Venclexta

Venetoclax.

VENCLEXTA tablets contain 10, 50, or 100 mg venetoclax as the active ingredient.
Venetoclax is a BCL-2 inhibitor. It is a light yellow to dark yellow solid with the empirical formula C₄₅H₅₀ClN₇O₇S and a molecular weight of 868.44. Venetoclax is described chemically as 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide).
Venetoclax has very low aqueous solubility.
Dosage Forms and Strengths: See Table 1.

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Excipients/Inactive Ingredients: Each tablet also contains the following inactive ingredients: copovidone, colloidal silicon dioxide, polysorbate 80, sodium stearyl fumarate, and calcium phosphate dibasic. In addition, the 10 mg and 100 mg coated tablets include the following: iron oxide yellow, polyvinyl alcohol, polyethylene glycol, talc, and titanium dioxide. The 50 mg coated tablets also include the following: iron oxide yellow, iron oxide red, iron oxide black, polyvinyl alcohol, talc, polyethylene glycol and titanium dioxide.

Pharmacology: Mechanism of Action: Venetoclax is a selective and orally bioavailable small-molecule inhibitor of BCL-2, an anti-apoptotic protein. Overexpression of BCL-2 has been demonstrated in CLL and AML cells where it mediates tumor cell survival and has been associated with resistance to chemotherapeutics. Venetoclax helps restore the process of apoptosis by binding directly to the BCL-2 protein, displacing pro-apoptotic proteins like BIM, triggering mitochondrial outer membrane permeabilization and the activation of caspases. In nonclinical studies, venetoclax has demonstrated cytotoxic activity in tumor cells that overexpress BCL-2.
Pharmacodynamics: Based on the exposure response analyses for efficacy, a relationship between drug exposure and a greater likelihood of response was observed in clinical studies in patients with CLL, and in patients with AML. Based on the exposure response analyses for safety, a relationship between drug exposure and a greater likelihood of some safety events was observed in clinical studies in patients with AML. No exposure-safety relationship was observed in patients with CLL at doses up to 1200 mg given as monotherapy and up to 600 mg given in combination with rituximab.
Cardiac Electrophysiology: The effect of multiple doses of VENCLEXTA up to 1200 mg once daily (2 times the maximum approved recommended dosage) on the QTc interval was evaluated in an open-label, single-arm trial in 176 patients with previously treated hematologic malignancies. VENCLEXTA had no large effect on QTc interval (i.e., >20 ms) and there was no relationship between venetoclax exposure and change in QTc interval.
Clinical Studies: Chronic Lymphocytic Leukemia: In Combination with Obinutuzumab: CLL14 (BO25323) was a randomized (1:1), multicenter, open-label, actively controlled trial (NCT02242942) that evaluated the efficacy and safety of VENCLEXTA in combination with obinutuzumab (VEN+G) versus obinutuzumab in combination with chlorambucil (GClb) for patients with previously untreated CLL with coexisting medical conditions (total Cumulative Illness Rating Scale [CIRS] score >6 or CLcr <70 mL/min). The trial required hepatic transaminases and total bilirubin ≤2 times upper limit of normal and excluded patients with Richter's transformation or any individual organ/system impairment score of 4 by CIRS except eye, ear, nose, and throat organ system.
All patients received obinutuzumab at 1000 mg on Days 1 (the first dose could be split as 100 mg and 900 mg on Days 1 and 2), 8 and 15 of Cycle 1, and on Day 1 of each subsequent cycle for a total of 6 cycles. Patients in the VEN+G arm began the VENCLEXTA 5-week ramp-up dosing schedule [see Recommended Dosage for Chronic Lymphocytic Leukemia and Risk Assessment and Prophylaxis for Tumor Lysis Syndrome under Dosage & Administration] on Day 22 of Cycle 1 and received VENCLEXTA 400 mg orally once daily from Cycle 3 Day 1 until the last day of Cycle 12. Patients randomized to the GClb arm received chlorambucil 0.5 mg/kg orally on Day 1 and Day 15 of Cycles 1 to 12. Each cycle was 28 days.
A total of 432 patients were randomized, 216 to each arm. Baseline demographic and disease characteristics were similar between the arms. The median age was 72 years (range: 41 to 89 years), 89% were White, 67% were male; 36% and 43% were Binet stage B and C, respectively, and 88% had Eastern Cooperative Oncology Group (ECOG) performance status <2. The median CIRS score was 8.0 (range: 0 to 28) and 58% of patients had CLcr <70 mL/min. A 17p deletion was detected in 8% of patients, TP53 mutations in 10%, 11q deletion in 19%, and unmutated IgVH in 57%.
Efficacy was based on progression-free survival (PFS) as assessed by an Independent Review Committee (IRC). The median duration of follow-up for PFS was 28 months (range: 0 to 36 months). Efficacy results for CLL14 are shown in Table 2. The Kaplan-Meier curve for PFS is shown in Figure 1. (See Table 2 and Figure 1.)

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At the time of analysis, median overall survival (OS) had not been reached, with fewer than 10% of patients experiencing an event. The median duration of follow-up for OS was 28 months.
Minimal residual disease (MRD) was evaluated using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The definition of negative status was less than one CLL cell per 10⁴ leukocytes. Rates of MRD negativity 3 months after the completion of treatment regardless of response and in patients who achieved CR are shown in Table 3. At this assessment, 134 patients in the VEN+G arm who were MRD negative in peripheral blood had matched bone marrow specimens; of these, 122 patients (91%) were MRD negative in both peripheral blood and bone marrow. (See Table 3.)

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Twelve months after the completion of treatment, MRD negativity rates in peripheral blood were 58% (126/216) in patients treated with VEN+G and 9% (20/216) in patients treated with GClb.
In Combination with Rituximab: MURANO was a randomized (1:1), multicenter, open-label trial (NCT02005471) that evaluated the efficacy and safety of VENCLEXTA in combination with rituximab (VEN+R) versus bendamustine in combination with rituximab (B+R) in patients with CLL who had received at least one line of prior therapy. Patients in the VEN+R arm completed the VENCLEXTA 5-week ramp-up dosing schedule [see Recommended Dosage for Chronic Lymphocytic Leukemia and Risk Assessment and Prophylaxis for Tumor Lysis Syndrome under Dosage & Administration] and received VENCLEXTA 400 mg orally once daily for 24 months from Cycle 1 Day 1 of rituximab in the absence of disease progression or unacceptable toxicity. Rituximab was initiated after the 5-week dose ramp-up at a dose of 375 mg/m² intravenously on Day 1 of Cycle 1 and 500 mg/m² intravenously on Day 1 of Cycles 2-6. Patients randomized to B+R received bendamustine 70 mg/m² intravenously on Days 1 and 2 for 6 cycles in combination with rituximab at the previously described dose and schedule. Each cycle was 28 days.
A total of 389 patients were randomized: 194 to the VEN+R arm and 195 to the B+R arm. Baseline demographic and disease characteristics were similar between the VEN+R and B+R arms. The median age was 65 years (range: 22 to 85 years), 97% were White, 74% were male, and 99% had ECOG performance status <2. Median prior lines of therapy was 1 (range: 1 to 5); 59% had received 1 prior therapy, 26% had received 2 prior therapies, and 16% had received 3 or more prior therapies. Prior therapies included alkylating agents (94%), anti-CD20 antibodies (77%), B-cell receptor pathway inhibitors (2%), and prior purine analogs (81%, including fludarabine/cyclophosphamide/rituximab in 55%). A 17p deletion was detected in 24% of patients, TP53 mutations in 25%, 11q deletion in 32%, and unmutated IgVH in 63%.
Efficacy was based on PFS as assessed by an IRC. The median follow-up for PFS was 23.4 months (range: 0 to 37.4+ months). Efficacy results for MURANO are shown in Table 4. The Kaplan-Meier curve for PFS is shown in Figure 2. (See Table 4 and Figure 2.)

