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MONARCH 2 adverse reactions (ARs)1

MONARCH 2 Adverse ReactionsMONARCH 2 Adverse Reactions
  • 85% of diarrhea events recovered or resolved with supportive treatment and/or dose reductions2
  • 1% of patients taking Verzenio + fulvestrant experienced febrile neutropenia1
  • 1% of patients taking Verzenio + fulvestrant permanently discontinued treatment due to diarrhea1
  • Electrocardiogram tests are not required per Prescribing Information1
  • Additional ARs in MONARCH 2 included venous thromboembolic events (deep vein thrombosis [DVT], pulmonary embolism, cerebral venous sinus thrombosis, subclavian vein thrombosis, axillary vein thrombosis, and DVT inferior vena cava), which were reported in 5% of patients treated with Verzenio + fulvestrant vs 0.9% of patients treated with placebo + fulvestrant1

Discontinuation due to adverse events was 9% with Verzenio + fulvestrant vs 3% with placebo + fulvestrant1

*Includes neutropenia, neutrophil count decreased.1

Includes asthenia, fatigue.1

Includes upper respiratory tract infection, urinary tract infection, lung infection, pharyngitis, conjunctivitis, sinusitis, vaginal infection, and sepsis.1

§Includes abdominal pain, abdominal pain (upper), abdominal pain (lower), abdominal discomfort, and abdominal tenderness.1

IIIncludes anemia, hematocrit decreased, hemoglobin decreased, red blood cell count decreased.1

Includes leukopenia, white blood cell count decreased.1

#Includes platelet count decreased, thrombocytopenia.1

ALT=alanine aminotransferase; AST=aspartate aminotransferase.

MONARCH 2 laboratory abnormalities1

MONARCH 2 Lab AbnormalitiesMONARCH 2 Lab Abnormalities

Increases in serum creatinine from baseline (mean increase, 0.2 mg/dL)1*:

  • Occurred early
  • Remained elevated but stable
  • Were reversible with treatment discontinuation
  • Verzenio has been shown to increase serum creatinine due to inhibition of renal tubular transporters without affecting glomerular function1
  • With Verzenio + fulvestrant, 0.5% of patients (n=2) experienced dose reductions and 1.4% of patients (n=6) experienced dose omissions due to increased serum creatinine3

Increases in serum creatinine from baseline were not accompanied by worsening in kidney function1

The most common adverse reactions reported (all grades, ≥20%) in the Verzenio arm were diarrhea, fatigue, neutropenia, nausea, infections, abdominal pain, anemia, leukopenia, decreased appetite, vomiting, and headache. The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, diarrhea, leukopenia, anemia, and infections.1

*MONARCH 2 used the Common Terminology Criteria for Adverse Events version 4.0, which defines Grade 1 creatinine increase as >1 to 1.5 times baseline or higher than the upper limit of normal to 1.5 times the upper limit of normal.3

MONARCH 1 ARs1

MONARCH 1 Adverse ReactionsMONARCH 1 Adverse Reactions
  • 8% of patients discontinued Verzenio because of treatment-related ARs: abdominal pain, arterial thrombosis, AST increased, blood creatinine increased, chronic kidney disease, diarrhea, electrocardiogram QT prolonged, fatigue, hip fracture, and lymphopenia (1 patient each)1
  • 77% of patients who received post-study therapy (n=65) were able to receive chemotherapy

*Includes asthenia, fatigue.1

Includes neutropenia, neutrophil count decreased. One patient experienced Grade 4 febrile neutropenia during study follow-up while on cytotoxic chemotherapy (19 days after discontinuing Verzenio).1,4

Includes anemia, hematocrit decreased, hemoglobin decreased, red blood cell count decreased.1

§Includes platelet count decreased, thrombocytopenia.1

IIIncludes leukopenia, white blood cell count decreased.1

119 patients discontinued Verzenio treatment and 84 received additional anticancer treatment.1,4

MONARCH 1 laboratory abnormalities1

MONARCH 1 Lab AbnormalitiesMONARCH 1 Lab Abnormalities

Increases in serum creatinine from baseline (mean increase, 0.3 mg/dL)1,5*

  • Occurred early
  • Remained elevated but stable,
  • Were reversible with treatment discontinuation
  • Verzenio has been shown to increase serum creatinine due to inhibition of renal tubular transporters, without affecting glomerular function1
  • With Verzenio, 1.5% of patients (n=2) experienced dose reductions and 1.5% of patients (n=2) experienced dose omissions due to increased serum creatinine5

