Venetoclax is a BCL-2 inhibitor. It is a light yellow to dark yellow solid with the empirical formula C 45 H 50 ClN 7 O 7 S and a molecular weight of 868.44. Venetoclax is described chemically as 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)- N -({3-nitro-4-[(tetrahydro-2 H -pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1 H -pyrrolo[2,3- b ]pyridin-5-yloxy)benzamide) and has the following chemical structure: Venetoclax has very low aqueous solubility. VENCLEXTA tablets for oral use are supplied as pale yellow or beige tablets that contain 10 mg, 50 mg, or 100 mg venetoclax as the active ingredient. Each tablet also contains the following inactive ingredients: copovidone, colloidal silicon dioxide, polysorbate 80, sodium stearyl fumarate, and calcium phosphate dibasic. In addition, the 10 mg and 100 mg coated tablets include the following: iron oxide yellow, polyvinyl alcohol, polyethylene glycol, talc, and titanium dioxide. The 50 mg coated tablets also include the following: iron oxide yellow, iron oxide red, iron oxide black, polyvinyl alcohol, talc, polyethylene glycol and titanium dioxide. Each tablet is debossed with “V” on one side and “10”, “50” or “100” corresponding to the tablet strength on the other side. the following chemical structure for Venetoclax is a BCL-2 inhibitor. It is a light yellow to dark yellow solid with the empirical formula C45H50ClN7O7S and a molecular weight of 868.44. Venetoclax is described chemically as 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide).

VENCLEXTA is a BCL-2 inhibitor indicated: For the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma VENCLEXTA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)

Acute Myeloid Leukemia VENCLEXTA is indicated in combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.

Table 9. VENCLEXTA Tablet Strength and Description Tablet Strength Description of Tablet 10 mg Round, biconvex shaped, pale yellow film-coated tablet debossed with “V” on one side and “10” on the other side 50 mg Oblong, biconvex shaped, beige film-coated tablet debossed with “V” on one side and “50” on the other side 100 mg Oblong, biconvex shaped, pale yellow film-coated tablet debossed with “V” on one side and “100” on the other side Tablets: 10 mg, 50 mg, 100 mg

See Full Prescribing Information for recommended VENCLEXTA dosages. Take VENCLEXTA tablets orally once daily with a meal and water. Do not chew, crush, or break tablets. Provide prophylaxis for tumor lysis syndrome

Important Safety Information 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

Recommended Dosage for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma VENCLEXTA dosing begins with a 5-week ramp-up. The 5-week ramp-up dosing schedule is designed to gradually reduce tumor burden (debulk) and decrease the risk of TLS. VENCLEXTA 5-week Dose Ramp-Up Schedule Administer VENCLEXTA according to the 5-week ramp-up dosing schedule to the recommended dosage of 400 mg orally once daily as shown in Table 1 . Table 1. Dosing Schedule for 5-Week Ramp-up Phase for Patients with CLL/SLL VENCLEXTA Oral Daily Dose Week 1 20 mg Week 2 50 mg Week 3 100 mg Week 4 200 mg Week 5 and beyond 400 mg The CLL/SLL Starting Pack provides the first 4 weeks of VENCLEXTA according to the ramp-up schedule . In Combination with Acalabrutinib Cycle 1 Day 1: Start acalabrutinib 100 mg orally approximately every 12 hours until disease progression, unacceptable toxicity or completion of 14 cycles of treatment. Each cycle is 28 days. Refer to the acalabrutinib prescribing information for additional dosing information. Cycle 3 Day 1: start VENCLEXTA according to the 5-week ramp-up dosing schedule . After completing the ramp-up phase, continue VENCLEXTA at a dose of 400 mg orally once daily until disease progression, unacceptable toxicity, or until the last day of Cycle 14. 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 1,000 mg on Days 8 and 15 of Cycle 1 and on Day 1 of each subsequent 28-day cycle for a total of 6 cycles. Refer to the obinutuzumab prescribing information for additional dosing information. On Cycle 1 Day 22, start VENCLEXTA according to the 5-week ramp-up dosing schedule . After completing the ramp-up phase on Cycle 2 Day 28, continue VENCLEXTA at a dose of 400 mg orally once daily from Cycle 3 Day 1 until the last day of Cycle 12. In Combination with Rituximab Start rituximab administration after the patient has completed the 5-week ramp-up dosing schedule for VENCLEXTA and has received VENCLEXTA at the recommended dosage of 400 mg orally once daily for 7 days. Administer rituximab on Day 1 of each 28-day cycle for 6 cycles, at a dose of 375 mg/m 2 intravenously for Cycle 1 and 500 mg/m 2 intravenously for Cycles 2-6. Continue VENCLEXTA 400 mg orally once daily for 24 months from Cycle 1 Day 1 of rituximab. Refer to the rituximab prescribing information for additional dosing information. Monotherapy The recommended dosage of VENCLEXTA is 400 mg once daily after completion of the 5-week ramp-up dosing schedule . Continue VENCLEXTA until disease progression or unacceptable toxicity

