Adverse reactions : תופעות לוואי

4.8    Undesirable effects
Summary of the safety profile

Monotherapy

This section provides information based on all adverse reactions from clinical studies, post-marketing studies or spontaneous reports. In the pooled dataset of fulvestrant monotherapy, the most frequently reported adverse reactions were injection site reactions, asthenia, nausea, and increased hepatic enzymes (ALT, AST, ALP).

In table 1, the following frequency categories for adverse drug reactions (ADRs) were calculated based on the Faslodex 500 mg treatment group in pooled safety analyses of studies that compared Faslodex 500 mg with Faslodex 250 mg [CONFIRM (Study D6997C00002), FINDER 1 (Study D6997C00004), FINDER 2 (Study D6997C00006), and NEWEST (Study D6997C00003) studies] or from FALCON (Study D699BC00001) alone that compared Faslodex 500 mg with anastrozole 1 mg.

Where frequencies differ between the pooled safety analysis and FALCON, the highest frequency is presented. The frequencies in Table 1 were based on all reported adverse drug reactions, regardless of the investigator assessment of causality. The median duration of fulvestrant 500 mg treatment across the pooled dataset (including the studies mentioned above plus FALCON) was 6.5 months.


Tabulated list of adverse reactions
Adverse reactions listed below are classified according to frequency and System Organ Class (SOC).
Frequency groupings are defined according to the following convention: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100). Within each frequency grouping adverse reactions are reported in order of decreasing seriousness.

Table 1    Adverse Drug Reactions reported in patients treated with Faslodex monotherapy Adverse reactions by system organ class and frequency
Infections and infestations                Common                     Urinary tract infections Blood and lymphatic system disorders       Common                     Reduced platelet counte Immune system disorders                    Very Common                Hypersensitivity reactionse Uncommon                   Anaphylactic reactions
Metabolism and nutrition disorders         Common                     Anorexiaa Nervous system disorders                   Common                     Headache Vascular disorders                         Very Common                Hot flushese Common                     Venous thromboembolisma
Gastrointestinal disorders                 Very common                Nausea Common                     Vomiting, diarrhoea
Hepatobiliary disorders                    Very common                Elevated Hepatic Enzymes (ALT, AST, ALP) a
Common                     Elevated bilirubina
Uncommon                   Hepatic failurec,f, hepatitisf,
elevated gamma-GTf
Skin and subcutaneous tissue disorders     Very common                Rashe Musculoskeletal and connective tissue         Very common                  Joint and musculoskeletal paind disorders                                     Common                       Back paina Reproductive system and breast                Common                       Vaginal haemorrhagee disorders                                     Uncommon                     Vaginal Moniliasisf, Leukorrhoeaf
General disorders and administration          Very common                  Astheniaa, Injection site site conditions                                                            reactionsb Common                       Neuropathy peripherale,
sciaticae
Uncommon                     Injection site haemorrhagef,
injection site haematomaf ,
neuralgiac,f a   Includes adverse drug reactions for which the exact contribution of Faslodex cannot be assessed due to the underlying disease.
b The   term injection site reactions does not include the terms injection site haemorrhage, injection site haematoma, sciatica, neuralgia and neuropathy peripheral.
c The   event was not observed in major clinical studies (CONFIRM, FINDER 1, FINDER 2, NEWEST).
The frequency has been calculated using the upper limit of the 95% confidence interval for the point estimate. This is calculated as 3/560 (where 560 is the number of patients in the major clinical studies), which equates to a frequency category of uncommon .
d Includes:   arthralgia, and less frequently musculoskeletal pain, myalgia and pain in extremity.
e Frequency    category differs between pooled safety dataset and FALCON.
f ADR   was not observed in FALCON.

Description of selected adverse reactions
The descriptions included below are based on the safety analysis set of 228 patients who received at least one (1) dose of fulvestrant and 232 patients who received at least one (1) dose of anastrozole, respectively in the Phase 3 FALCON study.


