Venclexta (Venetoclax) kit
AbbVie Inc.

AbbVie Inc.
AbbVie Inc.
Venclexta
Venetoclax
Venclexta
Venetoclax
Venetoclax
Venetoclax
COPOVIDONE K25-31
SILICON DIOXIDE
POLYSORBATE 80
SODIUM STEARYL FUMARATE
ANHYDROUS DIBASIC CALCIUM PHOSPHATE
FERRIC OXIDE YELLOW
Talc
TITANIUM DIOXIDE
POLYVINYL ALCOHOL, UNSPECIFIED
POLYETHYLENE GLYCOL, UNSPECIFIED
pale yellow
V;10
round, biconvex
Venclexta
Venetoclax
Venetoclax
Venetoclax
COPOVIDONE K25-31
SILICON DIOXIDE
POLYSORBATE 80
SODIUM STEARYL FUMARATE
ANHYDROUS DIBASIC CALCIUM PHOSPHATE
FERRIC OXIDE YELLOW
Talc
TITANIUM DIOXIDE
FERRIC OXIDE RED
FERROSOFERRIC OXIDE
POLYVINYL ALCOHOL, UNSPECIFIED
POLYETHYLENE GLYCOL, UNSPECIFIED
beige
V;50
oblong, biconvex
Venclexta
Venetoclax
Venetoclax
Venetoclax
COPOVIDONE K25-31
SILICON DIOXIDE
POLYSORBATE 80
SODIUM STEARYL FUMARATE
ANHYDROUS DIBASIC CALCIUM PHOSPHATE
FERRIC OXIDE YELLOW
Talc
TITANIUM DIOXIDE
POLYVINYL ALCOHOL, UNSPECIFIED
POLYETHYLENE GLYCOL, UNSPECIFIED
pale yellow
V;100
oblong, biconvex
Venclexta
Venetoclax
Venetoclax
Venetoclax
COPOVIDONE K25-31
SILICON DIOXIDE
POLYSORBATE 80
SODIUM STEARYL FUMARATE
ANHYDROUS DIBASIC CALCIUM PHOSPHATE
FERRIC OXIDE YELLOW
Talc
TITANIUM DIOXIDE
POLYVINYL ALCOHOL, UNSPECIFIED
POLYETHYLENE GLYCOL, UNSPECIFIED
pale yellow
V;100
oblong, biconvex
Venclexta
Venetoclax
Venetoclax
Venetoclax
COPOVIDONE K25-31
SILICON DIOXIDE
POLYSORBATE 80
SODIUM STEARYL FUMARATE
ANHYDROUS DIBASIC CALCIUM PHOSPHATE
FERRIC OXIDE YELLOW
Talc
TITANIUM DIOXIDE
POLYVINYL ALCOHOL, UNSPECIFIED
POLYETHYLENE GLYCOL, UNSPECIFIED
pale yellow
V;100
oblong, biconvex
Venclexta
Venetoclax
Venetoclax
Venetoclax
COPOVIDONE K25-31
SILICON DIOXIDE
POLYSORBATE 80
SODIUM STEARYL FUMARATE
ANHYDROUS DIBASIC CALCIUM PHOSPHATE
FERRIC OXIDE YELLOW
Talc
TITANIUM DIOXIDE
POLYETHYLENE GLYCOL, UNSPECIFIED
POLYVINYL ALCOHOL, UNSPECIFIED
pale yellow
V;10
round, biconvex
Venclexta
Venetoclax
Venetoclax
Venetoclax
COPOVIDONE K25-31
SILICON DIOXIDE
POLYSORBATE 80
SODIUM STEARYL FUMARATE
ANHYDROUS DIBASIC CALCIUM PHOSPHATE
FERRIC OXIDE RED
FERROSOFERRIC OXIDE
FERRIC OXIDE YELLOW
Talc
TITANIUM DIOXIDE
POLYETHYLENE GLYCOL, UNSPECIFIED
POLYVINYL ALCOHOL, UNSPECIFIED
beige
V;50
oblong, biconvex

Dosage and Administration (2.2, 2.8)                         6/2022

1 INDICATIONS AND USAGE

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)
  • 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)

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).

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.

2 DOSAGE AND ADMINISTRATION

  • See Full Prescribing Information for recommended VENCLEXTA dosages. (2.2, 2.3)
  • Take VENCLEXTA tablets orally once daily with a meal and water. Do not chew, crush, or break tablets. (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 )].

2.4 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 and Table 5 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 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.

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 Reactionsa in 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,b resume at reduced dose following resolution (see Table 5).
Non-Hematologic Adverse Reactions
Grade 3 or 4 non-hematologic toxicities [see Adverse Reactions ( 6.1 )] 1st occurrence Interrupt VENCLEXTA.
Upon resolution to Grade 1 or baseline level, resume VENCLEXTA at the same dose.
  2nd and subsequent occurrences Interrupt VENCLEXTA.
Follow dose reduction guidelines in Table 5 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 )] 1st occurrence Interrupt VENCLEXTA.
Upon resolution to Grade 1 or baseline level, resume VENCLEXTA at the same dose.
2nd and subsequent occurrences Interrupt VENCLEXTA.
Follow dose reduction guidelines in Table 5 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.
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.

