Ribociclib, a selective inhibitor of cyclin-dependent kinases 4 (CDK4) and 6 (CDK6), is an antineoplastic agent.1, 2, 4, 14
Ribociclib is used in combination with an aromatase inhibitor for the adjuvant treatment of adults with hormone receptor-positive, human epidermal growth receptor type 2 (HER2)-negative stage II and III early breast cancer at high risk of recurrence.1 Ribociclib is also used for the treatment of adults with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy or fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy.1, 2
Advanced or Metastatic Disease - Combination Therapy with an Aromatase Inhibitor
Ribociclib is used for the treatment of adults with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy.1, 2, 14, 19, 22 A statistically significant progression-free survival benefit has been observed in postmenopausal women with previously untreated, hormone receptor-positive, HER2-negative advanced or metastatic breast cancer receiving combined therapy with ribociclib and letrozole compared with patients receiving placebo in combination with letrozole.1, 2 Combined therapy with ribociclib, a nonsteroidal aromatase inhibitor, and goserelin also demonstrated a statistically significant progression-free survival benefit in premenopausal and perimenopausal women compared with patients receiving placebo in combination with a nonsteroidal aromatase inhibitor and goserelin.1, 19
The current indication for ribociclib is based principally on the results of 2 randomized, double-blind, placebo-controlled, phase 3 studies (MONALEESA-2 and MONALEESA-7) in women with previously untreated hormone receptor-positive, HER2-negative advanced breast cancer1, 2, 19 and results from a cohort of 39 male patients with hormone receptor-positive, HER2-negative advanced breast cancer from an open-label, phase 3b study (COMPLEEMENT-1).1, 22
In the MONALEESA-2 study, 668 postmenopausal women with previously untreated hormone receptor-positive, HER2-negative advanced breast cancer were randomized (stratified by site of metastases) to receive either ribociclib (600 mg orally once daily for 21 days followed by a 7-day rest period) in combination with letrozole (2.5 mg orally once daily continuously) or placebo in combination with letrozole (2.5 mg orally once daily continuously).1, 2 Treatment was continued until disease progression, death, or unacceptable toxicity occurred or treatment was discontinued for other reasons.1, 2 Patients randomized to receive placebo were not permitted to cross over to open-label ribociclib therapy upon disease progression.2 The primary measure of efficacy was progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST).1, 2 The median age of patients was 62 years; 82% of the patients were white; 34% had de novo metastatic disease, 21% had bone-only disease, and 59% had visceral involvement; 47% had received prior chemotherapy, and 51% had received neoadjuvant or adjuvant endocrine therapy prior to diagnosis of advanced breast cancer.1 All patients enrolled in the study had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.1
At the time of the initial interim analysis of MONALEESA-2 results, the progression-free survival benefit observed in patients receiving ribociclib in combination with letrozole was statistically significant, although the median duration of progression-free survival had not yet been reached; the median progression-free survival in patients receiving placebo in combination with letrozole was 14.7 months.1, 2 The results of the progression-free survival analysis based on an independent, blinded, central radiologic assessment were consistent with the investigator assessment.2 Ribociclib and letrozole combination therapy was associated with higher rates of progression-free survival at 12 and 18 months (72.8 and 63%, respectively) compared with those receiving placebo in combination with letrozole (60.9 and 42.2%, respectively).2 Among patients with measurable disease, patients receiving ribociclib in combination with letrozole had higher overall response rates compared with those receiving placebo in combination with letrozole (52.7 versus 37.1%).1, 2 A subset analysis of progression-free survival based on clinically relevant baseline patient and disease characteristics consistently showed treatment benefit with ribociclib and letrozole combination therapy compared with placebo in combination with letrozole.1, 2 At the time of the second interim analysis (median follow-up duration of 26.4 months), patients receiving ribociclib in combination with letrozole had a longer median progression-free survival (25.3 versus 16 months) compared with patients receiving placebo in combination with letrozole; overall response rates also were higher in patients with measurable disease receiving ribociclib in combination with letrozole compared with those receiving placebo in combination with letrozole (42.5 versus 28.7%).21 Median overall survival had not been reached at the time of the second interim analysis.21 In the protocol-specified final MONALEESA-2 analysis, there were fewer deaths in the ribociclib in combination with letrozole group as compared to the placebo in combination with letrozole group (181 versus 219) after a median follow-up of 6.6 years.23 Median overall survival was significantly improved with ribociclib in combination with letrozole (63.9 months versus 51.4 months).23
In the MONALEESA-7 study, 672 premenopausal or perimenopausal women with previously untreated hormone receptor-positive, HER2-negative advanced breast cancer were randomized (stratified according to site of metastases and prior therapy) to receive ribociclib (600 mg orally once daily for 21 days followed by a 7-day rest period) in combination with endocrine therapy (letrozole 2.5 mg orally, anastrozole 1 mg orally, or tamoxifen 20 mg orally once daily continuously) or placebo in combination with endocrine therapy; all patients in the study received goserelin (3.6 mg by subcutaneous injection on day 1 of each 28-day cycle).1, 19 Treatment was continued until disease progression, death, or unacceptable toxicity occurred or treatment was discontinued for other reasons.1, 19 The primary measure of efficacy was progression-free survival as assessed by the investigator according to RECIST.1 The median age of patients was 44 years; 58% of the patients were white, 29% were Asian, and 3% were Black; 40% had de novo metastatic disease, 24% had bone-only disease, and 57% had visceral involvement; 33% had received prior adjuvant chemotherapy, 18% had received prior neoadjuvant chemotherapy, 40% had received adjuvant endocrine therapy, and 0.7% had received neoadjuvant endocrine therapy.1