Recommended Dosage for Acute Myeloid Leukemia The recommended dosage and ramp-up of VENCLEXTA depends upon the combination agent. Follow the dosing schedule, including the 3-day or 4-day dose ramp-up, as shown in Table 2. Start VENCLEXTA administration on Cycle 1 Day 1 in combination with: Azacitidine 75 mg/m 2 intravenously or subcutaneously once daily on Days 1-7 of each 28-day cycle; OR Decitabine 20 mg/m 2 intravenously once daily on Days 1-5 of each 28-day cycle; OR Cytarabine 20 mg/m 2 subcutaneously once daily on Days 1-10 of each 28-day cycle. Table 2. Dosing Schedule for 3- or 4-Day Ramp-up Phase in Patients with AML VENCLEXTA Oral Daily Dose Day 1 100 mg Day 2 200 mg Day 3 400 mg Days 4 and beyond 400 mg orally once daily of each 28-day cycle in combination with azacitidine or decitabine 600 mg orally once daily of each 28-day cycle in combination with low-dose cytarabine Continue VENCLEXTA, in combination with azacitidine or decitabine or low-dose cytarabine, until disease progression or unacceptable toxicity. Refer to Clinical Studies and Prescribing Information for azacitidine, decitabine, or cytarabine for additional dosing information

Risk Assessment and Prophylaxis for Tumor Lysis Syndrome Patients treated with VENCLEXTA may develop tumor lysis syndrome (TLS). Refer to the appropriate section below for specific details on management. Assess patient-specific factors for level of risk of 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 5-week 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. TLS can also occur upon resumption of VENCLEXTA following a dosage interruption. See Table 4 , Table 5 , and Table 6 for dose modifications of VENCLEXTA after interruption. The risk of TLS is a continuum based on multiple factors, particularly reduced renal function (creatinine clearance [CLcr] <80 mL/min) and tumor burden; splenomegaly may also increase the risk of TLS. 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. Reassess the risk of TLS when reinitiating VENCLEXTA after a dosage interruption lasting more than 1 week during the ramp-up phase, or more than 2 weeks after completion of ramp-up. Institute prophylaxis and monitoring as needed. Table 3. Recommended TLS Prophylaxis Based on Tumor Burden in Patients with CLL/SLL Tumor Burden Prophylaxis Blood Chemistry Monitoring c,d Hydration a Anti- hyperuricemics b Setting and Frequency of Assessments Low All LN <5 cm AND ALC <25 x10 9 /L Oral (1.5 to 2 L) Allopurinol Outpatient For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours For subsequent ramp-up doses: Pre-dose Medium Any LN 5 to <10 cm OR ALC ≥25 x10 9 /L Oral (1.5 to 2 L) and consider additional intravenous Allopurinol Outpatient For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours For subsequent ramp-up doses: Pre-dose For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CLcr <80ml/min; see below for monitoring in hospital High Any LN ≥10 cm OR ALC ≥25 x10 9 /L AND any LN ≥5 cm Oral (1.5 to 2 L) and intravenous (150 to 200 mL/hr as tolerated) Allopurinol; consider rasburicase if baseline uric acid is elevated In hospital For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12, and 24 hours Outpatient For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours ALC = absolute lymphocyte count; CLcr = creatinine clearance; LN = lymph node. a Administer intravenous hydration for any patient who cannot tolerate oral hydration. b Start allopurinol or xanthine oxidase inhibitor 2 to 3 days prior to initiation of VENCLEXTA. c Evaluate blood chemistries (potassium, uric acid, phosphorus, calcium, and creatinine); review in real time. d For patients at risk of TLS, monitor blood chemistries at 6 to 8 hours and at 24 hours at each subsequent ramp-up dose. Acute Myeloid Leukemia All patients should have white blood cell count less than 25 × 10 9 /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), consider additional measures, including increased laboratory monitoring and reducing VENCLEXTA starting dose

