Kryxana Special Precautions

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), 1.6% of KRYXANA-treated patients had ILD/pneumonitis (any Grade, 0.4% had Grade 3-4, and 0.1% had a fatal outcome). Additional cases of ILD/pneumonitis have occurred in the postmarketing setting, some resulting in death [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 severe ILD/pneumonitis or any recurrent symptomatic 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].
Avoid KRYXANA in patients who are at significant risk of developing Torsades de Pointes (TdP), including those with: congenital long QT syndrome; uncontrolled or significant cardiac disease, recent myocardial infarction, heart failure, unstable angina, bradyarrhythmias, uncontrolled hypertension, high degree atrioventricular block, severe aortic stenosis, or uncontrolled hypothyroidism; electrolyte abnormalities; taking 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, 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].
In patients with advanced or metastatic breast cancer (MONALEESA-2, MONALEESA-3, and MONALEESA-7) who received 600 mg KRYXANA plus NSAI or fulvestrant, 15 out of 1054 patients (1.4%) had a >500 ms post-baseline QTcF value and 61 out of 1054 patients (6%) had a >60 ms QTcF increase from baseline. QTcF prolongation was reversible with dose interruption. The majority of QTcF prolongation occurred within the first four weeks of KRYXANA. There were no reported cases of Torsades de Pointes.
In MONALEESA-2, in 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].
Perform ECG in all patients prior to starting KRYXANA. 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 KRYXANA at the beginning of the first 6 cycles, and as clinically indicated. Correct any abnormality before starting KRYXANA [see Dose Modifications under Dosage & Administration].
Increased QT Prolongation With Concomitant Use of Tamoxifen: Avoid use of tamoxifen with KRYXANA. 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 (NSAIs) 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].
Hepatotoxicity: In patients with advanced or metastatic breast cancer, drug-induced liver injury and increases in transaminases occurred with KRYXANA.
In patients with advanced or metastatic breast cancer (MONALEESA-2, MONALEESA-7 and MONALEESA-3) treated with KRYXANA Grade 3 or 4 increases in ALT and AST occurred in 11% and 8%, respectively. Among the patients who had Grade ≥3 ALT/AST elevation, the median time-to-onset was 92 days for the KRYXANA plus aromatase inhibitor or fulvestrant treatment arms. The median time to resolution to Grade ≤2 was 21 days in the KRYXANA plus aromatase inhibitor or fulvestrant treatment arms. 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 (Hy's Law) occurred in 6 (1%) patients and all patients recovered after discontinuation of KRYXANA.
Perform liver function tests (LFTs) in all patietns before initiating KRYXANA. Monitor LFTs every 2 weeks for first 2 cycles, at the beginning of each of the 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].
Neutropenia: KRYXANA causes concentration-dependent neutropenia.
In patients with advanced or metastatic breast cancer (MONALEESA-2, MONALEESA-7, and MONALEESA-3) who received KRYXANA plus NSAI or fulvestrant, 75% had neutropenia, 62% had Grade 3 or 4 decrease in neutrophil count (based on laboratory findings), and 1.7% had febrile neutropenia. The median time to Grade ≥2 neutropenia was 17 days. The median time to resolution of Grade ≥3 neutropenia to Grade <3 was 12 days. Treatment discontinuation due to neutropenia was required in 1% of patients.
Perform a complete blood count (CBC) in all patients before initiating 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 breast cancer who have mild hepatic impairment (Child-Pugh class A) [see Pharmacology: Pharmacokinetics under Actions]. A reduced starting dose of 400 mg is recommended in patients with advanced or metastatic breast cancer who have moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) [see Dose Modifications under Dosage & Administration].
Renal Impairment: No dose adjustment is necessary in patients with breast cancer who have mild to moderate (30 mL/min to 89 mL/min/1.73 m² ≤estimated glomerular filtration rate (eGFR)) renal impairment. A reduced starting dose of 200 mg is recommended in patients with breast cancer who have severe renal impairment [see Dose Modifications under Dosage & Administration, 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 with advanced or metastatic breast cancer 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 with advanced or metastatic breast cancer who received KRYXANA in MONALEESA-3, 226 patients (47%) were ≥65 years of age and 65 patients (14%) were ≥75 years of age. Of 248 patients with advanced or metastatic breast cancer who received KRYXANA in MONALEESA-7, no patients were ≥65 years of age. No overall differences in safety or effectiveness of KRYXANA were observed between older and younger adults with advanced or metastatic breast cancer.