Usual Adult Dose for Lymphoma

Weekly ramp-up schedule over 5 weeks (CLL/SLL):
Week 1: 20 mg orally once a day
Week 2: 50 mg orally once a day
Week 3: 100 mg orally once a day
Week 4: 200 mg orally once a day
Week 5 and beyond: 400 mg orally once a day

MONOTHERAPY:

• Start after the patient has completed the 5-week dose ramp-up schedule: 400 mg orally once a day until disease progression or unacceptable toxicity

IN COMBINATION WITH OBINUTUZUMAB:

• Start obinutuzumab at 100 mg orally on Cycle 1 Day 1, followed by 900 mg on Cycle 1 Day 2 then 1000 mg orally 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 recommended obinutuzumab dosing information.
• On Cycle 1 Day 22, start venetoclax according to the 5-week ramp-up schedule; after completing the ramp-up schedule on Cycle 2 Day 28, patients should continue with 400 mg once daily from Cycle 3 Day 1 until the last day of Cycle 12.

IN COMBINATION WITH RITUXIMAB:

• Start rituximab after the patient has completed the 5-week dose ramp-up schedule and has received the 400 mg dose of venetoclax for 7 days.
• Administer rituximab on Day 1 of each 28-day cycle for 6 cycles, with rituximab dosed at 375 mg/m2 IV for Cycle 1 and 500 mg/m2 IV for Cycles 2 through 6.
• Patients should continue venetoclax 400 mg orally once daily for 24 months from Cycle 1 Day 1 of rituximab.

Comments:

• All dose regimens begin with a 5-week ramp-up schedule to gradually reduce tumor burden and decrease risk of tumor lysis syndrome (TLS).
• Assess patient level of risk of tumor lysis syndrome (TLS) and provide prophylactic hydration and antihyperuricemics prior to the first dose.

Uses:

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

Usual Adult Dose for Leukemia

Weekly ramp-up schedule over 5 weeks (CLL/SLL):
Week 1: 20 mg orally once a day
Week 2: 50 mg orally once a day
Week 3: 100 mg orally once a day
Week 4: 200 mg orally once a day
Week 5 and beyond: 400 mg orally once a day

MONOTHERAPY:

• Start after the patient has completed the 5-week dose ramp-up schedule: 400 mg orally once a day until disease progression or unacceptable toxicity

IN COMBINATION WITH OBINUTUZUMAB:

• Start obinutuzumab at 100 mg orally on Cycle 1 Day 1, followed by 900 mg on Cycle 1 Day 2 then 1000 mg orally 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 recommended obinutuzumab dosing information.
• On Cycle 1 Day 22, start venetoclax according to the 5-week ramp-up schedule; after completing the ramp-up schedule on Cycle 2 Day 28, patients should continue with 400 mg once daily from Cycle 3 Day 1 until the last day of Cycle 12.

IN COMBINATION WITH RITUXIMAB:

• Start rituximab after the patient has completed the 5-week dose ramp-up schedule and has received the 400 mg dose of venetoclax for 7 days.
• Administer rituximab on Day 1 of each 28-day cycle for 6 cycles, with rituximab dosed at 375 mg/m2 IV for Cycle 1 and 500 mg/m2 IV for Cycles 2 through 6.
• Patients should continue venetoclax 400 mg orally once daily for 24 months from Cycle 1 Day 1 of rituximab.

Comments:

• All dose regimens begin with a 5-week ramp-up schedule to gradually reduce tumor burden and decrease risk of tumor lysis syndrome (TLS).
• Assess patient level of risk of tumor lysis syndrome (TLS) and provide prophylactic hydration and antihyperuricemics prior to the first dose.

Uses:

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

Usual Geriatric Dose for Acute Myeloid Leukemia

75 years and older:
NOTE: The dose and ramp-up of venetoclax depends on the combination agent:
Start venetoclax on Cycle 1 Day 1 in combination with:
Azacitidine 75 mg/m2 IV or subcutaneously once daily on Days 1 through 7 of each 28-day cycle
OR
Decitabine 20 mg/m2 IV once daily on Days 1 through 5 of each 28-day cycle
OR
Cytarabine 20 mg/m2 subcutaneously once daily on Days 1 through 10 of each 28-day cycle
DOSE SCHEDULE FOR RAMP-UP PHASE IN PATIENTS WITH AML:
Day 1: 100 mg orally
Day 2: 200 mg orally
Day 3: 400 mg orally
Day 4 and beyond: 400 mg orally once a day of each 28-day cycle when dosing in combination with azacytidine or decitabine OR 600 mg orally once a day of each 28-day cycle when dosing in combination with low dose cytarabine until disease progression or unacceptable toxicity

Comments:

• Assess patient level of risk of tumor lysis syndrome (TLS) and provide prophylactic hydration and antihyperuricemics prior to the first dose.

