ABBREVIATED PRESCRIBING INFORMATION

VENCLYXTO® (venetoclax) 10 mg/50 mg/100 mg film-coated tablets

Please refer to the Summary of Product Characteristics (SmPC) before prescribing.

PRESENTATIONS: Each film-coated tablet contains 10mg, 50mg or 100mg of venetoclax.

INDICATIONS: Venclyxto in combination with obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL) (see section 5.1 of SmPC). Venclyxto in combination with rituximab is indicated for the treatment of adult patients with CLL who have received at least one prior therapy. Venclyxto monotherapy is indicated for the treatment of CLL in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor or in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor. Venclyxto in combination with a hypomethylating agent is indicated for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy.

DOSAGE AND ADMINISTRATION: Oral. Patients should swallow the tablets whole with water at approximately the same time each day. The tablets should be taken with a meal. Treatment to 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). Refer to SmPC for specific details on TLS management by disease indication. See SmPC for full posology. Posology (CLL): 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. Post-titration dose for venetoclax in combination with rituximab: The recommended dose of venetoclax in combination with rituximab is 400 mg once daily. Administer rituximab after the patient has completed the dose-titration schedule and has received the recommended daily dose of 400 mg venetoclax for 7 days. Venetoclax is taken for 24 months from Cycle 1 Day 1 of rituximab. 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 in SmPC) 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. Post-titration dose for venetoclax monotherapy: the recommended dose of venetoclax is 400 mg once daily. Treatment is continued until disease progression or no longer tolerated by the patient. Posology (AML): Day 1: 100mg; Day 2: 200mg; Day 3 (and beyond): 400mg. Azacitidine should be administered at 75 mg/m² either intravenously or subcutaneously on Days 1-7 of each 28- day cycle beginning on Cycle 1 Day 1. Decitabine should be administered at 20 mg/m² intravenously on Days 1-5 of each 28-day cycle beginning on Cycle 1 Day 1. Venetoclax dosing may be interrupted as needed for management of hematologic toxicities and blood count recovery. Venetoclax, in combination with a hypomethylating agent, should be continued until disease progression or unacceptable toxicity is observed. Prevention of tumour lysis syndrome (TLS): Blood chemistry must be assessed, and pre-existing abnormalities corrected prior to initiation of treatment. See SmPC for full details of prophylaxis measures and dose modifications. Patients with CLL: Prior to initiating venetoclax, tumour burden assessment, including radiographic evaluation must be performed for all patients. The following prophylaxis measures should be followed to minimise the risk of TLS and more intensive measures should be employed as overall risk increases; adequate hydration, administration of anti-hyperuricaemic agents, and blood chemistry monitoring. All patient comorbidities should be considered for risk-appropriate prophylaxis and monitoring, either outpatient or in hospital. Patients with AML: All patients should have a white blood cell count <25 × 10⁹/l prior to initiation and cytoreduction prior to treatment may be required. Patients should be adequately hydrated and receive anti-hyperuricaemic agents prior to initiation of first dose of venetoclax and during dose-titration phase. Monitor blood chemistries for TLS at pre-dose, 6 to 8 hours after each new dose during titration and 24 hours after reaching final dose. Increased laboratory monitoring and reduction of starting dose should be considered for patients with risk factors for TLS.

Special Populations: Elderly: No dose adjustment required. Renal impairment: No dose adjustment is needed for patients with mild, moderate, severe renal impairment or end-stage renal disease requiring dialysis. Venclyxto should be administered to patients with severe renal impairment (CrCl ≥15 ml/min and <30 ml/min) or end-stage renal disease (ESRD) requiring dialysis (CrCL <15 ml/min) only if the benefit outweighs the risk and patients should be monitored closely for signs of toxicity due to increased risk of TLS. Patients with reduced renal function may require more intensive prophylaxis to reduce the risk of TLS and closer monitoring. Safety in patients with severe renal impairment or on dialysis has not been established, and a recommended dose for these patients has not been determined. Hepatic impairment: No dose adjustment is recommended in patients with mild or moderate hepatic impairment. Patients with moderate hepatic impairment should be monitored more closely for signs of toxicity. A dose reduction of at least 50% throughout treatment is recommended for patients with severe hepatic impairment. These patients should be monitored more closely for signs of toxicity. Paediatric Population: The safety and efficacy of Venclyxto in children aged less than 18 years has not been established. Data are currently available but no recommendation on a posology can be made.

CONTRAINDICATIONS: Hypersensitivity to any of the active substances or excipients. In patients with CLL, concomitant use of strong CYP3A inhibitors at initiation and during the dose- titration phase. In all patients, concomitant use of preparations containing St. John’s wort.

SPECIAL WARNINGS AND PRECAUTIONS: Tumour lysis syndrome (TLS): The risk of TLS is a continuum based on multiple factors, including comorbidities (particularly reduced renal function), tumour burden and splenomegaly in CLL. Reduced renal function (CrCL < 80mL/min) further increases the risk. Assess patient-specific factors for level of risk of TLS and provide prophylactic hydration and anti-hyperuricaemics to patients prior to first dose to reduce risk of TLS. Blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) should be assessed, and pre-existing abnormalities corrected. Dosing should be interrupted if needed; when restarting venetoclax, dose modification guidance should be followed. More intensive measures should be employed as overall risk increases. Neutropenia and infections: In patients with CLL, grade 3 or 4 neutropenia has been reported. 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. Neutropenia can recur with subsequent cycles of therapy. Complete blood counts should be monitored throughout the treatment period. Dose interruptions or reductions are recommended for patients with severe neutropenia. Serious infections, including sepsis with fatal outcome, have been reported. Monitoring of any signs and symptoms of infection is required. Suspected infections are to receive prompt treatment, including antimicrobials and dose interruption or reduction as appropriate and the use of growth factors (e.g., G-CSF) as appropriate. Immunisation: Live vaccines should not be administered during treatment and thereafter until B-cell recovery as the safety and efficacy has not yet been established. CYP3A inducers: Co-administration of CYP3A4 inducers may lead to decreased Venclyxto exposure and consequently a risk for lack of efficacy. Concomitant use of Venclyxto with strong or moderate CYP3A4 inducers should be avoided. Women of childbearing potential: Women of childbearing potential must use a highly effective method of contraception while taking Venclyxto. Effects on ability to drive and use machines: Fatigue and dizziness should be considered when assessing a patients ability to drive or operate machines.

