Reference ID: 4866490
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`VENCLEXTA safely and effectively. See full prescribing information for
`VENCLEXTA.
`
`VENCLEXTA® (venetoclax tablets), for oral use
`Initial U.S. Approval: 2016
`
`RECENT MAJOR CHANGES
`Indications and Usage, AML (1.2)
`Dosage and Administration (2.1, 2.3, 2.4, 2.5, 2.8)
`Warnings and Precautions, Tumor Lysis Syndrome (5.1)
`Warnings and Precautions, Neutropenia (5.2)
`
`10/2020
`11/2020
`11/2020
`10/2020
`
`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)
`
`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)
`
`DOSAGE FORMS AND STRENGTHS
`Tablets: 10 mg, 50 mg, 100 mg (3)
`
`CONTRAINDICATIONS
`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)
`
`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)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1 INDICATIONS AND USAGE
`1.1 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
`1.2 Acute Myeloid Leukemia
`2 DOSAGE AND ADMINISTRATION
`2.1 Important Safety Information
`2.2 Recommended Dosage for Chronic Lymphocytic Leukemia/Small
`Lymphocytic Lymphoma
`2.3 Recommended Dosage for Acute Myeloid Leukemia
`2.4 Risk Assessment and Prophylaxis for Tumor Lysis Syndrome
`2.5 Dosage Modifications for Adverse Reactions
`2.6 Dosage Modifications for Drug Interactions
`2.7 Dosage Modifications for Patients with Severe Hepatic Impairment
`2.8 Administration
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Tumor Lysis Syndrome
`5.2 Neutropenia
`5.3 Infections
`5.4 Immunization
`5.5 Embryo-Fetal Toxicity
`5.6 Increased Mortality in Patients with Multiple Myeloma when
`VENCLEXTA is Added to Bortezomib and Dexamethasone
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`7 DRUG INTERACTIONS
`7.1 Effects of Other Drugs on VENCLEXTA
`
`• 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)
`
`ADVERSE REACTIONS
`In CLL/SLL, the most common adverse reactions (≥20%) for VENCLEXTA
`when given in combination with obinutuzumab or rituximab or as
`monotherapy were 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 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. (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.
`
`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)
`
`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)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`Revised: 10/2021
`
`7.2 Effect of VENCLEXTA on Other Drugs
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.3 Females and Males of Reproductive Potential
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`14.1 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
`14.2 Acute Myeloid Leukemia
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
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`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`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
`2.1 Important Safety Information
`Assess patient-specific factors for level of risk of tumor lysis syndrome (TLS) and provide
`prophylactic hydration and anti-hyperuricemics to patients prior to first dose of VENCLEXTA to
`reduce risk of TLS [see Dosage and Administration (2.4) and Warnings and Precautions (5.1)].
`2.2 Recommended Dosage for Chronic Lymphocytic Leukemia/Small Lymphocytic
`Lymphoma
`VENCLEXTA dosing begins with a 5-week ramp-up. The 5-week ramp-up dosing schedule is
`designed to gradually reduce tumor burden (debulk) and decrease the risk of TLS.
`VENCLEXTA 5-week Dose Ramp-Up Schedule
`Administer VENCLEXTA according to the 5-week ramp-up dosing schedule to the
`recommended dosage of 400 mg orally once daily as shown in Table 1.
`Table 1. Dosing Schedule for 5-Week Ramp-up Phase for Patients with CLL/SLL
`VENCLEXTA
`Oral Daily Dose
`20 mg
`Week 1
`50 mg
`Week 2
`100 mg
`Week 3
`200 mg
`Week 4
`400 mg
`Week 5 and beyond
`The CLL/SLL Starting Pack provides the first 4 weeks of VENCLEXTA according to the ramp-
`up schedule. The 400 mg dose is achieved using 100 mg tablets supplied in bottles [see How
`Supplied/Storage and Handling (16)].
