Venetoclax, a selective inhibitor of B-cell lymphoma 2 (BCL-2), is an antineoplastic agent.1
Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma
Venetoclax is used as monotherapy or as a component of combination therapy for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).1, 2, 16, 17, 18, 19, 20, 21, 22, 23 Venetoclax has been designated an orphan drug by FDA for the treatment of these cancers.3 Venetoclax is generally recommended among first-line treatment options for symptomatic CLL.2000, 2001
Clinical Experience as Combination Therapy
Efficacy and safety of venetoclax in combination with obinutuzumab or in combination with rituximab for the treatment of CLL and SLL are based principally on the results of 2 open-label, multicenter, randomized, phase 3 studies (CLL14 and MURANO).1, 16, 17, 18
In the CLL14 study, 432 patients with previously untreated CD20+ CLL (Binet stage C or symptomatic disease) and concomitant medical conditions (total Cumulative Illness Rating Scale [CIRS] score exceeding 6 or creatinine clearance less than 70 mL/minute) were randomized in a 1:1 ratio to receive obinutuzumab (1 g by IV infusion on days 1, 8, and 15 during cycle 1, followed by 1 g by IV infusion every 28 days for an additional 5 cycles) in combination with either venetoclax (400 mg orally once daily [after an initial 5-week dose-escalation period] on day 1 of cycle 3) or chlorambucil (0.5 mg/kg orally on days 1 and 15).1, 16 Treatment cycles were repeated every 28 days for 12 cycles.1, 16 Patients with Richter transformation or an organ/system impairment score of 4 according to CIRS (except for the eye, ear, nose, or throat) were excluded from the study.1 The median age of patients was 72 years; 89% were white, 88% had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, 58% of patients had a creatinine clearance of less than 70 mL/minute, and 36 or 43% of patients had Binet stage B or C disease, respectively.1, 16 The median CIRS score was 8.0.1, 16 Presence of a 17p deletion chromosomal abnormality, TP53 mutation, 11q deletion, or unmutated IgVH was detected in 8, 10, 19, or 57% of patients, respectively.1, 16 The primary efficacy endpoint was progression-free survival as assessed by an independent review committee using the 2008 International Workshop Criteria for CLL (IWCLL) guidelines.1, 16 At a median follow-up duration of 28 months, median progression-free or overall survival had not been reached; however, progression-free survival was significantly prolonged in patients receiving venetoclax in combination with obinutuzumab compared with those receiving chlorambucil in combination with obinutuzumab (estimated hazard ratio of 0.33 with a 95% confidence interval of 0.22-0.51).1, 16 The overall response rate was 85% in patients receiving venetoclax in combination with obinutuzumab compared with 71% in patients receiving chlorambucil in combination with obinutuzumab; complete remission or complete remission with incomplete bone marrow recovery was achieved in 50 or 23% of venetoclax- or chlorambucil-treated patients, respectively.1, 16 In the intent-to-treat population, minimal residual disease negativity (defined as the presence of less than 0.01% CLL cells) in peripheral blood 3 months after completion of therapy was reported in 76 or 35% of patients receiving venetoclax in combination with obinutuzumab or chlorambucil in combination with obinutuzumab, respectively; negative minimal residual disease in the bone marrow was reported in 57 or 17% of patients in the respective treatment groups.1, 16 Among patients who achieved complete remission, 87 or 69% of these patients receiving venetoclax in combination with obinutuzumab were minimal residual disease negative in peripheral blood or bone marrow, respectively, 3 months after completion of therapy compared with 62 or 45% of those receiving chlorambucil in combination with obinutuzumab, respectively.1 Twelve months after completion of therapy, minimal residual disease negativity in peripheral blood was reported in 58% in patients receiving venetoclax in combination with obinutuzumab compared with 9% of those receiving chlorambucil in combination with obinutuzumab.1 Progression-free survival benefit in patients receiving venetoclax in combination with obinutuzumab compared with those receiving chlorambucil in combination with obinutuzumab at a median follow-up of 39.6 months remained similar to the initial results.17 Progression-free survival at 3 years was 81.9 or 49.5% in venetoclax- or chlorambucil-treated patients, respectively.17
In the MURANO study, 389 patients with CLL previously treated with at least 1 therapy, were randomized in a 1:1 ratio to receive rituximab (375 mg/m2 IV on day 1 of cycle 1, followed by 500 mg/m2 on day 1 of cycles 2-6) in combination with either venetoclax (400 mg orally once daily [after an initial 5-week dose-escalation period] for 24 months) or bendamustine (70 mg/m2 IV on days 1 and 2 of each 28-day cycle for 6 cycles).1, 18 Patients previously treated with bendamustine were eligible if the duration of response following bendamustine therapy was at least 24 months.18 The median age of patients was 65 years; 97% were white, 74% were male, and 99% had a baseline ECOG performance status of 0 or 1.1, 18 Presence of a 17p deletion chromosomal abnormality, TP53 mutation, 11q deletion, or unmutated IgVH was detected in 24, 25, 32, or 63% of patients, respectively.1 The median number of prior therapies was 1; 59 or 26% of patients had received 1 or 2 prior therapies, respectively.1, 18 Prior therapies included an alkylating agent, anti-CD20 monoclonal antibodies, B-cell receptor (BCR) pathway inhibitors, and purine analogs.1 The primary efficacy endpoint was progression-free survival using the 2008 IWCLL guidelines.1, 18 At a median follow-up 23.4 months, median progression-free survival had not been reached in patients receiving venetoclax in combination with rituximab; however, progression-free survival was significantly prolonged in patients receiving venetoclax in combination with rituximab compared with those receiving bendamustine in combination with rituximab (estimated hazard ratio of 0.19 with a 95% confidence interval of 0.13-0.28).1, 18 The overall response rate was 92% in patients receiving venetoclax in combination with rituximab compared with 72% in patients receiving bendamustine in combination with rituximab; complete remission or complete remission with incomplete bone marrow recovery was achieved in 8% of venetoclax-treated patients and in 4% of bendamustine-treated patients.1, 18 Among patients who achieved a partial response or better, 53 or 12% of these patients receiving venetoclax in combination with rituximab or bendamustine in combination with rituximab, respectively, were minimal residual disease negative (defined as the presence of less than 0.01% CLL cells) in peripheral blood 3 months after completion of rituximab combination therapy.1 Among patients who achieved complete remission or complete remission with incomplete bone marrow recovery, 3 or 2% of these patients receiving venetoclax in combination with rituximab or bendamustine in combination with rituximab, respectively, were minimal residual disease negative (defined as the presence of less than 0.01% CLL cells) in peripheral blood 3 months after completion of rituximab combination therapy.1 At a median follow-up duration of 22.9 months, median overall survival had not been reached in either group;1 however, the 24-month overall survival rate was 92 or 87% in patients receiving venetoclax combination therapy or bendamustine combination therapy, respectively.18 Progression-free and overall survival benefit in patients receiving venetoclax in combination with rituximab compared with those receiving bendamustine in combination with rituximab at 4 years' follow-up remained similar to the initial results.19, 20 Estimated rates of 4-year progression-free survival were 57.3 and 4.6% for patients receiving venetoclax combination therapy and bendamustine combination therapy, respectively.20 After an overall follow-up period of 71 months, median progression-free survival was 53.6 months in patients receiving venetoclax in combination with rituximab compared with 17 months in those receiving bendamustine in combination with rituximab; median overall survival had not been reached in either arm.1
