Venetoclax

See Full Prescribing Information for recommended VENCLEXTA dosages. ( 2.2 , 2.3 ) Take VENCLEXTA tablets orally once daily with a meal and water. ( 2.8 ) Provide prophylaxis for tumor lysis syndrome. ( 2.1 , 2.4 )

2.1 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 [see Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5.1 )].

2.2 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 [see How Supplied/Storage and Handling ( 16 )] . 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 (see Table 1 ). 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 (see Table 1 ). 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 (see Table 1 ) 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 (see Table 1 ). Continue VENCLEXTA until disease progression or unacceptable toxicity.

2.3 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 ( 14.2 ) and Prescribing Information for azacitidine, decitabine, or cytarabine for additional dosing information.

2.4 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 [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.6 )] . 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.

2.5 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) [see Dosage and Administration ( 2.2 , 2.4 )]. 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 [see Dosage and Administration ( 2.2 , 2.4 )] . 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 [see Warnings and Precautions ( 5.1 )] 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 (see Table 4 ). For any events of clinical TLS, b resume at reduced dose following resolution (see Table 4 ). Non-Hematologic Adverse Reactions Grade 3 or 4 non-hematologic toxicities [see Adverse Reactions ( 6.1 )] 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) [see Warnings and Precautions ( 5.2 )] 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 [see Adverse Reactions ( 6.1 )] . 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 [see Warnings and Precautions ( 5.2 )] 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 [see Adverse Reactions ( 6.1 )] 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.

2.6 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 [see Drug Interactions ( 7.1 )] 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 [see Drug Interactions ( 7.1 )] . 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 .

2.7 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 [see Use in Specific Populations ( 8.7 )] .

2.8 Administration Instruct patients of the following: Take VENCLEXTA with a meal and water. Take VENCLEXTA at approximately the same time each day. The recommended dosage of VENCLEXTA may be delivered using any of the approved tablet strengths. For patients who are unable to swallow a VENCLEXTA tablet whole, the tablets can be crushed [see Clinical Pharmacology ( 12.3 )] . Mix the entire dose with 120 mL (4 ounces) of water, apple juice, apple sauce, or yogurt. Take the entire dose immediately with a meal and water. Do not crush more than one dose at a time. 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.

5 WARNINGS AND PRECAUTIONS 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. ( 2.4 , 5.1 ) Neutropenia: Monitor blood counts. Interrupt dosing and resume at same or reduced dose. Consider supportive care measures. ( 2.5 , 5.2 ) 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. ( 2.5 , 5.3 ) Immunization: Do not administer live attenuated vaccines prior to, during, or after treatment with VENCLEXTA until B-cell recovery. ( 5.4 ) 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. ( 5.5 ) Treatment of patients with multiple myeloma with VENCLEXTA in combination with bortezomib plus dexamethasone is not recommended outside of controlled clinical trials. ( 5.6 )

5.1 Tumor Lysis Syndrome Tumor lysis syndrome (TLS), including fatal events and renal failure requiring dialysis, has occurred in patients treated with VENCLEXTA [see Adverse Reactions ( 6.1 )]. 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 [see Adverse Reactions ( 6.1 )] . 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) [see Adverse Reactions ( 6.1 )]. 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 [see Dosage and Administration ( 2.1 , 2.2 , 2.3 , 2.4 ) and Use in Specific Populations ( 8.6 )]. 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 [see Contraindications ( 4 )]. 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 [see Dosage and Administration ( 2.6 ) and Drug Interactions ( 7.1 )].

5.2 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 [see Adverse Reactions ( 6.1 )] . 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 [see Adverse Reactions ( 6.1 )] . 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 [see Dosage and Administration ( 2.5 )]. Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF).

5.3 Infections Fatal and serious infections, such as pneumonia and sepsis, have occurred in patients treated with VENCLEXTA [see Adverse Reactions ( 6.1 )] . 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 [see Dosage and Administration ( 2.5 )] . 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 [see Clinical Studies ( 14.1 )] .

5.4 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.

5.5 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 [see Use in Specific Populations ( 8.1 , 8.3 )] .

5.6 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.

