PRESCRIBING INFORMATION (PI)

VENCLYXTO^® (venetoclax) 10 mg film-coated tablets, 50 mg film-coated tablets and 100 mg film-coated tablets

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

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

INDICATION: Venetoclax 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: 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). Risk assessment, prophylactic measures, dose-titration schedule, laboratory monitoring and drug interactions should be followed to prevent and reduce the risk of TLS. Posology: The venetoclax dose is increased daily from 100mg to 400mg over 3 days. 100mg of venetoclax on day 1, 200mg on day 2 and 400mg on day 3 and beyond, in combination with a hypomethylating agent. If used in combination with azacitidine, 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. If used in combination with decitabine, decitabine should be administered at 20mg/m² intravenously on days 1-5 of each 28-day cycle beginning on cycle 1 day 1. Venetoclax in combination with a hypomethylating agent should be continued until disease progression or unacceptable toxicity is observed. Patients should swallow the tablets whole with water at approximately the same time each day. The tablets should be taken with a meal. Prevention of tumour lysis syndrome (TLS): The following prophylaxis measures should be followed: All patients should have a white blood cell count <25 × 10⁹/l prior to initiation and cytoreduction prior to treatment may be required. All patients should be adequately hydrated and receive anti-hyperuricaemic agents prior to initiation of the first dose of venetoclax and during the dose-titration phase. Blood chemistries should be assessed and pre-existing abnormalities corrected prior to initiation of treatment with venetoclax. Blood chemistries should be monitored for TLS at pre-dose, 6 to 8 hours after each new dose during titration and 24 hours after reaching the final dose. For patients with risk factors for TLS, additional measures should be considered, including increased laboratory monitoring and the reducing of the venetoclax starting dose. Dose modifications for other toxicities: Monitor blood counts frequently throughout resolution of cytopenias. Dose modification and interruptions for cytopenias are dependent on remission status. See SmPC for full details of recommended dose modifications for haematologic and non-haematologic adverse reactions. Dose modifications for use with CYP3A inhibitors: Concomitant use of venetoclax with strong or moderate CYP3A inhibitors increases venetoclax exposure and may increase the risk for TLS at initiation and during the dose titration phase and for other toxicities. If a CYP3A inhibitor must be used the venetoclax dose should be adjusted and patients should be monitored more closely for signs of toxicities. See SmPC for full details of the recommended dose modifications when used with CYP3A inhibitors. Missed dose: If a patient misses a dose of venetoclax within 8 hours of the time it is usually taken, the patient should take the missed dose as soon as possible on the same day. If a patient misses a dose by more than 8 hours, the patient should not take the missed dose and should resume usual dosing schedule the following day. If a patient vomits following dosing, no additional dose should be taken that day. The next prescribed dose should be taken at the usual time the following day. Special Populations: Elderly: No dose adjustment required. Renal impairment: Patients with reduced renal function (CrCl <80 ml/min) may require more intensive prophylaxis measures and monitoring to reduce the risk of TLS at initiation and during the dose-titration phase. Venetoclax should be administered to patients with severe renal impairment (CrCl ≥15 ml/min and <30 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. No dose adjustment required in patients with mild, moderate or severe renal impairment (CrCl ≥15 ml/min and <90 ml/min). Hepatic impairment: No dose adjustment is recommended in patients with mild or moderate hepatic impairment, but 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 venetoclax in children aged less than 18 years has not been established, no data are available.

CONTRAINDICATIONS: Hypersensitivity to any of the active substances or excipients. Concomitant use of preparations containing St. John’s wort.

SPECIAL WARNINGS AND PRECAUTIONS: TLS: TLS, including fatal events and renal failure requiring dialysis, has occurred in patients treated with venetoclax. The risk of TLS is a continuum based on multiple factors, including comorbidities (particularly reduced renal function). Patients with high tumour burden are at greater risk of TLS when initiating venetoclax. 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. Dosing should be interrupted if needed. More intensive measures should be employed as overall risk increases. Concomitant use of this medicinal product with strong or moderate CYP3A inhibitors increases venetoclax exposure and may increase the risk for TLS at initiation and during the dose-titration phase. Neutropenia and infections: In patients with AML, grade 3 or 4 neutropenia are common before starting treatment. 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. Refer to the SmPC for recommended dose modifications based on cytopenias. Serious infections, including events of sepsis with fatal outcome, have been reported. Monitoring of signs and symptoms of infection is required. Suspected infections require prompt treatment, including antimicrobials, dose interruption or reduction, and use of growth factors as appropriate. Immunisation: Live vaccines should not be administered during treatment and thereafter until B-cell recovery. Safety and efficacy of live vaccines during or after venetoclax has not yet been established. CYP3A inducers: Co-administration of CYP3A4 inducers may lead to decreased venetoclax exposure and consequently a risk for lack of efficacy. Concomitant use of venetoclax 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 venetoclax. Excipients with known effect: This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium free”.

