Adverse reactions : תופעות לוואי

7      ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
•       Diarrhea [see Warnings and Precautions (6.1)].
•       Neutropenia [see Warnings and Precautions (6.2)].
•       Interstitial Lung Disease (ILD) or Pneumonitis [see Warnings and Precautions (6.3)].
•       Hepatotoxicity [see Warnings and Precautions (6.4)].
•       Venous Thromboembolism [see Warnings and Precautions (6.5)].

7.1    Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety population described in the Warnings and Precautions reflect exposure to VERZENIO in 3691 patients from four clinical trials: monarchE, MONARCH 1, MONARCH 2, and MONARCH 3. The safety population includes exposure to VERZENIO as a single agent at 200 mg twice daily in 132 patients in MONARCH 1 and to VERZENIO at 150 mg twice daily in 3559 patients administered in combination with fulvestrant, tamoxifen, or an aromatase inhibitor in monarchE, MONARCH 2, and MONARCH 3. The median duration of exposure ranged from 4.5 months in MONARCH 1 to 24 months in monarchE. The most common adverse reactions (incidence ≥20%) across clinical trials were: diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, and thrombocytopenia.

Early Breast Cancer monarchE: VERZENIO in Combination with Tamoxifen or an Aromatase Inhibitor as Adjuvant Treatment Adult patients with HR-positive, HER2-negative, node-positive early breast cancer at a high risk of recurrence 
The safety of VERZENIO was evaluated in monarchE, a study of 5591 adult patients receiving VERZENIO plus endocrine therapy (tamoxifen or an aromatase inhibitor) or endocrine therapy (tamoxifen or an aromatase inhibitor) alone [see Clinical Studies (14.1)]. Patients were randomly assigned to receive 150 mg of VERZENIO orally, twice daily, plus tamoxifen or an aromatase inhibitor, or tamoxifen or an aromatase inhibitor, for two years or until discontinuation criteria were met. The median duration of VERZENIO treatment was 24 months.


The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, leukopenia, diarrhea, and lymphopenia.

Fatal adverse reactions occurred in 0.8% of patients who received VERZENIO plus endocrine therapy (tamoxifen or an aromatase inhibitor), including: cardiac failure (0.1%), cardiac arrest, myocardial infarction, ventricular fibrillation, cerebral hemorrhage, cerebrovascular accident, pneumonitis, hypoxia, diarrhea and mesenteric artery thrombosis (0.03% each).

Permanent VERZENIO treatment discontinuation due to an adverse reaction was reported in 19% of patients receiving VERZENIO, plus tamoxifen or an aromatase inhibitor. Of the patients receiving tamoxifen or an aromatase inhibitor, 1% permanently discontinued due to an adverse reaction. The most common adverse reactions leading to VERZENIO discontinuations were diarrhea (5%), fatigue (2%), and neutropenia (0.9%).

Dose interruption of VERZENIO due to an adverse reaction occurred in 62% of patients receiving VERZENIO plus tamoxifen or aromatase inhibitors. Adverse reactions leading to VERZENIO dose interruptions in ≥5% of patients were diarrhea (20%), neutropenia (16%), leukopenia (7%), and fatigue (5%).

Dose reductions of VERZENIO due to an adverse reaction occurred in 44% of patients receiving VERZENIO plus endocrine therapy (tamoxifen or an aromatase inhibitor). Adverse reactions leading to VERZENIO dose reductions in ≥5% were diarrhea (17%), neutropenia (8%), and fatigue (5%).

The most common adverse reactions reported (≥20%) in the VERZENIO, plus tamoxifen or an aromatase inhibitor, arm and ≥2% higher than the tamoxifen or an aromatase inhibitor arm were: diarrhea, infections, neutropenia, fatigue, leukopenia, nausea, anemia, and headache. Adverse reactions are shown in Table 8 and laboratory abnormalities are shown in Table 9.

