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Interstitial Lung Disease/Pneumonitis: Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with KRYXANA and other CDK4/6 inhibitors.
Across clinical trials (MONALEESA-2, MONALEESA-3, MONALEESA-7), 1.1% of KRYXANA-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 [see Postmarketing Experience under Adverse Reactions].
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 KRYXANA immediately and evaluate the patient. Permanently discontinue KRYXANA in patients with recurrent symptomatic or severe ILD/pneumonitis [see Dose Modifications under Dosage & Administration].
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) can occur in patients treated with KRYXANA [see Postmarketing Experience under Adverse Reactions].
If signs or symptoms of severe cutaneous reactions occur, interrupt KRYXANA until the etiology of the reaction has been determined [see Dose Modifications under Dosage & Administration]. Early consultation with a dermatologist is recommended to ensure greater diagnostic accuracy and appropriate management.
If SJS, TEN, or DiHS/DRESS is confirmed, permanently discontinue KRYXANA. Do not reintroduce KRYXANA in patients who have experienced SCARs or other life threatening cutaneous reactions during KRYXANA treatment.
QT Interval Prolongation: KRYXANA 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, KRYXANA may require dose interruption, reduction or discontinuation as described in Table 8 [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 KRYXANA 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 KRYXANA 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 KRYXANA 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 KRYXANA therapy [see Dose Modifications under Dosage & Administration].
Avoid the use of KRYXANA 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 KRYXANA with drugs known to prolong 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: KRYXANA 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 KRYXANA and tamoxifen combination and in 18/245 (7%) of patients receiving KRYXANA 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 alanine aminotransferase (ALT) (10% vs. 2%) and aspartate aminotransferase (AST) (7% vs. 2%) were reported in the KRYXANA and placebo arms, respectively.
Among the patients who had Grade ≥ 3 ALT/AST elevation, the median time-to-onset was 85 days for the KRYXANA plus aromatase inhibitor or fulvestrant treatment group. The median time to resolution to Grade ≤ 2 was 22 days in the KRYXANA 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 KRYXANA. No cases occurred in MONALEESA-7.
Perform liver function tests (LFTs) before initiating therapy with KRYXANA. 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, KRYXANA may require dose interruption, reduction, or discontinuation as described in Table 9 (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 KRYXANA 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 KRYXANA plus aromatase inhibitor or fulvestrant treatment group. Febrile neutropenia was reported in 1% of patients receiving KRYXANA plus an aromatase inhibitor or fulvestrant. Treatment discontinuation due to neutropenia was 0.8%.
Perform complete blood count (CBC) before initiating therapy with KRYXANA. 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, KRYXANA may require dose interruption, reduction or discontinuation as described in Table 10 [see Dose Modifications under Dosage & Administration].
Embryo-Fetal Toxicity: Based on findings from animal studies and the mechanism of action, KRYXANA 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 KRYXANA and for at least 3 weeks after the last dose [see Pregnancy and Females and Males of Reproductive Potential under Use in Pregnancy & Lactation and Pharmacology: Mechanism of Action under Actions].
Hepatic Impairment: No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A). A reduced starting dose of 400 mg is recommended in patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class 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/1.73 m2 ≤ estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2) or moderate (30 mL/min/1.73 m2 ≤ eGFR < 60 mL/min/1.73 m2) 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/1.73 m2), a starting dose of 200 mg is recommended. KRYXANA 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 KRYXANA in pediatric patients has not been established.
Use in the Elderly: Of 334 patients who received KRYXANA 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 KRYXANA 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 KRYXANA were observed between these patients and younger patients.
