Ribociclib (Monograph)

Brand name: Kisqali
Drug class: Antineoplastic Agents
- Cyclin-dependent Kinase 4/6 Inhibitor
- CDK4/6 Inhibitor
Chemical name: C23H30N8O
Molecular formula: 7-Cyclopentyl-N,N-dimethyl-2-[[5-(1-piperazinyl)-2-pyridinyl]amino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide
CAS number: 1211441-98-3

Medically reviewed by Drugs.com on Apr 5, 2024. Written by ASHP.

Introduction

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

Uses for Ribociclib

Breast Cancer

In combination with an aromatase inhibitor for initial treatment of hormone receptor-positive, human epidermal growth factor receptor type 2 (HER2)-negative advanced or metastatic breast cancer in men and premenopausal, perimenopausal, or postmenopausal women.

In combination with fulvestrant for initial treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer in men and postmenopausal women.

In combination with fulvestrant for treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer in men and postmenopausal women with disease progression following endocrine therapy.

Ribociclib 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 treatment.

• Obtain baseline liver function tests.

• Obtain baseline CBC.

• Verify pregnancy status in females of reproductive potential prior to initiating treatment with ribociclib.

Patient Monitoring

• Repeat ECG at approximately day 14 of the first cycle, at the beginning of the 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 the beginning of the first 6 cycles and as clinically indicated. Correct any abnormalities before initiating ribociclib therapy.

• Monitor liver function tests every 2 weeks for the first 2 cycles, at the beginning of the subsequent 4 cycles, and as clinically indicated. Monitor more frequently if grade 2 or greater abnormalities are observed.

• Monitor CBC every 2 weeks for the first 2 cycles, at the beginning of the subsequent 4 cycles, and as clinically indicated.

• Monitor patients for pulmonary symptoms indicative of interstitial lung disease (ILD)/pneumonitis (e.g., hypoxia, cough, dyspnea).

Other Considerations

• Commercially available alone (Kisqali) and copackaged with letrozole (Kisqali Femara Co-Pack).

• Clinicians should consult the respective manufacturers' labelings for information on dosage and administration (including dosage adjustments), adverse effects, and contraindications of other antineoplastic agents used in combination regimens.

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.

Dosage

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

Adults

Initial Therapy for Advanced Breast Cancer

Combination Therapy with an Aromatase Inhibitor

Oral

600 mg once daily on days 1–21 of each 28-day cycle in combination with an aromatase inhibitor. In principal efficacy studies, therapy was continued until disease progression or unacceptable toxicity occurred.

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

Combination Therapy with Fulvestrant

Oral

600 mg once daily on days 1–21 of each 28-day cycle in combination with fulvestrant 500 mg IM on days 1 and 15 of cycle 1 and then on day 1 of each 28-day cycle thereafter. In principal efficacy study, therapy was continued until disease progression or unacceptable toxicity occurred.

Treat male patients receiving combination therapy with ribociclib and fulvestrant with an LHRH agonist (e.g., goserelin) according to current standards of care.

Previously Treated Advanced Breast Cancer

Combination Therapy with Fulvestrant

Oral

600 mg once daily on days 1–21 of each 28-day cycle in combination with fulvestrant 500 mg IM on days 1 and 15 of cycle 1, and then on day 1 of each 28-day cycle thereafter. In principal efficacy study, therapy was continued until disease progression or unacceptable toxicity occurred.

Treat male patients receiving combination therapy with ribociclib and fulvestrant with an LHRH agonist (e.g., goserelin) according to current standards of care.

Dosage Modification for Toxicity

Oral

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

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.

Dosages <200 mg once daily not recommended; discontinue drug 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 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

If QT_c interval >480 msec occurs, temporarily interrupt ribociclib therapy; resume therapy at same dosage when QT_c interval improves to <481 msec. If QT_c-interval prolongation (i.e., ≥481 msec) recurs, temporarily interrupt ribociclib therapy; resume therapy at reduced dosage when QT_c interval improves to <481 msec.

If QT_c interval >500 msec occurs, temporarily interrupt ribociclib therapy; resume therapy at reduced dosage when QT_c interval improves to <481 msec.

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 ≥38.5ºC or fever >38ºC lasting >1 hour and/or 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.

Concomitant Use with Drugs and Foods Affecting Hepatic Microsomal Enzymes

Oral

If used concomitantly with a potent CYP3A inhibitor, reduce ribociclib dosage to 400 mg once daily.

Prescribing Limits

Adults

Breast Cancer

Oral

Dosages <200 mg once daily not recommended.

