Ribociclib Succinate (Monograph)

Brand name: Kisqali
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Feb 10, 2025. Written by ASHP.

Introduction

Antineoplastic agent; a selective inhibitor of cyclin-dependent kinases 4 (CDK4) and 6 (CDK6).

Uses for Ribociclib Succinate

Breast Cancer

In combination with an aromatase inhibitor for adjuvant treatment of adults with hormone receptor-positive, human epidermal growth factor receptor type 2 (HER2)-negative stage II and III early breast cancer at high risk of recurrence.

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 in adults with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer.

The American Society of Clinical Oncology (ASCO) recommends CDK4/6 inhibitors (in combination with an aromatase inhibitor or fulvestrant) as first-line therapy for the treatment of hormone receptor-positive, HER2-negative, metastatic breast cancer.

Ribociclib Succinate Dosage and Administration

General

Pretreatment Screening

Obtain baseline ECG. Initiate therapy only in patients with corrected QT (QT_c) interval <450 msec.
Measure serum electrolytes (including potassium, calcium, phosphorous, and magnesium) and correct any abnormalities prior to initiation of therapy.
Obtain baseline liver function tests.
Obtain baseline CBC.
Verify pregnancy status in females of reproductive potential.

Patient Monitoring

Repeat ECG at approximately day 14 of first cycle, at beginning of second cycle, and as clinically indicated. Monitor ECG more frequently in patients with prolonged QT_c interval.
Monitor serum electrolytes (including potassium, calcium, phosphorous, and magnesium) at beginning of first 6 cycles and as clinically indicated. Correct any abnormalities before initiating ribociclib therapy.
Monitor liver function tests every 2 weeks for first 2 cycles, at beginning of subsequent 4 cycles, and as clinically indicated. Monitor more frequently if grade 2 or greater abnormalities are observed.
Monitor CBC every 2 weeks for first 2 cycles, at beginning of subsequent 4 cycles, and as clinically indicated.
Monitor for pulmonary symptoms indicative of interstitial lung disease (ILD)/pneumonitis (e.g., hypoxia, cough, dyspnea).

Administration

Oral Administration

Administer orally once daily without regard to food at approximately the same time each day, preferably in the morning.

Swallow tablets whole; do not break, chew, crush, or split.

If a dose is missed or vomited, take the next dose at the regularly scheduled time. Do not double the dose or take extra doses.

Commercially available as a single entity (Kisqali) or copackaged with letrozole (Kisqali Femara Co-Pack). 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.

Dosage

Available as ribociclib succinate; dosage expressed in terms of ribociclib.

Adults

Breast Cancer

Early Disease

Oral

400 mg once daily on days 1-21 of each 28-day cycle in combination with an aromatase inhibitor. Continue treatment for 3 years or until disease progression or unacceptable toxicity occurs.

Advanced or Metastatic Disease

Oral

600 mg once daily on days 1–21 of each 28-day cycle in combination with endocrine therapy (fulvestrant or an aromatase inhibitor).

Treat men and premenopausal or perimenopausal women receiving combination therapy with ribociclib and an aromatase inhibitor or fulvestrant with a luteinizing hormone-releasing hormone (LHRH) agonist (e.g., goserelin) according to current standards of care.

Dosage Modification for Toxicity

Adverse effects may require temporary interruption, dosage reduction, or permanent discontinuance. Adjust dosage based on individual safety and tolerability.

Early breast cancer: If dosage reduction from 400 mg once daily is required, reduce dosage to 200 mg once daily. If toxicity recurs at 200 mg once daily dosage, discontinue ribociclib.

Advanced or metastatic breast cancer: Up to 2 dosage reductions for toxicity may be made. If dosage reduction from 600 mg once daily is necessary, initially reduce dosage to 400 mg once daily. If further dosage reduction necessary, reduce dosage to 200 mg once daily.

Discontinue ribociclib if 200-mg daily dosage is not tolerated.

Interstitial Lung Disease (ILD)/Pneumonitis

Oral

If grade 3 or 4 or recurrent symptomatic ILD/pneumonitis occurs, permanently discontinue ribociclib therapy.