Clinical Experience as Monotherapy
Efficacy and safety of venetoclax monotherapy for the treatment of CLL and SLL are based principally on the results of 3 open-label, noncomparative, phase 1 and 2 studies (M13-982, M12-175, and M14-032).1, 2, 21, 22, 23
In the M13-982 study, 106 adults with relapsed or refractory 17p deletion CLL (confirmed by the Vysis® fluorescent in situ hybridization [FISH] kit) received single-agent venetoclax (400 mg orally once daily [after an initial 5-week dose-escalation period]) until disease progression or unacceptable toxicity occurred.1, 2 Patients in this study had received a median of 2.5 prior therapies for their disease and had a median time since diagnosis of 6.6 years.1 The median age of patients was 67 years; 97% were white, 92% had a baseline ECOG performance status of 0 or 1, 50% had an absolute lymphocyte count of 25,000/mm3 or greater, and 53% had one or more lymph nodes measuring 5 cm or greater.1 The primary end point of this study was overall response rate as assessed by an independent review committee using the 2008 IWCLL guidelines.1, 2 The overall response rate was 85%; complete remission or complete remission with incomplete bone marrow recovery was achieved in 8% of the patients.1, 2 Among 8 patients who achieved complete remission, 3 patients were minimal residual disease negative (defined as the presence of less than 0.01% CLL cells) in peripheral blood and bone marrow.1 At the time of analysis, the median duration of response had not been reached in this study.1, 2 However, the median time to first response was 0.8 months.1, 2
In the M12-175 study, 67 adult patients with previously treated CLL or SLL (59 or 8 patients, respectively) received venetoclax 400 mg once daily (after an initial 5-week dose-escalation period) until disease progression or unacceptable toxicity occurred.1, 21 The median age of patients was 65 years; 87% were white, 78% were male, 67% had one or more lymph nodes measuring 5 cm or greater, 33% had documented unmutated IgVH , and 21% had documented 17p deletion.1 Baseline absolute lymphocyte count was at least 25,000/mm3 in 30% of patients.1 The overall response rate was 76% as assessed by an independent review committee using the 2008 IWCLL guidelines; complete remission or complete remission with incomplete bone marrow recovery was achieved in 10% of the patients.1 The median duration of response was 36.2 months.1 In the M14-032 study, 127 adult patients with CLL previously treated with and progressed on or after ibrutinib or idelalisib therapy received venetoclax 400 mg once daily (after an initial 3- or 5-week dose-escalation period) until disease progression or unacceptable toxicity occurred.1, 22, 23 The median age was 66 years; 92% were white, 70% were male, 41% had one or more lymph nodes measuring 5 cm or greater, 57% had documented unmutated IgVH , and 39% had documented 17p deletion.1 Baseline absolute lymphocyte count was at least 25,000/mm3 in 31% of patients, and the median number of prior treatments was 4.1 The overall response rate was 70% (as assessed by an independent review committee using the 2008 IWCLL guidelines); complete remission or complete remission with incomplete bone marrow recovery was achieved in 5% of patients.1 At a median follow-up duration of 19.9 months, the median duration of response had not been reached.1 Among patients previously treated with ibrutinib or idelalisib, investigator-assessed overall response rate was 65 or 67%, respectively.22, 23 Median progression-free survival and overall survival had not been reached at the time of analysis.22, 23
Venetoclax with or without rituximab or obinutuzumab is among one of several recommended treatment options for first-line therapy of CLL.2000, 2001 Some experts suggest that choice of a specific agent be based on presence or absence of 17p deletion or TP53 mutation, IgHV mutational status, age, comorbidities, and concomitant medications.2000, 2001
Venetoclax is used in combination with azacitidine, decitabine, or low-dose cytarabine for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients who are 75 years of age or older, or those who have comorbidities (e.g., ECOG performance status of 2 or 3, moderate hepatic impairment, creatinine clearance of less than 45 mL/minute, severe cardiac or pulmonary disease) that preclude use of intensive induction chemotherapy.1, 24, 25, 26, 27, 28, 29, 30 Venetoclax has been designated an orphan drug by FDA for treatment of this cancer.3
Clinical Experience for Venetoclax in Combination with Azacitidine or Decitabine
Efficacy and safety of venetoclax in combination with azacitidine or decitabine for the treatment of newly diagnosed AML in patients 75 years of age or older or those with comorbidities are based principally on the results of a randomized, double-blind, multicenter, placebo-controlled, phase 3 study (VIALE-A) and an open-label, noncomparative, phase 1b study (M14-358).1, 24, 25, 26, 27
In the VIALE-A study, 431 patients with newly diagnosed AML who were not candidates for standard induction chemotherapy were randomized in a 2:1 ratio to receive either venetoclax 400 mg orally once daily (after a 3-day dose escalation during cycle 1) in combination with azacitidine 75 mg/m2 subcutaneously or intravenously on days 1-7 of each 28-day cycle or placebo in combination with the same dosage of azacitidine.1, 24 If complete remission was achieved following cycle 1 (defined as less than 5% blasts in bone marrow with cytopenia), venetoclax or placebo was interrupted for up to 14 days or until ANC reached 500/mm3 or greater and platelet count reached 50,000/mm3 or greater.1 If complete remission was not achieved at the end of cycle 1, bone marrow assessment was repeated after cycle 2 or 3 and as clinically indicated.1 Azacitidine was resumed on the same day as venetoclax or placebo following interruption of therapy.1 Treatment was continued until disease progression or unacceptable toxicity occurred.1, 24 The median age of patients was 76 years; 76% were white, 60% were male, 55% had a baseline ECOG performance status of 0 or 1, 29% had a baseline bone marrow blast count below 30%, 25% had secondary AML, and 38% had poor cytogenetic risk factors.1, 24 Approximately one-half of the patients had at least two reasons for ineligibility for intensive induction chemotherapy.24 The primary efficacy endpoint of the study was overall survival.1 Median overall survival was prolonged in patients receiving venetoclax in combination with azacitidine compared with those receiving placebo in combination with azacitidine (14.7 versus 9.6 months, respectively).1, 24 Complete remission (defined as ANC exceeding 1,000/mm3, platelet count exceeding 100,000/mm3, RBC transfusion independence, and less than 5% blasts in bone marrow) was achieved in 37 or 18% of venetoclax- or placebo-treated patients, respectively.1 Complete remission and complete remission with partial hematologic recovery (defined as less than 5% blasts in bone marrow without evidence of disease, platelet count exceeding 50,000/mm3, and ANC exceeding 500/mm3) was achieved in 65 or 23% of venetoclax- or placebo-treated patients, respectively.1 The median time to first complete remission was 1 month in patients receiving venetoclax in combination with azacitidine.1 The median duration of complete remission, including complete remission with partial hematologic recovery, was 17.8 months in patients receiving the venetoclax combination and 13.9 months in those receiving the placebo combination.1, 24 Among venetoclax- or placebo-treated patients who were transfusion dependent (RBC and/or platelet) at baseline, 49 or 27%, respectively, became transfusion independent during any consecutive 56 days or more period during the study. 1 Among venetoclax- or placebo-treated patients who were transfusion independent at baseline, 69 or 42%, respectively, remained transfusion independent during any consecutive 56 day or more period during the study.1
