VENCLEXTA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by an FDA approved test, who have received at least one prior therapy.
This indication is approved under accelerated approval based on overall response rate [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection

Select patients for the treatment of relapsed or refractory CLL with VENCLEXTA based on the presence of 17p deletions in blood specimens[see Indications and Usage (1) and Clinical Studies (14)]. Patients without 17p deletion at diagnosis should be retested at relapse because acquisition of 17p deletion can occur. Information on FDA-approved tests for the detection of 17p deletions in CLL is available at: http://www.fda.gov/CompanionDiagnostics.
2.2 Recommended Dosage

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 (2.3) and Warnings and Precautions (5.1)]. Administer the VENCLEXTA dose according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg as shown in Table 1. The 5-week ramp-up dosing schedule is designed to gradually reduce tumor burden (debulk) and decrease the risk of TLS.
Instruct patients to take VENCLEXTA tablets with a meal and water at approximately the same time each day. VENCLEXTA tablets should be swallowed whole and not chewed, crushed, or broken prior to swallowing.
 
Table 1. Dosing Schedule for Ramp-Up Phase

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

 
The Starting Pack provides the first 4 weeks of VENCLEXTA according to the ramp-up schedule. Once the ramp-up phase is completed, the 400 mg dose is achieved using 100 mg tablets supplied in bottles [see How Supplied/Storage and Handling (16)].
VENCLEXTA should be taken orally once daily until disease progression or unacceptable toxicity is observed.
2.3 Risk Assessment and Prophylaxis for Tumor Lysis Syndrome

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.
The risk of TLS is a continuum based on multiple factors, including tumor burden and comorbidities. Perform tumor burden assessments, including radiographic eva luation (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. Reduced renal function (creatinine clearance [CrCl] <80 mL/min) further increases the risk. The risk may decrease as tumor burden decreases [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].
Table 2 below describes the recommended TLS prophylaxis and monitoring during VENCLEXTA treatment based on tumor burden determination from clinical trial data.
 
Table 2. Recommended TLS Prophylaxis Based on Tumor Burden From Clinical Trial Data (consider all patient co-morbidities before final determination of prophylaxis and monitoring schedule)

Tumor Burden		Prophylaxis		Blood Chemistry Monitoringc,d
		Hydrationa	Anti-hyperuricemics	Setting and Frequency of Assessments
Low	All LN <5 cm AND ALC <25 x109/L	Oral (1.5-2 L)	Allopurinolb	Outpatient Pre-dose, 6 to 8 hours, 24 hours at first dose of 20 mg and 50 mg Pre-dose at subsequent ramp-up doses
Medium	Any LN 5 cm to <10 cm OR ALC ≥25 x109/L	Oral (1.5-2 L) and consider additional intravenous	Allopurinol	Outpatient Pre-dose, 6 to 8 hours, 24 hours at first dose of 20 mg and 50 mg Pre-dose at subsequent ramp-up doses Consider hospitalization for patients with CrCl <80ml/min at first dose of 20 mg and 50 mg; see below for monitoring in hospital
High	Any LN ≥10 cm OR ALC ≥25 x109/L AND any LN ≥5 cm	Oral (1.5-2L) and intravenous (150-200 mL/hr as tolerated)	Allopurinol; consider rasburicase if baseline uric acid is elevated	In hospital at first dose of 20 mg and 50 mg Pre-dose, 4, 8,12 and 24 hours Outpatient at subsequent ramp-up doses Pre-dose, 6 to 8 hours, 24 hours
ALC = absolute lymphocyte count; 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. ceva luate 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.

 2.4 Dose Modifications Based on Toxicities

Interrupt dosing or reduce dose for toxicities. See Table 3 for dose modifications for hematologic and other toxicities related to VENCLEXTA, and Table 4 for dose. 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 when at the daily dose of 400 mg, 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, 2.3)].
 
Table 3. Recommended Dose Modifications for Toxicities^a

Event	Occurrence	Action
Tumor Lysis Syndrome
Blood chemistry changes or symptoms suggestive of TLS	Any	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 (see Table 4) [see Dosage and Administration (2.3)].
		For any events of clinical TLS,b resume at a reduced dose following resolution (see Table 4) [see Dosage and Administration (2.3)].
Non-Hematologic Toxicities
Grade 3 or 4 non-hematologic toxicities	1st occurrence	Interrupt VENCLEXTA. Once the toxicity has resolved to Grade 1 or baseline level, VENCLEXTA therapy may be resumed at the same dose. No dose modification is required.
	2nd and subsequent occurrences	Interrupt VENCLEXTA. Follow dose reduction guidelines in Table 4 when resuming treatment with VENCLEXTA after resolution. A larger dose reduction may occur at the discretion of the physician.
Hematologic Toxicities
Grade 3 or 4 neutropenia with infection or fever; or Grade 4 hematologic toxicities (except lymphopenia) [see Warnings and Precautions (5.2)]	1st occurrence	Interrupt VENCLEXTA. To reduce the infection risks associated with neutropenia, granulocyte-colony stimulating factor (G-CSF) may be administered with VENCLEXTA if clinically indicated. Once the toxicity has resolved to Grade 1 or baseline level, VENCLEXTA therapy may be resumed at the same dose.
	2nd and subsequent occurrences	Interrupt VENCLEXTA. Consider using G-CSF as clinically indicated. Follow dose reduction guidelines in Table 4 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.