If grade 2 ILD/pneumonitis occurs, temporarily interrupt ribociclib therapy; may resume therapy at reduced dosage when toxicity improves to grade 1 or less. Consider potential benefits and risks of resuming therapy. If grade 2 ILD/pneumonitis recurs, discontinue ribociclib therapy.

If grade 1 ILD/pneumonitis occurs, no dosage adjustment required. Initiate appropriate medical interventions and monitor as clinically indicated.

Dermatologic Toxicity

Oral

If 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]) occurs, permanently discontinue ribociclib therapy.

If 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]) occurs, interrupt ribociclib therapy until etiology is determined. If etiology is a severe cutaneous adverse reaction (SCAR), permanently discontinue ribociclib. If etiology other than SCAR is found, resume ribociclib at the same dosage when toxicity improves to grade ≤1. If grade 3 cutaneous toxicity (that is not SCAR) recurs, withhold ribociclib until improvement to grade ≤1, then resume at the next lower dosage level.

If 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 occurs, no dosage adjustment is necessary; however, initiate appropriate medical interventions and monitor as clinically indicated.

Cardiovascular Toxicity

Oral

Early breast cancer: If QT_c interval >480 msec and ≤500 msec occurs, temporarily interrupt ribociclib therapy; resume therapy at same dosage when QT_c interval improves to ≤480 msec. If QT_c-interval prolongation (i.e., ≥480 msec) recurs, temporarily interrupt ribociclib therapy again; resume therapy at the next lower dosage level when QT_c interval improves to ≤480 msec.

If QT_c interval >500 msec occurs, temporarily interrupt ribociclib therapy; resume therapy at the next lower dosage level when QT_c interval improves to ≤480 msec. If QT_C interval >500 msec recurs, discontinue ribociclib.

Advanced or metastatic breast cancer: If the QT_cinterval is >480 msec and ≤500 msec, interrupt ribociclib therapy; resume therapy at the next lower dosage level when the QT_c interval improves to ≤480 msec. If QT_c-interval prolongation (i.e., >480 msec) recurs, withhold therapy again; resume therapy at the next lower dose level when the QT_c interval improves to ≤480 msec.

If the QT_c interval is >500 msec, interrupt ribociclib therapy; resume therapy at the next lower dose level when the QT_c-interval improves to ≤480 msec. If QT_c interval >500 msec recurs, discontinue ribociclib.

When QT_c-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, permanently discontinue ribociclib therapy.

Hepatic Toxicity

Oral

If grade 4 serum ALT and/or AST elevations (>20 times the ULN) with total bilirubin concentrations ≤2 times the ULN occur, discontinue ribociclib therapy.

For first occurrence of grade 3 serum ALT and/or AST elevations (>5 times the ULN, but ≤20 times the ULN) with total bilirubin concentrations ≤2 times the ULN, temporarily interrupt ribociclib therapy; upon recovery to baseline or better grade, resume therapy at reduced dosage. If grade 3 hepatotoxicity recurs at reduced dosage, discontinue ribociclib therapy.

For first occurrence of grade 2 serum ALT and/or AST elevations (>3 times the ULN, but ≤5 times the ULN) with total bilirubin concentrations ≤2 times the ULN in patients with preexisting ALT and/or AST concentrations ≤3 times the ULN, temporarily interrupt ribociclib therapy; upon recovery to baseline or better grade, resume therapy at same dosage. For subsequent occurrences, temporarily interrupt ribociclib therapy; upon recovery to baseline or better grade, resume therapy at reduced dosage.

If grade 2 serum ALT and/or AST elevations with total bilirubin concentrations ≤2 times the ULN persist in patients with preexisting ALT and/or AST concentrations >3 times the ULN, but ≤5 times the ULN, continue ribociclib therapy without interruption.

If grade 1 serum ALT and/or AST elevations (i.e., exceeding the ULN, but ≤3 times the ULN) with total bilirubin concentrations ≤2 times the ULN occur, no dosage modification required.

