IMPORTANT SAFETY INFORMATION


Interstitial lung disease/pneumonitis. Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with KISQALI and other CDK4/6 inhibitors...

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Indications. KISQALI® (ribociclib) is a kinase inhibitor indicated in combination with: an aromatase inhibitor for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, as initial endocrine-based therapy; or fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine-based therapy or following disease progression on endocrine therapy

Safety Profile

CONSISTENT AND WELL-CHARACTERIZED SAFETY PROFILES

Postmenopausal Women With KISQALI + Fulvestrant

Majority of adverse reactions were transient, manageable, and reversible1-4

  • Dose reductions due to ARs: 32% with KISQALI® (ribociclib) + fulvestrant vs 3% with placebo + fulvestrant
  • Permanent discontinuations: 8% with KISQALI + fulvestrant vs 4% with placebo + fulvestrant
  • Patients may require dose interruption, reduction, or discontinuation for adverse reactions. Monitoring should include: pulmonary symptoms, ECGs, serum electrolytes, LFTs, and CBCs. See Warnings & Precautions for risk of ILD/pneumonitis, SCARs, QT prolongation, hepatobiliary toxicity, and neutropenia
  • The most common ARs (reported at a frequency ≥20% in the KISQALI arm and ≥2% higher than placebo): neutropenia, infections, leukopenia, cough, nausea, diarrhea, vomiting, constipation, pruritus, and rash
  • Most common grade 3/4 ARs (reported at a frequency ≥5%): neutropenia, leukopenia, infections, and abnormal liver function tests

 

ADVERSE REACTIONS OCCURRING IN ≥10% AND ≥2% HIGHER THAN PLACEBO4


 
KISQALI + fulvestrant
(n=483)
Placebo + fulvestrant
(n=241)
 
Grade 3
Grade 4
ALL
 
Grade 3
Grade 4
ALL
Neutropenia
46%
7%
69%
 
0%
0%
2%
Leukopenia
12%
<1%
27%
 
0%
0%
<1%
ALT increased
7%
2%
15%
 
<1%
0%
5%
AST increased
5%
1%
13%
 
<1%
0%
5%
Infections
5%
0%
42%
 
2%
0%
30%
Anemia
3%
0%
17%
 
2%
0%
5%
Dyspnea
1%
<1%
15%
 
2%
0%
12%
Nausea
1%
0%
45%
 
<1%
0%
28%
Vomiting
1%
0%
27%
 
0%
0%
13%
Abdominal pain
1%
0%
17%
 
<1%
0%
13%
Diarrhea
<1%
0%
29%
 
<1%
0%
20%
Constipation
<1%
0%
25%
 
0%
0%
12%
Rash
<1%
0%
23%
 
0%
0%
7%
Pruritus
<1%
0%
20%
 
0%
0%
7%
Decreased appetite
<1%
0%
16%
 
0%
0%
13%
Dizziness
<1%
0%
13%
 
0%
0%
8%
Pyrexia
<1%
0%
11%
 
0%
0%
7%
Cough
0%
0%
22%
 
0%
0%
15%
Alopecia
0%
0%
19%
 
0%
0%
5%
Edema peripheral
0%
0%
15%
 
0%
0%
7%
  • Infections included urinary and respiratory tract infections, gastroenteritis, and sepsis (<1%)

LABORATORY ABNORMALITIES4


 
KISQALI + fulvestrant
(n=483)
Placebo + fulvestrant
(n=241)
 