In the M14-358 study, 80 patients with newly diagnosed AML who were not candidates for intensive induction chemotherapy (i.e., 75 years of age or older, severe cardiac disease, severe pulmonary disease, moderate hepatic impairment, creatinine clearance of less than 45 mL/minute) received venetoclax 400 mg orally once daily (after a dose-escalation period) in combination with either azacitidine (75 mg/m2 IV or subcutaneously on days 1-7 of each 28-day cycle) or decitabine (20 mg/m2 IV on days 1-5 of each 28-day cycle).1, 25, 26, 27 If complete remission was achieved following cycle 1 (defined as less than 5% blasts in bone marrow with cytopenia), venetoclax was interrupted for up to 14 days or until ANC reached 500/mm3 or greater and platelet count reached 50,000/mm3 or greater.1 Therapy was continued until disease progression or unacceptable toxicity occurred.1 At a median duration of follow-up of 15.9 months in patients receiving venetoclax in combination with azacitidine, complete remission or complete remission with partial hematologic recovery was achieved in 43 or 18%, respectively, of patients; the median time to first complete remission, including complete remission with partial hematologic recovery, was 1 month and the median duration of response was 23.8 months.1 Among the patients receiving venetoclax in combination with azacitidine, 12% subsequently underwent stem cell transplantation.1 At a median duration of follow-up of 11 months in patients receiving venetoclax in combination with decitabine, complete remission or complete remission with partial hematologic recovery was achieved in 54 or 7.7% of patients, respectively; the median time to first complete remission, including complete remission with partial hematologic recovery, was 1.9 months and the median duration of response was 12.7 months.1 In the subgroup of patients 60 to less than 75 years of age without relevant comorbidities who received venetoclax in combination with azacitidine, 35 or 41% of 17 patients achieved complete remission or complete remission with partial hematologic recovery, respectively; 53% of these patients subsequently underwent stem cell transplantation.1 In the subgroup of patients 65-74 years of age without relevant comorbidities who received venetoclax in combination with decitabine, 56 or 22% of 18 patients achieved complete remission or complete remission with partial hematologic recovery, respectively; 22% of these patients subsequently underwent stem cell transplantation.1 In the overall study population, which included patients 60 to less than 75 years of age without relevant comorbidities, median overall survival was 16.4 months in patients receiving venetoclax in combination with azacitidine (at a median duration of follow-up of 29 months) and 16.2 months in those receiving venetoclax in combination with decitabine (at a median duration of follow-up of 40 months).27
Clinical Experience for Venetoclax in Combination with Low-Dose Cytarabine
Efficacy and safety of venetoclax in combination with low-dose cytarabine for the treatment of newly diagnosed AML in patients 75 years of age or older or those with comorbidities is based principally on the results of a multicenter, randomized, double-blind, placebo-controlled, phase 3 study (VIALE-C) and an open-label, noncomparative, phase 1b/2 study (M14-387).1, 28, 29, 30
In the VIALE-C study, 211 patients with newly diagnosed AML who were not candidates for standard induction chemotherapy were randomized in a 2:1 ratio to receive either venetoclax 600 mg orally once daily (after a 4-day dose-escalation period) in combination with low-dose cytarabine 20 mg/m2 subcutaneously on days 1-10 of each 28-day cycle or placebo in combination with low-dose cytarabine.1, 28 If complete remission was achieved following cycle 1 (defined as less than 5% blasts in bone marrow with cytopenia), venetoclax or placebo was interrupted for up to 14 days or until ANC reached 500/mm3 or greater and platelet count reached 50,000/mm3 or greater.1 If complete remission was not achieved at the end of cycle 1, bone marrow assessment was repeated after cycle 2 or 3 and as clinically indicated.1 Low-dose cytarabine was resumed on the same day as venetoclax or placebo following interruption of therapy.1 Therapy was continued until disease progression or unacceptable toxicity occurred.1 The primary efficacy endpoint of the study was overall survival.28 At a median follow-up duration of 12 months, median overall survival was 7.2 months in patients receiving venetoclax in combination with low-dose cytarabine and 4.1 months in patients receiving placebo in combination with low-dose cytarabine; however, the difference was not statistically significant.1, 28 Complete remission occurred in 27 or 7.4% of patients receiving the venetoclax and placebo combinations, respectively; the median duration of complete remission was 11.1 or 8.3 months in these respective groups.1, 28 Complete remission or complete remission with partial hematologic recovery was achieved in 47 or 15% of venetoclax- or placebo-treated patients, respectively; the median duration of response was 11.1 or 6.2 months in these respective groups, and the median time to first complete remission or complete remission with partial hematologic recovery was 1 month in patients receiving venetoclax in combination with low-dose cytarabine.1 Among venetoclax- or placebo-treated patients who were transfusion dependent (RBC and/or platelet) at baseline, 33 or 13%, respectively, became transfusion independent during any consecutive 56 day or more period during the study. 1 Among venetoclax- or placebo-treated patients who were transfusion independent at baseline, 50 or 31%, respectively, remained transfusion independent during any consecutive 56 day or more period during the study.1 After an additional 6 months of follow-up (median follow-up, 17.5 months), median overall survival was 8.4 months in patients receiving venetoclax in combination with low-dose cytarabine and 4.1 months in patients receiving placebo in combination with low-dose cytarabine.30
In the M14-387 study, 82 patients with newly diagnosed AML, including those with prior exposure to a hypomethylating agent for an antecedent hematologic disorder, were treated with venetoclax 600 mg once daily (after a 4- or 5-day dose-escalation period) and cytarabine 20 mg/m2 on days 1-10 of each 28-day cycle.1, 29 If complete remission was achieved following cycle 1 (defined as less than 5% blasts in bone marrow with cytopenia), venetoclax was interrupted for up to 14 days or until ANC reached 500/mm3 or greater and platelet count reached 50,000/mm3 or greater.1 Therapy was continued until disease progression or unacceptable toxicity occurred.1 At a median follow-up of 7.3 months in the subgroup of patients who were 75 years of age or older or had relevant comorbidities, 21 or 21% of these patients achieved complete remission or complete remission with partial hematologic recovery, respectively, with a median time to first complete remission or complete remission with partial hematologic recovery of 1 month; the median duration of complete remission or complete remission with partial hematologic recovery was 22.9 or 14.3 months, respectively.1 In the subgroup of patients who were 60 to less than 75 years of age without relevant comorbidities receiving venetoclax in combination with low-dose cytarabine, complete remission or complete remission with partial hematologic recovery was achieved in 33 or 24% of patients, respectively; one of these patients subsequently underwent stem cell transplantation.1 In the overall study population, which included patients 60 to less than 75 years of age without relevant comorbidities, median overall survival was 10.1 months.29
Treatment options for newly diagnosed AML include intensive chemotherapy or less-intensive regimens.3015 Although more-intensive therapy is generally recommended over less-intensive regimens when tolerable, decisions should be individualized based on the relative risks and benefits of treatment.3016 In older adults or adults with significant comorbid conditions, venetoclax plus hypomethylating agents (azacitidine and decitabine) or low-dose cytarabine may be used as one of several less-intensive treatment regimens for AML.3015
Tumor Burden | Prophylaxis | Monitoring |
|---|---|---|
