Verzenio 50 Mg Oral Tablet

Missed Dose

If a dose of VERZENIO is missed, skip the missed dose and take the next dose at the next scheduled time.

Vomited Dose

If vomiting occurs after taking a dose of VERZENIO, do not take an additional dose. Take the next dose at the next scheduled time.

monarchE: VERZENIO in Combination with Tamoxifen or an Aromatase Inhibitor as Adjuvant Treatment

MONARCH 3: VERZENIO in Combination with an Aromatase Inhibitor (Anastrozole or Letrozole) as Initial Endocrine-Based Therapy

MONARCH 2: VERZENIO in Combination with Fulvestrant

EMBER-3: VERZENIO in Combination with Imlunestrant in Advanced or Metastatic Breast Cancer

The safety of VERZENIO in combination with imlunestrant was evaluated in 535 patients with ER+, HER2- locally advanced or metastatic breast cancer previously treated with endocrine therapy with or without a prior CDK4/6 inhibitor in EMBER-3 [see Clinical Studies (14.2)]. Patients received VERZENIO 150 mg orally twice daily in combination with imlunestrant 400 mg orally once daily (N=208), or imlunestrant monotherapy 400 mg, once daily (n=327). Among patients who were treated with VERZENIO in combination with imlunestrant, the median duration of exposure was 7.7 months (range 1 day to 25.3 months).

Serious adverse reactions occurred in 21% of patients who received VERZENIO in combination with imlunestrant. Serious adverse reactions in >1% of patients included pneumonia (2.4%), abdominal pain, and renal failure (each 1.4%). Fatal adverse reactions occurred in 3.8% of patients who received VERZENIO in combination with imlunestrant, including pneumonia (1.4%), myocardial infarction, interstitial lung disease and sepsis (0.5%, each).

Permanent discontinuation of VERZENIO due to an adverse reaction occurred in 3.4% of patients. Adverse reactions which resulted in permanent discontinuation of VERZENIO included: increased ALT (1.4%), bile duct stone, diarrhea, drug-induced liver injury, prolonged QT interval, fatigue, maculo-papular rash, renal failure, and vomiting (0.5% each).

Dosage interruptions of VERZENIO due to an adverse reaction occurred in 59% of patients. Adverse reactions which required dosage interruptions of VERZENIO in ≥2% of patients included diarrhea (20%), neutropenia (10%), decreased neutrophils (8%), anemia (6%), nausea (6%), increased AST (2.4%), fatigue (2.4%), and vomiting (2.4%).

Dose reductions of VERZENIO due to an adverse reaction occurred in 42% of patients. Adverse reactions which required dose reductions of VERZENIO in ≥1% of patients included: diarrhea (20%), neutropenia (5%), nausea (3.4%), decreased neutrophils (3.4%), fatigue (2.4%), anemia (1.9%), increased AST (1.9%), increased ALT (1.4%).

The most common (≥10%) adverse reactions, including laboratory abnormalities were: decreased neutrophils, diarrhea, decreased hemoglobin, decreased lymphocytes, nausea, decreased platelets, fatigue, increased triglycerides, infections, increased AST, increased creatinine, increased ALT, vomiting, musculoskeletal pain, abdominal pain, decreased appetite, increased cholesterol, rash, cough, headache and decreased weight.

Table 14 and 15 summarizes the adverse reactions and laboratory abnormalities, respectively, in EMBER-3.

Clinically relevant adverse reactions (<10%) in patients who received VERZENIO in combination with imlunestrant included: constipation (9%), stomatitis (9%), fever (9%), urinary tract infection (8%), dizziness (8%), hot flush (6%), insomnia (6%), arrhythmia (6%), alopecia (5%), back pain (4.8%), venous thromboembolic event (4.8%) and interstitial lung disease or pneumonitis (2.9%).

MONARCH 1: VERZENIO Administered as a Monotherapy in Metastatic Breast Cancer

Ketoconazole

Avoid concomitant use of ketoconazole. Ketoconazole is predicted to increase the AUC of abemaciclib by up to 16-fold [see Clinical Pharmacology (12.3)].

Other Strong CYP3A Inhibitors

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 with concomitant use of strong CYP3A inhibitors other than ketoconazole. 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 with concomitant use of strong CYP3A inhibitors. If a patient taking VERZENIO discontinues a strong CYP3A inhibitor, increase the VERZENIO dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the inhibitor. Patients should avoid grapefruit products [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

Moderate CYP3A Inhibitors

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.

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.

Females

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

Males

Based on findings in animals, VERZENIO may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].

Effect of Food

A high-fat, high-calorie meal (approximately 800 to 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) administered to healthy subjects increased the AUC of abemaciclib plus its active metabolites by 9% and increased C_max by 26%.

Metabolism

Hepatic metabolism is the main route of clearance for abemaciclib. Abemaciclib is metabolized to several metabolites primarily by cytochrome P450 (CYP) 3A4, with formation of N-desethylabemaciclib (M2) representing the major metabolism pathway. Additional metabolites include hydroxyabemaciclib (M20), hydroxy-N-desethylabemaciclib (M18), and an oxidative metabolite (M1). M2, M18, and M20 are equipotent to abemaciclib and their AUCs accounted for 25%, 13%, and 26% of the total circulating analytes in plasma, respectively.