Table 8: Adverse Reactions (≥10%) of Patients Receiving VERZENIO Plus Tamoxifen or an Aromatase Inhibitor [with a Difference between Arms of ≥2%] in monarchE

VERZENIO Plus
Tamoxifen or an Aromatase                 Tamoxifen or an Aromatase
Inhibitor                                 Inhibitor
N=2791                                    N=2800
All Gradesa      Grade 3      Grade 4     All Gradesb      Grade 3      Grade 4 %             %            %              %             %            % Gastrointestinal Disorders
Diarrhea                                        84              8           0              9            0.2            0 Nausea                                          30             0.5          0              9            <0.1           0 Vomiting                                        18             0.5          0             4.6           0.1            0 Stomatitisc                                     14             0.1          0              5              0            0 Infections and Infestations
Infectionsd                                     51             4.9         0.6            39            2.7           0.1 General Disorders and Administration Site Conditions
Fatiguee                                        41             2.9          0             18            0.1            0 Nervous System Disorders
Headache                                        20             0.3          0             15            0.2            0 Dizziness                                       11             0.1          0              7            <0.1           0 Metabolism and Nutrition Disorders
Decreased appetite                              12             0.6          0             2.4           <0.1           0 Skin and Subcutaneous Tissue Disorders


Rashf                                       11            0.4          0            4.5            0            0 Alopecia                                    11             0           0            2.7            0            0 a    Includes the following fatal adverse reactions: diarrhea (n=1), and infections (n=4) b    Includes the following fatal adverse reactions: infections (n=5) c    Includes mouth ulceration, mucosal inflammation, oropharyngeal pain, stomatitis.
d    Includes all reported preferred terms that are part of the Infections and Infestations system organ class. Most common infections (>5%) include upper respiratory tract infection, urinary tract infection, and nasopharyngitis.
e    Includes asthenia, fatigue.
f    Includes exfoliative rash, mucocutaneous rash, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash maculovesicular, rash morbilliform, rash papular, rash papulosquamous, rash pruritic, rash vesicular, vulvovaginal rash.

Clinically relevant adverse reactions in <10% of patients who received VERZENIO in combination with tamoxifen or an aromatase inhibitor in monarchE include:
• Pruritus-9%
• Dyspepsia-8%
• Nail disorder-6% (includes nail bed disorder, nail bed inflammation, nail discoloration, nail disorder, nail dystrophy, nail pigmentation, nail ridging, nail toxicity, onychalgia, onychoclasis, onycholysis, onychomadesis)
• Lacrimation increased-6%
• Dysgeusia-5%
• Interstitial lung disease (ILD)/pneumonitis-3% (includes pneumonitis, radiation pneumonitis, interstitial lung disease, pulmonary fibrosis, organizing pneumonia, radiation fibrosis – lung, lung opacity, sarcoidosis)
• Venous thromboembolic events (VTEs)-3% (includes catheter site thrombosis, cerebral venous thrombosis, deep vein thrombosis, device related thrombosis, embolism, hepatic vein thrombosis, jugular vein occlusion, jugular vein thrombosis, ovarian vein thrombosis, portal vein thrombosis, pulmonary embolism, subclavian vein thrombosis, venous thrombosis limb)


Table 9: Laboratory Abnormalities (≥10%) in Patients Receiving VERZENIO Plus Tamoxifen or an Aromatase Inhibitor [with a Difference between Arms of ≥2%] in monarchE

VERZENIO
Plus Tamoxifen or an Aromatase            Tamoxifen or an Aromatase
Inhibitor                              Inhibitor
N=2791                                 N=2800
All Grades    Grade 3      Grade 4     All Grades     Grade 3      Grade 4 %          %            %              %           %            %
Creatinine increased                            99           0.5          0             91          <0.1          0 White blood cell decreased                      89           19          <0.1           28           1.1          0 Neutrophil count decreased                      84           18          0.7            23           1.6         0.3 Anemia                                          68           1.0          0             17           0.1          0 Lymphocyte count decreased                      59           13          0.2            24           2.4         0.1 Platelet count decreased                        37           0.7         0.2            10           0.1         0.1 Alanine aminotransferase increased              37           2.5         <0.1           24           1.2          0 Aspartate aminotransferase increased            31           1.5         <0.1           18           0.9          0 Hypokalemia                                     11           1.2         0.1           3.8           0.1         0.1 


Advanced or Metastatic Breast Cancer

MONARCH 3: VERZENIO in Combination with a Non-steroidal Aromatase Inhibitor (Anastrozole or Letrozole) as Initial Endocrine-Based Therapy
Postmenopausal Women with HR-positive, HER2-negative locoregionally recurrent or metastatic breast cancer with no prior systemic therapy in this disease setting

The safety of VERZENIO was evaluated in MONARCH 3, a study of 488 women receiving VERZENIO plus a non- steroidal aromatase inhibitor or placebo plus an aromatase inhibitor [see Clinical Studies (14.2)]. Patients were randomly assigned to receive 150 mg of VERZENIO or placebo orally twice daily, plus physician’s choice of anastrozole or letrozole once daily. Median duration of treatment was 15.1 months for the VERZENIO arm and 13.9 months for the placebo arm.

