Dosing & Uses
Dosage Forms & Strengths
tablets, copackaged cartons
- Packaged for a 28-day medication cycle depending on the ribociclib daily dose
- 3 Blister packs, containing 21 tablets (200mg/tablet; 600mg daily dose) of ribociclib plus one 28-tablet count bottle of letrozole 2.5mg/tablet
- 3 Blister packs, containing 14 tablets (200mg/tablet; 400mg daily dose) of ribociclib plus one 28-tablet count bottle of letrozole 2.5mg/tablet
- 1 blister pack, containing 21 tablets (200mg/tablet; 200mg daily dose) of ribociclib plus one 28-tablet count bottle of letrozole 2.5mg/tablet
Breast Cancer
Indicated as initial endocrine-based therapy for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer
Ribociclib (initial dose): 600 mg PO qDay for 21 consecutive days followed by 7 days off treatment resulting in a 28-day cycle
Letrozole: 2.5 mg PO qDay taken through the 28-day cycle
Pre/perimenopausal women treated with ribociclib/letrozole should be treated with a luteinizing hormone-releasing hormone (LHRH) agonist (eg, goserelin, leuprolide) according to clinical practice standards
Dosage Modifications (ribociclib)
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 treatment
Neutropenia
- Grade 1-2 (ANC 1000/mm3 to
- 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
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AST and/or ALT increased from baseline WITHOUT increased total bilirubin >2 x ULN
- Grade 1 (>ULN to 3 x ULN): No dose adjustment required
- Grade 2 (>3-5 x ULN), baseline at
- Grade 2 (>3-5 x ULN), baseline at Grade 2: No dose interruption
- Grade 3 (>5-20 x 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 (>20 x ULN): Discontinue
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AST and/or ALT increased from baseline WITH increased total bilirubin, in the absence of cholestasis
- Discontinue ribociclib if ALT and/or AST >3 x ULN plus total bilirubin >2 x ULN irrespective of baseline grade
QT prolongation
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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
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ECGs with QTcF >500 msec
- Interrupt KISQALI treatment if QTcF greater than 500 msec on at least 2 separate ECGs (within same visit)
- 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
Interstitial lung disease/pneumonitis (ILD)
- Grade 1 (asymptomatic): No dose interruption or adjustment required; initiate appropriate medical therapy and monitor as clinically indicated
- Grade 2 (symptomatic): Dose interruption until recovery to Grade ≤1 then consider resuming at the next lower dose level; if Grade 2 recurs, discontinue treatment
- Grade 3 (severe symptomatic) or 4 (life-threatening): Discontinue treatment
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
Coadministration with strong CYP3A inhibitors
- Avoid use with strong CYP3A inhibitors and consider an alternative drug with less potential for CYP3A inhibition
- If a strong CYP3A inhibitor must be coadministered, reduce ribociclib dose to 400 mg/day
- If the strong CYP3A inhibitor is discontinued, change ribociclib dose (after at least 5 half-lives of the strong CYP3A inhibitor) to the dose used before initiating the strong CYP3A inhibitor
Hepatic impairment
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Ribociclib
- Mild (Child-Pugh class A): No dose adjustment necessary
- Moderate or severe (Child-Pugh classes B/C): Reduce starting dose to 400 mg/day
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Letrozole
- Mild (Child-Pugh classes A/B): No dose adjustment necessary
- Patients with cirrhosis and severe hepatic dysfunction: Reduce dose by 50% (ie, 2.5 mg every other day)
- Noncirrhotic patients with elevated bilirubin levels have not been studied
Renal impairment
-
Ribociclib
- 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
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Letrozole
- Mild-to-moderate (CrCl ≥30 mL/min): No dose adjustment necessary
- Severe (CrCl 10-30 mL/min): No dose adjustment necessary
Dosing Considerations (ribociclib)
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
>10%
Percentage includes all grades of toxicity unless otherwise stated
Leukocyte count decreased (93%)
Neutrophil count decreased (93%)
Neutropenia (75%)
Hemoglobin decreased (57%)
Nausea (52%)
Lymphocyte count decreased (51%)
Neutropenia, grade 3 (50%)
Neutrophil count decreased, grade 3 (49%)
AST/ALT increased (44-46%)
Fatigue (37%)
Diarrhea (35%)
Leukopenia (33%)
Alopecia (33%)
Leukocyte count decreased, grade 3 (31%)
Platelets decreased (29%)
Vomiting (29%)
Constipation (25%)
Headache (22%)
Leukopenia, grade 3 (20%)
Back pain (20%)
Creatinine increased (20%)
Decreased appetite (19%)
Anemia (18%)
Abnormal LFTs (18%)
Rash (17%)
Pruritus (14%)