Use: This drug in combination with azacitidine, or decitabine, or low dose cytarabine for newly diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy

Renal Dose Adjustments

• Mild (CrCl 60 to less than 90 mL/min) to moderate (CrCl 30 to less than 60 mL/min) renal impairment: No adjustment recommended.
• Severe renal impairment (CrCl less than 30 mL/min): Data not available

Liver Dose Adjustments

• Mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment: No adjustment recommended.
• Severe (Child-Pugh C) hepatic impairment: Reduce the once daily dose by 50%.

Dose Adjustments

RISK ASSESSMENT AND PROPHYLAXIS FOR TUMOR LYSIS SYNDROME (TLS):

• Patients taking this drug may develop TLS.
• Assess patient-specific factors for level of risk of TLS and provide prophylactic hydration and antihyperuricemics prior to the first dose to reduce risk of TLS.

CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)/SMALL LYMPHOCYTIC LYMPHOMA (SLL):

• This drug can cause rapid reduction in tumor and thus poses a risk for TLS in the initial 5-week ramp-up phase.
• TLS can occur as early as 6 to 8 hours following the first dose and at each dose increase.
• The risk of TLS is based on multiple factors, including tumor burden and comorbidities. Reduced renal function (CrCl less than 80 mL/min) further increases the risk.
• 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 therapy.
• The risk may decrease as tumor burden decreases.

RECOMMENDED TLS PROPHYLAXIS BASED ON TUMOR BURDEN IN PATIENTS WITH CLL/SLL:
LOW TUMOR BURDEN (All lymph node [LN] less than 5 cm AND absolute lymphocyte count [ALC] less than 25 x 10(9)/L):

• Prophylaxis: Oral (or IV if oral is not tolerated) hydration of 1.5 to 2 L and allopurinol (start allopurinol or xanthine oxidase inhibitor 2 to 3 days prior to initiation of this drug).
• Blood chemistry monitoring: Evaluate blood chemistries (potassium, uric acid, phosphorus, calcium, and creatinine); review in real time; for patients at risk of TLS, monitor blood chemistries at 6 to 8 hours and at 24 hours at each subsequent ramp-up dose: Outpatient: For first dose of 20 mg and 50 mg: Predose, 6 to 8 hours, 24 hours; for subsequent ramp-up doses: Predose

MEDIUM TUMOR BURDEN (Any LN 5 cm to less than 10 cm OR ALC 25 x 10(9)/L or greater):

• Prophylaxis: Oral (or IV if oral is not tolerated) hydration of 1.5 to 2 L and consider additional IV hydration and allopurinol (start allopurinol or xanthine oxidase inhibitor 2 to 3 days prior to initiation of this drug).
• Blood chemistry monitoring: Evaluate blood chemistries (potassium, uric acid, phosphorus, calcium, and creatinine); review in real time; for patients at risk of TLS, monitor blood chemistries at 6 to 8 hours and at 24 hours at each subsequent ramp-up dose: Outpatient: For first dose of 20 mg and 50 mg: Predose, 6 to 8 hours, 24 hours; for subsequent ramp-up doses: Predose; For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl less than 80 mL/min

HIGH TUMOR BURDEN (Any LN 10 cm or greater OR ALC 25 x 10(9)/L or greater AND any LN 5 cm or greater:

• Prophylaxis: Oral hydration of 1.5 to 2 L and IV hydration of 150 to 200 mL/hour as tolerated and allopurinol (start allopurinol or xanthine oxidase inhibitor 2 to 3 days prior to initiation of this drug).
• Blood chemistry monitoring: Evaluate blood chemistries (potassium, uric acid, phosphorus, calcium, and creatinine); review in real time; for patients at risk of TLS, monitor blood chemistries at 6 to 8 hours and at 24 hours at each subsequent ramp-up dose: In hospital: For first dose of 20 mg and 50 mg: Predose, 4, 8, 12 and 24 hours; Outpatient: For subsequent ramp-up doses: Predose, 6 to 8 hours, 24 hours.