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At 3 months after the last dose of rituximab, the MRD negativity rate in peripheral blood in patients who achieved PR or better was 54% (104/194) in the VEN+R arm and 12% (23/195) in the B+R arm. The MRD-negative CR/CRi rate at this timepoint was 3% (6/194) in the VEN+R arm and 2% (3/195) in the B+R arm.
71-Month Follow-Up: With an overall follow-up of 71 months, the investigator-assessed median PFS was 53.6 months (95% CI: 48.4, 57.0) in the VEN+R arm and 17.0 months (95% CI: 15.5, 21.7) in the B+R arm. Median OS had not been reached in either arm. Death occurred in 16% (32/194) of patients in the VEN+R arm and 33% (64/195) of patients in the B+R arm (stratified HR 0.40; 95% CI [0.26, 0.62]). The Kaplan-Meier curve for OS is shown in Figure 3. (See Figure 3.)

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Monotherapy: The efficacy of VENCLEXTA monotherapy in previously treated CLL is based on three single-arm trials.
M13-982: M13-982 (NCT01889186) was an open-label, multicenter trial that enrolled 106 patients with CLL with 17p deletion who had received at least one prior therapy. In the trial, 17p deletion was confirmed in peripheral blood specimens from patients using Vysis CLL FISH Probe Kit, which is FDA approved for selection of patients for VENCLEXTA treatment. Patients received VENCLEXTA 400 mg orally once daily following completion of the ramp-up dosing schedule [see Recommended Dosage for Chronic Lymphocytic Leukemia and Risk Assessment and Prophylaxis for Tumor Lysis Syndrome under Dosage & Administration].
Efficacy was based on overall response rate (ORR) as assessed by an IRC.
Table 5 summarizes the baseline demographic and disease characteristics of the trial population. (See Table 5.)

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The median time on treatment at the time of evaluation was 12.1 months (range: 0 to 21.5 months). Efficacy results are shown in Table 6. (See Table 6.)

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The median time to first response was 0.8 months (range: 0.1 to 8.1 months).
Based on a later data cutoff date and investigator-assessed efficacy, the duration of response (DOR) ranged from 2.9 to 32.8+ months. The median DOR has not been reached with median follow-up of 22 months.
Minimal residual disease was evaluated in peripheral blood and bone marrow for patients who achieved CR or CRi, following treatment with VENCLEXTA. Three percent (3/106) achieved MRD negativity in the peripheral blood and bone marrow (less than one CLL cell per 10⁴ leukocytes).
M12-175: M12-175 (NCT01328626) was an open-label, multicenter trial that enrolled previously treated patients with CLL, including those with 17p deletion. Efficacy was evaluated in 67 patients (59 with CLL) who had received VENCLEXTA 400 mg orally once daily following completion of a ramp-up dosing schedule. Patients continued this dose until disease progression or unacceptable toxicity. The median duration of treatment at the time of evaluation was 22.1 months (range: 0.5 to 71.7 months).
The median age was 65 years (range: 42 to 84 years), 78% were male and 87% were White. The median number of prior treatments was 3 (range: 1 to 11). At baseline, 67% of patients had one or more nodes ≥5 cm, 30% of patients had ALC ≥25 x 10⁹/L, 33% had documented unmutated IgVH, and 21% had documented 17p deletion.
Efficacy was based on 2008 IWCLL guidelines and assessed by an IRC. The ORR was 76% (95% CI: 64%, 86%), with a CR + CRi rate of 10% and PR rate of 66%. The median DOR was 36.2 months (range: 2.4 to 52.4 months).
M14-032: M14-032 (NCT02141282) was an open-label, multicenter trial that enrolled patients with CLL who had been previously treated with and progressed on or after ibrutinib or idelalisib. Patients received VENCLEXTA 400 mg orally once daily following completion of the ramp-up dosing schedule [see Recommended Dosage for Chronic Lymphocytic Leukemia and Risk Assessment and Prophylaxis for Tumor Lysis Syndrome under Dosage & Administration]. Patients continued this dose until disease progression or unacceptable toxicity. At the time of analysis, the median duration of treatment was 19.5 months (range: 0.1 to 39.5 months).
Of the 127 patients treated (91 with prior ibrutinib, 36 with prior idelalisib), the median age was 66 years (range: 28 to 85 years), 70% were male and 92% were White. The median number of prior treatments was 4 (range: 1 to 15). At baseline, 41% of patients had one or more nodes ≥5 cm, 31% had an ALC ≥25 x 10⁹/L, 57% had documented unmutated IgVH, and 39% had documented 17p deletion.
Efficacy was based on 2008 IWCLL guidelines and was assessed by an IRC. The ORR was 70% (95% CI: 61%, 78%), with a CR + CRi rate of 5% and PR rate of 65%. The median DOR was not reached with a median follow-up time of 19.9 months (range: 2.9 to 36 months).
Acute Myeloid Leukemia: VENCLEXTA was studied in adult patients with newly diagnosed AML who were 75 years or older, or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline ECOG performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, CLcr <45 mL/min, or other comorbidity.
In Combination with Azacitidine or Decitabine: VIALE-A was a randomized (2:1), double-blind, placebo-controlled, multicenter trial (NCT02993523) that evaluated the efficacy and safety of VENCLEXTA in combination with azacitidine (VEN+AZA) versus placebo with azacitidine (PBO+AZA).
Patients received VENCLEXTA 400 mg orally once daily on Days 1-28 following completion of the ramp-up dosing schedule [see Recommended Dosage for Acute Myeloid Leukemia under Dosage & Administration] or placebo in combination with azacitidine 75 mg/m² either intravenously or subcutaneously on Days 1-7 of each 28-day cycle beginning on Cycle 1 Day 1. During the ramp-up, patients received TLS prophylaxis and were hospitalized for monitoring.
Once bone marrow assessment confirmed a remission, defined as less than 5% leukemia blasts with cytopenia following Cycle 1 treatment, VENCLEXTA or placebo was interrupted up to 14 days or until ANC ≥500/microliter and platelet count ≥50 × 10³/microliter. For patients with resistant disease at the end of Cycle 1, a bone marrow assessment was performed after Cycle 2 or 3 and as clinically indicated. Azacitidine was resumed on the same day as VENCLEXTA or placebo following interruption. Azacitidine dose reduction was implemented in the clinical trial for management of hematologic toxicity [see Dosage Modifications for Adverse Reactions under Dosage & Administration]. Patients continued treatment until disease progression or unacceptable toxicity.
A total of 431 patients were randomized: 286 to the VEN+AZA arm and 145 to the PBO+AZA arm. The baseline demographic and disease characteristic are shown in Table 7. (See Table 7.)

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Efficacy was based on overall survival (OS), measured from the date of randomization to death from any cause. The combination of VEN+AZA was superior in OS to PBO+AZA.
The Kaplan-Meier curve for OS is shown in Figure 4. The efficacy results of VIALE-A are shown in Table 8. (See Figure 4 and Table 8.)

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Among the patients treated with VEN+AZA, 155 were dependent on red blood cell (RBC) and/or platelets transfusions at baseline; of these patients, 49% (76/155) became independent of RBC and platelet transfusions during any consecutive ≥56-day post-baseline period. Of the patients treated with VEN+AZA, 131 were independent of both RBC and platelet transfusions at baseline, 69% (90/131) remained transfusion independent during any consecutive ≥56-day post-baseline period. Among the patients treated with PBO+AZA, 81 were dependent on RBC and/or platelets transfusions at baseline; of these patients, 27% (22/81) patients became independent of RBC and platelet transfusions during any consecutive ≥56-day post-baseline period. Of the patients treated with PBO+AZA, 64 were independent of both RBC and platelet transfusions at baseline, 42% (27/64) remained transfusion independent during any consecutive ≥56-day post-baseline period.
The median time to first response of CR or CRh was 1.0 months (range: 0.6 to 14.3 months) with VEN+AZA treatment.
M14-358: M14-358 (NCT02203773) was a non-randomized, open-label trial that evaluated the efficacy of VENCLEXTA in combination with azacitidine (N=84) or decitabine (N=31) in patients with newly diagnosed AML. Of those patients, 67 who received azacitidine combination and 13 who received decitabine combination were 75 years or older, or had comorbidities that precluded the use of intensive induction chemotherapy.
Patients received VENCLEXTA 400 mg orally once daily following completion of the ramp-up dosing schedule [see Recommended Dosage for Acute Myeloid Leukemia under Dosage & Administration] in combination with azacitidine (75 mg/m² either intravenously or subcutaneously on Days 1-7 of each 28-day cycle beginning on Cycle 1 Day 1) or decitabine (20 mg/m² intravenously on Days 1-5 of each 28-day cycle beginning on Cycle 1 Day 1). During the ramp-up phase, patients received TLS prophylaxis and were hospitalized for monitoring. Patients continued treatment until disease progression or unacceptable toxicity. Once bone marrow assessment confirmed a remission, defined as less than 5% leukemia blasts, with cytopenia following Cycle 1 treatment, VENCLEXTA was interrupted up to 14 days or until ANC ≥500/microliter and platelet count ≥50 × 10³/microliter. Azacitidine dose reduction was implemented in the clinical trial for management of hematologic toxicity [see Dosage Modifications for Adverse Reactions under Dosage & Administration]. Dose reductions for decitabine were not implemented in the clinical trial. Baseline demographic and disease characteristic are shown in Table 9. (See Table 9.)