Low tumor burden: All lymph nodes with diameter <5 cm AND absolute lymphocyte count <25,000/mm3 | Assess blood chemistries (i.e., potassium, phosphorus, calcium, uric acid, creatinine) prior to, at 6-8 and 24 hours following the first 20- and 50-mg doses of venetoclax, and prior to each subsequent escalating dose (100, 200, and 400 mg) | |
Medium tumor burden: Any lymph node diameter 5 cm to <10 cm OR absolute lymphocyte count ≥25,000/mm3 | Assess blood chemistries (i.e., potassium, phosphorus, calcium, uric acid, creatinine) prior to, at 6-8 and 24 hours following the first 20- and 50-mg doses of venetoclax, and prior to each subsequent escalating dose (100, 200, and 400 mg) | |
Medium tumor burden: Any lymph node diameter 5 cm to <10 cm OR absolute lymphocyte count ≥25,000/mm3 | Consider additional IV hydration | In patients with Clcr<80 mL/minute prior to the first 20- and 50-mg doses, consider hospitalization for drug administration and more intensive hydration and monitoring (see the following recommendations for monitoring in hospital) |
High tumor burden: Any lymph node diameter ≥10 cm OR any lymph node diameter ≥5 cm and absolute lymphocyte count ≥25,000/mm3 | Oral (1.5-2 L)a , b and IV (150-200 mL/hour as tolerated) hydration and allopurinolc | Hospitalize patients for administration of the first 20- and 50-mg doses of venetoclax; assess blood chemistries (i.e., potassium, phosphorus, calcium, uric acid, creatinine) prior to and at 4, 8, 12, and 24 hours following each dose |
High tumor burden: Any lymph node diameter ≥10 cm OR any lymph node diameter ≥5 cm and absolute lymphocyte count ≥25,000/mm3 | Consider rasburicase if baseline uric acid concentrations are elevated | Administer subsequent escalating doses (100, 200, and 400 mg) in the outpatient setting; assess blood chemistries prior to and at 6-8 and 24 hours following each dose |
a Administer IV hydration if oral hydration is not tolerated
b Begin oral hydration 2 days prior to initiating venetoclax, on the day of the first dose, and every time the dose is increased
c Initiate antihyperuricemic agent (e.g., allopurinol) 2-3 days prior to initiating venetoclax
Venetoclax is administered orally once daily with a meal and a full glass of water at approximately the same time each day.1, 6, 12 Venetoclax tablets should be swallowed intact and should not be chewed, crushed, or broken.1 The recommended dosage of venetoclax may be delivered using any combination of the approved tablet strengths.1
Store venetoclax at or below 30°C in its original container to protect from moisture.1
Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia
For the treatment of CLL or SLL, the recommended adult dosage of venetoclax is 400 mg once daily; to reduce tumor burden (i.e., debulk) and minimize the risk of tumor lysis syndrome, initiate venetoclax therapy at a low dosage and increase gradually over 5 weeks to the recommended dosage according to the following schedule: 20 mg daily in the first week, 50 mg daily in the second week, 100 mg daily in the third week, 200 mg daily in the fourth week, and 400 mg daily thereafter.1
Venetoclax in Combination with Obinutuzumab
During cycle 1, the recommended dosage of obinutuzumab is 100 mg IV on day 1, followed by 900 mg IV on day 2, and then 1 g on day 8 and day 15.1 During cycles 2-6, the recommended dosage of obinutuzumab is 1 g IV every 4 weeks (day 1 of each cycle).1 Do not continue obinutuzumab beyond 6 cycles.1
On cycle 1 day 22, initiate venetoclax at a low dosage and titrate over 5 weeks according to the following schedule: 20 mg daily in first week, 50 mg daily in second week, 100 mg daily in third week, 200 mg daily in fourth week, then 400 mg daily thereafter.1 After completing the dosage escalation phase on cycle 2 day 28, continue venetoclax at a dosage of 400 mg once daily from cycle 3 day 1 until the last day of cycle 12.1
Venetoclax in Combination with Rituximab
Initiate venetoclax therapy at a low dosage and increased gradually over 5 weeks to the recommended dosage according to the following schedule: 20 mg daily in the first week, 50 mg daily in the second week, 100 mg daily in the third week, 200 mg daily in the fourth week, and 400 mg daily thereafter.1 Continue venetoclax 400 mg once daily for 24 months starting from day 1 of cycle 1 of rituximab.1
Initiate rituximab after patient has completed the 5-week dose-escalation for venetoclax and has received venetoclax at the recommended dosage of 400 mg once daily for 7 days.1 The recommended dosage of rituximab is 375 mg/m2 IV on day 1 of cycle 1, followed by 500 mg/m2 IV on day 1 of cycles 2-6.1 Treatment cycles are repeated every 28 days.1 Do not continue rituximab beyond 6 cycles.1
When venetoclax is used as monotherapy for the treatment of CLL or SLL, the recommended adult dosage of venetoclax is 400 mg once daily after the recommended 5-week dose titration; to minimize the risk of tumor lysis syndrome, initiate venetoclax therapy at a low dosage and increase gradually over 5 weeks to the recommended dosage according to the following schedule: 20 mg daily in the first week, 50 mg daily in the second week, 100 mg daily in the third week, 200 mg daily in the fourth week, and 400 mg daily thereafter.1
Continue therapy until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity in Patients with CLL/SLL
If adverse reactions occur during venetoclax therapy in patients with CLL or SLL, temporary interruption of therapy, dosage reduction, and/or discontinuance of the drug may be necessary.1 If dosage reduction is required, the manufacturer recommends reducing the dosage of venetoclax as described in Table 2.1
If a dosage reduction occurs during the initial dose-titration period, continue the reduced dosage for 1 week before escalating back to the previous dosage.1
If interruption of therapy is necessary for more than 1 week during the initial dose-titration period or for more than 2 weeks while receiving a steady dosage of venetoclax (e.g., 400 mg once daily), reassess patients for risk of tumor lysis syndrome to determine if a reduced dosage is necessary when resuming therapy.1
Current Venetoclax Dosage | Dosage Reduction after Recovery from Toxicitya |
|---|---|
400 mg | Restart at 300 mg once daily |
300 mg | Restart at 200 mg once daily |
200 mg | Restart at 100 mg once daily |
100 mg | Restart at 50 mg once daily |
50 mg | Restart at 20 mg once daily |
20 mg | Restart at 10 mg once daily |
a Larger dose reductions may be required at the discretion of the clinician1
The following Recommended Dosage Modification for Venetoclax Toxicity in Patients with CLL or SLL table indicates the recommended dosage modification (i.e., temporary interruption of therapy, dosage reduction) for adverse effects according to severity.1
Adverse Reaction and Severity | Modification |
|---|---|
Tumor Lysis Syndrome: Blood chemistry abnormalities or symptoms consistent with tumor lysis syndrome | Withhold therapy If resolution occurs within 24-48 hours of the last dose, resume therapy at the same dosa however, if laboratory abnormalities require >48 hours to resolve or if clinical tumor lysis syndrome (clinical sequelae may include acute renal failure, cardiac arrhythmias, sudden death, and/or seizures) occurs, resume therapy at a reduced dosage when resolution occurs (see Table 2) |
Hematologic Toxicity: Grade 3 neutropenia associated with fever or infection | First occurrence: Withhold therapy; when toxicity improves to grade 1 or less, resume at same dosage |
Hematologic Toxicity: Grade 3 neutropenia associated with fever or infection | Subsequent occurrences: Withhold therapy, resume therapy at a reduced dosage when the toxicity resolves (see Table 2) |
Hematologic Toxicity: Grade 4 (except for lymphopenia) | First occurrence: Withhold therapy; when toxicity improves to grade 1 or less, resume at same dosage |
Hematologic Toxicity: Grade 4 (except for lymphopenia) | Subsequent occurrences: Withhold therapy, resume therapy at a reduced dosage when the toxicity resolves (see Table 2) |
Nonhematologic Toxicity: Grade 3 or 4 | First occurrence: Withhold therapy; when toxicity improves to grade 1 or less, resume at same dosage |
Nonhematologic Toxicity: Grade 3 or 4 | Subsequent occurrences: Withhold therapy, resume therapy at a reduced dosage when the toxicity resolves (see Table 2) |