Grade 3
Grade 4
ALL
 
Grade 3
Grade 4
ALL
HEMATOLOGY
Neutrophil
count decreased
46%
7%
92%
 
<1%
0%
21%
Leukocyte
count decreased
25%
<1%
95%
 
<1%
0%
26%
Lymphocyte
count decreased
14%
1%
69%
 
4%
<1%
35%
Hemoglobin
decreased
4%
0%
60%
 
3%
0%
35%
Platelet count
decreased
<1%
1%
33%
 
0%
0%
11%
CHEMISTRY
ALT
increased
8%
3%
44%
 
2%
0%
37%
GGT
increased
6%
1%
52%
 
8%
2%
49%
AST
increased
5%
2%
49%
 
3%
0%
43%
Phosphorus
decreased
5%
0%
18%
 
<1%
0%
8%
Creatinine
increased
<1%
<1%
65%
 
<1%
0%
33%
Glucose serum
decreased
0%
0%
23%
 
0%
0%
18%
Albumin
decreased
0%
0%
12%
 
0%
0%
8%

Premenopausal Women With KISQALI + NSAI + Goserelin

Majority of adverse reactions were transient, manageable, and reversible1-4

  • Dose reductions due to ARs: 33% for patients taking KISQALI + NSAI + goserelin vs 4% with placebo + NSAI + goserelin
  • Permanent discontinuations: 3% for patients taking KISQALI + NSAI vs 2% with placebo + NSAI
  • Patients may require dose interruption, reduction, or discontinuation for adverse reactions. Monitoring should include: pulmonary symptoms, ECGs, serum electrolytes, LFTs, and CBCs. See Warnings & Precautions for risk of ILD/pneumonitis, SCARs, QT prolongation, hepatobiliary toxicity, and neutropenia
  • The most common ARs (reported at a frequency ≥20% in the KISQALI arm and ≥2% higher than placebo): neutropenia, infections, leukopenia, arthralgia, nausea, and alopecia
  • Most common grade 3/4 ARs (reported at a frequency ≥5%): neutropenia, leukopenia, and abnormal liver function tests

 

ADVERSE REACTIONS OCCURRING IN ≥10% AND ≥2% HIGHER THAN PLACEBO4


 
KISQALI + NSAI + goserelin
(n=248)
Placebo + NSAI + goserelin
(n=247)
 
Grade 3
Grade 4
ALL
 
Grade 3
Grade 4
ALL
Neutropenia
55%
10%
78%
 
2%
<1%
7%
Leukopenia
13%
<1%
29%
 
<1%
0%
3%
ALT increased
5%
0%
13%
 
1%
0%
9%
AST increased
4%
0%
13%
 
1%
0%
10%
Anemia
3%
0%
19%
 
1%
0%
8%
Infections
2%
0%
35%
 
<1%
0%
24%
Arthralgia
<1%
0%
33%
 
1%
0%
29%
Rash
<1%
0%
17%
 
0%
0%
9%
Pyrexia
<1%
0%
17%
 
0%
0%
6%
Nausea
0%
0%
31%
 
0%
0%
20%
Alopecia
0%
0%
21%
 
0%
0%
13%
Constipation
0%
0%
16%
 
0%
0%
12%
Cough
0%
0%
15%
 
0%
0%
10%
Pain in extremity
0%
0%
10%
 
1%
0%
8%
Stomatitis
0%
0%
10%
 
<1%
0%
8%
Pruritus
0%
0%
10%
 
0%
0%
4%
  • Infections included urinary and respiratory tract infections, gastroenteritis, and sepsis (<1%)

LABORATORY ABNORMALITIES4


 
KISQALI + NSAI + goserelin
(n=248)
Placebo + NSAI + goserelin
(n=247)
 
Grade 3
Grade 4
ALL
 
Grade 3
Grade 4
ALL
HEMATOLOGY
Leukocyte
count decreased
34%
2%
93%
 
<1%
<1%
30%
Neutrophil
count decreased
54%
9%
92%
 
2%
0%
27%
Hemoglobin
decreased
2%
0%
84%
 
<1%
0%
51%
Lymphocyte
count decreased
12%
2%
55%
 
2%
<1%
18%
Platelet count
decreased
<1%
0%
26%
 
0%
<1%
9%
CHEMISTRY
ALT
increased
6%
0%
33%
 
1%
<1%
31%
AST
increased
5%
0%
37%
 
1%
<1%
35%
Creatinine
increased
2%
<1%
21%
 
<1%
<1%
20%
Phosphorus
decreased
2%
0%
14%
 
<1%
<1%
11%
Potassium
decreased
<1%
<1%
11%
 
<1%
<1%
14%
GGT
increased
5%
2%
42%
 
8%
1%
42%
Glucose serum
decreased
<1%
0%
10%
 
<1%
0%
10%

Monitoring

Get the most out of treatment with early monitoring4

SCHEDULED MONITORING4

 
Cycle 1
Cycle 2
Cycle 3-6
(28-day cycle)
CBC and LFT
Electrolytes
Baseline and mid-cycle
Beginning and mid-cycle
Beginning of each cycle
Baseline
Beginning of each cycle
3 ECGs
QTcF
Baseline and mid-cycle
Beginning
 

 

NO SCHEDULED MONITORING BEYOND CYCLE 6

 

  • For LFTs, if grade ≥2 abnormalities are noted, more frequent monitoring is recommended
  • Correct any electrolyte abnormalities prior to treatment
  • KISQALI should only be initiated in patients with QTcF <450 ms. In case of QTcF prolongation during therapy, more frequent monitoring is recommended
  • Any additional monitoring should be performed as clinically indicated

Monitoring for KISQALI may sync with the dosing schedule for fulvestrant or an LHRH agonist

 

For information about dosing and administration, continue to the next page >

ALT=alanine aminotransferase; AR=adverse reaction; AST=aspartate aminotransferase; CBC=complete blood count; ECGs=electrocardiograms; GGT=gamma-glutamyl transferase; ILD=interstitial lung disease; LFT=liver function test; LHRH=luteinizing hormone-releasing hormone; NSAI=nonsteroidal aromatase inhibitor; QTcF=QT interval corrected by Fridericia's formula.