If serum ALT and/or AST elevations >3 times the ULN with concomitant total bilirubin concentrations >2 times the ULN (irrespective of baseline hepatic function) occur in the absence of cholestasis, discontinue ribociclib therapy.

Hematologic Toxicity

Oral

If grade 4 neutropenia (ANC <500/mm³) occurs, temporarily interrupt ribociclib therapy. When neutropenia improves to grade 2 or less, resume therapy at reduced dosage.

If grade 3 febrile neutropenia (ANC 500 to <1000/mm³ with fever >38.3ºC or fever ≥38ºC lasting >1 hour and/or concurrent infection) occurs, temporarily interrupt ribociclib therapy. When neutropenia improves to grade 2 or less, resume therapy at reduced dosage.

For first occurrence of grade 3 neutropenia (ANC 500 to <1000/mm³), temporarily interrupt ribociclib therapy; upon recovery to grade 2 or less, resume therapy at same dosage. For subsequent occurrences of grade 3 neutropenia, temporarily interrupt ribociclib therapy; upon return to grade 2 or less, resume therapy at reduced dosage.

If grade 1 or 2 neutropenia (ANC 1000/mm³ to less than the lower limit of normal [LLN]), no dosage modification required.

Other Toxicity

Oral

If grade 4 adverse reactions occur, discontinue ribociclib therapy.

If grade 3 adverse reactions occur, temporarily interrupt ribociclib therapy; resume therapy at same dosage when toxicity improves to grade 1 or less. For subsequent occurrences of grade 3 adverse reactions, temporarily interrupt ribociclib therapy; resume therapy at reduced dosage when toxicity improves to grade 1 or less.

If grade 1 or 2 adverse reactions occur, no dosage modification required; initiate appropriate medical therapy and additional monitoring as clinically indicated.

Special Populations

Hepatic Impairment

Patients with early breast cancer and mild to severe hepatic impairment: no dosage adjustment necessary.

Patients with advanced or metastatic breast cancer and moderate or severe hepatic impairment (Child-Pugh class B or C): 400 mg once daily. No dosage adjustment required for mild hepatic impairment (Child-Pugh class A).

Patients with preexisting grade 3 or greater ALT and/or AST elevations: No specific dosage recommendations at this time.

Renal Impairment

Severe renal impairment (eGFR 15 to <30 mL/minute per 1.73 m²): 200 mg once daily.

Mild or moderate renal impairment (eGFR 30 to <90 mL/minute per 1.73 m²): No dosage adjustment required.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Ribociclib Succinate

Contraindications

None.

Warnings/Precautions

Interstitial lung disease (ILD)/Pneumonitis

Severe, life-threatening, or fatal ILD/pneumonitis reported with CDK4 and CDK6 inhibitors, including ribociclib.

Monitor patients clinically and by radiographic imaging for manifestations of pneumonitis.

If manifestations of ILD or pneumonitis occur and other etiologies (e.g., infection, neoplastic) have been excluded, temporary interruption, dosage reduction, or discontinuance of ribociclib may be necessary.

Dermatologic Toxicity

Severe cutaneous adverse reactions (SCARs), including SJS, TEN, and drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DRESS), reported.

If dermatologic toxicity occurs, temporary interruption, dosage reduction, or discontinuance of ribociclib may be necessary.

If signs or symptoms of SCARs occur, interrupt therapy until the etiology of the reaction has been determined. Early consultation with a dermatologist recommended.

If SJS, TEN, or DRESS is confirmed, permanently discontinue drug; do not reintroduce in patients who have experienced SCARs or other life-threatening cutaneous reactions during ribociclib therapy.

Prolongation of QT Interval

QT_c-interval prolongation, including one fatal case, reported. Prolongation appears to occur in a plasma concentration-dependent manner. Generally occurs within first 4 weeks of therapy and recovers upon dosage interruption. Torsades de pointes not observed in principal efficacy studies.

Increased risk of QT_c-interval prolongation following concomitant use of ribociclib and tamoxifen; ribociclib is not FDA-labeled for use in combination with tamoxifen.