Dosage Modification for Concomitant Use with CYP3A or P-gp Inhibitors in Patients with CLL/SLL
Concomitant use of venetoclax with a potent or moderate CYP3A inhibitor or a P-gp inhibitor may be contraindicated or reduction of the venetoclax dosage may be necessary in patients with CLL/SLL as described in Table 4.1 When the potent or moderate CYP3A inhibitor or P-gp inhibitor is discontinued, resume the dosage of venetoclax that was used prior to initiating the CYP3A inhibitor or P-gp inhibitor after 2-3 days. 1
Coadministered Drug | Concomitant Use During Initial Venetoclax Dosage Escalation | Concomitant Use with Steady Daily Dosage of Venetoclax (After Dosage Escalation) |
|---|---|---|
Posaconazole | Contraindicated | Consider using an alternative drug with no or less CYP3A inhibition potential If concomitant use cannot be avoided, reduce venetoclax dosage to 70 mg daily; monitor frequently for toxicities |
Other potent CYP3A inhibitor | Contraindicated | Consider using an alternative drug with no or less CYP3A inhibition potential If concomitant use cannot be avoided, reduce venetoclax dosage to 100 mg daily; monitor frequently for toxicities |
Moderate CYP3A inhibitor | Reduce venetoclax dosage by at least 50% and monitor frequently for toxicities | Reduce venetoclax dosage by at least 50% and monitor frequently for toxicities |
P-gp inhibitor | Reduce venetoclax dosage by at least 50% and monitor frequently for toxicities | Reduce venetoclax dosage by at least 50% and monitor frequently for toxicities |
Venetoclax in Combination with Azacitidine
When venetoclax is used in combination with azacitidine for the treatment of newly diagnosed AML in patients 75 years of age or older, or those who are not candidates for intensive induction chemotherapy, initiate venetoclax therapy at a low dosage and increase gradually to the recommended dosage according to the following schedule: 100 mg on day 1, 200 mg on day 2, and 400 mg daily thereafter.1
The recommended dosage of azacitidine is 75 mg/m2 intravenously or subcutaneously once daily on days 1-7 of each 28-day cycle.1
Continue therapy until disease progression or unacceptable toxicity occurs.1
Venetoclax in Combination with Decitabine
When venetoclax is used in combination with decitabine for the treatment of newly diagnosed AML in patients 75 years of age or older, or those who are not candidates for intensive induction chemotherapy, initiate venetoclax therapy at a low dosage and increased gradually to the recommended dosage according to the following schedule: 100 mg on day 1, 200 mg on day 2, and 400 mg daily thereafter.1
The recommended dosage of decitabine is 20 mg/m2 intravenously once daily on days 1-5 of each 28-day cycle.1
Continue therapy until disease progression or unacceptable toxicity occurs.1
Venetoclax in Combination with Low-Dose Cytarabine
When venetoclax is used in combination with low-dose cytarabine for the treatment of newly diagnosed AML in patients 75 years of age or older, or those who are not candidates for intensive induction chemotherapy, initiate venetoclax therapy at a low dosage and increased gradually to the recommended dosage according to the following schedule: 100 mg on day 1, 200 mg on day 2, 400 mg on day 3, and 600 mg daily thereafter.1
The recommended dosage of cytarabine is 20 mg/m2 subcutaneously once daily on days 1-10 of each 28-day cycle.1
Continue therapy until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity in Patients with AML
If adverse reactions occur during venetoclax therapy in patients with AML, dosage modification or temporary interruption of therapy may be necessary as described in Table 5.1
Adverse Reaction and Severity | Occurrence | Modification |
|---|---|---|
Hematologic Toxicity: Grade 4 neutropenia with or without fever or infection | Prior to achieving remission | In most instances, do not interrupt venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine Bone marrow evaluation recommended |
Hematologic Toxicity: Grade 4 neutropenia with or without fever or infection | First occurrence after achieving remission and lasts ≥7 days | Delay subsequent cycle of venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine and monitor CBCs Resume venetoclax at same dosage in combination with azacitidine, decitabine, or low-dose cytarabine when toxicity resolves to grade 1 or 2 |
Hematologic Toxicity: Grade 4 neutropenia with or without fever or infection | Subsequent occurrences in cycles after achieving remission and lasting ≥7 days | Delay subsequent cycle of venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine and monitor CBCs Resume venetoclax at same dosage in combination with azacitidine, decitabine, or low-dose cytarabine when toxicity resolves to grade 1 or 2, and reduce duration of venetoclax therapy by 7 days during each subsequent cycle (e.g., 28 days reduced to 21 days) |
Hematologic Toxicity: Grade 4 thrmbocytopenia | Prior to achieving remission | In most instances, do not interrupt venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine Bone marrow evaluation recommended |
Hematologic Toxicity: Grade 4 thrmbocytopenia | First occurrence after achieving remission and lasts ≥7 days | Delay subsequent cycle of venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine and monitor CBCs Resume venetoclax at same dosage in combination with azacitidine, decitabine, or low-dose cytarabine when toxicity resolves to grade 1 or 2 |
Hematologic Toxicity: Grade 4 thrmbocytopenia | Subsequent occurrences in cycles after achieving remission and lasting ≥7 days | Delay subsequent cycle of venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine and monitor CBCs Resume venetoclax at same dosage in combination with azacitidine, decitabine, or low-dose cytarabine when toxicity resolves to grade 1 or 2, and reduce duration of venetoclax therapy by 7 days during each subsequent cycle (e.g., 28 days reduced to 21 days) |
Nonhematologic toxicity: Grade 3 or 4 | Any occurrence | If persists despite supportive care, withhold venetoclax therapy; resume venetoclax at same dosage when toxicity resolves to grade 1 or less |
Dosage Modification for Concomitant Use with CYP3A or P-gp Inhibitors in Patients with AML
Avoid concomitant use of venetoclax with a potent or moderate cytochrome P-450 (CYP) 3A inhibitor or a P-glycoprotein (P-gp) inhibitor.1 If concomitant use of potent or moderate CYP3A inhibitors or P-gp inhibitors cannot be avoided, the manufacturer recommends reducing the dosage of venetoclax as described in Table 6.1 When the potent or moderate CYP3A inhibitor or P-gp inhibitor is discontinued, resume the dosage of venetoclax that was used prior to initiating the CYP3A inhibitor or P-gp inhibitor after 2-3 days.1
Coadministered Drug | During Dosage Escalation | After Dosage Escalation |
|---|---|---|
Posaconazole | Day 1: 10 mg | Reduce venetoclax dosage to 70 mg daily and monitor frequently for toxicities |
Day 2: 20 mg | ||
Day 3: 50 mg | ||
Day 4: 70 mg | ||
Other potent CYP3A inhibitor | Day 1: 10 mg | Reduce venetoclax dosage to 100 mg daily and monitor frequently for toxicities |
Day 2: 20 mg | ||
Day 3: 50 mg | ||
Day 4: 100 mg | ||
Moderate CYP3A inhibitor | Reduce venetoclax dosage by at least 50% and monitor frequently for toxicities | Reduce venetoclax dosage by at least 50% and monitor frequently for toxicities |
P-gp inhibitor | Reduce venetoclax dosage by at least 50% and monitor frequently for toxicities | Reduce venetoclax dosage by at least 50% and monitor frequently for toxicities |
No dosage adjustment is necessary in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment.1 For patients with severe hepatic impairment (Child-Pugh class C), the manufacturer recommends reducing the once-daily dosage of venetoclax by 50% and closely monitoring such patients for adverse reactions.1
No dosage adjustment is necessary in patients with mild, moderate, or severe renal impairment (creatinine clearance of 15 mL/minute or greater).1 Venetoclax has not been studied in patients with end-stage renal disease (creatinine clearance of less than 15 mL/minute) or in those requiring dialysis.1
The manufacturer makes no specific dosage recommendations for geriatric patients.