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The efficacy results are shown in Table 10. (See Table 10.)

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The median follow-up was 15.9 months (range: 0.4 to 40.3 months) for VENCLEXTA in combination with azacitidine. The median duration of CR was 23.8 months (95% CI: 15.4, -), and the median duration of CR+CRh was 26.5 months (95% CI: 17.4, -).
The median follow-up was 11.0 months (range: 0.7 to 38.8 months) for VENCLEXTA in combination with decitabine. The median duration of CR was 12.7 months (95% CI: 1.4, -) and median duration of CR+CRh was 12.7 months (95% CI: 1.4, 20.0). Duration of CR is defined as time from the first documentation of CR to the first date of relapse, clinical disease progression or death due to disease progression, whichever occurred earliest. Duration of CR+CRh is defined as time from the first documentation of either CR or CRh to the first date of relapse, clinical disease progression or death due to disease progression, whichever occurred earliest.
Median time to first CR or CRh for patients treated with VENCLEXTA in combination with azacitidine was 1.0 month (range: 0.7 to 8.9 months).
Median time to first CR or CRh for patients treated with VENCLEXTA in combination with decitabine was 1.9 months (range: 0.8 to 4.2 months).
Of patients treated with VENCLEXTA in combination with azacitidine, 12% (8/67) subsequently received stem cell transplant.
The trial enrolled 35 additional patients (age range: 65 to 74 years) who did not have known comorbidities that precluded the use of intensive induction chemotherapy and were treated with VENCLEXTA in combination with azacitidine (N=17) or decitabine (N=18).
For the 17 patients treated with VENCLEXTA in combination with azacitidine, the CR rate was 35% (95% CI: 14%, 62%). The CRh rate was 41% (95% CI: 18%, 67%). Nine (53%) patients subsequently received stem cell transplant.
For the 18 patients treated with VENCLEXTA in combination with decitabine, the CR rate was 56% (95% CI: 31%, 79%). The CRh rate was 22% (95% CI: 6.4%, 48%). Four (22%) patients subsequently received stem cell transplant.
In Combination with Low-Dose Cytarabine: VIALE-C was a randomized (2:1), double-blind, placebo-controlled, multicenter trial (NCT03069352) that evaluated the efficacy and safety of VENCLEXTA in combination with low-dose cytarabine (VEN+LDAC) versus placebo with low-dose cytarabine (PBO+LDAC).
Patients received VENCLEXTA 600 mg orally once daily on Days 1-28 following completion of the ramp-up dosing schedule [see Recommended Dosage for Acute Myeloid Leukemia under Dosage & Administration] or placebo in combination with cytarabine 20 mg/m² subcutaneously once daily on Days 1-10 of each 28-day cycle beginning on Cycle 1 Day 1. During the ramp-up phase, patients received TLS prophylaxis and were hospitalized for monitoring.
Once bone marrow assessment confirmed a remission, defined as less than 5% leukemia blasts with cytopenia following Cycle 1 treatment, VENCLEXTA or placebo was interrupted up to 14 days or until ANC ≥500/microliter and platelet count ≥50 × 10³/microliter. For patients with resistant disease at the end of Cycle 1, a bone marrow assessment was performed after Cycle 2 or 3 and as clinically indicated. LDAC was resumed on the same day as VENCLEXTA or placebo following interruption. Patients continued to receive treatment until disease progression or unacceptable toxicity. Baseline demographic and disease characteristic are shown in Table 11. (See Table 11.)

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Efficacy was based on the rate of CR and duration of CR with supportive evidence of rate of CR+CRh, duration of CR+CRh, and the rate of conversion from transfusion dependence to transfusion independence. The CR rate in the VEN+LDAC arm was 27% (95% CI: 20%, 35%) with a median duration of CR of 11.1 months (95% CI: 6.1, -), and the CR rate in the PBO+LDAC arm was 7.4% (95% CI: 2.4%, 16%) with a median duration of CR of 8.3 months (95% CI: 3.1, -). The CR+CRh rate in the VEN+LDAC arm was 47% (95% CI: 39%, 55%) and in the PBO+LDAC arm was 15% (95% CI: 7.3%, 25%) with a median duration of CR+CRh of 11.1 months with VEN+LDAC treatment and 6.2 months with PBO+LDAC treatment. The median time to first response of CR or CRh was 1.0 month (range: 0.7 to 5.8 months) with VEN+LDAC treatment.
Among the patients treated with VEN+LDAC, 111 were dependent on RBC and/or platelets transfusions at baseline; of these patients, 33% (37/111) patients became independent of RBC and platelet transfusions during any consecutive ≥56-day post-baseline period. Of the patients treated with VEN+LDAC, 32 were independent of both RBC and platelet transfusions at baseline, 50% (16/32) remained transfusion independent during any consecutive ≥56-day post-baseline period.
Among the patients treated with PBO+LDAC, 55 were dependent on RBC and/or platelets transfusions at baseline; of these patients, 13% (7/55) patients became independent of RBC and platelet transfusions during any consecutive ≥56-day post-baseline period. Of the patients treated with PBO+LDAC, 13 were independent of both RBC and platelet transfusions at baseline, 31% (4/13) remained transfusion independent during any consecutive ≥56-day post-baseline period.
VEN+LDAC did not significantly improve OS versus PBO+LDAC. The hazard ratio (HR) for OS was 0.75 (95% CI: 0.52, 1.07); p-value 0.114. The median OS for VEN+LDAC arm was 7.2 months (95% CI: 5.6, 10.1) and for PBO+LDAC arm was 4.1 months (95% CI: 3.1, 8.8).
M14-387: M14-387 (NCT02287233) was a non-randomized, open-label trial that evaluated the efficacy of VEN+LDAC (N=82) in patients with newly diagnosed AML, including patients with previous exposure to a hypomethylating agent for an antecedent hematologic disorder. Of those patients, 61 were 75 years or older, or had comorbidities that precluded the use of intensive induction chemotherapy.
Patients received VENCLEXTA 600 mg orally once daily on Days 1-28 following completion of the ramp-up phase [see Recommended Dosage for Acute Myeloid Leukemia under Dosage & Administration] in combination with cytarabine 20 mg/m² subcutaneously once daily on Days 1-10 of each 28-day cycle beginning on Cycle 1 Day 1. During the ramp-up, patients received TLS prophylaxis and were hospitalized for monitoring. Once bone marrow assessment confirmed a remission, defined as less than 5% leukemia blasts with cytopenia following Cycle 1 treatment, VENCLEXTA was interrupted up to 14 days or until ANC ≥500/microliter and platelet count ≥50 × 10³/microliter. Patients continued treatment until disease progression or unacceptable toxicity. Baseline demographic and disease characteristic are shown in Table 12. (See Table 12.)

