Important Safety Information (cont'd)

Tumor Lysis Syndrome

• Tumor lysis syndrome, including fatal events and renal failure requiring dialysis, has occurred in patients treated with VENCLEXTA.
• VENCLEXTA can cause rapid reduction in tumor and thus poses a risk for TLS at initiation and during the ramp-up phase in all patients, and during reinitiation after dosage interruption in patients with CLL/SLL. 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. TLS, including fatal cases, has been reported after a single 20 mg dose.
• In patients with CLL/SLL who followed the current (5-week) dose ramp-up and the TLS prophylaxis and monitoring measures, the rate of TLS was 2% in the VENCLEXTA CLL/SLL monotherapy trials. The rate of TLS remained consistent with VENCLEXTA in combination with obinutuzumab or rituximab. With a 2- to 3-week dose ramp-up and higher starting dose in patients with CLL/SLL, the TLS rate was 13% and included deaths and renal failure.
• The risk of TLS is a continuum based on multiple factors, particularly reduced renal function, tumor burden, and type of malignancy. Splenomegaly may also increase the risk of TLS in patients with CLL/SLL.
• Assess all patients for risk and provide appropriate prophylaxis for TLS, including hydration and anti-hyperuricemics. Monitor blood chemistries and manage abnormalities promptly. Employ more intensive measures (IV hydration, frequent monitoring, hospitalization) as overall risk increases. Interrupt dosing if needed; when restarting VENCLEXTA, follow dose modification guidance in the Prescribing Information.
• Concomitant use of VENCLEXTA with P-gp inhibitors or strong or moderate CYP3A inhibitors increases venetoclax exposure, which may increase the risk of TLS at initiation and during the ramp-up phase, and requires VENCLEXTA dose reduction.

Neutropenia

• In patients with CLL, Grade 3 or 4 neutropenia developed in 63% to 64% of patients and Grade 4 neutropenia developed in 31% to 33% of patients when treated with VENCLEXTA in monotherapy and in combination studies with obinutuzumab or rituximab; febrile neutropenia occurred in 4% to 6% of patients. Grade 3 or 4 neutropenia developed in 38% of patients and Grade 4 neutropenia developed in 15% of patients when treated with VENCLEXTA in combination with acalabrutinib; febrile neutropenia occurred in 2% of patients.
• Monitor complete blood counts. Interrupt dosing for severe neutropenia and resume at same or reduced dose. Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF).

Infections

• Fatal and serious infections, such as pneumonia and sepsis, have occurred in patients treated with VENCLEXTA. Monitor patients for signs and symptoms of infection and treat promptly. Withhold VENCLEXTA for Grade 3 and 4 infection until resolution and resume at same or reduced dose.
• In AMPLIFY, a randomized study in patients with previously untreated CLL/SLL, serious or Grade 3 or higher infections occurred in 14% of patients who received VENCLEXTA in combination with acalabrutinib (VEN+A), most commonly due to COVID-19; fatal infections occurred in 3.1% of patients.
• In an additional cohort of patients receiving VENCLEXTA in combination with acalabrutinib and obinutuzumab (AVO) (an unapproved regimen for previously untreated CLL/SLL in AMPLIFY), serious or Grade 3 or higher infections occurred in 25%, most commonly due to COVID-19; fatal infections occurred in 6% of patients. The safety and effectiveness of AVO have not been established by the FDA in patients with previously untreated CLL/SLL.

Immunization

• Do not administer live attenuated vaccines prior to, during, or after treatment with VENCLEXTA until B-cell recovery occurs. Advise patients that vaccinations may be less effective.

Embryo-Fetal Toxicity

• VENCLEXTA may cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment and for 30 days after the last dose.

Increased Mortality in Patients with Multiple Myeloma when VENCLEXTA is Added to Bortezomib and Dexamethasone

• In a randomized trial (BELLINI; NCT02755597) in patients with relapsed or refractory multiple myeloma, the addition of VENCLEXTA to bortezomib plus dexamethasone, a use for which VENCLEXTA is not indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with VENCLEXTA in combination with bortezomib plus dexamethasone is not recommended outside of controlled clinical trials.

Adverse Reactions

• In patients with CLL receiving combination therapy with acalabrutinib, serious adverse reactions were most often due to COVID-19 including COVID-19 pneumonia (9%), second primary malignancies (2.7%), and neutropenia (2.1%). The most common adverse reactions (≥20%) of any grade were neutropenia (78%), headache (35%), diarrhea (33%), musculoskeletal pain (25%), and COVID-19 (21%). Fatal adverse reactions occurred in 3.4% of patients, most often from COVID-19 and COVID-19 pneumonia.
• In patients with CLL receiving combination therapy with obinutuzumab, serious adverse reactions were most often due to febrile neutropenia and pneumonia (5% each). The most common adverse reactions (≥20%) of any grade were neutropenia (60%), diarrhea (28%), and fatigue (21%). Fatal adverse reactions that occurred in the absence of disease progression and with onset within 28 days of the last study treatment were reported in 2% (4/212) of patients, most often from infection.
• In patients with CLL receiving combination therapy with rituximab, the most frequent serious adverse reaction (≥5%) was pneumonia (9%). The most common adverse reactions (≥20%) of any grade were neutropenia (65%), diarrhea (40%), upper respiratory tract infection (39%), fatigue (22%), and nausea (21%). Fatal adverse reactions that occurred in the absence of disease progression and within 30 days of the last VENCLEXTA treatment and/or 90 days of the last rituximab were reported in 2% (4/194) of patients.

Drug Interactions

• Concomitant use with a P-gp inhibitor or a strong or moderate CYP3A inhibitor increases VENCLEXTA exposure, which may increase VENCLEXTA toxicities, including the risk of TLS. Concomitant use with a strong CYP3A inhibitor at initiation and during ramp-up phase in patients with CLL/SLL is contraindicated. Consider alternative medications or adjust VENCLEXTA dosage and monitor more frequently for adverse reactions in patients taking a steady daily dosage (after ramp-up phase). Resume the VENCLEXTA dosage that was used prior to concomitant use of a P-gp inhibitor or a strong or moderate CYP3A inhibitor 2 to 3 days after discontinuation of the inhibitor.
• Patients should avoid grapefruit products, Seville oranges, and starfruit during treatment as they contain inhibitors of CYP3A.
• Avoid concomitant use of strong or moderate CYP3A inducers.
• Monitor international normalized ratio (INR) more frequently in patients receiving warfarin.
• Avoid concomitant use of VENCLEXTA with a P-gp substrate. If concomitant use is unavoidable, separate dosing of the P-gp substrate at least 6 hours before VENCLEXTA.

Lactation

• Advise women not to breastfeed during treatment with VENCLEXTA and for 1 week after the last dose.

Females and Males of Reproductive Potential

• Advise females of reproductive potential to use effective contraception during treatment with VENCLEXTA and for 30 days after the last dose.
• Based on findings in animals, VENCLEXTA may impair male fertility.

Hepatic Impairment

• Reduce the dose of VENCLEXTA for patients with severe hepatic impairment (Child-Pugh C); monitor these patients more frequently for adverse reactions. No dose adjustment is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.