Tumor lysis syndrome, sometimes fatal or resulting in renal failure requiring dialysis, has been reported in patients receiving venetoclax.1, 7 The risk of tumor lysis syndrome generally is greatest when the drug is first administered and during the dose-escalation period in all patients, and, in patients with CLL or SLL, during reinitiation of therapy following a dosage interruption; laboratory abnormalities consistent with tumor lysis syndrome that require prompt medical treatment may occur as early as 6-8 hours following the initial dose of venetoclax and after each dosage increase.1, 7 Tumor lysis syndrome, including fatal cases, has occurred in patients following a single 20-mg dose of venetoclax.1
In clinical studies evaluating venetoclax monotherapy (using a 5-week dose-escalation schedule and following tumor lysis syndrome prophylaxis and monitoring procedures) in patients with CLL/SLL, tumor lysis syndrome occurred in 2% of patients; the incidence of tumor lysis syndrome was similar to that observed in patients receiving venetoclax in combination with obinutuzumab or rituximab.1 When a higher initial dosage and shorter dose-escalation period (i.e., 2-3 weeks) was used in patients with CLL/SLL, tumor lysis syndrome occurred in 13% of patients, and resulted in death and renal failure in some cases.1
In the VIALE-A study evaluating venetoclax in combination with azacitidine in patients with AML, tumor lysis syndrome occurred in 1.1% of patients; this study employed a 3-day dose-escalation schedule along with prophylaxis and monitoring for tumor lysis syndrome.1 In addition, 3 patients receiving venetoclax in combination with azacitidine developed transient blood chemistry changes consistent with tumor lysis syndrome during the 3-day dose-escalation period; these laboratory abnormalities resolved with uricosuric therapy and supplemental calcium without venetoclax or azacitidine dosage interruption.24
In the VIALE-C study evaluating venetoclax in combination with low-dose cytarabine in patients with AML, tumor lysis syndrome occurred in 5.6% of patients, and resulted in death and renal failure in some cases; this study employed a 4-day dose-escalation schedule along with prophylaxis and monitoring for tumor lysis syndrome.1
Assess patients for their risk of developing tumor lysis syndrome and administer appropriate interventions (e.g., prophylactic antihyperuricemic therapy, adequate hydration, monitoring) prior to and during venetoclax therapy.1 The risk is a continuum based on multiple factors (e.g., type of malignancy, tumor burden, renal impairment, splenomegaly).1 Concomitant use of certain drugs (e.g., inhibitors of CYP3A or P-glycoprotein [P-gp]) may further increase this risk.1 Perform tumor burden assessments, including radiographic evaluation (e.g., CT scan), and blood chemistries (i.e., potassium, phosphorus, calcium, uric acid, creatinine) and correct any abnormalities prior to initiating venetoclax therapy and during the dose-escalation period.1 As the overall risk increases, employ more intensive measures (i.e., IV hydration, more frequent monitoring, hospitalization).1
If tumor lysis syndrome occurs, temporary interruption of therapy may be necessary.1 In patients with CLL or SLL, dosage reduction may be necessary when therapy is resumed.1
Grade 3 or 4 neutropenia occurs commonly in patients receiving venetoclax as monotherapy or as a component of combination therapy.1, 7 In clinical studies evaluating venetoclax as monotherapy or a component of combination therapy in patients with CLL, grade 3 or 4 neutropenia occurred in 63-64% of patients receiving the drug; grade 4 neutropenia occurred in 31-33% of venetoclax-treated patients, and 4-6% of patients developed febrile neutropenia.1 In patients with AML, baseline neutrophil counts worsened in 95-100% of patients receiving venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine.1 Neutropenia may recur with subsequent cycles.1
Monitor CBC counts periodically during venetoclax therapy.1 In patients who develop hematologic toxicity, temporary interruption of therapy or dosage modification may be required.1 Consider supportive therapy with hematopoietic growth factors (e.g., granulocyte colony-stimulating factor [G-CSF]) and/or anti-infective agents.1
Fatal and serious infections, such as pneumonia and sepsis, have occurred in patients treated with venetoclax.1
Monitor patients for manifestations of infection and initiate appropriate treatment promptly.1 If grade 3 or 4 infection occurs, withhold venetoclax therapy until resolution of the infection occurs; venetoclax dosage reduction may be necessary.1
Safety and efficacy of immunization with live, attenuated vaccines during or following venetoclax therapy have not been established.1 Immune response to vaccines may be reduced.1 The manufacturer recommends that live, attenuated vaccines be avoided prior to, during, and following venetoclax therapy until B-cell counts have recovered.1
Fetal/Neonatal Morbidity and Mortality
Based on its mechanism of action and animal findings, venetoclax may cause fetal harm.1 Embryofetal toxicity (i.e., postimplantation loss, decreased fetal weight) was observed in animals at venetoclax exposure levels equivalent to the human exposure at 400 mg once daily; no evidence of teratogenicity was observed.1
Instruct patients to avoid pregnancy during venetoclax therapy.1 Perform pregnancy testing in females of reproductive potential prior to initiating venetoclax therapy and instruct such patients to use an effective method of contraception while receiving the drug and for at least 30 days after discontinuance of therapy.1 If venetoclax is used during pregnancy or if the patient becomes pregnant while receiving the drug, apprise the patient of the potential fetal hazard.1
Increased mortality has been reported in clinical trials in patients with multiple myeloma† receiving venetoclax in combination with bortezomib and dexamethasone;1, 13, 14 venetoclax is not currently FDA-labeled for use in patients with multiple myeloma.1, 13 The manufacturer recommends against the use of this combination for the treatment of multiple myeloma outside of a controlled clinical trial.1
In a randomized, controlled phase 3 trial (BELLINI) that enrolled 291 patients with multiple myeloma, interim analyses indicated that the risk of death was increased by 103% in patients receiving venetoclax in combination with bortezomib and dexamethasone compared with those receiving bortezomib and dexamethasone.13 Because of these findings, the BELLINI trial was terminated at FDA's request.13 However, patients experiencing benefit from the drug may continue therapy with venetoclax in combination with bortezomib and dexamethasone, but only after the risks associated with use of the drug combination have been discussed completely with the patient and a new written informed consent has been obtained.13
There are no adequate and well-controlled studies of venetoclax in pregnant women; however, animal studies suggest that venetoclax may cause fetal harm.1
It is not known whether venetoclax is distributed into human milk.1 When a single venetoclax 150-mg/kg dose was administered to lactating rats 8 to 10 days after parturition, drug concentrations in milk were 1.6 times lower than in maternal plasma, and were mostly unchanged drug.1 Because of the potential for serious adverse reactions to venetoclax in nursing infants, advise patients to discontinue nursing during venetoclax therapy and for 1 week after the final dose.1 The effects of the drug on nursing infants or milk production are unknown.1
Females and Males of Reproductive Potential
Results of animal studies suggest that venetoclax may impair male fertility.1 Testicular toxicity (germ cell loss) was observed in male dogs receiving venetoclax at exposure levels 0.5 times the human exposure at the recommended dosage.1
Perform pregnancy testing in females of reproductive potential prior to initiating venetoclax therapy and instruct patients to use an effective method of contraception while receiving the drug and for at least 30 days after discontinuance of therapy.1
Safety and efficacy of venetoclax have not been established in pediatric patients.1
In a juvenile toxicology study in animals, clinical signs of venetoclax toxicity (i.e., body weight changes, decreased activity, dehydration, hunched posture, skin pallor, death) have been reported in mice receiving venetoclax from 7 to 60 days of age.1 Reversible decreases in lymphocyte counts also were observed in mice receiving venetoclax at a dosage approximately 0.06 times the human dosage of 400 mg on a mg/m2 basis for a 20-kg child.1