Dosage Modifications for Adverse Reactions Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma The recommended dose reductions for VENCLEXTA for adverse reactions are provided in Table 4 . The recommended dosage modifications for VENCLEXTA for adverse reactions are provided in Table 5 and Table 6 . For patients having a dosage interruption lasting more than 1 week during the ramp-up phase, or more than 2 weeks after completion of ramp-up, 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 Dose Reduction for Adverse Reactions for VENCLEXTA in CLL/SLL Dose at Interruption, mg Restart Dose, mg a,b 400 300 300 200 200 100 100 50 50 20 20 10 a During the ramp-up phase, continue the reduced dose for 1 week before increasing the dose. b If a dosage interruption lasts more than 1 week during the ramp-up phase or more than 2 weeks after completion of ramp-up, reassess the risk of TLS and determine if reinitiation at a reduced dosage is necessary . Table 5. Recommended VENCLEXTA Dosage Modifications for Adverse Reactions a in Patients with CLL/SLL Receiving VENCLEXTA in Combination with Obinutuzumab, with Rituximab or as Monotherapy Adverse Reaction Occurrence Dosage Modification Tumor Lysis Syndrome Blood chemistry changes or symptoms suggestive of TLS Any Withhold the next day’s dose. If resolved within 24 to 48 hours of last dose, resume at same dose. For any blood chemistry changes requiring more than 48 hours to resolve, resume at reduced dose . For any events of clinical TLS, b resume at reduced dose following resolution . Non-Hematologic Adverse Reactions Grade 3 or 4 non-hematologic toxicities 1 st occurrence Interrupt VENCLEXTA. Upon resolution to Grade 1 or baseline level, resume VENCLEXTA at the same dose. 2 nd and subsequent occurrences Interrupt VENCLEXTA. Follow dose reduction guidelines in Table 4 when resuming treatment with VENCLEXTA after resolution. A larger dose reduction may occur at the discretion of the physician. Hematologic Adverse Reactions Grade 3 neutropenia with infection or fever; or Grade 4 hematologic toxicities (except lymphopenia) 1 st occurrence Interrupt VENCLEXTA. Upon resolution to Grade 1 or baseline level, resume VENCLEXTA at the same dose. 2 nd and subsequent occurrences Interrupt VENCLEXTA. Follow dose reduction guidelines in Table 4 when resuming treatment with VENCLEXTA after resolution. A larger dose reduction may occur at the discretion of the physician. Consider discontinuing VENCLEXTA for patients who require dose reductions to less than 100 mg for more than 2 weeks. a Adverse reactions were graded using NCI CTCAE version 4.0. b Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures . Table 6: Recommended Dosage Modifications for Adverse Reactions in Patients with CLL/SLL Receiving VENCLEXTA in Combination with Acalabrutinib Adverse Reaction a Adverse Reaction Occurrence Dose Modification Grade 3 or 4 neutropenia with or without fever and/or infection; Grade 4 neutropenia lasting more than 7 days First occurrence Interrupt VENCLEXTA and/or acalabrutinib. b Once toxicity resolves to Grade ≤ 1 or baseline, restart VENCLEXTA and/or acalabrutinib at same dose. Second occurrence Interrupt VENCLEXTA and/or acalabrutinib. b Once toxicity resolves to Grade ≤ 1 or baseline, restart VENCLEXTA at one lower dose level and restart acalabrutinib at same dose. Subsequent occurrence Withhold VENCLEXTA and/or acalabrutinib until toxicity resolves to Grade ≤ 1 or baseline. b,c Grade 3 or 4 thrombocytopenia and/or bleeding e First occurrence Interrupt VENCLEXTA and/or acalabrutinib. When bleeding resolves and thrombocytopenia is Grade ≤ 1 or baseline without transfusion support for 5 consecutive days, restart VENCLEXTA and/or acalabrutinib at same dose. Second occurrence Interrupt VENCLEXTA and acalabrutinib until resolution of bleeding and thrombocytopenia resolves to Grade ≤ 1 or baseline. Restart VENCLEXTA at one lower dose level and restart acalabrutinib at same dose. d Subsequent occurrences of severe thrombocytopenia Interrupt