The following clinically significant adverse reactions are described elsewhere in the labeling: Tumor Lysis Syndrome [see Warnings and Precautions ( 5.1 )] Neutropenia [see Warnings and Precautions ( 5.2 )] Infections [see Warnings and Precautions ( 5.3 )] In CLL/SLL, the most common adverse reactions (≥20%) for VENCLEXTA when given in combination with obinutuzumab or rituximab or as monotherapy are neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infection, cough, musculoskeletal pain, fatigue, and edema. ( 6.1 ) In CLL/SLL, the most common adverse reactions (≥20%) for VENCLEXTA when given in combination with acalabrutinib are neutropenia, headache, diarrhea, musculoskeletal pain, and COVID-19. ( 6.1 ) In AML, the most common adverse reactions (≥30%) in combination with azacitidine or decitabine or low-dose cytarabine are nausea, diarrhea, thrombocytopenia, constipation, neutropenia, febrile neutropenia, fatigue, vomiting, edema, pyrexia, pneumonia, dyspnea, hemorrhage, anemia, rash, abdominal pain, sepsis, musculoskeletal pain, dizziness, cough, oropharyngeal pain, and hypotension. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. In CLL/SLL, the safety population reflects exposure to VENCLEXTA as monotherapy in patients in M13-982, M14-032, and M12-175 and in combination with obinutuzumab or rituximab in patients in CLL14 and MURANO. In this CLL/SLL safety population, the most common adverse reactions (≥20%) for VENCLEXTA were neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infection, cough, musculoskeletal pain, fatigue, and edema. In the CLL/SLL safety population that reflects exposure to VENCLEXTA in combination with acalabrutinib, the most common adverse reactions (≥20%) were neutropenia, headache, diarrhea, musculoskeletal pain, and COVID-19. In AML, the safety population reflects exposure to VENCLEXTA in combination with decitabine, azacitidine, or low-dose cytarabine in patients in M14-358, VIALE-A, and VIALE-C. In this safety population, the most common adverse reactions (≥30% in any trial) were nausea, diarrhea, thrombocytopenia, constipation, neutropenia, febrile neutropenia, fatigue, vomiting, edema, pyrexia, pneumonia, dyspnea, hemorrhage, anemia, rash, abdominal pain, sepsis, musculoskeletal pain, dizziness, cough, oropharyngeal pain, and hypotension. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma VENCLEXTA in Combination with Acalabrutinib The safety of VENCLEXTA in combination with acalabrutinib (VEN+A) (N=291) versus fludarabine plus cyclophosphamide plus rituximab or bendamustine plus rituximab (FCR/BR) (N=259) was evaluated in AMPLIFY, a randomized, multicenter, open-label study in patients with previously untreated CLL [ see Clinical S tudies ( 14.1 ) ] . The median duration of exposure to VENCLEXTA was 11.1 months (range: 2 to 14 months) and to acalabrutinib was 12.9 months (range: 1 to 18 months) in the VEN+A arm. Among patients who received VEN+A, 96% were exposed for 6 months or longer and 91% were exposed for greater than one year. Serious adverse reactions were reported in 25% of patients receiving VEN+A. The most common adverse reaction (≥2%) were COVID-19 including COVID-19 pneumonia (9%), second primary malignancies (2.7%), and neutropenia (2.1%). Fatal adverse events occurred in 3.4% of patients. The most common fatal adverse events included COVID-19 and COVID-19 pneumonia. In the VEN+A arm, adverse reactions led to treatment discontinuation in 8% of patients. Neutropenia led to discontinuation of VENCLEXTA in 0.3% of patients, dose reduction in 7%, and dose interruption in 21%. Table 10 presents adverse reactions identified in AMPLIFY. Table 10. Adverse Reactions (≥15% Any Grade) in Patients with Previously Untreated CLL Who Received VEN+A in AMPLIFY Body System Adverse Reactions* VENCLEXTA plus acalabrutinib (N = 291) Investigator’s choice of FCR or BR (N = 259) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Nervous system disorders Headache 35 1.4 8 0.4 Gastrointestinal disorders Diarrhea 33 1.7 11 0.4 Nausea 15 0 36 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain a 25 0.7 14 0.8 Infections COVID-19 21 6 3.9 1.5 General disorders Fatigue b 18 0.3 17 1.5 Skin and subcutaneous tissue disorders Bruising c 17 0 1.5 0 Rash d 16 1 16 1.5 *Excludes laboratory terms. a Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain, non-cardiac chest pain and pain in jaw. b Includes fatigue and asthenia. c Includes increased tendency to bruise, contusion, and ecchymosis. d Includes rash, dermatitis, and other related terms. Other clinically relevant adverse reactions reported in <15% of patients receiving VEN+A included upper respiratory tract infections, lower respiratory tract infection, arthralgia, pneumonia, hemorrhage, dizziness, constipation, vomiting, second primary malignancy and hypertension. Table 11 presents laboratory abnormalities in AMPLIFY. Table 11. New or Worsening Clinically Important Laboratory Abnormalities (≥15% Any Grade) in Patients with Previously Untreated CLL Who Received VEN+A in AMPLIFY Laboratory Abnormality VENCLEXTA plus acalabrutinib a Investigator’s choice of FCR or BR a All grade (%) Grade 3 or 4 (%) All grade (%) Grade 3 or 4 (%) Hematology Neutropenia 78 38 80 53 Lymphopenia 56 12 92 73 Thrombocytopenia 43 5 59 15 Anemia 35 7 56 8 Chemistry Glucose increased 74 0 84 0 Calcium decreased 30 0.7 25 2.3 ALT increased 26 3.1 28 1.6 Urate increased 25 25 23 23 LDH increased 24 0 40 0 Potassium increased 22 2.4 12 3.1 AST increased 22 1.4 28 1.6 ALP increased 20 0 15 0 Glucose decreased 20 0.3 5 0 Creatinine increased 19 0.3 12 0.8 Sodium increased 15 0.3 9 0.4 a The denominator used to calculate the rate varied between 256 and 290 based on the number of patients with a baseline value and at least one post-treatment value. Grade 4 laboratory abnormalities that developed in ≥15% of patients treated with VEN+A include absolute neutrophil count decreased (15%). VENCLEXTA in Combination with Obinutuzumab The safety of VENCLEXTA in combination with obinutuzumab (VEN+G) (N=212) versus obinutuzumab in combination with chlorambucil (GClb) (N=214) was evaluated in CLL14, a randomized, open-label, actively controlled trial in patients with previously untreated CLL [see Clinical Studies ( 14.1 )] . Patients randomized to the VEN+G arm were treated with VENCLEXTA and obinutuzumab in combination for six cycles, then with VENCLEXTA as monotherapy for an additional six cycles. Patients initiated the first dose of the 5-week ramp-up for VENCLEXTA on Day 22 of Cycle 1 and once completed, continued VENCLEXTA 400 mg orally once daily for a total of 12 cycles. The trial required a total Cumulative Illness Rating Scale (CIRS) >6 or CLcr <70 mL/min, hepatic transaminases and total bilirubin ≤2 times upper limit of normal and excluded patients with any individual organ/system impairment score of 4 by CIRS except eye, ear, nose, and throat organ system. The median duration of exposure to VENCLEXTA was 10.5 months (range: 0 to 13.5 months) and the median number of cycles of obinutuzumab was 6 in the VEN+G arm. Serious adverse reactions were reported in 49% of patients in the VEN+G arm, most often due to febrile neutropenia and pneumonia (5% each). 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 the VEN+G arm, adverse reactions led to treatment discontinuation in 16% of patients, dose reduction in 21%, and dose interruption in 74%. Neutropenia led to discontinuation of VENCLEXTA in 2% of patients, dose reduction in 13%, and dose interruption in 41%. Table 12 presents adverse reactions identified in CLL14. Table 12. Adverse Reactions (≥10%) in Patients Treated with VEN+G in CLL14 Adverse Reaction VENCLEXTA + Obinutuzumab (N = 212) Obinutuzumab + Chlorambucil (N = 214) All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%) Blood and lymphatic system disorders Neutropenia a 60 56 62 52 Anemia a 17 8 20 7 Gastrointestinal disorders Diarrhea 28 4 15 1 Nausea 19 0 22 1 Constipation 13 0 9 0 Vomiting 10 1 8 1 General disorders and administration site conditions Fatigue a 21 2 23 1 Infections and infestations Upper respiratory tract infection a 17 1 17 1 a Includes multiple adverse reaction terms. Other clinically important adverse reactions (All Grades) reported in <10% of patients treated with VEN+G are presented below: Blood and lymphatic system disorders: febrile neutropenia (6%) Infection and infestations (all include multiple adverse reaction terms): pneumonia (9%), urinary tract infection (6%), sepsis (4%) Metabolism and nutrition disorder: tumor lysis syndrome (1%) During treatment with VENCLEXTA monotherapy after completion of VEN+G, the adverse reaction that occurred in ≥10% of patients was neutropenia (26%). The grade ≥3 adverse reactions that occurred in ≥2% of patients were neutropenia (23%) and anemia (2%). Table 13 presents laboratory abnormalities CLL14. Table 13. New or Worsening Clinically Important Laboratory Abnormalities (≥10%) in Patients Treated with VEN+G in CLL14 Laboratory Abnormality a VENCLEXTA + Obinutuzumab (N = 212) Obinutuzumab + Chlorambucil (N = 214) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology Leukopenia 90 46 89 41 Lymphopenia 87 57 87 51 Neutropenia 83 63 79 56 Thrombocytopenia 68 28 71 26 Anemia 53 15 46 11 Chemistry Blood creatinine increased 80 6 74 2 Hypocalcemia 67 9 58 4 Hyperkalemia 41 4 35 3 Hyperuricemia 38 38 38 38 a Includes laboratory abnormalities that were new or worsening, or with worsening from baseline unknown. Grade 4 laboratory abnormalities that developed in ≥2% of patients treated with VEN+G included neutropenia (32%), leukopenia and lymphopenia (10%), thrombocytopenia (8%), hypocalcemia (8%), hyperuricemia (7%), blood creatinine increased (3%), hypercalcemia (3%), and hypokalemia (2%). VENCLEXTA in Combination with Rituximab The safety of VENCLEXTA in combination with rituximab (VEN+R) (N=194) versus bendamustine in combination with rituximab (B+R) (N=188) was evaluated in MURANO [see Clinical Studies ( 14.1 )] . Patients randomized to VEN+R completed the scheduled ramp-up (5 weeks) and received VENCLEXTA 400 mg once daily, in combination with rituximab for 6 cycles followed by VENCLEXTA monotherapy, for a total of 24 months after ramp-up. At the time of analysis, the median duration of exposure to VENCLEXTA was 22 months and the median number of cycles of rituximab was 6 in the VEN+R arm. Serious adverse reactions were reported in 46% of patients in the VEN+R arm, with most frequent (≥5%) being pneumonia (9%). 