In 3 open-label studies evaluating venetoclax monotherapy in patients with previously treated CLL/SLL, 57% of patients were 65 years of age or older, and 18% were 75 years of age or older.1 No overall differences in efficacy or safety were observed between geriatric and younger patients when venetoclax was used as monotherapy or as a component of combination therapy.1
In the VIALE-A, M14-358, and VIALE-C clinical studies evaluating venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine in patients with AML, 96, 100, and 92%, respectively, of patients were 65 years of age or older, and 60, 62, and 57%, respectively, were 75 years of age or older.1 Experience in younger adults with AML is insufficient to determine whether they respond differently from patients 65 years of age or older.1
Venetoclax is principally eliminated by the liver.1 Systemic exposure to venetoclax was similar in patients with mild or moderate hepatic impairment and those with normal hepatic function.1 Following a single 50-mg dose of venetoclax, systemic exposure to venetoclax increased 2.7-fold in patients with severe hepatic impairment (Child-Pugh class C) compared with those with normal hepatic function.1
No clinically important differences in the pharmacokinetics of venetoclax have been observed in patients with mild, moderate, or severe renal impairment (creatinine clearance 15-89 mL/minute) compared with patients with normal renal function.1 The pharmacokinetics of venetoclax have not been evaluated in patients with end-stage renal disease (creatinine clearance less than 15 mL/minute) or those requiring dialysis; however, substantial removal of the drug by dialysis is unlikely because of the drug's large volume of distribution and extensive protein binding.1
Patients with reduced renal function (creatinine clearance less than 80 mL/minute) have an increased risk of tumor lysis syndrome; therefore, more intensive prophylaxis and monitoring are necessary during initiation of venetoclax therapy.1
In patients with CLL/SLL receiving venetoclax in combination with obinutuzumab or rituximab or as monotherapy, adverse effects reported in 20% or more of patients include neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infection, cough, musculoskeletal pain, fatigue, and edema.1
In patients with AML receiving venetoclax in combination with azacitidine or decitabine or low-dose cytarabine, adverse effects reported in 30% or more of patients include 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.1
Venetoclax is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4/5.1, 5 In vitro studies indicate that venetoclax is a weak inhibitor of CYP isoenzymes 2C8 and 2C9 and uridine diphosphate-glucuronosyltransferase (UGT) 1A1;1 however, inhibition is not predicted to be clinically relevant because of high plasma protein binding.1, 15 In vitro, venetoclax does not inhibit or induce CYP isoenzymes 1A2, 2B6, 2C19, 2D6, or 3A4.1, 4 Venetoclax also does not inhibit UGT1A4, 1A6, 1A9, or 2B7 in vitro.1
In vitro, venetoclax is a substrate and inhibitor of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and a weak inhibitor of organic anion transport protein (OATP) 1B1.1, 4 Venetoclax does not inhibit OATP1B3, organic cation transporter (OCT) 1, OCT2, renal organic anion transporter (OAT) 1, OAT3, multidrug and toxic compound extrusion (MATE) 1, or MATE2K.1
Drugs and Foods Affecting Hepatic Microsomal Enzymes
Concomitant use of venetoclax with potent or moderate inhibitors of CYP3A may result in increased peak plasma concentrations and systemic exposure (area under the concentration-time curve [AUC]) of venetoclax, and increased risk of tumor lysis syndrome and other toxicities.1, 8
In patients with CLL/SLL , concomitant use of venetoclax with potent inhibitors of CYP3A (e.g., ketoconazole, posaconazole, ritonavir) during the initial dose-escalation period of venetoclax is contraindicated.1 Venetoclax and potent inhibitors of CYP3A may be used concomitantly, if necessary, once the dose titration has been completed and the patient is receiving a steady daily dosage of venetoclax; however, clinicians should consider using an alternative drug with no or minimal CYP3A inhibition potential.1 If concomitant use with a potent inhibitor is necessary once the dose titration has been completed and the patient is on a steady daily dosage of venetoclax, reduce the dosage of venetoclax, and monitor for toxicity more frequently.1 If concomitant use of the potent CYP3A inhibitor is discontinued, return the venetoclax dosage to the dosage used prior to initiation of the potent CYP3A inhibitor in 2-3 days.1 When venetoclax (during or after the initial dose-escalation period) is used in combination with moderate CYP3A inhibitors, reduce the venetoclax dosage by at least 50%.1
In patients with AML , reduce the dosage of venetoclax when the drug is used concomitantly with potent inhibitors of CYP3A, and monitor for toxicity more frequently.1 If concomitant use of the potent CYP3A inhibitor is discontinued, return the venetoclax dosage to the dosage used prior to initiation of the potent CYP3A inhibitor in 2-3 days.1 When venetoclax (during or after the initial dose-escalation period) is used in combination with moderate CYP3A inhibitors, reduce the venetoclax dosage by at least 50%, and monitor for toxicity more frequently.1
Grapefruit products, Seville oranges, and starfruit contain components that inhibit CYP3A; avoid these products during venetoclax therapy.1
Concomitant use of venetoclax with potent or moderate inducers of CYP3A may result in decreased peak plasma concentrations and AUC of venetoclax, and potentially decrease venetoclax efficacy.1
Avoid concomitant use of venetoclax with potent or moderate inducers of CYP3A.1
Drugs Affecting Efflux Transport Systems
Concomitant use of venetoclax with inhibitors of P-gp may result in increased peak plasma concentrations and AUC of venetoclax, and increased risk of tumor lysis syndrome and other toxicities.1
Reduce the dosage of venetoclax by 50% when the drug is used concomitantly with inhibitors of P-gp, and monitor for toxicity more frequently.1 If concomitant use of the P-gp inhibitor is discontinued, return the venetoclax dosage to the dosage used prior to initiation of the P-gp inhibitor in 2-3 days.1
Substrates of Efflux Transport Systems
Concomitant use of venetoclax with substrate drugs of P-gp may result in increased peak plasma concentrations and systemic exposure to the P-gp substrate drug, and increased risk of toxicity.1 When a single 100-mg dose of venetoclax was administered concomitantly with the P-gp substrate digoxin (0.5 mg), peak plasma concentrations and systemic exposure to digoxin increased by 35 and 9%, respectively.1 Avoid concomitant use of venetoclax with P-gp substrates.1 If such concomitant therapy is necessary, the manufacturer recommends administering the substrate drug at least 6 hours prior to venetoclax.1
Drugs Affecting Gastric Acidity
The pharmacokinetics of venetoclax are not substantially altered when used concomitantly with gastric acid-reducing agents.1 In a population pharmacokinetic analysis, concomitant administration of gastric acid-reducing agents (e.g., antacids, histamine H2-receptor antagonists, proton-pump inhibitors) with venetoclax did not result in clinically important changes in the bioavailability of venetoclax.1, 8
The pharmacokinetics of venetoclax are not substantially altered when coadministered with azacitidine, cytarabine, decitabine, obinutuzumab, or rituximab.1
The pharmacokinetics of venetoclax are not substantially altered when coadministered with azithromycin.1
Ketoconazole is a potent CYP3A, P-gp, and BCRP inhibitor.1 Concomitant administration of ketoconazole (400 mg daily for 7 days) with venetoclax increased the peak plasma concentration and AUC of venetoclax by 130 and 540%, respectively.1
Concomitant use may be contraindicated or reduction in venetoclax dosage may be required.1
Posaconazole is a potent CYP3A and P-gp inhibitor.1 Concomitant administration of posaconazole (300 mg daily for 7 days) with venetoclax (50 mg daily for 7 days) increased the peak plasma concentration and AUC of venetoclax by 61 and 90%, respectively, compared with venetoclax 400 mg alone; when the dosage of venetoclax was increased to 100 mg daily, peak plasma concentration and AUC of venetoclax increased by 86 and 144%, respectively, compared with venetoclax 400 mg alone.1