The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, diarrhea, leukopenia, increased ALT, and anemia.

Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 11 cases (3%) of VERZENIO plus a non-steroidal aromatase inhibitor treated patients versus 3 cases (2%) of placebo plus a non-steroidal aromatase inhibitor treated patients. Causes of death for patients receiving VERZENIO plus a non-steroidal aromatase inhibitor included: 3 (0.9%) patient deaths due to underlying disease, 3 (0.9%) due to lung infection, 3 (0.9%) due to VTE, 1 (0.3%) due to pneumonitis, and 1 (0.3%) due to cerebral infarction.

Permanent treatment discontinuation due to an adverse reaction was reported in 13% of patients receiving VERZENIO plus a non-steroidal aromatase inhibitor and in 3% of patients receiving placebo plus a non-steroidal aromatase inhibitor.
Adverse reactions leading to permanent discontinuation for patients receiving VERZENIO plus a non-steroidal aromatase inhibitor were diarrhea (2%), ALT increased (2%), infection (1%), venous thromboembolic events (VTE) (1%), neutropenia (0.9%), renal impairment (0.9%), AST increased (0.6%), dyspnea (0.6%), pulmonary fibrosis (0.6%) and anemia, rash, weight decreased and thrombocytopenia (each 0.3%).

Dose interruption of VERZENIO due to an adverse reaction occurred in 56% of patients receiving VERZENIO plus anastrazole or letrozole. Adverse reactions leading to VERZENIO dose interruptions in ≥5% of patients were neutropenia (16%) and diarrhea (15%).

Dose reductions due to an adverse reaction occurred in 43% of patients receiving VERZENIO plus anastrozole or letrozole. Adverse reactions leading to dose reductions in ≥5% of patients were diarrhea and neutropenia. VERZENIO dose reductions due to diarrhea of any grade occurred in 13% of patients receiving VERZENIO plus a non-steroidal aromatase inhibitor compared to 2% of patients receiving placebo plus a non-steroidal aromatase inhibitor. VERZENIO dose reductions due to neutropenia of any grade occurred in 11% of patients receiving VERZENIO plus a non-steroidal aromatase inhibitor compared to 0.6% of patients receiving placebo plus a non-steroidal aromatase inhibitor.

The most common adverse reactions reported (≥20%) in the VERZENIO arm and ≥2% than the placebo arm were: diarrhea, neutropenia, fatigue, infections, nausea, abdominal pain, anemia, vomiting, alopecia, decreased appetite, and leukopenia. Adverse reactions are shown in Table 10 and laboratory abnormalities in Table 11. Diarrhea incidence was greatest during the first month of VERZENIO dosing.
The median time to onset of the first diarrhea event was 8 days, and the median durations of diarrhea for Grades 2 and for Grade 3 were 11 days and 8 days, respectively. Most diarrhea events recovered or resolved (88%) with supportive treatment and/or dose reductions [see Dosage and Administration (3.2)].
Nineteen percent of patients with diarrhea required a dose omission and 13% required a dose reduction. The median time to the first dose reduction due to diarrhea was 38 days.



Table 10: Adverse Reactions (≥10%) in Patients Receiving VERZENIO Plus Anastrozole or Letrozole [with a Difference between Arms of ≥2%] in MONARCH 3

