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QT Interval Prolongation: KISQALI has been shown to prolong the QT interval in a concentration-dependent manner (see Pharmacology: Pharmacodynamics under Actions). Based on the observed QT prolongation during treatment, KISQALI may require dose interruption, reduction or discontinuation as described in Table 7 (see Dose Modifications under Dosage & Administration and Drugs That Prolong the QT Interval under Interactions).
Across MONALEESA-2, MONALEESA-7, and MONALEESA-3 in patients with advanced or metastatic breast cancer who received the combination of KISQALI plus an aromatase inhibitor or fulvestrant, 14 out of 1054 patients (1%) had a > 500 ms post-baseline QTcF value, and 59 out of 1054 patients (6%) had a > 60 ms increase from baseline in QTcF intervals.
These ECG changes were reversible with dose interruption and the majority occurred within the first four weeks of treatment. There were no reported cases of Torsades de Pointes.
In MONALEESA-2, on the KISQALI plus letrozole treatment arm, there was one (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 (see Adverse Reactions).
Assess ECG prior to initiation of treatment. Initiate treatment with KISQALI only in patients with QTcF values less than 450 ms. Repeat ECG at approximately Day 14 of the first cycle and the beginning of the second cycle, and as clinically indicated.
Monitor serum electrolytes (including potassium, calcium, phosphorous and magnesium) prior to the initiation of treatment, at the beginning of the first 6 cycles, and as clinically indicated. Correct any abnormality before starting KISQALI therapy (see Dose Modifications under Dosage & Administration).
Avoid the use of KISQALI 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 with drugs known to prolong QT 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 as described in Table 7 (see Dose Modifications under Dosage & Administration and Drugs That Prolong the QT Interval under Interactions).
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 plus placebo subgroup compared with the non-steroidal aromatase inhibitors (NSAI) plus placebo subgroup. In the placebo arm, an increase of > 60 ms from baseline occurred in 6/90 (7%) of patients receiving tamoxifen, and in no patients receiving an NSAI. An increase of > 60 ms from baseline in the QTcF interval was observed in 14/87 (16%) of patients in the KISQALI and tamoxifen combination and in 18/245 (7%) of patients receiving KISQALI plus an NSAI (see Pharmacology: Pharmacodynamics under Actions).
Hepatobiliary Toxicity: In MONALEESA-2, MONALEESA-7 and MONALEESA-3, increases in transaminases were observed. Across all studies, Grade 3 or 4 increases in ALT (10% vs. 2%) and 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 for the KISQALI plus aromatase inhibitor or fulvestrant treatment group. The median time to resolution to Grade ≤ 2 was 22 days in the KISQALI plus aromatase inhibitor or fulvestrant treatment group. In MONALEESA-2 and MONALEESA-3, concurrent elevations in ALT or AST greater than three times the ULN and total bilirubin greater than two 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 MONALESSA-7.
Perform LFTs before initiating therapy with KISQALI. Monitor LFTs every 2 weeks for first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated (see Dose Modifications under Dosage & Administration).
Based on the severity of the transaminase elevations, KISQALI may require dose interruption, reduction, or discontinuation as described in Table 6 (Dose Modification and Management for Hepatobiliary Toxicity) (see Dose Modifications under Dosage & Administration). Recommendations for patients who have elevated AST/ALT Grade ≥ 3 at baseline have not been established.
Neutropenia: In MONALEESA-2, MONALEESA-7 and MONALEESA-3, neutropenia was the most frequently reported adverse reaction (74%) and a Grade 3/4 decrease in neutrophil count (based on laboratory findings) was reported in 58% of patients receiving KISQALI plus an aromatase inhibitor or fulvestrant. Among the patients who had Grade 2, 3, or 4 neutropenia, the median time to Grade ≥ 2 neutropenia was 16 days. The median time to resolution of Grade ≥ 3 (to normalization or Grade < 3) was 12 days in the KISQALI plus aromatase inhibitor or fulvestrant treatment group. Febrile neutropenia was reported in 1% of patients receiving KISQALI plus an aromatase inhibitor or fulvestrant. Treatment discontinuation due to neutropenia was 0.8%.
Perform CBC before initiating therapy with KISQALI. Monitor CBC every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated.
Based on the severity of the neutropenia, KISQALI may require dose interruption, reduction or discontinuation as described in Table 5 (see Dose Modifications under Dosage & Administration).
Embryo-Fetal 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 ribociclib to pregnant rats and rabbits during organogenesis caused embryo-fetal toxicities at maternal exposures that were 0.6 and 1.5 times the human clinical exposure, respectively, based on area under the curve (AUC). 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 (see Use in Pregnancy & Lactation and Pharmacology: Pharmacodynamics: Mechanism of Action under Actions).
Use in Specific Populations: Hepatic Impairment: No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh A). A reduced starting dose of 400 mg is recommended in patients with moderate (Child-Pugh B) and severe hepatic impairment (Child-Pugh C) (see Dose Modifications under Dosage & Administration). Based on a pharmacokinetic trial in patients with hepatic impairment, mild hepatic impairment had no effect on the exposure of ribociclib. The mean exposure for ribociclib was increased less than 2-fold in patients with moderate (geometric mean ratio [GMR]: 1.44 for Cmax; 1.28 for AUCinf) and severe (GMR: 1.32 for Cmax; 1.29 for AUCinf) hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Renal Impairment: Based on a population pharmacokinetic analysis, no dose adjustment is necessary in patients with mild (60 mL/min/1.73m2 ≤ estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73m2) or moderate (30 mL/min/1.73m2 ≤ eGFR < 60 mL/min/1.73m2) renal impairment. Based on a renal impairment study in healthy subjects and non-cancer subjects with severe renal impairment (eGFR 15 to < 30 mL/min/1.73m2), a starting dose of 200 mg is recommended. KISQALI has not been studied in breast cancer patients with severe renal impairment (see Dose Modifications under Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Use in Children: The safety and efficacy of KISQALI in pediatric patients has not been established.
Use in Elderly: Of 334 patients who received KISQALI in MONALEESA-2, 150 patients (45%) were ≥65 years of age and 35 patients (11%) were ≥75 years of age. Of 484 patients who received KISQALI in MONALEESA-3, 226 patients (47%) were ≥ 65 years of age and 65 patients (14%) were ≥ 75 years of age. No overall differences in safety or effectiveness of KISQALI were observed between these patients and younger patients.