VENCLEXTA and acalabrutinib until resolution of bleeding and thrombocytopenia resolves to Grade ≤ 1 or baseline. Restart VENCLEXTA at one lower dose level and resume acalabrutinib at a reduced frequency of 100 mg once daily. c,d Grade 3 or 4 tumour lysis syndrome (TLS) First and subsequent episodes If a patient experiences blood chemistry changes suggestive of TLS, the following day’s VENCLEXTA and acalabrutinib dose should be withheld. If resolved within 24–48 hours of last dose, treatment can be resumed at the same dose. For events of clinical TLS or blood chemistry changes requiring more than 48 hours to resolve, resume VENCLEXTA at one lower dose level. When resuming treatment after interruption due to TLS, monitor for TLS and provide prophylaxis. Grade 3 other non-hematologic events f First occurrence Interrupt VENCLEXTA and/or acalabrutinib until toxicity resolves to Grade ≤ 1. Restart VENCLEXTA and/or acalabrutinib at same dose. Second occurrence Interrupt VENCLEXTA and/or acalabrutinib until toxicity resolves to Grade ≤ 1 c . Grade 4 other non-hematologic events f First occurrence Interrupt VENCLEXTA and/or acalabrutinib until toxicity resolves to Grade ≤ 1. Restart VENCLEXTA at one lower dose level and restart acalabrutinib at a reduced frequency of 100 mg once daily. e Second occurrence Interrupt VENCLEXTA and/or acalabrutinib until toxicity resolves to Grade ≤ 1 c . a Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. b Growth factor may be used at physician discretion. c Clinical judgment of the treating physician should guide the management plan of each patient based on the individual benefit/risk assessment for treatment with VENCLEXTA in combination with acalabrutinib. d Acalabrutinib dose may be re-escalated at the discretion of the physician if patient tolerates a reduced dose for ≥4 weeks. e Platelets may be used at physician discretion. f Certain treatment-emergent non-hematologic AEs (e.g., venous thromboembolic events) may be managed and become clinically stable following medical intervention but may not improve to Grade ≤ 1 according to the NCI CTCAE definitions. In such cases, if a subject is clinically stable, resumption of VENCLEXTA may be possible based on clinical judgement of the treating physician. Acute Myeloid Leukemia Monitor blood counts frequently through resolution of cytopenias. Dose modification and interruptions for cytopenias are dependent on remission status. Dose modifications of VENCLEXTA for adverse reactions are provided in Table 7. Table 7. Recommended VENCLEXTA Dosage Modifications for Adverse Reactions in AML Adverse Reaction Occurrence Dosage Modification Hematologic Adverse Reactions Grade 4 neutropenia with or without fever or infection; or Grade 4 thrombocytopenia Occurrence prior to achieving remission a In most instances, do not interrupt VENCLEXTA in combination with azacitidine, decitabine, or low-dose cytarabine due to cytopenias prior to achieving remission. First occurrence after achieving remission and lasting at least 7 days Delay subsequent cycle of VENCLEXTA in combination with azacitidine, decitabine, or low-dose cytarabine and monitor blood counts. Upon resolution to Grade 1 or 2, resume VENCLEXTA at the same dose in combination with azacitidine, decitabine, or low-dose cytarabine. Subsequent occurrences in cycles after achieving remission and lasting 7 days or longer Delay subsequent cycle of VENCLEXTA in combination with azacitidine, or decitabine, or low-dose cytarabine and monitor blood counts. Upon resolution to Grade 1 or 2, resume VENCLEXTA at the same dose in combination with azacitidine, decitabine, or low-dose cytarabine, and reduce VENCLEXTA duration by 7 days during each of the subsequent cycles, such as 21 days instead of 28 days. Non-Hematologic Adverse Reactions Grade 3 or 4 non-hematologic toxicities Any occurrence Interrupt VENCLEXTA if not resolved with supportive care. Upon resolution to Grade 1 or baseline level, resume VENCLEXTA at the same dose. a Recommend bone marrow evaluation