2.6 Dosage Modifications for Drug Interactions

Strong or Moderate CYP3A Inhibitors or P-gp Inhibitors

Table 7 describes VENCLEXTA contraindication or dosage modification based on concomitant use with a strong or moderate CYP3A inhibitor or 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 7. 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
aIn patients with CLL/SLL, consider alternative medications or reduce the VENCLEXTA dose as described in Table 7.

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.
  • 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.

3 DOSAGE FORMS AND STRENGTHS

Table 8. VENCLEXTA Tablet Strength and Description
Tablet Strength Description of Tablet
10 mg Round, biconvex shaped, pale yellow film-coated tablet debossed with “V” on one side and “10” on the other side
50 mg Oblong, biconvex shaped, beige film-coated tablet debossed with “V” on one side and “50” on the other side
100 mg Oblong, biconvex shaped, pale yellow film-coated tablet debossed with “V” on one side and “100” on the other side

Tablets: 10 mg, 50 mg, 100 mg (3)

4 CONTRAINDICATIONS

Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation and during the ramp-up phase is contraindicated in patients with CLL/SLL due to the potential for increased risk of tumor lysis syndrome [see Dosage and Administration ( 2.6 ) and Drug Interactions ( 7.1 )].

Concomitant use with strong CYP3A inhibitors at initiation and during ramp-up phase in patients with CLL/SLL is contraindicated. (2.6, 4, 7.1)

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 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 4 for CLL and Table 6 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 4 for CLL and Table 6 for AML [see Dosage and Administration ( 2.5 )].

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.

6 ADVERSE REACTIONS

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 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 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 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 9 presents adverse reactions identified in CLL14.

Table 9. 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
   Neutropeniaa 60 56 62 52
   Anemiaa 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
   Fatiguea 21 2 23 1
Infections and infestations
   Upper respiratory
   tract infectiona
17 1 17 1
aIncludes 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 10 presents laboratory abnormalities CLL14.

Table 10. 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
aIncludes 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 11 presents adverse reactions identified in MURANO.

Table 11. 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
  Neutropeniaa 65 62 50 44
  Anemiaa 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 infectiona
39 2 23 2
  Lower respiratory
  tract infectiona
18 2 10 2
  Pneumoniaa 10 7 14 10
General disorders and administration site conditions
  Fatiguea 22 2 26 <1
aIncludes 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 12 presents laboratory abnormalities identified in MURANO.

Table 12. 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
aIncludes 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 13 presents adverse reactions identified in these trials.

Table 13. 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
Neutropeniaa 50 45
Anemiaa 33 18
Thrombocytopeniaa 29 20
Lymphopeniaa 11 7
Febrile neutropenia 6 6
Gastrointestinal disorders
Diarrhea 43 3
Nausea 42 1
Abdominal paina 18 3
Vomiting 16 1
Constipation 16 <1
Mucositisa 13 <1
Infections and infestations
Upper respiratory tract infectiona 36 1
Pneumoniaa 14 8
Lower respiratory tract infectiona 11 2
General disorders and administration site conditions
Fatiguea 32 4
Edemaa 22 2
Pyrexia 18 <1
Musculoskeletal and connective tissue disorders
Musculoskeletal paina 29 2
Arthralgia 12 <1
Respiratory, thoracic, and mediastinal disorders
Cougha 22 0
Dyspneaa 13 1
Nervous system disorders
Headache 18 <1
Dizzinessa 14 0
Skin and subcutaneous tissue disorders
Rasha 18 <1
Adverse reactions graded using NCI Common Terminology Criteria for Adverse Events version 4.0.
aIncludes multiple adverse reaction terms.

Table 14  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 14. 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
aIncludes 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 12.

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 109/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/m2 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 15 presents adverse reactions identified in VIALE-A.