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 last rituximab were reported in 2% (4/194) of patients. In the VEN+R arm, adverse reactions led to treatment discontinuation in 16% of patients, dose reduction in 15%, and dose interruption in 71%. Neutropenia and thrombocytopenia each led to discontinuation of VENCLEXTA in 3% of patients. Neutropenia led to dose interruption of VENCLEXTA in 46% of patients. Table 14 presents adverse reactions identified in MURANO. Table 14. Adverse Reactions (≥10%) in Patients Treated with VEN+R in MURANO Adverse Reaction VENCLEXTA + Rituximab (N = 194) Bendamustine + Rituximab (N = 188) All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%) Blood and lymphatic system disorders Neutropenia a 65 62 50 44 Anemia a 16 11 23 14 Gastrointestinal disorders Diarrhea 40 3 17 1 Nausea 21 1 34 1 Constipation 14 <1 21 0 Infections and infestations Upper respiratory tract infection a 39 2 23 2 Lower respiratory tract infection a 18 2 10 2 Pneumonia a 10 7 14 10 General disorders and administration site conditions Fatigue a 22 2 26 <1 a Includes multiple adverse reaction terms. Other clinically important adverse reactions (All Grades) reported in <10% of patients treated with VEN+R are presented below: Blood and lymphatic system disorders: febrile neutropenia (4%) Gastrointestinal disorders: vomiting (8%) Infections and infestations: sepsis (<1%) Metabolism and nutrition disorders: tumor lysis syndrome (3%) During treatment with VENCLEXTA monotherapy after completion of VEN+R combination treatment, adverse reactions that occurred in ≥10% of patients were upper respiratory tract infection (21%), diarrhea (19%), neutropenia (16%), and lower respiratory tract infections (11%). The Grade 3 or 4 adverse reactions that occurred in ≥2% of patients were neutropenia (12%) and anemia (3%). Table 15 presents laboratory abnormalities identified in MURANO. Table 15. New or Worsening Clinically Important Laboratory Abnormalities (≥10%) in Patients Treated with VEN+R in MURANO Laboratory Abnormality VENCLEXTA + Rituximab (N = 194) Bendamustine + Rituximab (N = 188) All Grades a (%) Grade 3 or 4 (%) All Grades a (%) Grade 3 or 4 (%) Hematology Leukopenia 89 46 81 35 Lymphopenia 87 56 79 55 Neutropenia 86 64 84 59 Anemia 50 12 63 15 Thrombocytopenia 49 15 60 20 Chemistry Blood creatinine increased 77 <1 78 1 Hypocalcemia 62 5 51 2 Hyperuricemia 36 36 33 33 Hyperkalemia 24 3 19 2 a Includes laboratory abnormalities that were new or worsening, or with worsening from baseline unknown. Grade 4 laboratory abnormalities that developed in ≥2% of patients treated with VEN+R included neutropenia (31%), lymphopenia (16%), leukopenia (6%), thrombocytopenia (6%), hyperuricemia (4%), hypocalcemia (2%), hypoglycemia (2%), and hypermagnesemia (2%). VENCLEXTA as Monotherapy The safety of VENCLEXTA was evaluated in pooled data from three single-arm trials (M13-982, M14-032, and M12-175). Patients received VENCLEXTA 400 mg orally once daily after completing the ramp-up phase (N=352). The median duration of treatment with VENCLEXTA at the time of data analysis was 14.5 months (range: 0 to 50 months). Fifty-two percent of patients received VENCLEXTA for more than 60 weeks. In the pooled dataset, the median age was 66 years (range: 28 to 85 years), 93% were White, and 68% were male. The median number of prior therapies was 3 (range: 0 to 15). Serious adverse reactions were reported in 52% of patients, with the most frequent (≥5%) being pneumonia (9%), febrile neutropenia (5%), and sepsis (5%). Fatal adverse reactions that occurred in the absence of disease progression and within 30 days of venetoclax treatment were reported in 2% of patients in the VENCLEXTA monotherapy studies, most often (2 patients) from septic shock. Adverse reactions led to treatment discontinuation in 9% of patients, dose reduction in 13%, and dose interruption in 36%. The most frequent adverse reactions leading to drug discontinuation were thrombocytopenia and autoimmune hemolytic anemia. The most frequent adverse reaction (≥5%) leading to dose reductions or interruptions was neutropenia (8%). Table 16 presents adverse reactions identified in these trials. Table 16. Adverse Reactions Reported in ≥10% (All Grades) or ≥5% (Grade ≥3) of Patients with Previously Treated CLL/SLL Who Received VENCLEXTA Monotherapy Adverse Reaction VENCLEXTA (N = 352) All Grades (%) Grade ≥3 (%) Blood and lymphatic system disorders Neutropenia a 50 45 Anemia a 33 18 Thrombocytopenia a 29 20 Lymphopenia a 11 7 Febrile neutropenia 6 6 Gastrointestinal disorders Diarrhea 43 3 Nausea 42 1 Abdominal pain a 18 3 Vomiting 16 1 Constipation 16 <1 Mucositis a 13 <1 Infections and infestations Upper respiratory tract infection a 36 1 Pneumonia a 14 8 Lower respiratory tract infection a 11 2 General disorders and administration site conditions Fatigue a 32 4 Edema a 22 2 Pyrexia 18 <1 Musculoskeletal and connective tissue disorders Musculoskeletal pain a 29 2 Arthralgia 12 <1 Respiratory, thoracic, and mediastinal disorders Cough a 22 0 Dyspnea a 13 1 Nervous system disorders Headache 18 <1 Dizziness a 14 0 Skin and subcutaneous tissue disorders Rash a 18 <1 Adverse reactions graded using NCI Common Terminology Criteria for Adverse Events version 4.0. a Includes multiple adverse reaction terms. Table 17 presents laboratory abnormalities reported throughout treatment that were new or worsening from baseline. The most common (>5%) Grade 4 laboratory abnormalities observed with VENCLEXTA monotherapy were hematologic laboratory abnormalities, including neutropenia (33%), leukopenia (11%), thrombocytopenia (15%), and lymphopenia (9%). Table 17. New or Worsening Laboratory Abnormalities in ≥40% (All Grades) or ≥10% (Grade 3 or 4) of Patients with Previously Treated CLL/SLL Who Received VENCLEXTA Monotherapy Laboratory Abnormality VENCLEXTA (N = 352) All Grades a (%) Grade 3 or 4 (%) Hematology Leukopenia 89 42 Neutropenia 87 63 Lymphopenia 74 40 Anemia 71 26 Thrombocytopenia 64 31 Chemistry Hypocalcemia 87 12 Hyperglycemia 67 7 Hyperkalemia 59 5 AST increased 53 3 Hypoalbuminemia 49 2 Hypophosphatemia 45 11 Hyponatremia 40 9 a Includes laboratory abnormalities that were new or worsening, or worsening from baseline unknown. Important Adverse Reactions in CLL/SLL Tumor Lysis Syndrome Tumor lysis syndrome is an important identified risk when initiating VENCLEXTA. CLL14 The incidence of TLS was 1% (3/212) in patients treated with VEN+G [see Warnings and Precautions ( 5.1 )] . All three events of TLS resolved and did not lead to withdrawal from the trial. Obinutuzumab administration was delayed in two cases in response to the TLS events. MURANO The incidence of TLS was 3% (6/194) in patients treated with VEN+R. After 77/389 patients were enrolled in the trial, the protocol was amended to incorporate the current TLS prophylaxis and monitoring measures described in sections 2.2 and 2.4 [see Dosage and Administration ( 2.2 , 2.4 )] . All events of TLS occurred during the VENCLEXTA ramp-up period and were resolved within two days. All six patients completed the ramp-up and reached the recommended daily dose of 400 mg of VENCLEXTA. No clinical TLS was observed in patients who followed the current 5-week ramp-up schedule and TLS prophylaxis and monitoring measures [see Dosage and Administration ( 2.2 , 2.4 )] . Rates of laboratory abnormalities relevant to TLS for patients treated with VEN+R are presented in Table 14 . Monotherapy Studies (M13-982 and M14-032) In 168 patients with CLL treated according to recommendations described in sections 2.1 and 2.2, the rate of TLS was 2% [see Dosage and Administration ( 2.2 , 2.4 )] . All events either met laboratory TLS criteria (laboratory abnormalities that met ≥2 of the following within 24 hours of each other: potassium >6 mmol/L, uric acid >476 µmol/L, calcium <1.75 mmol/L, or phosphorus >1.5 mmol/L), or were reported as TLS events. The events occurred in patients who had a lymph node(s) ≥5 cm and/or absolute lymphocyte count (ALC) ≥25 x 10 9 /L. All events resolved within 5 days. No TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures was observed in these patients. All patients had CLcr ≥50 mL/min. Laboratory abnormalities relevant to TLS were hyperkalemia (17% all Grades, 1% Grade ≥3), hyperphosphatemia (14% all Grades, 2% Grade ≥3), hypocalcemia (16% all Grades, 2% Grade ≥3), and hyperuricemia (10% all Grades, <1% Grade ≥3). In the initial Phase 1 dose-finding trials, which had shorter (2-3 week) ramp-up phase and higher starting doses, the incidence of TLS was 13% (10/77; 5 laboratory TLS, 5 clinical TLS), including 2 fatal events and 3 events of acute renal failure, 1 requiring