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The median follow-up was 7.3 months (range: 0.3 to 54.0 months). The CR rate was 21% (95% CI: 12, 34) and CRh rate was 21% (95% CI: 12, 34).
The median duration of CR was 22.9 months (95% CI: 5.1, -) and the median duration of CR+CRh was 14.3 months (95% CI: 6.1, 31.2).
Median time to first CR or CRh for patients treated with VEN+LDAC was 1.0 month (range: 0.8 to 9.4 months).
The trial enrolled 21 additional patients (age range: 67 to 74 years) who did not have known comorbidities that precluded the use of intensive induction chemotherapy and were treated with VEN+LDAC. The CR rate was 33% (95% CI: 15%, 57%). The CRh rate was 24% (95% CI: 8.2%, 47%). One patient (4.8%) subsequently received stem cell transplant.
Pharmacokinetics: Venetoclax mean (± standard deviation) steady state C_max was 2.1 ± 1.1 mcg/mL and AUC_0-24h was 32.8 ± 16.9 mcg·h/mL following administration of 400 mg once daily with a low-fat meal. Venetoclax steady state AUC increased proportionally over the dose range of 150 to 800 mg (0.25 to 1.33 times the maximum approved recommended dosage). The pharmacokinetics of venetoclax does not change over time.
Absorption: Maximum plasma concentration of venetoclax was reached 5 to 8 hours following multiple oral administration under fed conditions.
Effect of Food: Administration with a low-fat meal (approximately 512 kilocalories, 25% fat calories, 60% carbohydrate calories, and 15% protein calories) increased venetoclax exposure by approximately 3.4-fold and administration with a high-fat meal (approximately 753 kilocalories, 55% fat calories, 28% carbohydrate calories, and 17% protein calories) increased venetoclax exposure by 5.1- to 5.3-fold compared with fasting conditions.
Distribution: Venetoclax is highly bound to human plasma protein with unbound fraction in plasma <0.01 across a concentration range of 1-30 micromolar (0.87-26 mcg/mL). The mean blood-to-plasma ratio was 0.57. The apparent volume of distribution (Vd_ss/F) of venetoclax ranged from 256-321 L in patients.
Elimination: The terminal elimination half-life of venetoclax was approximately 26 hours.
Metabolism: Venetoclax is predominantly metabolized by CYP3A in vitro. The major metabolite identified in plasma, M27, has an inhibitory activity against BCL-2 that is at least 58-fold lower than venetoclax in vitro and its AUC represented 80% of the parent AUC.
Excretion: After single oral dose of radiolabeled [¹⁴C]-venetoclax 200 mg to healthy subjects, >99.9% of the dose was recovered in feces (21% as unchanged) and <0.1% in urine within 9 days.
Specific Populations: No clinically significant differences in the pharmacokinetics of venetoclax were observed based on age (19 to 93 years), sex, weight, mild to severe renal impairment (CLcr 15 to 89 mL/min, calculated by Cockcroft-Gault), or mild to moderate hepatic impairment (normal total bilirubin and aspartate transaminase (AST) > upper limit of normal (ULN) or total bilirubin 1 to 3 times ULN). The effect of end-stage renal disease (CLcr <15 mL/min) or dialysis on venetoclax pharmacokinetics is unknown.
Racial or Ethnic Groups: No clinically significant differences in the pharmacokinetics of venetoclax were observed in White, Black, and Asian patients enrolled in the United States. Of 771 patients with AML, Asian patients from Asian countries [China (5.6%), Japan (5.5%), South Korea (2.1%), and Taiwan (0.9%)] had 63% higher venetoclax exposure than non-Asian populations.
Patients with Hepatic Impairment: Following a single dose of VENCLEXTA 50 mg, venetoclax systemic exposure (AUC_0-INF) was 2.7-fold higher in subjects with severe hepatic impairment (Child-Pugh C) compared to subjects with normal hepatic function [see Dosage Modifications for Patients with Severe Hepatic Impairment under Dosage & Administration; Hepatic Impairment under Precautions]. No clinically relevant differences in venetoclax systemic exposure were observed between subjects with mild or moderate hepatic impairment and subjects with normal hepatic function.
Drug Interactions Studies: Clinical Studies: No clinically significant differences in venetoclax pharmacokinetics were observed when coadministered with azacitidine, azithromycin, cytarabine, decitabine, gastric acid reducing agents, obinutuzumab, or rituximab.
Ketoconazole: Concomitant use of ketoconazole (a strong CYP3A, P-gp, and BCRP inhibitor) 400 mg once daily for 7 days increased venetoclax C_max by 130% and AUC_0-INF by 540% [see Effects of Other Drugs on VENCLEXTA under Interactions].
Ritonavir: Concomitant use of ritonavir (a strong CYP3A, P-gp, and OATP1B1/B3 inhibitor) 50 mg once daily for 14 days increased venetoclax C_max by 140% and AUC by 690% [see Effects of Other Drugs on VENCLEXTA under Interactions].
Posaconazole: Concomitant use of posaconazole (a strong CYP3A and P-gp inhibitor) 300 mg with VENCLEXTA 50 mg and 100 mg for 7 days resulted in 61% and 86% higher venetoclax C_max, respectively, compared with VENCLEXTA 400 mg administered alone. The venetoclax AUC_0-24h was 90% and 144% higher, respectively [see Effects of Other Drugs on VENCLEXTA under Interactions].
Rifampin: Concomitant use of a single dose of rifampin (an OATP1B1/1B3 and P-gp inhibitor) 600 mg increased venetoclax C_max by 106% and AUC_0-INF by 78%. Concomitant use of multiple doses of rifampin (as a strong CYP3A inducer) 600 mg once daily for 13 days decreased venetoclax C_max by 42% and AUC_0-INF by 71% [see Effects of Other Drugs on VENCLEXTA under Interactions].
Warfarin: Concomitant use of a single 400 mg dose of VENCLEXTA with 5 mg of warfarin resulted in 18% to 28% increase in C_max and AUC_0-INF of R-warfarin and S-warfarin [see Effect of VENCLEXTA on Other Drugs under Interactions].
Digoxin: Concomitant use of a single dose of VENCLEXTA 100 mg with digoxin (a P-gp substrate) 0.5 mg increased digoxin C_max by 35% and AUC_0-INF by 9% [see Effect of VENCLEXTA on Other Drugs under Interactions].
In Vitro Studies: Venetoclax is not an inhibitor or inducer of CYP1A2, CYP2B6, CYP2C19, CYP2D6, or CYP3A4. Venetoclax is a weak inhibitor of CYP2C8, CYP2C9, and UGT1A1.
Venetoclax is not an inhibitor of UGT1A4, UGT1A6, UGT1A9, or UGT2B7.
Venetoclax is an inhibitor and substrate of P-gp and BCRP and weak inhibitor of OATP1B1.
Venetoclax is not an inhibitor of OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, or MATE2K.
Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Neither venetoclax nor M27, a major human metabolite, were carcinogenic in a 6-month transgenic (Tg.rasH2) mouse study at oral doses up to 400 mg/kg/day of venetoclax, and at a single oral dose level of 250 mg/kg/day of M27.
Venetoclax was not mutagenic in an in vitro bacterial mutagenicity (Ames) assay, did not induce numerical or structural aberrations in an in vitro chromosome aberration assay using human peripheral blood lymphocytes, and 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 in in vitro Ames and chromosome aberration assays.
Fertility and early embryonic development studies were conducted in male and female mice. These studies evaluate mating, fertilization, and embryonic development through implantation. There were no effects of venetoclax on estrous cycles, mating, fertility, corpora lutea, uterine implants or live embryos per litter at dosages up to 600 mg/kg/day. However, a risk to human male fertility exists based on testicular toxicity (germ cell loss) observed in dogs at exposures as low as 0.5 times the human AUC exposure at a dose of 400 mg.
Animal Toxicology and/or Pharmacology: In dogs, venetoclax caused single-cell necrosis in various tissues, including the gallbladder, exocrine pancreas, and stomach with no evidence of disruption of tissue integrity or organ dysfunction; these findings were minimal to mild in magnitude. Following a 4-week dosing period and subsequent 4-week recovery period, minimal single-cell necrosis was still present in some tissues and reversibility has not been assessed following longer periods of dosing or recovery.
In addition, after approximately 3 months of daily dosing in dogs, venetoclax caused progressive white discoloration of the hair coat due to loss of melanin pigment.

