ribociclib

rye-boe-SYE-klib

Therapeutic Classification: antineoplastics

Pharmacologic Classification: kinase inhibitors

High Alert

Adjuvant treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative stage II and III early breast cancer in patients at high risk of recurrence.
Advanced or metastatic HR-positive, HER2-negative breast cancer (as initial endocrine-based therapy) (in combination with an aromatase inhibitor).
Advanced or metastatic HR-positive, HER2-negative breast cancer (as initial endocrine-based therapy or following disease progression on endocrine therapy) (in combination with fulvestrant).

Inhibits kinases (cyclin-dependent kinases 4 and 6) that are part of the signaling pathway for cell proliferation.

Therapeutic effects:

Improved survival and decreased spread of breast cancer.

Absorption: 66% absorbed following oral administration.

Distribution: Extensively distributed to the tissues.

Metabolism/Excretion: Mostly metabolized in the liver by the CYP3A4 isoenzyme; 17% excreted unchanged in feces, 12% in urine.

Half-Life: 32 hr.

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	1–4 hr	unknown

Contraindicated in:

Congenital long QT syndrome;
Uncorrected hypokalemia or hypomagnesemia;
Recent MI, HF, unstable angina, bradycardia, uncontrolled hypertension, high degree atrioventricular block, severe aortic stenosis, or uncontrolled hypothyroidism;
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Severe renal impairment (↓ dose);
Moderate or severe hepatic impairment (↓ dose);
Rep: Women of reproductive potential;
Pedi: Safety and effectiveness not established in children.

CV: peripheral edema, QT interval prolongation, syncope

Derm: alopecia, pruritus, rash, DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS), STEVENS-JOHNSON SYNDROME (SJS), TOXIC EPIDERMAL NECROLYSIS (TEN)

F and E: hypokalemia, hypophosphatemia

GI: ↑liver enzymes, abdominal pain, constipation, diarrhea, nausea, stomatitis, vomiting, HEPATOTOXICITY, hyperbilirubinemia

GU: ↑serum creatinine, ↓fertility (men)

Hemat: anemia, neutropenia, thrombocytopenia

Metab: ↓appetite

MS: back pain

Neuro: fatigue, headache, insomnia

Resp: dyspnea, INTERSTITIAL LUNG DISEASE (ILD)

Misc: fever

Drug-drug:

Strong CYP3A4 inhibitors, including clarithromycin, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, or voriconazole, may ↑ levels and the risk of toxicity; avoid concurrent use, if possible; if unavoidable, ↓ dose of ribociclib.
Strong CYP3A4 inducers, including carbamazepine, phenytoin, or rifampin, can ↓ levels and effectiveness; avoid concurrent use.
May ↑ levels and risk of toxicity of cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, midazolam, pimozide, quinidine, sirolimus, and tacrolimus; if concurrent use is required, dose ↓ may be necessary.
QT-interval-prolonging medications, including amiodarone, chloroquine, clarithromycin, disopyramide, haloperidol, methadone, moxifloxacin, ondansetron, pimozide, procainamide, quinidine, sotalol, and tamoxifen, may ↑ risk of QT interval prolongation; avoid concurrent use.

Drug-Natural Products:

St. John's wort may ↓ levels and effectiveness; avoid concurrent use.

Grapefruit/grapefruit juice or pomegranate/pomegranate juice may ↑ levels and risk of toxicity; avoid ingestion.

Early Breast Cancer

PO (Adults ): 400 mg once daily for 21 days, followed by 7 days off to complete a 28-day treatment cycle; continue treatment cycles for 3 yr or until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 200 mg once daily for 21 days, followed by 7 days off to complete a 28-day treatment cycle; continue treatment cycles for 3 yr or until disease progression or unacceptable toxicity.

Renal Impairment

PO (Adults ): Severe renal impairment: 200 mg once daily for 21 days, followed by 7 days off to complete a 28-day treatment cycle; continue treatment cycles for 3 yr or until disease progression or unacceptable toxicity.

Advanced or Metastatic Breast Cancer

PO (Adults ): 600 mg once daily for 21 days, followed by 7 days off to complete a 28-day treatment cycle; continue treatment cycles until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 400 mg once daily for 21 days, followed by 7 days off to complete a 28-day treatment cycle; continue treatment cycles until disease progression or unacceptable toxicity.

Renal Impairment

PO (Adults ): Severe renal impairment: 200 mg once daily for 21 days, followed by 7 days off to complete a 28-day treatment cycle; continue treatment cycles until disease progression or unacceptable toxicity.

Hepatic Impairment

PO (Adults ): Moderate or severe hepatic impairment: 400 mg once daily for 21 days, followed by 7 days off to complete a 28-day treatment cycle; continue treatment cycles until disease progression or unacceptable toxicity.