ACUTE MYELOID LEUKEMIA (AML):

• All patients should have white blood cell count less than 25 x 10(9)/L prior to initiation of therapy. Cytoreduction prior to therapy initiation may be required.
• Prior to the first dose, provide prophylactic hydration and antihyperuricemics and continue during ramp-up phase.
• Assess blood chemistry (e.g., potassium, uric acid, phosphorus, calcium, creatinine) and correct preexisting abnormalities prior to initiation of therapy.
• Monitor blood chemistries for TLS at predose, 6 to 8 hours after each new dose during ramp-up, and 24 hours after reaching the 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, reduced renal function) additional measures should be considered, including increased laboratory monitoring and reducing the starting dose.

DOSAGE MODIFICATIONS BASED ON TOXICITIES:
CLL/SLL:

• Interrupt dosing or reduce dose for toxicities.
• For patients who have had a dosing interruption greater than 1 week during the first 5 weeks of ramp-up phase or greater than 2 weeks after completing the ramp-up phase, 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).

RECOMMENDED DOSE MODIFICATIONS FOR TOXICITIES IN CLL/SLL:
TUMOR LYSIS SYNDROME (TLS):
Blood chemistry changes or symptoms of TLS:

• Any occurrence: Withhold the next day's dose; if resolved within 24 to 48 hours of last dose, resume at the same dose; for any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose; for any events of clinical TLS (e.g., acute renal failure, cardiac arrhythmias, sudden death and/or seizures) resume at a reduced dose following resolution.

NONHEMATOLOGIC TOXICITIES:
Grade 3 or 4 nonhematologic toxicities:

• First occurrence: Interrupt therapy; when toxicity has resolved to Grade 1 or baseline level, resume at the same dose. No dose modification is required.
• Second and subsequent occurrences: Interrupt therapy; follow dose reduction guidelines after resolution. A larger dose reduction may occur at the discretion of the physician.

HEMATOLOGIC TOXICITIES:
Grade 3 neutropenia with infection or fever or Grade 4 hematologic toxicities (except lymphopenia):

• First occurrence: Interrupt therapy; upon resolution to Grade 1 or baseline, resume at the same dose.
• Second and subsequent occurrences: Interrupt therapy; consider using G-CSF as indicated; follow dose reduction guidelines when resuming therapy after resolution; a larger dose reduction may occur at the discretion of the physician.

NOTE: Consider discontinuing therapy for patients who require dose reductions to less than 100 mg for more than 2 weeks.

DOSE REDUCTION FOR TOXICITY DURING TREATMENT IN CLL/SLL:

• Dose interruption at 400 mg: Restart dose at 300 mg (during the ramp-up phase, continue the reduced dose for 1 week before increasing the dose).
• Dose interruption at 300 mg: Restart dose at 200 mg (during the ramp-up phase, continue the reduced dose for 1 week before increasing the dose).
• Dose interruption at 200 mg: Restart dose at 100 mg (during the ramp-up phase, continue the reduced dose for 1 week before increasing the dose).
• Dose interruption at 100 mg: Restart dose at 50 mg (during the ramp-up phase, continue the reduced dose for 1 week before increasing the dose).
• Dose interruption at 50 mg: Restart dose at 20 mg (during the ramp-up phase, continue the reduced dose for 1 week before increasing the dose).
• Dose interruption at 20 mg: Restart dose at 10 mg (during the ramp-up phase, continue the reduced dose for 1 week before increasing the dose).

ACUTE MYELOID LEUKEMIA (AML):

• Monitor blood counts frequently through resolution of cytopenias.
• Management of some adverse reactions may require dose interruptions or permanent discontinuation of therapy.

RECOMMENDED DOSE MODIFICATIONS FOR TOXICITIES IN AML:
HEMATOLOGIC TOXICITIES:
Grade 4 neutropenia with or without fever or infection or Grade 4 thrombocytopenia:

• Occurrence prior to achieving remission: In most instances, do not interrupt therapy 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 therapy in combination with azacitidine, decitabine, or low dose cytarabine and monitor blood counts; upon resolution to Grade 1 or 2, resume therapy 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 treatment cycle of therapy in combination with azacitidine, or decitabine, or low dose cytarabine and monitor blood counts; upon resolution to Grade 1 or 2, resume at the same dose in combination with azacitidine, decitabine or low dose cytarabine, and reduce venetoclax duration by 7 days during each of the subsequent cycles, such as 21 days instead of 28 days.