Table 15. 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
   Diarrheaa 43 5 33 3
   Vomitingb 30 2 23 <1
   Stomatitisc 18 1 13 0
   Abdominal paind 18 <1 13 0
Blood and lymphatic system disorders
   Febrile neutropenia 42 42 19 19
Musculoskeletal and connective tissue disorders
   Musculoskeletal paine 36 2 28 1
General disorders and administration site conditions
   Fatiguef 31 6 23 2
   Edemag 27 <1 19 0
Vascular disorders
   Hemorrhageh 27 7 24 3
   Hypotensioni 12 5 8 3
Metabolism and nutrition disorders
   Decreased appetitej 25 4 17 <1
Skin and subcutaneous tissue disorders
   Rashk 25 1 15 0
Infections and infestations
   Sepsisl (excluding fungal) 22 22 16 14
   Urinary tract infectionm 16 6 9 6
Respiratory, thoracic and mediastinal disorders
   Dyspnean 18 4 10 2
Nervous system disorders
   Dizzinesso 17 <1 8 <1
aIncludes diarrhea and colitis.
bIncludes vomiting and hematemesis.
cIncludes stomatitis, mouth ulceration, mucosal inflammation, cheilitis, aphthous ulcer, glossitis, and tongue ulceration.
dIncludes abdominal pain, abdominal pain upper, abdominal discomfort, and abdominal pain lower.
eIncludes 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.
fIncludes fatigue and asthenia.
gIncludes edema peripheral, edema, generalized edema, eyelid edema, face edema, penile edema, periorbital edema, and swelling.
hIncludes 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.
iIncludes hypotension and orthostatic hypotension.
jIncludes decreased appetite and hypophagia.
kIncludes 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.
lIncludes 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.
mIncludes urinary tract infection, escherichia urinary tract infection, cystitis, urinary tract infection enterococcal, urinary tract infection bacterial, pyelonephritis acute, and urinary tract infection pseudomonal.
nIncludes dyspnea, dyspnea exertional, and dyspnea at rest.
oIncludes dizziness and vertigo.

Other clinically important adverse reactions (All Grades) at ≥10% that did not meet criteria for Table 15 or <10% are presented below:

Hepatobiliary disorders: cholecystitis/cholelithiasisa (4%)

Infections and infestations: pneumoniab (33%)

Metabolism and nutrition disorders: tumor lysis syndrome (1%)

Nervous system disorders: headachec (11%)

Investigations: weight decreased (13%).

aIncludes cholecystitis acute, cholelithiasis, cholecystitis, and cholecystitis chronic.
bIncludes 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.
cIncludes headache and tension headache.

Table 16 presents laboratory abnormalities identified in VIALE-A.

Table 16. 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/m2 either intravenously or subcutaneously on Days 1-7 of each 28-day cycle) or decitabine (20 mg/m2 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 (≥10%) were neutropenia (38%), febrile neutropenia (23%), leukopenia (15%), and pneumonia (15%).

The most common adverse reactions (≥30%) were febrile neutropenia (69%), fatigue (62%), constipation (62%), musculoskeletal pain (54%), dizziness (54%), nausea (54%), abdominal pain (46%), diarrhea (46%), pneumonia (46%), sepsis (excluding fungal; 46%), cough (38%), pyrexia (31%), hypotension (31%), oropharyngeal pain (31%), edema (31%), and vomiting (31%). The most common laboratory abnormalities (≥30%) were neutrophils decreased (100%), lymphocytes decreased (100%), white blood cells decreased (100%), platelets decreased (92%), calcium decreased (85%), hemoglobin decreased (69%), glucose increased (69%), magnesium decreased (54%), potassium decreased (46%), bilirubin increased (46%), albumin decreased (38%), alkaline phosphatase increased (38%), sodium decreased (38%), ALT increased (31%), creatinine increased (31%), and potassium increased (31%).

VENCLEXTA in Combination with Low-Dose Cytarabine

VIALE-C

The safety of VENCLEXTA in combination with low-dose cytarabine (VEN+LDAC) (N=142) versus placebo with low-dose cytarabine (PBO+LDAC) (N=68) was evaluated in VIALE-C, a double-blind randomized trial in 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 were randomized to receive VENCLEXTA 600 mg orally once daily after completion of a 4-day ramp-up phase in combination with low-dose cytarabine (20 mg/m2 subcutaneously once daily on Days 1-10 of each 28-day cycle) or placebo in combination with low-dose cytarabine. Among patients who received VEN+LDAC, the median duration of exposure to VENCLEXTA was 3.9 months (range: <0.1 to 17.1 months).

Serious adverse reactions were reported in 65% of patients who received VEN+LDAC, with the most frequent (≥10%) being pneumonia (17%), febrile neutropenia (16%), and sepsis (excluding fungal; 12%). Fatal adverse reactions occurred in 23% of patients who received VEN+LDAC, with the most frequent (≥5%) being pneumonia (6%) and sepsis (excluding fungal; 7%).

Adverse reactions led to permanent discontinuation of VENCLEXTA in 25% of patients, dose reductions in 9%, and dose interruptions in 63%. The most frequent adverse reaction (>2%) which resulted in permanent discontinuation of VENCLEXTA was pneumonia (6%). Adverse reactions which required a dose reduction in ≥1% of patients were pneumonia (1%) and thrombocytopenia (1%), and the adverse reactions which required a dose interruption in ≥5% of patients included neutropenia (20%), thrombocytopenia (15%), pneumonia (8%), febrile neutropenia (6%), and sepsis (excluding fungal; 6%). Among patients who achieved bone marrow clearance of leukemia, 32% underwent dose interruptions for ANC <500/microliter.

Table 17 presents adverse reactions identified in VIALE-C.