At the time of analysis of MONALEESA-7 results, patients receiving ribociclib in combination with a nonsteroidal aromatase inhibitor (letrozole or anastrozole) and goserelin had a longer median progression-free survival (27.5 versus 13.8 months) compared with patients receiving placebo in combination with a nonsteroidal aromatase inhibitor and goserelin.1 Patients receiving ribociclib in combination with a nonsteroidal aromatase inhibitor and goserelin also had higher overall response rates compared with those receiving placebo in combination with a nonsteroidal aromatase inhibitor and goserelin (50.5 versus 36.2%).1 A subset analysis of progression-free survival based on clinically relevant baseline patient and disease characteristics consistently showed treatment benefit with ribociclib, nonsteroidal aromatase inhibitor, and goserelin combination therapy compared with placebo, nonsteroidal aromatase inhibitor, and goserelin combination therapy.1 Median overall survival was 40.7 months in patients receiving placebo, nonsteroidal aromatase inhibitor, and goserelin combination therapy and had not been reached in patients receiving ribociclib, nonsteroidal aromatase inhibitor, and goserelin combination therapy at the time of the efficacy analysis.1 At the time of the efficacy analysis, 61 (24.6%) of 248 patients receiving ribociclib, nonsteroidal aromatase inhibitor, and goserelin combination therapy and 80 (32.4%) of 247 patients receiving placebo, nonsteroidal aromatase inhibitor, and goserelin combination therapy had died, resulting in a hazard ratio of 0.7 (95% confidence interval: 0.501-0.976).1 In an updated overall survival analysis of MONALEESA-7, ribociclib in combination with a nonsteroidal aromatase inhibitor and goserelin continued to result in a significantly longer median overall survival at the time of data cutoff (58.7 versus 48 months).24 Survival rates at 4 years were 60% with ribociclib versus 50% with placebo and were 53% versus 44%, respectively, at 54 months.24
In the COMPLEEMENT-1 study, patients who have received no prior hormonal therapy for advanced disease received open-label ribociclib (600 mg orally once daily for 21 days followed by a 7-day rest period) in combination with hormonal therapy (letrozole 2.5 mg orally once daily for 28 days), and goserelin (3.6 mg by injectable subcutaneous implant) or leuprolide (7.5 mg by intramuscular injection on day 1 of each 28-day cycle).1, 22 Treatment was continued until disease progression, death, or unacceptable toxicity occurred or treatment was discontinued for other reasons.1, 22 In the cohort of 39 male patients, the median age was 62 years (range: 33-80 years); 72% were white, 8% were Asian, and 3% were Black, and 97% had an ECOG performance score of 0 or 1.1 The majority (97%) of patients in this cohort had ≤4 metastatic sites, which were primarily bone and visceral (69% each).1 In 32 male patients with measurable disease, an overall response rate of 46.9% was observed; 12 (80%) of the responding patients had a duration of response of ≥12 months.1
Advanced or Metastatic Disease - Combination Therapy with Fulvestrant
Ribociclib is for the treatment of adults with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer in combination with fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy.1, 20 A statistically significant progression-free survival benefit has been observed in postmenopausal women with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer receiving combined therapy with ribociclib and fulvestrant compared with patients receiving placebo in combination with fulvestrant.1, 20
The current indication for ribociclib is based principally on the results of a randomized, double-blind, placebo-controlled phase 3 study (MONALEESA-3) in postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer.1, 20 Patients were enrolled in the study if they had previously untreated disease or had disease progression following one line of endocrine therapy.1, 20 In this study, 726 patients were randomized (stratified according to site of metastases and prior endocrine therapy) to receive either ribociclib (600 mg orally once daily for 21 days followed by a 7-day rest period) in combination with fulvestrant (500 mg IM on days 1 and 15 during cycle 1 and then on day 1 of each 4-week cycle thereafter) or placebo in combination with fulvestrant.1 Treatment was continued until disease progression, death, or unacceptable toxicity occurred or treatment was discontinued for other reasons.1, 20 The primary measure of efficacy was progression-free survival as assessed by the investigator according to RECIST.1 The median age of patients was 63 years; 85% of the patients were white, 9% were Asian, and 0.7% were Black; 21% had bone-only disease and 61% had visceral involvement; 43% had received prior adjuvant chemotherapy, 13% had received prior neoadjuvant chemotherapy, 59% had received adjuvant endocrine therapy, and 1% had received neoadjuvant endocrine therapy.1
In this study, patients receiving ribociclib in combination with fulvestrant had a longer median progression-free survival (20.5 versus 12.8 months) compared with patients receiving placebo in combination with fulvestrant.1, 20 Patients receiving ribociclib in combination with fulvestrant also had higher overall response rates compared with those receiving placebo in combination with fulvestrant (40.9 versus 28.7%).1 A subset analysis of progression-free survival based on clinically relevant baseline patient and disease characteristics consistently showed treatment benefit with ribociclib and fulvestrant combination therapy compared with placebo in combination with fulvestrant.1 Median overall survival was 40 months in patients receiving placebo in combination with fulvestrant and had not been reached in patients receiving ribociclib in combination with fulvestrant at the time of the efficacy analysis.1 At the time of the efficacy analysis, 167 (34.5%) of 484 patients receiving ribociclib and fulvestrant and 108 (44.6%) of 242 patients receiving placebo and fulvestrant had died, resulting in a hazard ratio of 0.72 (95% confidence interval: 0.568-0.924).1
Early Disease - Adjuvant Treatment in Combination With an Aromatase Inhibitor
Ribociclib is used for the adjuvant treatment of adults with hormone receptor-positive, HER2-negative stage II and III early breast cancer at high risk of recurrence in combination with an aromatase inhibitor.1, 25 A significant invasive disease-free survival benefit has been observed in patients with hormone receptor-positive, HER2-negative stage II or III early breast cancer receiving combined therapy with ribociclib and a nonsteroidal aromatase inhibitor compared with patients receiving a nonsteroidal aromatase inhibitor alone.1, 25
The current indication for ribociclib is based principally on the results of an open-label, multicenter, randomized, phase 3 study (NATALEE).1, 25 In this study, 5101 patients were randomized to receive either ribociclib (400 mg orally once daily for 21 days followed by a 7-day rest period given for 36 months) in combination with a nonsteroidal aromatase inhibitor (letrozole 2.5 mg orally once daily or anastrozole 1 mg orally once daily on a continuous schedule for 60 months) or a nonsteroidal aromatase inhibitor alone.1, 25 Goserelin 3.6 mg subcutaneously once every 28 days was also administered as indicated.1, 25 The primary measure of efficacy was invasive disease-free survival.1, 25 The median age of patients was 52 years; >99% were female; 73% of the patients were white, 13% were Asian, 8.5% were Hispanic or Latino, and 1.7% were Black or African American.1
