Kryxana

Kryxana

ribociclib

Manufacturer:

Novartis Healthcare

Distributor:

Novartis Healthcare
Full Prescribing Info
Contents
Ribociclib.
Description
Each film-coated tablet contains ribociclib succinate, equivalent to 200 mg ribociclib.
Excipients/Inactive Ingredients: Tablet core: Microcrystalline cellulose; low-substituted hydroxypropylcellulose; crospovidone (Type A); colloidal silicon dioxide; magnesium stearate.
Coating material: Polyvinyl alcohol (partially hydrolysed); titanium dioxide (E171); iron oxide black (E172); iron oxide red (E172); talc; lecithin (soy) (E322); xanthan gum.
Action
Pharmacology: Mechanism of action (MOA): Ribociclib is a selective inhibitor of CDK 4 and 6. These kinases are activated upon binding to D-cyclins and play a crucial role in signaling pathways which lead to cell cycle progression and cellular proliferation. The cyclin D-CDK4/6 complex regulates cell cycle progression through phosphorylation of the retinoblastoma protein (pRb).
In vitro, ribociclib decreased pRb phosphorylation, leading to arrest in the G1 phase of the cell cycle, and reduced cell proliferation in breast cancer cell lines. In vivo, treatment with single-agent ribociclib led to tumor regressions which correlated with inhibition of pRb phosphorylation at well-tolerated doses.
In vivo studies using patient-derived estrogen-positive breast cancer xenograft models combination of ribociclib and antiestrogens (i.e. letrozole) resulted in superior inhibition of tumor growth compared to each drug alone. Tumor regrowth was delayed for 33 days after stopping dosing. Additionally, the in vivo antitumor activity of ribociclib in combination with fulvestrant was assessed in immune-deficient mice bearing the ZR751 ER+ human breast cancer xenografts. The combination of ribociclib and fulvestrant resulted in complete tumor growth inhibition.
Pharmacodynamics: Ribociclib inhibits the CDK4/cyclin-D1 and CDK6/cyclin-D3 enzyme complexes with concentration resulting in 50% inhibition (IC50) values of 0.01 (4.3 ng/mL) and 0.039 micromolar (16.9 ng/mL) in biochemical assays, respectively.
In cell-based assays, ribociclib inhibits CDK4/6-dependent pRb phosphorylation with an average IC50 of 0.06 micromolar (26 ng/mL). Ribociclib halts G1 to S phase cell cycle progression measured by flow cytometry with an average IC50 of 0.11 micromolar (47.8 ng/mL). Ribociclib also inhibits cellular proliferation measured by bromodeoxyuridine (BrdU) uptake with an IC50 of 0.8 micro molar (34.8 ng/mL). The similar IC50 values obtained from the target modulation, cell cycle and proliferation assays confirms that the blockade of pRb phosphorylation by ribociclib directly leads to G1 to S phase arrest and subsequent inhibition of cellular proliferation. When tested in a panel of breast cancer cell lines with known ER status, ribociclib was demonstrated to be more efficacious in ER+ breast cancer cell lines than in the ER- ones. In the preclinical models tested so far, intact pRb was required for ribociclib activity.
Cardiac electrophysiology: Serial, triplicate ECGs were collected following a single dose and at steady state to evaluate the effect of ribociclib on the QTc interval in patients with advanced cancer. A pharmacokinetic-pharmacodynamic analysis included a total of 997 patients treated with ribociclib at doses ranging from 50 to 1,200 mg. The analysis suggested that ribociclib causes concentration-dependent increases in the QTc interval. The estimated QTcF interval mean change from baseline for ribociclib 600 mg dose in combination with NSAI or fulvestrant was 22.00 ms (90% CI: 20.56, 23.44) and 23.7 ms (90% CI: 22.31, 25.08), respectively, at the geometric mean Cmax at steady state compared to 34.7◦ms (90% CI: 31.64, 37.78) in combination with tamoxifen. (see Precautions).
Clinical studies: Study CLEE011A2301 (MONALEESA-2): Ribociclib (Kryxana) was evaluated in a randomized, double-blind, placebo-controlled, multicenter phase III clinical study in the treatment of postmenopausal women with HR-positive, HER2-negative, advanced breast cancer who received no prior therapy for advanced disease in combination with letrozole versus letrozole alone.
A total of 668 patients were randomized in a 1:1 ratio to receive either ribociclib (Kryxana) 600 mg and letrozole (n= 334) or placebo and letrozole (n= 334), stratified according to the presence of liver and/or lung metastases Yes [n=292 (44%)] vs No [n=376 (56%)]). Demographics and baseline disease characteristics were balanced and comparable between study arms. Ribociclib was given orally at a dose of 600 mg daily for 21 consecutive days followed by 7 days off treatment in combination with letrozole 2.5 mg once daily for 28 days. Patients were not allowed to cross over from placebo to ribociclib during the study or after disease progression.
Patients enrolled in this study had a median age of 62 years (range 23 to 91). 44.2% patients were of age 65 years and older including 69 patients (10.3%) of age 75 years and older. The patients included were Caucasian (82.2%), Asian (7.6%), and Black (2.5%). All patients had an ECOG performance status of 0 or 1. A total of 43.6% of patients had received chemotherapy in the neoadjuvant or adjuvant setting and 51.8% had received antihormonal therapy in the neo/adjuvant setting prior to study entry. 34.1% of patients had de novo metastatic disease. 20.7% of patients had bone only disease and 59.0% of patients had visceral disease.
The primary endpoint for the study was met at the planned interim analysis conducted after observing 80% of targeted progression-free survival (PFS) events using Response Evaluation Criteria in Solid Tumors (RECIST v1.1), based on the investigator assessment in the full population (all randomized patients) and confirmed by a blinded independent central radiological assessment.
The primary endpoint for the study was met at the planned interim analysis conducted after observing 80% of targeted progression-free survival (PFS) events using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1), based on the investigator assessment in the full population (all randomized patients) and confirmed by a blinded independent central radiological assessment.
The efficacy results demonstrated a statistically significant improvement in PFS in patients receiving ribociclib plus letrozole compared to patients receiving placebo plus letrozole in the full analysis set (FAS) (HR:0.556; 95% CI: 0.429, 0.720; one-sided stratified log-rank test p-value = 0.00000329), with an estimated 44% reduction in risk of progression for patients treated with the combination of ribociclib plus letrozole. The median PFS was not reached in the ribociclib plus letrozole arm (95% CI: 19.3 NE) at the time of the primary analysis. The median PFS was 14.7 months (95% CI: 13.0, 16.5) for the placebo plus letrozole arm. Results were consistent across the sub-groups of age, race, prior adjuvant or neo-adjuvant chemotherapy or hormonal therapies, liver and/or lung involvement, and bone only metastasic disease.
Progression free survival is summarized in Table 1 and the Kaplan-Meier curve for PFS is provided in Figure 1. The results for PFS based on the blinded independent central radiological assessment were consistent with the primary efficacy results based on the investigator's assessment (HR: 0.592; 95% CI: (0.412, 0.852). The one-sided stratified log-rank test p-value was 0.002.
The global health status/Quality of Life (QoL) showed no relevant difference between the ribociclib (Kryxana) plus letrozole arm and the placebo plus letrozole control arm.
Overall survival (OS) was a key secondary endpoint. At the time of primary PFS analysis, overall survival was not mature with 11% of events.
A more mature update of efficacy data is provided in Table 2. Median PFS was 25.3 months (95% CI: 23.0, 30.3) for ribociclib plus letrozole treated patients and 16.0 months (95% CI: 13.4, 18.2) for patients receiving placebo plus letrozole. 54.7% of patients receiving ribociclib plus letrozole were estimated to be disease progression free at 24 months compared with 35.9% in the placebo plus letrozole arm. There was no statistically significant difference in overall survival (OS) between the ribociclib (Kryxana) plus letrozole arm and the placebo plus letrozole arm (HR 0.746; 95% CI 0.517, 1.078). OS data remain immature.
Hazard ratios based on a pre-specified subgroup analysis are in favor of the ribociclib plus letrozole arm, demonstrating that patients benefit independent of age, race, prior adjuvant/ neo-adjuvant chemotherapy or hormonal therapies, liver and/or lung involvement and bone only metastasis disease. (See Tables 1 and 2, and Figures 1 and 2.)