Tablets: 200 mg

Monitor ECG prior to therapy. Avoid administering if QT interval >450 msec. Repeat ECG on Day 14 of first cycle, beginning of 2nd cycle, and as indicated. If QT interval >480 msec, suspend therapy. If QT interval prolongation resolves to <481 msec, resume therapy at same dose or next ↓ dose in advanced or metastatic breast cancer. If QT interval ≥481 msec recurs, interrupt dose until QT interval resolves to <481 msec; then resume ribociclib at next ↓ dose. If QT interval >500 msec, withhold therapy if >500 msec on ≥2 separate ECGs (within same visit). If QT interval prolongation resolves to <481 msec, resume therapy at next ↓ dose. If QT 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 and symptoms of serious arrhythmia; or if dose <200 mg/day is required, permanently discontinue ribociclib.
Monitor for signs and symptoms of ILD/pneumonitis (hypoxia, cough, dyspnea) during therapy. If Grade 1 symptoms (asymptomatic) occur, continue and treat symptomatically. If Grade 2 symptoms occur, hold therapy until ≤Grade 1. Resume at next ↓ dose. If Grade 2 recurs, permanently discontinue ribociclib. If Grade 3 or Grade 4 symptoms (life-threatening) occur, permanently discontinue ribociclib.
Monitor for cutaneous reactions (rash, erythema, purpura) during therapy. If Grade 1 (<10% body surface area [BSA] with active skin toxicity, no signs of systemic involvement) or Grade 2 (10–30% BSA with active skin toxicity, no signs of systemic involvement) occurs, continue at same dose, initiate medical therapy, and monitor as clinically indicated. If Grade 3 (severe rash not responsive to medical management; >30% BSA with active skin toxicity; signs of systemic involvement present; SJS) occurs, hold ribociclib until the cause of has been determined. If the cause is SJS, TEN, or DRESS, permanently discontinue ribociclib. For other causes, hold dose until recovery to ≤Grade 1; then resume ribociclib at same dose level. If the cutaneous reaction recurs at Grade 3, resume ribociclib at the next ↓ dose. If Grade 4 (any % BSA associated with extensive superinfection, with IV antibiotics indicated; life-threatening consequences; TEN) occurs, permanently discontinue ribociclib.

Lab Test Considerations:

Verify negative pregnancy test prior to starting therapy.
- Monitor serum electrolytes (potassium, calcium, phosphorous, magnesium) prior to starting therapy, at beginning of 1st 6 cycles, and as indicated. Correct abnormalities before starting therapy.
- Monitor liver function before starting therapy, every 2 wk for 1st 2 cycles, at beginning of each subsequent 4 cycles, and as indicated. For AST and/or ALT ↑ from baseline, WITHOUT ↑ total bilirubin >2 times upper limit of normal (ULN): If Grade 1 (>ULN–3 times ULN), no dose adjustment. If Grade 2 (>3–5 times ULN), hold dose until recovery to ≤baseline grade; then resume at same dose. If Grade 2 recurs, resume ribociclib at next ↓ dose. Do not interrupt dose for Grade 2 at baseline. Grade 3 (>5–20 times ULN), withhold dose until recovery to ≤baseline grade; then resume at next lower dose. If Grade 3 recurs, discontinue ribociclib. If Grade 4 occurs (>20 times ULN), discontinue ribociclib. Combined ↑ in AST and/or ALT WITH total bilirubin ↑, in absence of cholestasis: If ALT and/or AST >3 times ULN along with total bilirubin >2 times ULN irrespective of baseline grade, discontinue ribociclib.
- Monitor CBC before starting therapy, every 2 wk for 1st 2 cycles, at beginning of each subsequent 4 cycles, and as indicated. If Grade 1 or 2 (ANC 1000/mm³ to <lower limit of normal) occurs, no dose adjustment required. If Grade 3 (ANC 500–1000/mm³) occurs, interrupt dose until recovery to Grade ≤2. Resume therapy at same dose. If toxicity recurs at Grade 3, hold dose until recovery; then resume ribociclib at next ↓ dose. If Grade 3 febrile neutropenia occurs, suspend therapy until recovery of neutropenia to Grade ≤2. Resume therapy at next ↓ dose. If Grade 4 (ANC <500/mm³) occurs, withhold therapy until recovery to Grade ≤2. Resume ribociclib at next ↓ dose.

Dose Reduction Schedule: Starting dose: 600 mg/day. 1st dose reduction: 400 mg/day. 2nd dose reduction: 200 mg/day.
PO: Administer once daily at the same time each day, preferably in the morning, without regard to food. DNC: Swallow tablets whole; do not crush, break, or chew. Do not administer tablets that are broken, cracked, or not intact.
- Pre/perimenopausal women or men taking ribociclib and an aromatase inhibitor or fulvestrant should be treated with a luteinizing hormone-releasing hormone agonist.

Instruct patient to take ribociclib as directed. If patient vomits after taking dose or misses dose, omit for that day. Take next dose at usual time the next day. Advise patient to read Patient Information prior to starting and with each Rx refill in case of changes.
Advise patient to avoid eating pomegranate or grapefruit and to avoid drinking pomegranate or grapefruit juice during therapy.
Advise patient to notify health care professional if signs and symptoms of heart rhythm problems (fast or irregular heart rate, dizziness, feeling faint), low white blood cell counts (fever and chills), liver problems (yellowing of skin or whites of eyes, jaundice, dark or brown tea-colored urine, feeling very tired, loss of appetite, pain on upper right side of abdomen, unusual bleeding or bruising), or skin reactions occur.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
Rep: May cause fetal harm. Advise women of reproductive potential to use effective contraception and to avoid breastfeeding during and for 3 wk after last dose of therapy. Inform male patients that ribociclib may impair fertility.

Improved survival and decreased spread of breast cancer.

Kisqali

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