References: 1. Tripathy D, Im S-A, Colleoni M, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018;19(7):904-915. 2. Slamon DJ, Neven P, Chia S, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol. 2018;36(24):2465-2472. 3. Data on file. Novartis Pharmaceuticals Corp; 2019. 4. Kisqali [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2020.

Indications
KISQALI is a kinase inhibitor indicated in combination with:
  • an aromatase inhibitor for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, as initial endocrine-based therapy; or
  • fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine-based therapy or following disease progression on endocrine therapy 

The KISQALI® (ribociclib) FEMARA® (letrozole) Co-Pack is indicated as initial endocrine-based therapy for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.

IMPORTANT SAFETY INFORMATION
Interstitial lung disease/pneumonitis. Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with KISQALI and other CDK4/6 inhibitors.

Across clinical trials in patients with advanced or metastatic breast cancer treated with KISQALI in combination with an aromatase inhibitor or fulvestrant (“KISQALI treatment groups”), 1.1% of KISQALI-treated patients had ILD/pneumonitis of any grade, 0.3% had grade 3 or 4, and 0.1% had a fatal outcome. Additional cases of ILD/pneumonitis have been observed in the postmarketing setting, with fatalities reported.

Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis, which may include hypoxia, cough, and dyspnea. In patients who have new or worsening respiratory symptoms suspected to be due to ILD or pneumonitis, interrupt treatment with KISQALI immediately and evaluate the patient. Permanently discontinue treatment with KISQALI in patients with recurrent symptomatic or severe ILD/pneumonitis.

Severe cutaneous adverse reactions. Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients treated with KISQALI in the postmarketing setting.

If signs or symptoms of SCARs occur, interrupt KISQALI until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended. If SCARs is confirmed, permanently discontinue KISQALI. Do not reintroduce KISQALI in patients who have experienced SCARs or other life-threatening cutaneous reactions during KISQALI treatment.

QT interval prolongation. KISQALI® (ribociclib) and the KISQALI® (ribociclib) FEMARA® (letrozole) Co-Pack have been shown to prolong the QT interval in a concentration-dependent manner. Based on the observed QT prolongation during treatment, KISQALI may require dose interruption, reduction, or discontinuation. Across clinical trials in patients with advanced or metastatic breast cancer treated with KISQALI in combination with an aromatase inhibitor or fulvestrant (“KISQALI treatment groups”), 14 of 1054 patients (1%) had >500 ms postbaseline QTcF value, and 59 of 1054 (6%) had a >60 ms increase from baseline in QTcF intervals. These ECG changes were reversible with dose interruption and most occurred within the first 4 weeks of treatment. No cases of torsades de pointes were reported. In MONALEESA-2, on the KISQALI + letrozole treatment arm, there was 1 (0.3%) sudden death in a patient with grade 3 hypokalemia and grade 2 QT prolongation. No cases of sudden death were reported in MONALEESA-7 or MONALEESA-3.

Assess ECG prior to initiation of treatment. Initiate treatment with KISQALI or the KISQALI FEMARA Co-Pack only in patients with QTcF values <450 ms. Repeat ECG at approximately Day 14 of the first cycle, at the beginning of the second cycle, and as clinically indicated. Monitor serum electrolytes (including potassium, calcium, phosphorus, and magnesium) prior to the initiation of treatment, at the beginning of each of the first 6 cycles, and as clinically indicated. Correct any abnormality before starting therapy with KISQALI or the KISQALI FEMARA Co-Pack therapy.

Avoid the use of KISQALI or the KISQALI FEMARA Co-Pack in patients who already have or who are at significant risk of developing QT prolongation, including patients with:

  • long QT syndrome
  • uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina, and bradyarrhythmias
  • electrolyte abnormalities

Avoid using KISQALI or the KISQALI FEMARA Co-Pack with drugs known to prolong the QT interval and/or strong CYP3A inhibitors, as this may lead to prolongation of the QTcF interval.

Increased QT prolongation with concomitant use of tamoxifen. KISQALI is not indicated for concomitant use with tamoxifen. In MONALEESA-7, the observed mean QTcF increase from baseline was ≥10 ms higher in the tamoxifen + placebo subgroup compared with the NSAI + placebo subgroup. In the placebo arm, an increase of >60 ms from baseline occurred in 6 of 90 patients (7%) receiving tamoxifen, and in no patients receiving an NSAI. An increase of >60 ms from baseline in the QTcF interval was observed in 14 of 87 (16%) patients in the KISQALI and tamoxifen combination and in 18 of 245 (7%) patients receiving KISQALI plus an NSAI.

