KISQALI FEMARA CO-PACK SIDE EFFECTS
SIDE EFFECTS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Interstitial Lung Disease/Pneumonitis
- Severe Cutaneous Adverse Reactions
- QT Interval Prolongation
- Hepatobiliary Toxicity
- Neutropenia
Clinical Trials 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.
MONALEESA-2: KISQALI In Combination With Letrozole
Postmenopausal Women with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy
The safety data reported below are based on MONALEESA-2, a clinical study of 668 postmenopausal women receiving KISQALI plus letrozole or placebo plus letrozole. The median duration of exposure to KISQALI plus letrozole was 13 months with 58% of patients exposed for ≥ 12 months.
Dose reductions due to adverse reactions (ARs) occurred in 45% of patients receiving KISQALI plus letrozole and in 3% of patients receiving placebo plus letrozole. Among patients receiving KISQALI plus letrozole, 7% were reported to have permanently discontinued both KISQALI and letrozole, and 7% were reported to have permanently discontinued KISQALI alone due to ARs. Among patients receiving placebo plus letrozole, 2% were reported to have permanently discontinued both, and 0.9% were reported to have permanently discontinued placebo alone due to ARs. Adverse reactions leading to treatment discontinuation of both KISQALI and letrozole in patients receiving KISQALI plus letrozole were ALT increased (4%), AST increased (3%), and vomiting (2%). Antiemetics and anti-diarrhea medications were used to manage symptoms as clinically indicated.
On-treatment deaths, regardless of causality, were reported in three cases (0.9%) of KISQALI plus letrozole treated patients vs. one case (0.3%) of placebo plus letrozole treated patients. Causes of death on KISQALI plus letrozole included one case each of the following: progressive disease, death (cause unknown), and sudden death (in the setting of Grade 3 hypokalemia and Grade 2 QT prolongation).
The most common ARs (reported at a frequency ≥ 20% on the KISQALI arm and ≥ 2% higher than placebo) were neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, and back pain.
The most common Grade 3/4 ARs (reported at a frequency ≥ 5%) were neutropenia, leukopenia, abnormal liver function tests, and lymphopenia.
In MONALEESA-2, syncope occurred in 9 patients (3%) in the KISQALI plus letrozole arm vs. 3 (1%) in placebo plus letrozole arm.
Adverse Reactions and laboratory abnormalities occurring in patients in MONALEESA-2 are listed in Table 8 and Table 1, respectively.
Table 1: Adverse Reactions Occurring in ≥ 10% and ≥ 2% Higher Than Placebo Arm in MONALEESA-2 (All Grades)
| Adverse Drug Reactions | KISQALI + letrozole N=334 |
Placebo + letrozole N=330 |
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| All Grades % | Grade 3 % | Grade 4 % | All Grades % | Grade 3 % | Grade 4 % | |
| Infections and Infestations | ||||||
| Urinary tract infection | 11 | 1 | 0 | 8 | 0 | 0 |
| Blood and Lymphatic System Disorders | ||||||
| Neutropenia | 75 | 50 | 10 | 5 | 1 | 0 |
| Leukopenia | 33 | 20 | 1 | 1 | <1 | 0 |
| Anemia | 18 | 1 | <1 | 5 | 1 | 0 |