Special Populations

Hepatic Impairment

Moderate or severe preexisting hepatic impairment (Child-Pugh class B or C): 400 mg once daily.

Mild preexisting hepatic impairment (Child-Pugh class A): No dosage adjustment required.

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

Contraindications

• Manufacturer states none known.

Warnings/Precautions

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

SCARs, including SJS, TEN, and drug-induced hypersensitivity syndrome/DRESS, reported with ribociclib.

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

If signs or symptoms of SCARs occur, interrupt ribociclib 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; the drug is not FDA-labeled for use in combination with tamoxifen.

Avoid use in patients with congenital long QT syndrome, uncontrolled or clinically important cardiac disease (e.g., MI, CHF, unstable angina, bradyarrhythmias), electrolyte abnormalities, or other risk factors for developing prolongation of QT interval.

Avoid concomitant use with potent CYP3A inhibitors or with drugs known to prolong the QT interval.

Monitor ECGs 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 intervals 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. Median time to onset of grade 3 or greater elevations in ALT/AST concentrations: 85 days; resolution to grade 2 or less occurred in a median of 22 days.

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. Median time to onset of grade 2 or greater neutropenia: 16 days. Median time to resolution of grade 3 or greater neutropenia: 12 days. 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.

Impairment of Fertility

Animal studies suggest ribociclib may impair male fertility.

Specific Populations

Pregnancy

May cause fetal harm.

Confirm pregnancy status prior to initiating ribociclib therapy.

Lactation

Distributed into milk in rats; not known whether distributed into human milk. Discontinue nursing during therapy and for ≥3 weeks after drug discontinuance.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Dose-limiting toxicities were fatigue and thrombocytopenia in pediatric patients with relapsed or refractory neuroblastoma, malignant rhabdoid tumors, or other tumors with documented cyclin D-CDK4/6-inhibitor of CDK4 (INK4)-retinoblastoma (Rb) pathway (cyclin D-CDK4/6-INK4-Rb pathway) abnormalities. Hematologic dose-limiting toxicities not observed in patients receiving ribociclib 350 mg/m² once daily.

Dosage of 350 mg/m² orally once daily for 21 days followed by a 7-day rest period recommended for phase 2 studies in pediatric patients.

Geriatric Use

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

Hepatic Impairment

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

Moderate to severe preexisting hepatic impairment (Child-Pugh class B or C): Increased mean systemic exposure less than twofold. Dosage adjustment required.

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.

Common Adverse Effects

Adverse effects reported in ≥20% of patients receiving combination therapy with an aromatase inhibitor or fulvestrant: Neutropenia, nausea, infection, fatigue, diarrhea, leukopenia, vomiting, alopecia, headache, constipation, rash, cough, back pain, anemia.

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; cause time-dependent inhibition of CYP1A2, 2C9, and 2D6; or 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

Potent 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 400 mg once daily. If potent CYP3A inhibitor is discontinued, resume ribociclib (after ≥5 terminal half-lives of the CYP3A inhibitor) at dosage used prior to initiation of potent CYP3A inhibitor.

Potent CYP3A inducers: Possible pharmacokinetic interaction (decreased plasma concentrations and AUC of ribociclib). Avoid concomitant use; consider choosing 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

Ribociclib 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 twofold 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

• Importance of advising patients to swallow ribociclib succinate tablets whole and not to break, chew, crush, or split the tablets.

• If a dose is missed or vomited, 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. Importance of informing clinician immediately if new or worsening cough (with or without mucus), chest pain, or shortness of breath occurs.

• Risk of SCARs. Importance of informing 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 advising them to contact their clinician immediately if any of these signs/symptoms occur.

• Risk of QT-interval prolongation. Importance of informing clinicians immediately if an abnormal heartbeat or feelings of dizziness or faintness occur.

• Risk of hepatotoxicity. Importance of advising 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. Importance of informing clinician immediately if signs or symptoms of neutropenia or infection (e.g., fever, chills) occur.

• Risk of male infertility.

• Risk of fetal harm. Necessity of advising females of reproductive potential to use an effective method of contraception during treatment and for ≥3 weeks after discontinuance of therapy. Importance of women informing clinicians if they are or plan to become pregnant. Apprise patient of potential fetal hazard if used during pregnancy.

• Importance of advising women to discontinue nursing during therapy and for ≥3 weeks after discontinuance of the drug.

• 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]).

• Importance of informing patients of other important precautionary information. (See Cautions.)

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.

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