Pyrexia (13%)
Phosphorus decreased (13%)
Peripheral edema (12%)
Stomatitis (12%)
Insomnia (12%)
Dyspnea (12%)
Lymphopenia (11%)
Urinary tract infection (11%)
Abdominal pain (11%)
Potassium decreased (11%)
1-10%
Neutropenia, grade 4 (10%)
Postmarketing Reports
Respiratory disorders: Interstitial lung disease (ILD)/pneumonitis
Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS)
Warnings
Contraindications
Hypersensitivity to active substance (letrozole), or to excipients of the formulation
Cautions
May cause fetal harm; advise women of reproductive potential to use effective contraception (see Pregnancy)
Severe cutaneous reactions
- Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis(TEN), and drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) can occur
- If signs or symptoms occur, interrupt treatment until the etiology of the reaction determined
- Early consultation with a dermatologist recommended to ensure greater diagnostic accuracy and appropriate management
- If SJS, TEN, or DiHS/DRESS confirmed, permanently discontinue; do not reintroduce in patients who have experienced SCARs or other life threatening cutaneous reactions during treatment
Interstitial lung disease/pneumonitis
- Severe, life-threatening, or fatal ILD and/or pneumonitis can occur; additional cases of ILD/pneumonitis have been observed in the postmarketing setting, with fatalities reported; monitor for pulmonary symptoms indicative of ILD/pneumonitis which may include hypoxia, cough, and dyspnea
- In patients who have new or worsening respiratory symptoms suspected to be due to ILD or pneumonitis, interrupt therapy immediately and evaluate patient; permanently discontinue therapy in patients with recurrent symptomatic or severe ILD/pneumonitis
QT prolongation
- Prolongs the QT interval in a concentration-dependent manner, with estimated mean increase in QTc interval exceeding 20 ms 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, or uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina, and bradyarrhythmias
- Avoid use in patients taking drugs known to prolong QTc interval and/or strong CYP3A inhibitors as this may lead to prolongation of the QTcF interval
- Based on observed QT prolongation during treatment, drug may require dose interruption, reduction or discontinuation
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
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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) and 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
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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
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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
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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), and other drugs that are known to prolong the QT interval (eg, chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, pimozide, ondansetron IV)
Pregnancy & Lactation
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
The combination of ribociclib and antiestrogen (eg, letrozole) increases tumor growth inhibition compared with each drug alone
Ribociclib
- 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)
Letrozole
- Nonsteroidal competitive inhibitor of the aromatase enzyme system by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues
Absorption
Peak plasma time: 1-4 hr (ribociclib)
Distribution
Protein bound
- Ribociclib: 70%
- Letrozole: Weakly protein bound
Vd
- Ribociclib: 1090 L
- Letrozole: 1.9 L/kg
Metabolism
Ribociclib
- 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%)
Letrozole
- Metabolism to a pharmacologically-inactive carbinol metabolite (4,4'methanol-bisbenzonitrile) and renal excretion of the glucuronide conjugate of this metabolite is the major pathway of letrozole clearance
Elimination
Half-life (ribociclib): 32 hr; 29.7-54.7 hr (terminal half-life)
Oral clearance (ribociclib): 25.5 L/hr
Excretion
- Ribociclib (within 22 days): 69% feces; 23% urine
- Letrozole: 90% urine (75% as glucuronide of the carbinol metabolite; 9% 2 unidentified metabolites, 6% unchanged)
Administration
Oral Administration
Administer with or without food
Take doses at about the same time each day, preferably in the morning
Swallow tablets whole, do not chew, crush, or split
Do not ingest tablets that are broken, cracked, or otherwise not intact
Vomited or missed doses
- Do not take an additional dose the remainder of the day if the dose if vomited or missed
- The next prescribed dose should be taken at the usual time
Storage
Store in original package at 20-25°C (68-77°F)
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Patient Handout
Formulary
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