dialysis. After this experience, TLS risk assessment, dosing regimen, TLS prophylaxis and monitoring measures were revised [see Dosage and Administration ( 2.2 , 2.4 )] . Acute Myeloid Leukemia VENCLEXTA in Combination with Azacitidine The safety of VENCLEXTA in combination with azacitidine (VEN+AZA) (N=283) versus placebo in combination with azacitidine (PBO+AZA) (N=144) was evaluated in VIALE-A, a double-blind, randomized trial, in patients with newly diagnosed AML [see Clinical Studies ( 14.2 )] . At baseline, patients were ≥75 years of age or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline ECOG performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, CLcr <45 mL/min, or other comorbidity. Patients were randomized to receive VENCLEXTA 400 mg orally once daily after completion of the ramp-up phase in combination with azacitidine (75 mg/m 2 either intravenously or subcutaneously on Days 1-7 of each 28-day cycle) or placebo in combination with azacitidine. Among patients who received VEN+AZA, the median duration of exposure to VENCLEXTA was 7.6 months (range: <0.1 to 30.7 months). Serious adverse reactions were reported in 83% of patients who received VEN+AZA, with the most frequent (≥5%) being febrile neutropenia (30%), pneumonia (22%), sepsis (excluding fungal; 19%), and hemorrhage (6%). Fatal adverse reactions occurred in 23% of patients who received VEN+AZA, with the most frequent (≥2%) being pneumonia (4%), sepsis (excluding fungal; 3%), and hemorrhage (2%). Adverse reactions led to permanent discontinuation of VENCLEXTA in 24% of patients, dose reductions in 2%, and dose interruptions in 72%. Adverse reactions which led to discontinuation of VENCLEXTA in ≥2% of patients were sepsis (excluding fungal; 3%) and pneumonia (2%). The most frequent adverse reaction leading to dose reduction was pneumonia (0.7%). Adverse reactions which required a dose interruption in ≥5% of patients included febrile neutropenia (20%), neutropenia (20%), pneumonia (14%), sepsis (excluding fungal; 11%), and thrombocytopenia (10%). Among patients who achieved bone marrow clearance of leukemia, 53% underwent dose interruptions for absolute neutrophil count (ANC) <500/microliter. Table 18 presents adverse reactions identified in VIALE-A. Table 18. Adverse Reactions (≥10%) in Patients with AML Who Received VEN+AZA with a Difference Between Arms of ≥5% for All Grades or ≥2% for Grade 3 or 4 Reactions Compared with PBO+AZA in VIALE-A Adverse Reaction VENCLEXTA + Azacitidine (N = 283) Placebo + Azacitidine (N = 144) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Gastrointestinal disorders Nausea 44 2 35 <1 Diarrhea a 43 5 33 3 Vomiting b 30 2 23 <1 Stomatitis c 18 1 13 0 Abdominal pain d 18 <1 13 0 Blood and lymphatic system disorders Febrile neutropenia 42 42 19 19 Musculoskeletal and connective tissue disorders Musculoskeletal pain e 36 2 28 1 General disorders and administration site conditions Fatigue f 31 6 23 2 Edema g 27 <1 19 0 Vascular disorders Hemorrhage h 27 7 24 3 Hypotension i 12 5 8 3 Metabolism and nutrition disorders Decreased appetite j 25 4 17 <1 Skin and subcutaneous tissue disorders Rash k 25 1 15 0 Infections and infestations Sepsis l (excluding fungal) 22 22 16 14 Urinary tract infection m 16 6 9 6 Respiratory, thoracic and mediastinal disorders Dyspnea n 18 4 10 2 Nervous system disorders Dizziness o 17 <1 8 <1 a Includes diarrhea and colitis. b Includes vomiting and hematemesis. c Includes stomatitis, mouth ulceration, mucosal inflammation, cheilitis, aphthous ulcer, glossitis, and tongue ulceration. d Includes abdominal pain, abdominal pain upper, abdominal discomfort, and abdominal pain lower. e Includes arthralgia, back pain, pain in extremity, musculoskeletal pain, bone pain, myalgia, neck pain, non-cardiac chest pain, arthritis, musculoskeletal chest pain, musculoskeletal stiffness, spinal pain, and musculoskeletal discomfort. f Includes fatigue and asthenia. g Includes edema peripheral, edema, generalized edema, eyelid edema, face edema, penile edema, periorbital edema, and swelling. h Includes epistaxis, hematuria, conjunctival hemorrhage, hemoptysis, hemorrhoidal hemorrhage, gingival bleeding, mouth hemorrhage, hemorrhage intracranial, vaginal hemorrhage, cerebral hemorrhage, gastrointestinal hemorrhage, muscle hemorrhage, skin hemorrhage, upper gastrointestinal hemorrhage, anal hemorrhage, eye hemorrhage, gastritis hemorrhagic, hemorrhage, hemorrhage urinary tract, hemorrhagic diathesis, hemorrhagic stroke, hemorrhagic vasculitis, lower gastrointestinal hemorrhage, mucosal hemorrhage, penile hemorrhage, post procedural hemorrhage, rectal hemorrhage, retinal hemorrhage, shock hemorrhagic, soft tissue hemorrhage, subdural hemorrhage, tongue hemorrhage, urethral hemorrhage, vessel puncture site hemorrhage, vitreous hemorrhage, and wound hemorrhage. i Includes hypotension and orthostatic hypotension. j Includes decreased appetite and hypophagia. k Includes rash, rash maculo-papular, rash macular, drug eruption, rash papular, rash pustular, eczema, rash erythematous, rash pruritic, dermatitis acneiform, rash morbilliform, dermatitis, eczema asteatotic, exfoliative rash, and perivascular dermatitis. l Includes sepsis, escherichia bacteremia, escherichia sepsis, septic shock, bacteremia, staphylococcal bacteremia, klebsiella bacteremia, staphylococcal sepsis, streptococcal bacteremia, enterococcal bacteremia, klebsiella sepsis, pseudomonal bacteremia, pseudomonal sepsis, urosepsis, bacterial sepsis, clostridial sepsis, enterococcal sepsis, neutropenic sepsis, and streptococcal sepsis. m Includes urinary tract infection, escherichia urinary tract infection, cystitis, urinary tract infection enterococcal, urinary tract infection bacterial, pyelonephritis acute, and urinary tract infection pseudomonal. n Includes dyspnea, dyspnea exertional, and dyspnea at rest. o Includes dizziness and vertigo. Other clinically important adverse reactions (All Grades) at ≥10% that did not meet criteria for Table 18 or <10% are presented below: Hepatobiliary disorders : cholecystitis/cholelithiasis a (4%) Infections and infestations : pneumonia b (33%) Metabolism and nutrition disorders : tumor lysis syndrome (1%) Nervous system disorders : headache c (11%) Investigations : weight decreased (13%). a Includes cholecystitis acute, cholelithiasis, cholecystitis, and cholecystitis chronic. b Includes pneumonia, lung infection, pneumonia fungal, pneumonia klebsiella, atypical pneumonia, lower respiratory tract infection, pneumonia viral, lower respiratory tract infection fungal, pneumonia hemophilus, pneumonia pneumococcal, and pneumonia respiratory syncytial viral. c Includes headache and tension headache. Table 19 presents laboratory abnormalities identified in VIALE-A. Table 19. New or Worsening Laboratory Abnormalities (≥10%) in Patients with AML Who Received VEN+AZA with a Difference Between Arms of ≥5% for All Grades or ≥2% for Grade 3 or 4 Reactions Compared with PBO+AZA in VIALE-A Laboratory Abnormality VENCLEXTA + Azacitidine Placebo + Azacitidine All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology Neutrophils decreased 98 98 88 81 Platelet decreased 94 88 94 80 Lymphocytes decreased 91 71 72 39 Hemoglobin decreased 61 57 56 52 Chemistry Bilirubin increased 53 7 40 4 Calcium decreased 51 6 39 9 Sodium decreased 46 14 47 8 Alkaline phosphatase increased 42 1 29 <1 Blood bicarbonate decreased 31 <1 25 0 The denominator used to calculate the rate varied from 85 to 144 in the PBO+AZA arm and from 125 to 283 in the VEN+AZA arm based on the number of patients with at least one post-treatment value. VENCLEXTA in Combination with Azacitidine or Decitabine The safety of VENCLEXTA in combination with azacitidine (N=67) or decitabine (N=13) was evaluated in M14-358, a non-randomized trial of patients with newly diagnosed AML. At baseline, patients were ≥75 years of age, or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline ECOG performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, CLcr <45 mL/min, or other comorbidity [see Clinical Studies ( 14.2 )] . Patients received VENCLEXTA 400 mg orally once daily after completion of the ramp-up phase in combination with azacitidine (75 mg/m 2 either intravenously or subcutaneously on Days 1-7 of each 28-day cycle) or decitabine (20 mg/m 2 intravenously on Days 1-5 of each 28-day cycle). Azacitidine The median duration of exposure to VENCLEXTA when administered in combination with azacitidine was 6.5 months (range: 0.1 to 38.1 months). The safety of VENCLEXTA in combination with azacitidine in this trial is consistent with that of VIALE-A. Decitabine The median duration of exposure to VENCLEXTA when administered in combination with decitabine was 8.4 months (range: 0.5 to 39 months). Serious adverse reactions were reported in 85% of patients who received VENCLEXTA with decitabine, the most frequent (≥10%) being sepsis (excluding fungal; 46%), febrile neutropenia (38%), and pneumonia (31%). One (8%) fatal adverse reaction of bacteremia occurred within 30 days of starting treatment. Permanent discontinuation of VENCLEXTA due to adverse reactions occurred in 38% of patients. The most frequent adverse reaction leading to permanent discontinuation (≥5%) was pneumonia (8%). Dosage reductions of VENCLEXTA due to adverse reactions occurred in 15% of patients. The most frequent adverse reaction leading to dose reduction (≥5%) was neutropenia (15%). Dosage interruptions of VENCLEXTA due to adverse reactions occurred in 69% of patients. The most frequent adverse reactions leading to dose interruption …