VERZENIO plus                              Placebo plus
Anastrozole or Letrozole                 Anastrozole or Letrozole
N=327                                    N=161
All Grades    Grade 3    Grade 4         All Grades Grade 3       Grade 4 %           %          %                 %           %          %
Gastrointestinal Disorders
Diarrhea                                           81             9            0            30           1.2            0 Nausea                                           39            0.9           0            20           1.2            0 Abdominal pain                                   29            1.2           0            12           1.2            0 Vomiting                                         28            1.2           0            12           1.9            0 Constipation                                     16            0.6           0            12            0             0 Infections and Infestations
Infectionsa                                      39            4.0          0.9           29           2.5            0.6 General Disorders and Administration Site Conditions
Fatigue                                    40                    1.8           0            32            0             0 Influenza like illness                            10             0            0            8             0             0 Skin and Subcutaneous Tissue Disorders
Alopecia                                          27             0            0            11            0             0 Rash                                             14            0.9           0            5             0             0 Pruritus                                          13             0            0            9             0             0 Metabolism and Nutrition Disorders
Decreased appetite                                24            1.2           0            9            0.6            0 Investigations
Weight decreased                                  10            0.6           0           3.1           0.6            0 Respiratory, Thoracic, and Mediastinal Disorders
Cough                                      13                    0            0            9             0             0 Dyspnea                                          12            0.6          0.3           6            0.6            0 Nervous System Disorders
Dizziness                                           11            0.3           0            9            0          0 a
Includes all reported preferred terms that are part of the Infections and Infestations system organ class. Most common infections (>1%) include upper respiratory tract infection, lung infection, and pharyngitis.

Additional adverse reactions in MONARCH 3 include venous thromboembolic events (deep vein thrombosis, pulmonary embolism, and pelvic venous thrombosis), which were reported in 5% of patients treated with VERZENIO plus anastrozole or letrozole as compared to 0.6% of patients treated with anastrozole or letrozole plus placebo.


Table 11: Laboratory Abnormalities (≥10%) in Patients Receiving VERZENIO Plus Anastrozole or Letrozole [with a Difference Between Arms of ≥2%] in MONARCH 3

VERZENIO plus                              Placebo plus
Anastrozole or Letrozole                 Anastrozole or Letrozole
N=327                                    N=161
All Grades       Grade 3      Grade 4     All Grades      Grade 3      Grade 4 Laboratory Abnormality
%             %            %              %            %            % 

Creatinine increased                              98           2.2           0             84            0           0 White blood cell decreased                        82            13           0             27           0.6          0 Anemia                                            82           1.6           0             28            0           0 Neutrophil count decreased                        80            19          2.9            21           2.6          0 Lymphocyte count decreased                        53            7           0.6            26           1.9          0 Platelet count decreased                          36           1.3          0.6            12           0.6          0 Alanine aminotransferase increased                48            6           0.6            25           1.9          0 Aspartate aminotransferase increased              37           3.8           0             23           0.6          0 
Creatinine Increased
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function [see Clinical Pharmacology (12.3)]. Across the clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of VERZENIO dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated GFR, which are not based on creatinine, may be considered to determine whether renal function is impaired.


MONARCH 2: VERZENIO in Combination with Fulvestrant
Women with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression on or after prior adjuvant or metastatic endocrine therapy


The safety of VERZENIO (150 mg twice daily) plus fulvestrant (500 mg) versus placebo plus fulvestrant was evaluated in MONARCH 2 [see Clinical Studies (14.2)]. The data described below reflect exposure to VERZENIO in 441 patients with HR-positive, HER2-negative advanced breast cancer who received at least one dose of VERZENIO plus fulvestrant in MONARCH 2.

Median duration of treatment was 12 months for patients receiving VERZENIO plus fulvestrant and 8 months for patients receiving placebo plus fulvestrant.

The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, diarrhea, leukopenia, anemia, and infections.

Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 18 cases (4%) of VERZENIO plus fulvestrant treated patients versus 10 cases (5%) of placebo plus fulvestrant treated patients. Causes of death for patients receiving VERZENIO plus fulvestrant included: 7 (2%) patient deaths due to underlying disease, 4 (0.9%) due to sepsis, 2 (0.5%) due to pneumonitis, 2 (0.5%) due to hepatotoxicity, and one (0.2%) due to cerebral infarction.

Permanent study treatment discontinuation due to an adverse reaction were reported in 9% of patients receiving VERZENIO plus fulvestrant and in 3% of patients receiving placebo plus fulvestrant. Adverse reactions leading to permanent discontinuation for patients receiving VERZENIO plus fulvestrant were infection (2%), diarrhea (1%), hepatotoxicity (1%), fatigue (0.7%), nausea (0.2%), abdominal pain (0.2%), acute kidney injury (0.2%), and cerebral infarction (0.2%).
Dose interruption of VERZENIO due to an adverse reaction occurred in 52% of patients receiving VERZENIO plus fulvestrant. Adverse reactions leading to VERZENIO dose interruptions in ≥5% of patients were diarrhea (19%) and neutropenia (16%).

