Venetoclax

• Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL):
• Treatment of adult patients with CLL or SLL with or without 17p deletion.
• Used both as monotherapy and in combination with other agents (e.g., rituximab).
• Acute Myeloid Leukemia (AML):
• Indicated in combination with azacitidine, decitabine, or low-dose cytarabine for newly diagnosed AML in adults who are 75 years or older or have comorbidities precluding intensive induction chemotherapy.
• Off-label Uses:
• Being investigated in other hematologic malignancies and some solid tumors but not yet approved.

• Route: Oral tablets.
• CLL/SLL Monotherapy:
• Initiate with a 5-week dose ramp-up schedule starting at 20 mg once daily, gradually increasing to 400 mg once daily maintenance dose to reduce tumor lysis syndrome (TLS) risk.
• CLL/SLL with Rituximab:
• Venetoclax dose ramp-up same as monotherapy; rituximab started on day 1 of cycle 2.
• AML (in combination):
• Venetoclax started at 100 mg on day 1, 200 mg on day 2, and 400 mg on day 3 with azacitidine, decitabine, or low-dose cytarabine; dose adjustments may be needed with strong CYP3A inhibitors.
• Dose Adjustments:
• Required in patients with moderate/severe hepatic impairment or with concomitant strong CYP3A inhibitors.
• Special Populations:
• No established dosing for pediatric patients.
• Administration:
• Take with food and water. Tablets should be swallowed whole, not crushed or chewed.
• Duration:
• Continue until disease progression or unacceptable toxicity.

Venetoclax is a selective, orally bioavailable inhibitor of the anti-apoptotic protein B-cell lymphoma 2 (BCL-2). BCL-2 is overexpressed in various hematologic malignancies, promoting cell survival by preventing mitochondrial apoptosis. Venetoclax binds with high affinity to BCL-2, displacing pro-apoptotic proteins, thereby restoring the apoptotic process and inducing programmed cell death of malignant cells.

• Absorption: Oral bioavailability is moderate; peak plasma concentration reached in 5–8 hours.
• Distribution: Approximately 99.9% bound to plasma proteins.
• Metabolism: Predominantly metabolized by CYP3A4 in the liver.
• Half-life: Approximately 19 hours.
• Excretion: Primarily fecal (approx. 69%) with renal excretion minor (~20%).
• Onset: Clinical responses generally seen within weeks of treatment initiation.

• Pregnancy: No adequate human data; animal studies show potential fetal harm. Use only if benefits outweigh risks.
• Lactation: Unknown if excreted in human milk; breastfeeding not recommended during treatment and for at least one week after the last dose.

• Antineoplastic agent.
• BCL-2 inhibitor (targeted therapy).

• Known hypersensitivity to venetoclax or any excipients.
• Concomitant use with strong CYP3A inhibitors without appropriate dose adjustment.
• Patients at high risk of tumor lysis syndrome without adequate prophylaxis.

• Tumor Lysis Syndrome (TLS):
• Risk is highest during dose ramp-up; requires close monitoring and prophylactic measures including hydration and uric acid-lowering agents.
• Myelosuppression:
• Monitor blood counts; risk of neutropenia, anemia, thrombocytopenia.
• Infections:
• Increased risk; prompt evaluation and treatment necessary.
• Hepatotoxicity:
• Monitor liver function tests during treatment.
• Embryo-fetal toxicity:
• Avoid in pregnancy; effective contraception advised.

• Common: Neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, fatigue, thrombocytopenia.
• Serious: Tumor lysis syndrome, febrile neutropenia, infections, sepsis, pneumonia, anemia requiring transfusion.
• Onset: Adverse effects often begin during dose ramp-up or early therapy phase and may persist.

• CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin): Increase venetoclax plasma levels; dose reduction recommended.
• CYP3A4 inducers (e.g., rifampin, phenytoin): May reduce venetoclax effectiveness; concomitant use not recommended.
• P-glycoprotein inhibitors: Potentially increase venetoclax levels; caution advised.
• Other myelosuppressive agents: Additive bone marrow toxicity.

• Approved expanded indications for frontline AML treatment in patients ineligible for intensive chemotherapy.
• Updated guidance emphasizes TLS risk mitigation protocols.
• EMA and FDA continue recommending close monitoring for hematologic toxicities.

• Store at 20°C to 25°C (68°F to 77°F).
• Protect from moisture and light.
• Keep in original container tightly closed.
• Do not freeze.