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Other secondary endpoints included overall response rate (ORR), time to deterioration of ECOG performance status, safety and tolerability and change in patient-reported outcomes (PROs) for health-related quality of life. In the FAS, the overall response rate according to the local radiologist assessment was 40.7% of patients (95% CI: 35.4%, 46.0%) in the ribociclib plus letrozole arm and 27.5% (95% CI: 22.8%, 32.3%) in the placebo plus letrozole arm (p=0.000155). The clinical benefit rate (CBR) was 79.6% of patients (95% CI: 75.3%, 84.0%) in the ribociclib plus letrozole arm and 72.8% (95% CI: 68.0%, 77.5%) in the placebo plus letrozole arm (p=0.018). In patients with measurable disease, the overall response rate according to the local radiologist assessment was 52.7% of patients (95% CI: 46.6%, 58.9%) in the ribociclib plus letrozole and 37.1% (95% CI: 31.1%, 43.2%) in the placebo plus letrozole arm (p=0.00028).
The clinical benefit rate was 80.1% (95% CI: 75.2%, 85.0%) in the ribociclib plus letrozole arm and 71.8% (95% CI: 66.2%, 77.5%) in the placebo plus letrozole arm (p=0.018) (see Table 3).
A series of pre-specified subgroup PFS analyses was performed based on prognostic factors and baseline characteristics to investigate the internal consistency of treatment effect. A reduction in the risk of disease progression or death in favor of the ribociclib plus letrozole arm was observed in all individual patient sub-groups of age, race, prior adjuvant or neo-adjuvant chemotherapy or hormonal therapies, liver and/or lung involvement and bone-only metastatic disease. This was evident for patients with liver and/or lung disease (HR: 0.561 [95% CI: 0.424, 0.743], median progression-free survival [mPFS] 24.8 months vs 13.4 months for the ribociclib and placebo arms, respectively the same) benefit was observed for those patients without liver and/or lung disease (HR of 0.597 [95% CI: 0.426, 0.837]; mPFS 27.6 months vs 18.2 months).
Updated results for overall response and clinical benefit rates are displayed in Table 4. (See Tables 3 and 4.)

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Study CLEE011E2301 (MONALEESA-7): Ribociclib was evaluated in a randomized, double-blind, placebo-controlled, multicenter phase III clinical study comparing ribociclib or placebo in combination with tamoxifen and goserelin or a non-steroidal aromatase inhibitor (NSAI) and goserelin for the treatment of pre and perimenopausal women with hormone receptor (HR) positive, HER2-negative, advanced breast cancer.
A total of 672 patients were randomized to receive either ribociclib 600 mg plus tamoxifen or NSAI plus goserelin (n= 335) or placebo plus tamoxifen or NSAI plus goserelin (n= 337), stratified according to the presence of liver and/or lung metastases (Yes [n=344 (51.2%)] vs No [n=328 (48.8%)]), prior chemotherapy for advanced disease (Yes [n=120 (17.9%)] vs No [n=552 (82.1%)]) and endocrine combination partner (NSAI and goserelin) [n=493 (73.4%)] vs tamoxifen and goserelin [n=179 (26.6%)]. Demographics and baseline disease characteristics were balanced and comparable between study arms.
Tamoxifen 20 mg or NSAI (letrozole 2.5 mg or anastrazole 1 mg) were given orally once daily on a continuous schedule, goserelin 3.6 mg was administered as subcutaneous injection on day 1 of each 28 day cycle, with either ribociclib 600 mg or placebo given orally once daily for 21 consecutive days followed by 7 days off until disease progression or unacceptable toxicity. Patients were not allowed to cross over from placebo to ribociclib during the study or after disease progression. Patients were not allowed to switch between endocrine combination partners.
Patients enrolled in the study had a median age of 44 years (range 25 to 58) and 27.7% of patients were younger than 40 years of age. The majority of patients were Caucasian (57.7%), Asian (29.5%), or Black (2.8%) and nearly all patients (99.0%) had an ECOG performance status of 0 or 1. Of these 672 patients, 14.0% had received prior chemotherapy for metastatic disease. Of the 672 patients, 32.6% of patients had received chemotherapy in the adjuvant vs 18.0% in neo-adjuvant setting and 39.6% had received endocrine therapy in the adjuvant vs 0.7% in the neoadjuvant setting. Prior to study entry 40.2% of patients had de novo metastatic disease, 23.7% had bone only disease, and 56.7% had visceral disease.
Primary analysis: The primary endpoint for the study was met after observing 318 progression-free survival (PFS) events using RECIST v1.1, based on the investigator assessment in the full analysis set (all randomized patients) and confirmed by a blinded independent central radiological assessment of a randomly selected subset of approximately 40% of randomized patients (BIRC). The median follow-up time at the time of the primary PFS analysis was 19.2 months.
In the overall study population, the median PFS (95% CI) was 23.8 months (19.2, NE) in the ribociclib plus tamoxifen or NSAI arm and 13.0 months (11.0, 16.4) in the placebo plus tamoxifen or NSAI arm [HR: 0.553 (95% CI: 0.441, 0.694); one-sided stratified long-rank test p-value 9.83x10-8]. Efficacy results are presented in the Kaplan-Meier curve for PFS in Figure 3. The results based on the BIRC were supportive of the primary efficacy results based on the investigator's assessment (HR: 0.427; 95% CI: 0.288, 0.633).
Overall response rate (ORR) per investigator assessment based on RECISTv1.1 was higher in the ribociclib arm (40.9%; 95% CI: 35.6, 46.2) compared to the placebo arm (29.7%; 95% CI: 24.8, 34.6, p = 0.00098).
The main prespecified QoL measure was Time-To-Deterioration (TTD) in global health status. Definitive 10% deterioration was defined as a worsening in the (EORTC QLQ-C30 global health scale score) by at least 10% compared to baseline, with no later improvement above this threshold observed during the treatment period, or death due to any cause. Addition of ribociclib to tamoxifen or NSAI resulted in delaying time-to-deterioration in the EORTC QLQ-C30 global health scale score compared with placebo plus tamoxifen or NSAI (median not estimable versus 21.2 months; HR of 0.699 [95% CI: 0.533, 0.916]; p=0.004. (See Figure 3.)