Chronic Lymphocytic Leukemia: VENCLEXTA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL).
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.

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 Risk Assessment and Prophylaxis for Tumor Lysis Syndrome as follows; Tumor Lysis Syndrome under Precautions].
Recommended Dosage for Chronic Lymphocytic Leukemia: 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 13. (See Table 13.)

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The blister 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 Presentation].
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 13). 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 13) 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 13). Continue VENCLEXTA until disease progression or unacceptable toxicity.
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 14. 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. (See Table 14.)

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Continue VENCLEXTA, in combination with azacitidine or decitabine or low-dose cytarabine, until disease progression or unacceptable toxicity.
Refer to Pharmacology: Pharmacodynamics: Clinical Studies: Acute Myeloid Leukemia under Actions and Prescribing Information for azacitidine, decitabine, or cytarabine for additional dosing information.
Risk Assessment and Prophylaxis for Tumor Lysis Syndrome: Patients treated with VENCLEXTA may develop tumor lysis syndrome (TLS). Refer to the appropriate section as follows 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: 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 16 and Table 17 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 Tumor Lysis Syndrome and Renal Impairment under Precautions].
Table 15 as follows 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. (See Table 15.)

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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.
Dosage Modifications for Adverse Reactions: Chronic Lymphocytic Leukemia: The recommended dosage modifications for VENCLEXTA for adverse reactions are provided in Table 16 and the recommended dose reductions for VENCLEXTA for adverse reactions are provided in Table 17.
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 Recommended Dosage for Chronic Lymphocytic Leukemia and Risk Assessment and Prophylaxis for Tumor Lysis Syndrome as previously mentioned]. (See Tables 16 and 17.)

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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 18. (See Table 18.)

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Dosage Modifications for Drug Interactions: Strong or Moderate CYP3A Inhibitors or P-gp Inhibitors: Table 19 describes VENCLEXTA contraindication or dosage modification based on concomitant use with a strong or moderate CYP3A inhibitor or a P-gp inhibitor [see Effects of Other Drugs on VENCLEXTA under Interactions] 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 Effects of Other Drugs on VENCLEXTA under Interactions]. (See Table 19.)

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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 Hepatic Impairment under Precautions].
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.

There is no specific antidote for VENCLEXTA. For patients who experience overdose, closely monitor and provide appropriate supportive treatment; during ramp-up phase interrupt VENCLEXTA and monitor carefully for signs and symptoms of TLS along with other toxicities [see Recommended Dosage for Chronic Lymphocytic Leukemia, Recommended Dosage for Acute Myeloid Leukemia, Risk Assessment and Prophylaxis for Tumor Lysis Syndrome, and Dosage Modifications for Adverse Reactions under Dosage & Administration]. Based on venetoclax large volume of distribution and extensive protein binding, dialysis is unlikely to result in significant removal of venetoclax.

Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation and during the ramp-up phase is contraindicated in patients with CLL due to the potential for increased risk of tumor lysis syndrome [see Dosage Modifications for Drug Interactions under Dosage & Administration; Effects of Other Drugs on VENCLEXTA under Interactions].

Tumor Lysis Syndrome: Tumor lysis syndrome (TLS), including fatal events and renal failure requiring dialysis, has occurred in patients treated with VENCLEXTA [see Clinical Trials Experience under Adverse Reactions].
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. 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 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 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, the TLS rate was 13% and included deaths and renal failure [see Clinical Trials Experience under Adverse Reactions].
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 Clinical Trials Experience under Adverse Reactions].
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.
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 Renal Impairment as follows; Important Safety Information, Recommended Dosage for Chronic Lymphocytic Leukemia, Recommended Dosage for Acute Myeloid Leukemia, and Risk Assessment and Prophylaxis for Tumor Lysis Syndrome under Dosage & Administration].
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, coadministration of VENCLEXTA with strong CYP3A inhibitors at initiation and during the 5-week ramp-up phase is contraindicated [see Contraindications]. 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 or AML, reduce the dose of VENCLEXTA when coadministered with moderate CYP3A4 inhibitors or P-gp inhibitors [see Dosage Modifications for Drug Interactions under Dosage & Administration; Effects of Other Drugs on VENCLEXTA under Interactions].
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 Clinical Trials Experience under Adverse Reactions].
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 16 for CLL and Table 18 for AML [see Dosage Modifications for Adverse Reactions under Dosage & Administration]. Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF).
Infections: Fatal and serious infections, such as pneumonia and sepsis, have occurred in patients treated with VENCLEXTA [see Clinical Trials Experience under Adverse Reactions].
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 16 for CLL and Table 18 for AML [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
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.
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 at least 30 days after the last dose [see Pregnancy and Females and Males of Reproductive Potential under Use in Pregnancy & Lactation].
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.
Renal Impairment: Due to the increased risk of TLS, patients with reduced renal function (CLcr <80 mL/min, calculated by Cockcroft-Gault formula) require more intensive prophylaxis and monitoring to reduce the risk of TLS when initiating treatment with VENCLEXTA [see Tumor Lysis Syndrome as previously mentioned; Important Safety Information, Recommended Dosage for Chronic Lymphocytic Leukemia, Recommended Dosage for Acute Myeloid Leukemia, and Risk Assessment and Prophylaxis for Tumor Lysis Syndrome under Dosage & Administration].
No dose adjustment is recommended for patients with mild, moderate or severe renal impairment (CLcr ≥15 mL/min) [see Pharmacology: Pharmacokinetics under Actions].
Hepatic Impairment: No dose adjustment is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.
Reduce the dose of VENCLEXTA for patients with severe hepatic impairment (Child-Pugh C); monitor these patients more frequently for adverse reactions [see Dosage Modifications for Adverse Reactions and Dosage Modifications for Patients with Severe Hepatic Impairment under Dosage & Administration; Pharmacology: Pharmacokinetics under Actions].
Use in Children: The safety and effectiveness of VENCLEXTA have not been established in pediatric patients.
Juvenile Animal Toxicity Data: In a juvenile toxicology study, mice were administered venetoclax at 10, 30, or 100 mg/kg/day by oral gavage from 7 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/m² basis for a 20 kg child.
Use in the Elderly: Chronic Lymphocytic Leukemia: Of the 352 patients with previously treated CLL 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. No clinically meaningful differences in safety and effectiveness were observed between older and younger patients in the combination and monotherapy studies.
Acute Myeloid Leukemia: 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.

Pregnancy: Risk Summary: Based on findings in animals and its mechanism of action [see Pharmacology: Mechanism of Action under Actions], 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.
Lactation: Risk Summary: There are no data on the presence of VENCLEXTA in human milk or the effects on the breastfed child or milk production. Venetoclax was present in the milk when administered to lactating rats (see Data as follows).
Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with VENCLEXTA and for 1 week after the last dose.
Data: Animal Data: Venetoclax was administered (single dose; 150 mg/kg oral) to lactating rats 8 to 10 days post-parturition. Venetoclax in milk was 1.6 times lower than in plasma. Parent drug (venetoclax) represented the majority of the total drug-related material in milk, with trace levels of three metabolites.
Females and Males of Reproductive Potential: VENCLEXTA may cause fetal harm when administered to pregnant women [see Pregnancy as previously mentioned].
Pregnancy Testing: Verify pregnancy status in females of reproductive potential prior to initiating VENCLEXTA.
Contraception: Advise females of reproductive potential to use effective contraception during treatment with VENCLEXTA and for at least 30 days after the last dose.
Infertility: Based on findings in animals, VENCLEXTA may impair male fertility [see Pharmacology: Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility under Actions].

The following clinically significant adverse reactions are described in Precautions: Tumor Lysis Syndrome; Neutropenia; Infections.
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, 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 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: 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 Pharmacology: Pharmacodynamics: Clinical Studies: Chronic Lymphocytic Leukemia under Actions]. 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.
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 20 presents adverse reactions identified in CLL14. (See Table 20.)

