Venetoclax, in combination with rituximab, is used for the treatment of adult patients with chronic lymphocytic leukemia (CLL) who have previously received at least one therapy. Venetoclax can also be used as a single-agent treatment for CLL in the following situations:

• In patients with 17p deletion or TP53 mutation who are not suitable for, or have not responded to, B-cell receptor pathway inhibitors.
• In patients without 17p deletion or TP53 mutation who have failed both chemoimmunotherapy and B-cell receptor pathway inhibitors.

Venetoclax is an orally active, selective inhibitor of the BCL-2 protein, which plays a key role in preventing apoptosis (programmed cell death).
In CLL, overexpression of BCL-2 allows cancer cells to survive and resist treatment. Venetoclax works by binding to BCL-2, displacing pro-apoptotic proteins such as BIM, and restoring the natural process of apoptosis. This leads to mitochondrial membrane changes and activation of caspases, ultimately causing cancer cell death. Preclinical studies have shown that venetoclax is effective in killing tumor cells with high BCL-2 expression.

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. The 5-week dose-titration schedule is designed to gradually reduce tumour burden (debulk) and decrease the risk of tumor lysis syndrome.

Post-titration dose for Venetoclax in combination with Rituximab: The recommended dose of Venetoclax in combination with Rituximab is 400 mg once daily. Rituximab should be administered after the patient has completed the dose-titration schedule and has received the recommended daily dose of 400 mg Venetoclax for 7 days. Venetoclax should be taken for 24 months from Cycle 1 Day 1 of Rituximab.

Post-titration dose for Venetoclax monotherapy: The recommended dose of Venetoclax is 400 mg once daily. Treatment should be continued until disease progression or no longer tolerated by the patient.

CYP3A Inhibitors: Strong CYP3A inhibitors (such as ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, and ritonavir) can significantly increase Venetoclax levels in the body, leading to a higher risk of tumor lysis syndrome (TLS).
Therefore, their use is contraindicated during treatment initiation and dose escalation.

Moderate CYP3A inhibitors (e.g., ciprofloxacin, diltiazem, erythromycin, fluconazole, verapamil) should be avoided during the initiation phase. If unavoidable, the Venetoclax dose should be reduced by at least 50%, and patients must be closely monitored.

For patients already on a stable dose, the Venetoclax dose should be reduced by: 50% with moderate CYP3A inhibitors, 75% with strong CYP3A inhibitors After stopping the inhibitor, the original dose should be resumed within 2–3 days.
Patients should avoid grapefruit, Seville oranges, and starfruit, as they can increase drug levels.

P-gp and BCRP Inhibitors: Venetoclax is a substrate of P-gp and BCRP transporters. Co-administration with inhibitors (e.g., rifampin) may increase drug exposure.
Their use should be avoided during treatment initiation and dose escalation. If unavoidable, close monitoring for toxicity is required.

CYP3A Inducers: Strong CYP3A inducers (such as carbamazepine, phenytoin, rifampin) and moderate inducers (e.g., bosentan, efavirenz, etravirine, modafinil) can significantly reduce Venetoclax levels, decreasing its effectiveness.
Their use should be avoided. Products containing St. John’s wort are contraindicated as they may reduce the effectiveness of Venetoclax.

Venetoclax is contraindicated in patients with hypersensitivity to the drug or any of its components. It should not be used together with strong CYP3A inhibitors during the initiation or dose-titration phase. Use with St. John’s wort-containing products is also contraindicated.

The most common side effects (occurring in more than 20% of patients) during combination therapy with rituximab include neutropenia, diarrhea, and upper respiratory tract infections. In monotherapy, common side effects include neutropenia, diarrhea, nausea, anemia, fatigue, and upper respiratory tract infections. Serious adverse effects reported include pneumonia, febrile neutropenia, and tumor lysis syndrome (TLS).

Women who can become pregnant should avoid pregnancy while taking Venetoclax and for at least 30 days after stopping it. Effective contraception must be used during treatment and for 30 days afterward. Since it is unclear whether Venetoclax affects hormonal contraceptives, women using such methods should also use a barrier method.

