ribociclib/letrozole (Rx)

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

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 the treatment

Neutropenia

• Grade 1-2 (ANC 1000/mm³ to <LLN): No dose adjustment required
• 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

• 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: Interrupt dose until recovery to ≤baseline grade, then resume at same dose level; if Grade 2 recurs, resume at next lower dose level
  • 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
• 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

• 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
• 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

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

• 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
• 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
• Letrozole
  • Mild-to-moderate (CrCl ≥30 mL/min): No dose adjustment necessary
  • Severe (CrCl 10-30 mL/min): No dose adjustment necessary

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