At the data cutoff date for a prespecified interim analysis, patients receiving ribociclib in combination with a nonsteroidal aromatase inhibitor had a significant improvement in invasive disease-free survival; invasive-disease-free survival was 90.4% with the combination of ribociclib with a nonsteroidal aromatase inhibitor versus 87.1% with a nonsteroidal aromatase inhibitor alone at 3 years.1, 25 Secondary end points, distant disease-free survival and recurrence-free survival, also favored the combination.25
Guidelines from the American Society of Clinical Oncology (ASCO) provide recommendations for treatment of hormone receptor-positive, HER2-negative, metastatic breast cancer.26, 27 For patients with hormone receptor-positive, HER2-negative, metastatic breast cancer who have not received any prior treatment, received treatment with tamoxifen only, or who have not recently (within 1 year) been treated with an aromatase inhibitor (i.e., anastrozole, exemestane, letrozole), first-line treatment should be initiated with an aromatase inhibitor plus a CDK4/6 inhibitor.26, 27 For patients recently exposed to aromatase inhibitor therapy or who experienced recurrence during treatment with an aromatase inhibitor, first-line treatment should be initiated with fulvestrant plus a CDK4/6 inhibitor.26, 27
Ribociclib is administered orally without regard to food at approximately the same time each day, preferably in the morning.1 The tablets should be swallowed intact and should not be broken, chewed, crushed, or split.1
If a dose of ribociclib is missed or vomited, patients should not take an extra dose.1 The next dose should be taken at the regularly scheduled time.1
Store ribociclib tablets at 20ºC to 25ºC for up to 2 months.1
Ribociclib is commercially available as a single entity (Kisqali®) and also available copackaged with letrozole (Kisqali® Femara® Co-Pack).1, 14 Clinicians should consult the respective manufacturers' labeling for information on dosage and administration (including dosage adjustments), adverse effects, and contraindications of other antineoplastic agents used in combination regimens.1
Dosage of ribociclib succinate is expressed in terms of ribociclib.1
For the adjuvant treatment of hormone receptor-positive, human epidermal growth factor receptor type 2 (HER2)-negative stage II and III early breast cancer at high recurrence risk, the recommended adult dosage of ribociclib is 400 mg orally once daily on days 1-21 of each 28-day cycle in combination with an aromatase inhibitor.1 Treatment should continue for 3 years or until disease progression or unacceptable toxicity occurs.1
Advanced or Metastatic Breast Cancer
For the treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer, the recommended adult dosage of ribociclib is 600 mg orally once daily on days 1-21 of each 28-day cycle in combination with endocrine therapy (fulvestrant or an aromatase inhibitor).1
Premenopausal or perimenopausal women and male patients receiving combination therapy with ribociclib and an aromatase inhibitor or fulvestrant should be treated with a luteinizing hormone-releasing hormone (LHRH) agonist according to current standards of care.1
Dosage Modification for Toxicity
Dosage interruption and/or reduction, or discontinuance of ribociclib therapy, may be necessary based on severity of adverse reactions.1 Dosage adjustment of ribociclib is recommended based on individual safety and tolerability.1
Early breast cancer : If dosage reduction from 400 mg once daily is necessary, the dosage should be reduced to 200 mg once daily.1 If the toxicity recurs at a dosage of 200 mg once daily, ribociclib therapy should be discontinued.1
Advanced or metastatic breast cancer: If dosage reduction from 600 mg once daily is necessary, the dosage should be reduced to 400 mg once daily.1 If the toxicity recurs at a dosage of 400 mg once daily, the dosage should be reduced to 200 mg once daily.1 If the toxicity recurs at a dosage of 200 mg once daily, ribociclib therapy should be discontinued.1
Interstitial Lung Disease/Pneumonitis
For grade 3 or 4 or recurrent symptomatic interstitial lung disease (ILD)/pneumonitis, ribociclib therapy should be permanently discontinued.1, 18
For grade 2 ILD/pneumonitis, ribociclib therapy should be interrupted; therapy may be resumed at a reduced dosage when the toxicity improves to grade 1 or less.1 The potential benefits and risks of resuming therapy should be considered.1 If grade 2 ILD/pneumonitis recurs, ribociclib therapy should be discontinued.1
For grade 1 ILD/pneumonitis, no dosage adjustment is necessary; however, appropriate medical interventions should be initiated.1 Monitoring should be continued as clinically indicated.1
For grade 4 cutaneous toxicity (any percentage of body surface area [BSA] involvement associated with extensive superinfection requiring IV antibiotics; life-threatening consequences; or toxic epidermal necrolysis [TEN; skin sloughing covering ≥30% BSA with associated symptoms such as erythema, purpura, epidermal detachment, and mucous membrane detachment]), ribociclib therapy should be permanently discontinued.1
For grade 3 cutaneous toxicity (severe rash not responsive to medical management; >30% BSA with active skin toxicity, signs of systemic involvement; or Stevens-Johnson syndrome [SJS; skin sloughing covering <10% BSA with associated symptoms such as erythema, purpura, epidermal detachment, and mucous membrane detachment]), ribociclib therapy should be interrupted until the etiology of the toxicity has been determined.1 If the etiology is a severe cutaneous adverse reaction (SCAR), ribociclib should be permanently discontinued.1 If an etiology other than SCAR is found, ribociclib may be resumed at the same dosage when the toxicity improves to grade 1 or less.1 If grade 3 cutaneous toxicity (that is not a SCAR) recurs, ribociclib should be withheld until improvement to grade 1 or less, and then resumed at the next lower dosage level.1
For grade 1 (<10% BSA with active skin toxicity and no signs of systemic involvement) or grade 2 (10-30% BSA with active skin toxicity and no signs of systemic involvement) cutaneous toxicity, no dosage adjustment is necessary; however, appropriate medical interventions should be initiated.1 Monitoring should be continued as clinically indicated.1
Early breast cancer : If the QTcinterval is >480 msec and ≤500 msec, ribociclib therapy should be interrupted; therapy may be resumed at the same dosage when the QTc interval improves to ≤480 msec.1 If QTc-interval prolongation (i.e., >480 msec) recurs, therapy should be withheld again; therapy may then be resumed at the next lower dosage level when the QTc interval improves to ≤480 msec.1
If the QTc interval is >500 msec, ribociclib therapy should be interrupted; therapy may be resumed at the next lower dosage level when the QTc-interval improves to ≤480 msec.1 If QTc interval >500 msec recurs, discontinue ribociclib.1
Advanced or metastatic breast cancer : If the QTcinterval is >480 msec and ≤500 msec, ribociclib therapy should be interrupted; therapy may be resumed at the next lower dosage level when the QTc interval improves to ≤480 msec.1 If QTc-interval prolongation (i.e., >480 msec) recurs, therapy should be withheld again; therapy may then be resumed at the next lower dose level when the QTc interval improves to ≤480 msec.1