Joint and musculoskeletal pain
In the FALCON study, the number of patients who reported an adverse reaction of joint and musculoskeletal pain was 65 (31.2%) and 48 (24.1%) for fulvestrant and anastrozole arms, respectively. Of the 65 patients in the Faslodex arm, 40% (26/65) of patients reported joint and musculoskeletal pain within the first month of treatment, and 66.2% (43/65) of patients within the first 3 months of treatment. No patients reported events that were CTCAE Grade ≥3 or that required a dose reduction, dose interruption, or discontinued treatment due to these adverse reactions.


Combination therapy

Combination Therapy with Palbociclib (PALOMA-3)
The safety of FASLODEX 500 mg plus palbociclib 125 mg/day versus FASLODEX plus placebo was evaluated in PALOMA-3. The data described below reflect exposure to FASLODEX plus palbociclib in 345 out of 517 patients with HR-positive, HER2-negative advanced or metastatic breast cancer who received at least 1 dose of treatment in PALOMA-3. The median duration of treatment for FASLODEX plus palbociclib was 10.8 months while the median duration of treatment for FASLODEX plus placebo arm was 4.8 months.


No dose reduction was allowed for FASLODEX in PALOMA-3. Dose reductions of palbociclib due to an adverse reaction of any grade occurred in 36% of patients receiving FASLODEX plus palbociclib.


Permanent discontinuation associated with an adverse reaction occurred in 19 of 345 (6%) patients receiving FASLODEX plus palbociclib, and in 6 of 172 (3%) patients receiving FASLODEX plus placebo. Adverse reactions leading to discontinuation for those patients receiving FASLODEX plus palbociclib included fatigue (0.6%), infections (0.6%), and thrombocytopenia (0.6%).


The most common adverse reactions (≥10%) of any grade reported in patients in the FASLODEX plus palbociclib arm by descending frequency were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, diarrhea, thrombocytopenia, vomiting, alopecia, rash, decreased appetite, and pyrexia.


The most frequently reported Grade >3 adverse reactions (≥5%) in patients receiving FASLODEX plus palbociclib in descending frequency were neutropenia (1%), and leukopenia.
Adverse reactions (≥10%) reported in patients who received FASLODEX plus palbociclib or FASLODEX plus placebo in PALOMA-3 are listed in Table 2, and laboratory abnormalities are listed in Table 3.


Table 2: Adverse Reaction (≥10%) in PALOMA-3
Adverse                FASLODEX plus palbociclib                FASLODEX plus placebo (N=172) Reactions              (N=345)
All          Grade 3       Grade4        All           Grade 3      Grade 4 Grades                                   Grades

%            %             %             %             %            % Infections and infestations
Infections1            472          3             1             31            3            0 Blood and lymphatic system
disorders
Neutropenia                   83             55             11              4              1                0 Leukopenia                    53             30              1              5              1               1 Anemia                        30             4               0             13              2               0 Thrombocytopenia              23             2               1              0              0               0 Metabolism and nutrition disorders
Decreased                     16             1               0              8              1               0 appetite
Gastrointestinal disorders
Nausea                        34             0               0             28              1               0 Stomatitis3                   28             1               0             13              0               0 Diarrhea                      24             0               0             19              1               0 Vomiting                      19             1               0             15              1               0 Skin and subcutaneous tissue disorders
Alopecia                     184            N/A            N/A             65            N/A               N/A Rash6                         17             1               0              6              0               0 General disorders and administration site conditions
Fatigue                       41             2               0             29              1               0 Pyrexia                       13             <1              0              5              0               0 Grading according to CTCAE 4.0.
CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable.
1. Infections includes all reported preferred terms (PTs) that are part of the System Organ Class Infections and infestations.
2. Most common infections (>1%) include: nasopharyngitis, upper respiratory infection, urinary tract infection, influenza, bronchitis, rhinitis, conjunctivitis, pneumonia, sinusitis, cystitis, oral herpes, respiratory tract infection, gastroenteritis, tooth infection, pharyngitis, eye infection, herpes simplex, paronychia.
3. Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, stomatitis.
4. Grade 1 events – 17%; Grade 2 events – 1%.
5. Grade 1 events – 6%.
6. Rash includes: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis acneiform, toxic skin eruption.