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Other clinically important adverse reactions (All Grades) reported in <10% of patients treated with VEN+G are presented as follows: Blood and lymphatic system disorders: febrile neutropenia (6%).
Infection and infestations (all include multiple adverse reaction terms): pneumonia (9%), urinary tract infection (6%), sepsis (4%).
Metabolism and nutrition disorder: tumor lysis syndrome (1%).
During treatment with VENCLEXTA monotherapy after completion of VEN+G, the adverse reaction that occurred in ≥10% of patients was neutropenia (26%). The grade ≥3 adverse reactions that occurred in ≥2% of patients were neutropenia (23%) and anemia (2%).
Table 21 presents laboratory abnormalities CLL14. (See Table 21.)

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Grade 4 laboratory abnormalities that developed in ≥2% of patients treated with VEN+G included neutropenia (32%), leukopenia and lymphopenia (10%), thrombocytopenia (8%), hypocalcemia (8%), hyperuricemia (7%), blood creatinine increased (3%), hypercalcemia (3%), and hypokalemia (2%).
VENCLEXTA in Combination with Rituximab: The safety of VENCLEXTA in combination with rituximab (VEN+R) (N=194) versus bendamustine in combination with rituximab (B+R) (N=188) was evaluated in MURANO [see Pharmacology: Pharmacodynamics: Clinical Studies: Chronic Lymphocytic Leukemia under Actions]. Patients randomized to VEN+R completed the scheduled ramp-up (5 weeks) and received VENCLEXTA 400 mg once daily, in combination with rituximab for 6 cycles followed by VENCLEXTA monotherapy, for a total of 24 months after ramp-up. At the time of analysis, the median duration of exposure to VENCLEXTA was 22 months and the median number of cycles of rituximab was 6 in the VEN+R arm.
Serious adverse reactions were reported in 46% of patients in the VEN+R arm, with most frequent (≥5%) being pneumonia (9%). Fatal adverse reactions that occurred in the absence of disease progression and within 30 days of the last VENCLEXTA treatment and/or 90 days of last rituximab were reported in 2% (4/194) of patients.
In the VEN+R arm, adverse reactions led to treatment discontinuation in 16% of patients, dose reduction in 15%, and dose interruption in 71%. Neutropenia and thrombocytopenia each led to discontinuation of VENCLEXTA in 3% of patients. Neutropenia led to dose interruption of VENCLEXTA in 46% of patients.
Table 22 presents adverse reactions identified in MURANO. (See Table 22.)

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Other clinically important adverse reactions (All Grades) reported in <10% of patients treated with VEN+R are presented as follows: Blood and lymphatic system disorders: febrile neutropenia (4%).
Gastrointestinal disorders: vomiting (8%).
Infections and infestations: sepsis (<1%).
Metabolism and nutrition disorders: tumor lysis syndrome (3%).
During treatment with VENCLEXTA monotherapy after completion of VEN+R combination treatment, adverse reactions that occurred in ≥10% of patients were upper respiratory tract infection (21%), diarrhea (19%), neutropenia (16%), and lower respiratory tract infections (11%). The Grade 3 or 4 adverse reactions that occurred in ≥2% of patients were neutropenia (12%) and anemia (3%).
Table 23 presents laboratory abnormalities identified in MURANO. (See Table 23.)

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Grade 4 laboratory abnormalities that developed in ≥2% of patients treated with VEN+R included neutropenia (31%), lymphopenia (16%), leukopenia (6%), thrombocytopenia (6%), hyperuricemia (4%), hypocalcemia (2%), hypoglycemia (2%), and hypermagnesemia (2%).
VENCLEXTA as Monotherapy: The safety of VENCLEXTA was evaluated in pooled data from three single-arm trials (M13-982, M14-032, and M12-175). Patients received VENCLEXTA 400 mg orally once daily after completing the ramp-up phase (N=352). The median duration of treatment with VENCLEXTA at the time of data analysis was 14.5 months (range: 0 to 50 months). Fifty-two percent of patients received VENCLEXTA for more than 60 weeks.
In the pooled dataset, the median age was 66 years (range: 28 to 85 years), 93% were White, and 68% were male. The median number of prior therapies was 3 (range: 0 to 15).
Serious adverse reactions were reported in 52% of patients, with the most frequent (≥5%) being pneumonia (9%), febrile neutropenia (5%), and sepsis (5%). Fatal adverse reactions that occurred in the absence of disease progression and within 30 days of venetoclax treatment were reported in 2% of patients in the VENCLEXTA monotherapy studies, most often (2 patients) from septic shock.
Adverse reactions led to treatment discontinuation in 9% of patients, dose reduction in 13%, and dose interruption in 36%. The most frequent adverse reactions leading to drug discontinuation were thrombocytopenia and autoimmune hemolytic anemia. The most frequent adverse reaction (≥5%) leading to dose reductions or interruptions was neutropenia (8%).
Table 24 presents adverse reactions identified in these trials. (See Table 24.)

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Table 25 presents laboratory abnormalities reported throughout treatment that were new or worsening from baseline. The most common (>5%) Grade 4 laboratory abnormalities observed with VENCLEXTA monotherapy were hematologic laboratory abnormalities, including neutropenia (33%), leukopenia (11%), thrombocytopenia (15%), and lymphopenia (9%). (See Table 25.)

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Important Adverse Reactions in CLL: Tumor Lysis Syndrome: Tumor lysis syndrome is an important identified risk when initiating VENCLEXTA.
CLL14: The incidence of TLS was 1% (3/212) in patients treated with VEN+G [see Tumor Lysis Syndrome under Precautions]. All three events of TLS resolved and did not lead to withdrawal from the trial. Obinutuzumab administration was delayed in two cases in response to the TLS events.
MURANO: The incidence of TLS was 3% (6/194) in patients treated with VEN+R. After 77/389 patients were enrolled in the trial, the protocol was amended to incorporate the current TLS prophylaxis and monitoring measures described in Recommended Dosage for Chronic Lymphocytic Leukemia and Risk Assessment and Prophylaxis for Tumor Lysis Syndrome under Dosage & Administration. All events of TLS occurred during the VENCLEXTA ramp-up period and were resolved within two days. All six patients completed the ramp-up and reached the recommended daily dose of 400 mg of VENCLEXTA. No clinical TLS was observed in patients who followed the current 5-week ramp-up schedule and TLS prophylaxis and monitoring measures [see Recommended Dosage for Chronic Lymphocytic Leukemia and Risk Assessment and Prophylaxis for Tumor Lysis Syndrome under Dosage & Administration]. Rates of laboratory abnormalities relevant to TLS for patients treated with VEN+R are presented in Table 23.
Monotherapy Studies (M13-982 and M14-032): In 168 patients with CLL treated according to recommendations described in Important Safety Information and Recommended Dosage for Chronic Lymphocytic Leukemia under Dosage & Administration, the rate of TLS was 2% [see Recommended Dosage for Chronic Lymphocytic Leukemia and Risk Assessment and Prophylaxis for Tumor Lysis Syndrome under Dosage & Administration]. All events either met laboratory TLS criteria (laboratory abnormalities that met ≥2 of the following within 24 hours of each other: potassium >6 mmol/L, uric acid >476 µmol/L, calcium <1.75 mmol/L, or phosphorus >1.5 mmol/L), or were reported as TLS events. The events occurred in patients who had a lymph node(s) ≥5 cm and/or absolute lymphocyte count (ALC) ≥25 x 10⁹/L. All events resolved within 5 days. No TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures was observed in these patients. All patients had CLcr ≥50 mL/min. Laboratory abnormalities relevant to TLS were hyperkalemia (17% all Grades, 1% Grade ≥3), hyperphosphatemia (14% all Grades, 2% Grade ≥3), hypocalcemia (16% all Grades, 2% Grade ≥3), and hyperuricemia (10% all Grades, <1% Grade ≥3).
In the initial Phase 1 dose-finding trials, which had shorter (2-3 week) ramp-up phase and higher starting doses, the incidence of TLS was 13% (10/77; 5 laboratory TLS, 5 clinical TLS), including 2 fatal events and 3 events of acute renal failure, 1 requiring dialysis. After this experience, TLS risk assessment, dosing regimen, TLS prophylaxis and monitoring measures were revised [see Recommended Dosage for Chronic Lymphocytic Leukemia and Risk Assessment and Prophylaxis for Tumor Lysis Syndrome under Dosage & Administration].
Acute Myeloid Leukemia: VENCLEXTA in Combination with Azacitidine: The safety of VENCLEXTA in combination with azacitidine (VEN+AZA) (N=283) versus placebo in combination with azacitidine (PBO+AZA) (N=144) was evaluated in VIALE-A, a double-blind, randomized trial, in patients with newly diagnosed AML [see Pharmacology: Pharmacodynamics: Clinical Studies: Acute Myeloid Leukemia under Actions]. At baseline, patients were ≥75 years of age or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline ECOG performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, CLcr <45 mL/min, or other comorbidity. Patients were randomized to receive VENCLEXTA 400 mg orally once daily after completion of the ramp-up phase in combination with azacitidine (75 mg/m² either intravenously or subcutaneously on Days 1-7 of each 28-day cycle) or placebo in combination with azacitidine. Among patients who received VEN+AZA, the median duration of exposure to VENCLEXTA was 7.6 months (range: <0.1 to 30.7 months).
Serious adverse reactions were reported in 83% of patients who received VEN+AZA, with the most frequent (≥5%) being febrile neutropenia (30%), pneumonia (22%), sepsis (excluding fungal; 19%), and hemorrhage (6%). Fatal adverse reactions occurred in 23% of patients who received VEN+AZA, with the most frequent (≥2%) being pneumonia (4%), sepsis (excluding fungal; 3%), and hemorrhage (2%).
Adverse reactions led to permanent discontinuation of VENCLEXTA in 24% of patients, dose reductions in 2%, and dose interruptions in 72%. Adverse reactions which led to discontinuation of VENCLEXTA in ≥2% of patients were sepsis (excluding fungal; 3%) and pneumonia (2%). The most frequent adverse reaction leading to dose reduction was pneumonia (0.7%). Adverse reactions which required a dose interruption in ≥5% of patients included febrile neutropenia (20%), neutropenia (20%), pneumonia (14%), sepsis (excluding fungal; 11%), and thrombocytopenia (10%). Among patients who achieved bone marrow clearance of leukemia, 53% underwent dose interruptions for absolute neutrophil count (ANC) <500/microliter.
Table 26 presents adverse reactions identified in VIALE-A. (See Table 26.)

