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.

INDICATIONS: In combination with obinutuzumab for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL). In combination with rituximab for the treatment of adult patients with CLL who have received at least one prior therapy. As monotherapy, for the treatment of CLL in the presence of 17p deletion or TP53 mutation in adult patients who either are unsuitable for or have failed a B-cell receptor pathway inhibitor. Also as monotherapy, for the treatment of CLL in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B‑cell receptor pathway inhibitor.

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 starting dose is 20 mg of venetoclax, once daily for 7 days. The dose must be gradually increased over 5 weeks up to the recommended daily dose of 400 mg. For monotherapy, venetoclax is continued until disease progression or no longer tolerated. Venetoclax in combination with obinutuzumab is given for 12 cycles, each cycle consisting of 28 days: 6 cycles in combination with obinutuzumab, followed by 6 cycles of venetoclax as a single agent.  Obinutuzumab administration should start at 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.  The 5-week venetoclax dose-titration should begin 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.  When combined with rituximab, rituximab should be administered after the patient has completed the dose-titration phase and has received the recommended dose of venetoclax for 7 days. Venetoclax should be taken for 24 months from Cycle 1 Day 1 of rituximab. 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 TLS: Prior to initiating venetoclax, tumour burden assessment, including radiographic evaluation must be performed for all patients with CLL. Blood chemistry must be assessed, and pre-existing abnormalities corrected. The risk of TLS is a continuum based on multiple factors, including comorbidities, particularly reduced renal function (CrCl<80ml/min), and tumour burden. Splenomegaly may contribute to the overall TLS risk. 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, blood chemistry monitoring and correction of pre-existing abnormalities. All patient comorbidities should be considered for risk-appropriate prophylaxis and monitoring either outpatient or in hospital. Temporary hospitalisation and close monitoring may be required in some patients, especially those at greater risk of TLS. Dose interruption and/or reductions for TLS or other toxicities may need to be considered during treatment. See SmPC for full details of prophylaxis measures and dose modifications. 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. In patients with CLL, concomitant use of strong CYP3A inhibitors is contraindicated at initiation and during the dose-titration phase. 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 recommended dose modifications for other toxicities and adverse reactions and 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 have not been established, no data are available.

CONTRAINDICATIONS: Hypersensitivity to any of the active substances or excipients. Concomitant use of strong CYP3A inhibitors at initiation and during the CLL dose-titration phase or 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), 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 should be employed as overall risk increases. Dosing should be interrupted if needed; when restarting venetoclax, dose modification guidance should be followed, see SmPC for full details. 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 CLL, Grade 3 or 4 neutropenia has been reported. 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 cytopaenias. 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 and dose interruption or reduction 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: In patients with CLL, concomitant use of venetoclax with strong CYP3A inhibitors at initiation and during the dose-titration phase is contraindicated due to increased risk for TLS. At initiation and during the dose-titration phase, concomitant use with moderate CYP3A inhibitors should be avoided. Alternative treatments should be considered. If a moderate CYP3A inhibitor must be used, the doses should be reduced by at least 50% and patients should be monitored more closely. After dose-titration, if a strong CYP3A inhibitor must be used, dose of venetoclax should be reduced to 100mg or less (or by at least 75% if modified for other reasons). 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 at least 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.

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, upper respiratory tract infection, neutropenia (including ≥3 grade), anaemia (including ≥3 grade), lymphopenia, hyperkalaemia, hyperphosphataemia, hypocalcaemia, diarrhoea, vomiting, nausea, constipation and fatigue.

Common side effects (≥1/100 to <1/10): Sepsis (including ≥3 grade), grade ≥3 pneumonia, urinary tract infection (including ≥3 grade), grade ≥3 upper respiratory tract infection, febrile neutropenia (including grade ≥3), grade ≥3 lymphopenia, TLS (including grade ≥3), hyperuricaemia (including grade ≥3), grade ≥3 hyperkalaemia, grade ≥3 hyperphosphataemia, grade ≥3 hypocalcaemia, grade ≥3 diarrhoea, grade ≥3 vomiting, grade ≥3 nausea, grade ≥3 fatigue and blood creatinine increased.

Serious side effects: The most frequently reported serious adverse reactions (≥2%) in patients receiving venetoclax monotherapy were pneumonia and febrile neutropenia. In combination with obinutuzumab or rituximab, the most frequently reported serious adverse reactions (≥2%) were pneumonia, sepsis, febrile neutropenia, and TLS.

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, Great Britain (GB) PLGB 41042/0035, Northern Ireland (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-00008-C

UK-VNCCLL-240075. Date of preparation: April 2024.