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In the pre-specified sub-group analysis of 495 patients who had received Ribociclib or placebo in combination with NSAI plus goserelin, the median PFS (95% CI) was 27.5 months (19.1, NE) in the ribociclib plus NSAI sub-group and 13.8 months (12.6, 17.4) in the placebo plus NSAI sub-group [HR: 0.569 (95% CI: 0.436, 0.743)]. Efficacy results are summarized in Table 5 and the Kaplan-Meier curves for PFS are provided in Figure 4. Results, in the ribociclib plus NSAI sub-group were consistent across sub-groups of age, race, prior adjuvant/ neo-adjuvant chemotherapy or hormonal therapies, liver and/or lung involvement and bone only metastatic disease.
In the NSAI sub-group, the median time to response (TTR) was not reached in either the ribociclib arm or the placebo arm and the probability of response by 6 months was 34.7% (95% CI: 29.0, 41.1) in the ribociclib arm and 23.7% (95% CI: 18.8, 29.6) in the placebo arm, indicating that a larger proportion of patients derived an earlier benefit in the ribociclib arm.
In the NSAI sub-group, the median duration of response (DOR) was not reached (95% CI: 18.3 months, NE) in the ribociclib arm and was 17.5 months (95% CI: 12.0, NE) in the placebo arm. Among patients with confirmed complete response or partial response, the probability of subsequent progression was 23.5% (95% CI: 15.6, 34.5) in the ribociclib arm and 36.4% (95% CI: 25.6, 49.8) in the placebo arm at 12 months. (See Tables 5 and 6, and Figure 4.)

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Final OS Analysis: The study met the key secondary endpoint of OS in the full analysis set demonstrating a statistically significant improvement in OS (hazard ratio [HR]: = 0.712; 95% CI: 0.535, 0.948; one- sided stratified log-rank test p-value: = 0.00973), resulting in an estimated relative risk reduction of death of approximately 29% in the ribociclib arm compared to the placebo arm. Median OS was not reached in the ribociclib arm and was 40.9 months (95% CI: 37.8, NE) in the placebo arm. The median duration of follow-up was 34.6 months.
In patients receiving a NSAI as endocrine combination partner, there were 61/248 deaths (24.6%) in the ribociclib arm and 80/247 (32.4%) in the placebo arm, with an OS hazard ratio of 0.699 (95% CI: 0.501, 0.976). Median OS was not reached in the ribociclib arm and was 40.7 months (95% CI: 37.4, NE) in the placebo arm (see Table 8 and Figure 6). Per the study protocol, OS was only formally tested in the overall study population.
The demonstrated OS benefit was consistent across exploratory subgroups and the safety profile of both treatment arms remained consistent with the results from the primary analysis.
Data for the full analysis set and for patients receiving NSAI as combination partner are presented in Table 7/Figure 5 and Table 8/Figure 6, respectively). (See Tables 7 and 8, and Figures 5 and 6.)

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Progression on subsequent line of therapy (PFS2): The probability of progression on next-line therapy or death (PFS2) in patients who received prior ribociclib was lower compared to patients in the placebo arm (HR: 0.692 (95% CI: 0.548, 0.875)) in the overall study population. The median PFS2 was 32.3 months (95% CI: 27.6, 38.3) in the placebo arm and was not reached (95% CI: 39.4, NE) in the ribociclib arm. Similar results were observed in the NSAI sub-group (HR: 0.660 (95% CI: 0.503, 0.868); median PFS2: 32.3 months (95% CI: 26.9, 38.3) in the placebo arm vs not reached (95% CI: 39.4, NE) in the ribociclib arm).
Study CLEE011F2301 (MONALEESA-3): Ribociclib was evaluated in a randomized double-blind, placebo controlled study of ribociclib in combination with fulvestrant for the treatment of men and postmenopausal women with hormone receptor (HR) positive, HER2-negative, advanced breast cancer who have received no or only one line of prior endocrine treatment.
A total of 726 patients were randomized in a 2:1 ratio to receive either ribociclib 600 mg and fulvestrant (n= 484) or placebo and fulvestrant (n= 242) stratified according to the presence of liver and/or lung metastases [Yes (n=351 (48.3%)) versus No (n=375 (51.7%))], prior endocrine therapy [A (n=354 (48.8%)) vs B (n=372 (51.2%)] (see Figure 7 footnote) Demographics and baseline disease characteristics were balanced and comparable between study arms. Ribociclib 600 mg or placebo was given orally daily for 21 consecutive days followed by 7 days off treatment in combination with fulvestrant 500 mg administered intramuscularly on Cycle 1, Day 1, Cycle 1, Day 15, Cycle 2, Day 1 and every 28 days thereafter.
Patients enrolled in this study had a median age of 63 years (range 31 to 89). 46.7% of patients were aged 65 years and older, including 13.8% patients aged 75 years and older. The patients included were Caucasian (85.3%), Asian (8.7%), or Black (0.7%). Nearly all patients (99.7%) had an ECOG performance status of 0 or 1. First and second line patients were enrolled in this study (of whom 19.1 % of patients had de novo metastatic disease). 42.7% of patients had received chemotherapy in the adjuvant vs 13.1% in the neo-adjuvant setting and 58.5% had received endocrine therapy in the adjuvant vs 1.4% in the neo-adjuvant setting. Prior to study entry 21.2% of patients had bone only disease and 60.5% of patients had visceral disease. Demographics and baseline disease characteristics were balanced and comparable between study arms.
The primary endpoint for the study was performed after observing 361 PFS events using RECIST v1.1, based on the investigator assessment in the full population (all randomized patients) and confirmed by a blinded independent central radiological assessment. The median follow-up time at the time of primary PFS analysis was 20.4 months.
The primary efficacy results demonstrated a statistically significant improvement in PFS in patients receiving ribociclib plus fulvestrant compared to patients receiving placebo plus fulvestrant in the full analysis set (HR: 0.593; 95% CI: 0.480, 0.732; one sided stratified log-rank test p-value 4.1x10-7), with an estimated 41% reduction in relative risk of progression or death in favor of the ribociclib plus fulvestrant arm. The median (95% CI) PFS was 20.5 months (18.5, 23.5) in the ribociclib plus fulvestrant and 12.8 months (10.9, 16.3) in the placebo plus fulvestrant arm. PFS is summarized in Table 9 and the Kaplan-Meier curve for PFS is provided in Figure 7.
In the subgroup of patients who were treatment naive in the metastatic/advanced disease setting, the HR (95% CI) was 0.577 (0.415, 0.802), with a median PFS (95% CI) not reached in the ribociclib arm and 18.3 months (14.8, 23.1) in the placebo arm.
In the subgroup of patients who had received up to 1 line of treatment for metastatic/advanced disease, the hazard ratio (95% CI) was 0.565 (0.428, 0.744), with a median PFS (95% CI) of 14.6 months (12.5, 18.5) and 9.1 months (6.1, 11.1) in the ribociclib and placebo arms, respectively.
Results were consistent across pre-specified subgroups of age, prior adjuvant or neo-adjuvant chemotherapy or hormonal therapies, liver and/or lung involvement, bone only metastatic disease.
The results for PFS based on the blinded independent central radiological assessment, which included a random subset of approximately 40% of randomized patients, were consistent with the primary efficacy results based on the investigator's assessment (HR: 0.492; 95% CI: (0.345, 0.703)).
The median TTR was not reached in either the ribociclib plus fulvestrant arm or the placebo plus fulvestrant arm, and the probability of having a response by 6 months was 26.6% (95% CI: 22.7, 31.0) in the ribociclib plus fulvestrant arm and 16.2% (95% CI: 12.0, 21.6) in the placebo plus fulvestrant arm, indicating that a larger proportion of patients derived an earlier benefit in the ribociclib plus fulvestrant arm.
The median DOR was neither reached (95% CI: 16.1, NE) in the ribociclib plus fulvestrant arm nor in placebo plus fulvestrant arm (95% CI: 13.8, NE). Among patients with confirmed CR PR, the probability of subsequent progression was 21.7% (95% CI: 15.5, 30.0) in the ribociclib plus fulvestrant arm and 25.2% (95% CI: 15.1, 40.2) in the placebo plus fulvestrant arm at month 12.
The global health status/ QoL were similar between the ribociclib plus fulvestrant arm and the placebo plus fulvestrant arm. The main prespecified QoL measure was TTD in global health status. A definitive 10% deterioration was defined as a worsening in score (EORTC QLQ-C30 global health scale score) by at least 10% compared to baseline, with no later improvement above this threshold observed during the treatment period, or death due to any cause. Addition of Ribociclib to fulvestrant resulted in delaying TTD in the EORTC QLQ-C30 global health scale score compared with placebo plus fulvestrant, (median not estimable versus 19.4 months; HR: of 0.795 [95% CI: 0.602, 1.050]; p-value 0.051.
At the time of primary PFS analysis, with a median follow-up of 20.4 months, OS was not mature with 34% of events (HR: 0.67 [95% CI: 0.47, 0.96]). (See Tables 9 and 10 and Figure 7.)