Table 17. Adverse Reactions (≥10%) in Patients with AML Who Received VEN+LDAC with a Difference Between Arms of ≥5% for All Grades or ≥2% for Grade 3 or 4 Compared with PBO+LDAC in VIALE-C
Adverse Reaction VENCLEXTA + Low-Dose
Cytarabine

(N = 142)
Placebo + Low-Dose
Cytarabine

(N = 68)
All Grades
(%)
Grade 3 or 4
(%)
All Grades
(%)
Grade 3 or 4
(%)
Gastrointestinal disorders
   Nausea 42 1 31 0
   Diarrhea 28 3 16 0
   Vomiting 25 <1 13 0
   Abdominal paina 15 <1 9 3
   Stomatitisb 15 1 6 0
Blood and lymphatic system disorders
   Febrile neutropenia 32 32 29 29
Infections and infestations
   Pneumoniac 29 19 21 21
Vascular Disorders
   Hemorrhaged 27 8 16 1
Hypotensione 11 5 4 1
Musculoskeletal and connective tissue disorders
   Musculoskeletal painf 23 3 18 0
General Disorders and Administration Site Conditions
   Fatigueg 22 2 21 0
Nervous System Disorders
   Headache 11 0 6 0
aIncludes abdominal pain, abdominal pain upper, abdominal discomfort, and abdominal pain lower.
bIncludes stomatitis, mouth ulceration, aphthous ulcer, glossitis, mucosal inflammation, and tongue ulceration.
cIncludes pneumonia, lung infection, lower respiratory tract infection, pneumonia fungal, lower respiratory tract infection fungal, pneumocystis jirovecii pneumonia, pneumonia aspiration, pneumonia cytomegaloviral, and pneumonia pseudomonal.
dIncludes epistaxis, conjunctival hemorrhage, hemoptysis, gastrointestinal hemorrhage, gingival bleeding, mouth hemorrhage, upper gastrointestinal hemorrhage, hematuria, retinal hemorrhage, catheter site hemorrhage, cerebral hemorrhage, gastric hemorrhage, gastritis hemorrhagic, hemorrhage intracranial, hemorrhage subcutaneous, lip hemorrhage, mucosal hemorrhage, pharyngeal hemorrhage, post procedural hemorrhage, pulmonary alveolar hemorrhage, pulmonary hemorrhage, tooth pulp hemorrhage, uterine hemorrhage, and vascular access site hemorrhage.
eIncludes hypotension and orthostatic hypotension.
fIncludes back pain, arthralgia, pain in extremity, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, arthritis, bone pain, musculoskeletal chest pain, and spinal pain.
gIncludes fatigue and asthenia.

Other clinically important adverse reactions (All Grades) at ≥10% that did not meet criteria for Table 17 or <10% are presented below:

Hepatobiliary disorders: cholecystitis/cholelithiasisa (1%)

Infections and infestations: sepsisb (excluding fungal; 15%), urinary tract infectionc (8%)

Metabolism and nutrition disorders: decreased appetite (19%), tumor lysis syndrome (6%)

Nervous system disorders: dizzinessd (9%)

Respiratory, thoracic, and mediastinal disorders: dyspneae (10%)

Investigations: weight decreased (9%).

aIncludes cholecystitis and cholecystitis acute.
bIncludes sepsis, bacteremia, septic shock, neutropenic sepsis, staphylococcal bacteremia, streptococcal bacteremia, bacterial sepsis, Escherichia bacteremia, pseudomonal bacteremia, and staphylococcal sepsis.
cIncludes urinary tract infection and escherichia urinary tract infection.
dIncludes dizziness and vertigo.
eIncludes dyspnea and dyspnea exertional.

Table 18 describes laboratory abnormalities identified in VIALE-C.

Table 18. New or Worsening Laboratory Abnormalities (≥10%) in Patients with AML Who Received VEN+LDAC with Difference Between Arms of ≥5% for All Grades or ≥2% for Grade 3 or 4 Reactions Compared with PBO+LDAC in VIALE-C
Laboratory Abnormality VENCLEXTA + Low-Dose
Cytarabine
Placebo + Low-Dose
Cytarabine
All Grades
(%)
Grade 3 or 4
(%)
All Grades
(%)
Grade 3 or 4
(%)
Hematology
   Platelets decreased 97 95 92 90
   Neutrophils decreased 95 92 82 71
   Lymphocytes decreased 92 69 65 24
   Hemoglobin decreased 63 57 57 54
Chemistry
   Bilirubin increased 61 7 38 7
   Albumin decreased 61 6 43 4
   Potassium decreased 56 16 42 14
   Calcium decreased 53 8 45 13
   Glucose increased 52 13 59 9
   AST increased 36 6 37 1
   Alkaline phosphatase increased 34 1 26 1
   ALT increased 30 4 26 1
   Sodium increased 11 3 6 1
The denominator used to calculate the rate varied from 38 to 68 in the PBO+LDAC arm and from 65 to 142 in the VEN+LDAC arm based on the number of patients with at least one post-treatment value.

