rye-boe-SYE-klib

Therapeutic Classification: antineoplastics

Pharmacologic Classification: kinase inhibitors

• Advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor 2 (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 postmenopausal women or in men) (in combination with fulvestrant).

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

• 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)

Contraindicated in:

• QT interval prolongation (QT interval 450 msec)
• Uncorrected hypokalemia or hypomagnesemia
• Recent MI, HF, unstable angina, or bradycardia
• OB: Pregnancy
• Lactation: Lactation.

Use Cautiously in:

• Severe renal impairment (↓ dose)
• Moderate or severe hepatic impairment (↓ dose)
• 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, hyperbilirubinemia.

GU: ↑serum creatinine, ↓ fertility (males).

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, conivaptan, 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 effects/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.

Drug-Food:

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

• 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.

• Tablets: 200 mg;

• Monitor ECG prior to starting therapy. Avoid administering ribociclib to patient with 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 level. If QT 481 msec recurs, interrupt dose until QT interval resolves to <481 msec; then resume ribociclib at next lower dose level. If QT interval >500 msec, withhold therapy if >500 msec on at least 2 separate ECGs (within same visit). If QT interval prolongation resolves to <481 msec, resume therapy at next lower 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, permanently discontinue ribociclib.
• Monitor for signs and symptoms of ILD/pneumonitis (hypoxia, cough, dyspnea) during therapy. If Grade 1 symptoms (asymptomatic) occur, continue dose and treat symptoms. If Grade 2 symptoms (symptomatic) occur, hold therapy until Grade 1. Resume at next lower dose. If Grade 2 recurs, discontinue ribociclib permanently. If Grade 3 (severe symptomatic) or Grade 4 symptoms (life-threatening) occur, permanently discontinue therapy.
• Monitor for signs and symptoms of cutaneous reactions (rash, erythema, purpura) during therapy. If reactions are 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), continue at same dose and initiate medical therapy and monitor as clinically indicated. If Grade 3 reaction (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 the reaction has been determined. If the cause is SJS, TEN, or DRESS, permanently discontinue therapy. If cause is not SJS, TEN, DRESS, hold dose until recovery to Grade 1, then resume ribociclib at same dose level. If the cutaneous adverse reaction still recurs at Grade 3, resume ribociclib at the next lower dose level. If Grade 4 reaction (any % BSA associated with extensive superinfection, with IV antibiotics indicated; life-threatening consequences; TEN) occurs, permanently discontinue ribociclib.

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

• Dose Reduction Schedule: Starting dose: 600 mg/day. First dose reduction: 400 mg/day. Second 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 should also be treated with a luteinizing hormone-releasing hormone (LHRH) agonist. Men taking ribociclib plus fulvestrant should be treated with an LHRH agonist.

• Instruct patient to take ribociclib as directed. If patient vomits after taking dose or misses dose, do not take more that day. Take next dose next day at usual time. 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 (change in heartbeat [fast or irregular], dizziness, feeling faint), low white blood cell counts (fever and chills), or 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.
• May cause fetal harm. Advise females of reproductive potential to use effective contraception and to avoid breastfeeding during and for at least 3 wk after last dose of therapy. Inform male patients that ribociclib may impair fertility.

• Improved survival and decreased spread of breast cancer.

Kisqali