements as demonstrated in Table 1, if necessary.

  Dose Modification for Patients with Severe Hepatic Impairment

  For patients with severe hepatic impairment (Child Pugh-C), reduce the VERZENIO dosing frequency to once daily

  [see Use in Specific Populations and Clinical Pharmacology ].

  Refer to the Full Prescribing Information for the coadministered fulvestrant, tamoxifen, or aromatase inhibitor for dose modification requirements for severe hepatic impairment.
  ,
  5.5 Venous Thromboembolism

  Across three clinical trials in 3559 patients (monarchE, MONARCH 2, MONARCH 3), venous thromboembolic events were reported in 2% to 5% of patients treated with VERZENIO. Venous thromboembolic events included deep vein thrombosis, pulmonary embolism, pelvic venous thrombosis, cerebral venous sinus thrombosis, subclavian and axillary vein thrombosis, and inferior vena cava thrombosis. In clinical trials, deaths due to venous thromboembolism have been reported in patients treated with VERZENIO.

  VERZENIO has not been studied in patients with early breast cancer who had a history of venous thromboembolism. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate. Dose interruption is recommended for early breast cancer patients with any grade venous thromboembolic event and for advanced or metastatic breast cancer patients with a Grade 3 or 4 venous thromboembolic event

  [see Dosage and Administration ]

  .
  )
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. (
  5.6 Embryo-Fetal Toxicity

  Based on findings from animal studies and the mechanism of action, VERZENIO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of abemaciclib to pregnant rats during the period of organogenesis caused teratogenicity and decreased fetal weight at maternal exposures that were similar to the human clinical exposure based on area under the curve (AUC) at the maximum recommended human dose.

  Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with VERZENIO and for 3 weeks after the last dose

  [see Use in Specific Populations and Clinical Pharmacology ]

  .
  ,
  8.1 Pregnancy

  Risk Summary

  Based on findings in animals and its mechanism of action, VERZENIO can cause fetal harm when administered to a pregnant woman

  [see Clinical Pharmacology ]

  . There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. In animal reproduction studies, administration of abemaciclib during organogenesis was teratogenic and caused decreased fetal weight at maternal exposures that were similar to human clinical exposure based on AUC at the maximum recommended human dose (

  see

  Data). Advise pregnant women of the potential risk to a fetus.

  The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.

  Data

  Animal Data

  In an embryo-fetal development study, pregnant rats received oral doses of abemaciclib up to 15 mg/kg/day during the period of organogenesis. Doses ≥4 mg/kg/day caused decreased fetal body weights and increased incidence of cardiovascular and skeletal malformations and variations. These findings included absent innominate artery and aortic arch, malpositioned subclavian artery, unossified sternebra, bipartite ossification of thoracic centrum, and rudimentary or nodulated ribs. At 4 mg/kg/day in rats, the maternal systemic exposures were approximately equal to the human exposure (AUC) at the recommended dose.
  ,
  8.3 Females and Males of Reproductive Potential

  Based on animal studies, VERZENIO can cause fetal harm when administered to a pregnant woman

  [see Use in Specific Populations ]

  .

  Pregnancy Testing

  Verify pregnancy status in females of reproductive potential prior to initiating treatment with VERZENIO.

  Contraception

  Females

  Advise females of reproductive potential to use effective contraception during VERZENIO treatment and for 3 weeks after the last dose.

  Infertility

  Males

  Based on findings in animals, VERZENIO may impair fertility in males of reproductive potential

  [see Nonclinical Toxicology ]

  .
  )