Increases in serum creatinine from baseline were not accompanied by worsening kidney function1,5

The most common reported adverse reactions (all grades, ≥20%) were diarrhea, fatigue, nausea, decreased appetite, abdominal pain, neutropenia, vomiting, infections, anemia, headache, and thrombocytopenia. Severe (Grade 3 and 4) neutropenia was observed in patients receiving Verzenio.1

*MONARCH 1 used the Common Terminology Criteria for Adverse Events version 4.0, which defines Grade 1 creatinine increase as >1 to 1.5 times baseline or higher than the upper limit of normal to 1.5 times the upper limit of normal.4

Diarrhea incidence was greatest during the first 28 days and lessened during subsequent cycles1

85% of diarrhea events in MONARCH 2 recovered or resolved with supportive treatment and/or dose reductions2

INCIDENCE OF GRADE 2 AND 3 DIARRHEA IN MONARCH 26
Diarrhea Incidence in MONARCH 2 TrialDiarrhea Incidence in MONARCH 2 Trial
  • The proportion of patients with Grade 2 and 3 diarrhea was 32% during the first cycle and lower during subsequent cycles7
  • 22% of patients with diarrhea required dose omission and 22% required a dose reduction1
  • Median time to onset of diarrhea (all grades) was 6 days with a median duration of Grade 2 and 3 diarrhea of 9 days and 6 days, respectively1
  • 1% of patients taking Verzenio + fulvestrant permanently discontinued treatment due to diarrhea1

In the MONARCH 1 study, the time to onset and resolution for diarrhea were similar to those in MONARCH 21*

*Please see dose modification instructions for diarrhea.

References: 1. Verzenio [package insert]. Indianapolis, IN: Eli Lilly and Company; 2017. 2. Data on file. Lilly USA, LLC. ONC20170921a. 3. Sledge GW Jr, Masakazu T, Neven P, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2− advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35:2875-2884. 4. Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH 1, a phase 2 study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2− metastatic breast cancer. Clin Cancer Res. 2017;23:5218-5224. 5. Data on file. Lilly USA, LLC. ONC20170802a. 6. Data on file. Lilly USA, LLC. ONC20170612a. 7. Data on file. Lilly USA, LLC. ONC20170608e.

Indication

Verzenio is indicated for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2−negative (HER2−) advanced or metastatic breast cancer (MBC):

  • In combination with fulvestrant for women with disease progression following endocrine therapy
  • In combination with an aromatase inhibitor (AI) for postmenopausal women as initial endocrine−based therapy
  • As a single agent for adult patients with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting

Important Safety Information

Diarrhea occurred in 81% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 86% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and 90% of patients receiving Verzenio alone in MONARCH 1. Grade 3 diarrhea occurred in 9% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 13% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and in 20% of patients receiving Verzenio alone in MONARCH 1. Episodes of diarrhea have been associated with dehydration and infection.

Diarrhea incidence was greatest during the first month of Verzenio dosing. In MONARCH 3, the median time to onset of the first diarrhea event was 8 days, and the median duration of diarrhea for Grades 2 and 3 were 11 and 8 days, respectively. In MONARCH 2, the median time to onset of the first diarrhea event was 6 days, and the median duration of diarrhea for Grades 2 and 3 were 9 days and 6 days, respectively. In MONARCH 3, 19% of patients with diarrhea required a dose omission and 13% required a dose reduction. In MONARCH 2, 22% of patients with diarrhea required a dose omission and 22% required a dose reduction. The time to onset and resolution for diarrhea were similar across MONARCH 3, MONARCH 2, and MONARCH 1.

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

Neutropenia occurred in 41% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 46% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and 37% of patients receiving Verzenio alone in MONARCH 1. A Grade ≥3 decrease in neutrophil count (based on laboratory findings) occurred in 22% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 32% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and in 27% of patients receiving Verzenio alone in MONARCH 1. In MONARCH 3, the median time to first episode of Grade ≥3 neutropenia was 33 days, and in MONARCH 2 and MONARCH 1, was 29 days. In MONARCH 3, median duration of Grade ≥3 neutropenia was 11 days, and for MONARCH 2 and MONARCH 1 was 15 days.

