VENCLYXTO

Treatment with venetoclax should be initiated and supervised by a physician experienced in the use of anticancer medicinal products. Patients treated with venetoclax may develop tumour lysis syndrome (TLS). Information described in this section, including risk assessment, prophylactic measures, dose-titration schedule, laboratory monitoring, and drug interactions should be followed to prevent and reduce the risk of TLS.

Posology Chronic lymphocytic leukaemia Dose-titration schedule The starting dose is 20 mg of venetoclax once daily for 7 days. The dose must be gradually increased over a period of 5 weeks up to the daily dose of 400 mg as shown in Table 1.

Table 1:

Dose increase schedule in patients with CLL Week Venetoclax daily dose 1 20 mg 2 50 mg 3 100 mg 4 200 mg 5 400 mg The 5-week dose-titration schedule is designed to gradually reduce tumour burden (debulk) and decrease the risk of TLS.

Venetoclax in combination with acalabrutinib with or without obinutuzumab Administer acalabrutinib 100 mg orally on Cycle 1 Day 1 approximately every 12 hours for a total of 14 cycles of treatment. Each cycle is 28 days. Start the 5-week venetoclax dose-titration schedule (Table 1) on Cycle 3 Day 1.

After completing the dose-titration schedule, the recommended dose of venetoclax is 400 mg once daily until the last day of Cycle 14. If venetoclax is given in combination with acalabrutinib and obinutuzumab, administer obinutuzumab 100 mg on Cycle 2 Day 1, followed by 900 mg, which may be administered on Day 1 or Day 2.

Administer 1000 mg on Days 8 and 15 of Cycle 2 and on Day 1 of Cycles 3 to 7. Obinutuzumab is administered for a total of 6 cycles. Venetoclax in combination with obinutuzumab Venetoclax is given for a total of 12 cycles, each cycle consisting of 28 days: 6 cycles in combination with obinutuzumab, followed by 6 cycles of venetoclax as a single agent.

Administer obinutuzumab 100 mg on Cycle 1 Day 1, followed by 900 mg which may be administered on Day 1 or Day 2. Administer 1000 mg on Days 8 and 15 of Cycle 1 and on Day 1 of each subsequent 28-day cycle, for a total of 6 cycles. Start the 5-week venetoclax dose-titration schedule (see Table 1) on Cycle 1 Day 22 and continue through Cycle 2 Day 28.

After completing the dose-titration schedule, the recommended dose of venetoclax is 400 mg once daily from Cycle 3 Day 1 of obinutuzumab to the last day of Cycle 12. Venetoclax in combination with ibrutinib Start ibrutinib (420 mg once daily) as a single agent for 3 cycles (1 cycle is 28 days), followed by 12 cycles of venetoclax in combination with ibrutinib.

Summary of safety profile Chronic lymphocytic leukaemia The overall safety profile of Venclyxto is based on data from 758 patients with CLL treated in clinical studies with venetoclax in combination with obinutuzumab or rituximab or as monotherapy.

The safety analysis included patients from two phase 3 studies (CLL14 and MURANO), two phase 2 studies (M13-982 and M14-032), and one phase 1 study (M12-175). CLL14 was a randomised, controlled study in which 212 patients with previously untreated CLL and comorbidities received venetoclax in combination with obinutuzumab.

MURANO was a randomised, controlled study in which 194 patients with previously treated CLL received venetoclax in combination with rituximab. 1). The most commonly occurring adverse reactions (≥20%) of any grade in patients receiving venetoclax in the combination studies with obinutuzumab or rituximab were neutropenia, diarrhoea, and upper respiratory tract infection.

In the monotherapy studies, the most common adverse reactions were neutropenia/neutrophil count decreased, diarrhoea, nausea, anaemia, fatigue, and upper respiratory tract infection. The most frequently reported serious adverse reactions (≥2%) in patients receiving venetoclax in combination with obinutuzumab or rituximab were pneumonia, sepsis, febrile neutropenia, and TLS.

In the monotherapy studies, the most frequently reported serious adverse reactions (≥2%) were pneumonia and febrile neutropenia. AMPLIFY was a randomised, controlled study in which 575 patients with previously untreated CLL without del(17p) or TP53 mutation received venetoclax in combination with acalabrutinib with or without obinutuzumab.

For a description of adverse reactions in patients receiving venetoclax in combination with acalabrutinib with or without obinutuzumab, refer to the acalabrutinib SmPC. GLOW (CLL3011) GLOW was an open-label randomized (1:1) phase 3 study in patients with previously untreated CLL/SLL who were 65 years or older, or patients <65 years of age with a Cumulative Illness Rating Scale (CIRS) score >6 or CrCL <70 mL/min.

8). Venetoclax can cause rapid reduction in tumour, and thus poses a risk for TLS at initiation and during the dose-titration phase. Changes in electrolytes consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of venetoclax and at each dose increase.

During post-marketing surveillance, TLS, including fatal events, has been reported after a single 20 mg dose of venetoclax. 2, including risk assessment, prophylactic measures, dose-titration and modification schedule, laboratory monitoring, and drug interactions should be followed to prevent and reduce the risk of TLS.

The risk of TLS is a continuum based on multiple factors, including comorbidities (particularly reduced renal function), tumour burden, and splenomegaly in CLL. All patients should be assessed for risk and should receive appropriate prophylaxis for TLS, including hydration and anti-hyperuricaemics.

Blood chemistries should be monitored and abnormalities managed promptly. More intensive measures (intravenous hydration, frequent monitoring, hospitalisation) should be employed as overall risk increases. Dosing should be interrupted if needed; when restarting venetoclax, dose modification guidance should be followed (see Table 4 and Table 5).

2). 3). 5). 8). In patients with AML, grade 3 or 4 neutropenia are common before starting treatment. The neutrophil counts can worsen with venetoclax in combination with a hypomethylating agent or low dose cytarabine. Neutropenia can recur with subsequent cycles of therapy.

Complete blood counts should be monitored throughout the treatment period. 2). 8). Monitoring of any signs and symptoms of infection is required. g. 2). Immunisation The safety and efficacy of immunisation with live attenuated vaccines during or following venetoclax therapy have not been studied.

Live vaccines should not be administered during treatment and thereafter until B-cell recovery. CYP3A inducers Co-administration of CYP3A4 inducers may lead to decreased venetoclax exposure and consequently a risk for lack of efficacy.

1. 5). In all patients, concomitant use of preparations containing St. 5).