Excretion

After a single 150 mg oral dose of radiolabeled abemaciclib, approximately 81% of the dose was recovered in feces and approximately 3% recovered in urine. The majority of the dose eliminated in feces was metabolites.

Age, Gender, and Body Weight

Based on a population pharmacokinetic analysis in patients with cancer, age (range 24-91 years), gender (134 males and 856 females), and body weight (range 36-175 kg) had no effect on the exposure of abemaciclib.

Patients with Renal Impairment

In a population pharmacokinetic analysis of 990 individuals, in which 381 individuals had mild renal impairment (60 mL/min ≤ CLcr <90 mL/min) and 126 individuals had moderate renal impairment (30 mL/min ≤ CLcr <60 mL/min), mild and moderate renal impairment had no effect on the exposure of abemaciclib [see Use in Specific Populations (8.6)]. The effect of severe renal impairment (CLcr <30 mL/min) on pharmacokinetics of abemaciclib is unknown.

Patients with Hepatic Impairment

Following a single 200 mg oral dose of abemaciclib, the relative potency adjusted unbound AUC_0-INF of abemaciclib plus its active metabolites (M2, M18, M20) in plasma increased 1.2-fold in subjects with mild hepatic impairment (Child-Pugh A, n=9), 1.1-fold in subjects with moderate hepatic impairment (Child-Pugh B, n=10), and 2.4-fold in subjects with severe hepatic impairment (Child-Pugh C, n=6) relative to subjects with normal hepatic function (n=10) [see Use in Specific Populations (8.7)]. In subjects with severe hepatic impairment, the mean plasma elimination half-life of abemaciclib increased to 55 hours compared to 24 hours in subjects with normal hepatic function.

Effects of Other Drugs on Abemaciclib

Strong CYP3A Inhibitors: Ketoconazole (a strong CYP3A inhibitor) is predicted to increase the AUC of abemaciclib by up to 16-fold.

Coadministration of 500 mg twice daily doses of clarithromycin (a strong CYP3A inhibitor) with a single 50 mg dose of VERZENIO (0.3 times the approved recommended 150 mg dosage) increased the relative potency adjusted unbound AUC_0-INF of abemaciclib plus its active metabolites (M2, M18, and M20) by 2.5-fold relative to abemaciclib alone in cancer patients.

Moderate CYP3A Inhibitors: Verapamil and diltiazem (moderate CYP3A inhibitors) are predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 1.6-fold and 2.4-fold, respectively.

Strong CYP3A Inducers: Coadministration of 600 mg daily doses of rifampin (a strong CYP3A inducer) with a single 200 mg dose of VERZENIO decreased the relative potency adjusted unbound AUC_0-INF of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 70% in healthy subjects.

Moderate CYP3A Inducers: Efavirenz, bosentan, and modafinil (moderate CYP3A inducers) are predicted to decrease the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 53%, 41%, and 29%, respectively.

Loperamide: Co-administration of a single 8 mg dose of loperamide with a single 400 mg dose of abemaciclib in healthy subjects increased the relative potency adjusted unbound AUC_0-INF of abemaciclib plus its active metabolites (M2 and M20) by 12%, which is not considered clinically relevant.

Endocrine Therapies: In clinical studies in patients with breast cancer, there was no clinically relevant effect of fulvestrant, imlunestrant, anastrozole, letrozole, exemestane, or tamoxifen on abemaciclib pharmacokinetics.

Effects of Abemaciclib on Other Drugs

In Vitro Studies

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

The efficacy of VERZENIO in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) was evaluated in monarchE (NCT03155997), a randomized, open-label, two cohort, multicenter study in 5637 adults with HR-positive, HER2-negative, node-positive, resected, early breast cancer with clinical and pathological features consistent with a high risk of disease recurrence of which 5120 (91%) were randomized in cohort 1. 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:

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 1:1 to receive VERZENIO 150 mg orally once daily for 2 years in combination with endocrine therapy (tamoxifen or an aromatase inhibitor); or endocrine therapy alone. Randomization 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 for VERZENIO in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) 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.

Of the 5120 patients randomized in cohort 1, the 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; 8% were Hispanic/Latino and 92% were not Hispanic/Latino and 0.2% were not reported/missing. 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 18 and Figure 1.

Postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer with no prior systemic therapy in this disease setting

The efficacy of VERZENIO in combination with an aromatase inhibitor was evaluated in MONARCH 3 (NCT02246621), a randomized, double-blinded, placebo-controlled, multicenter study in 493 postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer in combination with a nonsteroidal aromatase inhibitor as initial endocrine-based therapy, including patients not previously treated with systemic therapy for breast cancer. Patients were randomized 2:1 to VERZENIO 150 mg orally twice daily in combination with an aromatase inhibitor or placebo in combination with an aromatase inhibitor. Randomization was stratified by disease site (visceral, bone only, or other) and by prior (neo)adjuvant endocrine therapy (aromatase inhibitor versus other versus no prior endocrine therapy). Patients were treated until disease progression or unacceptable toxicity.