Lactation: Advise women not to breastfeed. ( 8.2 ) Hepatic Impairment: Reduce the VENCLEXTA dose by 50% in patients with severe hepatic impairment. ( 2.7 , 8.7 )

8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action [see Clinical Pharmacology ( 12.1 )] , VENCLEXTA may cause embryo-fetal harm when administered to a pregnant woman. There are no available data on VENCLEXTA use in pregnant women to inform a drug-associated risk. Administration of venetoclax to pregnant mice during the period of organogenesis was fetotoxic at exposures 1.2 times the human exposure at the recommended dose of 400 mg daily based on AUC. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal data In embryo-fetal development studies, venetoclax was administered to pregnant mice and rabbits during the period of organogenesis. In mice, venetoclax was associated with increased post-implantation loss and decreased fetal body weight at 150 mg/kg/day (maternal exposures approximately 1.2 times the human exposure at the recommended dose of 400 mg once daily). No teratogenicity was observed in either the mouse or the rabbit.

8.2 Lactation Risk Summary There are no data on the presence of VENCLEXTA in human milk or the effects on the breastfed child or milk production. Venetoclax was present in the milk when administered to lactating rats (see Data) . Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with VENCLEXTA and for 1 week after the last dose. Data Animal Data Venetoclax was administered (single dose; 150 mg/kg oral) to lactating rats 8 to 10 days post-parturition. Venetoclax in milk was 1.6 times lower than in plasma. Parent drug (venetoclax) represented the majority of the total drug-related material in milk, with trace levels of three metabolites.