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Pharmacokinetics: The pharmacokinetics of ribociclib were investigated in patients with advanced cancer following oral daily doses of 50 mg to 1,200 mg. Healthy subjects received single oral doses of 400 or 600 mg or repeated daily oral doses (8 days) of 400 mg.
Absorption: Following oral administration of ribociclib to patients with advanced solid tumors or lymphomas peak plasma levels (Cmax) of ribociclib were achieved between 1 and 4 hours (time to reach maximum concentration, Tmax). Ribociclib exhibited slightly over-proportional increases in exposure (Cmax and AUC) across the dose range tested (50 to 1,200 mg). Following repeated once-daily dosing, steady state was generally achieved after 8 days and ribociclib accumulated with a geometric mean accumulation ratio of 2.51 (range: 0.972 to 6.40).
Food effect: Compared to the fasted state, oral administration of a single 600 mg dose of ribociclib film-coated tablet formulation with a high-fat, high-calorie meal had no effect on the rate and extent of absorption of ribociclib (Cmax GMR: 1.00; 90% CI: 0.898, 1.11; AUCinf GMR: 1.06; 90% CI: 1.01, 1.12) (see Interactions).
Distribution: Binding of ribociclib to human plasma proteins in vitro was approximately 70% and independent of concentration (10 to 10,000 ng/mL). Ribociclib was equally distributed between red blood cells and plasma with a mean in vivo blood-to-plasma ratio of 1.04. The apparent volume of distribution at steady state (Vss/F) was 1,090 L based on the population pharmacokinetic analysis.
Biotransformation/metabolism: In vitro and in vivo studies indicated that ribociclib undergoes extensive hepatic metabolism mainly via CYP3A4 in humans. Following oral administration of a single 600 mg dose of [14C]ribociclib to humans, the primary metabolic pathways for ribociclib involved oxidation (dealkylation, C- and/or N-oxygenation, oxidation (-2H)) and combinations thereof. Phase II conjugates of ribociclib phase I metabolites involved N-acetylation, sulfation, cysteine conjugation, glycosylation and glucuronidation. Ribociclib was the major circulating drug-derived entity in plasma (43.5%). The major circulating metabolites included metabolite M13 (CCI284, N-hydroxylation), M4 (LEQ803, N-demethylation), and M1 (secondary glucuronide), each representing an estimated 9.39%, 8.60%, and 7.78% of total radioactivity, and 21.6%, 19.8%, and 17.9% of ribociclib exposure, respectively. Clinical activity (pharmacological and safety) of ribociclib was primarily due to parent drug, with negligible contribution from circulating metabolites.
Ribociclib was extensively metabolized with the unchanged drug accounting for 17.3% and 12.1% of the dose in feces and urine, respectively. Metabolite LEQ803 was a significant metabolite in excreta and represented approximately 13.9% and 3.74% of the administered dose in feces and urine, respectively. Numerous other metabolites were detected in both feces and urine in minor amounts (≤2.78% of the administered dose).
Elimination: The geometric mean plasma effective half-life (based on accumulation ratio) was 32.0 hours (63% CV) and the geometric mean apparent oral clearance (CL/F) was 25.5 L/hr (66% CV) at steady state at 600 mg in patients with advanced cancer. The geometric mean plasma terminal half-life (T½) of ribociclib ranged from 29.7 to 54.7 hours and the geometric mean CL/F of ribociclib ranged from 39.9 to 77.5 L/hr at 600 mg across studies in healthy subjects.
Ribociclib is eliminated mainly via the feces, with a small contribution from the renal route. In 6 healthy male subjects, following a single oral dose of [14C] ribociclib, 91.7% of the total administered radioactive dose was recovered within 21 days; feces was the major route of excretion (69.1%), with 22.6% of the dose recovered in the urine.
Linearity/non-linearity: Ribociclib exhibited slightly over-proportional increases in exposure (Cmax and AUC) across the dose range of 50 mg to 1,200 mg following both single dose and repeated doses. This analysis is limited by the small sample sizes for most of the dose cohorts, with a majority of the data coming from the 600 mg dose cohort.
Special populations: Renal impairment: The effect of renal function on the pharmacokinetics of ribociclib was also assessed in a renal impairment study in non-cancer subjects that included 14 subjects with normal renal function (estimated Glomerular Filtration Rate (eGFR ≥90 mL/min), 8 subjects with mild renal impairment (eGFR 60 to <90 mL/min), 6 subjects with moderate renal impairment (eGFR 30 to <60 mL/min), 7 subjects with severe renal impairment (eGFR 15 to <30 mL/min), and 3 subjects with end stage renal disease (ESRD) (eGFR <15 mL/min) at a single oral ribociclib dose of 400 mg/day.
AUCinf increased to 1.62-fold, 1.94-fold and 2.67-fold, and Cmax increased to 1.80-fold, 1.79-fold and 2.30-fold in subjects with mild, moderate and severe renal impairment, relative to the exposure in subjects with normal renal function. A fold difference for subjects with ESRD was not calculated due to the small number of subjects (see Dosage & Administration).
No dose adjustment is necessary in patients with mild or moderate renal impairment. The effect of renal function on the pharmacokinetics of ribociclib was also assessed in cancer patients. Based on a population pharmacokinetic analysis that included 438 cancer patients with normal renal function (eGFR ≥90 mL/min/1.73 m2), 488 patients with mild renal impairment (eGFR 60 to <90 mL/min/1.73m2) and 113 patients with moderate renal impairment (eGFR 30 to <60 mL/min/1.73 m2), mild and moderate renal impairment had no effect on the exposure of ribociclib. In addition, in a sub-group analysis of PK data from studies in cancer patients following oral administration of ribociclib 600 mg as a single dose or repeat doses (MONALEESA-7, CLEE011X2101 and CLEE011X2107), AUC and Cmax of ribociclib following a single dose or at steady state in patients with mild or moderate renal impairment were comparable to patients with normal renal function, suggesting no clinically meaningful effect of mild or moderate renal impairment on ribociclib exposure (see Dosage & Administration).
Hepatic impairment: No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh A); a dose adjustment is required in patients with moderate (Child-Pugh B) and severe hepatic impairment (Child-Pugh C) and a starting dose of 400 mg is recommended. 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. Based on a population pharmacokinetic analysis that included 160 patients with normal hepatic function and 47 patients with mild hepatic impairment, mild hepatic impairment had no effect on the exposure of ribociclib, further supporting the findings from the dedicated hepatic impairment study (see Dosage & Administration).
Effect of age, weight, gender and race: The population pharmacokinetic analysis showed that there are no clinically relevant effects of age, body weight, gender, or race on the systemic exposure of ribociclib that would require a dose adjustment.
Geriatric patients: Of the 334 patients who received ribociclib (Kryxana) in the phase III study (MONALEESA 2, ribociclib plus letrozole arm), 150 patients (44.9%) were ≥65 years of age and 35 patients (10.5%) were ≥75 years of age. Of 484 patients who received Ribociclib in the phase III study (MONALEESA 3, ribociclib plus fulvestrant arm), 226 patients (46.7%) were ≥65 years of age and 65 patients (13.4%) were ≥75 years of age. No overall differences in the safety or effectiveness of ribociclib were observed between these patients and younger patients (see Dosage & Administration).
Interactions: Strong CYP3A inhibitors: A drug interaction study in healthy subjects was conducted with ritonavir (strong CYP3A inhibitor). Compared to ribociclib alone, ritonavir (100 mg b.i.d for 14 days) increased ribociclib Cmax and AUCinf by 1.7-fold and 3.2-fold, respectively, following a single 400 mg ribociclib dose. Cmax and AUClast for LEQ803 (a prominent metabolite of ribociclib, accounting for less than 10% of parent exposure) decreased by 96% and 98%, respectively. Simulations using PBPK suggested that a moderate CYP3A4 inhibitor (erythromycin) may increase Cmax and AUC of ribociclib 400mg single dose by 1.3-fold and 1.9-fold, respectively (see Dosage & Administration, Precautions and Interactions).
