Usual Adult Dose for Breast Cancer

Letrozole: 2.5 mg orally once a day throughout the 28-day cycle
Ribociclib: 600 mg orally once a day for 21 consecutive days followed by 7 days off for a 28-day cycle

Use: 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

Renal Dose Adjustments

LETROZOLE:

• Mild (CrCl 60 to less than 90 mL/min) to moderate (CrCl 30 to less than 60 mL/min) renal impairment: No adjustment recommended.
• Severe (CrCl 15 to less than 30 mL/min) renal impairment: Start with 200 mg orally once a day in healthy subjects; there is no data for severe renal impairment dosing in breast cancer patients
• End-stage renal disease (ESRD [eGFR less than 15 mL/min/1.73 m2]: Data not available

• CrCl 10 mL/min or greater: No adjustment recommended.
• CrCl less than 10 mL/min: Data not available

Liver Dose Adjustments

Mild hepatic dysfunction (Child-Pugh A): No adjustment recommended (for both ribociclib and letrozole).
Moderate hepatic dysfunction (Child-Pugh B): Reduce the initial dose of ribociclib to 400 mg once a day; no adjustment recommended for letrozole.
Severe hepatic dysfunction (Child-Pugh C) and/or cirrhosis: Reduce the initial dose of ribociclib to 400 mg once a day; reduce the dose of letrozole by 50% to 2.5 mg every other day.

DOSE MODIFICATION OF RIBOCICLIB FOR HEPATOBILIARY TOXICITY:
AST and/or ALT ELEVATIONS FROM BASELINE (WITHOUT total bilirubin increase above 2 times upper limit of normal [ULN]):

• GRADE 1 (Greater than ULN to 3 x ULN): No adjustment recommended for either ribociclib or letrozole.
• GRADE 2 (Greater than 3 to 5 x ULN):

• GRADE 3 (Greater than 5 to 20 x ULN): Interrupt ribociclib dose until recovery to baseline or less, then resume at the next lower dose; no dose adjustment recommended for letrozole.
• GRADE 3 RECURRENCE OR GRADE 4 (Greater than 20 x ULN): Discontinue therapy.
• COMBINED ELEVATIONS IN AST and/or ALT WITH TOTAL BILIRUBIN INCREASE, IN THE ABSENCE OF CHOLESTASIS: If patients develop ALT and/or AST greater than 3 x ULN along with total bilirubin greater than 2 x ULN irrespective of baseline Grade: Discontinue therapy.

Dose Adjustments

CONCOMITANT USE WITH STRONG CYP450 3A INDUCERS AND/OR STRONG CYP450 3A INHIBITORS: Avoid concomitant use if possible; consider alternative concomitant medications.

• IF CONCOMITANT USE OF STRONG CYP450 3A INHIBITOR IS NECESSARY: Reduce the dose of ribociclib to 400 mg once a day; no dose adjustment recommended for letrozole.
• IF STRONG CYP450 3A INHIBITOR DISCONTINUED: Change the ribociclib dose (AFTER at least 5 half-lives of the strong CYP450 3A inhibitor) to the dose used prior to the initiation of the strong CYP450 3A inhibitor; no dose adjustment recommended for letrozole.

• Initial dose: 600 mg/day
• First dose reduction: 400 mg/day
• Second dose reduction: 200 mg/day
• Discontinue ribociclib if further dose reduction below 200 mg/day is required.
• Comments: No dose adjustment recommended for letrozole when it is administered with ribociclib (for the adverse reactions of ribociclib).

• GRADE 1 or 2 (Absolute neutrophil count [ANC] 1000/mm3 to less than lower limit of normal [LLN]): No adjustment recommended.
• GRADE 3 (ANC 500/mm3 to less than 1000/mm3): Interrupt dose until recovery to Grade 2 or less, then resume at the same dose.
• GRADE 3 RECURRENCE: Interrupt dose until recovery, then resume at the next lower dose.
• GRADE 3 febrile neutropenia (single episode of fever greater than 38.3 degrees Celsius OR above 38 degrees for more than 1 hour and/or concurrent infection) OR GRADE 4 (ANC Less than 500/mm3): Interrupt dose until recovery to Grade 2 or less, then resume at the next lower dose level.

• ECGs with QTcF greater than 480 msec: Interrupt dose; if QTcF resolves to less than 481 msec, resume therapy at the next lower dose level; if QTcF 481 msec or greater recurs, interrupt dose until QTcF resolves to less than 481 msec; then resume at next lower dose level.
• ECGs with QTcF greater than 500 msec: Interrupt dose if QTcF greater than 500 msec; if QTcF prolongation resolves to less than 481 msec, resume therapy at the next lower dose level.
• Permanently discontinue ribociclib if QTcF interval prolongation is either greater than 500 msec or greater than 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.

• GRADE 1 (asymptomatic): No dose adjustment or interruption required; initiate medical therapy and monitor as indicated.
• GRADE 2 (symptomatic): Interrupt dose until recovery to Grade 1 or less then consider resuming at the next lower dose level; if Grade 2 recurs, discontinue this drug.

• GRADE 1 or 2: No adjustment recommended; initiate appropriate medical therapy and monitor as clinically indicated.
• GRADE 3: Interrupt dose until recovery to Grade 1 or less, then resume at the same dose.
• GRADE 3 RECURRENCE: Interrupt dose until recovery to Grade 1 or less, then resume at the next lower dose level.
• GRADE 4: Discontinue this drug.

Precautions

CONTRAINDICATIONS:

• Hypersensitivity to the active component or any of the ingredients

Dialysis

Data not available.

Other Comments

Administration Advice:

• Administer this drug combination with or without food at approximately the same time each day (preferably in the morning).
• Swallow tablets whole; do not chew, crush, or split tablets.
• Do not make up a missed or vomited dose; administer the next scheduled dose at the usual time.
• This product is comprised of ribociclib tablets (200 mg per tablet) co-packaged with letrozole tablets (2.5 mg per tablet) to provide a 28-day therapy regimen.

• Store in the original package at 20C to 25C (68F to 77F).

• In vivo studies using patient-derived estrogen receptor positive breast cancer xenograft models demonstrated the combination of ribociclib and an antiestrogen (e.g., letrozole) resulted in increased tumor growth inhibition compared to each drug alone.
• There are no known cases of overdose with ribociclib and letrozole; initiate general symptomatic and supportive measures in all cases of overdosage as necessary.

• CARDIOVASCULAR: ECGs with ribociclib (before treatment initiation, at approximately Day 14 of the first cycle, at the beginning of the second cycle, and as clinically indicated; more frequent monitoring if QTcF prolongation occurs at any given time during treatment); serum electrolytes (before treatment initiation, at the beginning of the first 6 cycles, and as clinically indicated)
• HEMATOLOGICAL: CBC (before treatment initiation, every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated)
• HEPATIC: LFTs (before treatment initiation, every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated; more frequent monitoring if Grade 2 or greater abnormalities noted)

• Avoid pomegranate/pomegranate juice and grapefruit/grapefruit juice during therapy.
• This combination drug product contains 2 different types of medications; the violet tablet is ribociclib and the yellow tablet is letrozole.
• Immediately contact your healthcare provider if you develop a fever, particularly in association with any suspected infection.