Dosing & Uses
Dosage Forms & Strengths
tablet
- 200mg
Breast Cancer
Indicated in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer as follows
Pre/perimenopausal women or postmenopausal women
- In combination with aromatase inhibitor (eg, letrozole) as initial endocrine-based therapy
Postmenopausal women
- In combination with fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy
600 mg PO qDay for 21 consecutive days followed by 7 days off treatment resulting in a 28-day cycle
Refer to the prescribing information for the recommended dose of the aromatase inhibitor or fulvestrant
Dosage Modifications
Review the prescribing information for the coadministered aromatase inhibitor or fulvestrant for dosage modifications
Recommended dose modifications for adverse effects
- Starting dose: 600 mg/day
- First dose reduction: 400 mg/day
- Second dose reduction: 200 mg/day
- If further dose reduction below 200 mg/day is required, discontinue the treatment
Neutropenia
- Grade 1-2 (ANC 1000/mm³ to <LLN): No dose adjustment required
- Grade 3 (ANC 500 to <1000/mm³): Interrupt dose until recovery to Grade ≤2; resume at the same dose level; if toxicity recurs at Grade 3, interrupt dose until recovery, then resume at the next lower dose level
- Grade 3 febrile neutropenia (Grade 3 ANC with fever and/or concurrent infection): Dose interruption until recovery of neutropenia to Grade ≤2; resume at the next lower dose level
- Grade 4 (ANC <500/mm³): Dose interruption until recovery of neutropenia to Grade ≤2; resume at the next lower dose level
Hepatobiliary toxicity
- AST and/or ALT increased from baseline WITHOUT increased total bilirubin >2x ULN
- Grade 1 (>ULN to 3x ULN): No dose adjustment required
- Grade 2 (>3-5x ULN), baseline at <Grade 2: Interrupt dose until recovery to ≤baseline grade, then resume at same dose level; if Grade 2 recurs, resume at next lower dose level
- Grade 2 (>3-5x ULN), baseline at Grade 2: No dose interruption
- Grade 3 (>5-20x ULN): Interrupt dose until recovery to baseline (or less) before initiating treatment, then resume at next lower dose level; if Grade 3 recurs, discontinue
- Grade 4 (>20x ULN): Discontinue
- AST and/or ALT increased from baseline WITH increased total bilirubin, in the absence of cholestasis
- Discontinue ribociclib if ALT and/or AST >3x ULN plus total bilirubin >2x ULN irrespective of baseline grade
QT prolongation
- ECGs with QTcF >480 msec
- Interrupt treatment
- If QTcF resolves to <481 msec, resume treatment at same dose level
- If QTcF ≥481 msec recurs, interrupt dose until QTcF resolves to <481 msec; then resume at next lower dose level
- ECGs with QTcF >500 msec
- Interrupt treatment if QTcF greater than 500 msec
- If QTcF prolongation resolves to <481 msec, resume treatment at the next lower dose level
- Permanently discontinue if QTcF interval prolongation is either >500 msec or >60 msec change from baseline AND associated with any of the following: Torsades de Pointes, polymorphic ventricular tachycardia, unexplained syncope, or signs/symptoms of serious arrhythmia
Other toxicities
- Grade 1 or 2: No dose adjustment is required; initiate appropriate medical therapy and monitor as clinically indicated
- Grade 3: Interrupt dose until recovery to Grade ≤1, then resume at the same dose level; if Grade 3 recurs, resume at the next lower dose level
- Grade 4: Discontinue
Use with strong CYP3A inhibitors
- Avoid concomitant use with strong CYP3A inhibitors and consider an alternative concomitant medication with less potential for CYP3A inhibition
- If a strong CYP3A inhibitor must be coadministered, reduce the ribociclib dose to 400 mg/day
- If the strong inhibitor is discontinued, change the ribociclib dose (after at least 5 half-lives of the strong CYP3A inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor
Hepatic impairment
- Mild (Child-Pugh A): No dose adjustment required
- Moderate-to-severe (Child-Pugh B or C): Reduce starting dose to 400 mg/day
Renal impairment
- Mild-to-moderate (CrCl ≥30 mL/min): No dose adjustment necessary