| Lymphopenia | 11 | 0 | 1 | 2 | 1 | 0 |
| Metabolism and Nutrition Disorders | ||||||
| Decreased appetite | 19 | 2 | 0 | 15 | <1 | 0 |
| Nervous System Disorders | ||||||
| Headache | 22 | <1 | 0 | 19 | <1 | 0 |
| Insomnia | 12 | <1 | 0 | 9 | 0 | 0 |
| Respiratory, Thoracic and Mediastinal Disorders | ||||||
| Dyspnea | 12 | 1 | 0 | 9 | 1 | 0 |
| Musculoskeletal and Connective Tissue Disorders | ||||||
| Back pain | 20 | 2 | 0 | 18 | <1 | 0 |
| Gastrointestinal Disorders | ||||||
| Nausea | 52 | 2 | 0 | 29 | 1 | 0 |
| Diarrhea | 35 | 1 | 0 | 22 | 1 | 0 |
| Vomiting | 29 | 4 | 0 | 16 | 1 | 0 |
| Constipation | 25 | 1 | 0 | 19 | 0 | 0 |
| Stomatitis | 12 | <1 | 0 | 7 | 0 | 0 |
| Abdominal pain | 11 | 1 | 0 | 8 | 0 | 0 |
| Skin and Subcutaneous Tissue Disorders | ||||||
| Alopecia | 33 | 0 | 0 | 16 | 0 | 0 |
| Rash | 17 | 1 | 0 | 8 | 0 | 0 |
| Pruritus | 14 | 1 | 0 | 6 | 0 | 0 |
| General Disorders and Administration-site Conditions | ||||||
| Fatigue | 37 | 2 | <1 | 30 | 1 | 0 |
| Pyrexia | 13 | <1 | 0 | 6 | 0 | 0 |
| Edema peripheral | 12 | 0 | 0 | 10 | 0 | 0 |
| Investigations | ||||||
| Abnormal liver function tests1 | 18 | 8 | 2 | 6 | 2 | 0 |
| Grading according to Common Terminology Criteria for Adverse Event (CTCAE) version 4.03. 1Abnormal liver function tests: ALT increased, AST increased, blood bilirubin increased. |
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Additional adverse reactions in MONALEESA-2 for patients receiving KISQALI plus letrozole included interstitial lung disease (0.3%), lung infiltration (0.3%), pneumonitis (0.3%), and pulmonary fibrosis (0.6%).
Table 2: Laboratory Abnormalities Occurring in ≥ 10% of Patients in MONALEESA-2
| Laboratory Parameters | KISQALI + letrozole N = 334 |
Placebo + letrozole N = 330 |
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| All Grades % | Grade 3 % | Grade 4 % | All Grades % | Grade 3 % | Grade 4 % | |
| HEMATOLOGY | ||||||
| Leukocyte count decreased | 93 | 31 | 3 | 29 | 1 | < 1 |
| Neutrophil count decreased | 93 | 49 | 11 | 24 | 1 | < 1 |
| Hemoglobin decreased | 57 | 2 | 0 | 26 | 1 | 0 |
| Lymphocyte count decreased | 51 | 12 | 2 | 22 | 3 | 1 |
| Platelet count decreased | 29 | 1 | < 1 | 6 | 0 | < 1 |
| CHEMISTRY | ||||||
| Alanine aminotransferase increased | 46 | 8 | 36 | 36 | 1 | 0 |
| Aspartate aminotransferase increased | 44 | 6 | 32 | 32 | 2 | 0 |
| Creatinine increased | 20 | 1 | 6 | 6 | 0 | 0 |
| Phosphorous decreased | 13 | 5 | 4 | 4 | 1 | 0 |
| Potassium decreased | 11 | 1 | 7 | 7 | 1 | 0 |
Adverse Reactions listed are based on the data of KISQALI in combination with letrozole (FEMARA). For the complete list of known ARs with KISQALI or FEMARA, see the Full Prescribing Information of KISQALI or FEMARA.
Bone Effects
In MONALEESA-2, with a median duration of safety follow-up of 20.1 months, 12 patients (4%) in the ribociclib plus letrozole arm and 18 patients (6%) in the placebo plus letrozole arm experienced fractures. Osteoporosis (all Grades) was experienced in three patients (0.9%) in the ribociclib plus letrozole arm and 2 patients (0.6%) in the placebo plus letrozole arm.