M14-387

The safety of VENCLEXTA in combination with low-dose cytarabine (N=61) was evaluated in M14-387, a non-randomized, open- label trial of 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 received VENCLEXTA 600 mg orally once daily after completion of the ramp-up phase in combination with low-dose cytarabine (20mg/m2 subcutaneously on Days 1-10 of each 28-day cycle). The safety of VENCLEXTA in combination with low-dose cytarabine is consistent with that of VIALE-C.

7 DRUG INTERACTIONS

  • Strong or moderate CYP3A inhibitors or P-gp inhibitors: Adjust dosage of VENCLEXTA. (2.6, 7.1)
  • Strong or moderate CYP3A inducers: Avoid co-administration. (7.1)
  • P-gp substrates: Take at least 6 hours before VENCLEXTA. (7.2)

7.1 Effects of Other Drugs on VENCLEXTA

Strong or Moderate CYP3A Inhibitors or P-gp Inhibitors

Concomitant use with a strong or moderate CYP3A inhibitor or a P-gp inhibitor increases venetoclax Cmax and AUC0-INF [see Clinical Pharmacology ( 12.3 )], which may increase VENCLEXTA toxicities, including the risk of TLS [see Warnings and Precautions ( 5.1 )].

Concomitant use with a strong CYP3A inhibitor at initiation and during the ramp-up phase in patients with CLL/SLL is contraindicated [see Contraindications ( 4 )].

In patients with CLL/SLL taking a steady daily dosage (after ramp-up phase), consider alternative medications or adjust VENCLEXTA dosage and monitor more frequently for adverse reactions [see Dosage and Administration ( 2.5 , 2.6 )].

In patients with AML, adjust VENCLEXTA dosage and monitor more frequently for adverse reactions [see Dosage and Administration ( 2.5 , 2.6 )].

Resume the VENCLEXTA dosage that was used prior to concomitant use with a strong or moderate CYP3A inhibitor or a P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor [see Dosage and Administration ( 2.5 , 2.6 )].

Avoid grapefruit products, Seville oranges, and starfruit during treatment with VENCLEXTA, as they contain inhibitors of CYP3A.

Strong or Moderate CYP3A Inducers

Concomitant use with a strong CYP3A inducer decreases venetoclax Cmax and AUC0-INF [see Clinical Pharmacology ( 12.3 )], which may decrease VENCLEXTA efficacy. Avoid concomitant use of VENCLEXTA with strong CYP3A inducers or moderate CYP3A inducers.

7.2 Effect of VENCLEXTA on Other Drugs

Warfarin

Concomitant use of VENCLEXTA increases warfarin Cmax and AUC0-INF [see Clinical Pharmacology ( 12.3 )], which may increase the risk of bleeding. Monitor international normalized ratio (INR) more frequently in patients using warfarin concomitantly with VENCLEXTA.

P-gp Substrates

Concomitant use of VENCLEXTA increases Cmax and AUC0-INF of P-gp substrates [see Clinical Pharmacology ( 12.3 )], which may increase toxicities of these substrates. Avoid concomitant use of VENCLEXTA with a P-gp substrate. If a concomitant use is unavoidable, separate dosing of the P-gp substrate at least 6 hours before VENCLEXTA.

8 USE IN SPECIFIC POPULATIONS

  • 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/m2 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.

No clinically meaningful differences in safety and effectiveness were observed between older and younger patients in the combination and monotherapy studies.

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 )].

10 OVERDOSAGE

There is no specific antidote for VENCLEXTA. For patients who experience overdose, closely monitor and provide appropriate supportive treatment; during ramp-up phase interrupt VENCLEXTA and monitor carefully for signs and symptoms of TLS along with other toxicities [see Dosage and Administration ( 2.2 , 2.3 , 2.4 , 2.5 )]. Based on venetoclax large volume of distribution and extensive protein binding, dialysis is unlikely to result in significant removal of venetoclax.

11 DESCRIPTION

Venetoclax is a BCL-2 inhibitor. It is a light yellow to dark yellow solid with the empirical formula C45H50ClN7O7S and a molecular weight of 868.44. Venetoclax is described chemically as 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide) and has the following chemical structure:

the following chemical structure for Venetoclax is a BCL-2 inhibitor. It is a light yellow to dark yellow solid with the empirical formula C45H50ClN7O7S and a molecular weight of 868.44. Venetoclax is described chemically as 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide).

Venetoclax has very low aqueous solubility.

