QT interval prolongation. KISQALI has been shown to prolong the QT interval in a concentration-dependent manner, with estimated mean increase in QTc interval exceeding 20 ms (22.9 ms [90% CI: ...
KISQALI® (ribociclib) is indicated in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.
Important Safety Information
QT interval prolongation. KISQALI has been shown to prolong the QT interval in a concentration-dependent manner, with estimated mean increase in QTc interval exceeding 20 ms (22.9 ms [90% CI: 21.6-24.1]) at the mean steady-state Cmax following administration at the 600-mg once-daily dose. In MONALEESA-2, one patient (0.3%) had >500 msec postbaseline QTcF value (average of triplicate), and 9 of 329 patients (3.0%) had a >60 msec increase from baseline in QTcF intervals (average of triplicate). These electrocardiogram (ECG) changes occurred within the first 4 weeks of treatment and were reversible with dose interruption. There were no reported cases of torsades de pointes. Syncope occurred in 9 patients (2.7%) in the KISQALI + letrozole arm vs 3 patients (0.9%) in the placebo + letrozole arm. In the KISQALI + letrozole treatment arm, there was 1 (0.3%) sudden death in a patient with grade 3 hypokalemia and grade 2 QT prolongation.
Assess ECG prior to initiation of treatment. Initiate treatment with KISQALI only in patients with QTcF values <450 msec. 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.
Avoid the use of KISQALI in patients who already have or who are at significant risk of developing QTc prolongation, including patients with:
Avoid using KISQALI with drugs known to prolong the QTc interval and/or strong CYP3A inhibitors, as this may lead to prolongation of the QTcF interval. Based on the observed QT prolongation during treatment, KISQALI may require dose interruption, reduction, or discontinuation.
Hepatobiliary toxicity. In MONALEESA-2, increases in transaminases were observed. Grade 3 or 4 increases in alanine aminotransferase (ALT) (10% vs 1%) 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 57 days for the KISQALI + letrozole treatment group. The median time to resolution to grade ≤2 was 24 days in the KISQALI + letrozole treatment group.
Concurrent elevations in ALT or AST >3 times the upper limit of normal (ULN) and total bilirubin >2 times the ULN, with normal alkaline phosphatase, in the absence of cholestasis occurred in 4 patients (1%) in MONALEESA-2, and all patients recovered after discontinuation of KISQALI.
Perform liver function tests (LFTs) before initiating therapy with KISQALI. 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. In MONALEESA-2, neutropenia was the most frequently reported adverse reaction (AR) (75%), and a grade 3/4 decrease in neutrophil count (based on laboratory findings) was reported in 60% of patients receiving KISQALI + letrozole. 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 15 days in the KISQALI + letrozole treatment group. Febrile neutropenia was reported in 1.5% of patients receiving KISQALI and letrozole. Treatment discontinuation due to neutropenia was 0.9%.
Perform complete blood count (CBC) before initiating therapy with KISQALI. 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. Advise pregnant women of the potential risk to a fetus. Advise women of reproductive potential to use effective contraception during therapy with KISQALI and for at least 3 weeks after the last dose.
Adverse reactions. The most common ARs reported in the KISQALI + letrozole arm vs letrozole arm (incidence ≥20%) were neutropenia (75% vs 5%), nausea (52% vs 29%), fatigue (37% vs 30%), diarrhea (35% vs 22%), leukopenia (33% vs 1%), alopecia (33% vs 16%), vomiting (29% vs 16%), constipation (25% vs 19%), headache (22% vs 19%), and back pain (20% vs 18%). The most common grade 3/4 ARs (reported at a frequency >2%) were neutropenia (60% vs 1%), leukopenia (21% vs <1%), abnormal LFTs (10% vs 2%), lymphopenia (7% vs 1%), and vomiting (4% vs 1%), respectively.
Laboratory abnormalities. The most common laboratory abnormalities occurring in patients receiving KISQALI + letrozole vs letrozole arm (all grades, incidence ≥20%) were leukocyte count decrease (93% vs 29%), neutrophil count decrease (93% vs 24%), hemoglobin decrease (57% vs 26%), lymphocyte count decrease (51% vs 22%), ALT increase (46% vs 36%), AST increase (44% vs 32%), platelet count decrease (29% vs 6%), and creatinine increase (20% vs 6%). The most common grade 3/4 laboratory abnormalities (incidence >2%) were neutrophil count decrease (60% vs <2%), leukocyte count decrease (34% vs <2%), lymphocyte count decrease (14% vs 4%), ALT increase (10% vs 1%), AST increase (7% vs 2%), and phosphorus decrease (6% vs 1%), respectively.