Kisqali Side Effects Center

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Interstitial Lung Disease/Pneumonitis [see WARNINGS AND PRECAUTIONS]
• Severe Cutaneous Adverse Reactions [see WARNINGS AND PRECAUTIONS]
• QT Interval Prolongation [see WARNINGS AND PRECAUTIONS]
• Hepatobiliary Toxicity [see WARNINGS AND PRECAUTIONS]
• Neutropenia [see WARNINGS AND PRECAUTIONS]

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 KISQALI in patients receiving KISQALI plus letrozole were ALT increased (4%), AST increased (3%), vomiting (2%). Antiemetics and antidiarrhea 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 9, respectively.

Table 8: 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
	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	6	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.

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 9: Laboratory Abnormalities Occurring in ≥ 10% of Patients in MONALEESA-2

Laboratory Parameters	KISQALI + letrozole N=334			Placebo + letrozole N=330
	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	2	36	1	0
Aspartate aminotransferase increased	44	6	1	32	2	0
Creatinine increased	20	1	0	6	0	0
Phosphorous decreased	13	5	1	4	1	0
Potassium decreased	11	1	1	7	1	0

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 NSAI 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 11, respectively.

Table 10: 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
	All Grades %	Grade 3 %	Grade 4 %	All Grades %	Grade 3 %	Grade 4 %
Infections and Infestations
Infections1	35	2	0	24	< 1	0
Blood and Lymphatic System Disorders
Neutropenia	78	55	10	7	2	< 1
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	< 1	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 Common Terminology Criteria for Adverse Event (CTCAE) version 4.03. 1Infections: urinary tract infections; respiratory tract infections; gastroenteritis; sepsis (< 1%).

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

Laboratory Parameters	KISQALI + NSAI + goserelin N=248			Placebo + NSAI + goserelin N=247
	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	< 1	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

MONALEESA-3: KISQALI In Combination With Fulvestrant

Postmenopausal Patients with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy or After Disease Progression on Endocrine Therapy

The safety data reported below are based on MONALEESA-3, a clinical study of 724 postmenopausal women receiving KISQALI plus fulvestrant or placebo plus fulvestrant. The median duration of exposure to KISQALI plus fulvestrant was 15.8 months with 58% of patients exposed for ≥ 12 months.

Dose reductions due to ARs occurred in 32% of patients receiving KISQALI plus fulvestrant and in 3% of patients receiving placebo plus fulvestrant. Among patients receiving KISQALI plus fulvestrant, 8% were reported to have permanently discontinued both KISQALI and fulvestrant and 9% were reported to have discontinued KISQALI alone due to ARs. Among patients receiving placebo plus fulvestrant, 4% were reported to have permanently discontinued both and 2% were reported to have discontinued placebo alone due to ARs. Adverse reactions leading to treatment discontinuation of KISQALI in patients receiving KISQALI plus fulvestrant (as compared to the placebo arm) were ALT increased (5% vs. 0%), AST increased (3% vs. 0.6%), and vomiting (1% vs. 0%).

On-treatment deaths, regardless of causality, were reported in seven patients (1.4%) due to the underlying malignancy and six patients (1.2%) due to other causes while on treatment with KISQALI plus fulvestrant. Causes of death included one pulmonary embolism, one acute respiratory distress syndrome, one cardiac failure, one pneumonia, one hemorrhagic shock, and one ventricular arrhythmia. Seven patients (2.9%) died due to the underlying malignancy and 1 patient (0.4%) died due to pulmonary embolism while on placebo plus fulvestrant.

The most common ARs (reported at a frequency ≥ 20% on the KISQALI arm and ≥ 2% higher than placebo) were neutropenia, infections, leukopenia, cough, nausea, diarrhea, vomiting, constipation, pruritus, and rash. The most common Grade 3/4 ARs (reported at a frequency ≥ 5%) were neutropenia, leukopenia, infections, and abnormal liver function tests. See Table 12.

Adverse reactions and laboratory abnormalities occurring in patients in MONALEESA-3 are listed in Table 12 and Table 13, respectively.