Avoid use 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 MI, heart failure, unstable angina, bradyarrhythmias, uncontrolled hypertension, high degree of atrioventricular block, severe aortic stenosis, or uncontrolled hypothyroidism; electrolyte abnormalities, or taking medications known to prolong the QT interval and/or strong CYP3A inhibitors.

Monitor ECG at baseline, around day 14 of cycle 1, prior to initiation of cycle 2, and then as clinically indicated. More frequent ECG monitoring recommended in patients who develop QT_c-interval prolongation during therapy.

Monitor serum electrolytes (i.e., potassium, calcium, phosphorus, magnesium) at baseline, prior to initiation of cycles 1–6, and then as clinically indicated.

QT_c interval must be <450 msec and electrolyte abnormalities must be corrected prior to initiation of therapy.

If QT_c-interval prolongation occurs, temporary interruption, dosage reduction, or discontinuance of ribociclib may be necessary.

Hepatic Toxicity

Drug-induced hepatotoxicity reported.

Monitor liver function tests at baseline, every 2 weeks for cycles 1 and 2, prior to initiation of cycles 3–6, and then as clinically indicated. More frequent testing necessary in patients who develop AST/ALT elevations.

If hepatotoxicity occurs, temporary interruption, dosage reduction, or discontinuance of ribociclib may be necessary.

Neutropenia

Grade 3 or 4 neutropenia occurs frequently. Febrile neutropenia also reported.

Monitor CBC at baseline, every 2 weeks for cycles 1 and 2, prior to initiation of cycles 3–6, and then as clinically indicated.

If neutropenia occurs, temporary interruption, dosage reduction, or discontinuance of ribociclib may be necessary.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on mechanism of action; embryofetal toxicity and teratogenicity demonstrated in animals.

Confirm pregnancy status prior to initiating ribociclib therapy. Avoid pregnancy during therapy. Use effective contraceptive methods in females of reproductive potential while receiving ribociclib and for ≥3 weeks after drug is discontinued. Apprise patients of potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm based on mechanism of action and animal findings. No available human data to inform drug-associated risk.

Confirm pregnancy status prior to initiating ribociclib therapy.

Lactation

Distributed into milk in rats; not known whether distributed into human milk. Effects on nursing infants or milk production unknown. Discontinue breastfeeding during therapy and for ≥3 weeks after drug discontinuance.

Females and Males of Reproductive Potential

Confirm pregnancy status prior to initiation of ribociclib; females of reproductive potential should use effective contraceptive methods during and for at least 3 weeks after the last dose of ribociclib.

Results of animal studies suggest that ribociclib may impair male fertility.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

No overall differences in safety and efficacy relative to younger patients.

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Systemic exposure not substantially altered.

Moderate to severe hepatic impairment (Child-Pugh class B or C): Increased mean systemic exposure less than 2-fold.

Dosage adjustment required in patients with advanced or metastatic breast cancer who have moderate or severe hepatic impairment.

Renal Impairment

Mild to moderate renal impairment (eGFR 30 to <90 mL/minute per 1.73 m²): Systemic exposure not substantially altered.

Severe renal impairment (eGFR <30 mL/minute per 1.73 m²): Increased AUC and peak plasma concentrations. Dosage adjustment required in patients with severe renal impairment.

Common Adverse Effects

Adverse effects (≥20%) in patients with early breast cancer: decreased lymphocytes, leukocytes, neutrophils, and hemoglobin, increased ALT and AST, infections, increased creatinine, decreased platelets, headache, nausea, fatigue.

Adverse effects (≥20%) in patients with advanced or metastatic breast cancer: 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, decreased serum glucose.

Drug Interactions

Metabolized principally by CYP3A4. In vitro, reversible inhibitor of CYP1A2, 2E1, and 3A4/5 at clinically relevant concentrations; inhibition of CYP3A4/5 is time dependent.

In vitro, does not inhibit CYP2A6, 2B6, 2C8, 2C9, 2C19, and 2D6 or cause time-dependent inhibition of CYP1A2, 2C9, and 2D6; does not induce CYP1A2, 2B6, 2C9, and 3A4 at clinically relevant concentrations.

