Venclexta (venetoclax)

Venclexta is a prescription medicine used:

• to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
• in combination with azacitidine, or decitabine, or low-dose cytarabine to treat adults with newly-diagnosed acute myeloid leukemia (AML) who:
  • are 75 years of age or older, or
  • have other medical conditions that prevent the use of standard chemotherapy.

It is not known if Venclexta is safe and effective in children.

Venclexta can cause serious side effects, including:

• Low white blood cell count (neutropenia). Low white blood cell counts are common with Venclexta but can also be severe. Your healthcare provider will do blood tests to check your blood counts during treatment with Venclexta.
• Infections. Death and serious infections such as pneumonia and blood infection (sepsis) have happened during treatment with Venclexta. Your healthcare provider will closely monitor and treat you right away if you have fever or any signs of infection during treatment with Venclexta.

Tell your healthcare provider right away if you have a fever or any signs of an infection during treatment with Venclexta.

The most common side effects of Venclexta when used in combination with obinutuzumab or rituximab or alone in people with CLL or SLL include:

• low platelet counts
• low red blood cell counts
• diarrhea
• nausea
• upper respiratory tract infection
• cough
• muscle and joint pain
• tiredness
• swelling of your arms, legs, hands, and feet

The most common side effects of Venclexta in combination with azacitidine or decitabine or low-dose cytarabine in people with AML include:

• nausea
• diarrhea
• low platelet counts
• constipation
• fever with low white blood cell counts
• low red blood cell counts
• infection in blood
• rash
• dizziness
• low blood pressure
• fever
• swelling of your arms, legs, hands, and feet
• vomiting
• tiredness
• shortness of breath
• bleeding
• infection in lung
• stomach (abdominal) pain
• pain in muscles or back
• cough
• sore throat

Venclexta may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare provider if you have concerns about fertility.

These are not all the possible side effects of Venclexta. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA1088.

Recommended Dosage

• Assess patient-specific factors for level of risk of tumor lysis syndrome (TLS) and provide prophylactic hydration and anti-hyperuricemics to patients prior to first dose of Venclexta to reduce risk of TLS.
• Instruct patients to take Venclexta tablets with a meal and water at approximately the same time each day.
• Venclexta tablets should be swallowed whole and not chewed, crushed, or broken prior to swallowing.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

• Venclexta dosing begins with a 5-week ramp-up.
• Venclexta 5-week Dose Ramp-Up Schedule
• Administer the Venclexta dose according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg as shown in Table 1.
• The 5-week ramp-up dosing schedule is designed to gradually reduce tumor burden (debulk) and decrease the risk of TLS.

Table 1. Dosing Schedule for Ramp-Up Phase in Patients with CLL/SLL

• The CLL/SLL Starting Pack provides the first 4 weeks of Venclexta according to the ramp-up schedule. The 400 mg dose is achieved using 100 mg tablets supplied in bottles.

Venclexta in Combination with Obinutuzumab

• Start obinutuzumab administration at 100 mg on Cycle 1 Day 1, followed by 900 mg on Cycle 1 Day 2.
• Administer 1000 mg on Days 8 and 15 of Cycle 1 and on Day 1 of each subsequent 28day cycle, for a total of 6 cycles.
• Refer to the obinutuzumab prescribing information for recommended obinutuzumab dosing information.
• On Cycle 1 Day 22, start Venclexta according to the 5-week ramp-up schedule (see Table 1).
• After completing the ramp-up schedule on Cycle 2 Day 28, patients should continue Venclexta 400 mg once daily from Cycle 3 Day 1 until the last day of Cycle 12.

Venclexta in Combination with Rituximab

• Start rituximab administration after the patient has completed the 5-week dose ramp-up schedule with Venclexta (see Table 1) and has received the 400 mg dose of Venclexta for 7 days.
• Administer rituximab on Day 1 of each 28-day cycle for 6 cycles, with rituximab dosed at 375 mg/m² intravenously for Cycle 1 and 500 mg/m² intravenously for Cycles 2-6.
• Patients should continue Venclexta 400 mg once daily for 24 months from Cycle 1 Day 1 of rituximab.

Venclexta as Monotherapy

• The recommended dose of Venclexta is 400 mg once daily after the patient has completed the 5-week dose ramp-up schedule.
• Venclexta should be taken orally once daily until disease progression or unacceptable toxicity is observed.
• The dose of Venclexta depends upon the combination agent.
• The Venclexta dosing schedule (including ramp-up) is shown in Table 2. Initiate the azacitidine or decitabine or low-dose cytarabine on Day 1.

Table 2. Dosing Schedule for Ramp-up Phase in Patients with AML

• Continue Venclexta, in combination with azacitidine or decitabine or low-dose cytarabine, until disease progression or unacceptable toxicity is observed.

Risk Assessment And Prophylaxis For Tumor Lysis Syndrome

• Patients treated with Venclexta may develop tumor lysis syndrome.
• Refer to the appropriate section below for specific details on management.
• Assess patient-specific factors for level of risk of tumor lysis syndrome (TLS) and provide prophylactic hydration and anti-hyperuricemics to patients prior to first dose of Venclexta to reduce risk of TLS.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

• Venclexta can cause rapid reduction in tumor and thus poses a risk for TLS in the initial 5week ramp-up phase.
• Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of Venclexta and at each dose increase.
• The risk of TLS is a continuum based on multiple factors, including tumor burden and comorbidities. Reduced renal function (creatinine clearance [CLcr] <80 mL/min) further increases the risk.
• Perform tumor burden assessments, including radiographic evaluation (e.g., CT scan), assess blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) in all patients and correct pre-existing abnormalities prior to initiation of treatment with Venclexta.
• The risk may decrease as tumor burden decreases.
• Table 3 below describes the recommended TLS prophylaxis and monitoring during Venclexta treatment based on tumor burden determination from clinical trial data. Consider all patient comorbidities before final determination of prophylaxis and monitoring schedule.