INTERACTIONS: Venetoclax is predominantly metabolised by CYP3A. Agents that may alter venetoclax plasma concentrations: CYP3A inhibitors: For AML patients requiring concomitant use of venetoclax with strong or moderate CYP3A inhibitors, venetoclax dosing should be adjusted. Patients should be monitored more closely for signs of toxicities and dose may need to be further adjusted. See SmPC for full details of recommended dose modifications with CYP3A inhibitors. Grapefruit, Seville oranges and starfruit should be avoided during treatment. P-gp and BCRP inhibitors: Concomitant use of venetoclax 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 venetoclax with strong or moderate CYP3A inducers should be avoided. Alternative treatments with less CYP3A induction should be considered. Preparations containing St. John's wort are contraindicated during treatment with venetoclax. Bile acid sequestrants: Co-administration of bile acid sequestrants with venetoclax is not recommended as this may reduce the absorption of venetoclax. If a bile acid sequestrant is to be co-administered with venetoclax, the SmPC for the bile acid sequestrant should be followed to reduce the risk for an interaction, and venetoclax should be administered at least 4-6 hours after the sequestrant. Agents that may have their plasma concentrations altered by venetoclax: Warfarin: It is recommended that the international normalized 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 venetoclax 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 venetoclax administration as much as possible to minimise a potential interaction. If a statin is used concomitantly with venetoclax, 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 venetoclax and for at least 30 days after ending treatment. Women of childbearing potential must use highly effective contraceptive measures while taking venetoclax and for 30 days after stopping treatment. Women using hormonal contraceptives should add a barrier method. Pregnancy: There are no adequate and well-controlled data from the use of venetoclax in pregnant women. Studies in animals have shown reproductive toxicity. Venetoclax is not recommended during pregnancy and in women of childbearing potential not using highly effective contraception. Breast-feeding: It is unknown whether venetoclax or its metabolites are excreted in human milk. A risk to the breast-feeding child cannot be excluded. Breast-feeding should be discontinued during treatment with venetoclax. Fertility: No human data on the effect of venetoclax on fertility are available. Based on testicular toxicity in dogs at clinically relevant exposures, male fertility may be compromised by treatment with venetoclax. Before starting treatment, counselling on sperm storage may be considered in some male patients.

EFFECTS ON THE ABILITY TO DRIVE AND USE MACHINES: Venetoclax has no or negligible influence on the ability to drive and use machines. Fatigue and dizziness have been reported in some patients taking venetoclax and should be considered when assessing a patient's ability to drive or operate machines.

UNDESIRABLE EFFECTS: See SmPC for full details on side effects. 

Very common side effects (≥1/10): Pneumonia (including ≥3 grade), sepsis (including ≥3 grade), urinary tract infection, neutropenia (including ≥3 grade), febrile neutropenia (including ≥3 grade), anaemia (including ≥3 grade), thrombocytopenia (including ≥3 grade), hypokalaemia (including ≥3 grade), decreased appetite, dizziness/syncope, headache, hypotension, haemorrhage (including ≥3 grade), dyspnoea, nausea, diarrhoea, vomiting, stomatitis, abdominal pain, arthralgia, fatigue, asthenia, weight decreased, blood bilirubin increased. 

Common side effects (≥1/100 to <1/10): grade ≥3 urinary tract infection, TLS (including ≥3 grade), grade ≥3 decreased appetite, grade ≥3 dizziness /syncope, grade ≥3 hypotension, grade ≥3 dyspnoea, grade ≥3 nausea, grade ≥3 diarrhoea, grade ≥3 vomiting, cholecystitis/cholelithiasis (including ≥3 grade), grade ≥3 fatigue, grade ≥3 asthenia, grade ≥3 weight decreased, grade ≥3 blood bilirubin increased.

Serious side effects: The most frequently reported serious adverse reactions (≥5%) in patients receiving venetoclax in combination with azacitidine were febrile neutropenia, pneumonia, sepsis and haemorrhage; and in venetoclax in combination with decitabine were febrile neutropenia, pneumonia, bacteraemia and sepsis.

OVERDOSE
There is no specific antidote for venetoclax. Patients who experience overdose should be closely monitored and appropriate treatment provided. During dose-titration phase, treatment should be interrupted, and patients should be monitored carefully for signs and symptoms of TLS along with other toxicities. 

MARKETING AUTHORISATION NUMBERS/PRESENTATIONS/NHS LIST PRICES: 
10 mg film-coated tablet, 14 tablets, GB PLGB 41042/0035, NI EU/1/16/1138/002, £59.87; 50 mg film-coated tablet, 7 tablets, GB PLGB 41042/0037, NI EU/1/16/1138/004, £149.67; 100 mg film-coated tablet, 7 tablets, GB PLGB 41042/0036, NI EU/1/16/1138/005, £299.34; 100 mg film-coated tablet, 14 tablets, GB PLGB 41042/0036, NI EU/1/16/1138/006, £598.68; 100 mg film-coated tablet, 112 tablets, GB PLGB 41042/0036, NI EU/1/16/1138/007, £4,789.47

LEGAL CATEGORY: POM

MA HOLDER: Further information available from AbbVie Ltd, Maidenhead, SL6 4UB

DATE OF REVISION: March 2024

DOCUMENT NUMBER: BCL2-UK-00007-C

UK-VNCAML-240077. Date of preparation: April 2024