Additional adverse reactions occurring at an overall incidence of <10.0% of patients receiving 
FASLODEX       plus   palbociclib   in    PALOMA-3    included   asthenia   (7.5%),       aspartate  aminotransferase increased (7.5%), dysgeusia (6.7%), epistaxis (6.7%), lacrimation  increased (6.4%), dry skin (6.1%), alanine aminotransferase increased (5.8%), vision blurred 
(5.8%), dry eye (3.8%), and febrile neutropenia (0.9%).



Table 3: Laboratory Abnormalities in PALOMA-3
Laboratory            FASLODEX plus palbociclib (N=345)          FASLODEX plus placebo (N=172) Parameters            All Grades         Grade 3     Grade 4     All Grades     Grade 3           Grade 4 %               %            %            %                %               % WBC decreased             99               45           1            26               0               1 Neutrophils               96               56           11           14               0               1 decreased
Anemia                    78                 3          0            40               2               0 Platelets                 62                 2          1            10               0               0 decreased
Aspartate                43                 4          0            48               4               0 aminotransferase increased
Alanine                  36                 2          0            34               0               0 aminotransferase increased
N=number of patients; WBC=white blood cells.
Combination Therapy with Abemaciclib (MONARCH 2)

The safety of FASLODEX (500 mg) plus abemaciclib (150 mg twice daily) versus FASLODEX plus placebo was evaluated in MONARCH 2. The data described below reflect exposure to FASLODEX in 664 patients with HR-positive, HER2-negative advanced breast cancer who received at least one dose of FASLODEX plus abemaciclib or placebo in MONARCH 2.


Median duration of treatment was 12 months for patients receiving FASLODEX plus abemaciclib and 8 months for patients receiving FASLODEX plus placebo.
Dose reductions due to an adverse reaction occurred in 43% of patients receiving FASLODEX plus abemaciclib. Adverse reactions leading to dose reductions ≥5% of patients were diarrhea and neutropenia. Abemaciclib dose reduction due to diarrhea of any grade occurred in 19% of patients receiving FASLODEX plus abemaciclib compared to 0.4% of patients receiving FASLODEX plus placebo. Abemaciclib dose reductions due to neutropenia of any grade occurred in 10% of patients receiving FASLODEX plus abemaciclib compared to no patients receiving FASLODEX plus placebo.


Permanent study treatment discontinuation due to an adverse event was reported in 9% of patients receiving FASLODEX plus abemaciclib and in 3% of patients receiving FASLODEX plus placebo.
Adverse reactions leading to permanent discontinuation for patients receiving FASLODEX plus abemaciclib 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%).


Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 18 cases (4%) of FASLODEX plus abemaciclib treated patients versus 10 cases (5%) of FASLODEX plus placebo treated patients. Causes of death for patients receiving FASLODEX plus abemaciclib 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.


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


Table 4: Adverse Reactions ≥10% of Patients Receiving FASLODEX Plus Abemaciclib and ≥2% Higher Than FASLODEX Plus Placebo in MONARCH 2


Adverse Reactions                  FASLODEX plus Abemaciclib              FASLODEX plus Placebo N=441                                  N=223
All Grades    Grade 3    Grade 4     All Grades     Grade 3   Grade 4 %           %          %              %             %       %
Gastrointestinal Disorders
Diarrhea                             86           13          0             25         <1          0 Nausea                               45           3           0             23            1        0 Abdominal pain1                      35           2           0             16            1        0 Vomiting                             26           <1          0             10            2        0 Stomatitis                           15           <1          0             10            0        0 Infections and Infestations
Infections2                          43           5          <1             25            3       <1 Blood and Lymphatic System Disorders
Neutropenia3                                 46          24           3              4             1           <1 Anemia4                                      29           7           <1             4             1            0 Leukopenia5                                  28           9           <1             2             0            0 Thrombocytopenia6                            16           2           1              3             0           <1 General Disorders and Administration Site Conditions
Fatigue7                                     46           3           0             32            <1            0 Edema peripheral                             12           0           0              7             0            0 Pyrexia                                      11          <1           <1             6            <1            0 Metabolism and Nutrition Disorders
Decreased appetite                           27           1           0             12            <1            0 Respiratory, Thoracic, and Mediastinal Disorders
Cough                                        13           0           0             11             0            0 Skin and Subcutaneous Tissue Disorders
Alopecia                                     16           0           0              2             0            0 Pruritus                                     13           0           0              6             0            0 Rash                                         11           1           0              4             0            0 Nervous System Disorders
Headache                                     20           1           0             15            <1            0 Dysgeusia                                    18           0           0              3             0            0 Dizziness                                    12           1           0              6             0            0 Investigations


