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Neutropenia: In the 3 phase III clinical studies (MONALEESA-2 (A2301), MONALEESA-7 (E2301-NSAI) and MONALEESA-3 (F2301)), neutropenia was the most frequently reported adverse drug reaction (75.4%) and a Grade 3 or 4 decrease in neutrophil counts (based on laboratory findings) was reported in 62.0% of patients receiving ribociclib plus any combination in the phase III clinical studies.
Among the patients who had Grade 2, 3 or 4 neutropenia in the phase III clinical studies, the median time to Grade 2, 3 or 4 neutropenia was 17 days. The median time to resolution of Grade ≥3 (to normalization or Grade <3) was 12 days in the ribociclib plus any combination treatment group. Severity of neutropenia is concentration dependent. Febrile neutropenia was reported in 1.7% of patients exposed to ribociclib in the phase III clinical studies. Physicians should inform patients to promptly report any fever (see ADVERSE REACTIONS).
A complete blood count (CBC) should be performed before initiating therapy with ribociclib. CBC should be monitored every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles then as clinically indicated.
Based on the severity of the neutropenia, ribociclib may require dose interruption/reduction or discontinuation as described in Table 15 (see DOSAGE & ADMINISTRATION).
In patients who develop Grade 1 or 2 neutropenia, no ribociclib dose adjustment is required. In patients who develop Grade 3 neutropenia without fever, the ribociclib dose should be interrupted until recovery to Grade ≤2 and then ribociclib should be resumed at the same dose level. If Grade 3 neutropenia without fever recurs, ribociclib dose should be interrupted until recovery, then ribociclib should be resumed at the next lower dose level.
In patients who develop Grade 3 febrile neutropenia (ANC <1,000/mm3 with a single episode of fever >38.3°C or a sustained temperature above 38°C for more than one hour), or patients who develop Grade 4 neutropenia, ribociclib dose should be interrupted until recovery to Grade ≤2, then ribociclib should be resumed at the next lower dose level.
Hepatobiliary toxicity: In the phase III clinical studies, increases in transaminases were observed.
Grade 3 or 4 increases in ALT (11.2% vs. 1.7%) and AST (7.8% vs. 2.1%) were reported in the ribociclib plus any combination and placebo plus any combination arms, respectively. Grade 4 increases in ALT (2.0% vs. 0.2%) and AST (1.1% vs. 0.1%) were reported in the ribociclib plus any combination treatment and placebo plus any combination treatment arms respectively.
In the phase III clinical studies, 70.9% (90/127) of Grade 3 or 4 ALT or AST elevation events occurred within the first 6 months of treatment (see ADVERSE REACTIONS). The majority of increases in ALT and AST were reported without concurrent elevations of bilirubin. Among the patients who had Grade 3 or 4 ALT/AST elevation, the median time-to-onset was 92 days for the ribociclib plus any combination treatment group. The median time to resolution (to normalization or Grade ≤2) was 21 days in the ribociclib plus any combination treatment group.
Concurrent elevations of ALT or AST >3 x ULN and of total bilirubin >2 x ULN, with normal alkaline phosphatase levels and in the absence of cholestasis, occurred in 6 patients (4 patients in Study A2301, whose levels recovered to normal within 154 days; and 2 patients in Study F2301, whose levels recovered to normal within 121 and 532 days, respectively, after discontinuation of ribociclib. There were no such cases reported in Study E2301).
LFTs should be performed before initiating therapy with ribociclib. The LFTs should be monitored every 2 weeks for first 2 cycles, at the beginning of each of the subsequent 4 cycles, then as clinically indicated.
Based on the severity of the transaminase elevations, ribociclib may require dose interruption, reduction, or discontinuation as described in Table 16 (see DOSAGE & ADMINISTRATION). Recommendations for patients who have elevated AST/ALT Grade ≥3 at baseline have not been established.
The following dose modification and management guidelines are provided for hepatobiliary toxicity: For patients with AST and/or ALT elevations from baseline (prior to treatment initiation), without an increase in total bilirubin (TB) above 2 x ULN no ribociclib dose adjustment is required for Grade 1 (AST and/or ALT elevations of >ULN to 3 x ULN).
In patients with a baseline of Grade <2 (AST and/or ALT elevations of <ULN to 3 x ULN), if Grade 2 (AST and/or ALT elevations of >3 to 5 x ULN) develops, ribociclib dose should be interrupted until values return to ≤baseline Grade, then ribociclib should be resumed at the same dose level. If Grade 2 recurs, then ribociclib should be resumed at next lower dose level.
In patients with a baseline of Grade 2 (AST and/or ALT elevations of >3 to 5 x ULN), if Grade 2 continues, no ribociclib dose interruption is required.
In patients who develop Grade 3 (ALT and/or AST elevations of >5 to 20 x ULN), ribociclib dose should be interrupted until values return to ≤baseline Grade, then ribociclib should be resumed at next lower dose level. If Grade 3 recurs, ribociclib should be discontinued.
In patients who develop Grade 4 (ALT and/or AST elevations of >20 x ULN), ribociclib should be discontinued.