If the QTc interval is >500 msec, ribociclib therapy should be interrupted; therapy may be resumed at the next lower dose level when the QTc-interval improves to ≤480 msec.1 If QTc interval >500 msec recurs, discontinue ribociclib.1
When QTc-interval prolongation (>500 msec or increase of >60 msec from baseline) occurs concurrently with torsades de pointes, polymorphic ventricular tachycardia, unexplained syncope, or signs and/or symptoms of serious arrhythmia, ribociclib therapy should be permanently discontinued.1
For grade 4 serum aminotransferase (ALT and/or AST) elevations (i.e., exceeding 20 times the upper limit of normal [ULN]) with total bilirubin concentrations no more than 2 times the ULN, ribociclib therapy should be discontinued.1
For the first occurrence of grade 3 serum ALT and/or AST elevations (i.e., exceeding 5 times the ULN, but no more than 20 times the ULN) with total bilirubin concentrations no more than 2 times the ULN, ribociclib therapy should be interrupted; therapy may be resumed at a reduced dosage when the toxicity improves to baseline or better grade.1 If grade 3 hepatotoxicity recurs at a reduced dosage, ribociclib therapy should be discontinued.1
For the first occurrence of grade 2 serum ALT and/or AST elevations (i.e., exceeding 3 times the ULN, but no more than 5 times the ULN) with total bilirubin concentrations no more than 2 times the ULN in patients with preexisting ALT and/or AST concentrations no more than 3 times the ULN , ribociclib therapy should be interrupted; therapy may be resumed at the same dosage when the toxicity improves to baseline or better grade.1 For subsequent occurrences, ribociclib therapy should be withheld again; therapy may then be resumed at a reduced dosage when the toxicity improves to baseline or better grade.1
If grade 2 serum ALT and/or AST elevations with total bilirubin concentrations no more than 2 times the ULN persist in patients with preexisting ALT and/or AST concentrations exceeding 3 times the ULN, but no more than 5 times the ULN , ribociclib therapy may be continued without interruption.1
If grade 1 serum ALT and/or AST elevations (i.e., exceeding the ULN, but no more than 3 times the ULN) with total bilirubin concentrations no more than 2 times the ULN occur, ribociclib therapy may be continued without dosage adjustment.1
For serum ALT and/or AST elevations exceeding 3 times the ULN with concomitant total bilirubin concentrations exceeding 2 times the ULN (irrespective of baseline hepatic function) in the absence of cholestasis, ribociclib therapy should be discontinued.1
For grade 4 neutropenia (i.e., absolute neutrophil count [ANC] less than 500/mm3), ribociclib therapy should be interrupted until neutropenia improves to grade 2 or less.1 Upon resumption of therapy, the dosage of ribociclib should be reduced.1
For grade 3 febrile neutropenia (i.e., ANC 500 to less than 1000/mm3 associated with a single episode of fever >38.3°C or fever ≥38°C for more than 1 hour and/or concurrent infection), ribociclib therapy should be interrupted until neutropenia improves to grade 2 or less.1 Upon resumption of therapy, the dosage of ribociclib should be reduced.1
For the first occurrence of grade 3 neutropenia (i.e., ANC 500 to less than 1000/mm3), ribociclib therapy should be interrupted; therapy may be resumed at the same dosage when neutropenia improves to grade 2 or less.1 For subsequent occurrences of grade 3 neutropenia, ribociclib therapy should be withheld again; therapy may then be resumed at a reduced dosage when neutropenia improves to grade 2 or less.1
For grade 1 or 2 neutropenia (i.e., ANC 1000/mm3 to less than the lower limit of normal [LLN]), ribociclib therapy may be continued at the same dosage.1
For grade 4 adverse reactions, ribociclib therapy should be discontinued.1
For grade 3 adverse reactions, ribociclib therapy should be interrupted; therapy may be resumed at the same dosage when the toxicity improves to grade 1 or less.1 For subsequent occurrences of grade 3 adverse reactions, ribociclib therapy should be withheld again; therapy may then be resumed at a reduced dosage when the toxicity improves to grade 1 or less.1
For grade 1 or 2 adverse reactions, ribociclib therapy may be continued at the same dosa however, patients should receive appropriate medical therapy and additional monitoring as clinically indicated.1
Dosage Modifications for Drug Interactions
Concomitant use of ribociclib with drugs that are strong inhibitors of cytochrome P-450 (CYP) isoenzyme 3A should be avoided, and selection of an alternative drug with less CYP3A inhibition potential is recommended.1 If concomitant use of a strong CYP3A inhibitor cannot be avoided, the manufacturer recommends reducing the dosage of ribociclib to 200 mg once daily in patients with early breast cancer and 400 mg once daily in patients with advanced or metastatic breast cancer.1 When concomitant use of the strong CYP3A inhibitor is discontinued, the ribociclib dosage should be returned (after at least 5 elimination half-lives of the CYP3A inhibitor) to the dosage used prior to initiation of the strong CYP3A inhibitor.1
For patients with early breast cancer, no dosage adjustment is necessary in patients with mild to severe hepatic impairment (Child-Pugh class A, B, or C).1
For patients with advanced or metastatic breast cancer and moderate or severe hepatic impairment (Child-Pugh class B or C), the manufacturer recommends an initial ribociclib dosage of 400 mg once daily.1 No dosage adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A).1
The manufacturer provides no specific dosage recommendations in patients with baseline grade 3 or greater serum ALT and/or AST elevations.1
For patients with severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to less than 30 mL/minute per 1.73 m2), the manufacturer recommends an initial ribociclib dosage of 200 mg once daily.1 No dosage adjustment is necessary in patients with mild or moderate renal impairment (eGFR 30 to less than 90 mL/minute per 1.73 m2).1
There are currently no specific dosage recommendations for geriatric patients.1
Interstitial Lung Disease/Pneumonitis
Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis has occurred in patients receiving cyclin-dependent kinases 4 (CDK4) and 6 (CDK6) inhibitors, including ribociclib.1 In the NATALEE study in patients with early breast cancer, 1.5% of patients experienced ILD/pneumonitis.1 In the MONALEESA-2, MONALEESA-3, and MONALEESA-7 studies in patients with advanced or metastatic breast cancer, ILD or pneumonitis occurred in 1.6% of ribociclib-treated patients, and grade 3 or 4 ILD or pneumonitis occurred in 0.4% of patients receiving the drug.1 ILD or pneumonitis resulting in death occurred in 0.1% of patients receiving ribociclib.1 Cases of ILD or pneumonitis, including fatal cases, also have been reported during postmarketing experience in patients receiving ribociclib.1
Patients receiving ribociclib should be monitored clinically and by radiographic imaging for manifestations of ILD or pneumonitis.1, 18 If manifestations suggestive of ILD or pneumonitis (e.g., hypoxia, cough, dyspnea, interstitial infiltrates) occur, therapy with ribociclib should be temporarily interrupted and the possibility of other etiologies (e.g., infection, neoplastic) should be excluded.1, 18 Temporary interruption, dosage reduction, or discontinuance of ribociclib may be necessary if ILD or pneumonitis occurs during therapy with the drug.1, 18
Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported in patients receiving ribociclib.1 Temporary interruption, dosage reduction, or discontinuance of ribociclib may be necessary if dermatologic toxicity occurs during therapy with the drug.1
If signs or symptoms of severe cutaneous reactions occur, ribociclib therapy should be interrupted until the etiology of the reaction has been determined.1 Early consultation with a dermatologist is recommended to ensure greater diagnostic accuracy and appropriate management.1
If SJS, TEN, or DRESS is confirmed, ribociclib should be permanently discontinued.1 The drug should not be reintroduced in patients who have experienced SCARs or other life-threatening cutaneous reactions during ribociclib therapy.1
Prolongation of the corrected QT (QTc) interval has been observed in ribociclib-treated patients.1, 2 The prolongation appears to occur in a plasma concentration-dependent manner.1 In the NATALEE study in patients with early breast cancer given ribociclib 400 mg once daily in combination with a nonsteroidal aromatase inhibitor, 0.3% of patients had a >500 msec post-baseline QTc interval value and 2% had a >60 msec QTc increase from baseline; this prolongation was reversible following dose interruption.1 Most of these events occurred within the initial 4 weeks of ribociclib therapy.1 No cases of torsades de pointes were reported.1
Following administration of ribociclib 600 mg once daily in combination with an aromatase inhibitor or fulvestrant, an estimated mean increase in QTc interval exceeding 20 msec is expected at mean steady-state peak plasma concentrations.1 In a pharmacokinetic/pharmacodynamic study evaluating potential effects of ribociclib in combination with an aromatase inhibitor or fulvestrant on the QTc interval, the mean QTc interval increase from baseline was 22 or 23.7 msec, respectively.1 In the MONALEESA-2, MONALEESA-3, and MONALEESA-7 studies, an increase in the QTc interval exceeding 60 msec from baseline occurred in 6% of ribociclib-treated patients, and QTc intervals exceeding 500 msec occurred in 1.4% of ribociclib-treated patients.1 Prolongation of the QTc interval occurred within the first 4 weeks of treatment in the majority of patients and was reversible upon dosage interruption.1 Torsades de pointes was not observed in these studies.1 In the MONALEESA-2 study, syncope was reported in 3% of patients receiving combined therapy with ribociclib and letrozole compared with 1% of patients receiving placebo and letrozole.1 No cases of sudden death were reported in the MONALEESA-3 or MONALEESA-7 studies; however, sudden death occurred in one patient with grade 3 hypokalemia and grade 2 prolongation of the QT interval in the MONALEESA-2 study.1
Concomitant use of ribociclib and tamoxifen also is expected to increase the estimated mean QTc interval by greater than 20 msec at mean steady-state peak plasma concentrations; ribociclib is not currently FDA-labeled for use in combination with tamoxifen.1 In a pharmacokinetic/pharmacodynamic study evaluating potential effects of ribociclib in combination with tamoxifen on the QTc interval, the mean QTc interval increase from baseline was 34.7 msec.1 In the MONALEESA-7 study, the mean QTc interval increase from baseline was more than 10 msec higher in patients who received combined therapy with tamoxifen and placebo compared with those who received combined therapy with a nonsteroidal aromatase inhibitor and placebo.1 An increase in the QTc interval exceeding 60 msec from baseline occurred in 16% of patients who received tamoxifen in combination with ribociclib compared with 7% of those who received a nonsteroidal aromatase inhibitor in combination with ribociclib.1 An increase in the QTc interval exceeding 60 msec from baseline also occurred in 7% of patients receiving tamoxifen in combination with placebo compared with none of those receiving a nonsteroidal aromatase inhibitor in combination with placebo.1
Ribociclib should be avoided in patients who are at significant risk of developing torsades de pointes including those with congenital long QT syndrome; uncontrolled or clinically important cardiac disease, recent myocardial infarction, heart failure, unstable angina, bradyarrhythmias, uncontrolled hypertension, high degree atrioventricular block, severe aortic stenosis, or uncontrolled hypothyroidism, electrolyte abnormalities; or taking medications known to prolong the QT interval and/or strong CYP3A inhibitors.1
ECGs should be monitored at baseline, around day 14 of cycle 1, prior to initiation of cycle 2, and then as clinically indicated.1 More frequent ECG monitoring is recommended in patients who develop QTc-interval prolongation during therapy.1 In addition, serum electrolytes (i.e., potassium, calcium, phosphorus, magnesium) should be monitored at baseline, prior to initiation of cycles 1-6, and then as clinically indicated.1 Ribociclib therapy should only be initiated in patients with QTc intervals less than 450 msec.1 Electrolyte abnormalities should be corrected prior to administration of the drug.1 Temporary interruption, dosage reduction, or discontinuance of ribociclib may be necessary if QTc-interval prolongation occurs during therapy with the drug.1
Drug-induced hepatotoxicity has occurred in patients receiving ribociclib.1 In the NATALEE study in patients with early breast cancer, drug-induced hepatotoxicity was reported in 9 patients, with 5 patients experiencing grade ≥3 reactions.1 Grade 3 or 4 elevations in ALT and AST occurred in 8% and 4.7% of patients, respectively; these included grade 4 ALT increases (1.5%) and grade 4 AST increases (0.8%).1
In the MONALEESA-2, MONALEESA-3, and MONALEESA-7 studies, grade 3 or 4 elevations in serum ALT concentrations were reported in 11% of ribociclib-treated patients; grade 3 or 4 elevations in serum AST concentrations were reported in 8% of ribociclib-treated patients.1 The median time to onset of grade 3 or greater elevations in ALT/AST concentrations in patients receiving ribociclib in combination with an aromatase inhibitor or fulvestrant was 92 days; these elevations in ALT/AST resolved to grade 2 or less in a median of 21 days.1 In the MONALEESA-2 and MONALEESA-3 studies, serum aminotransferase elevations exceeding 3 times the upper limit of normal (ULN) with concurrent elevations in total bilirubin concentrations exceeding 2 times the ULN, normal alkaline phosphatase concentrations, and absence of cholestasis were reported in 1% of patients; these adverse hepatic effects were reversible upon discontinuance of ribociclib therapy.1
Liver function tests should be monitored at baseline, every 2 weeks during cycles 1 and 2, prior to initiation of cycles 3-6, and then as clinically indicated.1 More frequent monitoring is recommended if elevations in serum aminotransferase concentrations occur.1 Temporary interruption, dosage reduction, or discontinuance of ribociclib may be necessary if hepatotoxicity occurs during therapy with the drug.1