Alanine aminotransferase increased                                    13           4           <1             5             2            0 

Aspartate aminotransferase increased                                    12           2           0              7             3            0 

Creatinine increased
12          <1           0             <1             0            0
Weight decreased
10          <1           0              2            <1            0


1.   Includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, abdominal tenderness.
2.   Includes upper respiratory tract infection, urinary tract infection, lung infection, pharyngitis, conjunctivitis,
sinusitis, vaginal infection, sepsis.
3.   Includes neutropenia, neutrophil count decreased.
4.   Includes anemia, hematocrit decreased, hemoglobin decreased, red blood cell count decreased.
5.   Includes leukopenia, white blood cell count decreased.
6.   Includes platelet count decreased, thrombocytopenia.
7.   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 FASLODEX plus abemaciclib as compared to 0.9% of patients treated with FASLODEX plus placebo.


Table 5: Laboratory Abnormalities ≥10% in Patients Receiving FASLODEX Plus Abemaciclib and ≥2% Higher Than FASLODEX Plus Placebo in MONARCH 2


Laboratory Parameters                    Fulvestrant plus Abemaciclib         Fulvestrant plus Placebo N=441                               N=223
All Grades     Grade 3    Grade 4   All Grades    Grade 3        Grade 4 %              %          %         %             %              %
Creatinine increased                      98             1         0          74            0             0 White blood cell decreased                90             23        <1         33           <1             0 Neutrophil count decreased                87             29        4          30            4             <1 Anemia                                    84             3         0          33           <1             0 Lymphocyte count decreased                63             12        <1         32            2             0 Platelet count decreased                  53             <1        1          15            0             0 Alanine aminotransferase                  41             4         <1         32            1             0 increased
Aspartate aminotransferase                37             4         0          25            4             <1 increased


Combination Therapy with Ribociclib (MONALEESA-3)
The safety of FASLODEX 500 mg plus ribociclib 600 mg versus FASLODEX plus placebo was evaluated in MONALEESA-3. The data described below reflect exposure to FASLODEX plus ribociclib in 483 out of 724 postmenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy or after disease progression on endocrine therapy who received at least one dose of FASLODEX plus ribociclib or placebo in MONALEESA-3. Median duration of treatment was 15.8 months for FASLODEX plus ribociclib and 12 months for FASLODEX plus placebo.
Dose reductions due to adverse reactions occurred in 32% of patients receiving FASLODEX plus ribociclib and in 3% of patients receiving FASLODEX plus placebo. Among patients receiving FASLODEX plus ribociclib, 8% were reported to have permanently discontinued both FASLODEX plus ribociclib, and 9% were reported to have discontinued ribociclib alone due to ARs. Among patients receiving FASLODEX plus placebo, 4% were reported to have permanently discontinued both FASLODEX and placebo and 2% were reported to have discontinued placebo alone due to ARs.

Adverse reactions leading to treatment discontinuation of FASLODEX plus ribociclib (as compared to FASLODEX plus placebo) were ALT increased (5% vs. 0%), AST increased (3% vs. 0.6%), and vomiting (1% vs. 0%).

