KISQALI (Page 2 of 8)

3 DOSAGE FORMS AND STRENGTHS

Tablet: 200 mg ribociclib (equivalent to 254.40 mg ribociclib succinate).

Film coated, light greyish violet, round, curved with beveled edges, debossed with “RIC” on one side and “NVR” on the other side.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 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 (MONALEESA-2, MONALEESA-3, MONALEESA-7), 1.6% of KISQALI-treated patients had ILD/pneumonitis of any grade, 0.4% 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 Adverse Reactions (6.2)].

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 KISQALI immediately and evaluate the patient. Permanently discontinue KISQALI in patients with recurrent symptomatic or severe ILD/pneumonitis [see Dosage and Administration (2.2)].

5.2 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 KISQALI [see Adverse Reactions (6.2)].

If signs or symptoms of severe cutaneous reactions occur, interrupt KISQALI until the etiology of the reaction has been determined [see Dosage and Administration (2.2)]. 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 KISQALI. Do not reintroduce KISQALI in patients who have experienced SCARs or other life-threatening cutaneous reactions during KISQALI treatment.

5.3 QT Interval Prolongation

KISQALI has been shown to prolong the QT interval in a concentration-dependent manner [see Clinical Pharmacology (12.2)]. Based on the observed QT prolongation during treatment, KISQALI may require dose interruption, reduction or discontinuation as described in Table 4 [see Dosage and Administration (2.2), Drug Interactions (7.4)].

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, 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 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 (6)].

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 Dosage and Administration (2.2)].

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.

5.4 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 (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 KISQALI and tamoxifen combination and in 18/245 (7%) of patients receiving KISQALI plus an NSAI [see Clinical Pharmacology (12.2)].

5.5 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) (11% vs. 2.1%) and aspartate aminotransferase (AST) (8% 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 92 days for the KISQALI plus aromatase inhibitor or fulvestrant treatment group. The median time to resolution to Grade ≤ 2 was 21 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 MONALEESA-7.

Perform liver function tests (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 Dosage and Administration (2.2)].

Based on the severity of the transaminase elevations, KISQALI may require dose interruption, reduction, or discontinuation as described in Table 5 (Dose Modification and Management for Hepatobiliary Toxicity) [see Dosage and Administration (2.2)]. Recommendations for patients who have elevated AST/ALT Grade ≥ 3 at baseline have not been established.

5.6 Neutropenia

In MONALEESA-2, MONALEESA-7, and MONALEESA-3, neutropenia was the most frequently reported adverse reaction (75%), and a Grade 3/4 decrease in neutrophil count (based on laboratory findings) was reported in 62% 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 17 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 1.7% of patients receiving KISQALI plus an aromatase inhibitor or fulvestrant. Treatment discontinuation due to neutropenia was 1%.

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 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 6 [see Dosage and Administration (2.2)].

5.7 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 Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

  • Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1)]
  • Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)]
  • QT Interval Prolongation [see Warnings and Precautions (5.3, 5.4)]
  • Hepatobiliary Toxicity [see Warnings and Precautions (5.5)]
  • Neutropenia [see Warnings and Precautions (5.6)]

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