Hepatobiliary toxicity. Across clinical trials in patients with advanced or metastatic breast cancer, increases in transaminases were observed. Across all trials, grade 3 or 4 increases in alanine aminotransferase (ALT) (10% vs 2%) and aspartate aminotransferase (AST) (7% vs 2%) were reported in the KISQALI and placebo arms, respectively.

Among the patients who had grade ≥3 ALT/AST elevation, the median time to onset was 85 days and median time to resolution to grade ≤2 was 22 days for the KISQALI treatment groups.

In MONALEESA-2 and MONALEESA-3, concurrent elevations in ALT or AST greater than 3 times the ULN and total bilirubin greater than 2 times the ULN, with normal alkaline phosphatase, in the absence of cholestasis occurred in 6 (1%) patients and all patients recovered after discontinuation of KISQALI. No cases occurred in MONALEESA-7.

Perform liver function tests (LFTs) before initiating therapy with KISQALI or the KISQALI FEMARA Co-Pack. Monitor LFTs every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles, and as clinically indicated. Based on the severity of the transaminase elevations, KISQALI may require dose interruption, reduction, or discontinuation. Recommendations for patients who have elevated AST/ALT grade ≥3 at baseline have not been established. 

Neutropenia. Across clinical trials in patients with advanced or metastatic breast cancer, neutropenia was the most frequently reported adverse reaction (AR) (74%), and a grade 3/4 decrease in neutrophil count (based on laboratory findings) was reported in 58% of patients in the KISQALI treatment groups. Among the patients who had grade 2, 3, or 4 neutropenia, the median time to grade ≥2 was 16 days. The median time to resolution of grade ≥3 (to normalization or grade <3) was 12 days in the KISQALI treatment groups. Febrile neutropenia was reported in 1% of patients in the KISQALI treatment groups. Treatment discontinuation due to neutropenia was 0.8%.

Perform complete blood count (CBC) before initiating therapy with KISQALI or the KISQALI FEMARA Co-Pack. Monitor CBC every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles, and as clinically indicated. Based on the severity of the neutropenia, KISQALI may require dose interruption, reduction, or discontinuation.

Embryofetal toxicity. Based on findings from animal studies and the mechanism of action, KISQALI can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of KISQALI to pregnant rats and rabbits during organogenesis caused embryofetal toxicities at maternal exposures that were 0.6 and 1.5 times the human clinical exposure, respectively, based on area under the curve. Letrozole caused embryofetal toxicities in rats and rabbits at maternal exposures that were below the maximum recommended human dose (MRHD) on a milligrams per square meter basis. Advise pregnant women of the potential risk to a fetus. Advise women of reproductive potential to use effective contraception during therapy with KISQALI or the KISQALI FEMARA Co-Pack and for at least 3 weeks after the last dose.

Adverse reactions. Across clinical trials of patients with advanced or metastatic breast cancer, the most common ARs reported in the KISQALI treatment groups (pooled incidence ≥20%) were neutropenia (74% vs 5%), nausea (45% vs 27%), infections (41% vs 30%), fatigue (33% vs 30%), diarrhea (30% vs 22%), leukopenia (30% vs 3%), vomiting (27% vs 16%), alopecia (24% vs 12%), headache (24% vs 22%), constipation (24% vs 16%), rash (21% vs 9%), and cough (21% vs 16%). The most common grade 3/4 ARs (reported at a pooled frequency >5%) were neutropenia (59% vs 1%), leukopenia (16% vs 3%), abnormal LFTs (9% vs 2%), and lymphopenia (5% vs 1%).

Laboratory abnormalities. Across clinical trials of patients with advanced or metastatic breast cancer, the most common laboratory abnormalities reported in the KISQALI arm vs placebo arm (all grades, pooled incidence ≥20% and ≥5% higher than placebo arm) were leukocyte count decrease (94% vs 30%), neutrophil count decrease (93% vs 25%), hemoglobin decrease (66% vs 38%), lymphocyte count decrease (61% vs 26%), AST increase (47% vs 38%), ALT increase (44% vs 36%), creatinine increase (38% vs 13%), and platelet count decrease (31% vs 9%). The most common grade 3/4 laboratory abnormalities (incidence >5%) were neutrophil count decrease (59% vs 2%), leukocyte count decrease (32% vs 1%), lymphocyte count decrease (15% vs 4%), ALT increase (10% vs 2%), and AST increase (7% vs 2%).

Please see full Prescribing Information.