Pregnancy: Animal studies suggest Venetoclax may harm the fetus. There is insufficient data in pregnant women. Due to observed reproductive toxicity, it is not recommended during pregnancy or in women not using effective contraception.

Breast-feeding: It is unknown whether Venetoclax passes into breast milk. Since risk to the infant cannot be ruled out, breastfeeding should be stopped during treatment.

Fertility: No human data is available. Animal studies suggest potential effects on male fertility. Sperm preservation may be considered before treatment.

Tumour lysis syndrome: Tumour lysis syndrome (TLS), including fatal cases, has been reported in patients with previously treated chronic lymphocytic leukemia (CLL) who have a high tumour burden and are treated with Venetoclax. Venetoclax can rapidly reduce tumour size, which increases the risk of TLS, particularly during the initial 5-week dose-escalation period. Electrolyte abnormalities consistent with TLS may occur as early as 6 to 8 hours after the first dose and after each dose increase, requiring immediate management. The risk of TLS varies depending on several factors, including co-existing medical conditions. Patients with high tumour burden (e.g., lymph nodes >5 cm or ALC >25 × 10⁹/L) are at increased risk when starting Venetoclax. Impaired renal function (CrCl <80 ml/min) further elevates this risk. Patients should be evaluated for TLS risk and provided with appropriate preventive measures such as adequate hydration and anti-hyperuricaemic therapy. Blood chemistry levels must be closely monitored, and any abnormalities should be managed promptly. Treatment may need to be interrupted if required. For higher-risk patients, more intensive management such as intravenous hydration, frequent monitoring, or hospitalization may be necessary. Guidelines for the prevention of TLS should be strictly followed. Concurrent use of strong or moderate CYP3A inhibitors can increase Venetoclax exposure and raise the risk of TLS during treatment initiation and dose escalation. Similarly, P-gp or BCRP inhibitors may also increase Venetoclax levels.

Neutropenia: Grade 3 or 4 neutropenia has been observed in patients receiving Venetoclax, both in combination with Rituximab (G028667/MURANO study) and as monotherapy. Complete blood counts should be monitored regularly throughout treatment. Dose interruption or reduction is recommended in cases of severe neutropenia. Serious infections, including fatal sepsis, have been reported. Appropriate supportive care, including antimicrobial therapy, should be considered if infection is suspected.

Immunization: The safety and effectiveness of live attenuated vaccines during or after Venetoclax treatment have not been established. Live vaccines should be avoided during therapy and until B-cell recovery is confirmed.

CYP3A inducers: Co-administration with CYP3A4 inducers may reduce Venetoclax levels, potentially decreasing its effectiveness. Use of strong or moderate CYP3A4 inducers should be avoided.

Women of childbearing potential: Women who can become pregnant must use highly effective contraception during treatment with Venetoclax.

Elderly: No dose adjustment is required for patients aged over 65 years.

Renal impairment: No dose adjustment is required for patients with mild to moderate renal impairment (CrCl >30 ml/min and <90 ml/min). However, patients with reduced renal function (CrCl <80 ml/min) may require closer monitoring and preventive measures to reduce TLS risk during treatment initiation and dose escalation. The safety of Venetoclax in patients with severe renal impairment (CrCl <30 ml/min) or those on dialysis has not been established, and no recommended dose is available. Use in such patients should be considered only if the benefits outweigh the risks, with careful monitoring for toxicity.

Hepatic impairment: No dose adjustment is necessary for patients with mild or moderate hepatic impairment. Patients with moderate impairment should be monitored more closely during treatment initiation and dose escalation. For patients with severe hepatic impairment, at least a 50% dose reduction is recommended, along with close monitoring for toxicity.

Pediatric population: The safety and efficacy of Venetoclax in patients under 18 years of age have not been established. No data are available.

There is no specific antidote for Venetoclax overdose. Patients should be closely monitored, and supportive care should be provided. Symptoms of TLS and other toxicities should be carefully observed.

Cytotoxic chemotherapy

Store below 30°C in a cool, dry place. Protect from light and moisture. Keep out of reach of children.