In vitro, may inhibit breast cancer resistance protein (BCRP), organic cation transporter (OCT) 2, multidrug and toxic compound extrusion (MATE) 1, and bile salt export pump (BSEP); low potential for inhibition of P-glycoprotein (P-gp), MATE2K, OCT1, organic anion transport protein (OATP) 1B1, and OATP1B3 at clinically relevant concentrations. In vitro, not a substrate for OCT1, OATP1B1, or OATP1B3.

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Strong CYP3A inhibitors: Possible pharmacokinetic interaction (increased plasma concentrations and AUC of ribociclib). Avoid concomitant use; consider choosing alternative agent with less CYP3A inhibition potential. If concomitant use cannot be avoided, reduce ribociclib dosage to 200 mg once daily in patients with early breast cancer and 400 mg once daily in patients with advanced or metastatic breast cancer. If strong CYP3A inhibitor is discontinued, resume ribociclib (after ≥5 terminal half-lives of the CYP3A inhibitor) at dosage used prior to initiation of strong CYP3A inhibitor.

Strong CYP3A inducers: Possible pharmacokinetic interaction (decreased plasma concentrations and AUC of ribociclib). Avoid concomitant use; consider alternative agent with no or minimal CYP3A induction potential.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A: Possible pharmacokinetic interaction (increased plasma concentrations of CYP3A substrate). If concomitant use of ribociclib and CYP3A substrates with a narrow therapeutic index cannot be avoided, consider dosage reduction of CYP3A substrate.

Drugs Affecting Gastric Acidity

Pharmacokinetic interaction unlikely with drugs that increase gastric pH.

Drugs that Prolong QT Interval

Potential pharmacologic interaction (additive effect on QT-interval prolongation).