MONALEESA-7: KISQALI In Combination With An Aromatase Inhibitor
Pre/perimenopausal Patients with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy
MONALEESA-7 was conducted in 672 pre/perimenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer receiving either KISQALI plus a non-steroidal aromatase inhibitors (NSAIs) or tamoxifen plus goserelin or placebo plus NSAI or tamoxifen plus goserelin. The median duration of exposure on the KISQALI arm was 15.2 months with 66% of patients exposed for ≥ 12 months. The safety data reported below are based on 495 pre/perimenopausal patients receiving KISQALI plus NSAI plus goserelin or placebo plus NSAI plus goserelin.
Dose reductions due to ARs occurred in 33% of patients receiving KISQALI plus NSAI plus goserelin and in 4% of patients receiving placebo plus NSAI plus goserelin. Among patients receiving KISQALI plus NSAI, 3% were reported to have permanently discontinued both KISQALI and NSAI and 3% were reported to have permanently discontinued KISQALI alone due to ARs. Among patients receiving placebo plus NSAI, 2% were reported to have permanently discontinued both, and 0.8% were reported to have permanently discontinued placebo alone due to ARs. Adverse reactions leading to treatment discontinuation on KISQALI in patients receiving KISQALI plus NSAI (as compared to the placebo arm) were ALT increased (2% vs. 0.8%), AST increased (2% vs. 0.8%), drug-induced liver injury (1% vs. 0.4%). One patient (0.4%) died while on treatment with KISQALI plus NSAI plus goserelin, due to the underlying malignancy.
The most common ARs (reported at a frequency ≥ 20% on the KISQALI arm and ≥ 2% higher than placebo) were neutropenia, infections, leukopenia, arthralgia, nausea, and alopecia. The most common Grade 3/4 ARs (reported at a frequency ≥ 5%) were neutropenia, leukopenia, and abnormal liver function tests. See Table 10 below.
Adverse reactions and laboratory abnormalities occurring in patients in MONALEESA-7 are listed in Table 10 and Table 3, respectively.
Table 3: Adverse Reactions Occurring in ≥ 10% and ≥ 2% Higher Than Placebo Arm in MONALEESA-7 (NSAI) (All Grades)
| Adverse Drug Reactions | KISQALI + NSAI + goserelin N=248 |
Placebo + NSAI + goserelin N=247 |
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| All Grades % | Grade 3% | Grade 4 % | All Grades % | Grade 3 % | Grade 4 % | |
| Infections and Infestations | ||||||
| Infections1 | 35 | 2 | 0 | 24 | 0 | |
| Blood and Lymphatic System Disorders | ||||||
| Neutropenia | 78 | 55 | 10 | 7 | 2 | 0 |
| Leukopenia | 29 | 13 | < 1 | 3 | < 1 | 0 |
| Anemia | 19 | 3 | 0 | 8 | 1 | 0 |
| Respiratory, Thoracic and Mediastinal Disorders | ||||||
| Cough | 15 | 0 | 0 | 10 | 0 | 0 |
| Musculoskeletal and Connective Tissue Disorders | ||||||
| Arthralgia | 33 | < 1 | 0 | 29 | 1 | 0 |
| Gastrointestinal Disorders | ||||||
| Nausea | 31 | 0 | 0 | 20 | 0 | 0 |
| Constipation | 16 | 0 | 0 | 12 | 0 | 0 |
| Stomatitis | 10 | 0 | 0 | 8 | < 1 | 0 |
| Skin and Subcutaneous Tissue Disorders | ||||||
| Alopecia | 21 | 0 | 0 | 13 | 0 | 0 |
| Rash | 17 | 0 | 9 | 0 | 0 | |
| Pruritus | 10 | 0 | 0 | 4 | 0 | 0 |
| General Disorders and Administration-site Conditions | ||||||
| Pyrexia | 17 | < 1 | 0 | 6 | 0 | 0 |
| Pain in extremity | 10 | 0 | 0 | 8 | 1 | 0 |
| Investigations | ||||||
| Alanine aminotransferase increased | 13 | 5 | 0 | 9 | 1 | 0 |
| Aspartate aminotransferase increased | 13 | 4 | 0 | 10 | 1 | 0 |
| Abbreviation: NSAI, non-steroidal aromatase inhibitor. Grading according to CTCAE Common Terminology Criteria for Adverse Events version 4.03. 1Infections: urinary tract infections; respiratory tract infections; gastroenteritis; sepsis (< 1%). |
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Additional adverse reactions in MONALEESA-7 for patients receiving KISQALI plus NSAI included asthenia (12%), thrombocytopenia (9%), dry skin (8%), oropharyngeal pain (7%), dyspepsia (5%), lacrimation increased (4%), dry eye (4%), vitiligo (3%), hypocalcemia, (2%), blood bilirubin increased (1%), syncope (0.4%), and pneumonitis (0.4%).
