Venclexta

VENCLEXTA- venetoclax
VENCLEXTA- venetoclax tablet, film coated
AbbVie Inc.

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
Week 1	20 mg
Week 2	50 mg
Week 3	100 mg
Week 4	200 mg
Week 5 and beyond	400 mg

The CLL/SLL Starting Pack provides the first 4 weeks of VENCLEXTA according to the ramp-up schedule. The 400 mg dose is achieved using 100 mg tablets supplied in bottles [see How Supplied/Storage and Handling (16)].

In Combination with Obinutuzumab

Start obinutuzumab administration at 100 mg on Cycle 1 Day 1, followed by 900 mg on Cycle 1 Day 2. Administer 1000 mg on Days 8 and 15 of Cycle 1 and on Day 1 of each subsequent 28-day cycle for a total of 6 cycles. Refer to the obinutuzumab prescribing information for additional dosing information.

On Cycle 1 Day 22, start VENCLEXTA according to the 5-week ramp-up dosing schedule (see Table 1). After completing the ramp-up phase on Cycle 2 Day 28, continue VENCLEXTA at a dose of 400 mg orally once daily from Cycle 3 Day 1 until the last day of Cycle 12.

In Combination with Rituximab

Start rituximab administration after the patient has completed the 5-week ramp-up dosing schedule for VENCLEXTA (see Table 1) and has received VENCLEXTA at the recommended dosage of 400 mg orally once daily for 7 days. Administer rituximab on Day 1 of each 28-day cycle for 6 cycles, at a dose of 375 mg/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

	VENCLEXTAOral Daily Dose
Day 1	100 mg
Day 2	200 mg
Day 3	400 mg
Days 4 and beyond	400 mg orally once daily of each 28-day cyclein combination withazacitidine or decitabine	600 mg orally once daily of each 28-day cyclein combination withlow-dose cytarabine

Continue VENCLEXTA, in combination with azacitidine or decitabine or low-dose cytarabine, until disease progression or unacceptable toxicity.

Refer to Clinical Studies (14.2) and Prescribing Information for azacitidine, decitabine, or cytarabine for additional dosing information.

2.4 Risk Assessment and Prophylaxis for Tumor Lysis Syndrome

Patients treated with VENCLEXTA may develop tumor lysis syndrome (TLS). Refer to the appropriate section below for specific details on management. Assess patient-specific factors for level of risk of TLS and provide prophylactic hydration and anti-hyperuricemics to patients prior to first dose of VENCLEXTA to reduce risk of TLS.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

VENCLEXTA can cause rapid reduction in tumor and thus poses a risk for TLS in the initial 5-week ramp-up phase. Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLEXTA and at each dose increase.​ TLS can also occur upon resumption of VENCLEXTA following a dosage interruption. See Table 4 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 Monitoringc,d
		Hydrationa	Anti-hyperuricemicsb	Setting and Frequency of Assessments
Low	All LN <5 cm ANDALC <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 ORALC ≥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 ANDany LN ≥5 cm	Oral (1.5 to 2 L)and intravenous(150 to 200 mL/hras tolerated)	Allopurinol; consider rasburicase if baseline uric acid is elevated	In hospital For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12, and 24 hours Outpatient For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours
ALC = absolute lymphocyte count; CLcr = creatinine clearance; LN = lymph node.a Administer intravenous hydration for any patient who cannot tolerate oral hydration. b Start allopurinol or xanthine oxidase inhibitor 2 to 3 days prior to initiation of VENCLEXTA.c Evaluate blood chemistries (potassium, uric acid, phosphorus, calcium, and creatinine); review in real time. d For patients at risk of TLS, monitor blood chemistries at 6 to 8 hours and at 24 hours at each subsequent ramp-up dose.

Acute Myeloid Leukemia

• All patients should have white blood cell count less than 25 × 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.