Dose reductions due to an adverse reaction occurred in 43% of patients receiving VERZENIO plus fulvestrant. Adverse reactions leading to reductions in ≥5% of patients were diarrhea and neutropenia. VERZENIO dose reductions due to diarrhea of any grade occurred in 19% of patients receiving VERZENIO plus fulvestrant compared to 0.4% of patients receiving placebo and fulvestrant. VERZENIO dose reductions due to neutropenia of any grade occurred in 10% of patients receiving VERZENIO plus fulvestrant compared to no patients receiving placebo plus fulvestrant.

The most common adverse reactions reported (≥20%) in the VERZENIO arm were: diarrhea, fatigue, neutropenia, nausea, infections, abdominal pain, anemia, leukopenia, decreased appetite, vomiting, and headache. Adverse reactions are shown in Table 12 and laboratory abnormalities in Table 13.


Table 12: Adverse Reactions (≥10%) in Patients Receiving VERZENIO Plus Fulvestrant [with a Difference Between Arms of ≥2%] in MONARCH 2

VERZENIO plus Fulvestrant                     Placebo plus Fulvestrant N=441                                          N=223
All Grades       Grade 3       Grade 4       All Grades      Grade 3       Grade 4 %             %             %                %            %             % Gastrointestinal Disorders
Diarrhea                                            86             13              0             25            0.4            0 Nausea                                              45             2.7             0             23            0.9            0 Abdominal     paina                                 35             2.5             0             16            0.9            0 Vomiting                                            26             0.9             0             10            1.8            0 Stomatitis                                          15             0.5             0             10             0             0 Infections and Infestations
Infectionsb                                         43              5            0.7             25            3.1           0.4 General Disorders and Administration Site Conditions
Fatiguec                                            46             2.7             0             32            0.4            0 Edema peripheral                                    12              0              0             7              0             0 Pyrexia                                             11             0.5           0.2             6             0.4            0 Metabolism and Nutrition Disorders
Decreased appetite                                  27             1.1             0             12            0.4            0 Respiratory, Thoracic and Mediastinal Disorders
Cough                                               13              0              0             11             0             0 Skin and Subcutaneous Tissue Disorders
Alopecia                                            16              0              0            1.8             0             0 Pruritus                                            13              0              0             6              0             0 Rash                                                11             1.1             0            4.5             0             0 Nervous System Disorders
Headache                                            20             0.7             0             15            0.4            0 Dysgeusia                                           18              0              0            2.7             0             0 Dizziness                                           12             0.7             0             6              0             0 Investigations
Weight decreased                                    10             0.2             0            2.2            0.4            0 a
Includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, abdominal tenderness.
b
Includes upper respiratory tract infection, urinary tract infection, lung infection, pharyngitis, conjunctivitis, sinusitis, vaginal infection, sepsis.
c
Includes asthenia, fatigue.

Additional adverse reactions in MONARCH 2 include venous thromboembolic events (deep vein thrombosis, 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 plus fulvestrant as compared to 0.9% of patients treated with fulvestrant plus placebo.


Table 13: Laboratory Abnormalities (≥10%) in Patients Receiving VERZENIO Plus Fulvestrant [with a Difference Between Arms of ≥2%] in MONARCH 2

VERZENIO plus Fulvestrant               Placebo plus Fulvestrant
N=441                                    N=223
All Grades     Grade 3     Grade 4     All Grades     Grade 3     Grade 4 %           %           %              %           %           %
Creatinine increased                             98            1.2          0           74            0            0 White blood cell decreased                       90            23          0.7          33           0.9           0 Neutrophil count decreased                       87            29          3.5          30           3.7          0.5 Anemia                                           84            2.6          0           34           0.5           0 Lymphocyte count decreased                       63            12          0.2          32           1.8           0 Platelet count decreased                         53            0.9         1.2          15            0            0 Alanine aminotransferase increased               41            3.9         0.7          32           1.4           0 Aspartate aminotransferase increased             37            3.9          0           25           3.7          0.5 
Creatinine Increased
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function [see Clinical Pharmacology (12.3)]. In clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of VERZENIO dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated glomerular filtration rate (GFR), which are not based on creatinine, may be considered to determine whether renal function is impaired.