Table 4: Laboratory Abnormalities Occurring in ≥ 10% of Patients in MONALEESA-7
| Laboratory Parameters | KISQALI + NSAI + goserelin N=248 |
Placebo + NSAI + goserelin N=247 |
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| All Grades % | Grade 3 % | Grade 4 % | All Grades % | Grade 3 % | Grade 4 % | |
| HEMATOLOGY | ||||||
| Leukocyte count decreased | 93 | 34 | 2 | 30 | < 1 | < 1 |
| Neutrophil count decreased | 92 | 54 | 9 | 27 | 2 | 0 |
| Hemoglobin decreased | 84 | 2 | 0 | 51 | 0 | |
| Lymphocyte count decreased | 55 | 12 | 2 | 18 | 2 | < 1 |
| Platelet count decreased | 26 | < 1 | 0 | 9 | 0 | < 1 |
| CHEMISTRY | ||||||
| Alanine aminotransferase increased | 33 | 6 | 0 | 31 | 1 | < 1 |
| Aspartate aminotransferase increased | 37 | 5 | 0 | 35 | 1 | < 1 |
| Creatinine increased | 21 | 2 | < 1 | 20 | < 1 | < 1 |
| Phosphorous decreased | 14 | 2 | 0 | 11 | < 1 | < 1 |
| Potassium decreased | 11 | < 1 | < 1 | 14 | < 1 | < 1 |
| Gamma-glutamyl transferase increased | 42 | 5 | 2 | 42 | 8 | 1 |
| Glucose serum decreased | 10 | < 1 | 0 | 10 | < 1 | 0` |
Adverse Reactions listed are based on the data of KISQALI in combination with NSAI [anastrozole or letrozole (FEMARA)]. For the complete list of known ARs with KISQALI or FEMARA, see the Full Prescribing Information of KISQALI or FEMARA.
Bone Effects
In MONALEESA-7, with a median duration of safety follow-up of 26.5 months, 4 patients (2%) in the ribociclib plus NSAI subgroup and 7 patients (3%) in the placebo plus NSAI subgroup experienced fractures. No osteoporosis (all Grades) was reported in the ribociclib plus NSAI subgroup, and 1 patient (0.4%) experienced osteoporosis in the placebo plus NSAI subgroup.
COMPLEEMENT-1: KISQALI In Combination With Letrozole And Goserelin Or Leuprolide
Men with HR-positive, HER2-negative Advanced Breast Cancer for Initial Endocrine-Based Therapy
The safety of KISQALI in combination with letrozole was evaluated in men (n=39) in an open-label, multicenter clinical study for the treatment of adult patients with HR-positive, HER2-negative, advanced breast cancer who received no prior hormonal therapy for advanced disease (COMPLEEMENT-1).
The median duration of exposure to KISQALI was 20.8 months (range: 0.5 to 30.6 months).
Other adverse reactions occurring in men treated with KISQALI plus letrozole and goserelin or leuprolide were similar to those occurring in women treated with KISQALI plus endocrine therapy.
Postmarketing Experience
The following adverse events have been reported during post-approval use of KISQALI. Because these events 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/pneumonitis
Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome (SJS), Toxic epidermal necrolysis (TEN), Drug-induced hypersensitivity syndrome (DiHS)/Drug reaction with eosinophilia and systemic symptoms (DRESS).
SRC: NLM .