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Anastrozole	No effect on pharmacokinetics of anastrozole or ribociclib
Antiarrhythmic agents (e.g., amiodarone, disopyramide, procainamide, quinidine, sotalol)	Possible additive effects on QT-interval prolongation	Avoid concomitant use
Antiemetic agents that prolong QT interval (e.g., type 3 serotonin [5-HT3] receptor antagonists such as IV ondansetron)	Possible additive effects on QT-interval prolongation	Avoid concomitant use
Antifungals, azoles (e.g., itraconazole, ketoconazole, posaconazole, voriconazole)	Possible increased peak concentrations and exposure of ribociclib	Avoid concomitant use Select alternative agent with less CYP3A inhibition potential; if concomitant use unavoidable, reduce ribociclib dosage If strong CYP3A inhibitor discontinued, resume ribociclib (after ≥5 terminal half-lives of the CYP3A inhibitor) at dosage used prior to initiation of strong CYP3A inhibitor
Antipsychotic agents that prolong QT interval (e.g., haloperidol, pimozide)	Possible additive effects on QT-interval prolongation	Avoid concomitant use
Antiretrovirals, HIV protease inhibitors (e.g., nelfinavir, ritonavir, lopinavir/ritonavir)	Possible increased peak concentrations and exposure of ribociclib Ritonavir increased AUC and peak concentrations of ribociclib by 3.2- and 1.7-fold, respectively; AUC and peak concentrations of major metabolite, LEQ803, decreased by 98 and 96%, respectively	Avoid concomitant use Select alternative agent with less CYP3A inhibition potential; if concomitant use unavoidable, reduce ribociclib dosage If strong CYP3A inhibitor discontinued, resume ribociclib (after ≥5 terminal half-lives of the CYP3A inhibitor) at dosage used prior to initiation of strong CYP3A inhibitor
Caffeine	Peak concentrations of caffeine decreased by 10% and AUC increased by 20%
Carbamazepine	Possible decreased peak concentrations and exposure of ribociclib	Avoid concomitant use Select alternative agent with no or minimal CYP3A induction potential
Chloroquine	Possible additive effects on QT-interval prolongation	Avoid concomitant use
Conivaptan	Possible increased peak concentrations and exposure of ribociclib	Avoid concomitant use Select alternative agent with less CYP3A inhibition potential; if concomitant use unavoidable, reduce ribociclib dosage If conivaptan discontinued, resume ribociclib (after ≥5 terminal half-lives of conivaptan) at dosage used prior to initiation of conivaptan
Ergot derivatives (e.g., dihydroergotamine, ergotamine)	Possible increased concentrations of ergot derivative	Caution advised with CYP3A substrates with narrow therapeutic index; if concomitant use unavoidable, consider dosage reduction of ergot derivative
Exemestane	No effect on pharmacokinetics of exemestane or ribociclib
Fulvestrant	No effect on systemic exposure of ribociclib
Grapefruit or grapefruit juice	Possible increased peak concentrations and exposure of ribociclib	Avoid concomitant use
Immunosuppressive agents (e.g., cyclosporine, everolimus, sirolimus, tacrolimus)	Possible increased concentrations of immunosuppressive agents metabolized by CYP3A	Caution advised with CYP3A substrates with narrow therapeutic index; if concomitant use unavoidable, consider dosage reduction of CYP3A substrate
Letrozole	No effect on pharmacokinetics of letrozole or ribociclib
Macrolides (e.g., clarithromycin, erythromycin)	Possible increased peak concentrations and exposure of ribociclib Clarithromycin: Possible additive effects on QT-interval prolongation	Macrolides that prolong QT interval: Avoid concomitant use Strong CYP3A inhibitors: Avoid concomitant use; select alternative agent with less CYP3A inhibition potential If concomitant use of strong CYP3A inhibitor unavoidable, reduce ribociclib dosage; if strong CYP3A inhibitor is discontinued, resume ribociclib (after ≥5 terminal half-lives of the CYP3A inhibitor) at dosage used prior to initiation of strong CYP3A inhibitor
Methadone	Possible additive effects on QT-interval prolongation	Avoid concomitant use
Midazolam	Ribociclib 400 mg daily increased AUC and peak concentrations of midazolam by 3.8- and 2.1-fold, respectively Pharmacokinetic models suggest ribociclib 600 mg daily may increase AUC and peak concentrations of midazolam by 5.2- and 2.4-fold, respectively
Moxifloxacin	Possible additive effects on QT-interval prolongation	Avoid concomitant use
Nefazodone	Possible increased peak concentrations and exposure of ribociclib	Avoid concomitant use Select alternative agent with less CYP3A inhibition potential; if concomitant use unavoidable, reduce ribociclib dosage If nefazodone discontinued, resume ribociclib (after ≥5 terminal half-lives of nefazodone) at dosage used prior to initiation of nefazodone
Opiate agonists (e.g., alfentanil, fentanyl)	Possible increased concentrations of opiate agonists metabolized by CYP3A	Caution advised with CYP3A substrates with narrow therapeutic index; if concomitant use unavoidable, consider dosage reduction of CYP3A substrate
Phenytoin	Possible decreased peak concentrations and exposure of ribociclib	Avoid concomitant use Select alternative agent with no or minimal CYP3A induction potential
Pimozide	Possible increased concentrations of pimozide Possible additive effects on QT-interval prolongation	Avoid concomitant use
Proton-pump inhibitors	No substantial effect on absorption of ribociclib
Quinidine	Possible increased concentrations of quinidine Possible additive effects on QT-interval prolongation	Avoid concomitant use
Rifampin	Rifampin decreased AUC and peak concentrations of ribociclib by 89 and 81%, respectively; peak concentrations of major metabolite, LEQ803, increased by 1.7-fold and AUC decreased by 27%	Avoid concomitant use
St. John’s wort (Hypericum perforatum)	Possible decreased peak concentrations and exposure of ribociclib	Avoid concomitant use
Tamoxifen	Ribociclib 600 mg daily increased AUC and peak concentrations of tamoxifen by approximately 2-fold in patients with breast cancer Possible additive effects on QT-interval prolongation	Not FDA-labeled for use in combination with tamoxifen

Ribociclib Succinate Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentrations attained in 1–4 hours.