Strong CYP3A inducers: A drug interaction study in healthy subjects was conducted with rifampicin (strong CYP3A4 inducer). Compared to ribociclib alone, rifampicin (600 mg daily for 14 days) decreased ribociclib Cmax and AUCinf by 81% and 89%, respectively, following a single 600 mg ribociclib dose. LEQ803 Cmax increased 1.7-fold and AUCinf decreased by 27%, respectively. Simulations using PBPK suggested that a moderate CYP3A inducer (efavirenz) may decrease ribociclib single dose Cmax and AUC by 37% and 60%, respectively (see Interactions).
Cytochrome P450 enzymes (CYP3A4 and CYP1A2 substrates): A drug interaction study in healthy subjects was conducted as a cocktail study with midazolam (sensitive CYP3A4 substrate) and caffeine (sensitive CYP1A2 substrate). Compared to midazolam and caffeine alone, multiple doses of ribociclib (400 mg once daily for 8 days) increased midazolam Cmax and AUCinf by 2.1-fold and 3.8-fold, respectively. Simulations using PBPK suggested that at a 600 mg ribociclib dose, midazolam Cmax and AUC may increase 2.4-fold and 5.2-fold, respectively. The effect of multiple doses of ribociclib on caffeine was minimal, with Cmax decreasing by 10% and AUCinf increasing slightly by 20%. Simulations using PBPK suggested only weak inhibitory effects on CYP1A2 substrates at a 600 mg ribociclib dose (see Interactions).
Ribociclib exhibited no capacity to inhibit CYP2E1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6, and showed no apparent time-dependent inhibition of CYP1A2, CYP2C9, and CYP2D6 at clinically relevant concentrations. No induction of CYP1A2, CYP2B6, CYP2C9 or CYP3A4 was observed in vitro at clinically relevant concentrations (see Interactions).
Gastric pH-elevating agents: Ribociclib exhibits high solubility at or below pH 4.5 and in bio-relevant media (at pH 5.0 and 6.5). Co-administration of ribociclib with medicinal products that elevate the gastric pH was not evaluated in a clinical trial; however, altered ribociclib absorption was not observed in population pharmacokinetic analysis nor in simulations using PBPK models (see Dosage & Administration and Interactions).
Letrozole: Data from clinical trials in patients with breast cancer and a population PK analysis indicated no drug interaction between ribociclib and letrozole following co-administration of the drugs (see Interactions).
Exemestane: Data from a clinical trial in patients with breast cancer indicated no clinically relevant drug interaction between ribociclib and exemestane following co-administration of the drugs.
Anastrozole: Data from a clinical trial in patients with breast cancer indicated no clinically relevant drug interaction between ribociclib and anastrozole following coadministration of the drugs.
Fulvestrant: Data from a clinical trial in patients with breast cancer indicated no clinically relevant effect of fulvestrant on ribociclib exposure following co-administration of the drugs.
Tamoxifen: Data from a clinical trial in patients with breast cancer indicated that tamoxifen exposure was increased approximately 2-fold following coadministration of ribociclib and tamoxifen.
Effect of ribociclib on transporters: In vitro evaluations indicated that ribociclib has a low potential to inhibit the activities of the drug transporters P-gp, OATP1B1/B3, OCT1, MATE2K at clinically relevant concentrations. Ribociclib may inhibit BCRP, OCT2, MATE1, and human BSEP at clinically relevant concentrations (see Interactions).
Effect of transporters on ribociclib: Based on in vitro data, P-gp and BCRP mediated transport are unlikely to affect the extent of oral absorption of ribociclib at therapeutic doses. Ribociclib is not a substrate for hepatic uptake transporters OATP1B1/1B3 or OCT-1 in vitro (see Interactions).
Toxicology: Non-Clinical Safety Data: Ribociclib was evaluated in safety pharmacology, repeated dose toxicity, genotoxicity, reproductive toxicity, and phototoxicity studies.
Safety pharmacology: Ribociclib did not have effects on CNS or respiratory functions. In vivo cardiac safety studies in dogs demonstrated dose and concentration related QTc interval prolongation at an exposure that would be expected to be achieved in patients following the recommended dose of 600 mg. As well, there is potential to induce incidences of PVCs at elevated exposures (approximately 5 fold the anticipated clinical Cmax).
Repeated dose toxicity: Repeated dose toxicity studies (treatment schedule of 3 weeks on/1 week off) in rats up to 27 weeks duration and dogs up to 39 weeks duration, revealed the hepatobiliary system (proliferative changes, cholestasis, sand-like gallbladder calculi, and inspissated bile) as the primary target organ of toxicity of ribociclib. Target organs associated with the pharmacological action of ribociclib in repeat dose studies include bone marrow (hypocellularity), lymphoid system (lymphoid depletion), intestinal mucosa (atrophy), skin (atrophy), bone (decreased bone formation), kidney (concurrent degeneration and regeneration of tubular epithelial cells) and testes (atrophy). Besides the atrophic changes seen in the testes, which showed a trend towards reversibility, all other changes were fully reversible after a 4-week treatment free period. These effects can be linked to a direct anti-proliferative effect on the testicular germ cells resulting in atrophy of the seminiferous tubules. Exposure to ribociclib in animals in the toxicity studies was generally less than or equal to that observed in patients receiving multiple doses of 600 mg/day (based on AUC).
Reproductive toxicity/Fertility: See Use in Pregnancy & Lactation.
Genotoxicity: Genotoxicity studies in bacterial in vitro systems and in mammalian in vitro and in vivo systems with and without metabolic activation did not reveal any evidence for a mutagenic potential of ribociclib.
Phototoxicity: Ribociclib was shown to absorb light in the UV-B and UV-A range. An in vitro phototoxicity test did not identify a relevant phototoxicity potential for ribociclib. The risk that ribociclib causes photosensitization in patients is considered very low.
Carcinogenesis: No carcinogenesis studies have been conducted with ribociclib.
Indications/Uses
Ribociclib (Kryxana) is (a cyclin-dependent kinase inhibitor, CDKi) indicated for the treatment of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2) negative (locally) advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant.
In pre or peri-menopausal women, the endocrine therapy should be combined with a luteinizing hormone-releasing hormone (LHRH) agonist.
Dosage/Direction for Use
Treatment with ribociclib should be initiated by a physician experienced in the use of anticancer therapies.
Dosage regimen: General target population: The recommended dose is 600 mg (3 x 200 mg film-coated tablets) taken orally, once daily for 21 consecutive days followed by 7 days off treatment resulting in a complete cycle of 28 days. Ribociclib can be taken with or without food (see Interactions).
For dosing and administration with the aromatase inhibitor, refer to the applicable full prescribing information.
Patients should take their dose of ribociclib and the aromatase inhibitor at approximately the same time each day, preferably in the morning.
When co-administered with ribociclib, the recommended dose of fulvestrant is 500 mg administered intramuscularly on days 1, 15 and 29, and once monthly thereafter. Please refer to full prescribing information of fulvestrant.
Treatment of pre or peri-menopausal women with ribociclib co-administration should include an LHRH agonist according to local clinical practice standards.
Dose modifications: Management of severe or intolerable adverse drug reactions (ADRs) may require temporary dose interruption, reduction, or discontinuation of ribociclib. If dose reduction is required, the recommended dose reduction guidelines for adverse drug reactions (ADRs) are listed in Table 11. (See Table 11.)

