Venetoclax

eMC §4.2 (Venclyxto). Treatment must be initiated and supervised by a physician experienced in the use of anticancer medicinal products. CLL DOSE-TITRATION (Table 1): starting dose 20 mg once daily for 7 days, increased gradually over 5 weeks - week 1 20 mg, week 2 50 mg, week 3 100 mg, week 4 200 mg, week 5 400 mg daily; the 5-week schedule is designed to debulk tumour and reduce the risk of tumour lysis syndrome (TLS). CLL COMBINATION REGIMENS (all reach the same post-titration 400 mg once daily): with ACALABRUTINIB with or without obinutuzumab - acalabrutinib 100 mg orally approximately every 12 hours from Cycle 1 Day 1 for a total of 14 cycles (28-day cycles), start the venetoclax 5-week titration on Cycle 3 Day 1, then venetoclax 400 mg once daily to the last day of Cycle 14 (if obinutuzumab is added: 100 mg on Cycle 2 Day 1, then 900 mg on Day 1 or Day 2, then 1000 mg on Days 8 and 15 of Cycle 2 and Day 1 of Cycles 3 to 7, 6 cycles total). With OBINUTUZUMAB - 12 cycles total (6 with obinutuzumab then 6 as single agent); obinutuzumab 100 mg on Cycle 1 Day 1, then 900 mg on Day 1 or 2, then 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of each subsequent 28-day cycle for 6 cycles; start the venetoclax 5-week titration on Cycle 1 Day 22 through Cycle 2 Day 28, then 400 mg once daily from Cycle 3 Day 1 to the last day of Cycle 12. With IBRUTINIB - ibrutinib 420 mg once daily as a single agent for 3 cycles, then from Cycle 4 Day 1 start the venetoclax titration, then venetoclax 400 mg once daily with ibrutinib 420 mg once daily to the end of Cycle 15 (12 cycles of the combination). With RITUXIMAB - venetoclax 400 mg once daily; start rituximab only after the patient has completed the titration and had 400 mg venetoclax for 7 days; venetoclax is taken for 24 months from Cycle 1 Day 1 of rituximab. MONOTHERAPY - 400 mg once daily, continued until disease progression or no longer tolerated. ACUTE MYELOID LEUKAEMIA (Table 2, dose depends on the combination agent): Day 1 100 mg, Day 2 200 mg, Day 3 400 mg, Day 4 and beyond 400 mg daily when combined with a hypomethylating agent (azacitidine 75 mg/m2 IV or SC on Days 1-7, or decitabine 20 mg/m2 IV on Days 1-5, of each 28-day cycle) OR 600 mg daily when combined with low-dose cytarabine (20 mg/m2 SC once daily on Days 1-10 of each 28-day cycle); continue until disease progression or unacceptable toxicity. TLS PREVENTION: patients may develop TLS including fatal events and renal failure requiring dialysis; electrolyte changes needing prompt management can occur as early as 6-8 hours after the first dose and at each dose increase, and TLS has been reported post-marketing after a single 20 mg dose. Assess patient-specific TLS risk and give prophylactic hydration and anti-hyperuricaemics before the first dose; risk increases with comorbidity, reduced renal function (creatinine clearance <80 mL/min), tumour burden and splenomegaly. Before initiation, perform tumour burden assessment including radiographic evaluation (e.g. CT) in all patients and assess/correct blood chemistry (potassium, uric acid, phosphorus, calcium, creatinine). Monitor blood chemistries and use more intensive measures (IV hydration, frequent monitoring, hospitalisation) as risk increases; interrupt dosing if needed and follow the SPC dose-modification tables when restarting. PAEDIATRIC: the US prescribing information states safety and effectiveness have not been established in paediatric patients - verify any under-18 use against a children's formulary. ADMINISTRATION (US labelling): take tablets orally once daily with a meal and water. LIMITS OF THIS DRAFT: the fetched eMC §4.2 text is truncated at the TLS risk tables (Table 3 onwards), so the dose-modification, hepatic-impairment and renal-impairment tables are NOT captured here - clinician to complete from the full SPC.