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`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/m2 intravenously for Cycle 1 and 500 mg/m2
`intravenously for Cycles 2-6. Continue VENCLEXTA 400 mg orally once daily for 24 months
`from Cycle 1 Day 1 of rituximab.
`Refer to the rituximab prescribing information for additional dosing information.
`Monotherapy
`The recommended dosage of VENCLEXTA is 400 mg once daily after completion of the 5-week
`ramp-up dosing schedule (see Table 1). Continue VENCLEXTA until disease progression or
`unacceptable toxicity.
`2.3 Recommended Dosage for Acute Myeloid Leukemia
`The recommended dosage and ramp-up of VENCLEXTA depends upon the combination agent.
`Follow the dosing schedule, including the 3-day or 4-day dose ramp-up, as shown in Table 2.
`Start VENCLEXTA administration on Cycle 1 Day 1 in combination with:
` Azacitidine 75 mg/m2 intravenously or subcutaneously once daily on Days 1-7 of each 28-
`day cycle; OR
` Decitabine 20 mg/m2 intravenously once daily on Days 1-5 of each 28-day cycle; OR
` Cytarabine 20 mg/m2 subcutaneously once daily on Days 1-10 of each 28-day cycle.
`Table 2. Dosing Schedule for 3- or 4-Day Ramp-up Phase in Patients with AML
`VENCLEXTA
`Oral Daily Dose
`100 mg
`200 mg
`400 mg
`400 mg orally once daily of each 28-
`600 mg orally once daily of each 28-
`day cycle
`day cycle
`in combination with
`in combination with
`azacitidine or decitabine
`low-dose cytarabine
`
`Days 4 and
`beyond
`
`Day 1
`Day 2
`Day 3
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`Continue VENCLEXTA, in combination with azacitidine or decitabine or low-dose cytarabine,
`until disease progression or unacceptable toxicity.
`Refer to Clinical Studies (14.2) and Prescribing Information for azacitidine, decitabine, or
`cytarabine for additional dosing information.
`2.4 Risk Assessment and Prophylaxis for Tumor Lysis Syndrome
`Patients treated with VENCLEXTA may develop tumor lysis syndrome (TLS). Refer to the
`appropriate section below for specific details on management. Assess patient-specific factors for
`level of risk of TLS and provide prophylactic hydration and anti-hyperuricemics to patients prior
`to first dose of VENCLEXTA to reduce risk of TLS.
`Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
`VENCLEXTA can cause rapid reduction in tumor and thus poses a risk for TLS in the initial 5-
`week ramp-up phase. Changes in blood chemistries consistent with TLS that require prompt
`management can occur as early as 6 to 8 hours following the first dose of VENCLEXTA and at
`each dose increase. TLS can also occur upon resumption of VENCLEXTA following a dosage
`interruption. See Table 4 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
`
`Low
`
`All LN <5 cm
`AND
`ALC <25 x109/L
`
`Hydrationa
`
`Oral
`(1.5 to 2 L)
`
`Anti-
`hyperuricemicsb
`Allopurinol
`
`Blood Chemistry
`Monitoringc,d
`Setting and
`Frequency of
`Assessments
`Outpatient
`• For first dose of 20 mg
`and 50 mg: Pre-dose, 6 to
`8 hours, 24 hours
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`Tumor Burden
`
`Prophylaxis
`
`Hydrationa
`
`Anti-
`hyperuricemicsb
`
`Medium Any LN 5 to <10 cm
`OR
`ALC ≥25 x109/L
`
`Allopurinol
`
`Oral
`(1.5 to 2 L)
`and consider
`additional
`intravenous
`
`High Any LN ≥10 cm
`OR
`ALC ≥25 x109/L
`AND
`any LN ≥5 cm
`
`Blood Chemistry
`Monitoringc,d
`Setting and
`Frequency of
`Assessments
`• For subsequent ramp-up
`doses: Pre-dose
`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
`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.