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Tables 12, 13, 14 and 15 summarize recommendations for dose interruption, reduction, or discontinuation of ribociclib in the management of specific ADRs. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment (see Precautions and Adverse Reactions). (See Tables 12, 13, 14 and 15.)

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Refer to the full prescribing information for the coadministered aromatase inhibitor or fulvestrant or LHRH agonist for dose modification guidelines in the event of toxicity and other relevant safety information.
Dose modification for use of ribociclib (Kryxana) with strong CYP3A inhibitors: Concomitant use of ribociclib should be avoided with strong CYP3A inhibitors and an alternative concomitant medication should be considered with low potential for CYP3A inhibition. If a strong CYP3A inhibitor must be co-administered, the ribociclib dose should be reduced to 200 mg once daily. If the strong inhibitor is discontinued, the ribociclib dose should be changed (after at least 5 elimination half-lives of the strong CYP3A inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor (see Precautions, Interactions and Pharmacology under Actions).
Special populations: Renal impairment: Based on population pharmacokinetic analysis and data from cancer patients in clinical trials, no dose adjustment is necessary in patients with mild or moderate renal impairment (see Pharmacology under Actions).
Based on a renal impairment study in healthy subjects and non-cancer subjects with severe renal impairment, a starting dose of 200 mg is recommended. Ribociclib has not been studied in breast cancer patients with severe renal impairment (see Pharmacology under Actions).
Hepatic impairment: Based on a hepatic impairment study in healthy subjects and non-cancer subjects with impaired hepatic function, no dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A). A dose adjustment is required in patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) and the starting dose of 400 mg is recommended. Ribociclib has not been studied in breast cancer patients with moderate and severe hepatic impairment (see Pharmacology under Actions).
Review the full prescribing information for the aromatase inhibitor, fulvestrant, or the LHRH agonist for dose modifications related to hepatic impairment.
Pediatric patients: There are limited data in pediatric patients and the safety and efficacy of ribociclib in this population have not been established.
Geriatric patients (65 years of age or older): No dose adjustment is required in patients over 65 years of age (see Pharmacology under Actions).
Method of administration: Ribociclib should be taken orally once daily at the same time every day, preferably in the morning, with or without food. If the patient vomits after taking the dose or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time. The tablets should be swallowed whole (tablets should not be chewed, crushed or split prior to swallowing). Tablets that are broken, cracked, or otherwise not intact should not be ingested.
Overdosage
There is limited experience with reported cases of ribociclib overdose in humans. General symptomatic and supportive measures should be initiated in all cases of overdosage where necessary.
Contraindications
Ribociclib is contraindicated in patients with hypersensitivity to the active substance, or to any of the excipients.
Special Precautions
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 (73.7%) and a Grade 3 or 4 decrease in neutrophil counts (based on laboratory findings) was reported in 58.4% 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 16 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 1.4% 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 12 Dose Modification and Management for Neutropenia (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 beresumed 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 (9.7% vs. 1.5 %) and AST (6.7% vs. 2.1%) were reported in the ribociclib plus any combination and placebo plus any combination arms, respectively. Grade 4 increases in ALT (1.9% vs. 0.1%) 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, 83.2% (89/107) 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 85 days for the ribociclib plus any combination treatment group. The median time to resolution (to normalization or Grade ≤2) was 22 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 13 (see Dosage & Administration). Recommendations for patients who have elevated AST/ALT Grade ≥3 at baseline have not been established.
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 14 patients (1.3%) had >500 ms post-baseline QTcF interval value, and 59 patients (5.6%) 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 bradyarrhythmias; 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: Pharmacology: Clinical studies under Actions).
Based on the observed QT prolongation during treatment, ribociclib may require dose interruption, reduction or discontinuation as described in Table 14 (see Dosage & Administration, Adverse Reactions and Pharmacology under Actions).
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).
Use In Pregnancy & Lactation
Pregnancy: Risk summary: Based on animal data and its mechanism of action, it is possible that ribociclib can cause fetal harm when administered to a pregnant woman.
The patient should be advised of the risk to a fetus, if ribociclib is used during pregnancy or if the patient becomes pregnant while taking this medicinal product.
There are no adequate and well-controlled studies in pregnant women. Reproductive studies in rats and rabbits have demonstrated ribociclib-induced embryotoxicity, fetotoxicity and teratogenicity. Following prenatal exposure, increased incidences of post-implantation loss and reduced fetal weights were observed in rats and ribociclib was teratogenic in rabbits as evidenced by increased incidences of fetal abnormalities (malformations and external, visceral and skeletal variants) at exposures lower than or 1.5 times the exposure in humans, respectively, at the highest recommended dose of 600 mg/day based on AUC. There are no available human data informing the drug-associated risk.
Data: Animal Data: In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of ribociclib up to 1,000 mg/kg/day and 60 mg/kg/day, respectively, during the period of organogenesis.
