XERVEXTA STARTING PACK

Venetoclax is a

BCL-2 inhibitor that was initially approved by the FDA in April 2016 Label.

Proteins in the B cell

CLL/lymphoma 2 (BCL-2) family are important regulators of the apoptotic (programmed cell death) process 1, 2.

Venetoclax is used to treat chronic lymphocytic leukemia (CLL) and certain types of small lymphocytic lymphoma Label.

CLL is the most prevalent leukemia diagnosed in Western countries 7.

Venetoclax was developed through reverse engineering of the BCL-2 protein family inhibitor, navitoclax 7.

Venetoclax is approximately 10 times more potent than navitoclax with regard to induction of apoptosis in CLL cells 7.

A new indication was approved in for the treatment patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy Label.

Previously, this drug was indicated only for patients with 17p gene deletion 11.

Venetoclax is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

It is also used 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.

Venetoclax induces rapid and potent onset apoptosis of CLL cells, powerful enough to act within 24h and to lead to tumor lysis syndrome 5, Label, 2.

Selective targeting of

BCL2 with venetoclax has demonstrated a manageable safety profile and has been shown to induce significant response in patients with relapsed CLL (chronic lymphocytic leukemia) or SLL (small lymphocytic leukemia), including patients with poor prognostic features 6.

This drug is not expected to have a significant impact on the cardiac QT interval Label.

Venetoclax has demonstrated efficacy in various types of lymphoid malignancies, including relapsed/ refractory CLL harboring deletion 17p, with an overall response rate of approximately 80% 7.

Following several oral administrations after a meal, the maximum plasma concentration of venetoclax was reached 5-8 hours after the dose 3.

Venetoclax steady state

AUC (area under the curve) increased proportionally over the dose range of 150-800 mg.

When compared with the fasted state, venetoclax exposure increased by 3.4 times when ingested with a low-fat meal and 5.2 times with a high-fat meal.

When comparing low versus high fat, the Cmax and AUC were both increased by 50% when ingested with a high-fat meal.

FDA label indicataes that venetoclax should be taken with food 7, Label.

The population estimate for apparent volume of distribution (Vdss/F) of venetoclax ranged from 256-321 L Label.

In vitro studies demonstrated that venetoclax is predominantly metabolized as a substrate of CYP3A4/5 Label, 4, 10.

Hover over products below to view reaction partners Venetoclax M27.

After single oral administration of 200 mg radiolabeled -venetoclax dose to healthy subjects, >99.9% of the dose was found in feces and <0.1% of the dose was excreted in urine within 9 days, suggesting that hepatic elimination is responsible for the clearance of venetoclax from systemic circulation.

Unchanged venetoclax accounted for 20.8% of the radioactive dose excreted in feces Label.

The half-life of venetoclax is reported to be 19-26 hours, after administration of a single 50-mg dose 7, Label.

Mainly hepatic

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Acute toxicity: oral toxicity (LD50) >2001 mg/kg (mouse) 8.

Venetoclax may cause embryo-fetal harm when administered to a pregnant woman.

Patients should avoid pregnancy during treatment.

A risk to human male fertility exists based on the results of testicular toxicity (germ cell loss) seen in dogs at exposures as low as 0.5 times the human AUC exposure at the recommended dose Label.

Carcinogenicity studies have not yet been performed with venetoclax Label.

Venetoclax was not shown to be mutagenic in an in vitro bacterial mutagenicity (Ames) assay, did not induce aberrations in an in vitro chromosome aberration assay with human peripheral blood lymphocytes.

It 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 during both in vitro Ames and chromosome aberration assays Label.

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.

Concomitant use with strong

CYP3A inhibitors at initiation and during ramp-up phase in patients with CLL/SLL is contraindicated.

See Full Prescribing Information for recommended

VENCLEXTA dosages.

VENCLEXTA tablets orally once daily with a meal and water.

Do not chew, crush, or break tablets.

Provide prophylaxis for tumor lysis syndrome. 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. 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.

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 and beyond 400 mg The CLL/SLL Starting Pack provides the first 4 weeks of VENCLEXTA according to the ramp-up schedule.

Cycle 1 Day 1: Start acalabrutinib 100 mg orally approximately every 12 hours until disease progression, unacceptable toxicity or completion of 14 cycles of treatment.

Each cycle is 28 days.

Refer to the acalabrutinib prescribing information for additional dosing information.

Cycle 3 Day 1: start VENCLEXTA according to the 5-week ramp-up dosing schedule.

After completing the ramp-up phase, continue VENCLEXTA at a dose of 400 mg orally once daily until disease progression, unacceptable toxicity, or until the last day of Cycle 14.

Start obinutuzumab administration at 100 mg on Cycle 1 Day 1, followed by 900 mg on Cycle 1 Day 2.

Administer 1,000 mg on Days and 15 of Cycle and on Day 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.

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.

Start rituximab administration after the patient has completed the 5-week ramp-up dosing schedule for VENCLEXTA and has received VENCLEXTA at the recommended dosage of 400 mg orally once daily for 7 days.

Administer rituximab on

Day of each 28-day cycle for 6 cycles, at a dose of 375 mg/m 2 intravenously for Cycle and 500 mg/m 2 intravenously for Cycles 2-6.