AUC and peak plasma concentrations are more than dose proportional over dosage range of 50–1200 mg; mean accumulation ratio is 2.5.

Steady-state concentrations achieved in 8 days.

Food

Administration with high-fat, high-calorie meal (approximately 800–1000 calories with approximately 50% of calories from fat) does not substantially affect rate or extent of absorption.

Special Populations

Mean systemic exposure of ribociclib increased less than 2-fold in individuals with moderate or severe hepatic impairment (Child-Pugh class B or C). Mild hepatic impairment (Child-Pugh class A) does not affect systemic exposure.

Mild or moderate renal impairment (eGFR 30 to <90 mL/minute per 1.73 m²) does not substantially affect systemic exposure. In individuals (without cancer) with severe renal impairment (eGFR 15 to <30 mL/minute per 1.73 m²), AUC and peak plasma concentration increased 2.37- and 2.1-fold, respectively. In individuals (without cancer) with end-stage renal impairment (eGFR <15 mL/minute per 1.73 m²), AUC and peak plasma concentration increased 3.81- and 2.68-fold, respectively.

Age (23–84 years), gender, race, and body weight do not have clinically important effects on ribociclib exposure.

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

Approximately 70%.

Elimination

Metabolism

Principally metabolized by CYP3A4.

Elimination Route

Eliminated in feces (69%) and urine (23%).

Half-life

Mean terminal plasma half-life: 29.7–54.7 hours.

Stability

Storage

Oral

Tablets

20–25°C. Store in original container.

Actions

Selective inhibitor of cyclin-dependent kinases 4 (CDK4) and 6 (CDK6).
CDK4 and CDK6 involved in regulation of progression from the G1 into S phase of the cell cycle through regulation of phosphorylation of the tumor suppressor protein retinoblastoma.
Inhibits the G1 into S phase of the cell cycle and reduces cellular proliferation of breast cancer cells.
Ribociclib and an antiestrogen (e.g., letrozole, fulvestrant) increased cell growth arrest in patient-derived estrogen receptor-positive breast tumor xenografts compared with either drug alone.
Ribociclib reduced tumor volume, which correlated with inhibition of retinoblastoma protein phosphorylation, in xenograft models of human cancer.

Advice to Patients

Advise patients to swallow ribociclib tablets whole and not to break, chew, crush, or split the tablets.
If a dose is missed or vomited, stress importance of administering the next dose at the regularly scheduled time; do not administer an additional dose to make up for a missed dose.
Risk of ILD/pneumonitis. Stress importance of informing clinician immediately if new or worsening cough (with or without mucus), chest pain, or shortness of breath occurs.
Risk of SCARs. Inform patients of the signs and symptoms of SCARs (e.g., skin pain/burning, rapidly-spreading skin rash, and/or mucosal lesions accompanied by fever or flu-like symptoms) and advise them to contact their clinician immediately if any of these signs/symptoms occur.
Risk of QT-interval prolongation. Stress importance of informing clinicians immediately if an abnormal heartbeat or feelings of dizziness or faintness occur.
Risk of hepatotoxicity. Advise patients to immediately report possible symptoms of hepatotoxicity (e.g., fatigue, anorexia, right upper quadrant pain, jaundice, dark urine, bleeding) to their clinician.
Risk of neutropenia. Stress importance of informing clinician immediately if signs or symptoms of neutropenia or infection (e.g., fever, chills) occur.
Risk of fetal harm. Advise females of reproductive potential to use an effective method of contraception during treatment and for ≥3 weeks after discontinuance of therapy. Stress importance of patients informing clinicians if they are or plan to become pregnant. Apprise patient of potential fetal hazard if used during pregnancy.
Advise patients to discontinue nursing during therapy and for ≥3 weeks after discontinuance of the drug.
Stress importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses (e.g., hepatic impairment, cardiovascular disease [including congenital long QT syndrome]).
Inform patients of other important precautionary information.

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 [Web].

Preparations

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.

Ribociclib Succinate
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	200 mg (of ribociclib)	Kisqali	Novartis

Ribociclib Succinate Combinations
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