In rats, 1,000 mg/kg/day was lethal in the maternal animals. At 300 mg/kg/day, a slight, non-adverse trend towards reduced maternal body weight gain and fetal toxicity evidenced by reduced fetal weights accompanied by skeletal changes were considered to be transitory and/or related to the lower fetal weights. There were no effects upon embryo-fetal mortality or adverse effects on fetal morphology at 50 or 300 mg/kg/day. The no-observed-adverse-effect level (NOAEL) for maternal toxicity was considered to be 300 mg/kg/day. The no-observed-effect-level (NOEL) for embryo-fetal development was considered to be 50 mg/kg/day.
In rabbits at doses ≥30 mg/kg/day, there were adverse effects on embryo-fetal development as evidenced by increased incidences of fetal abnormalities (malformations and external, visceral and skeletal variants) and fetal growth (lower fetal weights). These findings included reduced/small lung lobes and additional vessel on the aortic arch and diaphragmatic hernia, absent accessory lobe or (partly) fused lung lobes and reduced/small accessory lung lobe (30 and 60 mg/kg), extra/rudimentary 13th ribs and misshapen hyoid bone and reduced number of phalanges in the pollex. There was no evidence of embryo-fetal mortality. The no-observed-effect level (NOEL) for maternal toxicity was considered to be at least 30 mg/kg/day and the NOEL for the embryo-fetal development was 10 mg/kg/day.
At 300 mg/kg/day in rats and 30 mg/kg/day in rabbits, the maternal systemic exposure (AUC) were 13,800 ng*hr/mL and 36,700 ng*hr/mL, lower than or at 1.5 times, the one achieved in patients at the highest recommended dose of 600 mg/day.
Lactation: Risk summary: It is not known if ribociclib is present in human milk. There are no data on the effects of ribociclib on the breastfed child or the effects of ribociclib on milk production. Ribociclib and its metabolites readily passed into the milk of lactating rats. Because of the potential for serious adverse reactions in nursing infants from ribociclib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. It is recommended that women taking ribociclib should not breastfeed for at least 21 days after the last dose.
Data: Animal data: In lactating rats administered a single dose of 50 mg/kg, exposure to ribociclib was 3.56-fold higher in milk than in maternal plasma.
Females and males of reproductive potential: Based on animal studies, ribociclib can cause fetal harm when administered to a pregnant woman (see Pharmacology: Toxicology: Non-Clinical Safety Data under Actions).
Pregnancy testing: For females of reproductive potential the pregnancy status should be verified prior to initiating treatment with ribociclib.
Contraception: Females of reproductive potential should be advised that animal studies have been performed showing ribociclib to be harmful to the developing fetus. Sexually active females of reproductive potential should use effective contraception (methods that result in < 1% pregnancy rates) when using ribociclib during treatment and for 21 days after stopping treatment.
Infertility: In a fertility study in female rats, ribociclib did not affect the reproductive function, fertility or early embryonic development at any dose up to 300 mg/kg/day (likely at an exposure lower than or equal to patients clinical exposure at the highest recommended dose of 600 mg/day based on AUC).
A fertility study in male rats has not been performed; however, atrophic changes in testes were reported in repeated-dose toxicity studies in rats and dogs at exposures that were less or equal to the human exposure at the highest recommended daily dose of 600 mg/day based on AUC (see Pharmacology: Toxicology: Non-Clinical Safety Data under Actions). There are no clinical data available regarding the effects of ribociclib on fertility. Based on animal studies, ribociclib may impair fertility in males of reproductive potential.
Adverse Reactions
Summary of the safety profile: The overall safety profile of ribociclib reported as follows is based on the pooled data set of 1065 patients who received ribociclib in combination with endocrine therapy (N=582 in combination with an aromatase inhibitor, and N=483 in combination with fulvestrant) in double-blind, placebo-controlled phase III clinical studies (MONALEESA-2, MONALEESA-7-NSAI arm, MONALEESA-3) in HR-positive, HER2-negative advanced or metastatic breast cancer. The median duration of exposure to ribociclib treatment across the pooled phase III studies dataset was 16.53 months with 61.7% patients exposed for ≥12 months.
Dose reductions due to adverse events (AEs), regardless of causality occurred in 37.3% of patients receiving ribociclib in phase III clinical studies regardless of the combination and in 3.4% of patients receiving placebo. Permanent discontinuations due to adverse events were reported in 7.0% of patients receiving ribociclib plus any combination and in 2.9% of patients receiving placebo plus any combination. The most common AEs leading to permanent discontinuation of ribociclib with any combination treatment partner were ALT increased (2.0%), AST increased (1.4%) and vomiting (0.8%).
In the pooled analysis of three phase III studies, on treatment deaths were reported in 21 patients (2.0%) treated with ribociclib plus any combination vs 16 patients (2.0%) treated with placebo plus any combination treatment. Excluding the most frequent cause of death disease progression, three treatment related causes of deaths were reported in patients treated with ribociclib plus any combination treatment. Causes of death were acute respiratory distress syndrome 1 (0.1%), acute respiratory failure 1 (0.1%), and sudden death (in the setting of Grade 3 hypokalemia and Grade 2 QT prolongation) 1 (0.1%).
The most common ADRs across the pooled phase III studies (reported at a frequency of ≥20% and exceeding the frequency for placebo) were infections, neutropenia, leukopenia, headache, cough, nausea, fatigue, diarrhea, vomiting, constipation, alopecia and rash.
The most common Grade 3/4 ADRs in the pooled data (reported at a frequency of ≥2% and for which the frequency for ribociclib exceeds the frequency for placebo) were neutropenia, infections, leukopenia, anemia, abnormal liver function tests, lymphopenia, hypophosphatemia, and vomiting.
Tabulated summary of adverse drug reactions based on pooled dataset from 3 phase III clinical studies: ADRs from the phase III clinical studies (Table 16) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). (See Table 16.)