- Severe (CrCl 15-30 mL/min): Decrease starting dose to 200 mg/day
- Only studied healthy subjects and noncancer subjects with severe renal impairment
Dosing Considerations
Complete blood count (CBC)
- Perform CBC before initiating treatment
- Monitor CBC q2wk for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated
Liver function tests (LFTs)
- Perform LFTs before initiating
- Monitor LFTs q2wk for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated
- If Grade ≥2 abnormalities observed, more frequent monitoring is recommended
Electrocardiograms (ECGs) and electrolytes
- ECGs should be assessed prior to initiation of treatment
- Repeat ECGs at ~Day 14 of the first cycle and at the beginning of the second cycle, and as clinically indicated
- In case of (QTcF) prolongation at any given time during treatment, more frequent ECG monitoring is recommended
- Monitor serum electrolytes (including potassium, calcium, phosphorous and magnesium) before initiating, at the beginning of the first 6 cycles, and as clinically indicated; correct any abnormality before starting ribociclib
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
Percentage includes all grades of toxicity unless otherwise stated
>10%
Neutropenia (75%)
Nausea (52%)
Neutropenia, grade 3 (50%)
Fatigue (37%)
Diarrhea (35%)
Leukopenia (33%)
Alopecia (33%)
Vomiting (29%)
Constipation (25%)
Headache (22%)
Leukopenia, grade 3 (20%)
Back pain (20%)
Decreased appetite (19%)
Anemia (18%)
Abnormal LFTs (18%)
Rash (17%)
Pruritus (14%)
Pyrexia (13%)
Peripheral edema (12%)
Stomatitis (12%)
Insomnia (12%)
Dyspnea (12%)
Lymphopenia (11%)
Urinary tract infection (11%)
Abdominal pain (11%)
1-10%
Neutropenia, grade 2 (10%)
Warnings
Contraindications
None
Cautions
Also see Dosage Modifications and Dosing Considerations for guidance on dose interruption and/or reduction, and monitoring for the cautions listed below
May cause fetal harm; advise women of reproductive potential to use effective contraception (see Pregnancy)
QT prolongation
- Prolongs the QT interval in a concentration-dependent manner, with estimated mean increase in QTc interval exceeding 20 ms at the mean steady-state peak plasma concentration following administration at 600 mg once daily dose
- Avoid use
- In patients who already have or who are at significant risk of developing QTc prolongation, including those with electrolyte abnormalities, long QT syndrome,
- Patients with uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina, and bradyarrhythmias
- In patients taking drugs known to prolong QTc interval and/or strong CYP3A inhibitors as this may lead to prolongation of the QTcF interval
Hepatobiliary toxicity
- Increased transaminases were observed in clinical trials
- In patients who had Grade ≥3 ALT/AST elevation, median time-to-onset was 57 days; whereas, Grade ≤2 was 24 days
Neutropenia
- Neutropenia is the most frequently reported adverse effect
- Among patients with neutropenia, the median time to Grade ≥2 is 16 days
- Median time to resolution of Grade ≥3 (to normalization or Grade <3) is 15 days
Drug interaction overview
- Ribociclib is a CYP3A4 substrate and CYP3A4 inhibitor
- Drugs that may increase ribociclib plasma concentrations
- Avoid concomitant use of strong CYP3A inhibitors (eg, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, and voriconazole)
- Consider alternative concomitant medications with less potential for CYP3A inhibition
- If coadministration with a strong CYP3A inhibitor cannot be avoided, reduce the ribociclib dose to 400 mg/day (also see Dosage Modifications)
- Instruct patients to avoid pomegranates or pomegranate juice, grapefruit, all of which are known to inhibit cytochrome CYP3A enzymes and may increase the exposure to ribociclib
- Drugs that may decrease ribociclib plasma concentrations
- Avoid concomitant use of strong CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, St John’s Wort) and consider an alternate concomitant medication with no or minimal potential to induce CYP3A