 
Table 4. Dose Modification for Toxicity During VENCLEXTA Treatment

Dose at Interruption, mg	Restart Dose, mga
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.

 2.5 Dose Modifications for Use with CYP3A and P-gp Inhibitors

Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation and during ramp-up phase is contraindicated. Concomitant use of VENCLEXTA with strong CYP3A inhibitors increases venetoclax exposure (i.e., C_max and AUC) and may increase the risk for TLS at initiation and during ramp-up phase [see Contraindications (4)]. For patients who have completed the ramp-up phase and are on a steady daily dose of VENCLEXTA, reduce the VENCLEXTA dose by at least 75% when strong CYP3A inhibitors must be used concomitantly.
Avoid concomitant use of VENCLEXTA with moderate CYP3A inhibitors or P-gp inhibitors. Consider alternative treatments. If a moderate CYP3A inhibitor or a P-gp inhibitor must be used, reduce the VENCLEXTA dose by at least 50%. Monitor these patients more closely for signs of toxicities [see Dosage and Administration (2.4)].
Resume the VENCLEXTA dose that was used prior to initiating the CYP3A inhibitor or P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor [see Dosage and Administration (2.4) and Drug Interactions (7.1)].
The recommendations for managing drug-drug interactions are summarized in Table 5.
 
Table 5. Management of Potential VENCLEXTA Interactions with CYP3A and P-gp Inhibitors

Inhibitors	Initiation and Ramp-Up Phase	Steady Daily Dose (After Ramp-Up Phase)
Strong CYP3A inhibitor	Contraindicated	Avoid inhibitor use or reduce the VENCLEXTA dose by at least 75%
Moderate CYP3A inhibitor	Avoid inhibitor use or reduce the VENCLEXTA dose by at least 50%
P-gp inhibitor

2.6 Missed Dose

If the patient misses a dose of VENCLEXTA within 8 hours of the time it is usually taken, the patient should 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, the patient should not take the missed dose and should resume the usual dosing schedule the next day.
If the patient vomits following dosing, no additional dose should be taken that day. The next prescribed dose should be taken at the usual time.
3 DOSAGE FORMS AND STRENGTHS

 
Table 6. 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

4 CONTRAINDICATIONS

Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation and during ramp-up phase is contraindicated [see Dosage and Administration (2.5) and Drug Interactions (7.1)].
5 WARNINGS AND PRECAUTIONS
5.1 Tumor Lysis Syndrome

Tumor lysis syndrome, including fatal events and renal failure requiring dialysis, has occurred in previously treated CLL patients with high tumor burden when treated with VENCLEXTA [see Adverse Reactions (6.1)].
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.
The risk of TLS is a continuum based on multiple factors, including tumor burden (see Table 2) and comorbidities. Reduced renal function (CrCl <80 mL/min) further increases the risk. Patients should be assessed for risk and should receive appropriate prophylaxis for TLS, including hydration and anti-hyperuricemics. Monitor blood chemistries and manage abnormalities promptly. Interrupt dosing if needed. Employ more intensive measures (intravenous hydration, frequent monitoring, hospitalization) as overall risk increases [see Dosage and Administration (2.3, 2.4) and Use in Specific Populations (8.6)].
Concomitant use of VENCLEXTA with strong or moderate CYP3A inhibitors and P-gp inhibitors increases venetoclax exposure, may increase the risk of TLS at initiation and during ramp-up phase and may require VENCLEXTA dose adjustment [see Dosage and Administration (2.5) and Drug Interactions (7.1)].
5.2 Neutropenia

Grade 3 or 4 neutropenia occurred in 41% (98/240) of patients treated with VENCLEXTA [see Adverse Reactions (6.1)]. Monitor complete blood counts throughout the treatment period. Interrupt dosing or reduce dose for severe neutropenia. Consider supportive measures including antimicrobials for signs of infection and use of growth factors (e.g., G-CSF) [see Dosage and Administration (2.4)].
5.3 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.
5.4 Embryo-Fetal Toxicity