VENCLEXTA tablets for oral use are supplied as pale yellow or beige tablets that contain 10, 50, or 100 mg venetoclax as the active ingredient. Each tablet also contains the following inactive ingredients: copovidone, colloidal silicon dioxide, polysorbate 80, sodium stearyl fumarate, and calcium phosphate dibasic. In addition, the 10 mg and 100 mg coated tablets include the following: iron oxide yellow, polyvinyl alcohol, polyethylene glycol, talc, and titanium dioxide. The 50 mg coated tablets also include the following: iron oxide yellow, iron oxide red, iron oxide black, polyvinyl alcohol, talc, polyethylene glycol and titanium dioxide. Each tablet is debossed with “V” on one side and “10”, “50” or “100” corresponding to the tablet strength on the other side.

the following chemical structure for Venetoclax is a BCL-2 inhibitor. It is a light yellow to dark yellow solid with the empirical formula C45H50ClN7O7S and a molecular weight of 868.44. Venetoclax is described chemically as 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide).

12 CLINICAL PHARMACOLOGY

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 Cmax was 2.1 ± 1.1 mcg/mL and AUC0-24h was 32.8 ± 16.9 mcgh/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.

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 (Vdss/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 [14C]-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 (AUC0-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 Cmax by 130% and AUC0-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 Cmax 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 Cmax, respectively, compared with VENCLEXTA 400 mg administered alone. The venetoclax AUC0-24h 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 Cmax by 106% and AUC0-INF by 78%. Concomitant use of multiple doses of rifampin (as a strong CYP3A inducer) 600 mg once daily for 13 days decreased venetoclax Cmax by 42% and AUC0-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 Cmax and AUC0-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 Cmax by 35% and AUC0-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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Neither venetoclax nor M27, a major human metabolite, were carcinogenic in a 6-month transgenic (Tg.rasH2) mouse study at oral doses up to 400 mg/kg/day of venetoclax, and at a single oral dose level of 250 mg/kg/day of M27.

Venetoclax was not mutagenic in an in vitro bacterial mutagenicity (Ames) assay, did not induce numerical or structural aberrations in an in vitro chromosome aberration assay using human peripheral blood lymphocytes, and was not clastogenic in an in vivo mouse bone marrow micronucleus assay at doses up to 835 mg/kg. The M27 metabolite was negative for genotoxic activity in in vitro Ames and chromosome aberration assays.

Fertility and early embryonic development studies were conducted in male and female mice. These studies evaluate mating, fertilization, and embryonic development through implantation. There were no effects of venetoclax on estrous cycles, mating, fertility, corpora lutea, uterine implants or live embryos per litter at dosages up to 600 mg/kg/day. However, a risk to human male fertility exists based on testicular toxicity (germ cell loss) observed in dogs at exposures as low as 0.5 times the human AUC exposure at a dose of 400 mg.

13.2 Animal Toxicology and/or Pharmacology

In dogs, venetoclax caused single-cell necrosis in various tissues, including the gallbladder, exocrine pancreas, and stomach with no evidence of disruption of tissue integrity or organ dysfunction; these findings were minimal to mild in magnitude. Following a 4-week dosing period and subsequent 4-week recovery period, minimal single-cell necrosis was still present in some tissues and reversibility has not been assessed following longer periods of dosing or recovery.

In addition, after approximately 3 months of daily dosing in dogs, venetoclax caused progressive white discoloration of the hair coat due to loss of melanin pigment.

14 CLINICAL STUDIES

Figure 1
Figure 2
Figure 3
Figure 4

14.1 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

In Combination with Obinutuzumab

CLL14 (BO25323) was a randomized (1:1), multicenter, open-label, actively controlled trial (NCT02242942) that evaluated the efficacy and safety of VENCLEXTA in combination with obinutuzumab (VEN+G) versus obinutuzumab in combination with chlorambucil (GClb) for patients with previously untreated CLL with coexisting medical conditions (total Cumulative Illness Rating Scale [CIRS] score >6 or CLcr <70 mL/min). The trial required hepatic transaminases and total bilirubin ≤2 times upper limit of normal and excluded patients with Richter’s transformation or any individual organ/system impairment score of 4 by CIRS except eye, ear, nose, and throat organ system.

All patients received obinutuzumab at 1000 mg on Days 1 (the first dose could be split as 100 mg and 900 mg on Days 1 and 2), 8 and 15 of Cycle 1, and on Day 1 of each subsequent cycle for a total of 6 cycles. Patients in the VEN+G arm began the VENCLEXTA 5-week ramp-up dosing schedule [see Dosage and Administration ( 2.2 , 2.4 )] on Day 22 of Cycle 1 and received VENCLEXTA 400 mg orally once daily from Cycle 3 Day 1 until the last day of Cycle 12. Patients randomized to the GClb arm received chlorambucil 0.5 mg/kg orally on Day 1 and Day 15 of Cycles 1 to 12. Each cycle was 28 days.

A total of 432 patients were randomized, 216 to each arm. Baseline demographic and disease characteristics were similar between the arms. The median age was 72 years (range: 41 to 89 years), 89% were White, 67% were male; 36% and 43% were Binet stage B and C, respectively, and 88% had Eastern Cooperative Oncology Group (ECOG) performance status <2. The median CIRS score was 8.0 (range: 0 to 28) and 58% of patients had CLcr <70 mL/min. A 17p deletion was detected in 8% of patients, TP53 mutations in 10%, 11q deletion in 19%, and unmutated IgVH in 57%.