Dosage Modifications for Drug Interactions Strong or Moderate CYP3A Inhibitors or P-gp Inhibitors Table 8 describes VENCLEXTA contraindication or dosage modification based on concomitant use with a strong or moderate CYP3A inhibitor or a 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 a P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor . Table 8. Management of Potential VENCLEXTA Interactions with CYP3A and P-gp Inhibitors Coadministered Drug Initiation and Ramp-Up Phase Steady Daily Dose (After Ramp-Up Phase) a Posaconazole CLL/SLL Contraindicated Reduce VENCLEXTA dose to 70 mg. AML Day 1 – 10 mg Day 2 – 20 mg Day 3 – 50 mg Day 4 – 70 mg Other strong CYP3A inhibitor CLL/SLL Contraindicated Reduce VENCLEXTA dose to 100 mg. AML Day 1 – 10 mg Day 2 – 20 mg Day 3 – 50 mg Day 4 – 100 mg Moderate CYP3A inhibitor Reduce the VENCLEXTA dose by at least 50%. P-gp inhibitor a In patients with CLL/SLL, consider alternative medications or reduce the VENCLEXTA dose as described in Table 8

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 adverse reactions

Administration Instruct patients of the following: Take VENCLEXTA with a meal and water. Take VENCLEXTA at approximately the same time each day. Swallow VENCLEXTA tablets whole. Do not chew, crush, or break tablets prior to swallowing. The recommended dosage of VENCLEXTA may be delivered using any of the approved tablet strengths (e.g., patients can take 2 x 50 mg tablets or 10 x 10 mg tablets instead of 1 x 100 mg tablet as needed). If the patient misses a dose of VENCLEXTA within 8 hours of the time it is usually taken, instruct the patient to 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, instruct the patient not to take the missed dose and resume the usual dosing schedule the next day. If the patient vomits following dosing, instruct the patient to not take an additional dose that day and to take the next prescribed dose at the usual time.