The major efficacy outcome for VERZENIO in combination with an aromatase inhibitor was progression free survival (PFS) by investigator assessment using Response Evaluation Criteria (RECIST) v1.1. Other efficacy measures included OS and objective response rate (ORR).

The median age was 63 years (range, 32-88 years), 45% age 65 or older; 58% White, 30% Asian, 1.6% Black or African American, 1.4% American Indian or Alaska Native, 0.2% Native Hawaiian or Other Pacific Islander, and 0.4% multiple races, and race was not reported for 7.9%; 8.9% were Hispanic/Latino and 72% were not Hispanic/Latino and 19% not reported/missing; and baseline ECOG performance status was 0 (60%), or 1 (40%). Most patients had visceral metastasis (53%) at baseline and 22% had bone-only disease. Of the patients enrolled, 51% had received prior systemic therapy and 39% of patients had received chemotherapy. Overall, 80% of patients received letrozole as investigator's choice aromatase inhibitor and 20% received anastrozole.

Efficacy results are summarized in Table 19 and Figure 2. PFS assessment based on a blinded independent radiologic review was consistent with the investigator assessment. Consistent PFS results were observed across patient stratification subgroups of disease site and prior (neo)adjuvant endocrine therapy.

Patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression on or after prior adjuvant or metastatic endocrine therapy

The efficacy of VERZENIO in combination with fulvestrant was evaluated in MONARCH 2 (NCT02107703), a randomized, placebo-controlled, multicenter study in 669 women with HR-positive, HER2-negative metastatic breast cancer with disease progression following endocrine therapy who had not received chemotherapy in the metastatic setting. Patients were randomized 2:1 to VERZENIO 150 mg orally twice daily or placebo orally twice daily in combination with fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then on day 1 of cycle 2 and beyond (28-day cycles). Randomization was stratified by disease site (visceral, bone only, or other) and by sensitivity to prior endocrine therapy (primary or secondary resistance). Primary endocrine therapy resistance was defined as relapse while on the first 2 years of adjuvant endocrine therapy or progressive disease within the first 6 months of first line endocrine therapy for metastatic breast cancer. Pre/perimenopausal women were enrolled in the study and received the gonadotropin-releasing hormone agonist goserelin for at least 4 weeks prior to and for the duration of MONARCH 2. Patients remained on continuous treatment until development of progressive disease or unmanageable toxicity.

The major efficacy outcome for VERZENIO in combination with fulvestrant was PFS by investigator assessment using RECIST v1.1. Other efficacy measures included OS and ORR.

The median age was 60 years (range, 32-91 years), 37% age 65 or older, 56% White, 32% Asian, 3.9% American Indian or Alaska Native, 2.1% Black or African American, and race was not reported for 6.3%; 12% were Hispanic/Latino and 70% were not Hispanic/Latino, 18% not reported/missing; ECOG performance status was 0 (60%), 1 (39%) or 2 (0.1%). Most patients had visceral disease (56%), 27% had bone-only disease, and 20% had de novo metastatic disease. Twenty-five percent (25%) of patients had primary endocrine therapy resistance. Seventeen percent (17%) of patients were pre- or perimenopausal.

Efficacy results are summarized in Table 20, Figure 3, and Figure 4. PFS assessment based on a blinded independent radiologic review was consistent with the investigator assessment. Consistent results were observed across patient stratification subgroups of disease site and endocrine therapy resistance for PFS and OS.

Patients with HR-positive, HER2-negative breast cancer who received prior endocrine therapy and 1-2 chemotherapy regimens in the metastatic setting

The efficacy of VERZENIO monotherapy was evaluated in MONARCH 1 (NCT02102490), a single-arm, open-label, multicenter study in 132 women with measurable HR-positive, HER2-negative metastatic breast cancer whose disease progressed during or after endocrine therapy, had received a taxane in any setting, and who received 1 or 2 prior chemotherapy regimens in the metastatic setting. Patients received VERZENIO 200 mg orally twice daily on a continuous schedule until development of progressive disease or unmanageable toxicity.

The major efficacy outcome was ORR. Duration of response (DoR) was another efficacy measure.

The median age was 58 years (range, 36-89 years), 32% age 65 or older; 85% White, 4.5% Black or African American, 1.5% Asian, and race was not reported for 9.1%; 6.1% were Hispanic/Latino and 85% were not Hispanic/Latino, and 9.1% not reported/missing; ECOG performance status was 0 (55%) or 1 (45%). The median duration of metastatic disease was 27.6 months. Ninety percent (90%) of patients had visceral metastases, and 51% of patients had 3 or more sites of metastatic disease. Fifty-one percent (51%) of patients had one line of chemotherapy in the metastatic setting. Sixty-nine percent (69%) of patients had received a taxane-based regimen in the metastatic setting and 55% had received capecitabine in the metastatic setting.

Efficacy results are summarized in Table 22.