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Other clinically important adverse reactions (All Grades) at ≥10% that did not meet criteria for Table 26 or <10% are presented as follows: Hepatobiliary disorders: cholecystitis/cholelithiasis^a (4%).
Infections and infestations: pneumonia^b (33%).
Metabolism and nutrition disorders: tumor lysis syndrome (1%).
Nervous system disorders: headache^c (11%).
Investigations: weight decreased (13%).
^a Includes cholecystitis acute, cholelithiasis, cholecystitis, and cholecystitis chronic.
^b Includes pneumonia, lung infection, pneumonia fungal, pneumonia klebsiella, atypical pneumonia, lower respiratory tract infection, pneumonia viral, lower respiratory tract infection fungal, pneumonia hemophilus, pneumonia pneumococcal, and pneumonia respiratory syncytial viral.
^c Includes headache and tension headache.
Table 27 presents laboratory abnormalities identified in VIALE-A. (See Table 27.)

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VENCLEXTA in Combination with Azacitidine or Decitabine: The safety of VENCLEXTA in combination with azacitidine (N=67) or decitabine (N=13) was evaluated in M14-358, a non-randomized trial of patients with newly diagnosed AML. At baseline, patients were ≥75 years of age, or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline ECOG performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, CLcr <45 mL/min, or other comorbidity [see Pharmacology: Pharmacodynamics: Clinical Studies: Acute Myeloid Leukemia under Actions]. Patients received VENCLEXTA 400 mg orally once daily after completion of the ramp-up phase in combination with azacitidine (75 mg/m² either intravenously or subcutaneously on Days 1-7 of each 28-day cycle) or decitabine (20 mg/m² intravenously on Days 1-5 of each 28-day cycle).
Azacitidine: The median duration of exposure to VENCLEXTA when administered in combination with azacitidine was 6.5 months (range: 0.1 to 38.1 months). The safety of VENCLEXTA in combination with azacitidine in this trial is consistent with that of VIALE-A.
Decitabine: The median duration of exposure to VENCLEXTA when administered in combination with decitabine was 8.4 months (range: 0.5 to 39 months).
Serious adverse reactions were reported in 85% of patients who received VENCLEXTA with decitabine, the most frequent (≥10%) being sepsis (excluding fungal; 46%), febrile neutropenia (38%), and pneumonia (31%). One (8%) fatal adverse reaction of bacteremia occurred within 30 days of starting treatment.
Permanent discontinuation of VENCLEXTA due to adverse reactions occurred in 38% of patients. The most frequent adverse reaction leading to permanent discontinuation (≥5%) was pneumonia (8%).
Dosage reductions of VENCLEXTA due to adverse reactions occurred in 15% of patients. The most frequent adverse reaction leading to dose reduction (≥5%) was neutropenia (15%).
Dosage interruptions of VENCLEXTA due to adverse reactions occurred in 69% of patients. The most frequent adverse reactions leading to dose interruption (≥10%) were neutropenia (38%), febrile neutropenia (23%), leukopenia (15%), and pneumonia (15%).
The most common adverse reactions (≥30%) were febrile neutropenia (69%), fatigue (62%), constipation (62%), musculoskeletal pain (54%), dizziness (54%), nausea (54%), abdominal pain (46%), diarrhea (46%), pneumonia (46%), sepsis (excluding fungal; 46%), cough (38%), pyrexia (31%), hypotension (31%), oropharyngeal pain (31%), edema (31%), and vomiting (31%). The most common laboratory abnormalities (≥30%) were neutrophils decreased (100%), lymphocytes decreased (100%), white blood cells decreased (100%), platelets decreased (92%), calcium decreased (85%), hemoglobin decreased (69%), glucose increased (69%), magnesium decreased (54%), potassium decreased (46%), bilirubin increased (46%), albumin decreased (38%), alkaline phosphatase increased (38%), sodium decreased (38%), ALT increased (31%), creatinine increased (31%), and potassium increased (31%).
VENCLEXTA in Combination with Low-Dose Cytarabine: VIALE-C: The safety of VENCLEXTA in combination with low-dose cytarabine (VEN+LDAC) (N=142) versus placebo with low-dose cytarabine (PBO+LDAC) (N=68) was evaluated in VIALE-C, a double-blind randomized trial in patients with newly diagnosed AML. At baseline, patients were ≥75 years of age, or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline ECOG performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, CLcr <45 mL/min, or other comorbidity [see Pharmacology: Pharmacodynamics: Clinical Studies: Acute Myeloid Leukemia under Actions]. Patients were randomized to receive VENCLEXTA 600 mg orally once daily after completion of a 4-day ramp-up phase in combination with low-dose cytarabine (20 mg/m² subcutaneously once daily on Days 1-10 of each 28-day cycle) or placebo in combination with low-dose cytarabine. Among patients who received VEN+LDAC, the median duration of exposure to VENCLEXTA was 3.9 months (range: <0.1 to 17.1 months).
Serious adverse reactions were reported in 65% of patients who received VEN+LDAC, with the most frequent (≥10%) being pneumonia (17%), febrile neutropenia (16%), and sepsis (excluding fungal; 12%). Fatal adverse reactions occurred in 23% of patients who received VEN+LDAC, with the most frequent (≥5%) being pneumonia (6%) and sepsis (excluding fungal; 7%).
Adverse reactions led to permanent discontinuation of VENCLEXTA in 25% of patients, dose reductions in 9%, and dose interruptions in 63%. The most frequent adverse reaction (>2%) which resulted in permanent discontinuation of VENCLEXTA was pneumonia (6%). Adverse reactions which required a dose reduction in ≥1% of patients were pneumonia (1%) and thrombocytopenia (1%), and the adverse reactions which required a dose interruption in ≥5% of patients included neutropenia (20%), thrombocytopenia (15%), pneumonia (8%), febrile neutropenia (6%), and sepsis (excluding fungal; 6%). Among patients who achieved bone marrow clearance of leukemia, 32% underwent dose interruptions for ANC <500/microliter.
Table 28 presents adverse reactions identified in VIALE-C. (See Table 28.)