Concentration-dependent neutropenia occurs in patients receiving ribociclib.1 In the NATALEE study in patients with early breast cancer, 94% experienced a reduction in neutrophil count (including 45% of patients with grade 3 or 4 reactions), 63% had an adverse reaction of neutropenia, and 0.3% experienced febrile neutropenia.1 The median time to occurrence of grade 2 or greater neutropenia was 18 days and the median time to resolution of grade 3 or greater neutropenia to less than grade 3 was 10 days.1 Treatment discontinuation due to neutropenia occurred in 1.1% of patients.1
In the MONALEESA-2, MONALEESA-3, and MONALEESA-7 studies, 75% of patients experienced neutropenia, grade 3 or 4 neutropenia occurred in 62% of patients, and 1.7% had febrile neutropenia.1 The median time to occurrence of grade 2 or greater neutropenia was 17 days.1 The median time to resolution of grade 3 or greater neutropenia to less than grade 3 was 12 days.1 Discontinuance of therapy due to neutropenia occurred in 1% of patients.1
Complete blood cell (CBC) counts should be monitored at baseline, every 2 weeks during cycles 1 and 2, prior to initiation of cycles 3-6, and then as clinically indicated.1 Temporary interruption, dosage reduction, or discontinuance of ribociclib may be necessary if neutropenia occurs during therapy with the drug.1
Fetal/Neonatal Morbidity and Mortality
There are no adequate and well-controlled studies of ribociclib in pregnant women; however, based on its mechanism of action and animal findings, ribociclib may cause fetal harm.1 Embryofetal toxicity (e.g., decreased fetal weight) and teratogenicity (e.g., external, visceral, and skeletal abnormalities) have been demonstrated in rats and rabbits receiving ribociclib at exposure levels of approximately 0.6 and 1.5 times, respectively, the human exposure at the recommended dosage.1 Maternal toxicity, abortion, and embryolethality were not observed in rabbits receiving ribociclib at exposure levels approximately 1.5 times the human exposure at the recommended dosa however, reduced maternal body weight gain was observed in rats receiving ribociclib at exposure levels approximately 0.6 times the human exposure at the recommended dosage.1
Pregnancy should be avoided during ribociclib therapy.1 The manufacturer recommends confirmation of pregnancy status prior to initiation of ribociclib, and females of reproductive potential should be advised to use effective contraceptive methods during and for at least 3 weeks after discontinuance of the drug.1 Patients should be apprised of the potential hazard to the fetus if ribociclib is used during pregnancy.1
Ribociclib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.) There are no available human data informing the drug-associated risk.1
Confirmation of pregnancy status prior to initiation of ribociclib therapy is recommended.1
Ribociclib and its metabolites are distributed into milk in rats; it is not known whether the drug is distributed into milk in humans.1 Because of the potential for serious adverse reactions to ribociclib in nursing infants, women should be advised to discontinue breastfeeding during and for at least 3 weeks after discontinuance of ribociclib therapy.1 The effects of the drug or its metabolites on nursing infants or on milk production are unknown.1
Females and Males of Reproductive Potential
Confirmation of pregnancy status prior to initiation of ribociclib is recommended; females of reproductive potential should use effective contraceptive methods during and for at least 3 weeks after the last dose of ribociclib.1
Results of animal studies suggest that ribociclib may impair male fertility.1
In a general toxicology study, testicular atrophy was observed following administration of ribociclib daily (at exposure levels as low as 0.03 times the human exposure at the recommended dosage) for 3 weeks of each 4-week cycle to male animals for 26-39 weeks.1
In a reproductive toxicity study, no effect on reproductive function, fertility, or early embryonic development was observed following administration of ribociclib (at exposure levels approximately 0.6 times the human exposure at the recommended dosage) for 14 days prior to mating and throughout the first week of gestation in female rats.1
Safety and efficacy of ribociclib have not been established in pediatric patients.1
In the NATALEE study, 16% of patients were 65 years of age and older and 2.4% of patients were 75 years of age and older.1 No overall differences in safety and efficacy were observed between geriatric patients and younger adults with early breast cancer.1
In the MONALEESA-2 or MONALEESA-3 study, 45 or 47%, respectively, of patients were 65 years of age or older and 11 or 14%, respectively, were 75 years of age or older.1 No overall differences in safety and efficacy were observed between geriatric patients and younger adults with advanced or metastatic breast cancer.1
Mean systemic exposure of ribociclib is increased less than 2-fold in individuals with preexisting moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment compared with individuals with normal hepatic function; however, systemic exposure of ribociclib was unaffected in individuals with preexisting mild (Child-Pugh class A) hepatic impairment.1, 3 Population pharmacokinetic analysis also indicated that systemic exposure to ribociclib in patients with mild hepatic impairment was similar to that in patients with normal hepatic function.1 Dosage adjustment is required in patients with advanced or metastatic breast cancer who have moderate or severe hepatic impairment.1
AUC and peak plasma concentrations of ribociclib were increased 2.4- and 2.1-fold, respectively, in individuals (without cancer) with severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to less than 30 mL/minute per 1.73 m2).1 AUC and peak plasma concentrations of ribociclib were increased 3.8- and 2.7-fold, respectively, in individuals (without cancer) with end-stage renal disease (eGFR less than 15 mL/minute per 1.73 m2).1 Dosage adjustment is required in patients with severe renal impairment.1
Population pharmacokinetic analysis indicated that systemic exposure to ribociclib in patients with mild or moderate renal impairment (eGFR 30 to less than 90 mL/minute per 1.73 m2) was similar to that in patients with normal renal function.1
Adverse effects reported in 20% or more of patients receiving ribociclib for early breast cancer include decreased lymphocytes, leukocytes, neutrophils, and hemoglobin, increased ALT and AST, infections, increased creatinine, decreased platelets, headache, nausea, and fatigue.1
Adverse effects reported in 20% or more of patients receiving ribociclib for advanced or metastatic breast cancer include decreased leukocytes, neutrophils, hemoglobin, and lymphocytes, increased ALT, AST, and gamma glutamyl transferase, infections, nausea, increased creatinine, fatigue, decreased platelets, diarrhea, vomiting, headache, constipation, alopecia, rash, cough, back pain, and decreased serum glucose.1
Ribociclib is metabolized mainly in the liver via oxidation by cytochrome P-450 (CYP) isoenzyme 3A4.1 In vitro studies indicate that ribociclib is a reversible inhibitor of CYP isoenzymes 1A2, 2E1, and 3A4/5 at clinically relevant concentrations; the drug demonstrates time-dependent inhibition of CYP3A4/5.1 In vitro studies indicate that ribociclib does not inhibit CYP isoenzymes 2A6, 2B6, 2C8, 2C9, 2C19, and 2D6 at clinically relevant concentrations.1 In vitro, ribociclib does not exhibit time-dependent inhibition of CYP isoenzymes 1A2, 2C9, and 2D6 or induce CYP isoenzymes 1A2, 2B6, 2C9, and 3A4 at clinically relevant concentrations.1