INTERACTIONS: See SmPC for full details. Venetoclax is predominantly metabolised by CYP3A. CYP3A inhibitors: In patients with CLL, concomitant use of venetoclax with strong CYP3A inhibitors is contraindicated at initiation and during the dose-titration phase due to increased risk for TLS. Alternative treatments should be considered. In all patients, if a CYP3A inhibitor must be used, follow the recommendations for managing drug-drug interactions. If a moderate CYP3A inhibitor must be used, the doses must be reduced and patients should be monitored more closely. After dose-titration, if a strong CYP3A inhibitor must be used, the dose of venetoclax should be reduced. Refer to SmPC for full details. Grapefruit, Seville oranges and starfruit should be avoided during treatment. P-gp and BCRP inhibitors: Concomitant use of Venclyxto with P-gp and BCRP inhibitors at initiation and during the dose titration phase should be avoided; if a P-gp and BCRP inhibitor must be used, patients should be monitored closely for signs of toxicities. CYP3A inducers: Concomitant use of Venclyxto with strong or moderate CYP3A inducers should be avoided. Preparations containing St. John's wort are contraindicated during treatment with venetoclax. Bile acid sequestrants: Co-administration of bile acid sequestrants with Venclyxto is not recommended as this may reduce the absorption of venetoclax. If a bile acid sequestrant is to be co-administered with Venclyxto, the SmPC for the bile acid sequestrant should be followed to reduce the risk for an interaction, and Venclyxto should be administered at least 4-6 hours after the sequestrant. Warfarin: It is recommended that the international normalised ratio be monitored closely in patients receiving warfarin. Substrates of P-gp, BCRP, and OATP1B1; Co-administration of narrow therapeutic index P-gp, or BCRP substrates with Venclyxto should be avoided. If a narrow therapeutic index P-gp or BCRP substrate must be used, it should be used with caution. For an orally administered P-gp or BCRP substrate sensitive to inhibition in the gastrointestinal tract its administration should be separated from Venclyxto administration as much as possible to minimise a potential interaction. If a statin is used concomitantly with Venclyxto, close monitoring of statin related toxicity is recommended.

FERTILITY, PREGNANCY AND LACTATION: Women of childbearing potential/Contraception in females: Women should avoid becoming pregnant while taking Venclyxto and for at least 30 days after ending treatment. Pregnancy: Venclyxto is not recommended during pregnancy and in women of childbearing potential not using highly effective contraception. Breast-feeding: Breast-feeding should be discontinued during treatment with Venclyxto. Fertility: Before starting treatment, counselling on sperm storage may be considered in some male patients.

UNDESIRABLE EFFECTS: Refer to Section 4.8 of the SmPC for details of other side effects, and for further information. Frequencies presented represent all grades, see SmPC for Grade ≥3 frequencies. In patients with CLL: Very common side effects (≥1/10): Pneumonia, upper respiratory tract infection, neutropenia, anaemia, lymphopenia, hyperphosphataemia, hyperkalaemia, hypocalcaemia, diarrhoea, vomiting, nausea, constipation and fatigue. Common side effects (≥1/100 to <1/10): Sepsis, urinary tract infection, febrile neutropenia, tumour lysis syndrome, hyperuricaemia, and blood creatinine increased. In patients with AML: Very common side effects (≥1/10): Pneumonia, sepsis, urinary tract infection, neutropenia, febrile neutropenia, anaemia, thrombocytopenia, hypokalaemia, decreased appetite, dizziness/syncope, headache, hypotension, haemorrhage, dyspnoea, nausea, diarrhoea, vomiting, stomatitis, abdominal pain, arthralgia, fatigue, asthenia, weight decreased and blood bilirubin increased. Common side effects (≥1/100 to <1/10): Tumour lysis syndrome and cholecystitis/cholelithiasis. Tumour lysis syndrome (TLS): TLS is an important identified risk when initiating Venclyxto.

Adverse events should be reported. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance; website: www.hpra.ie

LEGAL CATEGORY: POM (S1A)

MARKETING AUTHORISATION NUMBERS: 10mg film-coated tablet, 14 tablets, EU/1/16/1138/002; 50mg film-coated tablet, 7 tablets, EU/1/16/1138/004; 100mg film- coated tablet, 7 tablets, EU/1/16/1138/005; 100mg film-coated tablet, 14 tablets, EU/1/16/1138/006; 100mg film-coated tablet, 112 tablets, EU/1/16/1138/007.

MARKETING AUTHORISATION HOLDER: AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany.

Further information is available on request from: AbbVie Limited, 14 Riverwalk, Citywest Business Campus, Dublin 24, Ireland.

DATE OF REVISION: August 2025

PI/1138/014