`
`Allopurinol;
`consider
`rasburicase if
`baseline uric
`acid is elevated
`
`Oral
`(1.5 to 2 L)
`and
`intravenous
`(150 to 200
`mL/hr
`as tolerated)
`
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`•
`
`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
`
`Dosage Modification
`
`Occurrence
`Tumor Lysis Syndrome
`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
`1st occurrence
`Interrupt VENCLEXTA.
`Upon resolution to Grade 1 or baseline level,
`resume VENCLEXTA at the same dose.
`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
`1st occurrence
`Interrupt VENCLEXTA.
`Upon resolution to Grade 1 or baseline level,
`resume VENCLEXTA at the same dose.
`Interrupt VENCLEXTA.
`Follow dose reduction guidelines in Table 5
`when resuming treatment with VENCLEXTA
`
`Blood chemistry
`changes or symptoms
`suggestive of TLS [see
`Warnings and
`Precautions (5.1)]
`
`Grade 3 or 4 non-
`hematologic toxicities
`[see Adverse Reactions
`(6.1)]
`
`Grade 3 neutropenia
`with infection or fever;
`or Grade 4
`hematologic toxicities
`(except lymphopenia)
`[see Warnings and
`Precautions (5.2)]
`
`Any
`
`2nd and subsequent
`occurrences
`
`2nd and subsequent
`occurrences
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`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
`Restart Dose, mga,b
`Dose at Interruption, mg
`300
`400
`200
`300
`100
`200
`50
`100
`20
`50
`10
`20
`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
`
`Dosage Modification
`Occurrence
`Hematologic Adverse Reactions
`Grade 4 neutropenia
`Occurrence prior to
`In most instances, do not interrupt
`
`with or without fever or achieving remissiona
`VENCLEXTA in combination with
`infection; or Grade 4
`azacitidine, decitabine, or low-dose
`thrombocytopenia [see
`cytarabine due to cytopenias prior to
`achieving remission.
`Warnings and
`Precautions (5.2)]
`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.
`
`First occurrence after
`achieving remission and
`lasting at least 7 days
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`Adverse Reaction
`
`Occurrence
`Subsequent occurrences in
`cycles after achieving
`remission and lasting 7 days
`or longer
`
`Dosage Modification
`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.
`
`Grade 3 or 4 non-
`hematologic toxicities
`[see Adverse Reactions
`(6.1)]
`
`Non-Hematologic Adverse Reactions
`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
`
`Steady Daily Dose
`(After Ramp-Up Phase)a
`
`Initiation and
`Ramp-Up Phase
`CLL/SLL
`Contraindicated
`AML
`Day 1 – 10 mg
`Day 2 – 20 mg
`Day 3 – 50 mg
`Day 4 – 70 mg
`Contraindicated Reduce VENCLEXTA dose to 100
`Day 1 – 10 mg
`mg.
`Day 2 – 20 mg
`
`Posaconazole
`
`Other strong CYP3A
`inhibitor
`
`CLL/SLL
`AML
`
`Reduce VENCLEXTA dose to 70 mg.
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`Day 3 – 50 mg
`Day 4 – 100 mg
`
`Moderate CYP3A
`inhibitor
`P-gp inhibitor
`aIn patients with CLL/SLL, consider alternative medications or reduce the VENCLEXTA dose
`as described in Table 7.
`
`Reduce the VENCLEXTA dose by at least 50%.
`
`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.
`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
`Round, biconvex shaped, pale yellow film-coated tablet debossed
`with “V” on one side and “10” on the other side
`Oblong, biconvex shaped, beige film-coated tablet debossed with
`“V” on one side and “50” on the other side
`Oblong, biconvex shaped, pale yellow film-coated tablet debossed
`with “V” on one side and “100” on the other side
`
`10 mg
`
`50 mg
`
`100 mg
`
`4 CONTRAINDICATIONS
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`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)].
`
`5 WARNINGS AND PRECAUTIONS
`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
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`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.
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`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)]
`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.
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`Grade ≥3
`(%)
`
`Grade ≥3
`(%)
`
`Adverse Reaction
`
`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
`VENCLEXTA + Obinutuzumab
`Obinutu