- Effect of ribociclib on other drugs
- Caution if ribociclib is coadministered with CYP3A4 substrates that have a narrow therapeutic index (NTI), as ribociclib can increase their systemic exposure
- The dose of a sensitive CYP3A substrates with a NTI may need to be reduced
- CYP3A substrates with a NTI include (but are not limited to) alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus
- Drugs that prolong QT interval
- Avoid coadministration of ribociclib with drugs with a known potential to prolong QT
- Examples include antiarrhythmic medicines (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol)
- Drugs that are known to prolong the QT interval (eg, chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, pimozide, ondansetron IV)
- Not indicated for concomitant use with tamoxifen; in a clinical trial, an increase of >60 ms from baseline in the QTcF interval was observed in 16% of patients in the ribociclib and tamoxifen combination
Pregnancy
Pregnancy
There are no available human data informing the drug-associated risk
Based on findings from animal studies and the mechanism of action, can cause fetal harm when administered to a pregnant woman
In animal reproduction studies, administration during organogenesis resulted in increased incidences of postimplantation loss and reduced fetal weights in rats and increased incidences of fetal abnormalities in rabbits at exposures 0.6 or 1.5 times the exposure in humans
Infertility: Based on animal studies, may impair fertility in males
Contraception
- Females of reproductive potential should have a pregnancy test prior to starting treatment
- Females: Advise females of reproductive potential to use effective contraception (methods that result in <1% pregnancy rates) during treatment and for at least 3 weeks after the last dose
Lactation
Unknown if distributed in human breast milk
Because of the potential for serious adverse reactions in breastfed infants, advise lactating women not to breastfeed while taking ribociclib and for at least 3 weeks after the last dose
In lactating rats administered a single dose of 50 mg/kg, exposure to ribociclib was 3.56-fold higher in milk compared to maternal plasma
Pregnancy Categories
A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA:Information not available.
Pharmacology
Mechanism of Action
Inhibits cyclin dependent kinases (CDK) 4 and 6; blocks cellular proliferation of G1 into S phase of the cell cycle
These kinases are activated upon binding to D cyclins and play a crucial role in signaling pathways which lead to cell cycle progression and cellular proliferation; the cyclin D-CDK4/6 complex regulates cell cycle progression through phosphorylation of the retinoblastoma protein (pRb)
Absorption
Peak plasma time: 1-4 hr
Steady-state achieved: 8 days
Distribution
Protein bound: 70%
Vd: 1090 L (steady-state)
Metabolism
Undergoes extensive hepatic metabolism mainly via CYP3A4 in humans
Primary metabolic pathways for ribociclib involved oxidation (dealkylation, C and/or N-oxygenation, oxidation (-2H)) and combinations thereof
Phase II conjugates of ribociclib Phase I metabolites involved N-acetylation, sulfation, cysteine conjugation, glycosylation and glucuronidation
Ribociclib was the major circulating drug-derived entity in plasma (44%)
Elimination
Half-life: 32 hr; 29.7-54.7 hr (terminal half-life)
Oral clearance: 25.5 L/hr
Excretion (within 22 days): 69% feces; 23% urine
Administration
Oral Administration
Take ribociclib and letrozole at approximately the same time each day, preferably in the morning
May take with or without food
Swallow tablets whole; do not chew, crush, or split before swallowing
No tablet should be ingested if it is broken, cracked, or otherwise not intact
Missed or vomited dose: No additional dose should be taken that day; take the next dose at the usual time
Storage
Store at 20-25°C (68-77°F) in the original package
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Patient Handout
Formulary
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