8.3 Females and Males of Reproductive Potential VENCLEXTA may cause fetal harm when administered to pregnant women [see Use in Specific Populations ( 8.1 )] . Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating VENCLEXTA. Contraception Advise females of reproductive potential to use effective contraception during treatment with VENCLEXTA and for 30 days after the last dose. Infertility Based on findings in animals, VENCLEXTA may impair male fertility [see Nonclinical Toxicology ( 13.1 )] .

8.4 Pediatric Use The safety and effectiveness of VENCLEXTA have not been established in pediatric patients. Juvenile Animal Toxicity Data In a juvenile toxicology study, mice were administered venetoclax at 10, 30, or 100 mg/kg/day by oral gavage from 7 to 60 days of age. Clinical signs of toxicity included decreased activity, dehydration, skin pallor, and hunched posture at ≥30 mg/kg/day. In addition, mortality and body weight effects occurred at 100 mg/kg/day. Other venetoclax-related effects were reversible decreases in lymphocytes at ≥10 mg/kg/day; a dose of 10 mg/kg/day is approximately 0.06 times the clinical dose of 400 mg on a mg/m 2 basis for a 20 kg child.

8.5 Geriatric Use Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Of the 352 patients with previously treated CLL/SLL evaluated for safety from 3 open-label trials of VENCLEXTA monotherapy, 57% (201/352) were ≥65 years of age and 18% (62/352) were ≥75 years of age. Of the 406 patients with CLL/SLL evaluated for safety from VENCLEXTA in combination with rituximab or obinutuzumab, 67% (273/406) were ≥65 years of age and 24% (97/406) were ≥75 years of age. No clinically meaningful differences in safety and effectiveness were observed between older and younger patients in these studies. Of patients that received VENCLEXTA in combination with acalabrutinib in AMPLIFY, 33% (97/291) were ≥65 years of age, and 4.5% (13/291) were ≥75 years of age. In patients 65 years of age or older and younger than age 65, the fatal adverse reactions were 5% and 2.6%, respectively. No clinically relevant differences in efficacy were observed between patients ≥65 years of age and younger adults. Acute Myeloid Leukemia Of the 283 patients who received VENCLEXTA with azacitidine in VIALE-A, 96% were ≥65 years of age and 60% were ≥75 years of age. Of the 13 patients who received VENCLEXTA in combination with decitabine in M14-358, 100% were ≥65 years of age and 62% were ≥75 years of age. Of the 142 patients who received VENCLEXTA in combination with low-dose cytarabine in VIALE-C, 92% were ≥65 years of age and 57% were ≥75 years of age. Clinical studies of VENCLEXTA in patients with AML did not include sufficient numbers of younger adults to determine if patients 65 years of age and older respond differently from younger adults.

8.6 Renal Impairment Due to the increased risk of TLS, patients with reduced renal function (CLcr <80 mL/min, calculated by Cockcroft-Gault formula) require more intensive prophylaxis and monitoring to reduce the risk of TLS when initiating treatment with VENCLEXTA [see Dosage and Administration ( 2.1 , 2.2 , 2.3 , 2.4 ) and Warnings and Precautions ( 5.1 )] . No dose adjustment is recommended for patients with mild, moderate or severe renal impairment (CLcr ≥15 mL/min) [see Clinical Pharmacology ( 12.3 )] .