Efficacy was based on progression-free survival (PFS) as assessed by an Independent Review Committee (IRC). The median duration of follow-up for PFS was 28 months (range: 0 to 36 months). Efficacy results for CLL14 are shown in Table 19. The Kaplan-Meier curve for PFS is shown in Figure 1.  

Table 19. Efficacy Results in CLL14
Endpoint VENCLEXTA +
Obinutuzumab

(N = 216)
Obinutuzumab +
Chlorambucil

(N = 216)
Progression-free survival a
Number of events, n (%) 29 (13) 79 (37)
   Disease progression 14 (6) 71 (33)
   Death 15 (7) 8 (4)
Median, months Not Reached Not Reached
HR (95% CI)b 0.33 (0.22, 0.51)
p-valueb <0.0001
Response rate c , n (%)
ORRd 183 (85) 154 (71)
   95% CI (79, 89) (65, 77)
   CR 100 (46) 47 (22)
   CR+CRid 107 (50) 50 (23)
   PR 76 (35) 104 (48)
CI = confidence interval; CR = complete remission; CRi = complete remission with incomplete marrow recovery; HR = hazard ratio; ORR = overall response rate (CR + CRi + PR); PR = partial remission.
aFrom randomization until earliest event of disease progression or death due to any cause. IRC-assessed; Kaplan-Meier estimate.
bHR estimate is based on Cox-proportional hazards model stratified by Binet Stage and geographic region; p-value based on log rank test stratified by the same factors.
cPer 2008 International Workshop for Chronic Lymphocytic Leukemia (IWCLL) guidelines.
dp-values based on Cochran-Mantel-Haenszel test; p=0.0007 for ORR; p<0.0001 for CR+CRi.

Figure 1. Kaplan-Meier Curve of IRC-Assessed Progression-free Survival in CLL14

Figure 1

At the time of analysis, median overall survival (OS) had not been reached, with fewer than 10% of patients experiencing an event. The median duration of follow-up for OS was 28 months.

Minimal residual disease (MRD) was evaluated using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The definition of negative status was less than one CLL cell per 104 leukocytes. Rates of MRD negativity 3 months after the completion of treatment regardless of response and in patients who achieved CR are shown in Table 20. At this assessment, 134 patients in the VEN+G arm who were MRD negative in peripheral blood had matched bone marrow specimens; of these, 122 patients (91%) were MRD negative in both peripheral blood and bone marrow.

Table 20. Minimal Residual Disease Negativity Rates Three Months After the Completion of Treatment in CLL14
  VENCLEXTA +
Obinutuzumab
Obinutuzumab +
Chlorambucil
MRD negativity rate (ITT population)
N 216 216
Bone marrow, n (%) 123 (57) 37 (17)
   95% CI (50, 64) (12, 23)
   p-valuea <0.0001
Peripheral blood, n (%) 163 (76) 76 (35)
   95% CI (69, 81) (29, 42)
   p-valuea <0.0001
MRD negativity rate in patients with CR 
N 100 47
Bone marrow, n (%) 69 (69) 21 (45)
   95% CI (59, 78) (30, 60)
   p-valuea 0.0048
Peripheral blood, n (%) 87 (87) 29 (62)
   95% CI (79, 93) (46, 75)
   p-valuea 0.0005
CI = confidence interval; CR = complete remission.
ap-value based on Chi-square test.

Twelve months after the completion of treatment, MRD negativity rates in peripheral blood were 58% (126/216) in patients treated with VEN+G and 9% (20/216) in patients treated with GClb.

In Combination with Rituximab

MURANO was a randomized (1:1), multicenter, open-label trial (NCT02005471) that evaluated the efficacy and safety of VENCLEXTA in combination with rituximab (VEN+R) versus bendamustine in combination with rituximab (B+R) in patients with CLL who had received at least one line of prior therapy. Patients in the VEN+R arm completed the VENCLEXTA 5-week ramp-up dosing schedule [see Dosage and Administration ( 2.2 , 2.4 )] and received VENCLEXTA 400 mg orally once daily for 24 months from Cycle 1 Day 1 of rituximab in the absence of disease progression or unacceptable toxicity. Rituximab was initiated after the 5-week dose ramp-up at a dose of 375 mg/m2 intravenously on Day 1 of Cycle 1 and 500 mg/m2 intravenously on Day 1 of Cycles 2-6. Patients randomized to B+R received bendamustine 70 mg/m2 intravenously on Days 1 and 2 for 6 cycles in combination with rituximab at the above described dose and schedule. Each cycle was 28 days.