MONARCH 1: VERZENIO Administered as a Monotherapy in Metastatic Breast Cancer Adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy in the metastatic setting and prior 1-2 chemotherapy in the metastatic setting including taxane in adjuvant or metastatic setting.


The safety of VERZENIO was evaluated in MONARCH 1, a single-arm, open-label, multicenter study in 132 women with measurable HR-positive, HER2-negative metastatic breast cancer [see Clinical Studies (14.2)]. Patients received 200 mg VERZENIO orally twice daily until development of progressive disease or unmanageable toxicity. Median duration of treatment was 4.5 months. The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were diarrhea, neutropenia, fatigue, and leukopenia.

Deaths due to adverse reactions during treatment or during the 30-day follow up were reported in 2% of patients. Cause of death in these patients was due to infection (2 patients) or pneumonitis (1 patient).

Ten patients (8%) discontinued study treatment from adverse reactions due to (1 patient each), abdominal pain, arterial thrombosis, aspartate aminotransferase (AST) increased, blood creatinine increased, chronic kidney disease, diarrhea, ECG QT prolonged, fatigue, hip fracture, and lymphopenia.



Dose interruption of VERZENIO due to an adverse reaction occurred in 58% of patients. The most frequent (≥5%) adverse reactions leading to dose interruptions were diarrhea (24%), neutropenia (16%), fatigue (10%), vomiting (6%), and nausea (5%).
Forty-nine percent of patients had dose reductions due to an adverse reaction. The most frequent adverse reactions that led to dose reductions were diarrhea (20%), neutropenia (11%), and fatigue (9%).

The most common reported adverse reactions (≥20%) were diarrhea, fatigue, nausea, decreased appetite, abdominal pain, neutropenia, vomiting, infections, anemia, headache, and thrombocytopenia. Adverse reactions are shown in Table 14 and laboratory abnormalities in Table 15.
Table 14: Adverse Reactions (≥10%) of Patients in MONARCH 1

VERZENIO
N=132
All Grades                  Grade 3                     Grade 4
%                        %                           %
Gastrointestinal Disorders
Diarrhea                                    90                         20                          0 Nausea                                      64                         4.5                         0 Abdominal pain                              39                         2.3                         0 Vomiting                                    35                         1.5                         0 Constipation                                17                         0.8                         0 Dry mouth                                   14                          0                          0 Stomatitis                                  14                          0                          0 Infections and Infestations
Infections                                  31                         4.5                         0 General Disorders and Administration Site Conditions
Fatiguea                                    65                         13                          0 Pyrexia                                     11                          0                          0 Metabolism and Nutrition Disorders
Decreased appetite                          45                         3.0                         0 Dehydration                                 10                         2.3                         0 Respiratory, Thoracic and Mediastinal Disorders
Cough                                       19                          0                          0 Musculoskeletal and Connective Tissue Disorders
Arthralgia                                  15                          0                          0 Nervous System Disorders
Headache                                    20                          0                          0 Dysgeusia                                   12                          0                          0 Dizziness                                   11                          0                          0 Skin and Subcutaneous Tissue Disorders
Alopecia                                    12                          0                          0 Investigations
Weight decreased                            14                          0                          0 a
Includes asthenia, fatigue.
Table 15: Laboratory Abnormalities for Patients Receiving VERZENIO in MONARCH 1 
VERZENIO
N=132
All Grades                      Grade 3                      Grade 4
%                            %                            %
Creatinine increased                               99                             0.8                           0 White blood cell decreased                         91                             28                            0 Neutrophil count decreased                         88                             22                           4.6 Anemia                                             69                              0                            0 Lymphocyte count decreased                         42                             13                           0.8 Platelet count decreased                           41                             2.3                           0 ALT increased                                      31                             3.1                           0 AST increased                                      30                             3.8                           0 
Creatinine Increased
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function [see Clinical Pharmacology (12.3)]. In clinical studies, increases in serum creatinine (mean increase, 0.2- 0.3 mg/dL) occurred within the first 28-day cycle of VERZENIO dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated GFR, which are not based on creatinine, may be considered to determine whether renal function is impaired.

7.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of VERZENIO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Respiratory disorders: Interstitial lung disease (ILD)/pneumonitis [see Warnings and Precautions (6.3)].

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il