Venclexta (Venetoclax)

VENCLEXTA is a BCL-2 inhibitor indicated:

• For the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). (
  1.1 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).
  )
  
  
• 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. (
  1.2 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.
  )

• See Full Prescribing Information for recommended VENCLEXTA dosages. (
  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 Obinutuzumab

  Start obinutuzumab administration at 100 mg on Cycle 1 Day 1, followed by 900 mg on Cycle 1 Day 2. Administer 1000 mg on Days 8 and 15 of Cycle 1 and on Day 1 of each subsequent 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/m²intravenously for Cycle 1 and 500 mg/m²intravenously 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/m²intravenously or subcutaneously once daily on Days 1-7 of each 28-day cycle; OR
    
    
  • Decitabine 20 mg/m²intravenously once daily on Days 1-5 of each 28-day cycle; OR
    
    
  • Cytarabine 20 mg/m²subcutaneously 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.
  )
  
  
• Take VENCLEXTA tablets orally once daily with a meal and water. Do not chew, crush, or break tablets. (
  2.8 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.
  )
  
  
• Provide prophylaxis for tumor lysis syndrome. (
  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

  )].
  ,
  2.4 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 4and Table 5for 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 x109/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 x109/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 x109/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. aAdminister intravenous hydration for any patient who cannot tolerate oral hydration. bStart allopurinol or xanthine oxidase inhibitor 2 to 3 days prior to initiation of VENCLEXTA. cEvaluate blood chemistries (potassium, uric acid, phosphorus, calcium, and creatinine); review in real time. dFor 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 × 10⁹/L prior to initiation of VENCLEXTA. Cytoreduction prior to treatment may be required.
    
    
  • Prior to first VENCLEXTA dose, provide all patients with prophylactic measures including adequate hydration and anti-hyperuricemic agents and continue during ramp-up phase.
    
    
  • Assess blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) and correct pre-existing abnormalities prior to initiation of treatment with VENCLEXTA.
    
    
  • Monitor blood chemistries for TLS at pre-dose, 6 to 8 hours after each new dose during ramp-up, and 24 hours after reaching final dose.
    
    
  • For patients with risk factors for TLS (e.g., circulating blasts, high burden of leukemia involvement in bone marrow, elevated pretreatment lactate dehydrogenase [LDH] levels, or reduced renal function), consider additional measures, including increased laboratory monitoring and reducing VENCLEXTA starting dose.
  )

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

  )]

  .
  ,
  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

  )]

  .
  )

• 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 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 4and Table 5for 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 x109/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 x109/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 x109/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. aAdminister intravenous hydration for any patient who cannot tolerate oral hydration. bStart allopurinol or xanthine oxidase inhibitor 2 to 3 days prior to initiation of VENCLEXTA. cEvaluate blood chemistries (potassium, uric acid, phosphorus, calcium, and creatinine); review in real time. dFor 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 × 10⁹/L prior to initiation of VENCLEXTA. Cytoreduction prior to treatment may be required.
    
    
  • Prior to first VENCLEXTA dose, provide all patients with prophylactic measures including adequate hydration and anti-hyperuricemic agents and continue during ramp-up phase.
    
    
  • Assess blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) and correct pre-existing abnormalities prior to initiation of treatment with VENCLEXTA.
    
    
  • Monitor blood chemistries for TLS at pre-dose, 6 to 8 hours after each new dose during ramp-up, and 24 hours after reaching final dose.
    
    
  • For patients with risk factors for TLS (e.g., circulating blasts, high burden of leukemia involvement in bone marrow, elevated pretreatment lactate dehydrogenase [LDH] levels, or reduced renal function), consider additional measures, including increased laboratory monitoring and reducing VENCLEXTA starting dose.
  ,
  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

  )].
  )
  
  
• Neutropenia: Monitor blood counts. Interrupt dosing and resume at same or reduced dose. Consider supportive care measures. (
  2.5 Dosage Modifications for Adverse Reactions

  Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

  The recommended dosage modifications for VENCLEXTA for adverse reactions are provided in Table 4 and the recommended dose reductions for VENCLEXTA for adverse reactions are provided in Table 5.

  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 VENCLEXTA Dosage Modifications for Adverse Reactions^ain CLL/SLL

  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 5).
  		For any events of clinical TLS,bresume at reduced dose following resolution (see Table 5).
  Non-Hematologic Adverse Reactions
  Grade 3 or 4 non-hematologic toxicities [see Adverse Reactions ( 6.1 )]	1stoccurrence	Interrupt VENCLEXTA. Upon resolution to Grade 1 or baseline level, resume VENCLEXTA at the same dose.
  	2ndand subsequent occurrences	Interrupt VENCLEXTA. Follow dose reduction guidelines in Table 5when 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 )]	1stoccurrence	Interrupt VENCLEXTA. Upon resolution to Grade 1 or baseline level, resume VENCLEXTA at the same dose.
  	2ndand subsequent occurrences	Interrupt VENCLEXTA. Follow dose reduction guidelines in Table 5when 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. aAdverse reactions were graded using NCI CTCAE version 4.0. bClinical 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 5. 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
  aDuring the ramp-up phase, continue the reduced dose for 1 week before increasing the dose. bIf 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 )] .

  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 6.

  Table 6. 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 remissiona	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.
  aRecommend bone marrow evaluation.
  ,
  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 combination and monotherapy studies. Febrile neutropenia occurred in 4% to 6% of patients

  [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 4for CLL and Table 6 for AML

  [see Dosage and Administration (

  2.5

  )].

  Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF).
  )
  
  
• 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 Dosage Modifications for Adverse Reactions

  Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

  The recommended dosage modifications for VENCLEXTA for adverse reactions are provided in Table 4 and the recommended dose reductions for VENCLEXTA for adverse reactions are provided in Table 5.

  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 VENCLEXTA Dosage Modifications for Adverse Reactions^ain CLL/SLL

  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 5).
  		For any events of clinical TLS,bresume at reduced dose following resolution (see Table 5).
  Non-Hematologic Adverse Reactions
  Grade 3 or 4 non-hematologic toxicities [see Adverse Reactions ( 6.1 )]	1stoccurrence	Interrupt VENCLEXTA. Upon resolution to Grade 1 or baseline level, resume VENCLEXTA at the same dose.
  	2ndand subsequent occurrences	Interrupt VENCLEXTA. Follow dose reduction guidelines in Table 5when 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 )]	1stoccurrence	Interrupt VENCLEXTA. Upon resolution to Grade 1 or baseline level, resume VENCLEXTA at the same dose.
  	2ndand subsequent occurrences	Interrupt VENCLEXTA. Follow dose reduction guidelines in Table 5when 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. aAdverse reactions were graded using NCI CTCAE version 4.0. bClinical 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 5. 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
  aDuring the ramp-up phase, continue the reduced dose for 1 week before increasing the dose. bIf 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 )] .

  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 6.

  Table 6. 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 remissiona	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.
  aRecommend bone marrow evaluation.
  ,
  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 4for CLL and Table 6for AML

  [see Dosage and Administration (

  2.5

  )]

  .
  )
  
  
• Immunization: Do not administer live attenuated vaccines prior to, during, or after treatment with VENCLEXTA until B-cell recovery. (
  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.
  )
  
  
• 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 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

  )]

  .
  )
  
  
• Treatment of patients with multiple myeloma with VENCLEXTA in combination with bortezomib plus dexamethasone is not recommended outside of controlled clinical trials. (
  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.
  )