The most common adverse reactions (reported at a frequency ≥20% on the FASLODEX plus ribociclib arm and ≥2% higher than FASLODEX plus placebo) were neutropenia, infections, leukopenia, cough, nausea, diarrhea, vomiting, constipation, pruritus, and rash. The most frequently reported Grade 3/4 adverse reactions (reported at a frequency ≥5%) in patients receiving FASLODEX plus ribociclib in descending frequency were neutropenia, leukopenia, infections, and abnormal liver function tests.
Adverse reactions and laboratory abnormalities occurring in patients in MONALEESA-3 are listed in Table 6 and Table 7, respectively.


Table 6: Adverse Reactions Occurring in ≥10% and ≥2% higher than FASLODEX plus Placebo Arm in MONALEESA-3 (All Grades)


Arm in MONALEESA-3                 FASLODEX plus Ribociclib            FASLODEX plus Placebo (All Grades)                                  N=483                             N=241 Adverse Reactions                All Grades   Grade 3   Grade 4    All Grades    Grade 3     Grade 4 %           %        %            %            %           %
Infections and Infestations
Infections1                         42           5        0            30           2           0 Blood and Lymphatic System Disorders
Neutropenia                         69           46       7            2            0           0 Leukopenia                          27           12       <1           <1           0           0 Anemia                              17           3        0            5            2           0 Metabolism and Nutrition Disorders
Decreased appetite                  16           <1       0            13           0           0 Nervous System Disorders
Dizziness                           13           <1       0            8            0           0 Respiratory, Thoracic, and Mediastinal Disorders
Cough                               22           0        0            15           0           0 Dyspnea                                15            1           <1           12             2             0 Gastrointestinal Disorders
Nausea                                 45            1           0            28             <1            0 Diarrhea                               29            <1          0            20             <1            0 Vomiting                               27            1           0            13             0             0 Constipation                           25            <1          0            12             0             0 Abdominal pain                         17            1           0            13             <1            0 Skin and Subcutaneous Tissue Disorders
Alopecia                               19            0           0             5             0             0 Pruritus                               20            <1          0             7             0             0 Rash                                   23            <1          0             7             0             0 General Disorders and Administration Site Conditions
Edema peripheral                       15            0           0             7             0             0 Pyrexia                                11            <1          0             7             0             0 Investigations
Alanine aminotransferase
15            7           2             5             <1            0 increased
Aspartate aminotransferase                       13            5           1             5             <1            0 increased
Grading according to CTCAE 4.03. CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients
1   Infections; urinary tract infections; respiratory tract infections; gastroenteritis; sepsis (<1%).


Additional adverse reactions in MONALEESA-3 for patients receiving FASLODEX plus ribociclib included asthenia (14%), dyspepsia (10%), thrombocytopenia (9%), dry skin (8%), dysgeusia (7%), electrocardiogram QT prolonged (6%), dry mouth (5%), vertigo (5%), dry eye (5%), lacrimation increased (4%), erythema (4%), hypocalcemia (4%), blood bilirubin increased (1%), and syncope (1%).


Table 7: Laboratory Abnormalities Occurring in ≥10% of Patients in MONALEESA-3 

FASLODEX plus Ribociclib N=483           FASLODEX plus Placebo N=241
Laboratory parameters              All Grades      Grade 3     Grade 4      All Grades     Grade 3       Grade 4 %                  %            %               %             %         % Hematology
Leukocyte count decreased               95            25          <1               26         <1           0 Neutrophil count decreased              92            46             7             21         <1           0 Hemoglobin decreased                60          4           0           35            3          0 Lymphocyte count                    69                                  35 14           1                         4         <1 decreased
Platelet count decreased            33         <1           1           11            0          0 Chemistry
Creatinine increased                65         <1          <1           33           <1          0 Gamma-glutamyl                      52          6           1           49            8          2 transferase increased
Aspartate aminotransferase          49          5           2           43            3          0 increased
Alanine aminotransferase            44          8           3           37            2          0 increased
Glucose serum decreased             23          0           0           18            0          0 Phosphorous decreased               18          5           0            8           <1          0 Albumin decreased                   12          0           0            8            0          0 


Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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