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.

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

Grade ≥3 increases in alanine aminotransferase (ALT) (6% versus 2%) and aspartate aminotransferase (AST) (3% versus 1%) were reported in the Verzenio and placebo arms, respectively, in MONARCH 3. Grade ≥3 increases in ALT (4% versus 2%) and AST (2% versus 3%) were reported in the Verzenio and placebo arms respectively, in MONARCH 2.

In MONARCH 3, for patients receiving Verzenio plus an aromatase inhibitor with Grade ≥3 increases in ALT or AST, median time to onset was 61 and 71 days, respectively, and median time to resolution to Grade <3 was 14 and 15 days, respectively. In MONARCH 2, for patients receiving Verzenio plus fulvestrant with Grade ≥3 increases in ALT or AST, median time to onset was 57 and 185 days, respectively, and median time to resolution to Grade <3 was 14 and 13 days, respectively.

For assessment of potential hepatotoxicity, 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 Grade 3 or 4, hepatic transaminase elevation.

Venous thromboembolic events were reported in 5% of patients treated with Verzenio plus an aromatase inhibitor as compared to 0.6% of patients treated with an aromatase inhibitor plus placebo in MONARCH 3. Venous thromboembolic events were reported in 5% of patients treated with Verzenio plus fulvestrant in MONARCH 2 as compared to 0.9% of patients treated with fulvestrant plus placebo. 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. Across the clinical development program, deaths due to venous thromboembolism have been reported. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate.

Verzenio can cause fetal harm when administered to a pregnant woman based on findings from animal studies and the mechanism of action. 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 at least 3 weeks after the last dose. There are no data on the presence of Verzenio in human milk or its effects on the breastfed child or on milk production. Advise lactating women not to breastfeed during Verzenio treatment and for at least 3 weeks after the last dose because of the potential for serious adverse reactions in breastfed infants. Based on findings in animals, Verzenio may impair fertility in males of reproductive potential.

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 3 for Verzenio plus anastrozole or letrozole and ≥2% higher than placebo plus anastrozole or letrozole vs placebo plus anastrozole or letrozole were diarrhea (81% vs 30%), neutropenia (41% vs 2%), fatigue (40% vs 32%), infections (39% vs 29%), nausea (39% vs 20%), abdominal pain (29% vs 12%), vomiting (28% vs 12%), anemia (28% vs 5%), alopecia (27% vs 11%), decreased appetite (24% vs 9%), leukopenia (21% vs 2%), creatinine increased (19% vs 4%), constipation (16% vs 12%), ALT increased (16% vs 7%), AST increased (15% vs 7%), rash (14% vs 5%), pruritus (13% vs 9%), cough (13% vs 9%), dyspnea (12% vs 6%), dizziness (11% vs 9%), weight decreased (10% vs 3%), influenza-like illness (10% vs 8%), and thrombocytopenia (10% vs 2%).

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 2 for Verzenio plus fulvestrant and ≥2% higher than placebo plus fulvestrant vs placebo plus fulvestrant were diarrhea (86% vs 25%), neutropenia (46% vs 4%), fatigue (46% vs 32%), nausea (45% vs 23%), infections (43% vs 25%), abdominal pain (35% vs 16%), anemia (29% vs 4%), leukopenia (28% vs 2%), decreased appetite (27% vs 12%), vomiting (26% vs 10%), headache (20% vs 15%), dysgeusia (18% vs 3%), thrombocytopenia (16% vs 3%), alopecia (16% vs 2%), stomatitis (15% vs 10%), ALT increased (13% vs 5%), pruritus (13% vs 6%), cough (13% vs 11%), dizziness (12% vs 6%), AST increased (12% vs 7%), peripheral edema (12% vs 7%), creatinine increased (12% vs <1%), rash (11% vs 4%), pyrexia (11% vs 6%), and weight decreased (10% vs 2%).