Table 3. Recommended TLS Prophylaxis Based on Tumor Burden in Patients with CLL/SLL

Acute Myeloid Leukemia

• All patients should have white blood cell count less than 25 × 10⁹/L prior to initiation of Venclexta. Cytoreduction prior to treatment may be required.
• Prior to first Venclexta dose, provide all patients with prophylactic measures including adequate hydration and anti-hyperuricemic agents and continue during ramp-up phase.
• Assess blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) and correct pre-existing abnormalities prior to initiation of treatment with Venclexta.
• Monitor blood chemistries for TLS at pre-dose, 6 to 8 hours after each new dose during ramp-up and 24 hours after reaching final dose.
• For patients with risk factors for TLS (e.g., circulating blasts, high burden of leukemia involvement in bone marrow, elevated pretreatment lactate dehydrogenase (LDH) levels, or reduced renal function) additional measures should be considered, including increased laboratory monitoring and reducing Venclexta starting dose.

Dosage Modifications Based On Toxicities

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

• Interrupt dosing or reduce dose for toxicities. See Table 4 and Table 5 for recommended dose modifications for toxicities related to Venclexta.
• For patients who have had a dosing interruption greater than 1 week during the first 5 weeks of ramp-up phase or greater than 2 weeks after completing the ramp-up phase, reassess for risk of TLS to determine if reinitiation with a reduced dose is necessary (e.g., all or some levels of the dose ramp-up schedule).

Table 4. Recommended Venclexta Dose Modifications for Toxicities^a in CLL/SLL

Table 5. Dose Reduction for Toxicity During Venclexta Treatment in CLL/SLL

Monitor blood counts frequently through resolution of cytopenias. Management of some adverse reactions may require dose interruptions or permanent discontinuation of Venclexta. Table 6 shows the dose modification guidelines for hematologic toxicities.

Table 6. Recommended Dose Modifications for Toxicities^a in AML

Dosage Modifications For Concomitant Use With Strong Or Moderate CYP3A Inhibitors Or P-gp Inhibitors

Table 7 describes Venclexta contraindication or dosage modification based on concomitant use with a strong or moderate CYP3A inhibitor or P-gp inhibitor at initiation, during, or after the ramp-up phase.

Resume the Venclexta dosage that was used prior to concomitant use of a strong or moderate CYP3A inhibitor or P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor.

Table 7. Management of Potential Venclexta Interactions with CYP3A and P-gp Inhibitors

Dosage Modifications For Patients With Severe Hepatic Impairment

• Reduce the Venclexta once daily dose by 50% for patients with severe hepatic impairment (Child-Pugh C); monitor these patients more closely for signs of toxicity.

Missed Dose

• If the patient misses a dose of Venclexta within 8 hours of the time it is usually taken, the patient should take the missed dose as soon as possible and resume the normal daily dosing schedule.
• If a patient misses a dose by more than 8 hours, the patient should not take the missed dose and should resume the usual dosing schedule the next day.
• If the patient vomits following dosing, no additional dose should be taken that day. The next prescribed dose should be taken at the usual time.

Effects Of Other Drugs On Venclexta

Strong Or Moderate CYP3A Inhibitors Or P-gp Inhibitors

• Concomitant use with a strong or moderate CYP3A inhibitor or a P-gp inhibitor increases venetoclax Cmax and AUCinf, which may increase Venclexta toxicities, including the risk of TLS.
• Concomitant use with a strong CYP3A inhibitor at initiation and during the ramp-up phase in patients with CLL/SLL is contraindicated.
• In patients with CLL/SLL taking a steady daily dosage (after ramp-up phase), consider alternative medications or adjust Venclexta dosage and closely monitor for signs of Venclexta toxicities.
• In patients with AML, adjust Venclexta dosage and closely monitor for signs of Venclexta toxicities.
• Resume the Venclexta dosage that was used prior to concomitant use with a strong or moderate CYP3A inhibitor or a P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor.
• Avoid grapefruit products, Seville oranges, and starfruit during treatment with Venclexta, as they contain inhibitors of CYP3A.

Strong Or Moderate CYP3A Inducers

• Concomitant use with a strong CYP3A inducer decreases venetoclax Cmax and AUCinf, which may decrease Venclexta efficacy.
• Avoid concomitant use of Venclexta with strong CYP3A inducers or moderate CYP3A inducers.

Effect Of Venclexta On Other Drugs

Warfarin

• Concomitant use of Venclexta increases warfarin Cmax and AUCinf, which may increase the risk of bleeding. Closely monitor international normalized ratio (INR) in patients using warfarin concomitantly with Venclexta.

P-gp Substrates

• Concomitant use of Venclexta increases Cmax and AUCinf of P-gp substrates, which may increase toxicities of these substrates.
• Avoid concomitant use of Venclexta with a P-gp substrate.
• If a concomitant use is unavoidable, separate dosing of the P-gp substrate at least 6 hours before Venclexta.

• There are no available data on Venclexta use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage.
• Based on toxicity observed in mice, Venclexta may cause fetal harm when administered to pregnant women.
• In mice, venetoclax was fetotoxic at exposures 1.2 times the human clinical exposure based on AUC at a human dose of 400 mg daily.
• Advise pregnant women of the potential risk to a fetus.
• There are no data on the presence of Venclexta in human milk, the effects of Venclexta on the breastfed child, or the effects of Venclexta on milk production.
• Because many drugs are excreted in human milk and because the potential for serious adverse reactions in a breastfed child from Venclexta is unknown, advise nursing women to discontinue breastfeeding during treatment with Venclexta.