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Other clinically important adverse reactions (All Grades) at ≥10% that did not meet criteria for Table 28 or <10% are presented as follows: Hepatobiliary disorders: cholecystitis/cholelithiasis^a (1%).
Infections and infestations: sepsis^b (excluding fungal; 15%), urinary tract infection^c (8%).
Metabolism and nutrition disorders: decreased appetite (19%), tumor lysis syndrome (6%).
Nervous system disorders: dizziness^d (9%).
Respiratory, thoracic, and mediastinal disorders: dyspnea^e (10%).
Investigations: weight decreased (9%).
^a Includes cholecystitis and cholecystitis acute.
^b Includes sepsis, bacteremia, septic shock, neutropenic sepsis, staphylococcal bacteremia, streptococcal bacteremia, bacterial sepsis, escherichia bacteremia, pseudomonal bacteremia, and staphylococcal sepsis.
^c Includes urinary tract infection and escherichia urinary tract infection.
^d Includes dizziness and vertigo.
^e Includes dyspnea and dyspnea exertional.
Table 29 describes laboratory abnormalities identified in VIALE-C. (See Table 29.)

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M14-387: The safety of VENCLEXTA in combination with low-dose cytarabine (N=61) was evaluated in M14-387, a non-randomized, open-label trial of patients with newly diagnosed AML [see Pharmacology: Pharmacodynamics: Clinical Studies: Acute Myeloid Leukemia under Actions]. At baseline, patients were ≥75 years of age, or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline ECOG performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, CLcr <45 mL/min, or other comorbidity. Patients received VENCLEXTA 600 mg orally once daily after completion of the ramp-up phase in combination with low-dose cytarabine (20 mg/m² subcutaneously on Days 1-10 of each 28-day cycle). The safety of VENCLEXTA in combination with low-dose cytarabine is consistent with that of VIALE-C.

Effects of Other Drugs on VENCLEXTA: Strong or Moderate CYP3A Inhibitors or P-gp Inhibitors: Concomitant use with a strong or moderate CYP3A inhibitor or a P-gp inhibitor increases venetoclax C_max and AUC_0-INF [see Pharmacology: Pharmacokinetics under Actions], which may increase VENCLEXTA toxicities, including the risk of TLS [see Tumor Lysis Syndrome under Precautions].
Concomitant use with a strong CYP3A inhibitor at initiation and during the ramp-up phase in patients with CLL is contraindicated [see Contraindications].
In patients with CLL taking a steady daily dosage (after ramp-up phase), consider alternative medications or adjust VENCLEXTA dosage and monitor more frequently for adverse reactions [see Dosage Modifications for Adverse Reactions and Dosage Modifications for Drug Interactions under Dosage & Administration].
In patients with AML, adjust VENCLEXTA dosage and monitor more frequently for adverse reactions [see Dosage Modifications for Adverse Reactions and Dosage Modifications for Drug Interactions under Dosage & Administration].
Resume the VENCLEXTA dosage that was used prior to concomitant use with a strong or moderate CYP3A inhibitor or a P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor [see Dosage Modifications for Adverse Reactions and Dosage Modifications for Drug Interactions under Dosage & Administration].
Avoid grapefruit products, Seville oranges, and starfruit during treatment with VENCLEXTA, as they contain inhibitors of CYP3A.
Strong or Moderate CYP3A Inducers: Concomitant use with a strong CYP3A inducer decreases venetoclax C_max and AUC_0-INF [see Pharmacology: Pharmacokinetics under Actions], which may decrease VENCLEXTA efficacy. Avoid concomitant use of VENCLEXTA with strong CYP3A inducers or moderate CYP3A inducers.
Effect of VENCLEXTA on Other Drugs: Warfarin: Concomitant use of VENCLEXTA increases warfarin C_max and AUC_0-INF [see Pharmacology: Pharmacokinetics under Actions], which may increase the risk of bleeding. Monitor international normalized ratio (INR) more frequently in patients using warfarin concomitantly with VENCLEXTA.
P-gp Substrates: Concomitant use of VENCLEXTA increases C_max and AUC_0-INF of P-gp substrates [see Pharmacology: Pharmacokinetics under Actions], which may increase toxicities of these substrates. Avoid concomitant use of VENCLEXTA with a P-gp substrate. If a concomitant use is unavoidable, separate dosing of the P-gp substrate at least 6 hours before VENCLEXTA.

Store at or below 86°F (30°C).

Advise the patient to read the approved patient labeling (Medication Guide).
Tumor Lysis Syndrome: Advise patients of the potential risk of TLS, particularly at treatment initiation, during the ramp-up phase, and with resumption after an interruption and to immediately report any signs and symptoms associated with this event (fever, chills, nausea, vomiting, confusion, shortness of breath, seizure, irregular heartbeat, dark or cloudy urine, unusual tiredness, muscle pain, and/or joint discomfort) to their health care provider (HCP) for evaluation [see Tumor Lysis Syndrome under Precautions].
Advise patients to be adequately hydrated every day when taking VENCLEXTA to reduce the risk of TLS. The recommended volume is 6 to 8 glasses (approximately 56 ounces total) of water each day. Patients should drink water starting 2 days before and on the day of the first dose, and every time the dose is increased [see Risk Assessment and Prophylaxis for Tumor Lysis Syndrome under Dosage & Administration].
Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests [see Risk Assessment and Prophylaxis for Tumor Lysis Syndrome under Dosage & Administration].
Advise patients that it may be necessary to take VENCLEXTA in the hospital or medical office setting to allow monitoring for TLS.
Neutropenia: Advise patients to contact their HCP immediately if they develop a fever or any signs of infection. Advise patients of the need for periodic monitoring of blood counts [see Neutropenia under Precautions].
Infections: Advise patients to contact their HCP immediately if they develop a fever or any signs of infection [see Infections under Precautions].
Drug Interactions: Advise patients to avoid consuming grapefruit products, Seville oranges, or starfruit during treatment with VENCLEXTA. Advise patients that VENCLEXTA may interact with some drugs; therefore, advise patients to inform their health care provider of the use of any prescription medication, over-the-counter drugs, vitamins and herbal products [see Contraindications; Effects of Other Drugs on VENCLEXTA under Interactions].
Immunizations: Advise patients to avoid vaccination with live vaccines because they may not be safe or effective during treatment with VENCLEXTA [see Immunization under Precautions].
Embryo-Fetal Toxicity: Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Embryo-Fetal Toxicity under Precautions; Pregnancy under Use in Pregnancy & Lactation].
Advise female patients of reproductive potential to use effective contraception during therapy and for at least 30 days after the last dose [see Females and Males of Reproductive Potential under Use in Pregnancy & Lactation].
Lactation: Advise women not to breastfeed during treatment with VENCLEXTA and for 1 week after the last dose [see Lactation under Use in Pregnancy & Lactation].
Infertility: Advise males of reproductive potential that VENCLEXTA may impair fertility [see Females and Males of Reproductive Potential under Use in Pregnancy & Lactation].
Administration: Advise patients to take VENCLEXTA exactly as prescribed and not to change their dose or to stop taking VENCLEXTA unless they are told to do so by their HCP. Advise patients to take VENCLEXTA orally once daily, at approximately the same time each day, according to their HCP's instructions and that the tablets should be swallowed whole with a meal and water without being chewed, crushed, or broken [see Administration under Dosage & Administration].
Advise patients with CLL to keep VENCLEXTA in the original packaging during the first 4 weeks of treatment, and not to transfer the tablets to a different container.
Advise patients that if a dose of VENCLEXTA is missed by less than 8 hours, to take the missed dose right away and take the next dose as usual. If a dose of VENCLEXTA is missed by more than 8 hours, advise patients to wait and take the next dose at the usual time [see Administration under Dosage & Administration].
Advise patients not to take any additional dose that day if they vomit after taking VENCLEXTA, and to take the next dose at the usual time the following day.

Targeted Cancer Therapy

L01XX52 - venetoclax ; Belongs to the class of other antineoplastic agents. Used in the treatment of cancer.

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