In vitro studies indicate that ribociclib may inhibit breast cancer resistance protein (BCRP), organic cation transporter (OCT) 2, multidrug and toxic compound extrusion protein (MATE) 1, and bile salt export pump (BSEP), but has a low potential for inhibition of P-glycoprotein (P-gp), MATE2K, OCT1, organic anion transport protein (OATP) 1B1, and OATP1B3 at clinically relevant concentrations.1 In vitro, the drug is not a substrate for OCT1, OATP1B1, or OATP1B3.1
Drugs and Foods Affecting Hepatic Microsomal Enzymes
Concomitant use of ribociclib with strong inhibitors of CYP3A may result in increased peak plasma concentrations and systemic exposure (AUC) of ribociclib.1 When the strong CYP3A inhibitor ritonavir (100 mg twice daily for 14 days) was administered concomitantly with ribociclib (single 400-mg dose) in healthy individuals, the peak plasma concentrations and AUC of ribociclib were increased by 1.7- and 3.2-fold, respectively.1 In addition, peak plasma concentrations and AUC of a major metabolite of ribociclib (LEQ803) were decreased by 96 and 98%, respectively.1 Simulations using physiologically based pharmacokinetic models suggest that moderate inhibitors of CYP3A4 (e.g., erythromycin) may increase the peak plasma concentrations and AUC of ribociclib 400 mg once daily by 1.1- and 1.2-fold, respectively and ribociclib 600 mg once daily by 1.1- and 1.1-fold, respectively.1, 3
Concomitant use of ribociclib with strong inhibitors of CYP3A (e.g., clarithromycin, conivaptan, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, voriconazole) should be avoided, and selection of an alternative drug with less CYP3A inhibition potential should be considered.1 If concomitant use of a strong CYP3A inhibitor cannot be avoided, the manufacturer recommends dosage reduction of ribociclib to 200 mg once daily in patients with early breast cancer and 400 mg once daily in patients with advanced or metastatic breast cancer.1 If concomitant use of the strong CYP3A inhibitor is discontinued, the ribociclib dosage should be returned (after at least 5 terminal half-lives of the CYP3A inhibitor) to the dosage used prior to initiation of the strong CYP3A4 inhibitor.1
Grapefruit products are CYP3A inhibitors and should be avoided because of the potential for increased plasma ribociclib concentrations during concurrent use.1
Concomitant use of ribociclib with strong inducers of CYP3A may result in decreased peak plasma concentrations and AUC of ribociclib.1 When the strong CYP3A4 inducer rifampin (600 mg twice daily for 14 days) was administered concomitantly with ribociclib (single 600-mg dose) in healthy individuals, the peak plasma concentrations and AUC of ribociclib were decreased by 81 and 89%, respectively.1 In addition, peak plasma concentrations of LEQ803 increased by 1.7-fold and AUC decreased by 27%.1 Simulations using physiologically based pharmacokinetic models suggest that moderate inducers of CYP3A (e.g., efavirenz) may decrease the peak plasma concentrations and AUC of ribociclib 400 mg once daily by 55 and 74%, respectively, and ribociclib 600 mg once daily by 52% and 71%, respectively.1
Concomitant use of ribociclib with strong inducers of CYP3A (e.g., carbamazepine, phenytoin, rifampin, St. John's wort [ Hypericum perforatum ]) should be avoided, and selection of an alternative drug with no or minimal CYP3A induction potential should be considered.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Ribociclib inhibits CYP3A4/5 in vitro and potentially can increase plasma concentrations of other drugs metabolized by CYP3A.1 When the CYP3A4 substrate midazolam (single 5-mg dose on day 8) was administered concomitantly with ribociclib (400 mg once daily for 8 days), peak plasma concentrations and AUC of midazolam were increased by 2.1- and 3.8-fold, respectively.1, 3 Simulations using physiologically based pharmacokinetic models suggest that concomitant use of ribociclib 600 mg once daily with midazolam may increase the peak plasma concentrations and AUC of midazolam by 2.4- and 5.2-fold, respectively.1, 3 The manufacturer states that for CYP3A substrates where minimal increases in concentration may increase CYP3A substrate adverse reactions, clinicians should monitor for increased adverse reactions of the CYP3A substrate during ribociclib therapy.1 The CYP3A substrate dose may require reduction as ribociclib can increase its exposure.1
Ribociclib is a weak inhibitor of CYP1A2 at clinically relevant concentrations.1 When the CYP1A2 substrate caffeine (single 100-mg dose on day 8) was administered concomitantly with ribociclib (400 mg once daily for 8 days), peak plasma concentrations of caffeine decreased by 10% and AUC increased by 20%.1, 3
Drugs Affecting Gastric Acidity
In a population pharmacokinetic analysis, concomitant administration of ribociclib and drugs that increase gastric pH (e.g., proton-pump inhibitors) did not appear to affect the absorption of ribociclib.1, 3 Simulations using physiologically based pharmacokinetic models suggest that drugs affecting gastric acidity are not expected to affect the pharmacokinetics of ribociclib.1
Drugs that Prolong the QT Interval
Concomitant use of ribociclib with antiarrhythmic agents (e.g., amiodarone, disopyramide, procainamide, quinidine, sotalol) or other drugs that prolong the QT interval (e.g., chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, ondansetron, pimozide) should be avoided.1 If concomitant use cannot be avoided, clinicians should monitor ECG when starting therapy, during concomitant use, and as clinically indicated.1
Concomitant administration of ribociclib and anastrozole did not affect the pharmacokinetics of either drug.1
Concomitant administration of ribociclib and exemestane did not affect the pharmacokinetics of either drug.1
Concomitant administration of ribociclib and fulvestrant did not affect systemic exposure of ribociclib.1
Concomitant administration of ribociclib and letrozole did not affect the pharmacokinetics of either drug.1, 15
Concomitant use of ribociclib with tamoxifen may increase systemic exposure of tamoxifen.1 When tamoxifen was administered concomitantly with ribociclib (600 mg once daily), peak plasma concentrations and AUC of tamoxifen were increased by approximately 2-fold in patients with breast cancer.1 Concomitant use of ribociclib and tamoxifen also is expected to increase the risk of QT-interval prolongation; ribociclib is not currently FDA-labeled for use in combination with tamoxifen.1