Concomitant use may be contraindicated or reduction in venetoclax dosage may be required.1
Rifampin is a potent CYP3A inducer as well as an OATP1B1/1B3 and P-gp inhibitor.1 Concomitant administration of a single 600-mg dose of rifampin with venetoclax increased the peak plasma concentration and AUC of venetoclax by 106 and 78%, respectively.1, 5 Concomitant administration of repeated doses of rifampin as a strong CYP3A inducer (600 mg daily for 13 days) with venetoclax decreased the peak plasma concentration and AUC of venetoclax by 42 and 71%, respectively.1, 5
Avoid concomitant use.1
Concomitant administration of the potent CYP3A, P-gp, and OATP1B1/1B3 inhibitor ritonavir (50 mg once daily for 14 days) with venetoclax increased the peak plasma concentration and AUC of venetoclax by 140 and 690%, respectively.1
Concomitant use may be contraindicated or reduction in venetoclax dosage may be required.1
Concomitant administration of venetoclax (single 400-mg dose) with warfarin sodium (5 mg) in 3 healthy individuals increased peak plasma concentrations and systemic exposure of warfarin by 18-28%.1, 15 Venetoclax was not dosed to steady state in this study.15 The manufacturer recommends close monitoring of the international normalized ratio (INR) in patients receiving warfarin.1
Live, attenuated vaccines should not be administered prior to, during, and following venetoclax therapy until B-cell recovery occurs.1 The manufacturer states that vaccinations may be less effective in patients receiving venetoclax.1
Venetoclax is a potent and selective inhibitor of B-cell chronic lymphoma 2 (BCL-2); the drug is an antineoplastic agent.1, 2, 7, 9, 10 BCL-2, an anti-apoptotic protein, is overexpressed in AML and CLL and mediates tumor cell survival and has been associated with resistance to chemotherapy.1, 2, 9, 10 Following binding of venetoclax to BCL-2, displacement of pro-apoptotic proteins (e.g., BIM), mitochondrial outer membrane permeabilization, and caspase activation occur; these actions result in restoration of the intrinsic apoptotic pathway.1, 9, 10 In nonclinical studies, venetoclax demonstrated cytotoxic activity in tumor cells overexpressing BCL-2.1
Venetoclax exhibits linear pharmacokinetics over a dose range of 150-800 mg.1, 7 Peak plasma concentrations of the drug are achieved about 5-8 hours following oral administration under fed conditions.1, 7 Administration of venetoclax with a low-fat or high-fat meal increased systemic exposure by approximately 3.4- or 5.2-fold, respectively, compared with the fasting state.1, 6 Venetoclax is highly bound (over 99%) to plasma proteins.1 The mean terminal half-life of venetoclax is approximately 26 hours.1, 8 Venetoclax is metabolized to its major metabolite (M27) mainly by cytochrome P-450 (CYP) isoenzyme 3A4/5; the AUC for M27 represents 80% of the AUC of venetoclax.1 The major metabolite has demonstrated inhibitory activity against BCL-2 that is at least 58-fold lower than that of the parent drug.1 Following oral administration of a single radiolabeled dose of venetoclax, more than 99.9% of the radioactivity was recovered in feces (20.8% as unchanged drug) and less than 0.1% was recovered in urine within 9 days.1
Pharmacokinetic analyses indicate that age (19-93 years), sex, and body weight do not have clinically important effects on the pharmacokinetics of venetoclax.1, 8 No clinically important differences in pharmacokinetics of venetoclax were observed in white, Black, and Asian patients enrolled in clinical studies conducted in the US.1 Among 771 patients with AML, systemic venetoclax exposure was 63% higher in Asian patients from Asian countries (i.e., China, Japan, South Korea, Taiwan) compared with non-Asian populations.1
Advise patients to keep venetoclax in its original container, including the titration pack for CLL/SLL.1 Importance of taking venetoclax exactly as prescribed with food and water.1 Avoid grapefruit products, Seville oranges, and starfruit while taking the drug.1
Importance of advising patients to swallow venetoclax tablets whole and to not chew, crush, or break the tablets.1
If a dose is missed, importance of advising patients to take it as soon as they remember and resume the next dose at the regularly scheduled time unless the dose was missed by more than 8 hours, in which case they should not take the missed dose.1 If a dose is vomited, importance of administering the next dose at the regularly scheduled time; an additional dose should not be administered to make up for a missed dose.1
Risk of tumor lysis syndrome, particularly during initiation of therapy, initial dose escalation, and resumption of therapy following dosage interruption.1 Venetoclax may need to be administered in the hospital or medical office setting to allow monitoring for tumor lysis syndrome.1 Importance of maintaining scheduled appointments for blood work and other laboratory tests.1 Importance of immediately reporting any signs or symptoms of tumor lysis syndrome (e.g., fever, chills, nausea, vomiting, confusion, shortness of breath, seizure, arrhythmia, dark or cloudy urine, fatigue, muscle pain, joint discomfort).1 Importance of advising patients to maintain adequate hydration during venetoclax therapy.1 The recommended volume is 6-8 glasses (approximately 56 ounces) a day.1 Patients should start drinking water 2 days before initiating venetoclax, on the day of the first dose, and each time the dose is increased.1
Risk of neutropenia.1 Importance of monitoring complete blood cell (CBC) counts periodically during venetoclax therapy.1 Importance of immediately reporting any signs or symptoms of infection (e.g., fever).1
Risk of infection; importance of immediately reporting any signs or symptoms of infection (e.g., fever).1
Importance of avoiding use of live vaccines prior to, during, and following venetoclax therapy until B-cell recovery.1
Risk of fetal harm.1 Necessity of advising females of childbearing potential that they should use an effective method of contraception while receiving the drug and for at least 30 days after discontinuance of therapy.1 Importance of females informing clinicians if they are or plan to become pregnant.1 If pregnancy occurs, advise pregnant females of potential risk to the fetus.1
Risk of male infertility.1
Importance of advising females to avoid breast-feeding while receiving venetoclax and for 1 week after the last dose.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1
Importance of informing patients of other important precautionary information.1
Additional Information
For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web]. The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Venetoclax can only be obtained through designated specialty pharmacies and distributors. Contact manufacturer for specific availability information.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 10 mg | ||
50 mg | Venclexta® | Genentech | ||
100 mg | Venclexta® | Genentech | ||
Titration Pack (CLL/SLL) | 14 Tablets, Venetoclax 10 mg (Venclexta®) 7 Tablets, Venetoclax 50 mg (Venclexta®) 7 Tablets, Venetoclax 100 mg (Venclexta®) 14 Tablets, Venetoclax 100 mg (Venclexta®) | Venclexta® Starting Pack (CLL/SLL) | Genentech |
1. Genentech. Venclexta® (venetoclax) tablets prescribing information. South San Francisco, CA; 2022 Jun.
2. Stilgenbauer S, Eichhorst B, Schetelig J et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol . 2016; 17:768-78. [PubMed 27178240]
3. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2022 Jul 18. [Web]
4. Weiss J, Gajek T, Köhler BC et al. Venetoclax (ABT-199) Might Act as a Perpetrator in Pharmacokinetic Drug-Drug Interactions. Pharmaceutics . 2016; 8(1):5.
5. Agarwal SK, Hu B, Chien D et al. Evaluation of Rifampin's Transporter Inhibitory and CYP3A Inductive Effects on the Pharmacokinetics of Venetoclax, a Bcl-2 Inhibitor: Results of a Single- and Multiple-dose Study. J Clin Pharmacol . 2016; 56(11):1335-43.
6. Salem AH, Agarwal S, Dunbar M et al. Effect of Low and High Fat Meals on the Pharmacokinetics of Venetoclax, a Selective First-in-Class Bcl-2 Inhibitor. J Clin Pharmacol . 2016; 56(11):1355-61.
7. Roberts AW, Davids MS, Pagel JM et al. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med . 2016; 374:311-22. [PubMed 26639348]
8. Jones AK, Freise KJ, Agarwal SK et al. Clinical Predictors of Venetoclax Pharmacokinetics in Chronic Lymphocytic Leukemia and Non-Hodgkin's Lymphoma Patients: a Pooled Population Pharmacokinetic Analysis. AAPS J . 2016; 18(5):1192-1202. [PubMed 27233802]
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