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 1 with Verzenio were diarrhea (90%), fatigue (65%), nausea (64%), decreased appetite (45%), abdominal pain (39%), neutropenia (37%), vomiting (35%), infections (31%), anemia (25%), thrombocytopenia (20%), headache (20%), cough (19%), leukopenia (17%), constipation (17%), arthralgia (15%), dry mouth (14%), weight decreased (14%), stomatitis (14%), creatinine increased (13%), alopecia (12%), dysgeusia (12%), pyrexia (11%), dizziness (11%), and dehydration (10%).

The most frequently reported ≥5% Grade 3 or 4 adverse reactions that occurred in the Verzenio arm vs the placebo arm of MONARCH 3 were neutropenia (22% vs 2%), diarrhea (9% vs 1%), leukopenia (8% vs <1%), ALT increased (7% vs 2%), and anemia (6% vs 1%).

The most frequently reported ≥5% Grade 3 or 4 adverse reactions that occurred in the Verzenio arm vs the placebo arm of MONARCH 2 were neutropenia (27% vs 2%), diarrhea (13% vs <1%), leukopenia (9% vs 0%), anemia (7% vs 1%), and infections (6% vs 3%).

The most frequently reported ≥5% Grade 3 or 4 adverse reactions from MONARCH 1 with Verzenio were neutropenia (24%), diarrhea (20%), fatigue (13%), infections (7%), leukopenia (6%), anemia (5%), and nausea (5%).

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 3 in ≥10% for Verzenio plus anastrozole or letrozole and ≥2% higher than placebo plus anastrozole or letrozole vs placebo plus anastrozole or letrozole were increased serum creatinine (98% vs 84%; 2% vs 0%), decreased white blood cells (82% vs 27%; 13% vs <1%), anemia (82% vs 28%; 2% vs 0%), decreased neutrophil count (80% vs 21%; 22% vs 3%), decreased lymphocyte count (53% vs 26%; 8% vs 2%), decreased platelet count (36% vs 12%; 2% vs <1%), increased ALT (48% vs 25%; 7% vs 2%), and increased AST (37% vs 23%; 4% vs <1%).

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 2 in ≥10% for Verzenio plus fulvestrant and ≥2% higher than placebo plus fulvestrant vs placebo plus fulvestrant were increased serum creatinine (98% vs 74%; 1% vs 0%), decreased white blood cells (90% vs 33%; 23% vs 1%), decreased neutrophil count (87% vs 30%; 33% vs 4%), anemia (84% vs 33%; 3% vs <1%), decreased lymphocyte count (63% vs 32%; 12% vs 2%), decreased platelet count (53% vs 15%; 2% vs 0%), increased ALT (41% vs 32%; 5% vs 1%), and increased AST (37% vs 25%; 4% vs 4%).

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 1 with Verzenio were increased serum creatinine (98%; <1%), decreased white blood cells (91%; 28%), decreased neutrophil count (88%; 27%), anemia (68%; 0%), decreased lymphocyte count (42%; 14%), decreased platelet count (41%; 2%), increased ALT (31%; 3%), and increased AST (30%; 4%).

Strong CYP3A inhibitors increased the exposure of abemaciclib plus its active metabolites to a clinically meaningful extent and may lead to increased toxicity. Avoid concomitant use of ketoconazole. Ketoconazole is predicted to increase the AUC of abemaciclib by up to 16-fold. 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 other strong CYP3A inhibitors. 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 other strong CYP3A inhibitors. If a patient taking Verzenio discontinues a strong CYP3A inhibitor, increase the Verzenio dose (after 3 to 5 half-lives of the inhibitor) to the dose that was used before starting the strong inhibitor. Patients should avoid grapefruit products.

Avoid concomitant use of strong CYP3A inducers and consider alternative agents. Coadministration of Verzenio with rifampin, a strong CYP3A inducer, decreased the plasma concentrations of abemaciclib plus its active metabolites and may lead to reduced activity.

With severe hepatic impairment (Child-Pugh Class C), reduce the Verzenio dosing frequency to once daily. The pharmacokinetics of Verzenio in patients with severe renal impairment (CLcr <30 mL/min), end stage renal disease, or in patients on dialysis is unknown. No dosage adjustments are necessary in patients with mild or moderate hepatic (Child-Pugh A or B) and/or renal impairment (CLcr ≥30-89 mL/min).

Please see full Prescribing.Information for Verzenio.

AL HCP ISI 26FEB2018