Complete instructions for use of Venetoclax/Venetoclax

1. Common names: Venetoclax, Venetoclax

Product name: Venclexta, Venclyxto

2. Indications:

Venetoclax/Venetoclax is mainly suitable for the following conditions:

1. Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): It is suitable for the treatment of adult patients with CLL and SLL. It can be treated with a single drug or in combination with other drugs, such as Rituximab, Obinutuzumab, etc.

2. Acute myeloid leukemia (AML): It can be used in combination with azacitidine (Azacitidine), decitabine (Decitabine) or low-dose cytarabine (Cytarabine) for the treatment of newly diagnosed AML in adults aged 75 or above, or patients with comorbidities who cannot use intensive induction chemotherapy.

3. Usage and dosage:

1. Before use: Before starting drug treatment, doctors usually conduct a comprehensive assessment of the patient to understand their tumor lysis syndrome (TLS) risk level and provide appropriate preventive measures before the first dose, including hydration and anti-hyperuricemia treatment. These measures are designed to reduce the risk of TLS to ensure patient safety while taking the medication.

2. Recommended dosage:

1) For patients with CLL and SLL, the administration of venetoclax adopts a 5-week ascending dose schedule. The goal of this regimen is to gradually reduce tumor burden and thereby reduce the risk of TLS. In the first week, patients take 20 mg orally daily, increasing to 50 mg in the second week, 100 mg in the third week, 200 mg in the fourth week, and reaching the recommended maximum dose of 400 mg in the fifth week and beyond.

(1) In monotherapy, the recommended dose of venetoclax is 400 mg once daily, with treatment continued until disease progression or unacceptable toxicity.

（2) If used in combination with otuzumab, administration begins on day 1 of cycle 1, with specific dose allocation of 100 mg on the first day, 900 mg on the second day, and dosing schedules in subsequent cycles. In this regimen, the use of venetoclax will begin on Day 22 of Cycle 1. After completing 5 weeks of accelerated dosing, patients will continue to take 400 mg of venetoclax daily on Day 1 of Cycle 3 until the end of Cycle 12.

(3) If used in combination with rituximab, patients will begin treatment with rituximab after completing 5 weeks of escalating doses of venetoclax. In each 28-day treatment cycle, rituximab was administered intravenously at a dose of 375 mg/m² in the first cycle and 500 mg/m² in subsequent cycles. At the same time, starting from the first day of the first cycle of rituximab, the patient needs to continue to take 400 mg of venetoclax orally every day, and this administration method will be continued for 24 months.

2) For AML patients, the dosage and escalation schedule of venetoclax also depends on its combination with other drugs. The oral dose starts at 100 mg on day 1 of cycle 1, gradually increases to 400 mg on day 3, and is maintained at 400 mg daily thereafter. Patients may take other medications concurrently, such as azacitidine 75 mg/m² intravenously or subcutaneously daily on days 1-7 of each 28-day cycle, decitabine 20 mg/m² intravenously on days 1-5, or cytarabine 20 mg/m² subcutaneously on days 1-10.

3. Medication management: Venetoclax exists in the form of tablets. It needs to be taken with food and water. It should be taken at about the same time every day and swallow the whole tablet. Do not chew, crush, or break tablets before swallowing. The recommended dosage of venetoclax can be delivered using any approved tablet strength (e.g. patients may take 2*50mg tablets or 10*10mg tablets as needed, rather than 1*100mg tablet).

4. Adverse reactions:

In clinical studies for the treatment of CLL and SLL, the incidence rate of common adverse reactions exceeds 20%, including neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infection, cough, musculoskeletal pain, fatigue and edema, etc.

In clinical studies for the treatment ofAML, the side effects are more serious when used in combination, and the proportion of patients experiencing adverse reactions can reach more than 30%. Common side effects include: nausea, diarrhea, thrombocytopenia, constipation, neutropenia, fever, neutropenia, fatigue, vomiting, edema, pneumonia, dyspnea, bleeding, anemia, rash, abdominal pain, sepsis, musculoskeletal pain, dizziness, cough, oropharyngeal pain and hypotension.

5. Supply and storage:

Venetoclax is available as 10 mg, 50 mg, 100 mg film-coated tablets when stored in the original container at or below 86°F (30°C). Dispense medications to patients in their original containers to protect them from moisture.

6. Taboo:

Due to the possible increased risk of tumor lysis syndrome,venetoclax and strong CYP3A inhibitors are contraindicated in patients with CLL/SLL during the initiation and acceleration phases.

7. Mechanism of action:

Venetoclax is a selective and orally bioavailable small molecule inhibitor of BCL-2, an anti-apoptotic protein. Overexpression of BCL-2 has been demonstrated in CLL and AML cells, where it mediates tumor cell survival and is associated with resistance to chemotherapy drugs. Venetoclax helps restore the apoptotic process by directly binding to BCL-2 protein, replacing pro-apoptotic proteins such as BIM, triggering mitochondrial outer membrane permeability and caspase activation. In non-clinical studies, venetoclax has demonstrated cytotoxic activity in tumor cells overexpressing BCL-2.

8. Overdose:

Venetoclax has no specific antidote. For patients with overdose, monitor closely and provide appropriate supportive care; during the ramp-up phase, interrupt venetoclax and carefully monitor for signs and symptoms of TLS and other toxicities. Based on the substantial distribution and extensive protein binding of venetoclax, dialysis is unlikely to result in significant clearance of venetoclax.

Reference materials:https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b118a40d-6b56-cee3-10f6-ded821a97018