VENCLEXTA 400 mg orally once daily for 24 months from Cycle 1 Day 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.

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 in combination with: Azacitidine 75 mg/m 2 intravenously or subcutaneously once daily on Days 1-7 of each 28-day cycle; OR Decitabine 20 mg/m 2 intravenously once daily on Days 1-5 of each 28-day cycle; OR Cytarabine 20 mg/m 2 subcutaneously once daily on Days 1-10 of each 28-day cycle.

Table 2.

Schedule for 3.

• or 4-Day Ramp-up Phase in Patients with AML VENCLEXTA Oral Daily Dose Day 1 100 mg Day 2 200 mg Day 3 400 mg Days and beyond 400 mg orally once daily of each 28-day cycle in combination with azacitidine or decitabine 600 mg orally once daily of each 28-day cycle in combination with low-dose cytarabine Continue VENCLEXTA, in combination with azacitidine or decitabine or low-dose cytarabine, until disease progression or unacceptable toxicity.

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.

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 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.

Table 4, Table 5, and Table 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.

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 x10 9 /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 to <10 cm OR ALC ≥25 x10 9 /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 x10 9 /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. a Administer intravenous hydration for any patient who cannot tolerate oral hydration. b Start allopurinol or xanthine oxidase inhibitor 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 to 8 hours and at 24 hours at each subsequent ramp-up dose.

All patients should have white blood cell count less than 25 × 10 9 /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 dose reductions for VENCLEXTA for adverse reactions are provided in Table 4.

The recommended dosage modifications for

VENCLEXTA for adverse reactions are provided in Table and Table 6.

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) .

Table 4.

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 a During the ramp-up phase, continue the reduced dose for 1 week before increasing the dose. b If 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.

Table 5.

Recommended VENCLEXTA Dosage Modifications for Adverse Reactions a in Patients with CLL/SLL Receiving VENCLEXTA in Combination with Obinutuzumab, with Rituximab or as Monotherapy Adverse Reaction Occurrence Dosage Modification Tumor Lysis Syndrome Blood chemistry changes or symptoms suggestive of TLS Any Withhold the next day’s dose.

If resolved within 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.

For any events of clinical

TLS, b resume at reduced dose following resolution.

Grade 3 or 4 non-hematologic toxicities 1 st occurrence Interrupt VENCLEXTA.

Upon resolution to

Grade 1 or baseline level, resume VENCLEXTA at the same dose. 2 nd 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.

Grade 3 neutropenia with infection or fever; or Grade 4 hematologic toxicities (except lymphopenia) 1 st occurrence Interrupt VENCLEXTA.

Consider discontinuing

VENCLEXTA for patients who require dose reductions to less than 100 mg for more than 2 weeks. a Adv.

is dispensed as follows: Packaging Presentation Number of Tablets National Drug Code (NDC) CLL/SLL Starting Pack Each pack contains four weekly wallet blister packs: Week 1 (14 x 10 mg tablets) Week 2 (7 x 50 mg tablets) Week 3 (7 x 100 mg tablets) Week 4 (14 x 100 mg tablets) 0074-0579-28 Wallet containing 10 mg tablets 14 x 10 mg tablets 0074-0561-14 Wallet containing 50 mg tablets 7 x 50 mg tablets 0074-0566-07 Unit dose blister containing 10 mg tablets 2 x 10 mg tablets 0074-0561-11 Unit dose blister containing 50 mg tablet 1 x 50 mg tablet 0074-0566-11 Unit dose blister containing 100 mg tablet 1 x 100 mg tablet 0074-0576-11 Bottle containing 100 mg tablets 28 x 100 mg tablets 0074-0576-30 Bottle containing 100 mg tablets 120 x 100 mg tablets 0074-0576-22 VENCLEXTA 10 mg film-coated tablets are round, biconvex shaped, pale yellow debossed with “V” on one side and “10” on the other side.

VENCLEXTA 50 mg film-coated tablets are oblong, biconvex shaped, beige debossed with “V” on one side and “50” on the other side.

VENCLEXTA 100 mg film-coated tablets are oblong, biconvex shaped, pale yellow debossed with “V” on one side and “100” on the other side.

Store in original container at or below 86°F (30°C).

Dispense to patient in original container to protect from moisture.

Based on findings in animals and its mechanism of action, 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.

The safety and effectiveness of

VENCLEXTA have not been established in pediatric patients.

In a juvenile toxicology study, mice were administered venetoclax at 10, 30, or 100 mg/kg/day by oral gavage from 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/m 2 basis for a 20 kg child.

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.

Of the 406 patients with CLL/SLL evaluated for safety from VENCLEXTA in combination with rituximab or obinutuzumab, 67% (273/406) were ≥65 years of age and 24% (97/406) were ≥75 years of age.

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

Of patients that received

VENCLEXTA in combination with acalabrutinib in AMPLIFY, 33% (97/291) were ≥65 years of age, and 4.5% (13/291) were ≥75 years of age.

In patients 65 years of age or older and younger than age 65, the fatal adverse reactions were 5% and 2.6%, respectively.

No clinically relevant differences in efficacy were observed between patients ≥65 years of age and younger adults.

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.