Ribociclib, a selective inhibitor of cyclin-dependent kinases 4 (CDK4) and 6 (CDK6), is an antineoplastic agent.1, 2, 4, 14 Several mechanisms contribute to the dysregulation of the cell cycle during the G1 into S phase, including amplification or overexpression of the cyclin D oncogene or the loss of intrinsic CDK inhibitors (i.e., p16, p15, p18, p19, p21, p27, p57)6, 9, 11, 13 in breast cancer.5, 7, 8, 9, 10, 11, 12, 13 Ribociclib specifically inhibits CDK4 and CDK6 and blocks the interaction of CDK4 and CDK6 with cyclin D, resulting in inhibition of phosphorylation of the tumor suppressor protein retinoblastoma and inhibition of progression of the cell cycle from the G1 into S phase.1, 4 In vitro, ribociclib has demonstrated decreased phosphorylation of retinoblastoma protein and reduced cellular proliferation of breast cancer cell lines by inhibiting the G1 into S phase of the cell cycle.1, 4 In addition, ribociclib reduced tumor volume, which correlated with inhibition of retinoblastoma protein phosphorylation, in xenograft models of human cancer.1 The combination of ribociclib and an antiestrogen agent (e.g., letrozole, fulvestrant) also has demonstrated increased inhibition of tumor growth compared with either drug alone in patient-derived estrogen receptor-positive breast tumor xenografts.1
AUC and peak plasma concentrations of ribociclib are more than dose proportional over the dose range of 50-1200 mg.1, 15, 17 Peak plasma concentrations of ribociclib are achieved about 1-4 hours following oral administration of the drug.1, 15, 17 Following repeated doses of ribociclib 600 mg once daily, steady-state concentrations of the drug were achieved in 8 days and the mean accumulation ratio for the drug was 2.5.1, 15, 17 Oral administration of ribociclib with a high-fat, high-calorie meal (approximately 800-1000 calories with fat accounting for approximately 50% of the caloric content) did not affect the rate or extent of absorption of the drug.1, 3 Ribociclib is approximately 70% bound to plasma proteins.1 Ribociclib is metabolized mainly in the liver via oxidation by cytochrome P-450 (CYP) isoenzyme 3A4.1 Clinical activity from the main circulating metabolites (CCI284, LEQ803, and a secondary glucuronide) is negligible, and these metabolites account for 18-22% of total plasma concentrations of the drug.1 Following oral administration of a single radiolabeled dose of ribociclib, 69% of the radioactivity was recovered in feces and 23% was recovered in urine.1 The mean plasma elimination half-life of the drug is 29.7-54.7 hours.1
Population pharmacokinetic analysis indicated that age, gender, race, and body weight do not have clinically important effects on the exposure of ribociclib.1, 3
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at http://[Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Kit | Ribociclib succinate 200 mg (of ribociclib) (21, 42, or 63 film-coated tablets) Letrozole 2.5 mg (28 film-coated tablets) | Kisqali® Femara® Co-Pack | Novartis |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions February 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Novartis Pharmaceuticals. Kisqali® (ribociclib succinate) tablets prescribing information. East Hanover, NJ; 2024 Sept. [Web]
2. Hortobagyi GN, Stemmer SM, Burris HA et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J Med . 2016; 375:1738-1748. [PubMed 27717303]
3. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 209092Orig1s000: Multi-discipline review. From FDA website. Accessed 2024 Jul 15. [Web]
4. Tripathy D, Bardia A, Sellers WR. Ribociclib (LEE011): Mechanism of Action and Clinical Impact of This Selective Cyclin-Dependent Kinase 4/6 Inhibitor in Various Solid Tumors. Clin Cancer Res . 2017;
5. Morikawa A, Henry NL. Palbociclib for the Treatment of Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer. Clin Cancer Res . 2015; 21:3591-6. [PubMed 26100274]
6. Rocca A, Farolfi A, Bravaccini S et al. Palbociclib (PD 0332991) : targeting the cell cycle machinery in breast cancer. Expert Opin Pharmacother . 2014; 15:407-20. [PubMed 24369047]
7. Murphy CG, Dickler MN. The Role of CDK4/6 Inhibition in Breast Cancer. Oncologist . 2015; 20:483-90. [PubMed 25876993]
8. Mangini NS, Wesolowski R, Ramaswamy B et al. Palbociclib: A Novel Cyclin-Dependent Kinase Inhibitor for Hormone Receptor-Positive Advanced Breast Cancer. Ann Pharmacother . 2015; 49:1252-60. [PubMed 26324355]
9. Vidula N, Rugo HS. Cyclin-Dependent Kinase 4/6 Inhibitors for the Treatment of Breast Cancer: A Review of Preclinical and Clinical Data. Clin Breast Cancer . 2016; 16:8-17. [PubMed 26303211]
10. Hosford SR, Miller TW. Clinical potential of novel therapeutic targets in breast cancer: CDK4/6, Src, JAK/STAT, PARP, HDAC, and PI3K/AKT/mTOR pathways. Pharmgenomics Pers Med . 2014; 7:203-15. [PubMed 25206307]
11. Finn RS, Dering J, Conklin D et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res . 2009; 11:R77.
12. Sutherland RL, Musgrove EA. CDK inhibitors as potential breast cancer therapeutics: new evidence for enhanced efficacy in ER+ disease. Breast Cancer Res . 2009; 11:112. [PubMed 20067604]
13. DeMichele A, Clark AS, Tan KS et al. CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res . 2015; 21:995-1001. [PubMed 25501126]
14. Novartis Pharmaceuticals. Kisqali® Femara® Co-Pack (ribociclib succinate copackaged with letrozole) tablets prescribing information. East Hanover, NJ; 2024 Sept. [Web]
15. Curigliano G, Gómez Pardo P, Meric-Bernstam F et al. Ribociclib plus letrozole in early breast cancer: A presurgical, window-of-opportunity study. Breast . 2016; 28:191-8. [PubMed 27336726]
17. Infante JR, Cassier PA, Gerecitano JF et al. A Phase I Study of the Cyclin-Dependent Kinase 4/6 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas. Clin Cancer Res . 2016; 22:5696-5705. [PubMed 27542767]
18. Food and Drug Administration. Drug safety communication: FDA warns about rare but severe lung inflammation with Ibrance®, Kisqali®, and Verzenio® for breast cancer. Silver Spring, MD; 2019 Sept 13. From FDA website. [Web]
19. Tripathy D, Im SA, Colleoni M et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol . 2018; 19:904-915. [PubMed 29804902]
20. Slamon DJ, Neven P, Chia S et al. Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3. J Clin Oncol . 2018; 36:2465-2472. [PubMed 29860922]
21. Hortobagyi GN, Stemmer SM, Burris HA et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol . 2018; 29:1541-1547. [PubMed 29718092]
22. De Laurentiis M, Borstnar S, Campone M et al. Full population results from the core phase of CompLEEment-1, a phase 3b study of ribociclib plus letrozole as first-line therapy for advanced breast cancer in an expanded population. Breast Cancer Res Treat . 2021; 189:689-99. [PubMed 34414532]
23. Hortobagyi GN, Stemmer SM, Burns HA, et al. Overall survival with ribociclib plus letrozole in advanced breast cancer. N Engl J Med . 2022;386:942-50.
24. Lu YS, Im SA, Colleoni M, et al. Updated overall survival of ribociclib plus endocrine therapy versus endocrine therapy alone in pre- and perimenopausal patients with HR+/HER2- advanced breast cancer in MONALEESA-7: a phase III randomized clinical trial. Clin Cancer Res . 2022;28:851-9.
25. Slamon D, Lipatox Z, Nowecki N, et al. Ribociclib plus endocrine therapy in early breast cancer. N Engl J Med . 2024;390:1080-91.
26. Burstein HJ, DeMichele A, Fallowfield L, et al. Endocrine and targeted therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer-capivasertib-fulvestrant: ASCO rapid recommendation update. J Clin Oncol . 2024;42(12):1450-1453.
27. Burstein HJ, Somerfield MR, Barton DL et al. Endocrine treatment and targeted therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: ASCO guideline update. J Clin Oncol . 2021; 39:3959-3977.