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Laboratory abnormalities: Clinically relevant abnormalities of routine hematological or biochemical laboratory values from the dataset of 3 pooled phase III studies, are presented in Table 17. (See Table 17.)

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Description of selected adverse drug reactions: Neutropenia: Neutropenia was most frequently reported by laboratory findings in the phase III studies. Based on its severity, neutropenia was managed by laboratory monitoring, dose interruption and/or dose modification. Treatment discontinuation due to neutropenia was low (0.8%) in patients receiving ribociclib plus any combination partner (see Dosage & Administration and Precautions).
Hepatobiliary toxicity: In the phase III clinical studies, hepatobiliary toxicity events occurred in a higher proportion of patients in the ribociclib plus any combination arms vs the placebo plus any combination arms (23.2% vs 16.5%, respectively), with more Grade 3/4 AEs reported in patients treated with ribociclib any combination treatment (11.4% vs. 5.4%, respectively). Dose interruptions and/or adjustments due to hepatobiliary toxicity events were reported in 10.4% of ribociclib-treated patients, primarily due to ALT increased (6.9%) and/or AST increased (6.1%).Discontinuation of treatment with ribociclib plus letrozole due to abnormal liver function tests and hepatotoxicity occured in 2.3% and 0.4% of patients, respectively (see Precautions).
QT prolongation: In the phase III clinical studies, 8.4% of patients in the ribociclib arm and 3.2% in the placebo arm had at least one event of QT interval prolongation (including ECG QT interval prolonged, syncope). Dose interruptions-adjustments were reported in 2.3% of ribociclib treated patients due to electrocardiogram QT interval prolonged and syncope.
A central analysis of ECG data (average of triplicate) showed 52 patients (4.9%) and 11 patients (1.4%) with at least one post-baseline QTcF interval >480 m sec for the ribociclib treatment arm and the placebo arm respectively. Among the patients who had QTcF interval prolongation of >480 ms, the median time to onset was 15 days, regardless of the combination and these changes were reversible with dose interruption and/or dose adjustment (see Dosage & Administration, Precautions and Pharmacology under Actions).
Drug Interactions
Ribociclib is primarily metabolized by CYP3A and is a time-dependent inhibitor of CYP3A in vivo. Therefore, medicinal products which can influence CYP3A enzyme activity may alter the pharmacokinetics of ribociclib.
Medicinal products that may increase ribociclib plasma concentrations: Co-administration of a strong CYP3A4 inhibitor (ritonavir) increased ribociclib exposure in healthy subjects by 3.21-fold. Concomitant use of strong CYP3A inhibitors, including, but not limited to, clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir, ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, and voriconazole (see Precautions) should be avoided. Alternative concomitant medications with a low potential to inhibit CYP3A should be considered and patients should be monitored for ADRs (see Dosage & Administration, Precautions and Pharmacology under Actions).
If co-administration of ribociclib with a strong CYP3A inhibitor cannot be avoided, the ribociclib dose should be reduced to 200 mg. However, there are no clinical data with this dose adjustment (see Dosage & Administration). If the strong inhibitor is discontinued, the ribociclib dose should be resumed (after at least 5 elimination half-lives of the CYP3A inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Due to inter-patient variability, the recommended dose adjustments may not be optimal in all patients, therefore close monitoring for ADRs is recommended. In the event of ribociclib-related toxicity, the dose should be modified (see Dosage & Administration), or treatment should be interrupted until toxicity has resolved (see Dosage & Administration and Pharmacology under Actions).
Patients should be instructed to avoid grapefruits or grapefruit juice, all of which are known to inhibit cytochrome CYP3A enzymes and may increase the exposure to ribociclib.
Medicinal products that may decrease ribociclib plasma concentrations: Co-administration of a strong CYP3A4 inducer (rifampin) decreased the plasma exposure of ribociclib in healthy subjects by 89%. Avoid concomitant use of strong CYP3A inducers, including, but not limited to, phenytoin, rifampin, carbamazepine and St John's Wort (Hypericum perforatum). An alternate concomitant medication with no or minimal potential to induce CYP3A should be considered (see Precautions and Pharmacology under Actions).
Medicinal products that may have their plasma concentrations altered by ribociclib: Co-administration of midazolam (CYP3A4 substrate) with multiple doses of ribociclib (400 mg) increased the midazolam exposure by 280% (3.80-fold) in healthy subjects compared with administration of midazolam alone. Simulations using physiologically-based PK (PBPK) models suggested that ribociclib given at the clinically relevant dose of 600 mg is expected to increase the midazolam AUC by 5.2-fold. Therefore, caution is recommended when ribociclib is administered with CYP3A substrates with a narrow therapeutic index. The dose of a sensitive CYP3A substrate with a narrow therapeutic index, including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus, may need to be reduced as ribociclib has the potential to increase their exposure (see Pharmacology under Actions).
Co-administration of caffeine (CYP1A2 substrate) with multiple doses of ribociclib (400 mg) increased caffeine exposure by 20% (1.20-fold) in healthy subjects, compared with administration of caffeine alone. At the clinically relevant dose of 600 mg, simulations using PBPK models predicted only weak inhibitory effects of ribociclib on CYP1A2 substrates (<2-fold increase in AUC) (see Pharmacology under Actions).
Medicinal products that are substrates of transporters: In vitro evaluations indicated that ribociclib has a low potential to inhibit the activities of drug transporters P-gp, OAT1/3, OATP1B1/B3, MATE2K and OCT1 at clinically relevant concentrations. Ribociclib may inhibit BCRP, OCT2, MATE1, and human BSEP at clinically relevant concentrations (see Pharmacology under Actions).
Drug-food interactions: Ribociclib can be administered with or without food (see Dosage & Administration).
Compared to the fasted state, oral administration of a single 600 mg dose of ribociclib film-coated tablets with a high-fat, high-calorie meal had no effect on the rate and extent of absorption of ribociclib (Cmax GMR: 1.00; 90% CI: 0.898, 1.11; AUCinf GMR: 1.06; 90% CI: 1.01, 1.12 (see Pharmacology under Actions).
Gastric pH elevating medications: Ribociclib exhibits high solubility at or below pH 4.5 and in bio-relevant media (at pH 5.0 and 6.5). Co-administration with medicinal products that elevate the gastric pH was not evaluated in a clinical trial; however, altered ribociclib absorption was not observed in the population pharmacokinetic analysis nor in simulations using PBPK models (see Pharmacology under Actions).
Anticipated interactions: Antiarrhythmic medicines and other medicinal products that may prolong the QT interval: Co-administration of ribociclib should be avoided with medicinal products with known potential to prolong the QT interval such as antiarrhythmic medicines. Concomitant use of antiarrhythmic medicines (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol), other medicinal products that are known to prolong the QT interval, including but not limited to chloroquine, halofantrine, clarithromycin, ciprofloxacin, levofloxacin, azithromycin, haloperidol, methadone, moxifloxacin, bepridil, pimozide and ondansetron (i.v), should be avoided. Ribociclib is not recommended for use in combination with tamoxifen (see Precautions).
Caution For Usage
Incompatibilities: Not applicable.
Storage
Store at temperatures not exceeding 30°C.
ATC Classification
L01EF02 - ribociclib ; Belongs to the class of cyclin-dependent kinase (CDK) inhibitors. Used in the treatment of cancer.
Presentation/Packing
FC tab 200 mg (light greyish violet, unscored, round, curved with beveled edges, debossed with "RIC" on one side and "NVR" on the other side) x 21's.
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