NONHEMATOLOGIC ADVERSE REACTIONS:

• Grade 3 or 4 nonhematologic toxicities:
• Any occurrence: Interrupt therapy if not resolved with supportive care; upon resolution to Grade 1 or baseline; resume at the same dose.

DOSE MODIFICATIONS FOR CONCOMITANT USE WITH MODERATE OR STRONG CYP450 3A INHIBITORS OR P-GP INHIBITORS:
Note: Resume the venetoclax dose that was used prior to concomitant use of a strong or moderate CYP450 3A inhibitor or P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor.
VENETOCLAX COADMINISTERED WITH POSACONAZOLE IN CLL/SLL:

• Initiation and ramp-up phase: Contraindicated
• Steady daily dose (after ramp-up phase): Reduce venetoclax dose to 70 mg.

VENETOCLAX COADMINISTERED WITH POSACONAZOLE IN AML:

• Day 1: 10 mg
• Day 2: 20 mg
• Day 3: 50 mg
• Day 4: 70 mg
• Steady daily dose (after ramp-up phase): Reduce venetoclax dose to 70 mg.

VENETOCLAX COADMINISTERED WITH OTHER STRONG CYP450 3A INHIBITOR IN CLL/SLL:

• Initiation and ramp-up phase: Contraindicated
• Steady daily dose (after ramp-up phase): Reduce venetoclax dose to 100 mg.

VENETOCLAX COADMINISTERED WITH OTHER STRONG CYP450 3A INHIBITOR IN AML:

• Day 1: 10 mg
• Day 2: 20 mg
• Day 3: 50 mg
• Day 4: 100 mg
• Steady daily dose (after ramp-up phase): Reduce venetoclax dose to 100 mg.

VENETOCLAX COADMINISTERED WITH MODERATE CYP450 3A INHIBITOR: Reduce the venetoclax dose by at least 50%.
VENETOCLAX COADMINISTERED WITH P-GP INHIBITOR: Reduce the venetoclax dose by at least 50%.

Precautions

CONTRAINDICATIONS:

• Concomitant with strong CYP450 3A inhibitors at initiation and during the titration phase (due to the increased risk of tumor lysis syndrome)

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration Advice:

• This drug should be taken with a meal and water at approximately the same time each day.
• Tablets should be swallowed whole and not chewed, crushed, or broken prior to swallowing.
• If a patient misses a dose within 8 hours of the time it is usually taken, the patient should take the missed dose as soon as possible on the same day. If a patient misses a dose by more than 8 hours, the patient should not take the missed dose and should resume the usual dosing schedule the following day.
• If a patient vomits following dosing, no additional dose should be taken that day. The next dose should be taken at the usual time.

Storage requirements:

• This drug should be kept in the original packaging during the first 4 weeks of treatment.
• This drug should be stored at or below 86 degrees Fahrenheit (30 Celsius).

Grapefruit products, Seville oranges, and starfruit (carambola) should be avoided during treatment with venetoclax as they contain inhibitors of CYP450 3A.

General:

• Patients treated with this drug may develop tumor lysis syndrome. Assess patient-specific factors for level of risk of tumor lysis syndrome (TLS) and provide prophylactic hydration and antihyperuricemics to patients prior to the first dose to reduce risk of TLS.
• There is no specific antidote for overdosage of this drug; dialysis is unlikely to help.

Monitoring:

• HEMATOLOGIC: CBC (during treatment)
• METABOLIC: Tumor burden assessments, including radiographic evaluation (e.g., CT scan); blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine)

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

Patient Advice:

• Avoid eating or drinking products with grapefruit, Seville oranges, and starfruit during treatment.

Frequently asked questions

• Is Venclexta (venetoclax) chemotherapy?
• How effective is Venclexta?
• How long do you take Venclexta for?
• Can Venclexta be used for Multiple Myeloma?
• How is Venclexta (venetoclax) used for AML?
• How does Venclexta work?