The following dose modification and management guidelines are provided for patients with concurrent elevations in AST and/or ALT together with an increase in total bilirubin (TB), in the absence of cholestasis: In patients who develop total bilirubin >2 x ULN along with ALT and/or AST >3 x ULN, irrespective of baseline Grade, ribociclib should be discontinued.
QT interval prolongation: In the phase III clinical studies, in patients with advanced or metastatic breast cancer who received ribociclib plus any combination partners, review of ECG data showed that 15 patients (1.4%) had >500 ms post-baseline QTcF interval value, and 61 patients (5.8%) had a >60 ms QTcF interval increase from baseline. There were no reported cases of Torsade de Pointes.
In E2301 (MONALEESA-7), the observed mean QTcF interval increase from baseline was approximately more than 10 ms higher in the tamoxifen plus placebo sub-group compared with NSAI plus placebo sub-group, suggesting that tamoxifen had a QTcF interval prolongation effect which can contribute to the QTcF interval observed in the ribociclib plus tamoxifen group (see PHARMACOLOGY: PHARMACODYNAMICS: Cardiac electrophysiology under ACTIONS). In the placebo arm, an increase of >60 ms from baseline occurred in 6/90 (6.7%) 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 (16.1%) of patients receiving ribociclib plus tamoxifen and in 18/245 (7.3%) of patients receiving ribociclib plus an NSAI.
An ECG should be assessed prior to initiation of treatment. Treatment with ribociclib should be initiated only in patients with QTcF interval values less than 450 ms. The ECG should be repeated at approximately Day 14 of the first cycle, at the beginning of the second cycle and then as clinically indicated.
Appropriate monitoring of serum electrolytes (including potassium, calcium, phosphorous and magnesium) should be performed prior to initiation of treatment, at the beginning of the first 6 cycles and then as clinically indicated. Any abnormality should be corrected before and during ribociclib therapy.
Ribociclib should be avoided in patients who already have or who are at significant risk of developing QTc interval prolongation. This includes patients with: Long QT syndrome; Uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina and bradyarrhythmia; Electrolyte abnormalities.
Ribociclib should be avoided in combination with medicinal products known to prolong the QTc interval and/or strong CYP3A inhibitors as this may lead to clinically meaningful prolongation of the QTcF interval (see DOSAGE & ADMINISTRATION, INTERACTIONS and PHARMACOLOGY under ACTIONS). Based on the findings in MONALEESA-7 (E2301), ribociclib is not recommended for use in combination with tamoxifen (see PHARMACOLOGY: PHARMACODYNAMICS: CLINICAL STUDIES under ACTIONS).
Based on the observed QT prolongation during treatment, ribociclib may require dose interruption, reduction or discontinuation as described in Table 17 (see DOSAGE & ADMINISTRATION, ADVERSE REACTIONS and PHARMACOLOGY under ACTIONS).
In the event of ECGs with QTcF interval >480 ms: The treatment with ribociclib should be interrupted; If QTcF interval prolongation is resolved to <481 ms, ribociclib should be resumed at the next lower dose level; If QTcF interval ≥481 ms recurs, ribociclib dose should be interrupted until QTcF interval resolves to <481 ms, then ribociclib should be resumed at the next lower dose level.
In the event of ECGs with QTcF interval >500 ms, repeat ECG should be performed: The treatment with ribociclib should be interrupted; If QTcF interval prolongation resolves to <481 ms, ribociclib should be resumed at next lower dose level (see Dosage & Administration, Adverse Reactions and Pharmacology under Actions).
If QTcF interval prolongation greater than 500 ms recurs or the QTcF interval has a greater than 60 ms change from baseline in combination with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia, ribociclib should be permanently discontinued.
Reproductive toxicity: Based on animal findings and its mechanism of action, ribociclib can cause fetal harm when administered to a pregnant woman. Women of reproductive potential should be advised to use effective contraception during therapy with ribociclib and for at least 21 days after the last dose (see USE IN PREGNANCY & LACTATION).
Severe cutaneous reactions: Toxic epidermal necrolysis (TEN) has been reported with ribociclib treatment. If signs and symptoms suggestive of severe cutaneous reactions (e.g., progressive widespread skin rash often with blisters or mucosal lesions) appear, ribociclib should be immediately and permanently discontinued.
Interstitial Lung Disease (ILD)/Pneumonitis: ILD/pneumonitis has been reported with CDK4/6 inhibitors including reports of fatal cases.
In the three phase III clinical studies (MONALEESA-2 (A2301), MONALEESA-7 (E2301-NSAI) and MONALEESA-3 (F2301)), ILD (any grade 0.3%, including 0.1% grade 3) was reported in the ribociclib treated group, with no cases in the placebo treated group. Pneumonitis (any grade 0.6%, vs 0.4%) was reported in the ribociclib and placebo treated groups, respectively, with no grade 3/4 events in either treatment group. Additional cases of ILD/pneumonitis have been observed with ribociclib in the post-marketing setting (see ADVERSE REACTIONS).
Based on the severity of the ILD/pneumonitis patients may require treatment interruption, dose reduction or permanent discontinuation as described in Table 18 (see DOSAGE & ADMINISTRATION).
Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis which may include hypoxia, cough, and dyspnea.