8.7 Hepatic Impairment No dose adjustment is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Reduce the dose of VENCLEXTA for patients with severe hepatic impairment (Child-Pugh C); monitor these patients more frequently for adverse reactions [see Dosage and Administration ( 2.5 , 2.7 ) and Clinical Pharmacology ( 12.3 )] .

12.1 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 has been associated with resistance to chemotherapeutics. Venetoclax helps restore the process of apoptosis by binding directly to the BCL-2 protein, displacing pro-apoptotic proteins like BIM, triggering mitochondrial outer membrane permeabilization and the activation of caspases. In nonclinical studies, venetoclax has demonstrated cytotoxic activity in tumor cells that overexpress BCL-2.

12.2 Pharmacodynamics Based on the exposure response analyses for efficacy, a relationship between drug exposure and a greater likelihood of response was observed in clinical studies in patients with CLL/SLL, and in patients with AML. Based on the exposure response analyses for safety, a relationship between drug exposure and a greater likelihood of some safety events was observed in clinical studies in patients with AML. No exposure-safety relationship was observed in patients with CLL/SLL at doses up to 1200 mg given as monotherapy and up to 600 mg given in combination with rituximab. Cardiac Electrophysiology The effect of multiple doses of VENCLEXTA up to 1200 mg once daily (2 times the maximum approved recommended dosage) on the QTc interval was evaluated in an open-label, single-arm trial in 176 patients with previously treated hematologic malignancies. VENCLEXTA had no large effect on QTc interval (i.e., >20 ms) and there was no relationship between venetoclax exposure and change in QTc interval.

12.3 Pharmacokinetics Venetoclax mean (± standard deviation) steady state C max was 2.1 ± 1.1 mcg/mL and AUC 0-24h was 32.8 ± 16.9 mcg

• h/mL following administration of 400 mg once daily with a low-fat meal. Venetoclax steady state AUC increased proportionally over the dose range of 150 to 800 mg (0.25 to 1.33 times the maximum approved recommended dosage). The pharmacokinetics of venetoclax does not change over time. Administration of crushed VENCLEXTA tablets has no impact on venetoclax AUC. Absorption Maximum plasma concentration of venetoclax was reached 5 to 8 hours following multiple oral administration under fed conditions. Effect of Food Administration with a low-fat meal (approximately 512 kilocalories, 25% fat calories, 60% carbohydrate calories, and 15% protein calories) increased venetoclax exposure by approximately 3.4-fold and administration with a high-fat meal (approximately 753 kilocalories, 55% fat calories, 28% carbohydrate calories, and 17% protein calories) increased venetoclax exposure by 5.1- to 5.3-fold compared with fasting conditions. Distribution Venetoclax is highly bound to human plasma protein with unbound fraction in plasma <0.01 across a concentration range of 1-30 micromolar (0.87-26 mcg/mL). The mean blood-to-plasma ratio was 0.57. The apparent volume of distribution (Vd ss /F) of venetoclax ranged from 256-321 L in patients. Elimination The terminal elimination half-life of venetoclax was approximately 26 hours. Metabolism Venetoclax is predominantly metabolized by CYP3A in vitro. The major metabolite identified in plasma, M27, has an inhibitory activity against BCL-2 that is at least 58-fold lower than venetoclax in vitro and its AUC represented 80% of the parent AUC. Excretion After single oral dose of radiolabeled [ 14 C]-venetoclax 200 mg to healthy subjects, >99.9% of the dose was recovered in feces (21% as unchanged) and <0.1% in urine within 9 days. Specific Populations No clinically significant differences in the pharmacokinetics of venetoclax were observed based on age (19 to 93 years), sex, weight, mild to severe renal impairment (CLcr 15 to 89 mL/min, calculated by Cockcroft-Gault), or mild to moderate hepatic impairment (normal total bilirubin and aspartate transaminase (AST) > upper limit of normal (ULN) or total bilirubin 1 to 3 times ULN). The effect of end-stage renal disease (CLcr <15 mL/min) or dialysis on venetoclax pharmacokinetics is unknown. Racial or Ethnic Groups No clinically significant differences in the pharmacokinetics of venetoclax were observed in White, Black, and Asian patients enrolled in the United States. Of 771 patients with AML, Asian patients from Asian countries [China (5.6%), Japan (5.5%), South Korea (2.1%), and Taiwan (0.9%)] had 63% higher venetoclax exposure than non-Asian populations. Patients with Hepatic Impairment Following a single dose of VENCLEXTA 50 mg, venetoclax systemic exposure (AUC 0-INF ) was 2.7-fold higher in subjects with severe hepatic impairment (Child-Pugh C) compared to subjects with normal hepatic function [see Dosage and Administration ( 2.7 ) and Use in Specific Populations ( 8.7 )] . No clinically relevant differences in venetoclax systemic exposure were observed between subjects with mild or moderate hepatic impairment and subjects with normal hepatic function. Drug Interactions Studies Clinical Studies No clinically significant differences in venetoclax pharmacokinetics were observed when coadministered with azacitidine, azithromycin, cytarabine, decitabine, gastric acid reducing agents, obinutuzumab, or rituximab. Ketoconazole Concomitant use of ketoconazole (a strong CYP3A, P-gp, and BCRP inhibitor) 400 mg once daily for 7 days increased venetoclax C max by 130% and AUC 0-INF by 540% [see Drug Interactions ( 7.1 )] . Ritonavir Concomitant use of ritonavir (a strong CYP3A, P-gp, and OATP1B1/B3 inhibitor) 50 mg once daily for 14 days increased venetoclax C max by 140% and AUC by 690% [see Drug Interactions ( 7.1 )] . Posaconazole Concomitant use of posaconazole (a strong CYP3A and P-gp inhibitor) 300 mg with VENCLEXTA 50 mg and 100 mg for 7 days resulted in 61% and 86% higher venetoclax C max , respectively, compared with VENCLEXTA 400 mg administered alone. The venetoclax AUC 0-24h was 90% and 144% higher, respectively [see Drug Interactions ( 7.1 )] . Rifampin Concomitant use of a single dose of rifampin (an OATP1B1/1B3 and P-gp inhibitor) 600 mg increased venetoclax C max by 106% and AUC 0-INF by 78%. Concomitant use of multiple doses of rifampin (as a strong CYP3A inducer) 600 mg once daily for 13 days decreased venetoclax C max by 42% and AUC 0-INF by 71% [see Drug Interactions ( 7.1 )] . Warfarin Concomitant use of a single 400 mg dose of VENCLEXTA with 5 mg of warfarin resulted in 18% to 28% increase in C max and AUC 0-INF of R-warfarin and S-warfarin [see Drug Interactions ( 7.2 )] . Digoxin Concomitant use of a single dose of VENCLEXTA 100 mg with digoxin (a P-gp substrate) 0.5 mg increased digoxin C max by 35% and AUC 0-INF by 9% [see Drug Interactions ( 7.2 )] . In Vitro Studies Venetoclax is not an inhibitor or inducer of CYP1A2, CYP2B6, CYP2C19, CYP2D6, or CYP3A4. Venetoclax is a weak inhibitor of CYP2C8, CYP2C9, and UGT1A1. Venetoclax is not an inhibitor of UGT1A4, UGT1A6, UGT1A9, or UGT2B7. Venetoclax is an inhibitor and substrate of P-gp and BCRP and weak inhibitor of OATP1B1. Venetoclax is not an inhibitor of OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, or MATE2K.