Tumor Lysis Syndrome (TLS): Anticipate TLS; assess risk in all patients. Premedicate with anti-hyperuricemics and ensure adequate hydration. Employ more intensive measures (intravenous hydration, frequent monitoring, hospitalization) as overall risk increases. Neutropenia: Monitor blood counts. Interrupt dosing and resume at same or reduced dose. Consider supportive care measures. Infections: Monitor for signs and symptoms of infection and treat promptly. Withhold for Grade 3 and 4 infection until resolution and resume at same or reduced dose. Immunization: Do not administer live attenuated vaccines prior to, during, or after treatment with VENCLEXTA until B-cell recovery. Embryo-Fetal Toxicity: May cause embryo-fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. Treatment of patients with multiple myeloma with VENCLEXTA in combination with bortezomib plus dexamethasone is not recommended outside of controlled clinical trials. 5.1 Tumor Lysis Syndrome Tumor lysis syndrome (TLS), 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 of VENCLEXTA. 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 . In patients with AML who followed the current 3-day ramp-up dosing schedule and the TLS prophylaxis and monitoring measures, the rate of TLS was 1.1% in patients who received VENCLEXTA in combination with azacitidine (VIALE-A). In patients with AML who followed a 4-day ramp-up dosing schedule and the TLS prophylaxis and monitoring measures, the rate of TLS was 5.6% and included deaths and renal failure in patients who received VENCLEXTA in combination with low-dose cytarabine (VIALE-C) . 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 (intravenous hydration, frequent monitoring, hospitalization) as overall risk increases. Interrupt dosing if needed; when restarting VENCLEXTA, follow dose modification guidance . 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 of VENCLEXTA. For patients with CLL/SLL, coadministration of VENCLEXTA with strong CYP3A inhibitors at initiation and during the 5-week ramp-up phase is contraindicated . For patients with AML, reduce the dose of VENCLEXTA when coadministered with strong CYP3A inhibitors at initiation and during the 3- or 4-day ramp-up phase. For patients with CLL/SLL or AML, reduce the dose of VENCLEXTA when coadministered with moderate CYP3A4 inhibitors or P-gp inhibitors

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 studies and in combination studies with obinutuzumab or rituximab. Febrile neutropenia occurred in 4% to 6% of patients treated with VENCLEXTA in monotherapy studies and in combination studies with obinutuzumab or rituximab . In patients with CLL, 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 treated with VENCLEXTA in combination with acalabrutinib . In patients with AML, baseline neutrophil counts worsened in 95% to 100% of patients treated with VENCLEXTA in combination with azacitidine, decitabine, or low-dose cytarabine. Neutropenia can recur with subsequent cycles. Monitor complete blood counts throughout the treatment period. For interruption and dose resumption of VENCLEXTA for severe neutropenia, see Table 5 and Table 6 for CLL and Table 7 for AML . 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. For dose resumptions, see Table 5 and Table 6 for CLL and Table 7 for AML . 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. 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% receiving AVO compared to 14% in patients receiving VEN+A. Fatal infections occurred in 6% receiving AVO compared to 3.1% of patients receiving VEN+A, most commonly due to COVID-19. The safety and effectiveness of AVO has not been established 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. The safety and efficacy of immunization with live attenuated vaccines during or following VENCLEXTA therapy have not been studied. Advise patients that vaccinations may be less effective

Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, VENCLEXTA may cause embryo-fetal harm when administered to a pregnant woman. In an embryo-fetal study conducted in mice, administration of venetoclax to pregnant animals at exposures equivalent to that observed in patients at a dose of 400 mg daily resulted in post-implantation loss and decreased fetal weight. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with VENCLEXTA 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.

Strong or moderate CYP3A inhibitors or P-gp inhibitors: Adjust dosage of VENCLEXTA. Strong or moderate CYP3A inducers: Avoid co-administration. P-gp substrates: Take at least 6 hours before VENCLEXTA

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 C max and AUC 0-INF , 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 monitor more frequently for adverse reactions . In patients with AML, adjust VENCLEXTA dosage and monitor more frequently for adverse reactions . 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 C max and AUC 0-INF , 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 C max and AUC 0-INF , which may increase the risk of bleeding. Monitor international normalized ratio (INR) more frequently in patients using warfarin concomitantly with VENCLEXTA. P-gp Substrates Concomitant use of VENCLEXTA increases C max and AUC 0-INF 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.