ribociclib/letrozole (Rx)

>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)

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
• Increased in QT prolongation with concomitant use of tamoxifen; not indicated for concomitant use

Hepatobiliary toxicity

• Increased transaminases were observed in clinical trials; Grade 3 or 4 increases in ALT and AST reported
• 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 17 days
• Median time to resolution of Grade ≥3 (to normalization or Grade <3) is 12 days
• Monitor CBC every 2 weeks for first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated; based on the severity of the neutropenia, therapy may require dose interruption, reduction, or discontinuation

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) 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

• 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), and other drugs that are known to prolong the QT interval (eg, chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, pimozide, ondansetron IV)

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.

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)

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)