Venetoclax mean (± standard deviation) steady state C max was 2.1 ± 1.1 mcg/mL and AUC 0-24h was 32.8 ± 16.9 mcg

• h/mL following administration of 400 mg once daily with a low-fat meal. Venetoclax steady state AUC increased proportionally over the dose range of 150 to 800 mg (0.25 to 1.33 times the maximum approved recommended dosage). The pharmacokinetics of venetoclax does not change over time. Administration of crushed VENCLEXTA tablets has no impact on venetoclax AUC. Absorption Maximum plasma concentration of venetoclax was reached 5 to 8 hours following multiple oral administration under fed conditions. Effect of Food Administration with a low-fat meal (approximately 512 kilocalories, 25% fat calories, 60% carbohydrate calories, and 15% protein calories) increased venetoclax exposure by approximately 3.4-fold and administration with a high-fat meal (approximately 753 kilocalories, 55% fat calories, 28% carbohydrate calories, and 17% protein calories) increased venetoclax exposure by 5.1- to 5.3-fold compared with fasting conditions. Distribution Venetoclax is highly bound to human plasma protein with unbound fraction in plasma <0.01 across a concentration range of 1-30 micromolar (0.87-26 mcg/mL). The mean blood-to-plasma ratio was 0.57. The apparent volume of distribution (Vd ss /F) of venetoclax ranged from 256-321 L in patients. Elimination The terminal elimination half-life of venetoclax was approximately 26 hours. Metabolism Venetoclax is predominantly metabolized by CYP3A in vitro. The major metabolite identified in plasma, M27, has an inhibitory activity against BCL-2 that is at least 58-fold lower than venetoclax in vitro and its AUC represented 80% of the parent AUC. Excretion After single oral dose of radiolabeled [ 14 C]-venetoclax 200 mg to healthy subjects, >99.9% of the dose was recovered in feces (21% as unchanged) and <0.1% in urine within 9 days. Specific Populations No clinically significant differences in the pharmacokinetics of venetoclax were observed based on age (19 to 93 years), sex, weight, mild to severe renal impairment (CLcr 15 to 89 mL/min, calculated by Cockcroft-Gault), or mild to moderate hepatic impairment (normal total bilirubin and aspartate transaminase (AST) > upper limit of normal (ULN) or total bilirubin 1 to 3 times ULN). The effect of end-stage renal disease (CLcr <15 mL/min) or dialysis on venetoclax pharmacokinetics is unknown. Racial or Ethnic Groups No clinically significant differences in the pharmacokinetics of venetoclax were observed in White, Black, and Asian patients enrolled in the United States. Of 771 patients with AML, Asian patients from Asian countries [China (5.6%), Japan (5.5%), South Korea (2.1%), and Taiwan (0.9%)] had 63% higher venetoclax exposure than non-Asian populations. Patients with Hepatic Impairment Following a single dose of VENCLEXTA 50 mg, venetoclax systemic exposure (AUC 0-INF ) was 2.7-fold higher in subjects with severe hepatic impairment (Child-Pugh C) compared to subjects with normal hepatic function [see Dosage and Administration ( 2.7 ) and Use in Specific Populations ( 8.7 )] . No clinically relevant differences in venetoclax systemic exposure were observed between subjects with mild or moderate hepatic impairment and subjects with normal hepatic function. Drug Interactions Studies Clinical Studies No clinically significant differences in venetoclax pharmacokinetics were observed when coadministered with azacitidine, azithromycin, cytarabine, decitabine, gastric acid reducing agents, obinutuzumab, or rituximab. Ketoconazole Concomitant use of ketoconazole (a strong CYP3A, P-gp, and BCRP inhibitor) 400 mg once daily for 7 days increased venetoclax C max by 130% and AUC 0-INF by 540% [see Drug Interactions ( 7.1 )] . Ritonavir Concomitant use of ritonavir (a strong CYP3A, P-gp, and OATP1B1/B3 inhibitor) 50 mg once daily for 14 days increased venetoclax C max by 140% and AUC by 690% [see Drug Interactions ( 7.1 )] . Posaconazole Concomitant use of posaconazole (a strong CYP3A and P-gp inhibitor) 300 mg with VENCLEXTA 50 mg and 100 mg for 7 days resulted in 61% and 86% higher venetoclax C max , respectively, compared with VENCLEXTA 400 mg administered alone. The venetoclax AUC 0-24h was 90% and 144% higher, respectively [see Drug Interactions ( 7.1 )] . Rifampin Concomitant use of a single dose of rifampin (an OATP1B1/1B3 and P-gp inhibitor) 600 mg increased venetoclax C max by 106% and AUC 0-INF by 78%. Concomitant use of multiple doses of rifampin (as a strong CYP3A inducer) 600 mg once daily for 13 days decreased venetoclax C max by 42% and AUC 0-INF by 71% [see Drug Interactions ( 7.1 )] . Warfarin Concomitant use of a single 400 mg dose of VENCLEXTA with 5 mg of warfarin resulted in 18% to 28% increase in C max and AUC 0-INF of R-warfarin and S-warfarin [see Drug Interactions ( 7.2 )] . Digoxin Concomitant use of a single dose of VENCLEXTA 100 mg with digoxin (a P-gp substrate) 0.5 mg increased digoxin C max by 35% and AUC 0-INF by 9% [see Drug Interactions ( 7.2 )] . In Vitro Studies Venetoclax is not an inhibitor or inducer of CYP1A2, CYP2B6, CYP2C19, CYP2D6, or CYP3A4. Venetoclax is a weak inhibitor of CYP2C8, CYP2C9, and UGT1A1. Venetoclax is not an inhibitor of UGT1A4, UGT1A6, UGT1A9, or UGT2B7. Venetoclax is an inhibitor and substrate of P-gp and BCRP and weak inhibitor of OATP1B1. Venetoclax is not an inhibitor of OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, or MATE2K.