Table 12: Adverse Reactions Occurring in ≥ 10% and ≥ 2% Higher Than Placebo Arm in MONALEESA-3 (All Grades)

Adverse Drug Reactions	KISQALI + fulvestrant N = 483			Placebo + fulvestrant N = 241
	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 increased	15	7	2	5	< 1	0
Aspartate aminotransferase increased	13	5	1	5	< 1	0
Grading according to Common Terminology Criteria for Adverse Event (CTCAE) version 4.03. 1Infections: urinary tract infections; respiratory tract infections; gastroenteritis; sepsis (< 1%).

Additional adverse reactions in MONALEESA-3 for patients receiving KISQALI plus fulvestrant included asthenia (14%), dyspepsia (10%), thrombocytopenia (9%) dry skin (8%), dysgeusia (7%), dry mouth (5%), vertigo (5%), dry eye (5%), lacrimation increased (4%), erythema (4%), hypocalcemia (4%), blood bilirubin increased (1%), syncope (1%), interstitial lung disease (0.4%), pneumonitis (0.4%), hypersensitivity pneumonitis (0.2%), and acute respiratory distress syndrome (0.2%).

Table 13: Laboratory Abnormalities Occurring in ≥ 10% of Patients in MONALEESA-3

Laboratory Parameters	KISQALI + fulvestrant N=483			Placebo + fulvestrant N=241
	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 decreased	69	14	1	35	4	< 1
Platelet count decreased	33	< 1	1	11	0	0
CHEMISTRY
Creatinine increased	65	< 1	< 1	33	< 1	0
Gamma-glutamyl transferase increased	52	6	1	49	8	2
Aspartate aminotransferase increased	49	5	2	43	3	0
Alanine aminotransferase increased	44	8	3	37	2	0
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

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) [see Clinical Studies].

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)

DRUG INTERACTIONS

Drugs That May Increase Ribociclib Plasma Concentrations

CYP3A4 Inhibitors

Coadministration of a strong CYP3A4 inhibitor (ritonavir) increased ribociclib exposure in healthy subjects by 3.2-fold [see Clinical Studies]. Avoid concomitant use of strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, and voriconazole) and consider alternative concomitant medications with less potential for CYP3A inhibition.

If coadministration of KISQALI with a strong CYP3A inhibitor cannot be avoided, reduce the dose of KISQALI to 400 mg once daily [see DOSAGE AND ADMINISTRATION].

Instruct patients to avoid grapefruit or grapefruit juice, which are known to inhibit cytochrome CYP3A enzymes and may increase the exposure to ribociclib [see PATIENT INFORMATION].

Drugs That May Decrease Ribociclib Plasma Concentrations

CYP3A4 Inducers

Coadministration of a strong CYP3A4 inducer (rifampin) decreased the plasma exposure of ribociclib in healthy subjects by 89% [see Clinical Studies]. Avoid concomitant use of strong CYP3A inducers and consider an alternate concomitant medication with no or minimal potential to induce CYP3A (e.g., phenytoin, rifampin, carbamazepine, and St John’s wort (Hypericum perforatum)).

Effect Of KISQALI On Other Drugs

CYP3A Substrates With Narrow Therapeutic Index

Coadministration of midazolam (a sensitive CYP3A4 substrate) with multiple doses of KISQALI (400 mg) increased the midazolam exposure by 3.8-fold in healthy subjects, compared with administration of midazolam alone [see Clinical Studies]. KISQALI given at the clinically relevant dose of 600 mg is predicted to increase the midazolam AUC by 5.2-fold. Therefore, caution is recommended when KISQALI is administered with CYP3A substrates with a narrow therapeutic index. The dose of a sensitive CYP3A substrate with a narrow therapeutic index, including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus, may need to be reduced as ribociclib can increase their exposure.

Drugs That Prolong the QT Interval

Avoid coadministration of KISQALI with medicinal products with a known potential to prolong QT, such as antiarrhythmic medicines (including, but not limited to amiodarone, disopyramide, procainamide, quinidine, and sotalol), and other drugs that are known to prolong the QT interval (including, but not limited to, chloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil, pimozide, and ondansetron) [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Read the entire FDA prescribing information for Kisqali (Ribociclib Tablets)