A total of 389 patients were randomized: 194 to the VEN+R arm and 195 to the B+R arm. Baseline demographic and disease characteristics were similar between the VEN+R and B+R arms. The median age was 65 years (range: 22 to 85 years), 97% were White, 74% were male, and 99% had ECOG performance status <2. Median prior lines of therapy was 1 (range: 1 to 5); 59% had received 1 prior therapy, 26% had received 2 prior therapies, and 16% had received 3 or more prior therapies. Prior therapies included alkylating agents (94%), anti-CD20 antibodies (77%), B-cell receptor pathway inhibitors (2%), and prior purine analogs (81%, including fludarabine/cyclophosphamide/rituximab in 55%). A 17p deletion was detected in 24% of patients, TP53 mutations in 25%, 11q deletion in 32%, and unmutated IgVH in 63%.

Efficacy was based on PFS as assessed by an IRC. The median follow-up for PFS was 23.4 months (range: 0 to 37.4+ months). Efficacy results for MURANO are shown in Table 21. The Kaplan-Meier curve for PFS is shown in Figure 2.

Table 21. IRC-Assessed Efficacy Results in MURANO
Endpoint VENCLEXTA + Rituximab
(N = 194)
Bendamustine + Rituximab
(N = 195)
Progression-free survival a
Number of events, n (%) 35 (18) 106 (54)
   Disease progression, n 26 91
   Death events, n 9 15
   Median, months (95% CI) Not Reached 18.1 (15.8, 22.3)
HR (95% CI)b 0.19 (0.13, 0.28)
p-valueb <0.0001
Response rate c , n (%)
ORR 179 (92) 141 (72)
   95% CI (88, 96) (65, 78)
   CR+CRi 16 (8) 7 (4)
   nPR 3 (2) 1 (1)
   PR 160 (82) 133 (68)
CI = confidence interval; CR = complete remission; CRi = complete remission with incomplete marrow recovery; HR = hazard ratio; nPR = nodular partial remission; ORR = overall response rate (CR + CRi + nPR + PR); PR = partial remission.
aKaplan-Meier estimate.
bHR estimate is based on Cox-proportional hazards model stratified by 17p deletion, risk status, and geographic region; p-value based on log-rank test stratified by the same factors.
cPer 2008 International Workshop for Chronic Lymphocytic Leukemia (IWCLL) guidelines.

Figure 2. Kaplan-Meier Curve of IRC-Assessed Progression-free Survival in MURANO

Figure 2

At 3 months after the last dose of rituximab, the MRD negativity rate in peripheral blood in patients who achieved PR or better was 54% (104/194) in the VEN+R arm and 12% (23/195) in the B+R arm. The MRD-negative CR/CRi rate at this timepoint was 3% (6/194) in the VEN+R arm and 2% (3/195) in the B+R arm.

71-Month Follow-Up

With an overall follow-up of 71 months, the investigator-assessed median PFS was 53.6 months (95% CI: 48.4, 57.0) in the VEN+R arm and 17.0 months (95% CI: 15.5, 21.7) in the B+R arm. Median OS had not been reached in either arm. Death occurred in 16% (32/194) of patients in the VEN+R arm and 33% (64/195) of patients in the B+R arm (stratified HR 0.40; 95% CI [0.26, 0.62]). The Kaplan-Meier curve for OS is shown in Figure 3.

Figure 3. Kaplan-Meier Curve of Overall Survival in MURANO

Figure 3

Monotherapy

The efficacy of VENCLEXTA monotherapy in previously treated CLL or SLL is based on three single-arm trials.

M13-982

M13-982 (NCT01889186) was an open-label, multicenter trial that enrolled 106 patients with CLL with 17p deletion who had received at least one prior therapy. In the trial, 17p deletion was confirmed in peripheral blood specimens from patients using Vysis CLL FISH Probe Kit, which is FDA approved for selection of patients for VENCLEXTA treatment. Patients received VENCLEXTA 400 mg orally once daily following completion of the ramp-up dosing schedule [see Dosage and Administration ( 2.2 , 2.4 )].

Efficacy was based on overall response rate (ORR) as assessed by an IRC.  

Table 22 summarizes the baseline demographic and disease characteristics of the trial population.

Table 22. Baseline Patient Characteristics in M13-982
Characteristic N = 106
Age, years; median (range) 67 (37-83)
White; % 97
Male; % 65
ECOG performance status; %
     0
     1
     2

40
52
8
Tumor burden; %
     Absolute lymphocyte count ≥25 x 109/L
     One or more nodes ≥5 cm

50
53
Number of prior therapies; median (range) 2.5 (1-10)
Time since diagnosis, years; median (range)a 6.6 (0.1-32.1)
ECOG = Eastern Cooperative Oncology Group.
aN=105.

The median time on treatment at the time of evaluation was 12.1 months (range: 0 to 21.5 months). Efficacy results are shown in Table 23.

Table 23. Efficacy Results per IRC for Patients with Previously Treated CLL with 17p Deletion in M13-982
Endpoint VENCLEXTA
N
  =   106
ORR, n (%)a
   (95% CI)
85 (80)
(71, 87)
   CR + CRi, n (%)
     CR, n (%)
     CRi, n (%)